Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects nearly 1 million people in the US.¹ In addition to the accumulation of functional limitations, patients with MS commonly experience mental health and physical symptoms such as depression, anxiety, stress, fatigue, and pain. Day-to-day life with MS requires adaptation to challenges and active maintenance of health and well-being over time. Behavioral intervention and treatment, whether in the form of psychotherapy, health behavior coaching, or the promotion of active self-management, is an integral component of interprofessional care and key aspect of living well with MS.

Behavioral Comorbidities

Depression

Depression is a common concern among individuals with MS. Population-based studies suggest that individuals with MS have a roughly 1 in 4 chance of developing major depressive disorder over their lifetime.² However, at any given time, between 40% and 60% of individuals with MS report clinically meaningful levels of depressive symptoms.³ Although the relationship between MS disease characteristics and depression is unclear, some evidence suggests that depressive symptoms are more common at certain points in illness, such as early in the disease process as individuals grapple with the onset of new symptoms, late in the disease process as they accumulate greater disability, and during active clinical relapses.^3-5

Depression often is comorbid with, and adds to the symptom burden of, other common conditions in MS such as fatigue and cognitive dysfunction.^6-8 Thus, it is not surprising that it associated with poorer overall quality of life (QOL).⁹ Depression also is a risk factor for suicidal ideation and suicide for patients with MS.^10,11

Fortunately, several behavioral interventions show promise in treating depression in patients with MS. Both individual and group formats of cognitive behavioral therapy (CBT), a treatment focused on challenging maladaptive patterns of thought and behavior, have been shown to improve depressive symptoms for people with MS.^12,13 Several brief and efficient group-based programs grounded in CBT and focused on the development of specific skills, including problem solving, goal setting, relationship management, and managing emotions, have been shown to reduce depressive symptoms.^13,14 CBT for depression in MS has been shown to be effective when delivered via telephone.^15,16

Anxiety

Anxiety is common among individuals with MS. Existing data suggest more than one-third of individuals with MS will qualify for a diagnosis of anxiety disorder during their lifetime.¹⁷ The characteristics of anxiety disorders are broad and heterogenous, including generalized anxiety disorder, panic disorder, obsessive compulsive disorders, and health-specific phobias such as needle/injection anxiety. Some estimates suggest a point prevalence of 34% for the presence of clinically meaningful symptoms.¹⁸ Similar to depression, anxiety symptoms can be more common during periods of stress, threat, and transition including early in the disease course while adapting to new diagnosis, late in the disease course with increasing disability, and during clinical relapses.^19-21

The efficacy of behavioral interventions for anxiety in MS is less well established than it is for depression, but some preliminary evidence suggests that individual CBT may be effective for reducing general symptoms of anxiety as well as health-related anxiety.^22,23 Brief, targeted CBT also has been shown to improve injection anxiety, removing a barrier to self-care including the administration of MS disease modifying therapies (DMTs).²⁴

Stress

Stress is commonly conceptualized as a person’s perception that efforts to manage internal and external demands exceed available coping resources.²⁵ Such demands involve both psychological and physiological processes and come in many forms for people with MS and can include daily hassles, major life events, traumatic stress, and perceptions of global nonspecific stress. The relationship between stress and MS remains complex and poorly understood. Nonetheless, individuals with MS frequently report that stress exacerbates their symptoms.²⁶

Some evidence also suggests stress may exacerbate the MS disease process, resulting in more frequent relapses and increased lesion activity visible on MRI.^27,28 In addition to mindfulness (described below), stress inoculation training (CBT and relaxation training), and stress-focused group-based self-management have been shown to be beneficial.^29,30 In an intriguing and rigorous trial, a 24-week stress management therapy based on CBT was associated with the development of fewer new MS lesions visible on MRI.³¹

Adaptation to Illness

MS presents challenges that vary between patients and over time. Individuals may confront new physical and cognitive limitations that inhibit the completion of daily tasks, reduce independence, and limit participation in valued and meaningful activities. In addition, the unpredictability of the disease contributes to perceptions of uncertainty and uncontrollability, which in turn result in higher illness impact and poorer psychological outcomes.³² Building cognitive and behavioral skills to address these challenges can promote adaptation to illness and reduce overall distress associated with chronic illness.³³ Psychosocial intervention also can address the uncertainty commonly experienced by individuals with MS.³⁴

Self-Management

As with any chronic illness, living well with MS requires ongoing commitment and active engagement with health and personal care over time. The process of building knowledge and skills to manage the day-to-day physical, emotional, and social aspects of living with illness often is referred to as self-management.³⁵ For individuals with MS, this may take the form of participation in programs that address adaptation and psychological distress like those described above, but it also may include improving health behavior (eg, physical activity, DMT adherence, modification of maladaptive habits like smoking or hazardous alcohol use) and symptom management (eg, fatigue, pain). Self-management programs typically include education, the practice of identifying, problem solving, and following through with specific and realistic health and wellness goals, as well as the bolstering of self-efficacy.

Physical Activity

Once discouraged for patients with MS, physical activity is now considered a cornerstone of health and wellness. Physical activity and interventions that target various forms of exercise have been shown to improve strength and endurance, reduce functional decline, enhance QOL, and likely reduce mortality.^35-39 A variety of brief behavioral interventions have been shown to improve physical activity in MS. Structured group-based exercise classes focusing on various activities such as aerobic training (eg, cycling) or resistance training (eg, lower extremity strengthening) have demonstrated improvements in various measures of fitness and mood states such as depression and QOL. Brief home-based telephone counseling interventions based in social cognitive theory (eg, goal setting, navigating obstacles) and motivational interviewing strategies (eg, open-ended questions, affirmation, reflective listening, summarizing) also have been shown to be effective not only at increasing physical activity and improving depression and fatigue.^40,41

Adherence to Treatment

One primary focus of adherence to treatment is medication management. For individuals with MS, DMTs represent a primary means of reducing disease burden and delaying functional decline. Many DMTs require consistent self-administration over time. Some evidence suggests that poorer adherence is associated with a greater risk of relapse and more rapid disease progression.^42,43 Brief telephone counseling, again based on social cognitive theory, and principles of motivational interviewing combined with home telehealth monitoring by a care coordinator has been shown to improve adherence to DMTs.⁴⁴

Mindfulness

In recent years, mindfulness training has emerged as a popular and common behavioral intervention among individuals with MS. Programs like Mindfulness-Based Stress Reduction (MBSR) provide training in meditation techniques designed to promote mindfulness, which is defined as paying attention to present moment experience, including sensations, thoughts, and emotions, without judgment or attachment.⁴⁵ Cultivating mindfulness helps people with MS cope with and adapt to symptoms and stressors.⁴⁶ Mindfulness interventions typically are delivered in a group format. For example, MBSR consists of 8 in-person group sessions with daily meditation practice homework. Mindfulness interventions also have been delivered effectively with smartphone apps.⁴⁷ Mindfulness programs have been shown to improve depression, anxiety, fatigue, stress, and QOL for patients with MS.^48-50

Fatigue

More than 90% of individuals with MS report fatigue, and many identify it as their most disabling symptom.⁵¹ Often defined as “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities,” fatigue has been shown to be associated with longer disease duration, greater physical disability, progressive subtype, and depressive symptoms, although the relative and possibly overlapping impact of these issues is only partially understood.^52,53 Fatigue is associated with poorer overall mental health and negatively impacts work and social roles.⁵⁴

Several behavioral interventions have been developed to address fatigue in MS. Using both individual and group based formats and across several modalities (eg, in-person, telephone, online modules, or a combination), behavioral fatigue interventions most commonly combine traditional general CBT skills (eg, addressing maladaptive thoughts and behaviors) with a variety of fatigue-specific skill building exercises that may include fatigue education, energy conservation strategies, improving sleep, enlisting social support, and self-management goal setting strategies.^35,55-57

Pain

Chronic pain is common and disabling in people with MS.^58,59 Nearly 50% report experiencing moderate to severe chronic pain.^59,60 Individuals with MS reporting pain often are older, more disabled (higher Expanded Disability Status Scale score), and have longer disease duration that those who are not experiencing chronic pain.⁶¹ Patients report various types of pain in the following order of frequency: dysesthetic pain (18.1%), back pain (16.4%), painful tonic spasms (11.0%), Lhermitte sign (9.0%), visceral pain (2.9%), and trigeminal neuralgia (2.0%).⁶¹ Chronic pain has a negative impact on QOL in the areas of sleep, work, maintaining relationships, recreational activities, and overall life enjoyment.⁵⁹ Additionally, research has shown that greater pain intensity and pain-related interference with activities of daily living are both associated with greater depression severity.^62,63

The literature supports the use of behavioral interventions for pain in people with MS.⁶¹ Behavioral interventions include in-person exercise interventions (eg, water aerobics, cycling, rowing ergometer, treadmill walking, and resistance training), self-hypnosis, and telephone-based self-management programs based on CBT.^35,64,65 As described above, CBT-based self-management programs combine learning CBT skills (eg, modifying maladaptive thoughts) with pain-specific skill building such as pain education, pacing activities, and improving sleep. Of note, MS education including, but not limited to, pain was as effective as a CBT-based self-management program in reducing pain intensity and interference.³⁵ In addition, there is evidence to support acceptance- and mindfulness-based interventions for chronic pain, and online mindfulness-based cognitive therapy for MS related pain is currently being tested in a randomized controlled trial.^35,66

Conclusion

People with MS face significant challenges in coping with and adapting to a chronic and unpredictable disease. However, there is considerable evidence that behavioral interventions can improve many of the most common and disabling symptoms in MS including depression, anxiety, stress, fatigue, and pain as well as health behavior and self-care. Research also suggests that improvements in one of these problems (eg, physical inactivity) can influence improvement in other symptoms (eg, depression and fatigue). Unlike other treatment options, behavioral interventions can be delivered in various formats (eg, in-person and electronic health), are time-limited, and cause few (if any) undesirable systemic adverse effects. Behavioral interventions are therefore, an essential part of interprofessional care and rehabilitation for patients with MS.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects nearly 1 million people in the US.¹ In addition to the accumulation of functional limitations, patients with MS commonly experience mental health and physical symptoms such as depression, anxiety, stress, fatigue, and pain. Day-to-day life with MS requires adaptation to challenges and active maintenance of health and well-being over time. Behavioral intervention and treatment, whether in the form of psychotherapy, health behavior coaching, or the promotion of active self-management, is an integral component of interprofessional care and key aspect of living well with MS.

Behavioral Comorbidities

Depression

Depression is a common concern among individuals with MS. Population-based studies suggest that individuals with MS have a roughly 1 in 4 chance of developing major depressive disorder over their lifetime.² However, at any given time, between 40% and 60% of individuals with MS report clinically meaningful levels of depressive symptoms.³ Although the relationship between MS disease characteristics and depression is unclear, some evidence suggests that depressive symptoms are more common at certain points in illness, such as early in the disease process as individuals grapple with the onset of new symptoms, late in the disease process as they accumulate greater disability, and during active clinical relapses.^3-5

Depression often is comorbid with, and adds to the symptom burden of, other common conditions in MS such as fatigue and cognitive dysfunction.^6-8 Thus, it is not surprising that it associated with poorer overall quality of life (QOL).⁹ Depression also is a risk factor for suicidal ideation and suicide for patients with MS.^10,11

Fortunately, several behavioral interventions show promise in treating depression in patients with MS. Both individual and group formats of cognitive behavioral therapy (CBT), a treatment focused on challenging maladaptive patterns of thought and behavior, have been shown to improve depressive symptoms for people with MS.^12,13 Several brief and efficient group-based programs grounded in CBT and focused on the development of specific skills, including problem solving, goal setting, relationship management, and managing emotions, have been shown to reduce depressive symptoms.^13,14 CBT for depression in MS has been shown to be effective when delivered via telephone.^15,16

Anxiety

Anxiety is common among individuals with MS. Existing data suggest more than one-third of individuals with MS will qualify for a diagnosis of anxiety disorder during their lifetime.¹⁷ The characteristics of anxiety disorders are broad and heterogenous, including generalized anxiety disorder, panic disorder, obsessive compulsive disorders, and health-specific phobias such as needle/injection anxiety. Some estimates suggest a point prevalence of 34% for the presence of clinically meaningful symptoms.¹⁸ Similar to depression, anxiety symptoms can be more common during periods of stress, threat, and transition including early in the disease course while adapting to new diagnosis, late in the disease course with increasing disability, and during clinical relapses.^19-21

The efficacy of behavioral interventions for anxiety in MS is less well established than it is for depression, but some preliminary evidence suggests that individual CBT may be effective for reducing general symptoms of anxiety as well as health-related anxiety.^22,23 Brief, targeted CBT also has been shown to improve injection anxiety, removing a barrier to self-care including the administration of MS disease modifying therapies (DMTs).²⁴

Stress

Stress is commonly conceptualized as a person’s perception that efforts to manage internal and external demands exceed available coping resources.²⁵ Such demands involve both psychological and physiological processes and come in many forms for people with MS and can include daily hassles, major life events, traumatic stress, and perceptions of global nonspecific stress. The relationship between stress and MS remains complex and poorly understood. Nonetheless, individuals with MS frequently report that stress exacerbates their symptoms.²⁶

Some evidence also suggests stress may exacerbate the MS disease process, resulting in more frequent relapses and increased lesion activity visible on MRI.^27,28 In addition to mindfulness (described below), stress inoculation training (CBT and relaxation training), and stress-focused group-based self-management have been shown to be beneficial.^29,30 In an intriguing and rigorous trial, a 24-week stress management therapy based on CBT was associated with the development of fewer new MS lesions visible on MRI.³¹

Adaptation to Illness

MS presents challenges that vary between patients and over time. Individuals may confront new physical and cognitive limitations that inhibit the completion of daily tasks, reduce independence, and limit participation in valued and meaningful activities. In addition, the unpredictability of the disease contributes to perceptions of uncertainty and uncontrollability, which in turn result in higher illness impact and poorer psychological outcomes.³² Building cognitive and behavioral skills to address these challenges can promote adaptation to illness and reduce overall distress associated with chronic illness.³³ Psychosocial intervention also can address the uncertainty commonly experienced by individuals with MS.³⁴

Self-Management

As with any chronic illness, living well with MS requires ongoing commitment and active engagement with health and personal care over time. The process of building knowledge and skills to manage the day-to-day physical, emotional, and social aspects of living with illness often is referred to as self-management.³⁵ For individuals with MS, this may take the form of participation in programs that address adaptation and psychological distress like those described above, but it also may include improving health behavior (eg, physical activity, DMT adherence, modification of maladaptive habits like smoking or hazardous alcohol use) and symptom management (eg, fatigue, pain). Self-management programs typically include education, the practice of identifying, problem solving, and following through with specific and realistic health and wellness goals, as well as the bolstering of self-efficacy.

Physical Activity

Once discouraged for patients with MS, physical activity is now considered a cornerstone of health and wellness. Physical activity and interventions that target various forms of exercise have been shown to improve strength and endurance, reduce functional decline, enhance QOL, and likely reduce mortality.^35-39 A variety of brief behavioral interventions have been shown to improve physical activity in MS. Structured group-based exercise classes focusing on various activities such as aerobic training (eg, cycling) or resistance training (eg, lower extremity strengthening) have demonstrated improvements in various measures of fitness and mood states such as depression and QOL. Brief home-based telephone counseling interventions based in social cognitive theory (eg, goal setting, navigating obstacles) and motivational interviewing strategies (eg, open-ended questions, affirmation, reflective listening, summarizing) also have been shown to be effective not only at increasing physical activity and improving depression and fatigue.^40,41

Adherence to Treatment

One primary focus of adherence to treatment is medication management. For individuals with MS, DMTs represent a primary means of reducing disease burden and delaying functional decline. Many DMTs require consistent self-administration over time. Some evidence suggests that poorer adherence is associated with a greater risk of relapse and more rapid disease progression.^42,43 Brief telephone counseling, again based on social cognitive theory, and principles of motivational interviewing combined with home telehealth monitoring by a care coordinator has been shown to improve adherence to DMTs.⁴⁴

Mindfulness

In recent years, mindfulness training has emerged as a popular and common behavioral intervention among individuals with MS. Programs like Mindfulness-Based Stress Reduction (MBSR) provide training in meditation techniques designed to promote mindfulness, which is defined as paying attention to present moment experience, including sensations, thoughts, and emotions, without judgment or attachment.⁴⁵ Cultivating mindfulness helps people with MS cope with and adapt to symptoms and stressors.⁴⁶ Mindfulness interventions typically are delivered in a group format. For example, MBSR consists of 8 in-person group sessions with daily meditation practice homework. Mindfulness interventions also have been delivered effectively with smartphone apps.⁴⁷ Mindfulness programs have been shown to improve depression, anxiety, fatigue, stress, and QOL for patients with MS.^48-50

Fatigue

More than 90% of individuals with MS report fatigue, and many identify it as their most disabling symptom.⁵¹ Often defined as “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities,” fatigue has been shown to be associated with longer disease duration, greater physical disability, progressive subtype, and depressive symptoms, although the relative and possibly overlapping impact of these issues is only partially understood.^52,53 Fatigue is associated with poorer overall mental health and negatively impacts work and social roles.⁵⁴

Several behavioral interventions have been developed to address fatigue in MS. Using both individual and group based formats and across several modalities (eg, in-person, telephone, online modules, or a combination), behavioral fatigue interventions most commonly combine traditional general CBT skills (eg, addressing maladaptive thoughts and behaviors) with a variety of fatigue-specific skill building exercises that may include fatigue education, energy conservation strategies, improving sleep, enlisting social support, and self-management goal setting strategies.^35,55-57

Pain

Chronic pain is common and disabling in people with MS.^58,59 Nearly 50% report experiencing moderate to severe chronic pain.^59,60 Individuals with MS reporting pain often are older, more disabled (higher Expanded Disability Status Scale score), and have longer disease duration that those who are not experiencing chronic pain.⁶¹ Patients report various types of pain in the following order of frequency: dysesthetic pain (18.1%), back pain (16.4%), painful tonic spasms (11.0%), Lhermitte sign (9.0%), visceral pain (2.9%), and trigeminal neuralgia (2.0%).⁶¹ Chronic pain has a negative impact on QOL in the areas of sleep, work, maintaining relationships, recreational activities, and overall life enjoyment.⁵⁹ Additionally, research has shown that greater pain intensity and pain-related interference with activities of daily living are both associated with greater depression severity.^62,63

The literature supports the use of behavioral interventions for pain in people with MS.⁶¹ Behavioral interventions include in-person exercise interventions (eg, water aerobics, cycling, rowing ergometer, treadmill walking, and resistance training), self-hypnosis, and telephone-based self-management programs based on CBT.^35,64,65 As described above, CBT-based self-management programs combine learning CBT skills (eg, modifying maladaptive thoughts) with pain-specific skill building such as pain education, pacing activities, and improving sleep. Of note, MS education including, but not limited to, pain was as effective as a CBT-based self-management program in reducing pain intensity and interference.³⁵ In addition, there is evidence to support acceptance- and mindfulness-based interventions for chronic pain, and online mindfulness-based cognitive therapy for MS related pain is currently being tested in a randomized controlled trial.^35,66

Conclusion

People with MS face significant challenges in coping with and adapting to a chronic and unpredictable disease. However, there is considerable evidence that behavioral interventions can improve many of the most common and disabling symptoms in MS including depression, anxiety, stress, fatigue, and pain as well as health behavior and self-care. Research also suggests that improvements in one of these problems (eg, physical inactivity) can influence improvement in other symptoms (eg, depression and fatigue). Unlike other treatment options, behavioral interventions can be delivered in various formats (eg, in-person and electronic health), are time-limited, and cause few (if any) undesirable systemic adverse effects. Behavioral interventions are therefore, an essential part of interprofessional care and rehabilitation for patients with MS.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects nearly 1 million people in the US.¹ In addition to the accumulation of functional limitations, patients with MS commonly experience mental health and physical symptoms such as depression, anxiety, stress, fatigue, and pain. Day-to-day life with MS requires adaptation to challenges and active maintenance of health and well-being over time. Behavioral intervention and treatment, whether in the form of psychotherapy, health behavior coaching, or the promotion of active self-management, is an integral component of interprofessional care and key aspect of living well with MS.

