Click here to access the 2018 Directory of VA and DoD Facilities Digital Edition

Table of Contents

• Department of Defense Health Care Facilities

 

Click here to access the 2018 Directory of VA and DoD Facilities Digital Edition

Table of Contents

• Department of Defense Health Care Facilities

 

Click here to access the 2018 Directory of VA and DoD Facilities Digital Edition

Table of Contents

• Department of Defense Health Care Facilities

 

Click here to access the January 2018 Digital Edition.

Table of Contents

• Impact of Drug Shortages on Patient Safety and Pharmacy Operation Costs
• Pulmonary Mucormycosis in a Patient With Uncontrolled Diabetes
• Pilot Inpatient Pain Pharmacist Consult Service at the West Palm Beach VAMC
• The Right, and Now the Wrong of 2017
• Risk Factors Associated With Multidrug-Resistant Pneumonia in Nonhospitalized Patients
• Major General David N.W. Grant: An Early Leader in Air Force Medicine

Click here to access the January 2018 Digital Edition.

Table of Contents

• Impact of Drug Shortages on Patient Safety and Pharmacy Operation Costs
• Pulmonary Mucormycosis in a Patient With Uncontrolled Diabetes
• Pilot Inpatient Pain Pharmacist Consult Service at the West Palm Beach VAMC
• The Right, and Now the Wrong of 2017
• Risk Factors Associated With Multidrug-Resistant Pneumonia in Nonhospitalized Patients
• Major General David N.W. Grant: An Early Leader in Air Force Medicine

Click here to access the January 2018 Digital Edition.

Table of Contents

• Impact of Drug Shortages on Patient Safety and Pharmacy Operation Costs
• Pulmonary Mucormycosis in a Patient With Uncontrolled Diabetes
• Pilot Inpatient Pain Pharmacist Consult Service at the West Palm Beach VAMC
• The Right, and Now the Wrong of 2017
• Risk Factors Associated With Multidrug-Resistant Pneumonia in Nonhospitalized Patients
• Major General David N.W. Grant: An Early Leader in Air Force Medicine

Disorders of diminished motivation (DDM)—including apathy, abulia, and akinetic mutism—are characterized by impairment in goal-directed behavior, thought, and emotion.¹ These disorders can be observed clinically as a gross underproduction of speech, movement, and emotional response.

DDM are not classified as disorders within DSM-5, and it remains unclear if they are distinct disorders or symptoms that overlap in other conditions. Some sources support distinct diagnoses, while the traditional position is that DDM are variations along a spectrum, with apathy as the mildest form and akinetic mutism as the most severe form (Figure).^1-3 DDM can result from various neurologic, medical, psychiatric, socioeconomic, and drug-induced pathologies, and may represent differing severity of the same underlying pathology.^1,4 It is postulated that DDM arise from disruptions in the dopaminergic frontal-subcortical-mesolimbic networks.^1,4

CASE 1
Apathy secondary to glioblastoma multiforme

Ms. E, age 59, presents with wound drainage 3 weeks after a repeat right craniotomy for recurrent glioblastoma multiforme (GBM) of the temporal lobe. Her medical history is not believed to have contributed to her current presentation.

On hospital day 2, Ms. E undergoes debridement and reclosure at the craniotomy site. Prior to the procedure, the patient was noted to have anhedonia and flat affect. Her family reports that she seems to get little enjoyment from life and “only slept and ate.” Psychiatry is consulted on hospital day 3 for evaluation and management of a perceived depressed mood.

On initial psychiatric evaluation, Ms. E continues to have a constricted affect with delayed psychomotor processing speed. However, she denies dysphoria or anhedonia. Richmond Agitation-Sedation Scale⁶ score is 0 (alert and calm) and test of sustained attention (‘Vigilant A’) is intact (ie, based on the Confusion Assessment Method for the Intensive Care Unit [CAM-ICU],⁷ Ms. E does not have delirium). The NPI A/I frequency score is 15, with a severity score of 3, for a total score of 45, indicating moderate behavioral disturbance on the NPI A/I subsection. A diagnosis of neuropsychiatric apathy due to recurrent GBM or craniotomy is made, although substance-induced mood disorder due to concurrent dexamethasone and opiate use is considered. Methylphenidate, 2.5 mg/d, is started, and Ms. E’s blood pressure remains stable with the initial dose.

Methylphenidate is titrated to 5 mg, twice daily, over a 1-week period. Ms. E’s NPI A/I subscale score improves to 3 (mild behavioral problem), with 3 points for frequency and a multiplier of 1 for mild severity, reflecting an improvement in neuropsychiatric apathy, and she is transferred to a long-term care rehabilitation center.

CASE 2
Akinetic mutism secondary to subarachnoid hemorrhage

Ms. G, age 47, is brought to an outside hospital with syncope and a severe headache radiating to her neck. Upon arrival, she is unconscious and requires intubation. A non-contrast head CT scan shows diffuse subarachnoid hemorrhage, 6 mm right midline shift, and a small left frontal subdural hematoma. A CT angiography of her head and neck reveals a 0.7 cm anterior paraclinoid left internal carotid artery aneurysm with ophthalmic involvement. Evidence of underlying left and right carotid fibromuscular dysplasia is also seen. Ms. G is transferred to our facility for neurosurgical intervention.

Neurosurgery proceeds with aneurysm coiling, followed by left craniotomy with subdural evacuation and ventriculostomy placement. Her postoperative course is complicated by prolonged nasogastric hyperalimentation, mild hypernatremia and hyperglycemia, tracheostomy, and recurrent central fever. She also develops persistent vasospasm, which requires balloon angioplasty of the left middle cerebral artery.

The psychiatry team is consulted on postoperative day 29 to assess for delirium. The CAM-ICU is positive for delirium, with nocturnal accentuation of agitation. Ms. G demonstrates paucity of speech and minimal verbal comprehension. She starts oral ziprasidone, 5 mg/d at bedtime. In addition to her original CNS insult, scopolamine patch, 1.5 mg, to decrease respiratory secretions, and IV metronidazole, 500 mg every 8 hours, for skin-site infection, may have been contributing to her delirium.

Ms. G’s delirium quickly resolves; however, on day 32 she continues to demonstrate behavioral and cognitive slowing; The NPI A/I frequency score is 28, with a severity score of 3, for a total score of 84, indicating severe behavioral disturbance on the NPI A/I subsection. Methylphenidate, 2.5 mg/d, is started and the next day is increased to 5 mg twice a day to treat severe akinetic mutism. Ms. G also is switched from ziprasidone to olanzapine, 2.5 mg/d at night.

By day 37, the tracheostomy is decannulated, and Ms. G demonstrates a full level of alertness, awareness, and attention. Her affect is full range and appropriate; however, she demonstrates residual language deficits, including dysnomia. On day 38, Ms. G is discharged with an NPI A/I subscale score of 5, indicating a mild behavioral problem.
 

What these cases demonstrate about DDM

These 2 cases are part of a larger, emerging conversation about the role of dopamine in DDM. Although not fully elucidated, the pathophysiology of abulia, apathy, and akinetic mutism is thought to be related to multiple neurotransmitters—especially dopamine—involved in the cortico-striatal-pallidal-thalamic network.^1,8 This position has been supported by reports of clinical improvement in patients with DDM who are given dopaminergic agonists (Table 1).^3,9-32

The clinical improvement seen in both of our patients after initiating methylphenidate is consistent with previous reports.^10-13 Methylphenidate was selected because of its favorable adverse effect profile and potentially rapid onset of action in DDM.^10-13 In cases where oral medication cannot be administered, such as in patients with akinetic mutism, short-term adjunctive IM olanzapine may be helpful, although it is not a first-line treatment.^3,15

Interestingly, both of our patients showed improvement with low doses of methylphenidate. Ms. E showed rapid improvement at 2.5 mg/d, but eventually was increased to 10 mg/d. For Ms. G, who demonstrated severe akinetic mutism, rapid improvement was noted after the initial 2.5 mg/d dose; however, because of reports of efficacy of olanzapine in treating akinetic mutism, it is possible that these medications worked synergistically. The proposed mechanism of action of olanzapine in akinetic mutism is through increased dopamine transmission in the medial prefrontal cortex.^3,15 Ms. G’s methylphenidate dose was increased to 5 mg/d, which was still “subtherapeutic,” because most reports have used dosages ranging from 10 to 40 mg/d.^10-13 Although there were favorable acute results in both patients, their long-term requirements are unknown because of a lack of follow-up. Our findings are also limited by the fact that both patients were recovering from neurosurgical procedures, which could lead to natural improvement in symptoms over time.
 

Prevalence of DDM in psychiatric disorders

The successful treatment of DDM with dopaminergic drugs is meaningful because of the coexistence of DDM in various neuropsychiatric conditions. In Alzheimer’s disease (AD), disturbances in the dopaminergic system may explain the high comorbidity of apathy, which ranges from 47% in mild AD to 80% in moderate AD.³³ In the dopamine-reduced states of cocaine and amphetamine withdrawal, 67% of patients report apathy and lack of motivation.^8,34 Additionally, the prevalence of apathy is reported at 27% in Parkinson’s disease, 43% in mild cognitive impairment, 70% in mixed dementia, 94% in a major depressive episode, and 53% in schizophrenia.³⁵ In schizophrenia with predominately negative symptoms, in vivo and postmortem studies have found reduced dopamine receptors.⁸ Meanwhile, the high rate of akinetic mutism in Creutzfeldt-Jakob disease allows for its use as a reliable diagnostic criteria in this disorder.³⁶

However, the prevalence of DDM is best documented as it relates to stroke and traumatic brain injury (TBI). For instance, after experiencing a stroke, 20% to 25% of patients suffer from apathy.³⁷ Many case reports describe abulia and akinetic mutism after cerebral infarction or hemorrhage, although the incidence of these disorders is unknown.^2,38-40 Apathy following TBI is common, especially in younger patients who have sustained a severe injury.⁴¹ One study evaluated the prevalence of apathy after TBI among 83 consecutive patients in a neuropsychiatric clinic. Of the 83 patients, 10.84% had apathy without depression, and an equal number were depressed without apathy; another 60% of patients exhibited both apathy and depression. Younger patients (mean age, 29 years) were more likely to be apathetic than older patients, who were more likely to be depressed or depressed and apathetic (mean age, 42 and 38 years, respectively).⁴¹ Interestingly, DDM often are associated with cerebral lesions in distinct and distant anatomical locations that are not clearly connected to the neural circuits of motivational pathways. This phenomenon may be explained by the concept of diaschisis, which states that injury to one part of an interconnected neural network can affect other, separate parts of that network.² If this concept is accurate, it may broaden the impact of DDM, especially as it relates to stroke and TBI.

The differential diagnosis of DDM includes depression and hypokinetic delirium (Table 2^1,3,42-50). A potential overlapping but confounding condition is stuporous catatonia, with symptoms that include psychomotor slowing such as immobility, staring, and stupor.⁴⁷ It is important to differentiate these disorders because the treatment for each differs. As previously discussed, there is a clear role for dopamine receptor agonists in the treatment of DDM.

What to do when your patient’s presentation suggests DDM

Assessment of DDM should be structured, with input from the patient and the caregiver, and should incorporate the physician’s perspective. A history should be obtained applying recent criteria of apathy. The 3 core domains of apathy—behavior, cognition, and emotion—need to be evaluated. The revised criteria are based on the premise that change in motivation can be measured by examining a patient’s responsiveness to internal or external stimuli. Therefore, each of the 3 domains includes 2 symptoms: (1) self-initiated or “internal” behaviors, cognitions, and emotions (initiation symptom), and (2) the patient’s responsiveness to “external” stimuli (responsiveness symptom).⁵¹

One of the main diagnostic dilemmas is how to separate DDM from depression. The differentiation is difficult because of substantial overlap in the manifestation of key symptoms, such as a lack of interest, anergia, psychomotor slowing, and fatigue. Caregivers often mistakenly describe DDM as a depressive state, even though a lack of sadness, desperation, crying, and a depressive mood distinguish DDM from depression. Usually, DDM patients lack negative thoughts, emotional distress, sadness, vegetative symptoms, and somatic concerns, which are frequently observed in mood disorders.⁵¹

Several instruments have been developed for assessing neuropsychiatric symptoms. Some were specifically designed to measure apathy, whereas others were designed to provide a broader neuropsychiatric assessment. The NPI is the most widely used multidimensional instrument for assessing neuropsychiatric functioning in patients with neurocognitive disorders (NCDs). It is a valid, reliable instrument that consists of an interview of the patient’s caregiver. It is designed to assess the presence and severity of 10 symptoms, including apathy. The NPI includes both apathy and depression items, which can help clinicians distinguish the 2 conditions. Although beyond the scope of this article, more recent standardized instruments that can assess DDM include the Apathy Inventory, the Dementia Apathy Interview and Rating, and the Structured Clinical Interview for Apathy.⁵²

As previously mentioned, researchers have proposed that DDM are simply a continuum of severity of reduced behavior, and akinetic mutism may be the extreme form. The dilemma is how to formally diagnose states of abulia and akinetic mutism, given the lack of diagnostic criteria and paucity of standardized instruments. Thus, distinguishing between abulia and akinetic mutism (and apathy) is more of a quantitative than qualitative exercise. One could hypothesize that higher scores on a standardized scale to measure apathy (ie, NPI) could imply abulia or akinetic mutism, although to the best of our knowledge, no formal “cut-off scores” exist.⁵³

Treatment of apathy. The duration of pharmacotherapy to treat apathy is unknown and their usage is off-label. Further studies, including double-blind, randomized controlled trials (RCTs), are needed. Nonetheless, the 2 classes of medications that have the most evidence for treating apathy/DDM are psychostimulants and acetylcholinesterase inhibitors (AChEIs).

AChEIs are primarily used for treating cognitive symptoms in NCDs, but recent findings indicate that they have beneficial effects on noncognitive symptoms such as apathy. Of all medications used to treat apathy in NCDs, AChEIs have been used to treat the largest number of patients. Of 26 studies, 24 demonstrated improvement in apathy, with 21 demonstrating statistical significance. These studies ranged in duration from 8 weeks to 1 year, and most were open-label.⁵⁴

Five studies (3 RCTs and 2 open-label studies) assessed the efficacy of methylphenidate for treating apathy due to AD. All the studies demonstrated at least some benefit in apathy scores after treatment with methylphenidate. These studies ranged from 5 to 12 weeks in duration. Notably, some patients reported adverse effects, including delusions and irritability.⁵⁴

Although available evidence suggests AChEIs may be the most effective medications for treating apathy in NCDs, methylphenidate has been demonstrated to work faster.⁵⁵ Thus, in cases where apathy can significantly affect activities of daily living or instrumental activities of daily living, a quicker response may dictate treatment with methylphenidate. It is imperative to note that safety studies and more large-scale double-blind RCTs are needed to further demonstrate the effectiveness and safety of methylphenidate.

Published in 2007, the American Psychiatric Association (APA) guidelines⁵⁶ state that psychostimulants are a possible treatment option for patients with severe apathy. At the same time, clinicians are reminded that these agents—especially at higher doses—can produce various problematic adverse effects, including tachycardia, hypertension, restlessness, dyskinesia, agitation, sleep disturbances, psychosis, confusion, and decreased appetite. The APA guidelines recommend using low initial doses, with slow and careful titration. For example, methylphenidate should be started at 2.5 to 5 mg once in the morning, with daily doses not to exceed 30 to 40 mg. In our clinical experience, doses >20 mg/d have not been necessary.⁵⁷

Treatment of akinetic mutism and abulia. In patients with akinetic mutism and possible abulia, for whom oral medication administration is either impossible or contraindicated (ie, due to the potential risk of aspiration pneumonia), atypical antipsychotics, such as IM olanazapine, have produced a therapeutic response in apathetic patients with NCD. However, extensive use of antipsychotics in NCD is not recommended because this class of medications has been associated with serious adverse effects, including an increased risk of death.⁵⁵

Bottom Line

Apathy, abulia, and akinetic mutism have been categorized as disorders of diminished motivation (DDM). They commonly present after a stroke or traumatic brain injury, and should be differentiated from depression, hypokinetic delirium, and stuporous catatonia. DDM can be successfully treated with dopamine agonists.