Behavioral Comorbidities

Depression

Depression is a common concern among individuals with MS. Population-based studies suggest that individuals with MS have a roughly 1 in 4 chance of developing major depressive disorder over their lifetime.² However, at any given time, between 40% and 60% of individuals with MS report clinically meaningful levels of depressive symptoms.³ Although the relationship between MS disease characteristics and depression is unclear, some evidence suggests that depressive symptoms are more common at certain points in illness, such as early in the disease process as individuals grapple with the onset of new symptoms, late in the disease process as they accumulate greater disability, and during active clinical relapses.^3-5

Depression often is comorbid with, and adds to the symptom burden of, other common conditions in MS such as fatigue and cognitive dysfunction.^6-8 Thus, it is not surprising that it associated with poorer overall quality of life (QOL).⁹ Depression also is a risk factor for suicidal ideation and suicide for patients with MS.^10,11

Fortunately, several behavioral interventions show promise in treating depression in patients with MS. Both individual and group formats of cognitive behavioral therapy (CBT), a treatment focused on challenging maladaptive patterns of thought and behavior, have been shown to improve depressive symptoms for people with MS.^12,13 Several brief and efficient group-based programs grounded in CBT and focused on the development of specific skills, including problem solving, goal setting, relationship management, and managing emotions, have been shown to reduce depressive symptoms.^13,14 CBT for depression in MS has been shown to be effective when delivered via telephone.^15,16

Anxiety

Anxiety is common among individuals with MS. Existing data suggest more than one-third of individuals with MS will qualify for a diagnosis of anxiety disorder during their lifetime.¹⁷ The characteristics of anxiety disorders are broad and heterogenous, including generalized anxiety disorder, panic disorder, obsessive compulsive disorders, and health-specific phobias such as needle/injection anxiety. Some estimates suggest a point prevalence of 34% for the presence of clinically meaningful symptoms.¹⁸ Similar to depression, anxiety symptoms can be more common during periods of stress, threat, and transition including early in the disease course while adapting to new diagnosis, late in the disease course with increasing disability, and during clinical relapses.^19-21

The efficacy of behavioral interventions for anxiety in MS is less well established than it is for depression, but some preliminary evidence suggests that individual CBT may be effective for reducing general symptoms of anxiety as well as health-related anxiety.^22,23 Brief, targeted CBT also has been shown to improve injection anxiety, removing a barrier to self-care including the administration of MS disease modifying therapies (DMTs).²⁴

Stress

Stress is commonly conceptualized as a person’s perception that efforts to manage internal and external demands exceed available coping resources.²⁵ Such demands involve both psychological and physiological processes and come in many forms for people with MS and can include daily hassles, major life events, traumatic stress, and perceptions of global nonspecific stress. The relationship between stress and MS remains complex and poorly understood. Nonetheless, individuals with MS frequently report that stress exacerbates their symptoms.²⁶

Some evidence also suggests stress may exacerbate the MS disease process, resulting in more frequent relapses and increased lesion activity visible on MRI.^27,28 In addition to mindfulness (described below), stress inoculation training (CBT and relaxation training), and stress-focused group-based self-management have been shown to be beneficial.^29,30 In an intriguing and rigorous trial, a 24-week stress management therapy based on CBT was associated with the development of fewer new MS lesions visible on MRI.³¹

Adaptation to Illness

MS presents challenges that vary between patients and over time. Individuals may confront new physical and cognitive limitations that inhibit the completion of daily tasks, reduce independence, and limit participation in valued and meaningful activities. In addition, the unpredictability of the disease contributes to perceptions of uncertainty and uncontrollability, which in turn result in higher illness impact and poorer psychological outcomes.³² Building cognitive and behavioral skills to address these challenges can promote adaptation to illness and reduce overall distress associated with chronic illness.³³ Psychosocial intervention also can address the uncertainty commonly experienced by individuals with MS.³⁴

Self-Management

As with any chronic illness, living well with MS requires ongoing commitment and active engagement with health and personal care over time. The process of building knowledge and skills to manage the day-to-day physical, emotional, and social aspects of living with illness often is referred to as self-management.³⁵ For individuals with MS, this may take the form of participation in programs that address adaptation and psychological distress like those described above, but it also may include improving health behavior (eg, physical activity, DMT adherence, modification of maladaptive habits like smoking or hazardous alcohol use) and symptom management (eg, fatigue, pain). Self-management programs typically include education, the practice of identifying, problem solving, and following through with specific and realistic health and wellness goals, as well as the bolstering of self-efficacy.

Physical Activity

Once discouraged for patients with MS, physical activity is now considered a cornerstone of health and wellness. Physical activity and interventions that target various forms of exercise have been shown to improve strength and endurance, reduce functional decline, enhance QOL, and likely reduce mortality.^35-39 A variety of brief behavioral interventions have been shown to improve physical activity in MS. Structured group-based exercise classes focusing on various activities such as aerobic training (eg, cycling) or resistance training (eg, lower extremity strengthening) have demonstrated improvements in various measures of fitness and mood states such as depression and QOL. Brief home-based telephone counseling interventions based in social cognitive theory (eg, goal setting, navigating obstacles) and motivational interviewing strategies (eg, open-ended questions, affirmation, reflective listening, summarizing) also have been shown to be effective not only at increasing physical activity and improving depression and fatigue.^40,41

Adherence to Treatment

One primary focus of adherence to treatment is medication management. For individuals with MS, DMTs represent a primary means of reducing disease burden and delaying functional decline. Many DMTs require consistent self-administration over time. Some evidence suggests that poorer adherence is associated with a greater risk of relapse and more rapid disease progression.^42,43 Brief telephone counseling, again based on social cognitive theory, and principles of motivational interviewing combined with home telehealth monitoring by a care coordinator has been shown to improve adherence to DMTs.⁴⁴

Mindfulness

In recent years, mindfulness training has emerged as a popular and common behavioral intervention among individuals with MS. Programs like Mindfulness-Based Stress Reduction (MBSR) provide training in meditation techniques designed to promote mindfulness, which is defined as paying attention to present moment experience, including sensations, thoughts, and emotions, without judgment or attachment.⁴⁵ Cultivating mindfulness helps people with MS cope with and adapt to symptoms and stressors.⁴⁶ Mindfulness interventions typically are delivered in a group format. For example, MBSR consists of 8 in-person group sessions with daily meditation practice homework. Mindfulness interventions also have been delivered effectively with smartphone apps.⁴⁷ Mindfulness programs have been shown to improve depression, anxiety, fatigue, stress, and QOL for patients with MS.^48-50

Fatigue

More than 90% of individuals with MS report fatigue, and many identify it as their most disabling symptom.⁵¹ Often defined as “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities,” fatigue has been shown to be associated with longer disease duration, greater physical disability, progressive subtype, and depressive symptoms, although the relative and possibly overlapping impact of these issues is only partially understood.^52,53 Fatigue is associated with poorer overall mental health and negatively impacts work and social roles.⁵⁴

Several behavioral interventions have been developed to address fatigue in MS. Using both individual and group based formats and across several modalities (eg, in-person, telephone, online modules, or a combination), behavioral fatigue interventions most commonly combine traditional general CBT skills (eg, addressing maladaptive thoughts and behaviors) with a variety of fatigue-specific skill building exercises that may include fatigue education, energy conservation strategies, improving sleep, enlisting social support, and self-management goal setting strategies.^35,55-57

Pain

Chronic pain is common and disabling in people with MS.^58,59 Nearly 50% report experiencing moderate to severe chronic pain.^59,60 Individuals with MS reporting pain often are older, more disabled (higher Expanded Disability Status Scale score), and have longer disease duration that those who are not experiencing chronic pain.⁶¹ Patients report various types of pain in the following order of frequency: dysesthetic pain (18.1%), back pain (16.4%), painful tonic spasms (11.0%), Lhermitte sign (9.0%), visceral pain (2.9%), and trigeminal neuralgia (2.0%).⁶¹ Chronic pain has a negative impact on QOL in the areas of sleep, work, maintaining relationships, recreational activities, and overall life enjoyment.⁵⁹ Additionally, research has shown that greater pain intensity and pain-related interference with activities of daily living are both associated with greater depression severity.^62,63

The literature supports the use of behavioral interventions for pain in people with MS.⁶¹ Behavioral interventions include in-person exercise interventions (eg, water aerobics, cycling, rowing ergometer, treadmill walking, and resistance training), self-hypnosis, and telephone-based self-management programs based on CBT.^35,64,65 As described above, CBT-based self-management programs combine learning CBT skills (eg, modifying maladaptive thoughts) with pain-specific skill building such as pain education, pacing activities, and improving sleep. Of note, MS education including, but not limited to, pain was as effective as a CBT-based self-management program in reducing pain intensity and interference.³⁵ In addition, there is evidence to support acceptance- and mindfulness-based interventions for chronic pain, and online mindfulness-based cognitive therapy for MS related pain is currently being tested in a randomized controlled trial.^35,66

Conclusion

People with MS face significant challenges in coping with and adapting to a chronic and unpredictable disease. However, there is considerable evidence that behavioral interventions can improve many of the most common and disabling symptoms in MS including depression, anxiety, stress, fatigue, and pain as well as health behavior and self-care. Research also suggests that improvements in one of these problems (eg, physical inactivity) can influence improvement in other symptoms (eg, depression and fatigue). Unlike other treatment options, behavioral interventions can be delivered in various formats (eg, in-person and electronic health), are time-limited, and cause few (if any) undesirable systemic adverse effects. Behavioral interventions are therefore, an essential part of interprofessional care and rehabilitation for patients with MS.

A number of large registries exist for multiple sclerosis (MS) in North America and Europe. The Scandinavian countries have some of the longest running and integrated MS registries to date. The Danish MS Registry was initiated in 1948 and has been consistently maintained to track MS epidemiologic trends.² Similar databases exist in Swedenand Norway that were created in the later 20th century.^3,4 The Rochester Epidemiology Project, launched by Len Kurland at the Mayo Clinic, has tracked the morbidity of MS and many other conditions in Olmsted county Minnesota for > 60 years.⁵

The Canadian provinces of British Columbia, Ontario, and Manitoba also have long standing MS registries.^6-8 Other North American MS registries have gathered state-wide cases, such as the New York State MS Consortium.⁹ Some registries have gathered a population-based sample throughout the US, such as the Sonya Slifka MS Study.¹⁰ The North American Research Consortium on MS (NARCOMS) registry is a patient-driven registry within the US that has enrolled > 30,000 cases.¹¹ The MSBase is the largest online registry to date utilizing data from several countries.¹² The MS Bioscreen, based at the University of California San Francisco, is a recent effort to create a longitudinal clinical dataset.¹³ This electronic registry integrates clinical disease morbidity scales, neuroimaging, genetics and laboratory data for individual patients with the goal of providing predictive tools.

The US military provides a unique population to study MS and has the oldest and largest nation-wide MS cohort in existence starting with World War I service members and continuing through the recent Gulf War Era.¹⁴ With the advent of EHRs in the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) in the mid-1990s and large clinical databases, the possibility of an integrated registry for chronic conditions was created. In this report, we describe the creation of the VA MS Surveillance Registry (MSSR) and the initial roll out to several VA medical centers within the MS Center of Excellence (MSCoE). The MSSR is a unique platform with potential for improving MS patient care and clinical research.

Methods

The MSSR was designed by MSCoE health care providers in conjunction with IT specialists from the VA Northwest Innovation Center. Between 2012 and 2013, the team developed and tested a core template for data entry and refined an efficient data dashboard display to optimize clinical decisions. IT programmers created data entry templates that were tested by 4 to 5 clinicians who provided feedback in biweekly meetings. Technical problems were addressed and enhancements added and the trial process was repeated.

After creation of the prototype MS Assessment Tool (MSAT) data entry template that fed into the prototype MSSR, our team received a grant in 2013 for national development and sustainment. The MSSR was established on the VA Converged Registries Solution (CRS) platform, which is a hardware and software architecture designed to host individual clinical registries and eliminate duplicative development effort while maximizing the ability to create new patient registries. The common platform includes a relational database, Health Level 7 messaging, software classes, security modules, extraction services, and other components. The CR obtains data from the VA Corporate Data Warehouse (CDW), directly from the Veterans Health Information Systems and Technology Architecture (VISTA) and via direct user input using MSAT.

From 2016 to 2019, data from patients with MS followed in several VA MS regional programs were inputted into MSSR. A roll-out process to start patient data entry at VA medical centers began in 2017 that included an orientation, technical support, and quality assurance review. Twelve sites from Veteran Integrated Service Network (VISN) 5 (mid-Atlantic) and VISN 20 (Pacific Northwest) were included in the initial roll-out.

Results

After a live or remote telehealth or telephone visit, a clinician can access MSAT from the Computerized Patient Record System (CPRS) or directly from the MSSR online portal (Figure 1). The tool uses radio buttons and pull-down menus and takes about 5 to 15 minutes to complete with a list of required variables. Data is auto-saved for efficiency, and the key variables that are collected in MSAT are noted in Table 1. The MSAT subsequently creates a text integration utility progress note with health factors that is processed through an integration engine and eventually transmitted to VISTA and becomes part of the EHR and available to all health care providers involved in that patient’s care. Additionally, data from VA outpatient and inpatient utilization files, pharmacy, prosthetics, laboratory, and radiology databases are included in the CDW and are included in MSSR. With data from 1998 to the present, the MSAT and CDW databases can provide longitudinal data analysis.

Between 18,000 and 20,000 patients with MS are evaluated in the VHA annually, and 56,000 unique patients have been assessed since 1998. From 2016 to 2019, 1,743 patients with MS or related disorders were enrolled in MSSR (Table 2 and Figure 2). The mean (SD) age of patients was 56.0 (12.9) years and the male:female ratio was 2.7. Racial minorities make up 40% of the cohort. Among those with definite and possible MS, the mean disease duration was 22.7 years and the mean (SD) European Database for MS disability score was 4.7 (2.4) (Table 3). Three-quarters of the MSSR cohort have used ≥ 1 MS disease modifying therapy and 65% were classified as relapsing-remitting MS. An electronic dashboard was developed for health care providers to easily access demographic and clinical data for individuals and groups of patients (Figure 3). Standard and ad hoc reports can be generated from the MSSR. Larger longitudinal analyses can be performed with MSAT and clinical data from CDW. Data on comorbid conditions, pharmacy, radiology and prosthetics utilization, outpatient clinic and inpatient admission can be accessed for each patient or a group of patients.

In 2015, MSCoE published a larger national survey of the VA MS population.¹⁵ This study revealed that the majority of clinical features and demographics of the MSSR were not significantly different from other major US MS registries including the North American Research Committee on MS, the New York State MS Consortium, and the Sonya Slifka Study.^16-18

Discussion

The MSSR is novel in that it combines a traditional MS registry with individual clinical and utilization data within the largest integrated health system in the US. This new registry leverages the existing databases related to cost of care, utilization, and pharmacy services to provide surveillance tools for longitudinal follow-up of the MS population within the VHA. Because the structure of the MSAT and MSSR were developed in a partnership between IT developers and clinicians, there has been mutual buy-in for those who use it and maintain it. This registry can be a test bed for standardized patient outcomes including the recently released MS Quality measures from the American Academy of Neurology.¹⁹

To achieve greater numbers across populations, there has been efforts in Europe to combine registries into a common European Register for MS. A recent survey found that although many European registries were heterogeneous, it would be possible to have a minimum common data set for limited epidemiologic studies.²⁰ Still many registries do not have environmental or genetic data to evaluate etiologic questions.²¹ Additionally, most registries are not set up to evaluate cost or quality of care within a health care system.

Recommendations for maximizing the impact of existing MS registries were recently released by a panel of MS clinicians and researchers.²² The first recommendation was to create a broad network of registries that would communicate and collaborate. This group of MS registries would have strategic oversight and direction that would greatly streamline and leverage existing and future efforts. Second, registries should standardize data collection and management thereby enhancing the ability to share data and perform meta-analyses with aggregated data. Third, the collection of physician- and patient-reported outcomes should be encouraged to provide a more complete picture of MS. Finally, registries should prioritize research questions and utilize new technologies for data collection. These recommendations would help to coordinate existing registries and accelerate knowledge discovery.

The MSSR will contribute to the growing registry network of data. The MSSR can address questions about clinical outcomes, cost, quality with a growing data repository and linked biobank. Based on the CR platform, the MSSR allows for integration with other VA clinical registries, including registries for traumatic brain injuries, oncology, HIV, hepatitis C virus, and eye injuries. Identifying case outcomes related to other registries is optimized with the CR common structure.

Conclusion

The MSSR has been a useful tool for clinicians managing individual patients and their regional referral populations with real-time access to clinical and utilization data. It will also be a useful research tool in tracking epidemiological trends for the military population. The MSSR has enhanced clinical management of MS and serves as a national source for clinical outcomes.

A number of large registries exist for multiple sclerosis (MS) in North America and Europe. The Scandinavian countries have some of the longest running and integrated MS registries to date. The Danish MS Registry was initiated in 1948 and has been consistently maintained to track MS epidemiologic trends.² Similar databases exist in Swedenand Norway that were created in the later 20th century.^3,4 The Rochester Epidemiology Project, launched by Len Kurland at the Mayo Clinic, has tracked the morbidity of MS and many other conditions in Olmsted county Minnesota for > 60 years.⁵

The Canadian provinces of British Columbia, Ontario, and Manitoba also have long standing MS registries.^6-8 Other North American MS registries have gathered state-wide cases, such as the New York State MS Consortium.⁹ Some registries have gathered a population-based sample throughout the US, such as the Sonya Slifka MS Study.¹⁰ The North American Research Consortium on MS (NARCOMS) registry is a patient-driven registry within the US that has enrolled > 30,000 cases.¹¹ The MSBase is the largest online registry to date utilizing data from several countries.¹² The MS Bioscreen, based at the University of California San Francisco, is a recent effort to create a longitudinal clinical dataset.¹³ This electronic registry integrates clinical disease morbidity scales, neuroimaging, genetics and laboratory data for individual patients with the goal of providing predictive tools.

The US military provides a unique population to study MS and has the oldest and largest nation-wide MS cohort in existence starting with World War I service members and continuing through the recent Gulf War Era.¹⁴ With the advent of EHRs in the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) in the mid-1990s and large clinical databases, the possibility of an integrated registry for chronic conditions was created. In this report, we describe the creation of the VA MS Surveillance Registry (MSSR) and the initial roll out to several VA medical centers within the MS Center of Excellence (MSCoE). The MSSR is a unique platform with potential for improving MS patient care and clinical research.

Methods

The MSSR was designed by MSCoE health care providers in conjunction with IT specialists from the VA Northwest Innovation Center. Between 2012 and 2013, the team developed and tested a core template for data entry and refined an efficient data dashboard display to optimize clinical decisions. IT programmers created data entry templates that were tested by 4 to 5 clinicians who provided feedback in biweekly meetings. Technical problems were addressed and enhancements added and the trial process was repeated.

After creation of the prototype MS Assessment Tool (MSAT) data entry template that fed into the prototype MSSR, our team received a grant in 2013 for national development and sustainment. The MSSR was established on the VA Converged Registries Solution (CRS) platform, which is a hardware and software architecture designed to host individual clinical registries and eliminate duplicative development effort while maximizing the ability to create new patient registries. The common platform includes a relational database, Health Level 7 messaging, software classes, security modules, extraction services, and other components. The CR obtains data from the VA Corporate Data Warehouse (CDW), directly from the Veterans Health Information Systems and Technology Architecture (VISTA) and via direct user input using MSAT.

From 2016 to 2019, data from patients with MS followed in several VA MS regional programs were inputted into MSSR. A roll-out process to start patient data entry at VA medical centers began in 2017 that included an orientation, technical support, and quality assurance review. Twelve sites from Veteran Integrated Service Network (VISN) 5 (mid-Atlantic) and VISN 20 (Pacific Northwest) were included in the initial roll-out.

Results

After a live or remote telehealth or telephone visit, a clinician can access MSAT from the Computerized Patient Record System (CPRS) or directly from the MSSR online portal (Figure 1). The tool uses radio buttons and pull-down menus and takes about 5 to 15 minutes to complete with a list of required variables. Data is auto-saved for efficiency, and the key variables that are collected in MSAT are noted in Table 1. The MSAT subsequently creates a text integration utility progress note with health factors that is processed through an integration engine and eventually transmitted to VISTA and becomes part of the EHR and available to all health care providers involved in that patient’s care. Additionally, data from VA outpatient and inpatient utilization files, pharmacy, prosthetics, laboratory, and radiology databases are included in the CDW and are included in MSSR. With data from 1998 to the present, the MSAT and CDW databases can provide longitudinal data analysis.

Between 18,000 and 20,000 patients with MS are evaluated in the VHA annually, and 56,000 unique patients have been assessed since 1998. From 2016 to 2019, 1,743 patients with MS or related disorders were enrolled in MSSR (Table 2 and Figure 2). The mean (SD) age of patients was 56.0 (12.9) years and the male:female ratio was 2.7. Racial minorities make up 40% of the cohort. Among those with definite and possible MS, the mean disease duration was 22.7 years and the mean (SD) European Database for MS disability score was 4.7 (2.4) (Table 3). Three-quarters of the MSSR cohort have used ≥ 1 MS disease modifying therapy and 65% were classified as relapsing-remitting MS. An electronic dashboard was developed for health care providers to easily access demographic and clinical data for individuals and groups of patients (Figure 3). Standard and ad hoc reports can be generated from the MSSR. Larger longitudinal analyses can be performed with MSAT and clinical data from CDW. Data on comorbid conditions, pharmacy, radiology and prosthetics utilization, outpatient clinic and inpatient admission can be accessed for each patient or a group of patients.

In 2015, MSCoE published a larger national survey of the VA MS population.¹⁵ This study revealed that the majority of clinical features and demographics of the MSSR were not significantly different from other major US MS registries including the North American Research Committee on MS, the New York State MS Consortium, and the Sonya Slifka Study.^16-18

Discussion

The MSSR is novel in that it combines a traditional MS registry with individual clinical and utilization data within the largest integrated health system in the US. This new registry leverages the existing databases related to cost of care, utilization, and pharmacy services to provide surveillance tools for longitudinal follow-up of the MS population within the VHA. Because the structure of the MSAT and MSSR were developed in a partnership between IT developers and clinicians, there has been mutual buy-in for those who use it and maintain it. This registry can be a test bed for standardized patient outcomes including the recently released MS Quality measures from the American Academy of Neurology.¹⁹

To achieve greater numbers across populations, there has been efforts in Europe to combine registries into a common European Register for MS. A recent survey found that although many European registries were heterogeneous, it would be possible to have a minimum common data set for limited epidemiologic studies.²⁰ Still many registries do not have environmental or genetic data to evaluate etiologic questions.²¹ Additionally, most registries are not set up to evaluate cost or quality of care within a health care system.

Recommendations for maximizing the impact of existing MS registries were recently released by a panel of MS clinicians and researchers.²² The first recommendation was to create a broad network of registries that would communicate and collaborate. This group of MS registries would have strategic oversight and direction that would greatly streamline and leverage existing and future efforts. Second, registries should standardize data collection and management thereby enhancing the ability to share data and perform meta-analyses with aggregated data. Third, the collection of physician- and patient-reported outcomes should be encouraged to provide a more complete picture of MS. Finally, registries should prioritize research questions and utilize new technologies for data collection. These recommendations would help to coordinate existing registries and accelerate knowledge discovery.