Related Resources

• Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract. 2004;10(3):196-199.
• Dell’Osso B, Benatti B, Altamura AC, et al. Prevalence of selective serotonin reuptake inhibitor-related apathy in patients with obsessive compulsive disorder. J Clin Psychopharmacol. 2016;36(6):725-726.
• D’Souza G, Kakoullis A, Hegde N, et al. Recognition and management of abulia in the elderly. Prog Neurol Psychiatry. 2010;14(6):24-28.

Drug Brand Names

Bromocriptine • Parlodel
Bupropion • Wellbutrin XL, Zyban
Carbidopa • Lodosyn
Dexamethasone • DexPak, Ozurde
Donepezil • Aricept
Levodopa/benserazide • Prolopa
Levodopa/carbidopa • Pacopa Rytary Sinemet
Lorazepam • Ativan
Methylphenidate • Concerta, Methylin
Metronidazole • Flagyl, Metrogel
Modafinil • Provigil
Olanzapine • Zyprexa
Pramipexole • Mirapex
Rivastigmine • Exelon
Ropinirole • Requip
Rotigotine • Neurpro
Scopolamine • Transderm Scop
Ziprasidone • Geodon

Disorders of diminished motivation (DDM)—including apathy, abulia, and akinetic mutism—are characterized by impairment in goal-directed behavior, thought, and emotion.¹ These disorders can be observed clinically as a gross underproduction of speech, movement, and emotional response.

DDM are not classified as disorders within DSM-5, and it remains unclear if they are distinct disorders or symptoms that overlap in other conditions. Some sources support distinct diagnoses, while the traditional position is that DDM are variations along a spectrum, with apathy as the mildest form and akinetic mutism as the most severe form (Figure).^1-3 DDM can result from various neurologic, medical, psychiatric, socioeconomic, and drug-induced pathologies, and may represent differing severity of the same underlying pathology.^1,4 It is postulated that DDM arise from disruptions in the dopaminergic frontal-subcortical-mesolimbic networks.^1,4

CASE 1
Apathy secondary to glioblastoma multiforme

Ms. E, age 59, presents with wound drainage 3 weeks after a repeat right craniotomy for recurrent glioblastoma multiforme (GBM) of the temporal lobe. Her medical history is not believed to have contributed to her current presentation.

On hospital day 2, Ms. E undergoes debridement and reclosure at the craniotomy site. Prior to the procedure, the patient was noted to have anhedonia and flat affect. Her family reports that she seems to get little enjoyment from life and “only slept and ate.” Psychiatry is consulted on hospital day 3 for evaluation and management of a perceived depressed mood.

On initial psychiatric evaluation, Ms. E continues to have a constricted affect with delayed psychomotor processing speed. However, she denies dysphoria or anhedonia. Richmond Agitation-Sedation Scale⁶ score is 0 (alert and calm) and test of sustained attention (‘Vigilant A’) is intact (ie, based on the Confusion Assessment Method for the Intensive Care Unit [CAM-ICU],⁷ Ms. E does not have delirium). The NPI A/I frequency score is 15, with a severity score of 3, for a total score of 45, indicating moderate behavioral disturbance on the NPI A/I subsection. A diagnosis of neuropsychiatric apathy due to recurrent GBM or craniotomy is made, although substance-induced mood disorder due to concurrent dexamethasone and opiate use is considered. Methylphenidate, 2.5 mg/d, is started, and Ms. E’s blood pressure remains stable with the initial dose.

Methylphenidate is titrated to 5 mg, twice daily, over a 1-week period. Ms. E’s NPI A/I subscale score improves to 3 (mild behavioral problem), with 3 points for frequency and a multiplier of 1 for mild severity, reflecting an improvement in neuropsychiatric apathy, and she is transferred to a long-term care rehabilitation center.

CASE 2
Akinetic mutism secondary to subarachnoid hemorrhage

Ms. G, age 47, is brought to an outside hospital with syncope and a severe headache radiating to her neck. Upon arrival, she is unconscious and requires intubation. A non-contrast head CT scan shows diffuse subarachnoid hemorrhage, 6 mm right midline shift, and a small left frontal subdural hematoma. A CT angiography of her head and neck reveals a 0.7 cm anterior paraclinoid left internal carotid artery aneurysm with ophthalmic involvement. Evidence of underlying left and right carotid fibromuscular dysplasia is also seen. Ms. G is transferred to our facility for neurosurgical intervention.

Neurosurgery proceeds with aneurysm coiling, followed by left craniotomy with subdural evacuation and ventriculostomy placement. Her postoperative course is complicated by prolonged nasogastric hyperalimentation, mild hypernatremia and hyperglycemia, tracheostomy, and recurrent central fever. She also develops persistent vasospasm, which requires balloon angioplasty of the left middle cerebral artery.

The psychiatry team is consulted on postoperative day 29 to assess for delirium. The CAM-ICU is positive for delirium, with nocturnal accentuation of agitation. Ms. G demonstrates paucity of speech and minimal verbal comprehension. She starts oral ziprasidone, 5 mg/d at bedtime. In addition to her original CNS insult, scopolamine patch, 1.5 mg, to decrease respiratory secretions, and IV metronidazole, 500 mg every 8 hours, for skin-site infection, may have been contributing to her delirium.

Ms. G’s delirium quickly resolves; however, on day 32 she continues to demonstrate behavioral and cognitive slowing; The NPI A/I frequency score is 28, with a severity score of 3, for a total score of 84, indicating severe behavioral disturbance on the NPI A/I subsection. Methylphenidate, 2.5 mg/d, is started and the next day is increased to 5 mg twice a day to treat severe akinetic mutism. Ms. G also is switched from ziprasidone to olanzapine, 2.5 mg/d at night.

By day 37, the tracheostomy is decannulated, and Ms. G demonstrates a full level of alertness, awareness, and attention. Her affect is full range and appropriate; however, she demonstrates residual language deficits, including dysnomia. On day 38, Ms. G is discharged with an NPI A/I subscale score of 5, indicating a mild behavioral problem.
 

What these cases demonstrate about DDM

These 2 cases are part of a larger, emerging conversation about the role of dopamine in DDM. Although not fully elucidated, the pathophysiology of abulia, apathy, and akinetic mutism is thought to be related to multiple neurotransmitters—especially dopamine—involved in the cortico-striatal-pallidal-thalamic network.^1,8 This position has been supported by reports of clinical improvement in patients with DDM who are given dopaminergic agonists (Table 1).^3,9-32

The clinical improvement seen in both of our patients after initiating methylphenidate is consistent with previous reports.^10-13 Methylphenidate was selected because of its favorable adverse effect profile and potentially rapid onset of action in DDM.^10-13 In cases where oral medication cannot be administered, such as in patients with akinetic mutism, short-term adjunctive IM olanzapine may be helpful, although it is not a first-line treatment.^3,15

Interestingly, both of our patients showed improvement with low doses of methylphenidate. Ms. E showed rapid improvement at 2.5 mg/d, but eventually was increased to 10 mg/d. For Ms. G, who demonstrated severe akinetic mutism, rapid improvement was noted after the initial 2.5 mg/d dose; however, because of reports of efficacy of olanzapine in treating akinetic mutism, it is possible that these medications worked synergistically. The proposed mechanism of action of olanzapine in akinetic mutism is through increased dopamine transmission in the medial prefrontal cortex.^3,15 Ms. G’s methylphenidate dose was increased to 5 mg/d, which was still “subtherapeutic,” because most reports have used dosages ranging from 10 to 40 mg/d.^10-13 Although there were favorable acute results in both patients, their long-term requirements are unknown because of a lack of follow-up. Our findings are also limited by the fact that both patients were recovering from neurosurgical procedures, which could lead to natural improvement in symptoms over time.
 

Prevalence of DDM in psychiatric disorders

The successful treatment of DDM with dopaminergic drugs is meaningful because of the coexistence of DDM in various neuropsychiatric conditions. In Alzheimer’s disease (AD), disturbances in the dopaminergic system may explain the high comorbidity of apathy, which ranges from 47% in mild AD to 80% in moderate AD.³³ In the dopamine-reduced states of cocaine and amphetamine withdrawal, 67% of patients report apathy and lack of motivation.^8,34 Additionally, the prevalence of apathy is reported at 27% in Parkinson’s disease, 43% in mild cognitive impairment, 70% in mixed dementia, 94% in a major depressive episode, and 53% in schizophrenia.³⁵ In schizophrenia with predominately negative symptoms, in vivo and postmortem studies have found reduced dopamine receptors.⁸ Meanwhile, the high rate of akinetic mutism in Creutzfeldt-Jakob disease allows for its use as a reliable diagnostic criteria in this disorder.³⁶

However, the prevalence of DDM is best documented as it relates to stroke and traumatic brain injury (TBI). For instance, after experiencing a stroke, 20% to 25% of patients suffer from apathy.³⁷ Many case reports describe abulia and akinetic mutism after cerebral infarction or hemorrhage, although the incidence of these disorders is unknown.^2,38-40 Apathy following TBI is common, especially in younger patients who have sustained a severe injury.⁴¹ One study evaluated the prevalence of apathy after TBI among 83 consecutive patients in a neuropsychiatric clinic. Of the 83 patients, 10.84% had apathy without depression, and an equal number were depressed without apathy; another 60% of patients exhibited both apathy and depression. Younger patients (mean age, 29 years) were more likely to be apathetic than older patients, who were more likely to be depressed or depressed and apathetic (mean age, 42 and 38 years, respectively).⁴¹ Interestingly, DDM often are associated with cerebral lesions in distinct and distant anatomical locations that are not clearly connected to the neural circuits of motivational pathways. This phenomenon may be explained by the concept of diaschisis, which states that injury to one part of an interconnected neural network can affect other, separate parts of that network.² If this concept is accurate, it may broaden the impact of DDM, especially as it relates to stroke and TBI.

The differential diagnosis of DDM includes depression and hypokinetic delirium (Table 2^1,3,42-50). A potential overlapping but confounding condition is stuporous catatonia, with symptoms that include psychomotor slowing such as immobility, staring, and stupor.⁴⁷ It is important to differentiate these disorders because the treatment for each differs. As previously discussed, there is a clear role for dopamine receptor agonists in the treatment of DDM.

What to do when your patient’s presentation suggests DDM

Assessment of DDM should be structured, with input from the patient and the caregiver, and should incorporate the physician’s perspective. A history should be obtained applying recent criteria of apathy. The 3 core domains of apathy—behavior, cognition, and emotion—need to be evaluated. The revised criteria are based on the premise that change in motivation can be measured by examining a patient’s responsiveness to internal or external stimuli. Therefore, each of the 3 domains includes 2 symptoms: (1) self-initiated or “internal” behaviors, cognitions, and emotions (initiation symptom), and (2) the patient’s responsiveness to “external” stimuli (responsiveness symptom).⁵¹

One of the main diagnostic dilemmas is how to separate DDM from depression. The differentiation is difficult because of substantial overlap in the manifestation of key symptoms, such as a lack of interest, anergia, psychomotor slowing, and fatigue. Caregivers often mistakenly describe DDM as a depressive state, even though a lack of sadness, desperation, crying, and a depressive mood distinguish DDM from depression. Usually, DDM patients lack negative thoughts, emotional distress, sadness, vegetative symptoms, and somatic concerns, which are frequently observed in mood disorders.⁵¹

Several instruments have been developed for assessing neuropsychiatric symptoms. Some were specifically designed to measure apathy, whereas others were designed to provide a broader neuropsychiatric assessment. The NPI is the most widely used multidimensional instrument for assessing neuropsychiatric functioning in patients with neurocognitive disorders (NCDs). It is a valid, reliable instrument that consists of an interview of the patient’s caregiver. It is designed to assess the presence and severity of 10 symptoms, including apathy. The NPI includes both apathy and depression items, which can help clinicians distinguish the 2 conditions. Although beyond the scope of this article, more recent standardized instruments that can assess DDM include the Apathy Inventory, the Dementia Apathy Interview and Rating, and the Structured Clinical Interview for Apathy.⁵²

As previously mentioned, researchers have proposed that DDM are simply a continuum of severity of reduced behavior, and akinetic mutism may be the extreme form. The dilemma is how to formally diagnose states of abulia and akinetic mutism, given the lack of diagnostic criteria and paucity of standardized instruments. Thus, distinguishing between abulia and akinetic mutism (and apathy) is more of a quantitative than qualitative exercise. One could hypothesize that higher scores on a standardized scale to measure apathy (ie, NPI) could imply abulia or akinetic mutism, although to the best of our knowledge, no formal “cut-off scores” exist.⁵³

Treatment of apathy. The duration of pharmacotherapy to treat apathy is unknown and their usage is off-label. Further studies, including double-blind, randomized controlled trials (RCTs), are needed. Nonetheless, the 2 classes of medications that have the most evidence for treating apathy/DDM are psychostimulants and acetylcholinesterase inhibitors (AChEIs).

AChEIs are primarily used for treating cognitive symptoms in NCDs, but recent findings indicate that they have beneficial effects on noncognitive symptoms such as apathy. Of all medications used to treat apathy in NCDs, AChEIs have been used to treat the largest number of patients. Of 26 studies, 24 demonstrated improvement in apathy, with 21 demonstrating statistical significance. These studies ranged in duration from 8 weeks to 1 year, and most were open-label.⁵⁴

Five studies (3 RCTs and 2 open-label studies) assessed the efficacy of methylphenidate for treating apathy due to AD. All the studies demonstrated at least some benefit in apathy scores after treatment with methylphenidate. These studies ranged from 5 to 12 weeks in duration. Notably, some patients reported adverse effects, including delusions and irritability.⁵⁴

Although available evidence suggests AChEIs may be the most effective medications for treating apathy in NCDs, methylphenidate has been demonstrated to work faster.⁵⁵ Thus, in cases where apathy can significantly affect activities of daily living or instrumental activities of daily living, a quicker response may dictate treatment with methylphenidate. It is imperative to note that safety studies and more large-scale double-blind RCTs are needed to further demonstrate the effectiveness and safety of methylphenidate.

Published in 2007, the American Psychiatric Association (APA) guidelines⁵⁶ state that psychostimulants are a possible treatment option for patients with severe apathy. At the same time, clinicians are reminded that these agents—especially at higher doses—can produce various problematic adverse effects, including tachycardia, hypertension, restlessness, dyskinesia, agitation, sleep disturbances, psychosis, confusion, and decreased appetite. The APA guidelines recommend using low initial doses, with slow and careful titration. For example, methylphenidate should be started at 2.5 to 5 mg once in the morning, with daily doses not to exceed 30 to 40 mg. In our clinical experience, doses >20 mg/d have not been necessary.⁵⁷

Treatment of akinetic mutism and abulia. In patients with akinetic mutism and possible abulia, for whom oral medication administration is either impossible or contraindicated (ie, due to the potential risk of aspiration pneumonia), atypical antipsychotics, such as IM olanazapine, have produced a therapeutic response in apathetic patients with NCD. However, extensive use of antipsychotics in NCD is not recommended because this class of medications has been associated with serious adverse effects, including an increased risk of death.⁵⁵

Bottom Line

Apathy, abulia, and akinetic mutism have been categorized as disorders of diminished motivation (DDM). They commonly present after a stroke or traumatic brain injury, and should be differentiated from depression, hypokinetic delirium, and stuporous catatonia. DDM can be successfully treated with dopamine agonists.

Related Resources

• Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract. 2004;10(3):196-199.
• Dell’Osso B, Benatti B, Altamura AC, et al. Prevalence of selective serotonin reuptake inhibitor-related apathy in patients with obsessive compulsive disorder. J Clin Psychopharmacol. 2016;36(6):725-726.
• D’Souza G, Kakoullis A, Hegde N, et al. Recognition and management of abulia in the elderly. Prog Neurol Psychiatry. 2010;14(6):24-28.

Drug Brand Names

Bromocriptine • Parlodel
Bupropion • Wellbutrin XL, Zyban
Carbidopa • Lodosyn
Dexamethasone • DexPak, Ozurde
Donepezil • Aricept
Levodopa/benserazide • Prolopa
Levodopa/carbidopa • Pacopa Rytary Sinemet
Lorazepam • Ativan
Methylphenidate • Concerta, Methylin
Metronidazole • Flagyl, Metrogel
Modafinil • Provigil
Olanzapine • Zyprexa
Pramipexole • Mirapex
Rivastigmine • Exelon
Ropinirole • Requip
Rotigotine • Neurpro
Scopolamine • Transderm Scop
Ziprasidone • Geodon

Disorders of diminished motivation (DDM)—including apathy, abulia, and akinetic mutism—are characterized by impairment in goal-directed behavior, thought, and emotion.¹ These disorders can be observed clinically as a gross underproduction of speech, movement, and emotional response.

DDM are not classified as disorders within DSM-5, and it remains unclear if they are distinct disorders or symptoms that overlap in other conditions. Some sources support distinct diagnoses, while the traditional position is that DDM are variations along a spectrum, with apathy as the mildest form and akinetic mutism as the most severe form (Figure).^1-3 DDM can result from various neurologic, medical, psychiatric, socioeconomic, and drug-induced pathologies, and may represent differing severity of the same underlying pathology.^1,4 It is postulated that DDM arise from disruptions in the dopaminergic frontal-subcortical-mesolimbic networks.^1,4

CASE 1
Apathy secondary to glioblastoma multiforme

Ms. E, age 59, presents with wound drainage 3 weeks after a repeat right craniotomy for recurrent glioblastoma multiforme (GBM) of the temporal lobe. Her medical history is not believed to have contributed to her current presentation.

On hospital day 2, Ms. E undergoes debridement and reclosure at the craniotomy site. Prior to the procedure, the patient was noted to have anhedonia and flat affect. Her family reports that she seems to get little enjoyment from life and “only slept and ate.” Psychiatry is consulted on hospital day 3 for evaluation and management of a perceived depressed mood.

On initial psychiatric evaluation, Ms. E continues to have a constricted affect with delayed psychomotor processing speed. However, she denies dysphoria or anhedonia. Richmond Agitation-Sedation Scale⁶ score is 0 (alert and calm) and test of sustained attention (‘Vigilant A’) is intact (ie, based on the Confusion Assessment Method for the Intensive Care Unit [CAM-ICU],⁷ Ms. E does not have delirium). The NPI A/I frequency score is 15, with a severity score of 3, for a total score of 45, indicating moderate behavioral disturbance on the NPI A/I subsection. A diagnosis of neuropsychiatric apathy due to recurrent GBM or craniotomy is made, although substance-induced mood disorder due to concurrent dexamethasone and opiate use is considered. Methylphenidate, 2.5 mg/d, is started, and Ms. E’s blood pressure remains stable with the initial dose.

Methylphenidate is titrated to 5 mg, twice daily, over a 1-week period. Ms. E’s NPI A/I subscale score improves to 3 (mild behavioral problem), with 3 points for frequency and a multiplier of 1 for mild severity, reflecting an improvement in neuropsychiatric apathy, and she is transferred to a long-term care rehabilitation center.

CASE 2
Akinetic mutism secondary to subarachnoid hemorrhage

Ms. G, age 47, is brought to an outside hospital with syncope and a severe headache radiating to her neck. Upon arrival, she is unconscious and requires intubation. A non-contrast head CT scan shows diffuse subarachnoid hemorrhage, 6 mm right midline shift, and a small left frontal subdural hematoma. A CT angiography of her head and neck reveals a 0.7 cm anterior paraclinoid left internal carotid artery aneurysm with ophthalmic involvement. Evidence of underlying left and right carotid fibromuscular dysplasia is also seen. Ms. G is transferred to our facility for neurosurgical intervention.

Neurosurgery proceeds with aneurysm coiling, followed by left craniotomy with subdural evacuation and ventriculostomy placement. Her postoperative course is complicated by prolonged nasogastric hyperalimentation, mild hypernatremia and hyperglycemia, tracheostomy, and recurrent central fever. She also develops persistent vasospasm, which requires balloon angioplasty of the left middle cerebral artery.

The psychiatry team is consulted on postoperative day 29 to assess for delirium. The CAM-ICU is positive for delirium, with nocturnal accentuation of agitation. Ms. G demonstrates paucity of speech and minimal verbal comprehension. She starts oral ziprasidone, 5 mg/d at bedtime. In addition to her original CNS insult, scopolamine patch, 1.5 mg, to decrease respiratory secretions, and IV metronidazole, 500 mg every 8 hours, for skin-site infection, may have been contributing to her delirium.

Ms. G’s delirium quickly resolves; however, on day 32 she continues to demonstrate behavioral and cognitive slowing; The NPI A/I frequency score is 28, with a severity score of 3, for a total score of 84, indicating severe behavioral disturbance on the NPI A/I subsection. Methylphenidate, 2.5 mg/d, is started and the next day is increased to 5 mg twice a day to treat severe akinetic mutism. Ms. G also is switched from ziprasidone to olanzapine, 2.5 mg/d at night.

By day 37, the tracheostomy is decannulated, and Ms. G demonstrates a full level of alertness, awareness, and attention. Her affect is full range and appropriate; however, she demonstrates residual language deficits, including dysnomia. On day 38, Ms. G is discharged with an NPI A/I subscale score of 5, indicating a mild behavioral problem.
 

What these cases demonstrate about DDM

These 2 cases are part of a larger, emerging conversation about the role of dopamine in DDM. Although not fully elucidated, the pathophysiology of abulia, apathy, and akinetic mutism is thought to be related to multiple neurotransmitters—especially dopamine—involved in the cortico-striatal-pallidal-thalamic network.^1,8 This position has been supported by reports of clinical improvement in patients with DDM who are given dopaminergic agonists (Table 1).^3,9-32

The clinical improvement seen in both of our patients after initiating methylphenidate is consistent with previous reports.^10-13 Methylphenidate was selected because of its favorable adverse effect profile and potentially rapid onset of action in DDM.^10-13 In cases where oral medication cannot be administered, such as in patients with akinetic mutism, short-term adjunctive IM olanzapine may be helpful, although it is not a first-line treatment.^3,15

Interestingly, both of our patients showed improvement with low doses of methylphenidate. Ms. E showed rapid improvement at 2.5 mg/d, but eventually was increased to 10 mg/d. For Ms. G, who demonstrated severe akinetic mutism, rapid improvement was noted after the initial 2.5 mg/d dose; however, because of reports of efficacy of olanzapine in treating akinetic mutism, it is possible that these medications worked synergistically. The proposed mechanism of action of olanzapine in akinetic mutism is through increased dopamine transmission in the medial prefrontal cortex.^3,15 Ms. G’s methylphenidate dose was increased to 5 mg/d, which was still “subtherapeutic,” because most reports have used dosages ranging from 10 to 40 mg/d.^10-13 Although there were favorable acute results in both patients, their long-term requirements are unknown because of a lack of follow-up. Our findings are also limited by the fact that both patients were recovering from neurosurgical procedures, which could lead to natural improvement in symptoms over time.
 

Prevalence of DDM in psychiatric disorders

The successful treatment of DDM with dopaminergic drugs is meaningful because of the coexistence of DDM in various neuropsychiatric conditions. In Alzheimer’s disease (AD), disturbances in the dopaminergic system may explain the high comorbidity of apathy, which ranges from 47% in mild AD to 80% in moderate AD.³³ In the dopamine-reduced states of cocaine and amphetamine withdrawal, 67% of patients report apathy and lack of motivation.^8,34 Additionally, the prevalence of apathy is reported at 27% in Parkinson’s disease, 43% in mild cognitive impairment, 70% in mixed dementia, 94% in a major depressive episode, and 53% in schizophrenia.³⁵ In schizophrenia with predominately negative symptoms, in vivo and postmortem studies have found reduced dopamine receptors.⁸ Meanwhile, the high rate of akinetic mutism in Creutzfeldt-Jakob disease allows for its use as a reliable diagnostic criteria in this disorder.³⁶

However, the prevalence of DDM is best documented as it relates to stroke and traumatic brain injury (TBI). For instance, after experiencing a stroke, 20% to 25% of patients suffer from apathy.³⁷ Many case reports describe abulia and akinetic mutism after cerebral infarction or hemorrhage, although the incidence of these disorders is unknown.^2,38-40 Apathy following TBI is common, especially in younger patients who have sustained a severe injury.⁴¹ One study evaluated the prevalence of apathy after TBI among 83 consecutive patients in a neuropsychiatric clinic. Of the 83 patients, 10.84% had apathy without depression, and an equal number were depressed without apathy; another 60% of patients exhibited both apathy and depression. Younger patients (mean age, 29 years) were more likely to be apathetic than older patients, who were more likely to be depressed or depressed and apathetic (mean age, 42 and 38 years, respectively).⁴¹ Interestingly, DDM often are associated with cerebral lesions in distinct and distant anatomical locations that are not clearly connected to the neural circuits of motivational pathways. This phenomenon may be explained by the concept of diaschisis, which states that injury to one part of an interconnected neural network can affect other, separate parts of that network.² If this concept is accurate, it may broaden the impact of DDM, especially as it relates to stroke and TBI.

The differential diagnosis of DDM includes depression and hypokinetic delirium (Table 2^1,3,42-50). A potential overlapping but confounding condition is stuporous catatonia, with symptoms that include psychomotor slowing such as immobility, staring, and stupor.⁴⁷ It is important to differentiate these disorders because the treatment for each differs. As previously discussed, there is a clear role for dopamine receptor agonists in the treatment of DDM.

What to do when your patient’s presentation suggests DDM

Assessment of DDM should be structured, with input from the patient and the caregiver, and should incorporate the physician’s perspective. A history should be obtained applying recent criteria of apathy. The 3 core domains of apathy—behavior, cognition, and emotion—need to be evaluated. The revised criteria are based on the premise that change in motivation can be measured by examining a patient’s responsiveness to internal or external stimuli. Therefore, each of the 3 domains includes 2 symptoms: (1) self-initiated or “internal” behaviors, cognitions, and emotions (initiation symptom), and (2) the patient’s responsiveness to “external” stimuli (responsiveness symptom).⁵¹

One of the main diagnostic dilemmas is how to separate DDM from depression. The differentiation is difficult because of substantial overlap in the manifestation of key symptoms, such as a lack of interest, anergia, psychomotor slowing, and fatigue. Caregivers often mistakenly describe DDM as a depressive state, even though a lack of sadness, desperation, crying, and a depressive mood distinguish DDM from depression. Usually, DDM patients lack negative thoughts, emotional distress, sadness, vegetative symptoms, and somatic concerns, which are frequently observed in mood disorders.⁵¹

Several instruments have been developed for assessing neuropsychiatric symptoms. Some were specifically designed to measure apathy, whereas others were designed to provide a broader neuropsychiatric assessment. The NPI is the most widely used multidimensional instrument for assessing neuropsychiatric functioning in patients with neurocognitive disorders (NCDs). It is a valid, reliable instrument that consists of an interview of the patient’s caregiver. It is designed to assess the presence and severity of 10 symptoms, including apathy. The NPI includes both apathy and depression items, which can help clinicians distinguish the 2 conditions. Although beyond the scope of this article, more recent standardized instruments that can assess DDM include the Apathy Inventory, the Dementia Apathy Interview and Rating, and the Structured Clinical Interview for Apathy.⁵²

As previously mentioned, researchers have proposed that DDM are simply a continuum of severity of reduced behavior, and akinetic mutism may be the extreme form. The dilemma is how to formally diagnose states of abulia and akinetic mutism, given the lack of diagnostic criteria and paucity of standardized instruments. Thus, distinguishing between abulia and akinetic mutism (and apathy) is more of a quantitative than qualitative exercise. One could hypothesize that higher scores on a standardized scale to measure apathy (ie, NPI) could imply abulia or akinetic mutism, although to the best of our knowledge, no formal “cut-off scores” exist.⁵³

Treatment of apathy. The duration of pharmacotherapy to treat apathy is unknown and their usage is off-label. Further studies, including double-blind, randomized controlled trials (RCTs), are needed. Nonetheless, the 2 classes of medications that have the most evidence for treating apathy/DDM are psychostimulants and acetylcholinesterase inhibitors (AChEIs).

AChEIs are primarily used for treating cognitive symptoms in NCDs, but recent findings indicate that they have beneficial effects on noncognitive symptoms such as apathy. Of all medications used to treat apathy in NCDs, AChEIs have been used to treat the largest number of patients. Of 26 studies, 24 demonstrated improvement in apathy, with 21 demonstrating statistical significance. These studies ranged in duration from 8 weeks to 1 year, and most were open-label.⁵⁴

Five studies (3 RCTs and 2 open-label studies) assessed the efficacy of methylphenidate for treating apathy due to AD. All the studies demonstrated at least some benefit in apathy scores after treatment with methylphenidate. These studies ranged from 5 to 12 weeks in duration. Notably, some patients reported adverse effects, including delusions and irritability.⁵⁴

Although available evidence suggests AChEIs may be the most effective medications for treating apathy in NCDs, methylphenidate has been demonstrated to work faster.⁵⁵ Thus, in cases where apathy can significantly affect activities of daily living or instrumental activities of daily living, a quicker response may dictate treatment with methylphenidate. It is imperative to note that safety studies and more large-scale double-blind RCTs are needed to further demonstrate the effectiveness and safety of methylphenidate.

Published in 2007, the American Psychiatric Association (APA) guidelines⁵⁶ state that psychostimulants are a possible treatment option for patients with severe apathy. At the same time, clinicians are reminded that these agents—especially at higher doses—can produce various problematic adverse effects, including tachycardia, hypertension, restlessness, dyskinesia, agitation, sleep disturbances, psychosis, confusion, and decreased appetite. The APA guidelines recommend using low initial doses, with slow and careful titration. For example, methylphenidate should be started at 2.5 to 5 mg once in the morning, with daily doses not to exceed 30 to 40 mg. In our clinical experience, doses >20 mg/d have not been necessary.⁵⁷

Treatment of akinetic mutism and abulia. In patients with akinetic mutism and possible abulia, for whom oral medication administration is either impossible or contraindicated (ie, due to the potential risk of aspiration pneumonia), atypical antipsychotics, such as IM olanazapine, have produced a therapeutic response in apathetic patients with NCD. However, extensive use of antipsychotics in NCD is not recommended because this class of medications has been associated with serious adverse effects, including an increased risk of death.⁵⁵

Bottom Line

Apathy, abulia, and akinetic mutism have been categorized as disorders of diminished motivation (DDM). They commonly present after a stroke or traumatic brain injury, and should be differentiated from depression, hypokinetic delirium, and stuporous catatonia. DDM can be successfully treated with dopamine agonists.

Related Resources

• Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract. 2004;10(3):196-199.
• Dell’Osso B, Benatti B, Altamura AC, et al. Prevalence of selective serotonin reuptake inhibitor-related apathy in patients with obsessive compulsive disorder. J Clin Psychopharmacol. 2016;36(6):725-726.
• D’Souza G, Kakoullis A, Hegde N, et al. Recognition and management of abulia in the elderly. Prog Neurol Psychiatry. 2010;14(6):24-28.

Drug Brand Names

Bromocriptine • Parlodel
Bupropion • Wellbutrin XL, Zyban
Carbidopa • Lodosyn
Dexamethasone • DexPak, Ozurde
Donepezil • Aricept
Levodopa/benserazide • Prolopa
Levodopa/carbidopa • Pacopa Rytary Sinemet
Lorazepam • Ativan
Methylphenidate • Concerta, Methylin
Metronidazole • Flagyl, Metrogel
Modafinil • Provigil
Olanzapine • Zyprexa
Pramipexole • Mirapex
Rivastigmine • Exelon
Ropinirole • Requip
Rotigotine • Neurpro
Scopolamine • Transderm Scop
Ziprasidone • Geodon

There is a need for additional treatment options to improve symptoms, enhance the quality of life (QOL), and reduce suffering among patients who have chronic medical illness. Medical marijuana (MM) has the potential to help patients who have certain medical conditions in states where it is legal for prescription by a licensed medical provider.