The MSSR will contribute to the growing registry network of data. The MSSR can address questions about clinical outcomes, cost, quality with a growing data repository and linked biobank. Based on the CR platform, the MSSR allows for integration with other VA clinical registries, including registries for traumatic brain injuries, oncology, HIV, hepatitis C virus, and eye injuries. Identifying case outcomes related to other registries is optimized with the CR common structure.

Conclusion

The MSSR has been a useful tool for clinicians managing individual patients and their regional referral populations with real-time access to clinical and utilization data. It will also be a useful research tool in tracking epidemiological trends for the military population. The MSSR has enhanced clinical management of MS and serves as a national source for clinical outcomes.

A number of large registries exist for multiple sclerosis (MS) in North America and Europe. The Scandinavian countries have some of the longest running and integrated MS registries to date. The Danish MS Registry was initiated in 1948 and has been consistently maintained to track MS epidemiologic trends.² Similar databases exist in Swedenand Norway that were created in the later 20th century.^3,4 The Rochester Epidemiology Project, launched by Len Kurland at the Mayo Clinic, has tracked the morbidity of MS and many other conditions in Olmsted county Minnesota for > 60 years.⁵

The Canadian provinces of British Columbia, Ontario, and Manitoba also have long standing MS registries.^6-8 Other North American MS registries have gathered state-wide cases, such as the New York State MS Consortium.⁹ Some registries have gathered a population-based sample throughout the US, such as the Sonya Slifka MS Study.¹⁰ The North American Research Consortium on MS (NARCOMS) registry is a patient-driven registry within the US that has enrolled > 30,000 cases.¹¹ The MSBase is the largest online registry to date utilizing data from several countries.¹² The MS Bioscreen, based at the University of California San Francisco, is a recent effort to create a longitudinal clinical dataset.¹³ This electronic registry integrates clinical disease morbidity scales, neuroimaging, genetics and laboratory data for individual patients with the goal of providing predictive tools.

The US military provides a unique population to study MS and has the oldest and largest nation-wide MS cohort in existence starting with World War I service members and continuing through the recent Gulf War Era.¹⁴ With the advent of EHRs in the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) in the mid-1990s and large clinical databases, the possibility of an integrated registry for chronic conditions was created. In this report, we describe the creation of the VA MS Surveillance Registry (MSSR) and the initial roll out to several VA medical centers within the MS Center of Excellence (MSCoE). The MSSR is a unique platform with potential for improving MS patient care and clinical research.

Methods

The MSSR was designed by MSCoE health care providers in conjunction with IT specialists from the VA Northwest Innovation Center. Between 2012 and 2013, the team developed and tested a core template for data entry and refined an efficient data dashboard display to optimize clinical decisions. IT programmers created data entry templates that were tested by 4 to 5 clinicians who provided feedback in biweekly meetings. Technical problems were addressed and enhancements added and the trial process was repeated.

After creation of the prototype MS Assessment Tool (MSAT) data entry template that fed into the prototype MSSR, our team received a grant in 2013 for national development and sustainment. The MSSR was established on the VA Converged Registries Solution (CRS) platform, which is a hardware and software architecture designed to host individual clinical registries and eliminate duplicative development effort while maximizing the ability to create new patient registries. The common platform includes a relational database, Health Level 7 messaging, software classes, security modules, extraction services, and other components. The CR obtains data from the VA Corporate Data Warehouse (CDW), directly from the Veterans Health Information Systems and Technology Architecture (VISTA) and via direct user input using MSAT.

From 2016 to 2019, data from patients with MS followed in several VA MS regional programs were inputted into MSSR. A roll-out process to start patient data entry at VA medical centers began in 2017 that included an orientation, technical support, and quality assurance review. Twelve sites from Veteran Integrated Service Network (VISN) 5 (mid-Atlantic) and VISN 20 (Pacific Northwest) were included in the initial roll-out.

Results

After a live or remote telehealth or telephone visit, a clinician can access MSAT from the Computerized Patient Record System (CPRS) or directly from the MSSR online portal (Figure 1). The tool uses radio buttons and pull-down menus and takes about 5 to 15 minutes to complete with a list of required variables. Data is auto-saved for efficiency, and the key variables that are collected in MSAT are noted in Table 1. The MSAT subsequently creates a text integration utility progress note with health factors that is processed through an integration engine and eventually transmitted to VISTA and becomes part of the EHR and available to all health care providers involved in that patient’s care. Additionally, data from VA outpatient and inpatient utilization files, pharmacy, prosthetics, laboratory, and radiology databases are included in the CDW and are included in MSSR. With data from 1998 to the present, the MSAT and CDW databases can provide longitudinal data analysis.

Between 18,000 and 20,000 patients with MS are evaluated in the VHA annually, and 56,000 unique patients have been assessed since 1998. From 2016 to 2019, 1,743 patients with MS or related disorders were enrolled in MSSR (Table 2 and Figure 2). The mean (SD) age of patients was 56.0 (12.9) years and the male:female ratio was 2.7. Racial minorities make up 40% of the cohort. Among those with definite and possible MS, the mean disease duration was 22.7 years and the mean (SD) European Database for MS disability score was 4.7 (2.4) (Table 3). Three-quarters of the MSSR cohort have used ≥ 1 MS disease modifying therapy and 65% were classified as relapsing-remitting MS. An electronic dashboard was developed for health care providers to easily access demographic and clinical data for individuals and groups of patients (Figure 3). Standard and ad hoc reports can be generated from the MSSR. Larger longitudinal analyses can be performed with MSAT and clinical data from CDW. Data on comorbid conditions, pharmacy, radiology and prosthetics utilization, outpatient clinic and inpatient admission can be accessed for each patient or a group of patients.

In 2015, MSCoE published a larger national survey of the VA MS population.¹⁵ This study revealed that the majority of clinical features and demographics of the MSSR were not significantly different from other major US MS registries including the North American Research Committee on MS, the New York State MS Consortium, and the Sonya Slifka Study.^16-18

Discussion

The MSSR is novel in that it combines a traditional MS registry with individual clinical and utilization data within the largest integrated health system in the US. This new registry leverages the existing databases related to cost of care, utilization, and pharmacy services to provide surveillance tools for longitudinal follow-up of the MS population within the VHA. Because the structure of the MSAT and MSSR were developed in a partnership between IT developers and clinicians, there has been mutual buy-in for those who use it and maintain it. This registry can be a test bed for standardized patient outcomes including the recently released MS Quality measures from the American Academy of Neurology.¹⁹

To achieve greater numbers across populations, there has been efforts in Europe to combine registries into a common European Register for MS. A recent survey found that although many European registries were heterogeneous, it would be possible to have a minimum common data set for limited epidemiologic studies.²⁰ Still many registries do not have environmental or genetic data to evaluate etiologic questions.²¹ Additionally, most registries are not set up to evaluate cost or quality of care within a health care system.

Recommendations for maximizing the impact of existing MS registries were recently released by a panel of MS clinicians and researchers.²² The first recommendation was to create a broad network of registries that would communicate and collaborate. This group of MS registries would have strategic oversight and direction that would greatly streamline and leverage existing and future efforts. Second, registries should standardize data collection and management thereby enhancing the ability to share data and perform meta-analyses with aggregated data. Third, the collection of physician- and patient-reported outcomes should be encouraged to provide a more complete picture of MS. Finally, registries should prioritize research questions and utilize new technologies for data collection. These recommendations would help to coordinate existing registries and accelerate knowledge discovery.

The MSSR will contribute to the growing registry network of data. The MSSR can address questions about clinical outcomes, cost, quality with a growing data repository and linked biobank. Based on the CR platform, the MSSR allows for integration with other VA clinical registries, including registries for traumatic brain injuries, oncology, HIV, hepatitis C virus, and eye injuries. Identifying case outcomes related to other registries is optimized with the CR common structure.

Conclusion

The MSSR has been a useful tool for clinicians managing individual patients and their regional referral populations with real-time access to clinical and utilization data. It will also be a useful research tool in tracking epidemiological trends for the military population. The MSSR has enhanced clinical management of MS and serves as a national source for clinical outcomes.

The Veterans Health Administration (VHA) has established a number of centers of excellence (CoEs), including centers focused on posttraumatic stress disorder, suicide prevention, epilepsy, and, most recently, the Senator Elizabeth Dole CoE for Veteran and Caregiver Research. Some VA CoE serve as centralized locations for specialty care. For example, the VA Epilepsy CoE is a network of 16 facilities that provide comprehensive epilepsy care for veterans with seizure disorders, including expert and presurgical evaluations and inpatient monitoring.

In contrast, other CoEs, including the multiple sclerosis (MS) CoE, achieve their missions by serving as a resource center to a network of regional and supporting various programs to optimize the care of veterans across the nation within their home US Department of Veterans Affairs (VA) medical center (VAMC). The MSCoE are charged, through VHA Directive 1011.06, with establishing at least 1 VA MS Regional Program in each of the 21 Veteran Integrated Service Networks (VISNs) across the country and integrating these and affiliated MS Support Programs into the MS National Network. Currently, there are 29 MS regional programs and 49 MS support programs across the US.¹

Established in 2003, the MSCoE is dedicated to furthering the understanding of MS, its impact on veterans, and effective treatments to help manage the disease and its symptoms. In 2002, 2 coordinating centers were selected based on a competitive review process. The MSCoE-East is located at the Baltimore, Maryland and Washington, DC VAMC and serves VISNs 1 to 10. The MSCoE-West serves VISNs 11 to 23 and is jointly-based at VA Puget Sound Health Care System in Seattle, Washington and VA Portland Health Care System in Portland, Oregon. The MSCoEs were made permanent by The Veteran’ Benefits, Healthcare and Information Technology Act of 2006 (38 USC §7330). By partnering with veterans, caregivers, health care professionals, and other affiliates, the MSCoE endeavor to optimize health, activities, participation and quality of life for veterans with MS.

Core Functions

The MSCoE has a 3-part mission. First, the MSCoE seeks to expand care coordination between VAMCs by developing a national network of VA MSCoE Regional and Support Programs. Second, the MSCoE provides resources to VA health care providers (HCPs) through a collaborative approach to clinical care, education, research, and informatics. Third, the MSCoE improves the quality and consistency of health care services delivered to veterans diagnosed with MS nationwide. To meet its objectives, the MSCoE activities are organized around 4 functional cores: clinical care, research, education and training, and informatics and telemedicine.

Clinical Care

The MSCoE delivers high-quality clinical care by identifying veterans with MS who use VA services, understanding their needs, and facilitating appropriate interventions. Veterans with MS are a special cohort for many reasons including that about 70% are male. Men and women veterans not only have different genetics, but also may have different environmental exposures and other risk factors for MS. Since 1998, the VHA has evaluated > 50,000 veterans with MS. Over the past decade, between 18,000 and 20,000 veterans with MS have accessed care within the VHA annually.

The MSCoE advocates for appropriate and safe use of currently available MS disease modifying therapies through collaborations with the VA Pharmacy Benefits Management Service (PBM). The MSCoE partners with PBM to develop and disseminate Criteria For Use, safety, and economic monitoring of the impacts of the MS therapies. The MSCoE also provide national consultation services for complex MS cases, clinical education to VA HCPs, and mentors fellows, residents, and medical students.

The VA provides numerous resources that are not readily available in other health care systems and facilitate the care for patients with chronic diseases, including providing low or no co-pays to patients for MS disease modifying agents and other MS related medications, access to medically necessary adaptive equipment at no charge, the Home Improvement and Structural Alteration (HISA) grant for assistance with safe home ingress and egress, respite care, access to a homemaker/home health aide, and caregiver support programs. Eligible veterans also can access additional resources such as adaptive housing and an automobile grant. The VA also provides substantial hands-on assistance to veterans who are homeless. The clinical team and a veteran with MS can leverage VA resources through the National MS Society (NMSS) Navigator Program as well as other community resources.²

The VHA encourages physical activity and wellness through sports and leisure. Veterans with MS can participate in sports programs and special events, including the National Veterans Wheelchair Games, the National Disabled Veterans Winter Sports Clinic, the National Disabled Veterans TEE (Training, Exposure and Experience) golf tournament, the National Veterans Summer Sports Clinic, the National Veterans Golden Age Games, and the National Veterans Creative Sports Festival. HCPs or veterans who are not sure how to access any of these programs can contact the MSCoE or their local VA social workers.

Research

The primary goal of the MSCoE research core is to conduct clinical, health services, epidemiologic, and basic science research relevant to veterans with MS. The MSCoE serves to enhance collaboration among VAMCs, increase the participation of veterans in research, and provide research mentorship for the next generation of VA MS scientists. MSCoE research is carried out by investigators at the MSCoE and the MS Regional Programs, often in collaboration with investigators at academic institutions. This research is supported by competitive grant awards from a variety of funding agencies including the VA Research and Development Service (R&D) and the NMSS. Results from about 40 research grants in Fiscal Year 2019 were disseminated through 34 peer-reviewed publications, 30 posters, presentations, abstracts, and clinical practice guidelines.

There are many examples of recent high impact MS research performed by MSCoE investigators. For example, MSCoE researchers noted an increase in the estimated prevalence of MS to 1 million individuals in the US, about twice the previously estimated prevalence.^3-5 In addition, a multicenter study highlighted the prevalence of MS misdiagnosis and common confounders for MS.⁶ Other research includes pilot clinical trials evaluating lipoic acid as a potential disease modifying therapy in people with secondary progressive MS and the impact of a multicomponent walking aid selection, fitting, and training program for preventing falls in people with MS.^7,8 Clinical trial also are investigating telehealth counseling to improve physical activity in MS and a systematic review of rehabilitation interventions in MS.^9,10

Education and Training

A unified program of education is essential to effective management of MS nationally. The primary goal of the education and training core is to provide a national program of MS education for HCPs, veterans, and caregivers to improve knowledge, enhance access to resources, and promote effective management strategies. The MSCoE collaborate with the Paralyzed Veterans of America (PVA), the Consortium of MS Centers (CMSC), the NMSS, and other national service organizations to increase educational opportunities, share knowledge, and expand participation.

The MSCoE education and training core produces a range of products both veterans, HCPs, and others affected by MS. The MSCoE sends a biannual patient newsletter to > 20,000 veterans and a monthly email to > 1,000 VA HCPs. Specific opportunities for HCP education include accredited multidisciplinary MS webinars, sponsored symposia and workshops at the CMSC and PVA Summit annual meetings, and presentations at other university and professional conferences. Enduring educational opportunities for veterans, caregivers, and HCPs can also be found by visiting www.va.gov/ms.

The MSCoE coordinate postdoctoral fellowship training programs to develop expertise in MS health care for the future. It offers VA physician fellowships for neurologists in Baltimore and Portland and for physiatrists in Seattle as well as NMSS fellowships for education and research. In 2019, MSCoE had 6 MD Fellows and 1 PhD Fellow.

Clinical Informatics and Telehealth

The primary goal of the informatics and telemedicine core is to employ state-of-the-art informatics, telemedicine technology, and the MSCoE website, to improve MS health care delivery. The VA has a integrated electronic health record and various data repositories are stored in the VHA Corporate Data Warehouse (CDW). MSCoE utilizes the CDW to maintain a national MS administrative data repository to understand the VHA care provided to veterans with MS. Data from the CDW have also served as an important resource to facilitate a wide range of veteran-focused MS research. This research has addressed clinical conditions like pain and obesity; health behaviors like smoking, alcohol use, and exercise as well as issues related to care delivery such as specialty care access, medication adherence, and appointment attendance.^11-19

Monitoring the health of veterans with MS in the VA requires additional data not available in the CDW. To this end, we have developed the MS Surveillance Registry (MSSR), funded and maintained by the VA Office of Information Technology as part of their Veteran Integrated Registry Platform (VIRP). The purpose of the MSSR is to understand the unique characteristics and treatment patterns of veterans with MS in order to optimize their VHA care. HCPs input MS-specific clinical data on their patients into the MSSR, either through the MS Assessment Tool (MSAT) in the Computerized Patient Record System (CPRS) or through a secure online portal. Other data from existing databases from the CDW is also automatically fed into the MSSR. The MSSR continues to be developed and populated to serve as a resource for the future.

Neurologists, physiatrists, psychologists, and rehabilitation specialists can use telehealth to evaluate and treat veterans who have difficulty accessing outpatient clinics, either because of mobility limitations, or distance. Between 2012 and 2015, the VA MSCoE, together with the Epilepsy CoE and the Parkinson’s Disease Research and Clinical Centers in VISNs 5, 6 (mid-Atlantic) and 20 (Pacific Northwest) initiated an integrated teleneurology project. The goal of this project was to improve patient access to care at 4 tertiary and 12 regional VAMCs. A study team, with administrators and key clinical stakeholders, followed a traditional project management approach to design, plan, implement and evaluate an optimal model for communication and referrals with both live visits and telehealth (Table). Major outcomes of the project included: delivering subspecialty teleneurology to 47 patient sites, increasing interfacility consultation by 133% while reducing wait times by roughly 40%, and increasing telemedicine workload at these centers from 95 annual encounters in 2012 to 1,245 annual encounters in 2015 (Figure).

Today, telehealth for veterans with MS can be delivered to nearby VA facilities closer to their home, within their home, or anywhere else the veteran can use a cellphone or tablet. Telehealth visits can save travel time and expenses and optimize VA productivity and clinic use. The MSCoE and many of the MS regional programs are using telehealth for MS physician follow-up and therapies. The VA Office of Rural Health is also currently working with the MS network to use telehealth to increase access to physical therapy to those who have difficulty coming into clinic.

MSCoE Resources

The MSCoE is funded by VA Central Office through the Office of Specialty Care by Special Purpose funds. The directive specifies that funding for the regional and support programs is through Veterans Equitable Resource Allocation based on VISN and facility workload and complexity. Any research is funded separately through grants, some from VA R&D and others from other sources including the National Institutes of Health, the Patient Centered Outcome Research Institute, affiliated universities, the NMSS, the MS Society of Canada, the Consortium of MS Centers, foundations, and industry.

In 2019, MSCoE investigators received grants totaling > $18 million in funding. In-kind support also is provided by the PVA, the CMSC, the NMSS, and others. The first 3 foundations have been supporters since the inception of the MSCoE and have provided opportunities for the dissemination of education and research for HCPs, fellows, residents and medical students; travel; meeting rooms for MSCoE national meetings; exhibit space for HCP outreach; competitive research and educational grant support; programming and resources for veterans and significant others; organizational expertise; and opportunities for VA HCPs, veterans, and caregivers to learn how to navigate MS with others in the private sector.

Conclusion

The MSCoE had a tremendous impact on improving the consistency and quality of care for veterans with MS through clinical care, research, education and informatics and telehealth. Since opening in 2003, there has been an increase in the number of MS specialty clinics, served veterans with MS, and veterans receiving specialty neurologic and rehabilitation services in VA. Research programs in MS have been initiated to address key questions relevant to veterans with MS, including immunology, epidemiology, clinical care, and rehabilitation. Educational programs and products have evolved with technology and had a greater impact through partnerships with veteran and MS nonprofit organizations.

MSCoE strives to minimize impairment and maximize quality of life for veterans with MS by leveraging integrated electronic health records, data repositories, and telehealth services. These efforts have all improved veteran health, access and safety. We look forward to continuing into the next decade by bringing fresh ideas to the care of veterans with MS, their families and caregivers.

The Veterans Health Administration (VHA) has established a number of centers of excellence (CoEs), including centers focused on posttraumatic stress disorder, suicide prevention, epilepsy, and, most recently, the Senator Elizabeth Dole CoE for Veteran and Caregiver Research. Some VA CoE serve as centralized locations for specialty care. For example, the VA Epilepsy CoE is a network of 16 facilities that provide comprehensive epilepsy care for veterans with seizure disorders, including expert and presurgical evaluations and inpatient monitoring.

In contrast, other CoEs, including the multiple sclerosis (MS) CoE, achieve their missions by serving as a resource center to a network of regional and supporting various programs to optimize the care of veterans across the nation within their home US Department of Veterans Affairs (VA) medical center (VAMC). The MSCoE are charged, through VHA Directive 1011.06, with establishing at least 1 VA MS Regional Program in each of the 21 Veteran Integrated Service Networks (VISNs) across the country and integrating these and affiliated MS Support Programs into the MS National Network. Currently, there are 29 MS regional programs and 49 MS support programs across the US.¹

Established in 2003, the MSCoE is dedicated to furthering the understanding of MS, its impact on veterans, and effective treatments to help manage the disease and its symptoms. In 2002, 2 coordinating centers were selected based on a competitive review process. The MSCoE-East is located at the Baltimore, Maryland and Washington, DC VAMC and serves VISNs 1 to 10. The MSCoE-West serves VISNs 11 to 23 and is jointly-based at VA Puget Sound Health Care System in Seattle, Washington and VA Portland Health Care System in Portland, Oregon. The MSCoEs were made permanent by The Veteran’ Benefits, Healthcare and Information Technology Act of 2006 (38 USC §7330). By partnering with veterans, caregivers, health care professionals, and other affiliates, the MSCoE endeavor to optimize health, activities, participation and quality of life for veterans with MS.

Core Functions

The MSCoE has a 3-part mission. First, the MSCoE seeks to expand care coordination between VAMCs by developing a national network of VA MSCoE Regional and Support Programs. Second, the MSCoE provides resources to VA health care providers (HCPs) through a collaborative approach to clinical care, education, research, and informatics. Third, the MSCoE improves the quality and consistency of health care services delivered to veterans diagnosed with MS nationwide. To meet its objectives, the MSCoE activities are organized around 4 functional cores: clinical care, research, education and training, and informatics and telemedicine.

Clinical Care

The MSCoE delivers high-quality clinical care by identifying veterans with MS who use VA services, understanding their needs, and facilitating appropriate interventions. Veterans with MS are a special cohort for many reasons including that about 70% are male. Men and women veterans not only have different genetics, but also may have different environmental exposures and other risk factors for MS. Since 1998, the VHA has evaluated > 50,000 veterans with MS. Over the past decade, between 18,000 and 20,000 veterans with MS have accessed care within the VHA annually.

The MSCoE advocates for appropriate and safe use of currently available MS disease modifying therapies through collaborations with the VA Pharmacy Benefits Management Service (PBM). The MSCoE partners with PBM to develop and disseminate Criteria For Use, safety, and economic monitoring of the impacts of the MS therapies. The MSCoE also provide national consultation services for complex MS cases, clinical education to VA HCPs, and mentors fellows, residents, and medical students.

The VA provides numerous resources that are not readily available in other health care systems and facilitate the care for patients with chronic diseases, including providing low or no co-pays to patients for MS disease modifying agents and other MS related medications, access to medically necessary adaptive equipment at no charge, the Home Improvement and Structural Alteration (HISA) grant for assistance with safe home ingress and egress, respite care, access to a homemaker/home health aide, and caregiver support programs. Eligible veterans also can access additional resources such as adaptive housing and an automobile grant. The VA also provides substantial hands-on assistance to veterans who are homeless. The clinical team and a veteran with MS can leverage VA resources through the National MS Society (NMSS) Navigator Program as well as other community resources.²

The VHA encourages physical activity and wellness through sports and leisure. Veterans with MS can participate in sports programs and special events, including the National Veterans Wheelchair Games, the National Disabled Veterans Winter Sports Clinic, the National Disabled Veterans TEE (Training, Exposure and Experience) golf tournament, the National Veterans Summer Sports Clinic, the National Veterans Golden Age Games, and the National Veterans Creative Sports Festival. HCPs or veterans who are not sure how to access any of these programs can contact the MSCoE or their local VA social workers.

Research

The primary goal of the MSCoE research core is to conduct clinical, health services, epidemiologic, and basic science research relevant to veterans with MS. The MSCoE serves to enhance collaboration among VAMCs, increase the participation of veterans in research, and provide research mentorship for the next generation of VA MS scientists. MSCoE research is carried out by investigators at the MSCoE and the MS Regional Programs, often in collaboration with investigators at academic institutions. This research is supported by competitive grant awards from a variety of funding agencies including the VA Research and Development Service (R&D) and the NMSS. Results from about 40 research grants in Fiscal Year 2019 were disseminated through 34 peer-reviewed publications, 30 posters, presentations, abstracts, and clinical practice guidelines.

There are many examples of recent high impact MS research performed by MSCoE investigators. For example, MSCoE researchers noted an increase in the estimated prevalence of MS to 1 million individuals in the US, about twice the previously estimated prevalence.^3-5 In addition, a multicenter study highlighted the prevalence of MS misdiagnosis and common confounders for MS.⁶ Other research includes pilot clinical trials evaluating lipoic acid as a potential disease modifying therapy in people with secondary progressive MS and the impact of a multicomponent walking aid selection, fitting, and training program for preventing falls in people with MS.^7,8 Clinical trial also are investigating telehealth counseling to improve physical activity in MS and a systematic review of rehabilitation interventions in MS.^9,10

Education and Training

A unified program of education is essential to effective management of MS nationally. The primary goal of the education and training core is to provide a national program of MS education for HCPs, veterans, and caregivers to improve knowledge, enhance access to resources, and promote effective management strategies. The MSCoE collaborate with the Paralyzed Veterans of America (PVA), the Consortium of MS Centers (CMSC), the NMSS, and other national service organizations to increase educational opportunities, share knowledge, and expand participation.

The MSCoE education and training core produces a range of products both veterans, HCPs, and others affected by MS. The MSCoE sends a biannual patient newsletter to > 20,000 veterans and a monthly email to > 1,000 VA HCPs. Specific opportunities for HCP education include accredited multidisciplinary MS webinars, sponsored symposia and workshops at the CMSC and PVA Summit annual meetings, and presentations at other university and professional conferences. Enduring educational opportunities for veterans, caregivers, and HCPs can also be found by visiting www.va.gov/ms.

The MSCoE coordinate postdoctoral fellowship training programs to develop expertise in MS health care for the future. It offers VA physician fellowships for neurologists in Baltimore and Portland and for physiatrists in Seattle as well as NMSS fellowships for education and research. In 2019, MSCoE had 6 MD Fellows and 1 PhD Fellow.

Clinical Informatics and Telehealth

The primary goal of the informatics and telemedicine core is to employ state-of-the-art informatics, telemedicine technology, and the MSCoE website, to improve MS health care delivery. The VA has a integrated electronic health record and various data repositories are stored in the VHA Corporate Data Warehouse (CDW). MSCoE utilizes the CDW to maintain a national MS administrative data repository to understand the VHA care provided to veterans with MS. Data from the CDW have also served as an important resource to facilitate a wide range of veteran-focused MS research. This research has addressed clinical conditions like pain and obesity; health behaviors like smoking, alcohol use, and exercise as well as issues related to care delivery such as specialty care access, medication adherence, and appointment attendance.^11-19

Monitoring the health of veterans with MS in the VA requires additional data not available in the CDW. To this end, we have developed the MS Surveillance Registry (MSSR), funded and maintained by the VA Office of Information Technology as part of their Veteran Integrated Registry Platform (VIRP). The purpose of the MSSR is to understand the unique characteristics and treatment patterns of veterans with MS in order to optimize their VHA care. HCPs input MS-specific clinical data on their patients into the MSSR, either through the MS Assessment Tool (MSAT) in the Computerized Patient Record System (CPRS) or through a secure online portal. Other data from existing databases from the CDW is also automatically fed into the MSSR. The MSSR continues to be developed and populated to serve as a resource for the future.

Neurologists, physiatrists, psychologists, and rehabilitation specialists can use telehealth to evaluate and treat veterans who have difficulty accessing outpatient clinics, either because of mobility limitations, or distance. Between 2012 and 2015, the VA MSCoE, together with the Epilepsy CoE and the Parkinson’s Disease Research and Clinical Centers in VISNs 5, 6 (mid-Atlantic) and 20 (Pacific Northwest) initiated an integrated teleneurology project. The goal of this project was to improve patient access to care at 4 tertiary and 12 regional VAMCs. A study team, with administrators and key clinical stakeholders, followed a traditional project management approach to design, plan, implement and evaluate an optimal model for communication and referrals with both live visits and telehealth (Table). Major outcomes of the project included: delivering subspecialty teleneurology to 47 patient sites, increasing interfacility consultation by 133% while reducing wait times by roughly 40%, and increasing telemedicine workload at these centers from 95 annual encounters in 2012 to 1,245 annual encounters in 2015 (Figure).

Today, telehealth for veterans with MS can be delivered to nearby VA facilities closer to their home, within their home, or anywhere else the veteran can use a cellphone or tablet. Telehealth visits can save travel time and expenses and optimize VA productivity and clinic use. The MSCoE and many of the MS regional programs are using telehealth for MS physician follow-up and therapies. The VA Office of Rural Health is also currently working with the MS network to use telehealth to increase access to physical therapy to those who have difficulty coming into clinic.

MSCoE Resources

The MSCoE is funded by VA Central Office through the Office of Specialty Care by Special Purpose funds. The directive specifies that funding for the regional and support programs is through Veterans Equitable Resource Allocation based on VISN and facility workload and complexity. Any research is funded separately through grants, some from VA R&D and others from other sources including the National Institutes of Health, the Patient Centered Outcome Research Institute, affiliated universities, the NMSS, the MS Society of Canada, the Consortium of MS Centers, foundations, and industry.

In 2019, MSCoE investigators received grants totaling > $18 million in funding. In-kind support also is provided by the PVA, the CMSC, the NMSS, and others. The first 3 foundations have been supporters since the inception of the MSCoE and have provided opportunities for the dissemination of education and research for HCPs, fellows, residents and medical students; travel; meeting rooms for MSCoE national meetings; exhibit space for HCP outreach; competitive research and educational grant support; programming and resources for veterans and significant others; organizational expertise; and opportunities for VA HCPs, veterans, and caregivers to learn how to navigate MS with others in the private sector.

Conclusion

The MSCoE had a tremendous impact on improving the consistency and quality of care for veterans with MS through clinical care, research, education and informatics and telehealth. Since opening in 2003, there has been an increase in the number of MS specialty clinics, served veterans with MS, and veterans receiving specialty neurologic and rehabilitation services in VA. Research programs in MS have been initiated to address key questions relevant to veterans with MS, including immunology, epidemiology, clinical care, and rehabilitation. Educational programs and products have evolved with technology and had a greater impact through partnerships with veteran and MS nonprofit organizations.

MSCoE strives to minimize impairment and maximize quality of life for veterans with MS by leveraging integrated electronic health records, data repositories, and telehealth services. These efforts have all improved veteran health, access and safety. We look forward to continuing into the next decade by bringing fresh ideas to the care of veterans with MS, their families and caregivers.

The Veterans Health Administration (VHA) has established a number of centers of excellence (CoEs), including centers focused on posttraumatic stress disorder, suicide prevention, epilepsy, and, most recently, the Senator Elizabeth Dole CoE for Veteran and Caregiver Research. Some VA CoE serve as centralized locations for specialty care. For example, the VA Epilepsy CoE is a network of 16 facilities that provide comprehensive epilepsy care for veterans with seizure disorders, including expert and presurgical evaluations and inpatient monitoring.

In contrast, other CoEs, including the multiple sclerosis (MS) CoE, achieve their missions by serving as a resource center to a network of regional and supporting various programs to optimize the care of veterans across the nation within their home US Department of Veterans Affairs (VA) medical center (VAMC). The MSCoE are charged, through VHA Directive 1011.06, with establishing at least 1 VA MS Regional Program in each of the 21 Veteran Integrated Service Networks (VISNs) across the country and integrating these and affiliated MS Support Programs into the MS National Network. Currently, there are 29 MS regional programs and 49 MS support programs across the US.¹

Established in 2003, the MSCoE is dedicated to furthering the understanding of MS, its impact on veterans, and effective treatments to help manage the disease and its symptoms. In 2002, 2 coordinating centers were selected based on a competitive review process. The MSCoE-East is located at the Baltimore, Maryland and Washington, DC VAMC and serves VISNs 1 to 10. The MSCoE-West serves VISNs 11 to 23 and is jointly-based at VA Puget Sound Health Care System in Seattle, Washington and VA Portland Health Care System in Portland, Oregon. The MSCoEs were made permanent by The Veteran’ Benefits, Healthcare and Information Technology Act of 2006 (38 USC §7330). By partnering with veterans, caregivers, health care professionals, and other affiliates, the MSCoE endeavor to optimize health, activities, participation and quality of life for veterans with MS.

Core Functions

The MSCoE has a 3-part mission. First, the MSCoE seeks to expand care coordination between VAMCs by developing a national network of VA MSCoE Regional and Support Programs. Second, the MSCoE provides resources to VA health care providers (HCPs) through a collaborative approach to clinical care, education, research, and informatics. Third, the MSCoE improves the quality and consistency of health care services delivered to veterans diagnosed with MS nationwide. To meet its objectives, the MSCoE activities are organized around 4 functional cores: clinical care, research, education and training, and informatics and telemedicine.

Clinical Care

The MSCoE delivers high-quality clinical care by identifying veterans with MS who use VA services, understanding their needs, and facilitating appropriate interventions. Veterans with MS are a special cohort for many reasons including that about 70% are male. Men and women veterans not only have different genetics, but also may have different environmental exposures and other risk factors for MS. Since 1998, the VHA has evaluated > 50,000 veterans with MS. Over the past decade, between 18,000 and 20,000 veterans with MS have accessed care within the VHA annually.

The MSCoE advocates for appropriate and safe use of currently available MS disease modifying therapies through collaborations with the VA Pharmacy Benefits Management Service (PBM). The MSCoE partners with PBM to develop and disseminate Criteria For Use, safety, and economic monitoring of the impacts of the MS therapies. The MSCoE also provide national consultation services for complex MS cases, clinical education to VA HCPs, and mentors fellows, residents, and medical students.

The VA provides numerous resources that are not readily available in other health care systems and facilitate the care for patients with chronic diseases, including providing low or no co-pays to patients for MS disease modifying agents and other MS related medications, access to medically necessary adaptive equipment at no charge, the Home Improvement and Structural Alteration (HISA) grant for assistance with safe home ingress and egress, respite care, access to a homemaker/home health aide, and caregiver support programs. Eligible veterans also can access additional resources such as adaptive housing and an automobile grant. The VA also provides substantial hands-on assistance to veterans who are homeless. The clinical team and a veteran with MS can leverage VA resources through the National MS Society (NMSS) Navigator Program as well as other community resources.²

The VHA encourages physical activity and wellness through sports and leisure. Veterans with MS can participate in sports programs and special events, including the National Veterans Wheelchair Games, the National Disabled Veterans Winter Sports Clinic, the National Disabled Veterans TEE (Training, Exposure and Experience) golf tournament, the National Veterans Summer Sports Clinic, the National Veterans Golden Age Games, and the National Veterans Creative Sports Festival. HCPs or veterans who are not sure how to access any of these programs can contact the MSCoE or their local VA social workers.

Research

The primary goal of the MSCoE research core is to conduct clinical, health services, epidemiologic, and basic science research relevant to veterans with MS. The MSCoE serves to enhance collaboration among VAMCs, increase the participation of veterans in research, and provide research mentorship for the next generation of VA MS scientists. MSCoE research is carried out by investigators at the MSCoE and the MS Regional Programs, often in collaboration with investigators at academic institutions. This research is supported by competitive grant awards from a variety of funding agencies including the VA Research and Development Service (R&D) and the NMSS. Results from about 40 research grants in Fiscal Year 2019 were disseminated through 34 peer-reviewed publications, 30 posters, presentations, abstracts, and clinical practice guidelines.

There are many examples of recent high impact MS research performed by MSCoE investigators. For example, MSCoE researchers noted an increase in the estimated prevalence of MS to 1 million individuals in the US, about twice the previously estimated prevalence.^3-5 In addition, a multicenter study highlighted the prevalence of MS misdiagnosis and common confounders for MS.⁶ Other research includes pilot clinical trials evaluating lipoic acid as a potential disease modifying therapy in people with secondary progressive MS and the impact of a multicomponent walking aid selection, fitting, and training program for preventing falls in people with MS.^7,8 Clinical trial also are investigating telehealth counseling to improve physical activity in MS and a systematic review of rehabilitation interventions in MS.^9,10

Education and Training

A unified program of education is essential to effective management of MS nationally. The primary goal of the education and training core is to provide a national program of MS education for HCPs, veterans, and caregivers to improve knowledge, enhance access to resources, and promote effective management strategies. The MSCoE collaborate with the Paralyzed Veterans of America (PVA), the Consortium of MS Centers (CMSC), the NMSS, and other national service organizations to increase educational opportunities, share knowledge, and expand participation.

The MSCoE education and training core produces a range of products both veterans, HCPs, and others affected by MS. The MSCoE sends a biannual patient newsletter to > 20,000 veterans and a monthly email to > 1,000 VA HCPs. Specific opportunities for HCP education include accredited multidisciplinary MS webinars, sponsored symposia and workshops at the CMSC and PVA Summit annual meetings, and presentations at other university and professional conferences. Enduring educational opportunities for veterans, caregivers, and HCPs can also be found by visiting www.va.gov/ms.

The MSCoE coordinate postdoctoral fellowship training programs to develop expertise in MS health care for the future. It offers VA physician fellowships for neurologists in Baltimore and Portland and for physiatrists in Seattle as well as NMSS fellowships for education and research. In 2019, MSCoE had 6 MD Fellows and 1 PhD Fellow.

Clinical Informatics and Telehealth

The primary goal of the informatics and telemedicine core is to employ state-of-the-art informatics, telemedicine technology, and the MSCoE website, to improve MS health care delivery. The VA has a integrated electronic health record and various data repositories are stored in the VHA Corporate Data Warehouse (CDW). MSCoE utilizes the CDW to maintain a national MS administrative data repository to understand the VHA care provided to veterans with MS. Data from the CDW have also served as an important resource to facilitate a wide range of veteran-focused MS research. This research has addressed clinical conditions like pain and obesity; health behaviors like smoking, alcohol use, and exercise as well as issues related to care delivery such as specialty care access, medication adherence, and appointment attendance.^11-19

Monitoring the health of veterans with MS in the VA requires additional data not available in the CDW. To this end, we have developed the MS Surveillance Registry (MSSR), funded and maintained by the VA Office of Information Technology as part of their Veteran Integrated Registry Platform (VIRP). The purpose of the MSSR is to understand the unique characteristics and treatment patterns of veterans with MS in order to optimize their VHA care. HCPs input MS-specific clinical data on their patients into the MSSR, either through the MS Assessment Tool (MSAT) in the Computerized Patient Record System (CPRS) or through a secure online portal. Other data from existing databases from the CDW is also automatically fed into the MSSR. The MSSR continues to be developed and populated to serve as a resource for the future.

Neurologists, physiatrists, psychologists, and rehabilitation specialists can use telehealth to evaluate and treat veterans who have difficulty accessing outpatient clinics, either because of mobility limitations, or distance. Between 2012 and 2015, the VA MSCoE, together with the Epilepsy CoE and the Parkinson’s Disease Research and Clinical Centers in VISNs 5, 6 (mid-Atlantic) and 20 (Pacific Northwest) initiated an integrated teleneurology project. The goal of this project was to improve patient access to care at 4 tertiary and 12 regional VAMCs. A study team, with administrators and key clinical stakeholders, followed a traditional project management approach to design, plan, implement and evaluate an optimal model for communication and referrals with both live visits and telehealth (Table). Major outcomes of the project included: delivering subspecialty teleneurology to 47 patient sites, increasing interfacility consultation by 133% while reducing wait times by roughly 40%, and increasing telemedicine workload at these centers from 95 annual encounters in 2012 to 1,245 annual encounters in 2015 (Figure).

Today, telehealth for veterans with MS can be delivered to nearby VA facilities closer to their home, within their home, or anywhere else the veteran can use a cellphone or tablet. Telehealth visits can save travel time and expenses and optimize VA productivity and clinic use. The MSCoE and many of the MS regional programs are using telehealth for MS physician follow-up and therapies. The VA Office of Rural Health is also currently working with the MS network to use telehealth to increase access to physical therapy to those who have difficulty coming into clinic.

MSCoE Resources

The MSCoE is funded by VA Central Office through the Office of Specialty Care by Special Purpose funds. The directive specifies that funding for the regional and support programs is through Veterans Equitable Resource Allocation based on VISN and facility workload and complexity. Any research is funded separately through grants, some from VA R&D and others from other sources including the National Institutes of Health, the Patient Centered Outcome Research Institute, affiliated universities, the NMSS, the MS Society of Canada, the Consortium of MS Centers, foundations, and industry.

In 2019, MSCoE investigators received grants totaling > $18 million in funding. In-kind support also is provided by the PVA, the CMSC, the NMSS, and others. The first 3 foundations have been supporters since the inception of the MSCoE and have provided opportunities for the dissemination of education and research for HCPs, fellows, residents and medical students; travel; meeting rooms for MSCoE national meetings; exhibit space for HCP outreach; competitive research and educational grant support; programming and resources for veterans and significant others; organizational expertise; and opportunities for VA HCPs, veterans, and caregivers to learn how to navigate MS with others in the private sector.

Conclusion

The MSCoE had a tremendous impact on improving the consistency and quality of care for veterans with MS through clinical care, research, education and informatics and telehealth. Since opening in 2003, there has been an increase in the number of MS specialty clinics, served veterans with MS, and veterans receiving specialty neurologic and rehabilitation services in VA. Research programs in MS have been initiated to address key questions relevant to veterans with MS, including immunology, epidemiology, clinical care, and rehabilitation. Educational programs and products have evolved with technology and had a greater impact through partnerships with veteran and MS nonprofit organizations.

MSCoE strives to minimize impairment and maximize quality of life for veterans with MS by leveraging integrated electronic health records, data repositories, and telehealth services. These efforts have all improved veteran health, access and safety. We look forward to continuing into the next decade by bringing fresh ideas to the care of veterans with MS, their families and caregivers.

DSM-5 defines personality disorders (PDs) as the presence of an enduring pattern of inner experience and behavior that “deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adulthood, is stable over time, and leads to distress or impairment.”¹ As a general rule, PDs are not limited to episodes of illness, but reflect an individual’s long-term adjustment. These disorders occur in 10% to 15% of the general population; the rates are especially high in health care settings, in criminal offenders, and in those with a substance use disorder (SUD).² PDs nearly always have an onset in adolescence or early adulthood and tend to diminish in severity with advancing age. They are associated with high rates of unemployment, homelessness, divorce and separation, domestic violence, substance misuse, and suicide.³

Psychotherapy is the first-line treatment for PDs, but there has been growing interest in using pharmacotherapy to treat PDs. While much of the PD treatment literature focuses on borderline PD,^4-9 this article describes diagnosis, potential pharmacotherapy strategies, and methods to assess response to treatment for patients with all types of PDs.