Cannabis has a long history of medicinal use (Box 1^1-12). Two derivatives of the Cannabis plant—cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—are responsible for most of its effects. Some of these effects, including analgesia, decreased muscle spasticity, and reduced eye pressure, have been harnessed for their potential therapeutic effects (Box 2^13-19). As of November 2017, 29 states had legalized Cannabis for medical use, and several had legalized its recreational use.¹²

With the increasing availability of MM, psychiatrists are likely to encounter patients who are using it or who will ask them about it. This article reviews evidence related to using MM to treat patients with neuropathic pain; chemotherapyinduced nausea and vomiting (CINV); epilepsy; multiple sclerosis (MS); glaucoma; Crohn’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; dementia-related behavioral disturbances; posttraumatic stress disorder (PTSD); and anxiety.

Box 1 
Cannabis: A history of medicinal use

Medical illnesses

Neuropathic pain. Chronic neuropathic pain affects an estimated 7% to 8% of adults.²⁰ Patients with neuropathic pain are often treated with anticonvulsants, anti­depressants, opioids, and local anesthetics²¹; however, these medications may not provide substantial relief. Research has revealed that THC and CBD can improve central and peripheral neuropathic pain, as well as pain associated with rheumatoid arthritis and fibromyalgia.²²

Wilsey et al²³ evaluated the analgesic effects of smoked MM for neuropathic pain in a small (N = 38) double-blind, randomized controlled trial (RCT). Patients in this study had a preexisting diagnosis of complex regional pain syndrome, spinal cord injury, peripheral neuropathy, or nerve injury. To prevent any unforeseen adverse outcomes related to Cannabis use, participants were required to have previous exposure to Cannabis. Patients were excluded if they had major mental illness, substance abuse, or other major medical ailments.

Participants smoked high-dose Cannabis cigarettes (7% THC), low-dose Cannabis cigarettes (3.5% THC), or placebo cigarettes. Pain was measured on a visual analog scale (VAS) that ranged from 0 (no pain) to 100 (worst possible pain). Compared with the placebo group, significant analgesia was achieved in both Cannabis groups (P = .016). The high-dose group had greater neurocognitive impairment.

Ware et al²⁴ conducted a crossover RCT (N = 23) to determine the efficacy of smoked MM for neuropathic pain. Participants had neuropathic pain for at least 3 months that was caused by trauma or surgery, with an average weekly pain intensity score >4 on scale of 0 to 10. Patients with pain due to cancer, nociceptive causes, unstable medical conditions, current substance abuse, history of a psychotic disorder, or suicidal ideation were excluded. Participants were assigned to a 9.4% THC group or a 0% THC group. Pain intensity was evaluated daily via telephone. Participants in the 9.4% THC group had statistically lower pain intensity compared with the 0% THC group (P = .023). Common adverse effects reported by those in the 9.4% group included headache, dry eyes, burning sensation, dizziness, numbness, and cough.

Box 2
The effects of Cannabis

In an RCT of vaporized Cannabis, 39 patients with a diagnosis of complex regional pain syndrome, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury were assigned to a medium-dose (3.53% THC), low-dose (1.29% THC), or placebo group.²⁵ Serious mental illness, substance abuse, and medical conditions were cause for exclusion. Participants received vaporized marijuana (average 8 to 12 puffs per visit) over 3 sessions. A 30% pain reduction was achieved by 26% of those in the placebo group, 57% of those in the low-dose group, and 61% of individuals in the high-dose group; the difference between placebo and each Cannabis group was statistically significant.

Chemotherapy-induced nausea and vomiting. Up to 80% of patients who receive chemotherapy experience CINV, which occurs from 24 hours to 7 days after receiving such therapy.²⁶ CINV negatively influences a patient’s QOL and may impact the decision to continue with chemotherapy. Use of MM can help to diminish vomiting by binding to central CB₁ receptors and averting the proemetic effects of dopamine and serotonin.²⁷ Two synthetically derived cannabinoids, dronabinol and nabilone, are FDA-approved for treating CINV.

In a small (N = 64) parallel-group RCT, Meiri et al²⁷ compared dronabinol with the commonly used antiemetic ondansetron and with a combination of dronabinol and ondansetron for treating CINV in adults. The primary outcome was prevention of delayed-onset CINV. Patients were eligible for this study if they had a malignancy that did not involve bone marrow, were receiving treatment with a moderately to highly emetogenic regimen, were not pregnant, and had an estimated life expectancy of at least 6 weeks after chemotherapy. The patients were randomized to 1 of 4 treatment groups: dronabinol alone, ondansetron alone, dronabinol plus ondansetron, or placebo. Overall, 47% to 58% of the active treatment groups improved, compared with 20% of the placebo group. Combination therapy did not provide any benefit beyond any single agent alone. All active treatments reduced nausea compared with placebo; there was no difference between active treatment groups. This study was limited by low enrollment.

Tramèr et al²⁸ conducted a systematic review of 30 randomized comparisons of MM with placebo or antiemetics. The reviewed studies were completed between 1975 to 1997 and analyzed a total of 1,366 patients. Nabilone was evaluated in 16 trials; dronabinol was utilized in 13 trials; and IM levonantradol, a synthetic cannabinoid analog of dronabinol, was used in 1 trial. These agents were found to be more effective as an antiemetic compared with prochlorperazine, metoclopramide, chlorpromazine, thiethyl­perazine, haloperidol, domperidone, or alizapride. In addition, 38% to 90% of patients in these studies preferred MM over the traditional antiemetics.

A Cochrane review²⁹ suggested that MM may be a viable option for treatment-resistant CINV; however, further studies are needed because current studies have methodological limitations.

Epilepsy. Maa and Figi³⁰ reported a case of a 5-year-old girl who had Dravet syndrome, which resulted in 50 generalized tonic-clonic seizures daily; multiple anticonvulsants did not alleviate these seizures. Because of her recurring seizures, the patient had multiple cognitive and motor delays and needed a feeding tube. In addition to her existing antiepileptic drug regimen, she was started on adjunctive therapy with a sublingual Cannabis extract containing a high concentration of CBD. Her seizures decreased from 50 per day to 2 to 3 nocturnal convulsions per month. The treatment enabled her to stop using a feeding tube, resume walking and talking, and sleep soundly.

dos Santos et al³¹ reviewed studies of MM for treating epilepsy. One was a double-blind, placebo-controlled trial that included 15 patients ages 14 to 49 who had secondary generalized epilepsy with a temporal lobe focus. Eight patients received 200 to 300 mg/d of oral CBD for 8 to 18 weeks, and 7 received placebo. Seven patients had fewer seizures and 4 had no seizures. Only 1 patient in the placebo group demonstrated any improvement. Another study in this review included 19 children with treatment-resistant epilepsy: Dravet syndrome (n = 13), Doose syndrome (n = 4), Lennox-Gastaut syndrome (n = 1), or idiopathic epilepsy (n = 1). These patients experienced various types of seizures with a frequency ranging from 2 per week to 250 per day. Overall, 84% of children treated with CBD had fewer seizures: 11% were seizure-free, 42% had a >80% reduction in seizures, and 32% had a 25% to 60% reduction in seizures. Parents also noted additional benefits, including increased attention, improved mood, and improved sleep. CBD was well tolerated in most patients in both studies.

Despite these results, a Cochrane review³² found that no reliable conclusions can be drawn regarding the efficacy of MM for treating epilepsy.

Multiple sclerosis. According to American Academy of Neurology guidelines, physicians may provide MM as an alternative treatment for patients with MS-related spasticity.³³ Multiple studies have tested MM and MM-related extracts for treating spasticity related to MS.^34,35 In a placebo-controlled crossover study, Corey-Bloom et al³⁴ reported a significant reduction in spasticity, measured using the modified Ashworth scale, in MS patients receiving Cannabis cigarettes vs placebo cigarettes (P < .0001). However, compared with the placebo group, patients who received MM had significant adverse effects, primarily cognitive impairment (P = .003).

In a multicenter RCT (N = 572 patients with refractory MS spasticity), Novotna et al³⁶ evaluated nabiximols, an oral mucosal spray of a formulated extract of Cannabis that contains THC and CBD in a 1:1 ratio. They assessed spasticity using the Numerical Spasticity Rating Scale (NRS). Results were confirmed by measuring the number of daily spasms, self-report of sleep quality, and activities of daily living. After 4 weeks of single-blind treatment, patients who responded to nabiximols (≥20% improvement in spasticity) were randomized to a placebo group or nabiximols group for 12 additional weeks. After 12 weeks, compared with those who received placebo, those in the nabiximols group experienced a statistically significant reduction in spasticity based on NRS score (P = .0002).
 

For a summary of evidence on MM for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, see Box 3.^37-43

Box 3
Cannabis for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis

Psychiatric illnesses

Dementia-related behavioral disturbances. A few clinical trials with small sample sizes have found evidence supporting the use of MM compounds for alleviating neuropsychiatric symptoms of patients with dementia. An open-label pilot study of 6 individuals with late-stage dementia who received dronabinol, 2.5 mg/d, for 2 weeks, found a significant reduction (compared with baseline) in nighttime motor activity as measured with an actometer (P < .0028).⁴⁴ The secondary Neuropsychiatric Inventory (NPI) assessment found reductions in aberrant motor behavior (P = .042), agitation (P = .042), and nighttime behaviors (P = .42).

A 2014 retrospective analysis of 40 inpatients with dementia-related agitation and appetite loss who were treated with dronabinol (mean dosage: 7.03 mg/d) found reductions in all aspects of agitation, including aberrant vocalization, motor agitation, aggressiveness, and treatment resistance, as measured with the Pittsburgh Agitation Scale (P < .0001).⁴⁵ The study found no significant improvements in appetite, Global Assessment of Functioning mean score, or number of times patients awoke during the night. Adverse effects included sedation and delirium.

A RCT of 50 dementia patients with clinically relevant neuropsychiatric symptoms found no significant difference in mean NPI scores between patients given placebo and those who received nabiximols, 1.5 mg, 3 times daily.⁴⁶ There were no significant differences found in agitation, QOL, life activities, or caregiver-scored Caregiver Global Impression of Change scale.

In a small RCT, THC was safe and well tolerated in 10 older patients with dementia.⁴⁷ A 2009 Cochrane review⁴⁸ concluded that there was no evidence for the efficacy of MM in treating the neuropsychiatric symptoms related to dementia.

PTSD. Preclinical evidence shows that the endocannabinoid system is involved in regulating emotional memory. Evidence also suggests that cannabinoids may facilitate the extinction of aversive memories.^49,50

In 2009, New Mexico became the first state to authorize the use of MM for patients with PTSD. In a study of patients applying for the New Mexico Medical Cannabis Program, researchers used the Clinician Administered Posttraumatic Scale (CAPS) to assess PTSD symptoms.⁵¹ A retrospective chart review of the first 80 patients eval­uated found significant (P < .0001) reductions of several PTSD symptoms, including intrusive memories, distressing dreams, flashbacks, numbing and avoidance, and hyperarousal, in the group using MM vs those not using MM. There also was a significant difference in CAPS total score (P < .0001). Patients reported a 75% reduction in PTSD symptoms while using MM. This study has several limitations: It was a retrospective review, not an RCT, and patients were prescreened and knew before the study began that MM helped their PTSD symptoms.

In another retrospective study, researchers evaluated treatment with nabilone, 0.5 to 6 mg/d, in 104 incarcerated men with various major mental illnesses; most (91%) met criteria for Cannabis dependence.⁵² They found significant improvements in sleep and PTSD symptoms.

A double-blind RCT evaluated MM in 10 Canadian male soldiers with PTSD who experienced nightmares despite standard medication treatment. Adjunctive nabilone (maximum dose: 3 mg/d) resulted in a reduction in nightmares as measured by the CAPS recurrent distressing dream of the event item score.⁵³

Currently, there are no adequately powered RCTs of MM in a diverse group of PTSD patients. Most studies are open-label, enriched design, and included white male veterans. No well-conducted trials have evaluated patients with noncombat-related PTSD. Most of the relevant literature consists of case reports of Cannabis use by patients with PTSD.

Anxiety disorders.Patients frequently indicate that smoking Cannabis helps relieve their anxiety, although there is no replicated evidence based on double-blind RCTs to support this. However, in rat models CBD has been shown to facilitate extinction of conditioned fear via the endocannabinoid system.^54-56 The mechanism of action is not completely understood. CBD has been shown to have antagonistic action at CB₁ and CB₂ receptors. It may have similar effects on memory extinction and may be an adjunct to exposure therapies for anxiety disorders.

Das et al⁵⁷ studied the effects of CBD (32 mg) on extinction and consolidation of memory related to contextual fear in 48 individuals. They found that CBD can enhance extinction learning, and suggested it may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Caveats: Adverse effects, lack of RCTs

Cannabis use causes impairment of learning, memory, attention, and working memory. Adolescents are particularly vulnerable to the effects of Cannabis on brain development at a time when synaptic pruning and increased myelination occur. Normal brain development could be disrupted. Some studies have linked Cannabis use to abnormalities in the amygdala, hippocampus, frontal lobe, and cerebellum. From 1995 to 2014, the potency of Cannabis (THC concentration) increased from 4% to 12%.⁵⁸ This has substantial implications for increased abuse among adolescents and the deleterious effects of Cannabis on the brain.

Heavy Cannabis use impairs motivation and could precipitate psychosis in vulnerable individuals. Cannabis use may be linked to the development of schizophrenia.⁵⁹

There are no well-conducted RCTs on the efficacy of MM, and adequate safety data are lacking. There is also lack of consensus among qualified experts. There is soft evidence that MM may be helpful in some medical conditions, including but not limited to CINV, neuropathic pain, epilepsy, and MS-related spasticity. Currently, the benefits of using MM do not appear to outweigh the risks.

Bottom Line

Limited evidence suggests medical marijuana (MM) may be beneficial for treating a few medical conditions, including neuropathic pain and chemotherapy-induced nausea and vomiting. There is no clear and convincing evidence MM is beneficial for psychiatric disorders, and Cannabis can impair cognition and attention and may precipitate psychosis. The risk of deleterious effects are greater in adolescents.

Related Resources

• Nguyen DH, Thant TM. Caring for medical marijuana patients who request controlled prescriptions. Current Psychiatry. 2017;16(8):50-51.
• National Institute on Drug Abuse. Marijuana as medicine. https://www.drugabuse.gov/publications/drugfacts/ marijuana-medicine.

Drug Brand Names

Alizapride • Litican, Superan
Chlorpromazine • Thorazine
Domperidone • Motilium
Dronabinol • Marinol, Syndros
Haloperidol • Haldol
Metoclopramide • Reglan
Nabilone • Cesamet
Nabiximols • Sativex
Ondansetron • Zofran, Zuplenz
Prochlorperazine • Compazine
Thiethylperazine • Torecan

There is a need for additional treatment options to improve symptoms, enhance the quality of life (QOL), and reduce suffering among patients who have chronic medical illness. Medical marijuana (MM) has the potential to help patients who have certain medical conditions in states where it is legal for prescription by a licensed medical provider.

Cannabis has a long history of medicinal use (Box 1^1-12). Two derivatives of the Cannabis plant—cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—are responsible for most of its effects. Some of these effects, including analgesia, decreased muscle spasticity, and reduced eye pressure, have been harnessed for their potential therapeutic effects (Box 2^13-19). As of November 2017, 29 states had legalized Cannabis for medical use, and several had legalized its recreational use.¹²

With the increasing availability of MM, psychiatrists are likely to encounter patients who are using it or who will ask them about it. This article reviews evidence related to using MM to treat patients with neuropathic pain; chemotherapyinduced nausea and vomiting (CINV); epilepsy; multiple sclerosis (MS); glaucoma; Crohn’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; dementia-related behavioral disturbances; posttraumatic stress disorder (PTSD); and anxiety.