Recognizing and diagnosing personality disorders

The diagnosis of a PD requires an understanding of DSM-5 criteria combined with a comprehensive psychiatric history and mental status examination. The patient’s history is the most important basis for diagnosing a PD.² Collateral information from relatives or friends can help confirm the severity and pervasiveness of the individual’s personality problems. In some patients, long-term observation might be necessary to confirm the presence of a PD. Some clinicians are reluctant to diagnose PDs because of stigma, a problem common among patients with borderline PD.^10,11

To screen for PDs, a clinician might ask the patient about problems with interpersonal relationships, sense of self, work, affect, impulse control, and reality testing. Table 1¹² lists general screening questions for the presence of a PD from the Iowa Personality Disorders Screen. Structured diagnostic interviews and self-report assessments could boost recognition of PDs, but these tools are rarely used outside of research settings.^13,14

The PD clusters

DSM-5 divides 10 PDs into 3 clusters based on shared phenomenology and diagnostic criteria. Few patients have a “pure” case in which they meet criteria for only a single personality disorder.¹

Cluster A. “Eccentric cluster” disorders are united by social aversion, a failure to form close attachments, or paranoia and suspiciousness.¹⁵ These include paranoid, schizoid, and schizotypal PD. Low self-awareness is typical. There are no treatment guidelines for these disorders, although there is some clinical trial data for schizotypal PD.

Cluster B. “Dramatic cluster” disorders share dramatic, emotional, and erratic characteristics.¹⁴ These include narcissistic, antisocial, borderline, and histrionic PD. Antisocial and narcissistic patients have low self-awareness. There are treatment guidelines for antisocial and borderline PD, and a variety of clinical trial data is available for the latter.¹⁵

Continue to: Cluster C

Cluster C. “Anxious cluster” disorders are united by anxiousness, fearfulness, and poor self-esteem. Many of these patients also display interpersonal rigidity.¹⁵ These disorders include avoidant, dependent, and obsessive-compulsive PD. There are no treatment guidelines or clinical trial data for these disorders.

Why consider pharmacotherapy for personality disorders?

The consensus among experts is that psychotherapy is the treatment of choice for PDs.¹⁵ Despite significant gaps in the evidence base, there has been a growing interest in using psychotropic medication to treat PDs. For example, research shows that >90% of patients with borderline PD are prescribed medication, most typically antidepressants, antipsychotics, mood stabilizers, stimulants, or sedative-hypnotics.^16,17

Increased interest in pharmacotherapy for PDs could be related to research showing the importance of underlying neurobiology, particularly for antisocial and borderline PD.^18,19 This work is complemented by genetic research showing the heritability of PD traits and disorders.^20,21 Another factor could be renewed interest in dimensional approaches to the classification of PDs, as exemplified by DSM-5’s alternative model for PDs.¹ This approach aligns with some expert recommendations to focus on treating PD symptom dimensions, rather than the syndrome itself.²²

Importantly, no psychotropic medication is FDA-approved for the treatment of any PD. For that reason, prescribing medication for a PD is “off-label,” although prescribing a medication for a comorbid disorder for which the drug has an FDA-approved indication is not (eg, prescribing an antidepressant for major depressive disorder [MDD]).

Principles for prescribing

Despite gaps in research data, general principles for using medication to treat PDs have emerged from treatment guidelines for antisocial and borderline PD, clinical trial data, reviews and meta-analyses, and expert opinion. Clinicians should address the following considerations before prescribing medication to a patient with a PD.

Continue to: PD diagnosis

PD diagnosis. Has the patient been properly assessed and diagnosed? While history is the most important basis for diagnosis, the clinician should be familiar with the PDs and DSM-5 criteria. Has the patient been informed of the diagnosis and its implications for treatment?

Patient interest in medication. Is the patient interested in taking medication? Patients with borderline PD are often prescribed medication, but there are sparse data for the other PDs. The patient might have little interest in the PD diagnosis or its treatment.

Comorbidity. Has the patient been assessed for comorbid psychiatric disorders that could interfere with medication use (ie, an SUD) or might be a focus of treatment (eg, MDD)? Patients with PDs typically have significant comorbidity that a thorough evaluation will uncover.

PD symptom dimensions. Has the patient been assessed to determine cognitive or behavioral symptom dimensions of their PD? One or more symptom dimension(s) could be the focus of treatment. Table 2 lists examples of PD symptom dimensions.

Strategies to guide prescribing

Strategies to help guide prescribing include targeting any comorbid disorder(s), targeting important PD symptom dimensions (eg, impulsive aggression), choosing medication based on the similarity of the PD to another disorder known to respond to medication, and targeting the PD itself.

Continue to: Targeting comorbid disorders

Targeting comorbid disorders. National Institute for Health and Care Excellence guidelines for antisocial and borderline PD recommend that clinicians focus on treating comorbid disorders, a position echoed in Cochrane and other reviews.^4,9,22-26 For example, a patient with borderline PD experiencing a major depressive episode could be treated with an antidepressant. Targeting the depressive symptoms could boost the patient’s mood, perhaps lessening the individual’s PD symptoms or reducing their severity.

Targeting important symptom dimensions. For patients with borderline PD, several guidelines and reviews have suggested that treatment should focus on emotional dysregulation and impulsive aggression (mood stabilizers, antipsychotics), or cognitive-perceptual symptoms (antipsychotics).^4-6,15 There is some evidence that mood stabilizers or second-generation antipsychotics could help reduce impulsive aggression in patients with antisocial PD.²⁷

Choosing medication based on similarity to another disorder known to respond to medication. Avoidant PD overlaps with social anxiety disorder and can be conceptualized as a chronic, pervasive social phobia. Avoidant PD might respond to a medication known to be effective for treating social anxiety disorder, such as a selective serotonin reuptake inhibitor (SSRI) or venlafaxine.²⁸ Treating obsessive-compulsive PD with an SSRI is another example of this strategy, as 1 small study of fluvoxamine suggests.²⁹ Obsessive-compulsive PD is common in persons with obsessive-compulsive disorder, and overlap includes preoccupation with orders, rules, and lists, and an inability to throw things out.

Targeting the PD syndrome. Another strategy is to target the PD itself. Clinical trial data suggest the antipsychotic risperidone can reduce the symptoms of schizotypal PD.³⁰ Considering that this PD has a genetic association with schizophrenia, it is not surprising that the patient’s ideas of reference, odd communication, or transient paranoia might respond to an antipsychotic. Data from randomized controlled trials (RCTs) support the use of the second-generation antipsychotics aripiprazole and quetiapine to treat BPD.^31,32 While older guidelines^4,5 supported the use of the mood stabilizer lamotrigine, a recent RCT found that it was no more effective than placebo for borderline PD or its symptom dimensions.³³

What to do before prescribing

Before writing a prescription, the clinician and patient should discuss the presence of a PD and the desirability of treatment. The patient should understand the limited evidence base and know that medication prescribed for a PD is off-label. The clinician should discuss medication selection and its rationale, and whether the medication is targeting a comorbid disorder, symptom dimension(s), or the PD itself. Additional considerations for prescribing for patients with PDs are listed in Table 3.³⁴

Continue to: Avoid polypharmacy

Avoid polypharmacy. Many patients with borderline PD are prescribed multiple psychotropic medications.^16,17 This approach leads to greater expense and more adverse effects, and is not evidence-based.

Avoid benzodiazepines. Many patients with borderline PD are prescribed benzodiazepines, often as part of a polypharmacy regimen. These drugs can cause disinhibition, thereby increasing acting-out behaviors and self-harm.³⁵ Also, patients with PDs often have SUDs, which is a contraindication for benzodiazepine use.

Rate the patient’s improvement. Both the patient and clinician can benefit from monitoring symptomatic improvement. Several validated scales can be used to rate depression, anxiety, impulsivity, mood lability, anger, and aggression (Table 4^36-41).Some validated scales for borderline PD align with DSM-5 criteria. Two such widely used instruments are the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD)⁴² and the self-rated Borderline Evaluation of Severity Over Time (BEST).⁴³ Each has questions that could be pulled to rate a symptom dimension of interest, such as affective instability, anger dyscontrol, or abandonment fears (Table 5^42,43).

A visual analog scale is easy to use and can target symptom dimensions of interest.⁴⁴ For example, a clinician could use a visual analog scale to rate mood instability by asking a patient to rate their mood severity by making a mark along a 10-cm line (0 = “Most erratic emotions I have experienced,” 10 = “Most stable I have ever experienced my emotions to be”). This score can be recorded at baseline and subsequent visits.

Take-home points

PDs are common in the general population and health care settings. They are underrecognized by the general public and mental health professionals, often because of stigma. Clinicians could boost their recognition of these disorders by embedding simple screening questions in their patient assessments. Many patients with PDs will be interested in pharmacotherapy for their disorder or symptoms. Treatment strategies include targeting the comorbid disorder(s), targeting important PD symptom dimensions, choosing medication based on the similarity of the PD to another disorder known to respond to medication, and targeting the PD itself. Each strategy has its limitations and varying degrees of empirical support. Treatment response can be monitored using validated scales or a visual analog scale.

Continue to: Bottom Line

Bottom Line

Although psychotherapy is the first-line treatment and no medications are FDAapproved for treating personality disorders (PDs), there has been growing interest in using psychotropic medication to treat PDs. Strategies for pharmacotherapy include targeting comorbid disorders, PD symptom dimensions, or the PD itself. Choice of medication can be based on the similarity of the PD with another disorder known to respond to medication.

Related Resources

• Correa Da Costa S, Sanches M, Soares JC. Bipolar disorder or borderline personality disorder? Current Psychiatry. 2019;18(11):26-29,35-39.
• Bateman A, Gunderson J, Mulder R. Treatment of personality disorders. Lancet. 2015;385(9969):735-743.

Drug Brand Names

Aripiprazole • Abilify
Fluvoxamine • Luvox
Lamotrigine • Lamictal
Quetiapine • Seroquel
Risperidone • Risperdal
Venlafaxine • Effexor

DSM-5 defines personality disorders (PDs) as the presence of an enduring pattern of inner experience and behavior that “deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adulthood, is stable over time, and leads to distress or impairment.”¹ As a general rule, PDs are not limited to episodes of illness, but reflect an individual’s long-term adjustment. These disorders occur in 10% to 15% of the general population; the rates are especially high in health care settings, in criminal offenders, and in those with a substance use disorder (SUD).² PDs nearly always have an onset in adolescence or early adulthood and tend to diminish in severity with advancing age. They are associated with high rates of unemployment, homelessness, divorce and separation, domestic violence, substance misuse, and suicide.³

Psychotherapy is the first-line treatment for PDs, but there has been growing interest in using pharmacotherapy to treat PDs. While much of the PD treatment literature focuses on borderline PD,^4-9 this article describes diagnosis, potential pharmacotherapy strategies, and methods to assess response to treatment for patients with all types of PDs.

Recognizing and diagnosing personality disorders

The diagnosis of a PD requires an understanding of DSM-5 criteria combined with a comprehensive psychiatric history and mental status examination. The patient’s history is the most important basis for diagnosing a PD.² Collateral information from relatives or friends can help confirm the severity and pervasiveness of the individual’s personality problems. In some patients, long-term observation might be necessary to confirm the presence of a PD. Some clinicians are reluctant to diagnose PDs because of stigma, a problem common among patients with borderline PD.^10,11

To screen for PDs, a clinician might ask the patient about problems with interpersonal relationships, sense of self, work, affect, impulse control, and reality testing. Table 1¹² lists general screening questions for the presence of a PD from the Iowa Personality Disorders Screen. Structured diagnostic interviews and self-report assessments could boost recognition of PDs, but these tools are rarely used outside of research settings.^13,14

The PD clusters

DSM-5 divides 10 PDs into 3 clusters based on shared phenomenology and diagnostic criteria. Few patients have a “pure” case in which they meet criteria for only a single personality disorder.¹

Cluster A. “Eccentric cluster” disorders are united by social aversion, a failure to form close attachments, or paranoia and suspiciousness.¹⁵ These include paranoid, schizoid, and schizotypal PD. Low self-awareness is typical. There are no treatment guidelines for these disorders, although there is some clinical trial data for schizotypal PD.

Cluster B. “Dramatic cluster” disorders share dramatic, emotional, and erratic characteristics.¹⁴ These include narcissistic, antisocial, borderline, and histrionic PD. Antisocial and narcissistic patients have low self-awareness. There are treatment guidelines for antisocial and borderline PD, and a variety of clinical trial data is available for the latter.¹⁵

Continue to: Cluster C

Cluster C. “Anxious cluster” disorders are united by anxiousness, fearfulness, and poor self-esteem. Many of these patients also display interpersonal rigidity.¹⁵ These disorders include avoidant, dependent, and obsessive-compulsive PD. There are no treatment guidelines or clinical trial data for these disorders.

Why consider pharmacotherapy for personality disorders?

The consensus among experts is that psychotherapy is the treatment of choice for PDs.¹⁵ Despite significant gaps in the evidence base, there has been a growing interest in using psychotropic medication to treat PDs. For example, research shows that >90% of patients with borderline PD are prescribed medication, most typically antidepressants, antipsychotics, mood stabilizers, stimulants, or sedative-hypnotics.^16,17

Increased interest in pharmacotherapy for PDs could be related to research showing the importance of underlying neurobiology, particularly for antisocial and borderline PD.^18,19 This work is complemented by genetic research showing the heritability of PD traits and disorders.^20,21 Another factor could be renewed interest in dimensional approaches to the classification of PDs, as exemplified by DSM-5’s alternative model for PDs.¹ This approach aligns with some expert recommendations to focus on treating PD symptom dimensions, rather than the syndrome itself.²²

Importantly, no psychotropic medication is FDA-approved for the treatment of any PD. For that reason, prescribing medication for a PD is “off-label,” although prescribing a medication for a comorbid disorder for which the drug has an FDA-approved indication is not (eg, prescribing an antidepressant for major depressive disorder [MDD]).

Principles for prescribing

Despite gaps in research data, general principles for using medication to treat PDs have emerged from treatment guidelines for antisocial and borderline PD, clinical trial data, reviews and meta-analyses, and expert opinion. Clinicians should address the following considerations before prescribing medication to a patient with a PD.

Continue to: PD diagnosis

PD diagnosis. Has the patient been properly assessed and diagnosed? While history is the most important basis for diagnosis, the clinician should be familiar with the PDs and DSM-5 criteria. Has the patient been informed of the diagnosis and its implications for treatment?

Patient interest in medication. Is the patient interested in taking medication? Patients with borderline PD are often prescribed medication, but there are sparse data for the other PDs. The patient might have little interest in the PD diagnosis or its treatment.

Comorbidity. Has the patient been assessed for comorbid psychiatric disorders that could interfere with medication use (ie, an SUD) or might be a focus of treatment (eg, MDD)? Patients with PDs typically have significant comorbidity that a thorough evaluation will uncover.

PD symptom dimensions. Has the patient been assessed to determine cognitive or behavioral symptom dimensions of their PD? One or more symptom dimension(s) could be the focus of treatment. Table 2 lists examples of PD symptom dimensions.

Strategies to guide prescribing

Strategies to help guide prescribing include targeting any comorbid disorder(s), targeting important PD symptom dimensions (eg, impulsive aggression), choosing medication based on the similarity of the PD to another disorder known to respond to medication, and targeting the PD itself.

Continue to: Targeting comorbid disorders

Targeting comorbid disorders. National Institute for Health and Care Excellence guidelines for antisocial and borderline PD recommend that clinicians focus on treating comorbid disorders, a position echoed in Cochrane and other reviews.^4,9,22-26 For example, a patient with borderline PD experiencing a major depressive episode could be treated with an antidepressant. Targeting the depressive symptoms could boost the patient’s mood, perhaps lessening the individual’s PD symptoms or reducing their severity.

Targeting important symptom dimensions. For patients with borderline PD, several guidelines and reviews have suggested that treatment should focus on emotional dysregulation and impulsive aggression (mood stabilizers, antipsychotics), or cognitive-perceptual symptoms (antipsychotics).^4-6,15 There is some evidence that mood stabilizers or second-generation antipsychotics could help reduce impulsive aggression in patients with antisocial PD.²⁷

Choosing medication based on similarity to another disorder known to respond to medication. Avoidant PD overlaps with social anxiety disorder and can be conceptualized as a chronic, pervasive social phobia. Avoidant PD might respond to a medication known to be effective for treating social anxiety disorder, such as a selective serotonin reuptake inhibitor (SSRI) or venlafaxine.²⁸ Treating obsessive-compulsive PD with an SSRI is another example of this strategy, as 1 small study of fluvoxamine suggests.²⁹ Obsessive-compulsive PD is common in persons with obsessive-compulsive disorder, and overlap includes preoccupation with orders, rules, and lists, and an inability to throw things out.

Targeting the PD syndrome. Another strategy is to target the PD itself. Clinical trial data suggest the antipsychotic risperidone can reduce the symptoms of schizotypal PD.³⁰ Considering that this PD has a genetic association with schizophrenia, it is not surprising that the patient’s ideas of reference, odd communication, or transient paranoia might respond to an antipsychotic. Data from randomized controlled trials (RCTs) support the use of the second-generation antipsychotics aripiprazole and quetiapine to treat BPD.^31,32 While older guidelines^4,5 supported the use of the mood stabilizer lamotrigine, a recent RCT found that it was no more effective than placebo for borderline PD or its symptom dimensions.³³

What to do before prescribing

Before writing a prescription, the clinician and patient should discuss the presence of a PD and the desirability of treatment. The patient should understand the limited evidence base and know that medication prescribed for a PD is off-label. The clinician should discuss medication selection and its rationale, and whether the medication is targeting a comorbid disorder, symptom dimension(s), or the PD itself. Additional considerations for prescribing for patients with PDs are listed in Table 3.³⁴

Continue to: Avoid polypharmacy

Avoid polypharmacy. Many patients with borderline PD are prescribed multiple psychotropic medications.^16,17 This approach leads to greater expense and more adverse effects, and is not evidence-based.

Avoid benzodiazepines. Many patients with borderline PD are prescribed benzodiazepines, often as part of a polypharmacy regimen. These drugs can cause disinhibition, thereby increasing acting-out behaviors and self-harm.³⁵ Also, patients with PDs often have SUDs, which is a contraindication for benzodiazepine use.

Rate the patient’s improvement. Both the patient and clinician can benefit from monitoring symptomatic improvement. Several validated scales can be used to rate depression, anxiety, impulsivity, mood lability, anger, and aggression (Table 4^36-41).Some validated scales for borderline PD align with DSM-5 criteria. Two such widely used instruments are the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD)⁴² and the self-rated Borderline Evaluation of Severity Over Time (BEST).⁴³ Each has questions that could be pulled to rate a symptom dimension of interest, such as affective instability, anger dyscontrol, or abandonment fears (Table 5^42,43).

A visual analog scale is easy to use and can target symptom dimensions of interest.⁴⁴ For example, a clinician could use a visual analog scale to rate mood instability by asking a patient to rate their mood severity by making a mark along a 10-cm line (0 = “Most erratic emotions I have experienced,” 10 = “Most stable I have ever experienced my emotions to be”). This score can be recorded at baseline and subsequent visits.

Take-home points

PDs are common in the general population and health care settings. They are underrecognized by the general public and mental health professionals, often because of stigma. Clinicians could boost their recognition of these disorders by embedding simple screening questions in their patient assessments. Many patients with PDs will be interested in pharmacotherapy for their disorder or symptoms. Treatment strategies include targeting the comorbid disorder(s), targeting important PD symptom dimensions, choosing medication based on the similarity of the PD to another disorder known to respond to medication, and targeting the PD itself. Each strategy has its limitations and varying degrees of empirical support. Treatment response can be monitored using validated scales or a visual analog scale.

Continue to: Bottom Line

Bottom Line

Although psychotherapy is the first-line treatment and no medications are FDAapproved for treating personality disorders (PDs), there has been growing interest in using psychotropic medication to treat PDs. Strategies for pharmacotherapy include targeting comorbid disorders, PD symptom dimensions, or the PD itself. Choice of medication can be based on the similarity of the PD with another disorder known to respond to medication.

Related Resources

• Correa Da Costa S, Sanches M, Soares JC. Bipolar disorder or borderline personality disorder? Current Psychiatry. 2019;18(11):26-29,35-39.
• Bateman A, Gunderson J, Mulder R. Treatment of personality disorders. Lancet. 2015;385(9969):735-743.

Drug Brand Names

Aripiprazole • Abilify
Fluvoxamine • Luvox
Lamotrigine • Lamictal
Quetiapine • Seroquel
Risperidone • Risperdal
Venlafaxine • Effexor

DSM-5 defines personality disorders (PDs) as the presence of an enduring pattern of inner experience and behavior that “deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adulthood, is stable over time, and leads to distress or impairment.”¹ As a general rule, PDs are not limited to episodes of illness, but reflect an individual’s long-term adjustment. These disorders occur in 10% to 15% of the general population; the rates are especially high in health care settings, in criminal offenders, and in those with a substance use disorder (SUD).² PDs nearly always have an onset in adolescence or early adulthood and tend to diminish in severity with advancing age. They are associated with high rates of unemployment, homelessness, divorce and separation, domestic violence, substance misuse, and suicide.³

Psychotherapy is the first-line treatment for PDs, but there has been growing interest in using pharmacotherapy to treat PDs. While much of the PD treatment literature focuses on borderline PD,^4-9 this article describes diagnosis, potential pharmacotherapy strategies, and methods to assess response to treatment for patients with all types of PDs.

Recognizing and diagnosing personality disorders

The diagnosis of a PD requires an understanding of DSM-5 criteria combined with a comprehensive psychiatric history and mental status examination. The patient’s history is the most important basis for diagnosing a PD.² Collateral information from relatives or friends can help confirm the severity and pervasiveness of the individual’s personality problems. In some patients, long-term observation might be necessary to confirm the presence of a PD. Some clinicians are reluctant to diagnose PDs because of stigma, a problem common among patients with borderline PD.^10,11

To screen for PDs, a clinician might ask the patient about problems with interpersonal relationships, sense of self, work, affect, impulse control, and reality testing. Table 1¹² lists general screening questions for the presence of a PD from the Iowa Personality Disorders Screen. Structured diagnostic interviews and self-report assessments could boost recognition of PDs, but these tools are rarely used outside of research settings.^13,14

The PD clusters

DSM-5 divides 10 PDs into 3 clusters based on shared phenomenology and diagnostic criteria. Few patients have a “pure” case in which they meet criteria for only a single personality disorder.¹

Cluster A. “Eccentric cluster” disorders are united by social aversion, a failure to form close attachments, or paranoia and suspiciousness.¹⁵ These include paranoid, schizoid, and schizotypal PD. Low self-awareness is typical. There are no treatment guidelines for these disorders, although there is some clinical trial data for schizotypal PD.

Cluster B. “Dramatic cluster” disorders share dramatic, emotional, and erratic characteristics.¹⁴ These include narcissistic, antisocial, borderline, and histrionic PD. Antisocial and narcissistic patients have low self-awareness. There are treatment guidelines for antisocial and borderline PD, and a variety of clinical trial data is available for the latter.¹⁵

Continue to: Cluster C

Cluster C. “Anxious cluster” disorders are united by anxiousness, fearfulness, and poor self-esteem. Many of these patients also display interpersonal rigidity.¹⁵ These disorders include avoidant, dependent, and obsessive-compulsive PD. There are no treatment guidelines or clinical trial data for these disorders.

Why consider pharmacotherapy for personality disorders?

The consensus among experts is that psychotherapy is the treatment of choice for PDs.¹⁵ Despite significant gaps in the evidence base, there has been a growing interest in using psychotropic medication to treat PDs. For example, research shows that >90% of patients with borderline PD are prescribed medication, most typically antidepressants, antipsychotics, mood stabilizers, stimulants, or sedative-hypnotics.^16,17

Increased interest in pharmacotherapy for PDs could be related to research showing the importance of underlying neurobiology, particularly for antisocial and borderline PD.^18,19 This work is complemented by genetic research showing the heritability of PD traits and disorders.^20,21 Another factor could be renewed interest in dimensional approaches to the classification of PDs, as exemplified by DSM-5’s alternative model for PDs.¹ This approach aligns with some expert recommendations to focus on treating PD symptom dimensions, rather than the syndrome itself.²²

Importantly, no psychotropic medication is FDA-approved for the treatment of any PD. For that reason, prescribing medication for a PD is “off-label,” although prescribing a medication for a comorbid disorder for which the drug has an FDA-approved indication is not (eg, prescribing an antidepressant for major depressive disorder [MDD]).

Principles for prescribing

Despite gaps in research data, general principles for using medication to treat PDs have emerged from treatment guidelines for antisocial and borderline PD, clinical trial data, reviews and meta-analyses, and expert opinion. Clinicians should address the following considerations before prescribing medication to a patient with a PD.

Continue to: PD diagnosis

PD diagnosis. Has the patient been properly assessed and diagnosed? While history is the most important basis for diagnosis, the clinician should be familiar with the PDs and DSM-5 criteria. Has the patient been informed of the diagnosis and its implications for treatment?

Patient interest in medication. Is the patient interested in taking medication? Patients with borderline PD are often prescribed medication, but there are sparse data for the other PDs. The patient might have little interest in the PD diagnosis or its treatment.

Comorbidity. Has the patient been assessed for comorbid psychiatric disorders that could interfere with medication use (ie, an SUD) or might be a focus of treatment (eg, MDD)? Patients with PDs typically have significant comorbidity that a thorough evaluation will uncover.

PD symptom dimensions. Has the patient been assessed to determine cognitive or behavioral symptom dimensions of their PD? One or more symptom dimension(s) could be the focus of treatment. Table 2 lists examples of PD symptom dimensions.

Strategies to guide prescribing

Strategies to help guide prescribing include targeting any comorbid disorder(s), targeting important PD symptom dimensions (eg, impulsive aggression), choosing medication based on the similarity of the PD to another disorder known to respond to medication, and targeting the PD itself.

Continue to: Targeting comorbid disorders

Targeting comorbid disorders. National Institute for Health and Care Excellence guidelines for antisocial and borderline PD recommend that clinicians focus on treating comorbid disorders, a position echoed in Cochrane and other reviews.^4,9,22-26 For example, a patient with borderline PD experiencing a major depressive episode could be treated with an antidepressant. Targeting the depressive symptoms could boost the patient’s mood, perhaps lessening the individual’s PD symptoms or reducing their severity.

Targeting important symptom dimensions. For patients with borderline PD, several guidelines and reviews have suggested that treatment should focus on emotional dysregulation and impulsive aggression (mood stabilizers, antipsychotics), or cognitive-perceptual symptoms (antipsychotics).^4-6,15 There is some evidence that mood stabilizers or second-generation antipsychotics could help reduce impulsive aggression in patients with antisocial PD.²⁷

Choosing medication based on similarity to another disorder known to respond to medication. Avoidant PD overlaps with social anxiety disorder and can be conceptualized as a chronic, pervasive social phobia. Avoidant PD might respond to a medication known to be effective for treating social anxiety disorder, such as a selective serotonin reuptake inhibitor (SSRI) or venlafaxine.²⁸ Treating obsessive-compulsive PD with an SSRI is another example of this strategy, as 1 small study of fluvoxamine suggests.²⁹ Obsessive-compulsive PD is common in persons with obsessive-compulsive disorder, and overlap includes preoccupation with orders, rules, and lists, and an inability to throw things out.

Targeting the PD syndrome. Another strategy is to target the PD itself. Clinical trial data suggest the antipsychotic risperidone can reduce the symptoms of schizotypal PD.³⁰ Considering that this PD has a genetic association with schizophrenia, it is not surprising that the patient’s ideas of reference, odd communication, or transient paranoia might respond to an antipsychotic. Data from randomized controlled trials (RCTs) support the use of the second-generation antipsychotics aripiprazole and quetiapine to treat BPD.^31,32 While older guidelines^4,5 supported the use of the mood stabilizer lamotrigine, a recent RCT found that it was no more effective than placebo for borderline PD or its symptom dimensions.³³

What to do before prescribing

Before writing a prescription, the clinician and patient should discuss the presence of a PD and the desirability of treatment. The patient should understand the limited evidence base and know that medication prescribed for a PD is off-label. The clinician should discuss medication selection and its rationale, and whether the medication is targeting a comorbid disorder, symptom dimension(s), or the PD itself. Additional considerations for prescribing for patients with PDs are listed in Table 3.³⁴

Continue to: Avoid polypharmacy

Avoid polypharmacy. Many patients with borderline PD are prescribed multiple psychotropic medications.^16,17 This approach leads to greater expense and more adverse effects, and is not evidence-based.

Avoid benzodiazepines. Many patients with borderline PD are prescribed benzodiazepines, often as part of a polypharmacy regimen. These drugs can cause disinhibition, thereby increasing acting-out behaviors and self-harm.³⁵ Also, patients with PDs often have SUDs, which is a contraindication for benzodiazepine use.

Rate the patient’s improvement. Both the patient and clinician can benefit from monitoring symptomatic improvement. Several validated scales can be used to rate depression, anxiety, impulsivity, mood lability, anger, and aggression (Table 4^36-41).Some validated scales for borderline PD align with DSM-5 criteria. Two such widely used instruments are the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD)⁴² and the self-rated Borderline Evaluation of Severity Over Time (BEST).⁴³ Each has questions that could be pulled to rate a symptom dimension of interest, such as affective instability, anger dyscontrol, or abandonment fears (Table 5^42,43).

A visual analog scale is easy to use and can target symptom dimensions of interest.⁴⁴ For example, a clinician could use a visual analog scale to rate mood instability by asking a patient to rate their mood severity by making a mark along a 10-cm line (0 = “Most erratic emotions I have experienced,” 10 = “Most stable I have ever experienced my emotions to be”). This score can be recorded at baseline and subsequent visits.

Take-home points

PDs are common in the general population and health care settings. They are underrecognized by the general public and mental health professionals, often because of stigma. Clinicians could boost their recognition of these disorders by embedding simple screening questions in their patient assessments. Many patients with PDs will be interested in pharmacotherapy for their disorder or symptoms. Treatment strategies include targeting the comorbid disorder(s), targeting important PD symptom dimensions, choosing medication based on the similarity of the PD to another disorder known to respond to medication, and targeting the PD itself. Each strategy has its limitations and varying degrees of empirical support. Treatment response can be monitored using validated scales or a visual analog scale.

Continue to: Bottom Line

Bottom Line

Although psychotherapy is the first-line treatment and no medications are FDAapproved for treating personality disorders (PDs), there has been growing interest in using psychotropic medication to treat PDs. Strategies for pharmacotherapy include targeting comorbid disorders, PD symptom dimensions, or the PD itself. Choice of medication can be based on the similarity of the PD with another disorder known to respond to medication.

Related Resources

• Correa Da Costa S, Sanches M, Soares JC. Bipolar disorder or borderline personality disorder? Current Psychiatry. 2019;18(11):26-29,35-39.
• Bateman A, Gunderson J, Mulder R. Treatment of personality disorders. Lancet. 2015;385(9969):735-743.

Drug Brand Names

Aripiprazole • Abilify
Fluvoxamine • Luvox
Lamotrigine • Lamictal
Quetiapine • Seroquel
Risperidone • Risperdal
Venlafaxine • Effexor

Because treatment resistance is a pervasive problem in bipolar depression, the use of neuromodulation treatments such as transcranial magnetic stimulation (TMS) is increasing for patients with this disorder.^1-7 Patients with bipolar disorder tend to spend the majority of the time with depressive symptoms, which underscores the importance of providing effective treatment for bipolar depression, especially given the chronicity of this disease.^2,3,5 Only a few medications are FDA-approved for treating bipolar depression (Table).

In this article, we describe the case of a patient with treatment-resistant bipolar depression undergoing adjunctive TMS treatment who experienced an affective switch from depression to mania. We also discuss evidence regarding the likelihood of treatment-emergent mania for antidepressants vs TMS in bipolar depression.

CASE

Ms. W, a 60-year-old White female with a history of bipolar I disorder and attention-deficit/hyperactivity disorder (ADHD), presented for TMS evaluation during a depressive episode. Throughout her life, she had experienced numerous manic episodes, but as she got older she noted an increasing frequency of depressive episodes. Over the course of her illness, she had completed adequate trials at therapeutic doses of many medications, including second-generation antipsycho­tics (SGAs) (aripiprazole, lurasidone, olanzapine, quetiapine), mood stabilizers (lamotrigine, lithium), and antidepressants (bupropion, venlafaxine, fluoxetine, mirtazapine, trazodone). A course of electroconvulsive therapy was not effective. Ms. W had a long-standing diagnosis of ADHD and had been treated with stimulants for >10 years, although it was unclear whether formal neuropsychological testing had been conducted to confirm this diagnosis. She had >10 suicide attempts and multiple psychiatric hospitalizations.

At her initial evaluation for TMS, Ms. W said she had depressive symptoms predominating for the past 2 years, including low mood, hopelessness, poor sleep, poor appetite, anhedonia, and suicidal ideation without a plan. At the time, she was taking clonazepam, 0.5 mg twice a day; lurasidone, 40 mg/d at bedtime; fluoxetine, 60 mg/d; trazodone, 50 mg/d at bedtime; and methylphenidate, 40 mg/d, and was participating in psychotherapy consistently.

After Ms. W and her clinicians discussed alternatives, risks, benefits, and adverse effects, she consented to adjunctive TMS treatment and provided written informed consent. The treatment plan was outlined as 6 weeks of daily TMS therapy (NeuroStar; Neuronetics, Malvern, PA), 1 treatment per day, 5 days a week. Her clinical status was assessed weekly using the Quick Inventory of Depressive Symptomatology (QIDS) for depression, Generalized Anxiety Disorder 7-item scale (GAD-7) for anxiety, and Young Mania Rating Scale (YMRS) for mania. The Figure shows the trends in Ms. W’s QIDS, GAD-7, and YMRS scores over the course of TMS treatment.

Prior to initiating TMS, her baseline scores were QIDS: 25, GAD-7: 9, and YMRS: 7, indicating very severe depression, mild anxiety, and the absence of mania. Ms. W’s psychotropic regimen remained unchanged throughout the course of her TMS treatment. After her motor threshold was determined, her TMS treatment began at 80% of motor threshold and was titrated up to 95% at the first treatment. By the second treatment, it was titrated up to 110%. By the third treatment, it was titrated up to 120% of motor threshold, which is the percentage used for the remaining treatments.

Initially, Ms. W reported some improvement in her depression, but this improvement was short-lived, and she continued to have elevated QIDS scores throughout treatment. By treatment #21, her QIDS and GAD-7 scores remained elevated, and her YMRS score had increased to 12. Due to this increase in YMRS score, the YMRS was repeated on the next 2 treatment days (#22 and #23), and her score was 6 on both days. When Ms. W presented for treatment #25, she was disorganized, irritable, and endorsed racing thoughts and decreased sleep. She was involuntarily hospitalized for mania, and TMS was discontinued. Unfortunately, she did not complete any clinical scales on that day. Upon admission to the hospital, Ms. W reported that at approximately the time of treatment #21, she had a fluctuation in her mood that consisted of increased goal-directed activity, decreased need for sleep, racing thoughts, and increased frivolous spending. She was treated with lithium, 300 mg twice a day. Lurasidone was increased to 80 mg/d at bedtime, and she continued clonazepam, trazodone, and methylphenidate at the previous doses. Over 14 days, Ms. W’s mania gradually resolved, and she was discharged home.

Continue to: Mixed evidence on the risk of switching

Mixed evidence on the risk of switching

Currently, several TMS devices are FDA-cleared for treating unipolar major depressive disorder, obsessive-compulsive disorder, and certain types of migraine. In March 2020, the FDA granted Breakthrough Device Designation for one TMS device, the NeuroStar Advanced Therapy System, for the treatment of bipolar depression.⁸ This designation created an expedited pathway for prioritized FDA review of the NeuroStar Advanced Therapy clinical trial program. 

Few published clinical studies have evaluated using TMS to treat patients with bipolar depression.^9-15 As with any antidepressant treatment for bipolar depression, there is a risk of affective switch from depression to mania when using TMS. Most of the literature available regarding the treatment of bipolar depression focuses on the risk of antidepressant medications to induce an affective switch. This risk depends on the class of the antidepressant,¹⁶ and there is a paucity of studies examining the risk of switch with TMS.

Interpretation of available literature is limited due to inconsistencies in the definition of an affective switch, the variable length of treatment with antidepressants, the use of concurrent medications such as mood stabilizers, and confounders such as the natural course of switching in bipolar disorder.¹⁷ Overall, the evidence for treatment-emergent mania related to antidepressant use is mixed, and the reported rate of treatment-emergent mania varies. In a systematic review and meta-analysis of >20 randomized controlled trials that included 1,316 patients with bipolar disorder who received antidepressants, Fornaro et al¹⁸ found that the incidence of treatment-emergent mania was 11.8%. It is generally recommended that if antidepressants are used to treat patients with bipolar disorder, they should be given with a traditional mood stabilizer to prevent affective switches, although whether mood stabilizers can prevent such switches is unproven.¹⁹

In a literature review by Xia et al,²⁰ the affective switch rate in patients with bipolar depression who were treated with TMS was 3.1%, which was not statistically different from the affective switch rate with sham treatment.However, most of the patients included in this analysis were receiving other medications concurrently, and the length of treatment was 2 weeks, which is shorter than the average length of TMS treatment in clinical practice. In a recent literature review by Rachid,²¹ TMS was found to possibly induce manic episodes when used as monotherapy or in combination with antidepressants in patients with bipolar depression. To reduce the risk of treatment-emergent mania, current recommendations advise the use of a mood stabilizer for a minimum of 2 weeks before initiating TMS.¹

In our case, Ms. W was receiving antidepressants (fluoxetine and trazodone), lurasidone (an SGA that is FDA-approved for bipolar depression), and methylphenidate before starting TMS treatment. Fluoxetine, trazodone, and methylphenidate may possibly contribute to an increased risk of an affective switch.^1,22 Further studies are needed to clarify whether mood stabilizers or SGAs can prevent the development of mania in patients with bipolar depression who undergo TMS treatment.²⁰

Continue to: Because bipolar depression poses...

Because bipolar depression poses a major clinical challenge,^23,24 it is imperative to consider alternate treatments. When evaluating alternative treatment strategies, one may consider TMS in conjunction with a traditional mood stabilizer because this regimen may have a lower risk of treatment-emergent mania compared with antidepressants.^1,25

Acknowledgment

The authors thank Dr. Sy Saeed for his expertise and guidance on this article.

Bottom Line

For patients with bipolar depression, treatment with transcranial magnetic stimulation in conjunction with a mood stabilizer may have lower rates of treatment-emergent mania than treatment with antidepressants.

Related Resources

• Transcranial magnetic stimulation: clinical applications for psychiatric practice. Bermudes RA, Lanocha K, Janicak PG, eds. American Psychiatric Association Publishing; 2017.
• Gold AK, Ornelas AC, Cirillo P, et al. Clinical applications of transcranial magnetic stimulation in bipolar disorder. Brain Behav. 2019;9(10):e01419. doi: 10.1002/brb3.1419

Drug Brand Names

Aripiprazole • Abilify
Bupropion • Wellbutrin
Cariprazine • Vraylar
Clonazepam • Klonopin
Fluoxetine • Prozac
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Methylphenidate • Ritalin, Concerta
Mirtazapine • Remeron
Olanzapine • Zyprexa
Olanzapine-fluoxetine • Symbyax
Quetiapine • Seroquel
Trazodone • Desyrel
Venlafaxine • Effexor

Because treatment resistance is a pervasive problem in bipolar depression, the use of neuromodulation treatments such as transcranial magnetic stimulation (TMS) is increasing for patients with this disorder.^1-7 Patients with bipolar disorder tend to spend the majority of the time with depressive symptoms, which underscores the importance of providing effective treatment for bipolar depression, especially given the chronicity of this disease.^2,3,5 Only a few medications are FDA-approved for treating bipolar depression (Table).

In this article, we describe the case of a patient with treatment-resistant bipolar depression undergoing adjunctive TMS treatment who experienced an affective switch from depression to mania. We also discuss evidence regarding the likelihood of treatment-emergent mania for antidepressants vs TMS in bipolar depression.

CASE

Ms. W, a 60-year-old White female with a history of bipolar I disorder and attention-deficit/hyperactivity disorder (ADHD), presented for TMS evaluation during a depressive episode. Throughout her life, she had experienced numerous manic episodes, but as she got older she noted an increasing frequency of depressive episodes. Over the course of her illness, she had completed adequate trials at therapeutic doses of many medications, including second-generation antipsycho­tics (SGAs) (aripiprazole, lurasidone, olanzapine, quetiapine), mood stabilizers (lamotrigine, lithium), and antidepressants (bupropion, venlafaxine, fluoxetine, mirtazapine, trazodone). A course of electroconvulsive therapy was not effective. Ms. W had a long-standing diagnosis of ADHD and had been treated with stimulants for >10 years, although it was unclear whether formal neuropsychological testing had been conducted to confirm this diagnosis. She had >10 suicide attempts and multiple psychiatric hospitalizations.

At her initial evaluation for TMS, Ms. W said she had depressive symptoms predominating for the past 2 years, including low mood, hopelessness, poor sleep, poor appetite, anhedonia, and suicidal ideation without a plan. At the time, she was taking clonazepam, 0.5 mg twice a day; lurasidone, 40 mg/d at bedtime; fluoxetine, 60 mg/d; trazodone, 50 mg/d at bedtime; and methylphenidate, 40 mg/d, and was participating in psychotherapy consistently.

After Ms. W and her clinicians discussed alternatives, risks, benefits, and adverse effects, she consented to adjunctive TMS treatment and provided written informed consent. The treatment plan was outlined as 6 weeks of daily TMS therapy (NeuroStar; Neuronetics, Malvern, PA), 1 treatment per day, 5 days a week. Her clinical status was assessed weekly using the Quick Inventory of Depressive Symptomatology (QIDS) for depression, Generalized Anxiety Disorder 7-item scale (GAD-7) for anxiety, and Young Mania Rating Scale (YMRS) for mania. The Figure shows the trends in Ms. W’s QIDS, GAD-7, and YMRS scores over the course of TMS treatment.

Prior to initiating TMS, her baseline scores were QIDS: 25, GAD-7: 9, and YMRS: 7, indicating very severe depression, mild anxiety, and the absence of mania. Ms. W’s psychotropic regimen remained unchanged throughout the course of her TMS treatment. After her motor threshold was determined, her TMS treatment began at 80% of motor threshold and was titrated up to 95% at the first treatment. By the second treatment, it was titrated up to 110%. By the third treatment, it was titrated up to 120% of motor threshold, which is the percentage used for the remaining treatments.

Initially, Ms. W reported some improvement in her depression, but this improvement was short-lived, and she continued to have elevated QIDS scores throughout treatment. By treatment #21, her QIDS and GAD-7 scores remained elevated, and her YMRS score had increased to 12. Due to this increase in YMRS score, the YMRS was repeated on the next 2 treatment days (#22 and #23), and her score was 6 on both days. When Ms. W presented for treatment #25, she was disorganized, irritable, and endorsed racing thoughts and decreased sleep. She was involuntarily hospitalized for mania, and TMS was discontinued. Unfortunately, she did not complete any clinical scales on that day. Upon admission to the hospital, Ms. W reported that at approximately the time of treatment #21, she had a fluctuation in her mood that consisted of increased goal-directed activity, decreased need for sleep, racing thoughts, and increased frivolous spending. She was treated with lithium, 300 mg twice a day. Lurasidone was increased to 80 mg/d at bedtime, and she continued clonazepam, trazodone, and methylphenidate at the previous doses. Over 14 days, Ms. W’s mania gradually resolved, and she was discharged home.