Box 1 
Cannabis: A history of medicinal use

Medical illnesses

Neuropathic pain. Chronic neuropathic pain affects an estimated 7% to 8% of adults.²⁰ Patients with neuropathic pain are often treated with anticonvulsants, anti­depressants, opioids, and local anesthetics²¹; however, these medications may not provide substantial relief. Research has revealed that THC and CBD can improve central and peripheral neuropathic pain, as well as pain associated with rheumatoid arthritis and fibromyalgia.²²

Wilsey et al²³ evaluated the analgesic effects of smoked MM for neuropathic pain in a small (N = 38) double-blind, randomized controlled trial (RCT). Patients in this study had a preexisting diagnosis of complex regional pain syndrome, spinal cord injury, peripheral neuropathy, or nerve injury. To prevent any unforeseen adverse outcomes related to Cannabis use, participants were required to have previous exposure to Cannabis. Patients were excluded if they had major mental illness, substance abuse, or other major medical ailments.

Participants smoked high-dose Cannabis cigarettes (7% THC), low-dose Cannabis cigarettes (3.5% THC), or placebo cigarettes. Pain was measured on a visual analog scale (VAS) that ranged from 0 (no pain) to 100 (worst possible pain). Compared with the placebo group, significant analgesia was achieved in both Cannabis groups (P = .016). The high-dose group had greater neurocognitive impairment.

Ware et al²⁴ conducted a crossover RCT (N = 23) to determine the efficacy of smoked MM for neuropathic pain. Participants had neuropathic pain for at least 3 months that was caused by trauma or surgery, with an average weekly pain intensity score >4 on scale of 0 to 10. Patients with pain due to cancer, nociceptive causes, unstable medical conditions, current substance abuse, history of a psychotic disorder, or suicidal ideation were excluded. Participants were assigned to a 9.4% THC group or a 0% THC group. Pain intensity was evaluated daily via telephone. Participants in the 9.4% THC group had statistically lower pain intensity compared with the 0% THC group (P = .023). Common adverse effects reported by those in the 9.4% group included headache, dry eyes, burning sensation, dizziness, numbness, and cough.

Box 2
The effects of Cannabis

In an RCT of vaporized Cannabis, 39 patients with a diagnosis of complex regional pain syndrome, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury were assigned to a medium-dose (3.53% THC), low-dose (1.29% THC), or placebo group.²⁵ Serious mental illness, substance abuse, and medical conditions were cause for exclusion. Participants received vaporized marijuana (average 8 to 12 puffs per visit) over 3 sessions. A 30% pain reduction was achieved by 26% of those in the placebo group, 57% of those in the low-dose group, and 61% of individuals in the high-dose group; the difference between placebo and each Cannabis group was statistically significant.

Chemotherapy-induced nausea and vomiting. Up to 80% of patients who receive chemotherapy experience CINV, which occurs from 24 hours to 7 days after receiving such therapy.²⁶ CINV negatively influences a patient’s QOL and may impact the decision to continue with chemotherapy. Use of MM can help to diminish vomiting by binding to central CB₁ receptors and averting the proemetic effects of dopamine and serotonin.²⁷ Two synthetically derived cannabinoids, dronabinol and nabilone, are FDA-approved for treating CINV.

In a small (N = 64) parallel-group RCT, Meiri et al²⁷ compared dronabinol with the commonly used antiemetic ondansetron and with a combination of dronabinol and ondansetron for treating CINV in adults. The primary outcome was prevention of delayed-onset CINV. Patients were eligible for this study if they had a malignancy that did not involve bone marrow, were receiving treatment with a moderately to highly emetogenic regimen, were not pregnant, and had an estimated life expectancy of at least 6 weeks after chemotherapy. The patients were randomized to 1 of 4 treatment groups: dronabinol alone, ondansetron alone, dronabinol plus ondansetron, or placebo. Overall, 47% to 58% of the active treatment groups improved, compared with 20% of the placebo group. Combination therapy did not provide any benefit beyond any single agent alone. All active treatments reduced nausea compared with placebo; there was no difference between active treatment groups. This study was limited by low enrollment.

Tramèr et al²⁸ conducted a systematic review of 30 randomized comparisons of MM with placebo or antiemetics. The reviewed studies were completed between 1975 to 1997 and analyzed a total of 1,366 patients. Nabilone was evaluated in 16 trials; dronabinol was utilized in 13 trials; and IM levonantradol, a synthetic cannabinoid analog of dronabinol, was used in 1 trial. These agents were found to be more effective as an antiemetic compared with prochlorperazine, metoclopramide, chlorpromazine, thiethyl­perazine, haloperidol, domperidone, or alizapride. In addition, 38% to 90% of patients in these studies preferred MM over the traditional antiemetics.

A Cochrane review²⁹ suggested that MM may be a viable option for treatment-resistant CINV; however, further studies are needed because current studies have methodological limitations.

Epilepsy. Maa and Figi³⁰ reported a case of a 5-year-old girl who had Dravet syndrome, which resulted in 50 generalized tonic-clonic seizures daily; multiple anticonvulsants did not alleviate these seizures. Because of her recurring seizures, the patient had multiple cognitive and motor delays and needed a feeding tube. In addition to her existing antiepileptic drug regimen, she was started on adjunctive therapy with a sublingual Cannabis extract containing a high concentration of CBD. Her seizures decreased from 50 per day to 2 to 3 nocturnal convulsions per month. The treatment enabled her to stop using a feeding tube, resume walking and talking, and sleep soundly.

dos Santos et al³¹ reviewed studies of MM for treating epilepsy. One was a double-blind, placebo-controlled trial that included 15 patients ages 14 to 49 who had secondary generalized epilepsy with a temporal lobe focus. Eight patients received 200 to 300 mg/d of oral CBD for 8 to 18 weeks, and 7 received placebo. Seven patients had fewer seizures and 4 had no seizures. Only 1 patient in the placebo group demonstrated any improvement. Another study in this review included 19 children with treatment-resistant epilepsy: Dravet syndrome (n = 13), Doose syndrome (n = 4), Lennox-Gastaut syndrome (n = 1), or idiopathic epilepsy (n = 1). These patients experienced various types of seizures with a frequency ranging from 2 per week to 250 per day. Overall, 84% of children treated with CBD had fewer seizures: 11% were seizure-free, 42% had a >80% reduction in seizures, and 32% had a 25% to 60% reduction in seizures. Parents also noted additional benefits, including increased attention, improved mood, and improved sleep. CBD was well tolerated in most patients in both studies.

Despite these results, a Cochrane review³² found that no reliable conclusions can be drawn regarding the efficacy of MM for treating epilepsy.

Multiple sclerosis. According to American Academy of Neurology guidelines, physicians may provide MM as an alternative treatment for patients with MS-related spasticity.³³ Multiple studies have tested MM and MM-related extracts for treating spasticity related to MS.^34,35 In a placebo-controlled crossover study, Corey-Bloom et al³⁴ reported a significant reduction in spasticity, measured using the modified Ashworth scale, in MS patients receiving Cannabis cigarettes vs placebo cigarettes (P < .0001). However, compared with the placebo group, patients who received MM had significant adverse effects, primarily cognitive impairment (P = .003).

In a multicenter RCT (N = 572 patients with refractory MS spasticity), Novotna et al³⁶ evaluated nabiximols, an oral mucosal spray of a formulated extract of Cannabis that contains THC and CBD in a 1:1 ratio. They assessed spasticity using the Numerical Spasticity Rating Scale (NRS). Results were confirmed by measuring the number of daily spasms, self-report of sleep quality, and activities of daily living. After 4 weeks of single-blind treatment, patients who responded to nabiximols (≥20% improvement in spasticity) were randomized to a placebo group or nabiximols group for 12 additional weeks. After 12 weeks, compared with those who received placebo, those in the nabiximols group experienced a statistically significant reduction in spasticity based on NRS score (P = .0002).
 

For a summary of evidence on MM for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, see Box 3.^37-43

Box 3
Cannabis for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis

Psychiatric illnesses

Dementia-related behavioral disturbances. A few clinical trials with small sample sizes have found evidence supporting the use of MM compounds for alleviating neuropsychiatric symptoms of patients with dementia. An open-label pilot study of 6 individuals with late-stage dementia who received dronabinol, 2.5 mg/d, for 2 weeks, found a significant reduction (compared with baseline) in nighttime motor activity as measured with an actometer (P < .0028).⁴⁴ The secondary Neuropsychiatric Inventory (NPI) assessment found reductions in aberrant motor behavior (P = .042), agitation (P = .042), and nighttime behaviors (P = .42).

A 2014 retrospective analysis of 40 inpatients with dementia-related agitation and appetite loss who were treated with dronabinol (mean dosage: 7.03 mg/d) found reductions in all aspects of agitation, including aberrant vocalization, motor agitation, aggressiveness, and treatment resistance, as measured with the Pittsburgh Agitation Scale (P < .0001).⁴⁵ The study found no significant improvements in appetite, Global Assessment of Functioning mean score, or number of times patients awoke during the night. Adverse effects included sedation and delirium.

A RCT of 50 dementia patients with clinically relevant neuropsychiatric symptoms found no significant difference in mean NPI scores between patients given placebo and those who received nabiximols, 1.5 mg, 3 times daily.⁴⁶ There were no significant differences found in agitation, QOL, life activities, or caregiver-scored Caregiver Global Impression of Change scale.

In a small RCT, THC was safe and well tolerated in 10 older patients with dementia.⁴⁷ A 2009 Cochrane review⁴⁸ concluded that there was no evidence for the efficacy of MM in treating the neuropsychiatric symptoms related to dementia.

PTSD. Preclinical evidence shows that the endocannabinoid system is involved in regulating emotional memory. Evidence also suggests that cannabinoids may facilitate the extinction of aversive memories.^49,50

In 2009, New Mexico became the first state to authorize the use of MM for patients with PTSD. In a study of patients applying for the New Mexico Medical Cannabis Program, researchers used the Clinician Administered Posttraumatic Scale (CAPS) to assess PTSD symptoms.⁵¹ A retrospective chart review of the first 80 patients eval­uated found significant (P < .0001) reductions of several PTSD symptoms, including intrusive memories, distressing dreams, flashbacks, numbing and avoidance, and hyperarousal, in the group using MM vs those not using MM. There also was a significant difference in CAPS total score (P < .0001). Patients reported a 75% reduction in PTSD symptoms while using MM. This study has several limitations: It was a retrospective review, not an RCT, and patients were prescreened and knew before the study began that MM helped their PTSD symptoms.

In another retrospective study, researchers evaluated treatment with nabilone, 0.5 to 6 mg/d, in 104 incarcerated men with various major mental illnesses; most (91%) met criteria for Cannabis dependence.⁵² They found significant improvements in sleep and PTSD symptoms.

A double-blind RCT evaluated MM in 10 Canadian male soldiers with PTSD who experienced nightmares despite standard medication treatment. Adjunctive nabilone (maximum dose: 3 mg/d) resulted in a reduction in nightmares as measured by the CAPS recurrent distressing dream of the event item score.⁵³

Currently, there are no adequately powered RCTs of MM in a diverse group of PTSD patients. Most studies are open-label, enriched design, and included white male veterans. No well-conducted trials have evaluated patients with noncombat-related PTSD. Most of the relevant literature consists of case reports of Cannabis use by patients with PTSD.

Anxiety disorders.Patients frequently indicate that smoking Cannabis helps relieve their anxiety, although there is no replicated evidence based on double-blind RCTs to support this. However, in rat models CBD has been shown to facilitate extinction of conditioned fear via the endocannabinoid system.^54-56 The mechanism of action is not completely understood. CBD has been shown to have antagonistic action at CB₁ and CB₂ receptors. It may have similar effects on memory extinction and may be an adjunct to exposure therapies for anxiety disorders.

Das et al⁵⁷ studied the effects of CBD (32 mg) on extinction and consolidation of memory related to contextual fear in 48 individuals. They found that CBD can enhance extinction learning, and suggested it may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Caveats: Adverse effects, lack of RCTs

Cannabis use causes impairment of learning, memory, attention, and working memory. Adolescents are particularly vulnerable to the effects of Cannabis on brain development at a time when synaptic pruning and increased myelination occur. Normal brain development could be disrupted. Some studies have linked Cannabis use to abnormalities in the amygdala, hippocampus, frontal lobe, and cerebellum. From 1995 to 2014, the potency of Cannabis (THC concentration) increased from 4% to 12%.⁵⁸ This has substantial implications for increased abuse among adolescents and the deleterious effects of Cannabis on the brain.

Heavy Cannabis use impairs motivation and could precipitate psychosis in vulnerable individuals. Cannabis use may be linked to the development of schizophrenia.⁵⁹

There are no well-conducted RCTs on the efficacy of MM, and adequate safety data are lacking. There is also lack of consensus among qualified experts. There is soft evidence that MM may be helpful in some medical conditions, including but not limited to CINV, neuropathic pain, epilepsy, and MS-related spasticity. Currently, the benefits of using MM do not appear to outweigh the risks.

Bottom Line

Limited evidence suggests medical marijuana (MM) may be beneficial for treating a few medical conditions, including neuropathic pain and chemotherapy-induced nausea and vomiting. There is no clear and convincing evidence MM is beneficial for psychiatric disorders, and Cannabis can impair cognition and attention and may precipitate psychosis. The risk of deleterious effects are greater in adolescents.

Related Resources

• Nguyen DH, Thant TM. Caring for medical marijuana patients who request controlled prescriptions. Current Psychiatry. 2017;16(8):50-51.
• National Institute on Drug Abuse. Marijuana as medicine. https://www.drugabuse.gov/publications/drugfacts/ marijuana-medicine.

Drug Brand Names

Alizapride • Litican, Superan
Chlorpromazine • Thorazine
Domperidone • Motilium
Dronabinol • Marinol, Syndros
Haloperidol • Haldol
Metoclopramide • Reglan
Nabilone • Cesamet
Nabiximols • Sativex
Ondansetron • Zofran, Zuplenz
Prochlorperazine • Compazine
Thiethylperazine • Torecan

There is a need for additional treatment options to improve symptoms, enhance the quality of life (QOL), and reduce suffering among patients who have chronic medical illness. Medical marijuana (MM) has the potential to help patients who have certain medical conditions in states where it is legal for prescription by a licensed medical provider.

Cannabis has a long history of medicinal use (Box 1^1-12). Two derivatives of the Cannabis plant—cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—are responsible for most of its effects. Some of these effects, including analgesia, decreased muscle spasticity, and reduced eye pressure, have been harnessed for their potential therapeutic effects (Box 2^13-19). As of November 2017, 29 states had legalized Cannabis for medical use, and several had legalized its recreational use.¹²

With the increasing availability of MM, psychiatrists are likely to encounter patients who are using it or who will ask them about it. This article reviews evidence related to using MM to treat patients with neuropathic pain; chemotherapyinduced nausea and vomiting (CINV); epilepsy; multiple sclerosis (MS); glaucoma; Crohn’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; dementia-related behavioral disturbances; posttraumatic stress disorder (PTSD); and anxiety.

Box 1 
Cannabis: A history of medicinal use

Medical illnesses

Neuropathic pain. Chronic neuropathic pain affects an estimated 7% to 8% of adults.²⁰ Patients with neuropathic pain are often treated with anticonvulsants, anti­depressants, opioids, and local anesthetics²¹; however, these medications may not provide substantial relief. Research has revealed that THC and CBD can improve central and peripheral neuropathic pain, as well as pain associated with rheumatoid arthritis and fibromyalgia.²²

Wilsey et al²³ evaluated the analgesic effects of smoked MM for neuropathic pain in a small (N = 38) double-blind, randomized controlled trial (RCT). Patients in this study had a preexisting diagnosis of complex regional pain syndrome, spinal cord injury, peripheral neuropathy, or nerve injury. To prevent any unforeseen adverse outcomes related to Cannabis use, participants were required to have previous exposure to Cannabis. Patients were excluded if they had major mental illness, substance abuse, or other major medical ailments.