Continue to: Mixed evidence on the risk of switching

Mixed evidence on the risk of switching

Currently, several TMS devices are FDA-cleared for treating unipolar major depressive disorder, obsessive-compulsive disorder, and certain types of migraine. In March 2020, the FDA granted Breakthrough Device Designation for one TMS device, the NeuroStar Advanced Therapy System, for the treatment of bipolar depression.⁸ This designation created an expedited pathway for prioritized FDA review of the NeuroStar Advanced Therapy clinical trial program. 

Few published clinical studies have evaluated using TMS to treat patients with bipolar depression.^9-15 As with any antidepressant treatment for bipolar depression, there is a risk of affective switch from depression to mania when using TMS. Most of the literature available regarding the treatment of bipolar depression focuses on the risk of antidepressant medications to induce an affective switch. This risk depends on the class of the antidepressant,¹⁶ and there is a paucity of studies examining the risk of switch with TMS.

Interpretation of available literature is limited due to inconsistencies in the definition of an affective switch, the variable length of treatment with antidepressants, the use of concurrent medications such as mood stabilizers, and confounders such as the natural course of switching in bipolar disorder.¹⁷ Overall, the evidence for treatment-emergent mania related to antidepressant use is mixed, and the reported rate of treatment-emergent mania varies. In a systematic review and meta-analysis of >20 randomized controlled trials that included 1,316 patients with bipolar disorder who received antidepressants, Fornaro et al¹⁸ found that the incidence of treatment-emergent mania was 11.8%. It is generally recommended that if antidepressants are used to treat patients with bipolar disorder, they should be given with a traditional mood stabilizer to prevent affective switches, although whether mood stabilizers can prevent such switches is unproven.¹⁹

In a literature review by Xia et al,²⁰ the affective switch rate in patients with bipolar depression who were treated with TMS was 3.1%, which was not statistically different from the affective switch rate with sham treatment.However, most of the patients included in this analysis were receiving other medications concurrently, and the length of treatment was 2 weeks, which is shorter than the average length of TMS treatment in clinical practice. In a recent literature review by Rachid,²¹ TMS was found to possibly induce manic episodes when used as monotherapy or in combination with antidepressants in patients with bipolar depression. To reduce the risk of treatment-emergent mania, current recommendations advise the use of a mood stabilizer for a minimum of 2 weeks before initiating TMS.¹

In our case, Ms. W was receiving antidepressants (fluoxetine and trazodone), lurasidone (an SGA that is FDA-approved for bipolar depression), and methylphenidate before starting TMS treatment. Fluoxetine, trazodone, and methylphenidate may possibly contribute to an increased risk of an affective switch.^1,22 Further studies are needed to clarify whether mood stabilizers or SGAs can prevent the development of mania in patients with bipolar depression who undergo TMS treatment.²⁰

Continue to: Because bipolar depression poses...

Because bipolar depression poses a major clinical challenge,^23,24 it is imperative to consider alternate treatments. When evaluating alternative treatment strategies, one may consider TMS in conjunction with a traditional mood stabilizer because this regimen may have a lower risk of treatment-emergent mania compared with antidepressants.^1,25

Acknowledgment

The authors thank Dr. Sy Saeed for his expertise and guidance on this article.

Bottom Line

For patients with bipolar depression, treatment with transcranial magnetic stimulation in conjunction with a mood stabilizer may have lower rates of treatment-emergent mania than treatment with antidepressants.

Related Resources

• Transcranial magnetic stimulation: clinical applications for psychiatric practice. Bermudes RA, Lanocha K, Janicak PG, eds. American Psychiatric Association Publishing; 2017.
• Gold AK, Ornelas AC, Cirillo P, et al. Clinical applications of transcranial magnetic stimulation in bipolar disorder. Brain Behav. 2019;9(10):e01419. doi: 10.1002/brb3.1419

Drug Brand Names

Aripiprazole • Abilify
Bupropion • Wellbutrin
Cariprazine • Vraylar
Clonazepam • Klonopin
Fluoxetine • Prozac
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Methylphenidate • Ritalin, Concerta
Mirtazapine • Remeron
Olanzapine • Zyprexa
Olanzapine-fluoxetine • Symbyax
Quetiapine • Seroquel
Trazodone • Desyrel
Venlafaxine • Effexor

Because treatment resistance is a pervasive problem in bipolar depression, the use of neuromodulation treatments such as transcranial magnetic stimulation (TMS) is increasing for patients with this disorder.^1-7 Patients with bipolar disorder tend to spend the majority of the time with depressive symptoms, which underscores the importance of providing effective treatment for bipolar depression, especially given the chronicity of this disease.^2,3,5 Only a few medications are FDA-approved for treating bipolar depression (Table).

In this article, we describe the case of a patient with treatment-resistant bipolar depression undergoing adjunctive TMS treatment who experienced an affective switch from depression to mania. We also discuss evidence regarding the likelihood of treatment-emergent mania for antidepressants vs TMS in bipolar depression.

CASE

Ms. W, a 60-year-old White female with a history of bipolar I disorder and attention-deficit/hyperactivity disorder (ADHD), presented for TMS evaluation during a depressive episode. Throughout her life, she had experienced numerous manic episodes, but as she got older she noted an increasing frequency of depressive episodes. Over the course of her illness, she had completed adequate trials at therapeutic doses of many medications, including second-generation antipsycho­tics (SGAs) (aripiprazole, lurasidone, olanzapine, quetiapine), mood stabilizers (lamotrigine, lithium), and antidepressants (bupropion, venlafaxine, fluoxetine, mirtazapine, trazodone). A course of electroconvulsive therapy was not effective. Ms. W had a long-standing diagnosis of ADHD and had been treated with stimulants for >10 years, although it was unclear whether formal neuropsychological testing had been conducted to confirm this diagnosis. She had >10 suicide attempts and multiple psychiatric hospitalizations.

At her initial evaluation for TMS, Ms. W said she had depressive symptoms predominating for the past 2 years, including low mood, hopelessness, poor sleep, poor appetite, anhedonia, and suicidal ideation without a plan. At the time, she was taking clonazepam, 0.5 mg twice a day; lurasidone, 40 mg/d at bedtime; fluoxetine, 60 mg/d; trazodone, 50 mg/d at bedtime; and methylphenidate, 40 mg/d, and was participating in psychotherapy consistently.

After Ms. W and her clinicians discussed alternatives, risks, benefits, and adverse effects, she consented to adjunctive TMS treatment and provided written informed consent. The treatment plan was outlined as 6 weeks of daily TMS therapy (NeuroStar; Neuronetics, Malvern, PA), 1 treatment per day, 5 days a week. Her clinical status was assessed weekly using the Quick Inventory of Depressive Symptomatology (QIDS) for depression, Generalized Anxiety Disorder 7-item scale (GAD-7) for anxiety, and Young Mania Rating Scale (YMRS) for mania. The Figure shows the trends in Ms. W’s QIDS, GAD-7, and YMRS scores over the course of TMS treatment.

Prior to initiating TMS, her baseline scores were QIDS: 25, GAD-7: 9, and YMRS: 7, indicating very severe depression, mild anxiety, and the absence of mania. Ms. W’s psychotropic regimen remained unchanged throughout the course of her TMS treatment. After her motor threshold was determined, her TMS treatment began at 80% of motor threshold and was titrated up to 95% at the first treatment. By the second treatment, it was titrated up to 110%. By the third treatment, it was titrated up to 120% of motor threshold, which is the percentage used for the remaining treatments.

Initially, Ms. W reported some improvement in her depression, but this improvement was short-lived, and she continued to have elevated QIDS scores throughout treatment. By treatment #21, her QIDS and GAD-7 scores remained elevated, and her YMRS score had increased to 12. Due to this increase in YMRS score, the YMRS was repeated on the next 2 treatment days (#22 and #23), and her score was 6 on both days. When Ms. W presented for treatment #25, she was disorganized, irritable, and endorsed racing thoughts and decreased sleep. She was involuntarily hospitalized for mania, and TMS was discontinued. Unfortunately, she did not complete any clinical scales on that day. Upon admission to the hospital, Ms. W reported that at approximately the time of treatment #21, she had a fluctuation in her mood that consisted of increased goal-directed activity, decreased need for sleep, racing thoughts, and increased frivolous spending. She was treated with lithium, 300 mg twice a day. Lurasidone was increased to 80 mg/d at bedtime, and she continued clonazepam, trazodone, and methylphenidate at the previous doses. Over 14 days, Ms. W’s mania gradually resolved, and she was discharged home.

Continue to: Mixed evidence on the risk of switching

Mixed evidence on the risk of switching

Currently, several TMS devices are FDA-cleared for treating unipolar major depressive disorder, obsessive-compulsive disorder, and certain types of migraine. In March 2020, the FDA granted Breakthrough Device Designation for one TMS device, the NeuroStar Advanced Therapy System, for the treatment of bipolar depression.⁸ This designation created an expedited pathway for prioritized FDA review of the NeuroStar Advanced Therapy clinical trial program. 

Few published clinical studies have evaluated using TMS to treat patients with bipolar depression.^9-15 As with any antidepressant treatment for bipolar depression, there is a risk of affective switch from depression to mania when using TMS. Most of the literature available regarding the treatment of bipolar depression focuses on the risk of antidepressant medications to induce an affective switch. This risk depends on the class of the antidepressant,¹⁶ and there is a paucity of studies examining the risk of switch with TMS.

Interpretation of available literature is limited due to inconsistencies in the definition of an affective switch, the variable length of treatment with antidepressants, the use of concurrent medications such as mood stabilizers, and confounders such as the natural course of switching in bipolar disorder.¹⁷ Overall, the evidence for treatment-emergent mania related to antidepressant use is mixed, and the reported rate of treatment-emergent mania varies. In a systematic review and meta-analysis of >20 randomized controlled trials that included 1,316 patients with bipolar disorder who received antidepressants, Fornaro et al¹⁸ found that the incidence of treatment-emergent mania was 11.8%. It is generally recommended that if antidepressants are used to treat patients with bipolar disorder, they should be given with a traditional mood stabilizer to prevent affective switches, although whether mood stabilizers can prevent such switches is unproven.¹⁹

In a literature review by Xia et al,²⁰ the affective switch rate in patients with bipolar depression who were treated with TMS was 3.1%, which was not statistically different from the affective switch rate with sham treatment.However, most of the patients included in this analysis were receiving other medications concurrently, and the length of treatment was 2 weeks, which is shorter than the average length of TMS treatment in clinical practice. In a recent literature review by Rachid,²¹ TMS was found to possibly induce manic episodes when used as monotherapy or in combination with antidepressants in patients with bipolar depression. To reduce the risk of treatment-emergent mania, current recommendations advise the use of a mood stabilizer for a minimum of 2 weeks before initiating TMS.¹

In our case, Ms. W was receiving antidepressants (fluoxetine and trazodone), lurasidone (an SGA that is FDA-approved for bipolar depression), and methylphenidate before starting TMS treatment. Fluoxetine, trazodone, and methylphenidate may possibly contribute to an increased risk of an affective switch.^1,22 Further studies are needed to clarify whether mood stabilizers or SGAs can prevent the development of mania in patients with bipolar depression who undergo TMS treatment.²⁰

Continue to: Because bipolar depression poses...

Because bipolar depression poses a major clinical challenge,^23,24 it is imperative to consider alternate treatments. When evaluating alternative treatment strategies, one may consider TMS in conjunction with a traditional mood stabilizer because this regimen may have a lower risk of treatment-emergent mania compared with antidepressants.^1,25

Acknowledgment

The authors thank Dr. Sy Saeed for his expertise and guidance on this article.

Bottom Line

For patients with bipolar depression, treatment with transcranial magnetic stimulation in conjunction with a mood stabilizer may have lower rates of treatment-emergent mania than treatment with antidepressants.

Related Resources

• Transcranial magnetic stimulation: clinical applications for psychiatric practice. Bermudes RA, Lanocha K, Janicak PG, eds. American Psychiatric Association Publishing; 2017.
• Gold AK, Ornelas AC, Cirillo P, et al. Clinical applications of transcranial magnetic stimulation in bipolar disorder. Brain Behav. 2019;9(10):e01419. doi: 10.1002/brb3.1419

Drug Brand Names

Aripiprazole • Abilify
Bupropion • Wellbutrin
Cariprazine • Vraylar
Clonazepam • Klonopin
Fluoxetine • Prozac
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Methylphenidate • Ritalin, Concerta
Mirtazapine • Remeron
Olanzapine • Zyprexa
Olanzapine-fluoxetine • Symbyax
Quetiapine • Seroquel
Trazodone • Desyrel
Venlafaxine • Effexor

Do you ever leave work thinking “Why do I always feel so tired after my shift?” “How can I overcome this fatigue?” “Is this what I expected?” “How can I get over the dread of so much administrative work when I want more time for my patients?” As clinicians, we face these and many other questions every day. These questions are the result of feeling entrapped in a health care system that has forgotten that clinicians need enough time to get to know and connect with their patients. Burnout is real, and relying on wellness activities is not sufficient to overcome it. Instead, taking the time for some introspection and self-reflection can help to overcome these difficulties.

A valuable lesson

Ten months into my intern year as a psychiatry resident, while on a busy night shift at the psychiatry emergency unit, an 86-year-old man arrived alone, hopeless, and with persistent death wishes. He needed to be heard and comforted by someone. Although he understood the nonnegotiable need to be hospitalized, he was extremely hesitant. But why? After all, he expressed wanting to get better and feared going back home alone, yet he was unwilling to be admitted to the hospital for acute care.

I knew I had to address the reason behind my patient’s ambivalence by further exploring his history. Nonetheless, my physician-in-training mind was battling feelings of stress secondary to what at the time seemed to be a never-ending to-do list full of nurses’ requests and patient-related tasks. Despite an unconscious temptation to rush through the history to please my go, go, go! trainee mind, I do not regret having taken the time to ask and address the often-feared “why.” Why was my patient reluctant to accept my recommendation?

To my surprise, it turned out to be an important matter. He said, “I have 3 dogs back home I don’t want to leave alone. They are the only living memory of my wife, who passed away 5 months ago. They help me stay alive.” I was struck by a feeling of empathy, but also guilt for having almost rushed through the history and not being thorough enough to ask why.

Take time to explore ‘why’

Do we really recognize the importance of being inquisitive in our history-taking? What might seem a simple matter to us (in my patient’s case, his 3 dogs were his main support system) can be a significant cause of a patient’s distress. A patients’ hesitancy to accept our recommendations can be secondary to reasons that unfortunately at times we only partially explore, or do not explore at all. Asking why can open Pandora’s box. It can uncover feelings and emotions such as frustration, anger, anxiety, and sorrow. It can also reveal uncertainties regarding topics such as race, gender identity, sexual orientation, socioeconomic status, and religion. We should be driven by humble curiosity, and tailor the interview by purposefully asking questions with the goal of learning and understanding our patients’ concerns. This practice serves to cultivate honest and trustworthy physician-patient relationships founded on empathy and respect.

If we know that obtaining an in-depth history is crucial for formulating a patient’s treatment plan, why do we sometimes fall in the trap of obtaining superficial ones, at times limiting ourselves to checklists? Reasons for not delving into our patients’ histories include (but are not limited to) an overload of patients, time constraints, a physician’s personal style, unconscious bias, suboptimal mentoring, and burnout. Of all these reasons, I worry the most about burnout. Physicians face insurmountable academic, institutional, and administrative demands. These constraints inarguably contribute to feeling rushed, and eventually possibly burned out.

Using self-reflection to prevent burnout

Physician burnout—as well as attempts to define, identify, target, and prevent it—has been on the rise in the past decades. If burnout affects the physician-patient relationship, we should make efforts to mitigate it. One should try to rely on internal, rather than external, influences to positively influence our delivery of care. One way to do this is by really getting to know the patient in front of us: a father, mother, brother, sister, member of the community, etc. Understanding our patient’s needs and concerns promotes empathy and connectedness. Another way is to exercise self-reflection by asking ourselves: How do I feel about the care I delivered today? Did I make an effort to fully understand my patients’ concerns? Did I make each patient feel understood? Was I rushing through the day, or was I mindful of the person in front of me? Did I deliver the care I wish I had received?

Although there are innumerable ways to target physician burnout, these self-reflections are quick, simple exercises that easily can be woven into a clinician’s busy schedule. The goal is to be mindful of improving the quality of our interactions with patients to ultimately cultivate our own well-being by potentiating a sense of fulfilment and satisfaction with our profession. I encourage clinicians to always go after the “why.” After all, why not? Thankfully, after some persuasion, my patient accepted voluntary admission, and arranged with neighbors to take care of his 3 dogs.

Do you ever leave work thinking “Why do I always feel so tired after my shift?” “How can I overcome this fatigue?” “Is this what I expected?” “How can I get over the dread of so much administrative work when I want more time for my patients?” As clinicians, we face these and many other questions every day. These questions are the result of feeling entrapped in a health care system that has forgotten that clinicians need enough time to get to know and connect with their patients. Burnout is real, and relying on wellness activities is not sufficient to overcome it. Instead, taking the time for some introspection and self-reflection can help to overcome these difficulties.

A valuable lesson

Ten months into my intern year as a psychiatry resident, while on a busy night shift at the psychiatry emergency unit, an 86-year-old man arrived alone, hopeless, and with persistent death wishes. He needed to be heard and comforted by someone. Although he understood the nonnegotiable need to be hospitalized, he was extremely hesitant. But why? After all, he expressed wanting to get better and feared going back home alone, yet he was unwilling to be admitted to the hospital for acute care.

I knew I had to address the reason behind my patient’s ambivalence by further exploring his history. Nonetheless, my physician-in-training mind was battling feelings of stress secondary to what at the time seemed to be a never-ending to-do list full of nurses’ requests and patient-related tasks. Despite an unconscious temptation to rush through the history to please my go, go, go! trainee mind, I do not regret having taken the time to ask and address the often-feared “why.” Why was my patient reluctant to accept my recommendation?

To my surprise, it turned out to be an important matter. He said, “I have 3 dogs back home I don’t want to leave alone. They are the only living memory of my wife, who passed away 5 months ago. They help me stay alive.” I was struck by a feeling of empathy, but also guilt for having almost rushed through the history and not being thorough enough to ask why.

Take time to explore ‘why’

Do we really recognize the importance of being inquisitive in our history-taking? What might seem a simple matter to us (in my patient’s case, his 3 dogs were his main support system) can be a significant cause of a patient’s distress. A patients’ hesitancy to accept our recommendations can be secondary to reasons that unfortunately at times we only partially explore, or do not explore at all. Asking why can open Pandora’s box. It can uncover feelings and emotions such as frustration, anger, anxiety, and sorrow. It can also reveal uncertainties regarding topics such as race, gender identity, sexual orientation, socioeconomic status, and religion. We should be driven by humble curiosity, and tailor the interview by purposefully asking questions with the goal of learning and understanding our patients’ concerns. This practice serves to cultivate honest and trustworthy physician-patient relationships founded on empathy and respect.

If we know that obtaining an in-depth history is crucial for formulating a patient’s treatment plan, why do we sometimes fall in the trap of obtaining superficial ones, at times limiting ourselves to checklists? Reasons for not delving into our patients’ histories include (but are not limited to) an overload of patients, time constraints, a physician’s personal style, unconscious bias, suboptimal mentoring, and burnout. Of all these reasons, I worry the most about burnout. Physicians face insurmountable academic, institutional, and administrative demands. These constraints inarguably contribute to feeling rushed, and eventually possibly burned out.

Using self-reflection to prevent burnout

Physician burnout—as well as attempts to define, identify, target, and prevent it—has been on the rise in the past decades. If burnout affects the physician-patient relationship, we should make efforts to mitigate it. One should try to rely on internal, rather than external, influences to positively influence our delivery of care. One way to do this is by really getting to know the patient in front of us: a father, mother, brother, sister, member of the community, etc. Understanding our patient’s needs and concerns promotes empathy and connectedness. Another way is to exercise self-reflection by asking ourselves: How do I feel about the care I delivered today? Did I make an effort to fully understand my patients’ concerns? Did I make each patient feel understood? Was I rushing through the day, or was I mindful of the person in front of me? Did I deliver the care I wish I had received?

Although there are innumerable ways to target physician burnout, these self-reflections are quick, simple exercises that easily can be woven into a clinician’s busy schedule. The goal is to be mindful of improving the quality of our interactions with patients to ultimately cultivate our own well-being by potentiating a sense of fulfilment and satisfaction with our profession. I encourage clinicians to always go after the “why.” After all, why not? Thankfully, after some persuasion, my patient accepted voluntary admission, and arranged with neighbors to take care of his 3 dogs.

Do you ever leave work thinking “Why do I always feel so tired after my shift?” “How can I overcome this fatigue?” “Is this what I expected?” “How can I get over the dread of so much administrative work when I want more time for my patients?” As clinicians, we face these and many other questions every day. These questions are the result of feeling entrapped in a health care system that has forgotten that clinicians need enough time to get to know and connect with their patients. Burnout is real, and relying on wellness activities is not sufficient to overcome it. Instead, taking the time for some introspection and self-reflection can help to overcome these difficulties.

A valuable lesson

Ten months into my intern year as a psychiatry resident, while on a busy night shift at the psychiatry emergency unit, an 86-year-old man arrived alone, hopeless, and with persistent death wishes. He needed to be heard and comforted by someone. Although he understood the nonnegotiable need to be hospitalized, he was extremely hesitant. But why? After all, he expressed wanting to get better and feared going back home alone, yet he was unwilling to be admitted to the hospital for acute care.

I knew I had to address the reason behind my patient’s ambivalence by further exploring his history. Nonetheless, my physician-in-training mind was battling feelings of stress secondary to what at the time seemed to be a never-ending to-do list full of nurses’ requests and patient-related tasks. Despite an unconscious temptation to rush through the history to please my go, go, go! trainee mind, I do not regret having taken the time to ask and address the often-feared “why.” Why was my patient reluctant to accept my recommendation?

To my surprise, it turned out to be an important matter. He said, “I have 3 dogs back home I don’t want to leave alone. They are the only living memory of my wife, who passed away 5 months ago. They help me stay alive.” I was struck by a feeling of empathy, but also guilt for having almost rushed through the history and not being thorough enough to ask why.

Take time to explore ‘why’

Do we really recognize the importance of being inquisitive in our history-taking? What might seem a simple matter to us (in my patient’s case, his 3 dogs were his main support system) can be a significant cause of a patient’s distress. A patients’ hesitancy to accept our recommendations can be secondary to reasons that unfortunately at times we only partially explore, or do not explore at all. Asking why can open Pandora’s box. It can uncover feelings and emotions such as frustration, anger, anxiety, and sorrow. It can also reveal uncertainties regarding topics such as race, gender identity, sexual orientation, socioeconomic status, and religion. We should be driven by humble curiosity, and tailor the interview by purposefully asking questions with the goal of learning and understanding our patients’ concerns. This practice serves to cultivate honest and trustworthy physician-patient relationships founded on empathy and respect.

If we know that obtaining an in-depth history is crucial for formulating a patient’s treatment plan, why do we sometimes fall in the trap of obtaining superficial ones, at times limiting ourselves to checklists? Reasons for not delving into our patients’ histories include (but are not limited to) an overload of patients, time constraints, a physician’s personal style, unconscious bias, suboptimal mentoring, and burnout. Of all these reasons, I worry the most about burnout. Physicians face insurmountable academic, institutional, and administrative demands. These constraints inarguably contribute to feeling rushed, and eventually possibly burned out.

Using self-reflection to prevent burnout

Physician burnout—as well as attempts to define, identify, target, and prevent it—has been on the rise in the past decades. If burnout affects the physician-patient relationship, we should make efforts to mitigate it. One should try to rely on internal, rather than external, influences to positively influence our delivery of care. One way to do this is by really getting to know the patient in front of us: a father, mother, brother, sister, member of the community, etc. Understanding our patient’s needs and concerns promotes empathy and connectedness. Another way is to exercise self-reflection by asking ourselves: How do I feel about the care I delivered today? Did I make an effort to fully understand my patients’ concerns? Did I make each patient feel understood? Was I rushing through the day, or was I mindful of the person in front of me? Did I deliver the care I wish I had received?

Although there are innumerable ways to target physician burnout, these self-reflections are quick, simple exercises that easily can be woven into a clinician’s busy schedule. The goal is to be mindful of improving the quality of our interactions with patients to ultimately cultivate our own well-being by potentiating a sense of fulfilment and satisfaction with our profession. I encourage clinicians to always go after the “why.” After all, why not? Thankfully, after some persuasion, my patient accepted voluntary admission, and arranged with neighbors to take care of his 3 dogs.

Lithium has been used in psychiatry for more than half a century and is considered the gold standard for treating acute mania and maintenance treatment of bipolar disorder.¹ Evidence supports its use to reduce suicidal behavior and as an adjunctive treatment for major depressive disorder.² However, lithium has fallen out of favor because of its narrow therapeutic index as well as the introduction of newer psychotropic medications that have a quicker onset of action and do not require strict blood monitoring. For residents early in their training, keeping track of the laboratory monitoring and medical screening can be confusing. Different institutions and countries have specific guidelines and recommendations for monitoring patients receiving lithium, which adds to the confusion.

We completed a literature review to develop clear and concise recommendations for lithium monitoring for residents in our psychiatry residency program. These recommendations outline screening at baseline and after patients treated with lithium achieve stability. Table 1^3-11 outlines medical screening parameters, including bloodwork, that should be completed before initiating treatment, and how often such screening should be repeated. Table 2 incorporates these parameters into progress notes in the electronic medical record to keep track of the laboratory values and when they were last drawn. Our aim is to help residents stay organized and prevent missed screenings.

How often should lithium levels be monitored?

After starting a patient on lithium, check the level within 5 to 7 days, and 5 to 7 days after each dose change. Draw the lithium level 10 to 14 hours after the patient’s last dose (12 hours is best).¹ Because of dosage changes, lithium levels usually are monitored more frequently during the first 3 months of treatment until therapeutic levels are reached or symptoms are controlled. It is recommended to monitor lithium levels every 3 months for the first year and every 6 months after the first year of treatment once the patient is stable and considering age, medical health, and how consistently a patient reports symptoms/adverse effects.^3,5 Continue monitoring levels every 3 months in older adults; in patients with renal dysfunction, thyroid dysfunction, hypercalcemia, or other significant medical comorbidities; and in those who are taking medications that affect lithium, such as pain medications (nonsteroidal anti-inflammatory drugs can raise lithium levels), certain antihypertensives (angiotensin-converting-enzyme inhibitors can raise lithium levels), and diuretics (thiazide diuretics can raise lithium levels; osmotic diuretics and carbonic anhydrase inhibitors can reduce lithium levels).^1,3,5

Lithium levels could vary by up to 0.5 mEq/L during transition between manic, euthymic, and depressive states.¹² On a consistent dosage, lithium levels decrease during mania because of hemodilution, and increase during depression secondary to physiological effects specific to these episodes.^13,14

Recommendations for plasma lithium levels (trough levels)

Mania. Lithium levels of 0.8 to 1.2 mEq/L often are needed to achieve symptom control during manic episodes.¹⁵ As levels approach 1.5 mEq/L, patients are at increased risk for intolerable adverse effects (eg, nausea and vomiting) and toxicity.^16,17 Adverse effects at higher levels may result in patients abruptly discontinuing lithium. Patients who experience mania before a depressive episode at illness onsettend to have a better treatment response with lithium.¹⁸ Lithium monotherapy has been shown to be less effective for acute mania than antipsychotics or combination therapies.¹⁹ Consider combining lithium with valproate or antipsychotics for patients who have tolerated lithium in the past and plan to use lithium for maintenance treatment.²⁰

Maintenance. In adults, the lithium level should be 0.60 to 80mEq/L, but consider levels of 0.40 to 0.60 mEq/L in patients who have a good response to lithium but develop adverse effects at higher levels.²¹ For patients who do not respond to treatment, such as those with severe mania, maintenance levels can be increased to 0.76 to 0.90 mEq/L.²² These same recommendations for maintenance levels can be used for children and adolescents. In older adults, aim for maintenance levels of 0.4 to 0.6 mEq/L. For patients age 65 to 79, the maximum level is 0.7 to 0.8 mEq/L, and should not exceed 0.7 mEq/L in patients age >80. Lithium levels <0.4 mEq/L do not appear to be effective.²¹

Depression. Aim for a lithium level of 0.6 to 1.0 mEq/L for patients with depression.¹¹

Continue to: Renal function monitoring frequency

Obtain a basic metabolic panel or comprehensive metabolic panel to establish baseline levels of creatinine, blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR). Repeat testing at Week 12 and at 6 months to detect any changes. Renal function can be monitored every 6 to 12 months in stable patients, but should be closely watched when a patient’s clinical status changes.³ A new lower eGFR value after starting lithium therapy should be investigated with a repeat test in 2 weeks.²³ Mild elevations in creatinine should be monitored, and further medical workup with a nephrologist is recommended for patients with a creatinine level ≥1.6 mg/dL.²⁴ It is important to note that creatinine might remain within normal limits if there is considerable reduction in glomerular function. Creatinine levels could vary because of body mass and diet. Creatinine levels can be low in nonmuscular patients and elevated in patients who consume large amounts of protein.^23,25

Ordering a basic metabolic panel also allows electrolyte monitoring. Hypo­natremia and dehydration can lead to elevated lithium levels and result in toxicity; hypokalemia might increase the risk of lithium-induced cardiac toxicity. Monitor calcium (corrected serum calcium) because hypercalcemia has been seen in patients treated with lithium.

Thyroid function monitoring frequency

Obtain levels of thyroid-stimulating hormone with reflex to free T4 at baseline, 12 weeks, and 6 months. Monitor thyroid function every 6 to 12 months in stable patients and when a patient’s clinical status changes, such as with new reports of medical or psychiatric symptoms and when there is concern for thyroid dysfunction.³

Lithium and neurotoxicity

Lithium is known to have neurotoxic effects, such as effects on fast-acting neurons leading to dyscoordination or tremor, even at therapeutic levels.²⁶ This is especially the case when lithium is combined with an antipsychotic,^26,27 a combination that is used to treat bipolar I disorder with psychotic features. Older adults are at greater risk for neurotoxicity because of physiological changes associated with increasing age.²⁸

Educate patients about adherence, diet, and exercise

Patients might stop taking their psychotropic medications when they start feeling better. Instruct patients to discuss discontinuation with the prescribing clinician before they stop any medication. Educate patients that rapidly discontinuing lithium therapy puts them at high risk of relapse²⁹ and increases the risk of developing treatment-refractory symptoms.^23,30 Emphasize the importance of staying hydrated and maintaining adequate sodium in their diet.^17,31 Consuming excessive sodium can reduce lithium levels.^17,32 Lithium levels could increase when patients experience excessive sweating, such as during exercise or being outside on warm days, because of sodium and volume loss.^17,33

Lithium has been used in psychiatry for more than half a century and is considered the gold standard for treating acute mania and maintenance treatment of bipolar disorder.¹ Evidence supports its use to reduce suicidal behavior and as an adjunctive treatment for major depressive disorder.² However, lithium has fallen out of favor because of its narrow therapeutic index as well as the introduction of newer psychotropic medications that have a quicker onset of action and do not require strict blood monitoring. For residents early in their training, keeping track of the laboratory monitoring and medical screening can be confusing. Different institutions and countries have specific guidelines and recommendations for monitoring patients receiving lithium, which adds to the confusion.

We completed a literature review to develop clear and concise recommendations for lithium monitoring for residents in our psychiatry residency program. These recommendations outline screening at baseline and after patients treated with lithium achieve stability. Table 1^3-11 outlines medical screening parameters, including bloodwork, that should be completed before initiating treatment, and how often such screening should be repeated. Table 2 incorporates these parameters into progress notes in the electronic medical record to keep track of the laboratory values and when they were last drawn. Our aim is to help residents stay organized and prevent missed screenings.

How often should lithium levels be monitored?

After starting a patient on lithium, check the level within 5 to 7 days, and 5 to 7 days after each dose change. Draw the lithium level 10 to 14 hours after the patient’s last dose (12 hours is best).¹ Because of dosage changes, lithium levels usually are monitored more frequently during the first 3 months of treatment until therapeutic levels are reached or symptoms are controlled. It is recommended to monitor lithium levels every 3 months for the first year and every 6 months after the first year of treatment once the patient is stable and considering age, medical health, and how consistently a patient reports symptoms/adverse effects.^3,5 Continue monitoring levels every 3 months in older adults; in patients with renal dysfunction, thyroid dysfunction, hypercalcemia, or other significant medical comorbidities; and in those who are taking medications that affect lithium, such as pain medications (nonsteroidal anti-inflammatory drugs can raise lithium levels), certain antihypertensives (angiotensin-converting-enzyme inhibitors can raise lithium levels), and diuretics (thiazide diuretics can raise lithium levels; osmotic diuretics and carbonic anhydrase inhibitors can reduce lithium levels).^1,3,5

Lithium levels could vary by up to 0.5 mEq/L during transition between manic, euthymic, and depressive states.¹² On a consistent dosage, lithium levels decrease during mania because of hemodilution, and increase during depression secondary to physiological effects specific to these episodes.^13,14

Recommendations for plasma lithium levels (trough levels)

Mania. Lithium levels of 0.8 to 1.2 mEq/L often are needed to achieve symptom control during manic episodes.¹⁵ As levels approach 1.5 mEq/L, patients are at increased risk for intolerable adverse effects (eg, nausea and vomiting) and toxicity.^16,17 Adverse effects at higher levels may result in patients abruptly discontinuing lithium. Patients who experience mania before a depressive episode at illness onsettend to have a better treatment response with lithium.¹⁸ Lithium monotherapy has been shown to be less effective for acute mania than antipsychotics or combination therapies.¹⁹ Consider combining lithium with valproate or antipsychotics for patients who have tolerated lithium in the past and plan to use lithium for maintenance treatment.²⁰

Maintenance. In adults, the lithium level should be 0.60 to 80mEq/L, but consider levels of 0.40 to 0.60 mEq/L in patients who have a good response to lithium but develop adverse effects at higher levels.²¹ For patients who do not respond to treatment, such as those with severe mania, maintenance levels can be increased to 0.76 to 0.90 mEq/L.²² These same recommendations for maintenance levels can be used for children and adolescents. In older adults, aim for maintenance levels of 0.4 to 0.6 mEq/L. For patients age 65 to 79, the maximum level is 0.7 to 0.8 mEq/L, and should not exceed 0.7 mEq/L in patients age >80. Lithium levels <0.4 mEq/L do not appear to be effective.²¹

Depression. Aim for a lithium level of 0.6 to 1.0 mEq/L for patients with depression.¹¹

Continue to: Renal function monitoring frequency

Obtain a basic metabolic panel or comprehensive metabolic panel to establish baseline levels of creatinine, blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR). Repeat testing at Week 12 and at 6 months to detect any changes. Renal function can be monitored every 6 to 12 months in stable patients, but should be closely watched when a patient’s clinical status changes.³ A new lower eGFR value after starting lithium therapy should be investigated with a repeat test in 2 weeks.²³ Mild elevations in creatinine should be monitored, and further medical workup with a nephrologist is recommended for patients with a creatinine level ≥1.6 mg/dL.²⁴ It is important to note that creatinine might remain within normal limits if there is considerable reduction in glomerular function. Creatinine levels could vary because of body mass and diet. Creatinine levels can be low in nonmuscular patients and elevated in patients who consume large amounts of protein.^23,25

Ordering a basic metabolic panel also allows electrolyte monitoring. Hypo­natremia and dehydration can lead to elevated lithium levels and result in toxicity; hypokalemia might increase the risk of lithium-induced cardiac toxicity. Monitor calcium (corrected serum calcium) because hypercalcemia has been seen in patients treated with lithium.

Thyroid function monitoring frequency

Obtain levels of thyroid-stimulating hormone with reflex to free T4 at baseline, 12 weeks, and 6 months. Monitor thyroid function every 6 to 12 months in stable patients and when a patient’s clinical status changes, such as with new reports of medical or psychiatric symptoms and when there is concern for thyroid dysfunction.³

Lithium and neurotoxicity

Lithium is known to have neurotoxic effects, such as effects on fast-acting neurons leading to dyscoordination or tremor, even at therapeutic levels.²⁶ This is especially the case when lithium is combined with an antipsychotic,^26,27 a combination that is used to treat bipolar I disorder with psychotic features. Older adults are at greater risk for neurotoxicity because of physiological changes associated with increasing age.²⁸

Educate patients about adherence, diet, and exercise

Patients might stop taking their psychotropic medications when they start feeling better. Instruct patients to discuss discontinuation with the prescribing clinician before they stop any medication. Educate patients that rapidly discontinuing lithium therapy puts them at high risk of relapse²⁹ and increases the risk of developing treatment-refractory symptoms.^23,30 Emphasize the importance of staying hydrated and maintaining adequate sodium in their diet.^17,31 Consuming excessive sodium can reduce lithium levels.^17,32 Lithium levels could increase when patients experience excessive sweating, such as during exercise or being outside on warm days, because of sodium and volume loss.^17,33

Lithium has been used in psychiatry for more than half a century and is considered the gold standard for treating acute mania and maintenance treatment of bipolar disorder.¹ Evidence supports its use to reduce suicidal behavior and as an adjunctive treatment for major depressive disorder.² However, lithium has fallen out of favor because of its narrow therapeutic index as well as the introduction of newer psychotropic medications that have a quicker onset of action and do not require strict blood monitoring. For residents early in their training, keeping track of the laboratory monitoring and medical screening can be confusing. Different institutions and countries have specific guidelines and recommendations for monitoring patients receiving lithium, which adds to the confusion.

We completed a literature review to develop clear and concise recommendations for lithium monitoring for residents in our psychiatry residency program. These recommendations outline screening at baseline and after patients treated with lithium achieve stability. Table 1^3-11 outlines medical screening parameters, including bloodwork, that should be completed before initiating treatment, and how often such screening should be repeated. Table 2 incorporates these parameters into progress notes in the electronic medical record to keep track of the laboratory values and when they were last drawn. Our aim is to help residents stay organized and prevent missed screenings.

How often should lithium levels be monitored?

After starting a patient on lithium, check the level within 5 to 7 days, and 5 to 7 days after each dose change. Draw the lithium level 10 to 14 hours after the patient’s last dose (12 hours is best).¹ Because of dosage changes, lithium levels usually are monitored more frequently during the first 3 months of treatment until therapeutic levels are reached or symptoms are controlled. It is recommended to monitor lithium levels every 3 months for the first year and every 6 months after the first year of treatment once the patient is stable and considering age, medical health, and how consistently a patient reports symptoms/adverse effects.^3,5 Continue monitoring levels every 3 months in older adults; in patients with renal dysfunction, thyroid dysfunction, hypercalcemia, or other significant medical comorbidities; and in those who are taking medications that affect lithium, such as pain medications (nonsteroidal anti-inflammatory drugs can raise lithium levels), certain antihypertensives (angiotensin-converting-enzyme inhibitors can raise lithium levels), and diuretics (thiazide diuretics can raise lithium levels; osmotic diuretics and carbonic anhydrase inhibitors can reduce lithium levels).^1,3,5

Lithium levels could vary by up to 0.5 mEq/L during transition between manic, euthymic, and depressive states.¹² On a consistent dosage, lithium levels decrease during mania because of hemodilution, and increase during depression secondary to physiological effects specific to these episodes.^13,14

Recommendations for plasma lithium levels (trough levels)

Mania. Lithium levels of 0.8 to 1.2 mEq/L often are needed to achieve symptom control during manic episodes.¹⁵ As levels approach 1.5 mEq/L, patients are at increased risk for intolerable adverse effects (eg, nausea and vomiting) and toxicity.^16,17 Adverse effects at higher levels may result in patients abruptly discontinuing lithium. Patients who experience mania before a depressive episode at illness onsettend to have a better treatment response with lithium.¹⁸ Lithium monotherapy has been shown to be less effective for acute mania than antipsychotics or combination therapies.¹⁹ Consider combining lithium with valproate or antipsychotics for patients who have tolerated lithium in the past and plan to use lithium for maintenance treatment.²⁰

Maintenance. In adults, the lithium level should be 0.60 to 80mEq/L, but consider levels of 0.40 to 0.60 mEq/L in patients who have a good response to lithium but develop adverse effects at higher levels.²¹ For patients who do not respond to treatment, such as those with severe mania, maintenance levels can be increased to 0.76 to 0.90 mEq/L.²² These same recommendations for maintenance levels can be used for children and adolescents. In older adults, aim for maintenance levels of 0.4 to 0.6 mEq/L. For patients age 65 to 79, the maximum level is 0.7 to 0.8 mEq/L, and should not exceed 0.7 mEq/L in patients age >80. Lithium levels <0.4 mEq/L do not appear to be effective.²¹

Depression. Aim for a lithium level of 0.6 to 1.0 mEq/L for patients with depression.¹¹

Continue to: Renal function monitoring frequency

Obtain a basic metabolic panel or comprehensive metabolic panel to establish baseline levels of creatinine, blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR). Repeat testing at Week 12 and at 6 months to detect any changes. Renal function can be monitored every 6 to 12 months in stable patients, but should be closely watched when a patient’s clinical status changes.³ A new lower eGFR value after starting lithium therapy should be investigated with a repeat test in 2 weeks.²³ Mild elevations in creatinine should be monitored, and further medical workup with a nephrologist is recommended for patients with a creatinine level ≥1.6 mg/dL.²⁴ It is important to note that creatinine might remain within normal limits if there is considerable reduction in glomerular function. Creatinine levels could vary because of body mass and diet. Creatinine levels can be low in nonmuscular patients and elevated in patients who consume large amounts of protein.^23,25

Ordering a basic metabolic panel also allows electrolyte monitoring. Hypo­natremia and dehydration can lead to elevated lithium levels and result in toxicity; hypokalemia might increase the risk of lithium-induced cardiac toxicity. Monitor calcium (corrected serum calcium) because hypercalcemia has been seen in patients treated with lithium.

Thyroid function monitoring frequency

Obtain levels of thyroid-stimulating hormone with reflex to free T4 at baseline, 12 weeks, and 6 months. Monitor thyroid function every 6 to 12 months in stable patients and when a patient’s clinical status changes, such as with new reports of medical or psychiatric symptoms and when there is concern for thyroid dysfunction.³

Lithium and neurotoxicity

Lithium is known to have neurotoxic effects, such as effects on fast-acting neurons leading to dyscoordination or tremor, even at therapeutic levels.²⁶ This is especially the case when lithium is combined with an antipsychotic,^26,27 a combination that is used to treat bipolar I disorder with psychotic features. Older adults are at greater risk for neurotoxicity because of physiological changes associated with increasing age.²⁸

Educate patients about adherence, diet, and exercise

Patients might stop taking their psychotropic medications when they start feeling better. Instruct patients to discuss discontinuation with the prescribing clinician before they stop any medication. Educate patients that rapidly discontinuing lithium therapy puts them at high risk of relapse²⁹ and increases the risk of developing treatment-refractory symptoms.^23,30 Emphasize the importance of staying hydrated and maintaining adequate sodium in their diet.^17,31 Consuming excessive sodium can reduce lithium levels.^17,32 Lithium levels could increase when patients experience excessive sweating, such as during exercise or being outside on warm days, because of sodium and volume loss.^17,33