Participants smoked high-dose Cannabis cigarettes (7% THC), low-dose Cannabis cigarettes (3.5% THC), or placebo cigarettes. Pain was measured on a visual analog scale (VAS) that ranged from 0 (no pain) to 100 (worst possible pain). Compared with the placebo group, significant analgesia was achieved in both Cannabis groups (P = .016). The high-dose group had greater neurocognitive impairment.

Ware et al²⁴ conducted a crossover RCT (N = 23) to determine the efficacy of smoked MM for neuropathic pain. Participants had neuropathic pain for at least 3 months that was caused by trauma or surgery, with an average weekly pain intensity score >4 on scale of 0 to 10. Patients with pain due to cancer, nociceptive causes, unstable medical conditions, current substance abuse, history of a psychotic disorder, or suicidal ideation were excluded. Participants were assigned to a 9.4% THC group or a 0% THC group. Pain intensity was evaluated daily via telephone. Participants in the 9.4% THC group had statistically lower pain intensity compared with the 0% THC group (P = .023). Common adverse effects reported by those in the 9.4% group included headache, dry eyes, burning sensation, dizziness, numbness, and cough.

Box 2
The effects of Cannabis

In an RCT of vaporized Cannabis, 39 patients with a diagnosis of complex regional pain syndrome, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury were assigned to a medium-dose (3.53% THC), low-dose (1.29% THC), or placebo group.²⁵ Serious mental illness, substance abuse, and medical conditions were cause for exclusion. Participants received vaporized marijuana (average 8 to 12 puffs per visit) over 3 sessions. A 30% pain reduction was achieved by 26% of those in the placebo group, 57% of those in the low-dose group, and 61% of individuals in the high-dose group; the difference between placebo and each Cannabis group was statistically significant.

Chemotherapy-induced nausea and vomiting. Up to 80% of patients who receive chemotherapy experience CINV, which occurs from 24 hours to 7 days after receiving such therapy.²⁶ CINV negatively influences a patient’s QOL and may impact the decision to continue with chemotherapy. Use of MM can help to diminish vomiting by binding to central CB₁ receptors and averting the proemetic effects of dopamine and serotonin.²⁷ Two synthetically derived cannabinoids, dronabinol and nabilone, are FDA-approved for treating CINV.

In a small (N = 64) parallel-group RCT, Meiri et al²⁷ compared dronabinol with the commonly used antiemetic ondansetron and with a combination of dronabinol and ondansetron for treating CINV in adults. The primary outcome was prevention of delayed-onset CINV. Patients were eligible for this study if they had a malignancy that did not involve bone marrow, were receiving treatment with a moderately to highly emetogenic regimen, were not pregnant, and had an estimated life expectancy of at least 6 weeks after chemotherapy. The patients were randomized to 1 of 4 treatment groups: dronabinol alone, ondansetron alone, dronabinol plus ondansetron, or placebo. Overall, 47% to 58% of the active treatment groups improved, compared with 20% of the placebo group. Combination therapy did not provide any benefit beyond any single agent alone. All active treatments reduced nausea compared with placebo; there was no difference between active treatment groups. This study was limited by low enrollment.

Tramèr et al²⁸ conducted a systematic review of 30 randomized comparisons of MM with placebo or antiemetics. The reviewed studies were completed between 1975 to 1997 and analyzed a total of 1,366 patients. Nabilone was evaluated in 16 trials; dronabinol was utilized in 13 trials; and IM levonantradol, a synthetic cannabinoid analog of dronabinol, was used in 1 trial. These agents were found to be more effective as an antiemetic compared with prochlorperazine, metoclopramide, chlorpromazine, thiethyl­perazine, haloperidol, domperidone, or alizapride. In addition, 38% to 90% of patients in these studies preferred MM over the traditional antiemetics.

A Cochrane review²⁹ suggested that MM may be a viable option for treatment-resistant CINV; however, further studies are needed because current studies have methodological limitations.

Epilepsy. Maa and Figi³⁰ reported a case of a 5-year-old girl who had Dravet syndrome, which resulted in 50 generalized tonic-clonic seizures daily; multiple anticonvulsants did not alleviate these seizures. Because of her recurring seizures, the patient had multiple cognitive and motor delays and needed a feeding tube. In addition to her existing antiepileptic drug regimen, she was started on adjunctive therapy with a sublingual Cannabis extract containing a high concentration of CBD. Her seizures decreased from 50 per day to 2 to 3 nocturnal convulsions per month. The treatment enabled her to stop using a feeding tube, resume walking and talking, and sleep soundly.

dos Santos et al³¹ reviewed studies of MM for treating epilepsy. One was a double-blind, placebo-controlled trial that included 15 patients ages 14 to 49 who had secondary generalized epilepsy with a temporal lobe focus. Eight patients received 200 to 300 mg/d of oral CBD for 8 to 18 weeks, and 7 received placebo. Seven patients had fewer seizures and 4 had no seizures. Only 1 patient in the placebo group demonstrated any improvement. Another study in this review included 19 children with treatment-resistant epilepsy: Dravet syndrome (n = 13), Doose syndrome (n = 4), Lennox-Gastaut syndrome (n = 1), or idiopathic epilepsy (n = 1). These patients experienced various types of seizures with a frequency ranging from 2 per week to 250 per day. Overall, 84% of children treated with CBD had fewer seizures: 11% were seizure-free, 42% had a >80% reduction in seizures, and 32% had a 25% to 60% reduction in seizures. Parents also noted additional benefits, including increased attention, improved mood, and improved sleep. CBD was well tolerated in most patients in both studies.

Despite these results, a Cochrane review³² found that no reliable conclusions can be drawn regarding the efficacy of MM for treating epilepsy.

Multiple sclerosis. According to American Academy of Neurology guidelines, physicians may provide MM as an alternative treatment for patients with MS-related spasticity.³³ Multiple studies have tested MM and MM-related extracts for treating spasticity related to MS.^34,35 In a placebo-controlled crossover study, Corey-Bloom et al³⁴ reported a significant reduction in spasticity, measured using the modified Ashworth scale, in MS patients receiving Cannabis cigarettes vs placebo cigarettes (P < .0001). However, compared with the placebo group, patients who received MM had significant adverse effects, primarily cognitive impairment (P = .003).

In a multicenter RCT (N = 572 patients with refractory MS spasticity), Novotna et al³⁶ evaluated nabiximols, an oral mucosal spray of a formulated extract of Cannabis that contains THC and CBD in a 1:1 ratio. They assessed spasticity using the Numerical Spasticity Rating Scale (NRS). Results were confirmed by measuring the number of daily spasms, self-report of sleep quality, and activities of daily living. After 4 weeks of single-blind treatment, patients who responded to nabiximols (≥20% improvement in spasticity) were randomized to a placebo group or nabiximols group for 12 additional weeks. After 12 weeks, compared with those who received placebo, those in the nabiximols group experienced a statistically significant reduction in spasticity based on NRS score (P = .0002).
 

For a summary of evidence on MM for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, see Box 3.^37-43

Box 3
Cannabis for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis

Psychiatric illnesses

Dementia-related behavioral disturbances. A few clinical trials with small sample sizes have found evidence supporting the use of MM compounds for alleviating neuropsychiatric symptoms of patients with dementia. An open-label pilot study of 6 individuals with late-stage dementia who received dronabinol, 2.5 mg/d, for 2 weeks, found a significant reduction (compared with baseline) in nighttime motor activity as measured with an actometer (P < .0028).⁴⁴ The secondary Neuropsychiatric Inventory (NPI) assessment found reductions in aberrant motor behavior (P = .042), agitation (P = .042), and nighttime behaviors (P = .42).

A 2014 retrospective analysis of 40 inpatients with dementia-related agitation and appetite loss who were treated with dronabinol (mean dosage: 7.03 mg/d) found reductions in all aspects of agitation, including aberrant vocalization, motor agitation, aggressiveness, and treatment resistance, as measured with the Pittsburgh Agitation Scale (P < .0001).⁴⁵ The study found no significant improvements in appetite, Global Assessment of Functioning mean score, or number of times patients awoke during the night. Adverse effects included sedation and delirium.

A RCT of 50 dementia patients with clinically relevant neuropsychiatric symptoms found no significant difference in mean NPI scores between patients given placebo and those who received nabiximols, 1.5 mg, 3 times daily.⁴⁶ There were no significant differences found in agitation, QOL, life activities, or caregiver-scored Caregiver Global Impression of Change scale.

In a small RCT, THC was safe and well tolerated in 10 older patients with dementia.⁴⁷ A 2009 Cochrane review⁴⁸ concluded that there was no evidence for the efficacy of MM in treating the neuropsychiatric symptoms related to dementia.

PTSD. Preclinical evidence shows that the endocannabinoid system is involved in regulating emotional memory. Evidence also suggests that cannabinoids may facilitate the extinction of aversive memories.^49,50

In 2009, New Mexico became the first state to authorize the use of MM for patients with PTSD. In a study of patients applying for the New Mexico Medical Cannabis Program, researchers used the Clinician Administered Posttraumatic Scale (CAPS) to assess PTSD symptoms.⁵¹ A retrospective chart review of the first 80 patients eval­uated found significant (P < .0001) reductions of several PTSD symptoms, including intrusive memories, distressing dreams, flashbacks, numbing and avoidance, and hyperarousal, in the group using MM vs those not using MM. There also was a significant difference in CAPS total score (P < .0001). Patients reported a 75% reduction in PTSD symptoms while using MM. This study has several limitations: It was a retrospective review, not an RCT, and patients were prescreened and knew before the study began that MM helped their PTSD symptoms.

In another retrospective study, researchers evaluated treatment with nabilone, 0.5 to 6 mg/d, in 104 incarcerated men with various major mental illnesses; most (91%) met criteria for Cannabis dependence.⁵² They found significant improvements in sleep and PTSD symptoms.

A double-blind RCT evaluated MM in 10 Canadian male soldiers with PTSD who experienced nightmares despite standard medication treatment. Adjunctive nabilone (maximum dose: 3 mg/d) resulted in a reduction in nightmares as measured by the CAPS recurrent distressing dream of the event item score.⁵³

Currently, there are no adequately powered RCTs of MM in a diverse group of PTSD patients. Most studies are open-label, enriched design, and included white male veterans. No well-conducted trials have evaluated patients with noncombat-related PTSD. Most of the relevant literature consists of case reports of Cannabis use by patients with PTSD.

Anxiety disorders.Patients frequently indicate that smoking Cannabis helps relieve their anxiety, although there is no replicated evidence based on double-blind RCTs to support this. However, in rat models CBD has been shown to facilitate extinction of conditioned fear via the endocannabinoid system.^54-56 The mechanism of action is not completely understood. CBD has been shown to have antagonistic action at CB₁ and CB₂ receptors. It may have similar effects on memory extinction and may be an adjunct to exposure therapies for anxiety disorders.

Das et al⁵⁷ studied the effects of CBD (32 mg) on extinction and consolidation of memory related to contextual fear in 48 individuals. They found that CBD can enhance extinction learning, and suggested it may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Caveats: Adverse effects, lack of RCTs

Cannabis use causes impairment of learning, memory, attention, and working memory. Adolescents are particularly vulnerable to the effects of Cannabis on brain development at a time when synaptic pruning and increased myelination occur. Normal brain development could be disrupted. Some studies have linked Cannabis use to abnormalities in the amygdala, hippocampus, frontal lobe, and cerebellum. From 1995 to 2014, the potency of Cannabis (THC concentration) increased from 4% to 12%.⁵⁸ This has substantial implications for increased abuse among adolescents and the deleterious effects of Cannabis on the brain.

Heavy Cannabis use impairs motivation and could precipitate psychosis in vulnerable individuals. Cannabis use may be linked to the development of schizophrenia.⁵⁹

There are no well-conducted RCTs on the efficacy of MM, and adequate safety data are lacking. There is also lack of consensus among qualified experts. There is soft evidence that MM may be helpful in some medical conditions, including but not limited to CINV, neuropathic pain, epilepsy, and MS-related spasticity. Currently, the benefits of using MM do not appear to outweigh the risks.

Bottom Line

Limited evidence suggests medical marijuana (MM) may be beneficial for treating a few medical conditions, including neuropathic pain and chemotherapy-induced nausea and vomiting. There is no clear and convincing evidence MM is beneficial for psychiatric disorders, and Cannabis can impair cognition and attention and may precipitate psychosis. The risk of deleterious effects are greater in adolescents.

Related Resources

• Nguyen DH, Thant TM. Caring for medical marijuana patients who request controlled prescriptions. Current Psychiatry. 2017;16(8):50-51.
• National Institute on Drug Abuse. Marijuana as medicine. https://www.drugabuse.gov/publications/drugfacts/ marijuana-medicine.

Drug Brand Names

Alizapride • Litican, Superan
Chlorpromazine • Thorazine
Domperidone • Motilium
Dronabinol • Marinol, Syndros
Haloperidol • Haldol
Metoclopramide • Reglan
Nabilone • Cesamet
Nabiximols • Sativex
Ondansetron • Zofran, Zuplenz
Prochlorperazine • Compazine
Thiethylperazine • Torecan

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

• mild symptoms: tremor, akathisia, inducible clonus
• moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
• severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶
 

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

• mild symptoms: tremor, akathisia, inducible clonus
• moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
• severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶
 

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

• mild symptoms: tremor, akathisia, inducible clonus
• moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
• severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶
 

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

• Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
• High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
• Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
• In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuro­inflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hyper­cholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neuro­degeneration.¹⁶
 

A large study of 4,444 consecutive patients in Taiwan found that those with low total cholesterol (<160 mg/dL) had higher scores of anxiety, phobia, psychoticism, and aggressive hostility.¹⁷ In the same study, women with low high-density lipoprotein cholesterol (<35 mg/dL) had significantly higher scores for depression, phobia, anxiety, interpersonal sensitivity, somatization, and aggressive hostility.¹⁷

Not surprisingly, low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality,¹⁸ as well as a predictor of the depression severity and increased suicide risk.¹⁹ Clinical recovery in depression may be accompanied by a significant increase of total cholesterol²⁰ but, interestingly, a decrease in cholesterol levels after treatment of mania. High cholesterol was reported to predict poorer response to selective serotonin reuptake inhibitors, and total cholesterol levels >200 mg/dL were associated with lack of response to fluoxetine and nortriptyline.² Interestingly, clozapine, which elevates lipids, exerts a strong anti-suicide effect in schizophrenia and schizoaffective disorder, but that may not be the main reason for its efficacy in preventing suicide in patients with psychosis.

Cholesterol is an important lipid for brain function. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders (including antisocial personality disorder and borderline personality disorder). However, at high levels, it may improve cognition in schizophrenia and ameliorate the pace of AD and neurodegeneration. Psychiatrists should monitor patients for hypercholesterolemia and hypocholesterolemia, both of which are common among psychiatric patients. High levels may be genetic or the result of weight gain, hypercortisolemia, diabetes, or immune or inflammatory processes. Similarly, low levels may be genetic or secondary to statin therapy.

The bottom line: As psychiatric physicians, we should protect both the hearts and brains of our patients.

Ms. C, age 45, has a history of generalized anxiety disorder, which has been controlled for the past 6 weeks with extended-release (ER) venlafaxine, 37.5 mg/d. Previous medication trials included fluvoxamine, 300 mg/d, for 2 weeks; paroxetine, 20 mg/d, for 1 week; sertraline, 100 mg/d, for 1 week; and citalopram, 20 mg/d, for 2 weeks. For each trial, Ms. C was unable to tolerate standard doses because of substantial adverse effects; she complained that her anxiety would significantly worsen with each course of treatment. Although the adverse effects would eventually subside with continued treatment, they appeared to be the dose-limiting factor for treatment, even when much lower doses were started.

Ms. C’s son recently suggested that she undergo pharmacogenomics testing, and she brings in the results of this test­ing. The report states that Ms. C has cytochrome P450 (CYP) pharmacogenotypes CYP2D6 *5/*9, CYP2C19 *2/*3, CYP2C9 *2/*2, and CYP1A2 *1A/*1F. Ms. C wants to know if these results explain some of the issues she has had with previous medication trials, and if these results mean that she should be taking a different medication.

The human genome project was a vast, international effort to sequence the entire human genome¹ and identify individual differences in drug response, which serves as the basis for pharmacogenomics. Since completion of the human genome project in the early 2000s, the field of pharmaco­genomics has advanced, and using pharmacogenomic testing to make therapeutic decisions for medication management is becoming commonplace.² Although this critical change to how medicine is practiced is exciting, implementation of pharmacogenomics into practice has been varied.² Therefore, having an understanding of the resources available to guide pharmacogenomics into practice is critical, because the FDA now lists >160 medications that include specific pharmacogenomics information within their package insert.³

CPIC provides guidance for implementing pharmacogenomics

In 2000, the National Institutes of Health established the Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network (PGRN). These 2 resources provide information from cutting-edge research on genomic variation and therapeutic and adverse events, as well as practical implementation of this research.⁴ As part of their partnership, PharmGKB and PGRN established the Clinical Pharmacogenomics Implementation Consortium (CPIC), which has begun to provide clinical practice guidelines for implementing pharmacogenomic results. Although CPIC does not advocate for pharmacogenomics testing as a standard, it recognizes that this testing is becoming more commonplace, and therefore its guidelines can help clinicians make rational prescribing decisions.⁴

In a recent partnership among several PGRN members, investigators found that 1 out of 4 pharmacogenomic test results had a potential clinically actionable outcome.² There are currently >43 gene/drug pairs for which CPIC has provided guidelines; however, >200 other gene/drug pairs are being evaluated.⁵

Table 1⁵ lists the current CPIC gene/drug combinations with accompanying published guidelines that are pertinent to psychiatry. For each of these guidelines, experts reviewed the available literature to provide graded therapeutic recommendations: A (“preponderance of evidence is high or moderate in favor of changing prescribing”), B (“preponderance of evidence is weak with little conflicting data”), and C and D (“evidence levels can vary”).⁴ Looking at the specific genotypes for Ms. C, we can use the information within the CPIC to assign a drug metabolism phenotype for her genotype combinations (Table 2).⁶

Consider additional resources

In addition to those from the CPIC, guidelines have been developed by other scientific groups, such as the Dutch Pharmacogenetics Working Group and the European Pharmacogenomics Implementation Consortium. Although most of these guidelines are concordant with CPIC, differences exist, which makes it important to be aware of all available resources.

As well as working on the CPIC guidelines, PGRN investigators also provide numerous free online educational resources related to the principles behind pharmacogenomics, including additional resources necessary for systematic implementation. Examples include tables that outline all possible diplotypes (genotypes) for genes in the guidelines and how these are related to the metabolic phenotypes.^2,4 Drug metabolizing phenotypes, for example, often are described as poor, intermediate, extensive, and ultra-rapid; in this system, metabolizing ability labeled as poor is less-than-average, and ultra-rapid describes greater-than-average ability. The extensive phenotype is considered average. The data files on the CPIC Web site also can be used as resources to “double check” interpretation results for the diplo­type phenotype combinations currently available from various pharmacogenomics companies.⁷

Based on Ms. C’s presentation, as well as information from the CPIC guidelines, we expect that she might experience substantial adverse effects from most selective serotonin reuptake inhibitors and tricycle antidepressants because of her intermediate metabolizer status for CYP2D6 and poor metabolizer status for CYP2C19. The CPIC’s recommendation for using paroxetine and fluvoxamine in patients with a CYP2D6 intermediate metabolism phenotype is to initiate the recommend starting dose, but acknowledge that reduced metabolic capacity through CYP2D6 may result in higher blood levels and greater probability of adverse drug reactions. For a patient with the CYP2C19 poor metabolizer phenotype, the recommendation is to reduce the starting dose of citalopram or sertraline by 50%, or to prescribe a drug that is not metabolized by CYP2C19.⁸ Therefore, this pharmacogenomic information may help us understand why Ms. C is unable to tolerate these medications.

Although the CPIC guidelines do not address venlafaxine, the PharmGKB Web site contains literature supporting CYP2D6 as important in venlafaxine metabolism. Current recommendations from the Dutch Pharmacogenetics Working Group Guidelines⁹ are to either use a non–CYP2D6 metabolized medication or to adjust the dose to clinical response. Because Ms. C has been taking venlafaxine ER for the last 6 weeks and is taking a relatively low but effective dose, our recommendation is to continue current therapy.

It is also important to consider drug interactions when interpreting pharmacogenomic test results. In Ms. C’s case, the impact of a CYP2D6 intermediate metabolism phenotype would be increased if she also was taking a strong CYP2D6 inhibitor such as bupropion. Pharmacogenomics is another clinical tool and discontinuation of an effective treatment that is adequately tolerated should not be done based on pharmaco­genomics recommendations alone.

Ms. C, age 45, has a history of generalized anxiety disorder, which has been controlled for the past 6 weeks with extended-release (ER) venlafaxine, 37.5 mg/d. Previous medication trials included fluvoxamine, 300 mg/d, for 2 weeks; paroxetine, 20 mg/d, for 1 week; sertraline, 100 mg/d, for 1 week; and citalopram, 20 mg/d, for 2 weeks. For each trial, Ms. C was unable to tolerate standard doses because of substantial adverse effects; she complained that her anxiety would significantly worsen with each course of treatment. Although the adverse effects would eventually subside with continued treatment, they appeared to be the dose-limiting factor for treatment, even when much lower doses were started.

Ms. C’s son recently suggested that she undergo pharmacogenomics testing, and she brings in the results of this test­ing. The report states that Ms. C has cytochrome P450 (CYP) pharmacogenotypes CYP2D6 *5/*9, CYP2C19 *2/*3, CYP2C9 *2/*2, and CYP1A2 *1A/*1F. Ms. C wants to know if these results explain some of the issues she has had with previous medication trials, and if these results mean that she should be taking a different medication.

The human genome project was a vast, international effort to sequence the entire human genome¹ and identify individual differences in drug response, which serves as the basis for pharmacogenomics. Since completion of the human genome project in the early 2000s, the field of pharmaco­genomics has advanced, and using pharmacogenomic testing to make therapeutic decisions for medication management is becoming commonplace.² Although this critical change to how medicine is practiced is exciting, implementation of pharmacogenomics into practice has been varied.² Therefore, having an understanding of the resources available to guide pharmacogenomics into practice is critical, because the FDA now lists >160 medications that include specific pharmacogenomics information within their package insert.³

CPIC provides guidance for implementing pharmacogenomics

In 2000, the National Institutes of Health established the Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network (PGRN). These 2 resources provide information from cutting-edge research on genomic variation and therapeutic and adverse events, as well as practical implementation of this research.⁴ As part of their partnership, PharmGKB and PGRN established the Clinical Pharmacogenomics Implementation Consortium (CPIC), which has begun to provide clinical practice guidelines for implementing pharmacogenomic results. Although CPIC does not advocate for pharmacogenomics testing as a standard, it recognizes that this testing is becoming more commonplace, and therefore its guidelines can help clinicians make rational prescribing decisions.⁴

In a recent partnership among several PGRN members, investigators found that 1 out of 4 pharmacogenomic test results had a potential clinically actionable outcome.² There are currently >43 gene/drug pairs for which CPIC has provided guidelines; however, >200 other gene/drug pairs are being evaluated.⁵

Table 1⁵ lists the current CPIC gene/drug combinations with accompanying published guidelines that are pertinent to psychiatry. For each of these guidelines, experts reviewed the available literature to provide graded therapeutic recommendations: A (“preponderance of evidence is high or moderate in favor of changing prescribing”), B (“preponderance of evidence is weak with little conflicting data”), and C and D (“evidence levels can vary”).⁴ Looking at the specific genotypes for Ms. C, we can use the information within the CPIC to assign a drug metabolism phenotype for her genotype combinations (Table 2).⁶

Consider additional resources

In addition to those from the CPIC, guidelines have been developed by other scientific groups, such as the Dutch Pharmacogenetics Working Group and the European Pharmacogenomics Implementation Consortium. Although most of these guidelines are concordant with CPIC, differences exist, which makes it important to be aware of all available resources.

As well as working on the CPIC guidelines, PGRN investigators also provide numerous free online educational resources related to the principles behind pharmacogenomics, including additional resources necessary for systematic implementation. Examples include tables that outline all possible diplotypes (genotypes) for genes in the guidelines and how these are related to the metabolic phenotypes.^2,4 Drug metabolizing phenotypes, for example, often are described as poor, intermediate, extensive, and ultra-rapid; in this system, metabolizing ability labeled as poor is less-than-average, and ultra-rapid describes greater-than-average ability. The extensive phenotype is considered average. The data files on the CPIC Web site also can be used as resources to “double check” interpretation results for the diplo­type phenotype combinations currently available from various pharmacogenomics companies.⁷

Based on Ms. C’s presentation, as well as information from the CPIC guidelines, we expect that she might experience substantial adverse effects from most selective serotonin reuptake inhibitors and tricycle antidepressants because of her intermediate metabolizer status for CYP2D6 and poor metabolizer status for CYP2C19. The CPIC’s recommendation for using paroxetine and fluvoxamine in patients with a CYP2D6 intermediate metabolism phenotype is to initiate the recommend starting dose, but acknowledge that reduced metabolic capacity through CYP2D6 may result in higher blood levels and greater probability of adverse drug reactions. For a patient with the CYP2C19 poor metabolizer phenotype, the recommendation is to reduce the starting dose of citalopram or sertraline by 50%, or to prescribe a drug that is not metabolized by CYP2C19.⁸ Therefore, this pharmacogenomic information may help us understand why Ms. C is unable to tolerate these medications.

Although the CPIC guidelines do not address venlafaxine, the PharmGKB Web site contains literature supporting CYP2D6 as important in venlafaxine metabolism. Current recommendations from the Dutch Pharmacogenetics Working Group Guidelines⁹ are to either use a non–CYP2D6 metabolized medication or to adjust the dose to clinical response. Because Ms. C has been taking venlafaxine ER for the last 6 weeks and is taking a relatively low but effective dose, our recommendation is to continue current therapy.

It is also important to consider drug interactions when interpreting pharmacogenomic test results. In Ms. C’s case, the impact of a CYP2D6 intermediate metabolism phenotype would be increased if she also was taking a strong CYP2D6 inhibitor such as bupropion. Pharmacogenomics is another clinical tool and discontinuation of an effective treatment that is adequately tolerated should not be done based on pharmaco­genomics recommendations alone.

Ms. C, age 45, has a history of generalized anxiety disorder, which has been controlled for the past 6 weeks with extended-release (ER) venlafaxine, 37.5 mg/d. Previous medication trials included fluvoxamine, 300 mg/d, for 2 weeks; paroxetine, 20 mg/d, for 1 week; sertraline, 100 mg/d, for 1 week; and citalopram, 20 mg/d, for 2 weeks. For each trial, Ms. C was unable to tolerate standard doses because of substantial adverse effects; she complained that her anxiety would significantly worsen with each course of treatment. Although the adverse effects would eventually subside with continued treatment, they appeared to be the dose-limiting factor for treatment, even when much lower doses were started.

Ms. C’s son recently suggested that she undergo pharmacogenomics testing, and she brings in the results of this test­ing. The report states that Ms. C has cytochrome P450 (CYP) pharmacogenotypes CYP2D6 *5/*9, CYP2C19 *2/*3, CYP2C9 *2/*2, and CYP1A2 *1A/*1F. Ms. C wants to know if these results explain some of the issues she has had with previous medication trials, and if these results mean that she should be taking a different medication.

The human genome project was a vast, international effort to sequence the entire human genome¹ and identify individual differences in drug response, which serves as the basis for pharmacogenomics. Since completion of the human genome project in the early 2000s, the field of pharmaco­genomics has advanced, and using pharmacogenomic testing to make therapeutic decisions for medication management is becoming commonplace.² Although this critical change to how medicine is practiced is exciting, implementation of pharmacogenomics into practice has been varied.² Therefore, having an understanding of the resources available to guide pharmacogenomics into practice is critical, because the FDA now lists >160 medications that include specific pharmacogenomics information within their package insert.³

CPIC provides guidance for implementing pharmacogenomics

In 2000, the National Institutes of Health established the Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network (PGRN). These 2 resources provide information from cutting-edge research on genomic variation and therapeutic and adverse events, as well as practical implementation of this research.⁴ As part of their partnership, PharmGKB and PGRN established the Clinical Pharmacogenomics Implementation Consortium (CPIC), which has begun to provide clinical practice guidelines for implementing pharmacogenomic results. Although CPIC does not advocate for pharmacogenomics testing as a standard, it recognizes that this testing is becoming more commonplace, and therefore its guidelines can help clinicians make rational prescribing decisions.⁴

In a recent partnership among several PGRN members, investigators found that 1 out of 4 pharmacogenomic test results had a potential clinically actionable outcome.² There are currently >43 gene/drug pairs for which CPIC has provided guidelines; however, >200 other gene/drug pairs are being evaluated.⁵

Table 1⁵ lists the current CPIC gene/drug combinations with accompanying published guidelines that are pertinent to psychiatry. For each of these guidelines, experts reviewed the available literature to provide graded therapeutic recommendations: A (“preponderance of evidence is high or moderate in favor of changing prescribing”), B (“preponderance of evidence is weak with little conflicting data”), and C and D (“evidence levels can vary”).⁴ Looking at the specific genotypes for Ms. C, we can use the information within the CPIC to assign a drug metabolism phenotype for her genotype combinations (Table 2).⁶

Consider additional resources

In addition to those from the CPIC, guidelines have been developed by other scientific groups, such as the Dutch Pharmacogenetics Working Group and the European Pharmacogenomics Implementation Consortium. Although most of these guidelines are concordant with CPIC, differences exist, which makes it important to be aware of all available resources.

As well as working on the CPIC guidelines, PGRN investigators also provide numerous free online educational resources related to the principles behind pharmacogenomics, including additional resources necessary for systematic implementation. Examples include tables that outline all possible diplotypes (genotypes) for genes in the guidelines and how these are related to the metabolic phenotypes.^2,4 Drug metabolizing phenotypes, for example, often are described as poor, intermediate, extensive, and ultra-rapid; in this system, metabolizing ability labeled as poor is less-than-average, and ultra-rapid describes greater-than-average ability. The extensive phenotype is considered average. The data files on the CPIC Web site also can be used as resources to “double check” interpretation results for the diplo­type phenotype combinations currently available from various pharmacogenomics companies.⁷

Based on Ms. C’s presentation, as well as information from the CPIC guidelines, we expect that she might experience substantial adverse effects from most selective serotonin reuptake inhibitors and tricycle antidepressants because of her intermediate metabolizer status for CYP2D6 and poor metabolizer status for CYP2C19. The CPIC’s recommendation for using paroxetine and fluvoxamine in patients with a CYP2D6 intermediate metabolism phenotype is to initiate the recommend starting dose, but acknowledge that reduced metabolic capacity through CYP2D6 may result in higher blood levels and greater probability of adverse drug reactions. For a patient with the CYP2C19 poor metabolizer phenotype, the recommendation is to reduce the starting dose of citalopram or sertraline by 50%, or to prescribe a drug that is not metabolized by CYP2C19.⁸ Therefore, this pharmacogenomic information may help us understand why Ms. C is unable to tolerate these medications.

Although the CPIC guidelines do not address venlafaxine, the PharmGKB Web site contains literature supporting CYP2D6 as important in venlafaxine metabolism. Current recommendations from the Dutch Pharmacogenetics Working Group Guidelines⁹ are to either use a non–CYP2D6 metabolized medication or to adjust the dose to clinical response. Because Ms. C has been taking venlafaxine ER for the last 6 weeks and is taking a relatively low but effective dose, our recommendation is to continue current therapy.

It is also important to consider drug interactions when interpreting pharmacogenomic test results. In Ms. C’s case, the impact of a CYP2D6 intermediate metabolism phenotype would be increased if she also was taking a strong CYP2D6 inhibitor such as bupropion. Pharmacogenomics is another clinical tool and discontinuation of an effective treatment that is adequately tolerated should not be done based on pharmaco­genomics recommendations alone.

Editor’s note: Career Choices is a new feature of Residents’ Voices. It features a psychiatry resident/fellow interviewing a psychiatrist about why he (she) has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths. Future installments will feature interviews with psychiatrists who have focused their careers on consultation-liaison psychiatry, academic psychiatry, rural psychiatry, and other career paths.

In this first Career Choices, Cornel Stanciu, MD, talked with Samantha Gnanasegaram, MD, a state hospital psychiatrist at New Hampshire Hospital, where she treats severe and chronic mental illness and testifies in various court proceedings.

Dr. Stanciu: What made you choose to become a state hospital psychiatrist?

Dr. Gnanasegaram: When I started thinking about career options after residency, I knew I wanted to start my career in a facility where I could be challenged, remain up-to-date with the most current evidence-based literature, and have the support and mentorship of seasoned psychiatrists in the field. The opportunity to work under the auspices of a great academic institution with the “bread and butter” of psychiatry reminds me every day why I chose the field in the first place. The often chronic and sometimes refractory cases I encounter daily are extremely thought-provoking, and they motivate me to think and pursue more complex management options. [This setting] also enables me to work closely as [part of] an interdisciplinary team with nursing, social work, and recreational and occupational therapy in ensuring these individuals get the best care and aftercare plans.

We often forget that psychosis often takes weeks to respond [to treatment]. Unfortunately, often in private hospitals, the longer stays that are necessary for patient care are not always possible, leading to premature psychotropic changes and discharge. In this setting, I am able to practice medicine based on what is best for the patient from an evidence-based standpoint. Additionally, being in the state system also allows me to learn first-hand and work closely with the legal system in this state and to testify in various settings to ensure my patients get the best possible care.

Dr. Stanciu: How did your career path prepare you to become a state hospital psychiatrist?

Dr. Gnanasegaram: During my residency, I had exposure to the affiliated state psychiatric hospital and spent some time on various units, each geared toward different patient populations. I also became very familiar with a wide range of psychotropics, ranging from first-line to second- and third-tier medications, as well as off-label. The ECT exposure as well as Crisis Prevention Institute training in how to deal with violent and aggressive individuals certainly added extra layers to my proficiency.

Dr. Stanciu: How would you describe a physician who is well-suited for such a setting?

Dr. Gnanasegaram: This setting is great for someone who likes to be challenged and stay current with literature. Furthermore, this is a great setting for those who are comfortable with the use of medications such as [clozapine] and long-acting injectables, and procedures such as ECT. Additionally, an ideal candidate is someone who understands the chronicity and complexity of mental illness, and has the patience to follow the course and does not rush to make drastic changes or panics at the first sign of a patient taking a step back.

A good candidate also should be comfortable with medical comorbidities, because severe mental illness often leads to poor self-care, diabetes, hypertension, etc., and should be able to work effectively in a team setting and interact with other specialties. State hospital physicians need to be cognizant of outpatient resources available to prevent decompensation in the community and not only focus on acute stabilization. Additionally, this is a great setting for those who enjoy working in an interdisciplinary team and learning from the expertise of different members of a treatment team.

Dr. Stanciu: What challenges and surprises did you encounter when you first began to practice in this setting?

Dr. Gnanasegaram: When I started, the biggest challenge was learning about the differences in practice and legislature in a different state, because all states vary in their involuntary commitment laws, process, and ability to institute forced medications. Learning this as well as how they apply to my practice occurred quicker than I anticipated. As I started practicing, I became more proficient in being able to incorporate the resources I have available.

Dr. Stanciu: What are the disadvantages compared with other branches of psychiatry?

Dr. Gnanasegaram: This is a subjective question. Some physicians may desire a rapid turnaround of patients, which is not always the case in state psychiatric hospitals. Even at discharge, some patients may have low-functioning baselines, requiring guardianship and/or placement in a more supervised setting to ensure they receive the care they need. It is also important to realize these are primarily not voluntary patients, but rather patients committed here involuntarily for treatment due to impaired insight and judgment. At times, the acuity can be high, but the potential for violence is mitigated through comprehensive risk assessments, staff training, and prevention strategies to help ensure patient and staff safety.

Dr. Stanciu: What advice do you have for early career psychiatrists and trainees who are contemplating a state hospital career?

Dr. Gnanasegaram: I would recommend seeking exposure to working in a state psychiatric hospital early in your training so you can see the daily routine and protocol. It would help to obtain mentorship from a state hospital psychiatrist in the state where you intend to work. Ask as many questions as needed and seek their insight into the challenges and benefits of working there. During training, it’s important to familiarize yourself with managing difficult and refractory cases, and don’t shy away from challenging patients. The next step would be to apply for a position of interest to interview and learn more about the facility and the staff that you will be working with.

Dr. Stanciu: How important is the academic affiliation?

Dr. Gnanasegaram: Very important. Especially during the early phase of your career, it is important to have at your fingertips senior mentors and to be involved in the conferences and CME activities offered. This ensures good quality measures in patient care. The academic affiliation helps keep you up-to-date with advancements and maintains an atmosphere that fosters ongoing learning and the best possible care for your patients. Working with trainees at various levels, such as medical students, residents, and fellows, allows you to maintain an evidence-based practice approach as well as share your knowledge and experience with those in training. Being in this academic setting, you also have the opportunity for involvement in research activities and publications.

Editor’s note: Career Choices is a new feature of Residents’ Voices. It features a psychiatry resident/fellow interviewing a psychiatrist about why he (she) has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths. Future installments will feature interviews with psychiatrists who have focused their careers on consultation-liaison psychiatry, academic psychiatry, rural psychiatry, and other career paths.

In this first Career Choices, Cornel Stanciu, MD, talked with Samantha Gnanasegaram, MD, a state hospital psychiatrist at New Hampshire Hospital, where she treats severe and chronic mental illness and testifies in various court proceedings.

Dr. Stanciu: What made you choose to become a state hospital psychiatrist?

Dr. Gnanasegaram: When I started thinking about career options after residency, I knew I wanted to start my career in a facility where I could be challenged, remain up-to-date with the most current evidence-based literature, and have the support and mentorship of seasoned psychiatrists in the field. The opportunity to work under the auspices of a great academic institution with the “bread and butter” of psychiatry reminds me every day why I chose the field in the first place. The often chronic and sometimes refractory cases I encounter daily are extremely thought-provoking, and they motivate me to think and pursue more complex management options. [This setting] also enables me to work closely as [part of] an interdisciplinary team with nursing, social work, and recreational and occupational therapy in ensuring these individuals get the best care and aftercare plans.

We often forget that psychosis often takes weeks to respond [to treatment]. Unfortunately, often in private hospitals, the longer stays that are necessary for patient care are not always possible, leading to premature psychotropic changes and discharge. In this setting, I am able to practice medicine based on what is best for the patient from an evidence-based standpoint. Additionally, being in the state system also allows me to learn first-hand and work closely with the legal system in this state and to testify in various settings to ensure my patients get the best possible care.

Dr. Stanciu: How did your career path prepare you to become a state hospital psychiatrist?

Dr. Gnanasegaram: During my residency, I had exposure to the affiliated state psychiatric hospital and spent some time on various units, each geared toward different patient populations. I also became very familiar with a wide range of psychotropics, ranging from first-line to second- and third-tier medications, as well as off-label. The ECT exposure as well as Crisis Prevention Institute training in how to deal with violent and aggressive individuals certainly added extra layers to my proficiency.

Dr. Stanciu: How would you describe a physician who is well-suited for such a setting?

Dr. Gnanasegaram: This setting is great for someone who likes to be challenged and stay current with literature. Furthermore, this is a great setting for those who are comfortable with the use of medications such as [clozapine] and long-acting injectables, and procedures such as ECT. Additionally, an ideal candidate is someone who understands the chronicity and complexity of mental illness, and has the patience to follow the course and does not rush to make drastic changes or panics at the first sign of a patient taking a step back.

A good candidate also should be comfortable with medical comorbidities, because severe mental illness often leads to poor self-care, diabetes, hypertension, etc., and should be able to work effectively in a team setting and interact with other specialties. State hospital physicians need to be cognizant of outpatient resources available to prevent decompensation in the community and not only focus on acute stabilization. Additionally, this is a great setting for those who enjoy working in an interdisciplinary team and learning from the expertise of different members of a treatment team.

Dr. Stanciu: What challenges and surprises did you encounter when you first began to practice in this setting?

Dr. Gnanasegaram: When I started, the biggest challenge was learning about the differences in practice and legislature in a different state, because all states vary in their involuntary commitment laws, process, and ability to institute forced medications. Learning this as well as how they apply to my practice occurred quicker than I anticipated. As I started practicing, I became more proficient in being able to incorporate the resources I have available.

Dr. Stanciu: What are the disadvantages compared with other branches of psychiatry?

Dr. Gnanasegaram: This is a subjective question. Some physicians may desire a rapid turnaround of patients, which is not always the case in state psychiatric hospitals. Even at discharge, some patients may have low-functioning baselines, requiring guardianship and/or placement in a more supervised setting to ensure they receive the care they need. It is also important to realize these are primarily not voluntary patients, but rather patients committed here involuntarily for treatment due to impaired insight and judgment. At times, the acuity can be high, but the potential for violence is mitigated through comprehensive risk assessments, staff training, and prevention strategies to help ensure patient and staff safety.

Dr. Stanciu: What advice do you have for early career psychiatrists and trainees who are contemplating a state hospital career?

Dr. Gnanasegaram: I would recommend seeking exposure to working in a state psychiatric hospital early in your training so you can see the daily routine and protocol. It would help to obtain mentorship from a state hospital psychiatrist in the state where you intend to work. Ask as many questions as needed and seek their insight into the challenges and benefits of working there. During training, it’s important to familiarize yourself with managing difficult and refractory cases, and don’t shy away from challenging patients. The next step would be to apply for a position of interest to interview and learn more about the facility and the staff that you will be working with.

Dr. Stanciu: How important is the academic affiliation?

Dr. Gnanasegaram: Very important. Especially during the early phase of your career, it is important to have at your fingertips senior mentors and to be involved in the conferences and CME activities offered. This ensures good quality measures in patient care. The academic affiliation helps keep you up-to-date with advancements and maintains an atmosphere that fosters ongoing learning and the best possible care for your patients. Working with trainees at various levels, such as medical students, residents, and fellows, allows you to maintain an evidence-based practice approach as well as share your knowledge and experience with those in training. Being in this academic setting, you also have the opportunity for involvement in research activities and publications.

Editor’s note: Career Choices is a new feature of Residents’ Voices. It features a psychiatry resident/fellow interviewing a psychiatrist about why he (she) has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths. Future installments will feature interviews with psychiatrists who have focused their careers on consultation-liaison psychiatry, academic psychiatry, rural psychiatry, and other career paths.

In this first Career Choices, Cornel Stanciu, MD, talked with Samantha Gnanasegaram, MD, a state hospital psychiatrist at New Hampshire Hospital, where she treats severe and chronic mental illness and testifies in various court proceedings.

Dr. Stanciu: What made you choose to become a state hospital psychiatrist?

Dr. Gnanasegaram: When I started thinking about career options after residency, I knew I wanted to start my career in a facility where I could be challenged, remain up-to-date with the most current evidence-based literature, and have the support and mentorship of seasoned psychiatrists in the field. The opportunity to work under the auspices of a great academic institution with the “bread and butter” of psychiatry reminds me every day why I chose the field in the first place. The often chronic and sometimes refractory cases I encounter daily are extremely thought-provoking, and they motivate me to think and pursue more complex management options. [This setting] also enables me to work closely as [part of] an interdisciplinary team with nursing, social work, and recreational and occupational therapy in ensuring these individuals get the best care and aftercare plans.

We often forget that psychosis often takes weeks to respond [to treatment]. Unfortunately, often in private hospitals, the longer stays that are necessary for patient care are not always possible, leading to premature psychotropic changes and discharge. In this setting, I am able to practice medicine based on what is best for the patient from an evidence-based standpoint. Additionally, being in the state system also allows me to learn first-hand and work closely with the legal system in this state and to testify in various settings to ensure my patients get the best possible care.

Dr. Stanciu: How did your career path prepare you to become a state hospital psychiatrist?

Dr. Gnanasegaram: During my residency, I had exposure to the affiliated state psychiatric hospital and spent some time on various units, each geared toward different patient populations. I also became very familiar with a wide range of psychotropics, ranging from first-line to second- and third-tier medications, as well as off-label. The ECT exposure as well as Crisis Prevention Institute training in how to deal with violent and aggressive individuals certainly added extra layers to my proficiency.

Dr. Stanciu: How would you describe a physician who is well-suited for such a setting?

Dr. Gnanasegaram: This setting is great for someone who likes to be challenged and stay current with literature. Furthermore, this is a great setting for those who are comfortable with the use of medications such as [clozapine] and long-acting injectables, and procedures such as ECT. Additionally, an ideal candidate is someone who understands the chronicity and complexity of mental illness, and has the patience to follow the course and does not rush to make drastic changes or panics at the first sign of a patient taking a step back.

A good candidate also should be comfortable with medical comorbidities, because severe mental illness often leads to poor self-care, diabetes, hypertension, etc., and should be able to work effectively in a team setting and interact with other specialties. State hospital physicians need to be cognizant of outpatient resources available to prevent decompensation in the community and not only focus on acute stabilization. Additionally, this is a great setting for those who enjoy working in an interdisciplinary team and learning from the expertise of different members of a treatment team.

Dr. Stanciu: What challenges and surprises did you encounter when you first began to practice in this setting?

Dr. Gnanasegaram: When I started, the biggest challenge was learning about the differences in practice and legislature in a different state, because all states vary in their involuntary commitment laws, process, and ability to institute forced medications. Learning this as well as how they apply to my practice occurred quicker than I anticipated. As I started practicing, I became more proficient in being able to incorporate the resources I have available.

Dr. Stanciu: What are the disadvantages compared with other branches of psychiatry?

Dr. Gnanasegaram: This is a subjective question. Some physicians may desire a rapid turnaround of patients, which is not always the case in state psychiatric hospitals. Even at discharge, some patients may have low-functioning baselines, requiring guardianship and/or placement in a more supervised setting to ensure they receive the care they need. It is also important to realize these are primarily not voluntary patients, but rather patients committed here involuntarily for treatment due to impaired insight and judgment. At times, the acuity can be high, but the potential for violence is mitigated through comprehensive risk assessments, staff training, and prevention strategies to help ensure patient and staff safety.

Dr. Stanciu: What advice do you have for early career psychiatrists and trainees who are contemplating a state hospital career?

Dr. Gnanasegaram: I would recommend seeking exposure to working in a state psychiatric hospital early in your training so you can see the daily routine and protocol. It would help to obtain mentorship from a state hospital psychiatrist in the state where you intend to work. Ask as many questions as needed and seek their insight into the challenges and benefits of working there. During training, it’s important to familiarize yourself with managing difficult and refractory cases, and don’t shy away from challenging patients. The next step would be to apply for a position of interest to interview and learn more about the facility and the staff that you will be working with.

Dr. Stanciu: How important is the academic affiliation?

Dr. Gnanasegaram: Very important. Especially during the early phase of your career, it is important to have at your fingertips senior mentors and to be involved in the conferences and CME activities offered. This ensures good quality measures in patient care. The academic affiliation helps keep you up-to-date with advancements and maintains an atmosphere that fosters ongoing learning and the best possible care for your patients. Working with trainees at various levels, such as medical students, residents, and fellows, allows you to maintain an evidence-based practice approach as well as share your knowledge and experience with those in training. Being in this academic setting, you also have the opportunity for involvement in research activities and publications.