It does not adequately inform psychiatric practitioners about the many clinical and biologic features shared across the various diagnostic categories. It does not do justice to the galloping advances in the neurobiology of psychiatric brain disorders and the wealth of potential biomarkers that will eventually endow psychiatry with an objective and ultimately more valid, not just reliable, diagnostic model that is compatible with a future of precision medicine.

The Research Domain Criteria (RDoC) Project¹ is a valiant attempt to transcend the DSM’s “Chinese menu” approach to diagnosis. It was championed by the former director of the National Institute of Mental Health (NIMH), who used his authority to encourage investigators applying for federal grants to employ the RDoC principles in their research programs. Who does not recall the awkward moment, a few weeks before the official baptism of DSM-5 as psychiatry’s latest diagnostic Bible in May 2013? The NIMH director’s unflattering portrayal of the incipient DSM-5 was a well-publicized shot across the bow. The kerfuffle was later resolved, but its effects linger among clinical researchers who relentlessly hope for neuroscience advances to translate into a more objective diagnostic approach to psychiatric diagnoses. The neurobiologic foundations of psychopathology are bound to guide us to a more valid set of diagnostic categories, yet the pace remains painfully slow.

However, the copious advances in brain research are providing other dividends beyond a better diagnostic forest. Many intriguing insights are emerging about the connectedness among major psychiatric “trees,” including schizophrenia, bipolar disorders, and major depressive disorder. The following are examples of neurobiologic, clinical, and treatment commonalities across those psychotic and mood disorders.

Shared neurobiology

Progressive brain tissue loss/neurodegeneration. Numerous studies have established that abnormal neuroplasticity is a common theme during psychotic, manic, and depressive episodes. These findings have demonstrated that the more recurrent the episodes, the more prominent the atrophy in either overall brain volume or specific brain regions, especially in the hippocampus, prefrontal cortex, and cerebellum as measured on MRI.

White matter pathology. Multiple studies have reported loss of myelin integrity in psychotic and mood disorders. Abnormalities are detected by using diffusion tensor imaging and measuring anisotropy and diffusivity of water flow in white matter traits. White matter pathology can be associated with intra- and inter-hemispheric disconnectivity and impairment of brain functional integration that may contribute to positive, negative, and cognitive symptoms.

Neuroinflammation. Acute psychotic and mood episodes have been shown to be associated with significant elevation in inflammatory cytokines in CSF and serum, including interleukins (such as interleukin-6), tumor necrosis factor-alpha, interferon gamma, and C-reactive protein. Those inflammatory biomarkers subside when the acute episodes are treated. It is believed that activation of the microglia leads to release of proinflammatory cytokines.

Mitochondrial dysfunction. Many studies document various dysfunctions of the mitochondria in schizophrenia, bipolar disorders, and major depressive disorder. The consequences include oxidative stress due to a decrease in the antioxidant glutathione, produced in the mitochondria, which is vital for neutralizing the reactive oxygen and nitrogen species referred to as free radicals. There is a substantial increase of free radicals during acute psychotic and mood episodes, which contributes to neurodegeneration.

Glutamate pathway abnormalities. A large body of literature has focused on the glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction as a key pathophysiology in schizo­phrenia and mood disorders. Interestingly, the NMDAR appears to be hypo­active in schizophrenia as evidenced by the schizophrenia-like effects of potent NMDAR antagonism by phencyclidine and hyperactive in unipolar and bipolar depression as evidenced by the remarkably rapid improvement of treatment-resistant depression with the NMDAR antagonists ketamine or nitrous oxide. Glutamate pathways may ultimately shed light on the neurochemical pathology underpinning psychotic and mood disorders. The NMDAR is also likely linked to both neuroplasticity and cognitive impairments in the major psychiatric disorders because both are related to calcium passing through the NMDAR ion channel.

Gene/environment interaction. Neurogenetic advances have demonstrated some shared genes among schizophrenia, bipolar disorders, and major depressive disorder (such as the CACNA1C gene).² Also, environmental factors, such as severe childhood maltreatment, lead to high rates of psychosis and mood disorders in adulthood. Risk genes in schizophrenia and mood disorders are likely to be over­expressed with adverse environmental factors and epigenetics.

Shortened telomeres. Patients with psychotic and mood disorders have been reported to have shorter telomeres—proteins that cap the end of chromosomes and shorten with repeated cycles of mitosis and aging—at a younger age, predicting early senescence and mortality. Telomere shortening is associated with multiple factors, including chronic stress, smoking, poor diet, obesity, infections, inflammation, and free radicals, all shared by major psychiatric disorders.

Genetic heterogeneity. Schizophrenia, bipolar disorders, and major depressive disorder are associated with complex genetics (eg, risk genes, mutations, and copy number variants) and various perinatal complications (eg, infections, gestational diabetes, vitamin D deficiency, hypoxia at delivery), which makes them highly heterogeneous syndromes, comprised of hundreds of biotypes. There are many established endophenotypes that a future diagnostic system should adopt.

Elevated cortisol levels. Increased serum cortisol levels are found in depression and schizophrenia related to HPA axis dysregulation as well as life stress. Hypercortisolemia can contribute to neurodegeneration as well as to multiple systemic medical disorders often encountered in mood and psychotic disorders.

Shared clinical features

Psychotic and mood disorders share several key clinical features, including:

• cognitive deficits
• substance use disorders (especially Cannabis and alcohol) as a common comorbidity
• increased suicide risk
• high prevalence of smoking
• premature mortality, by 10 to 20 years
• anxiety as a common comorbidity
• elevated cardiometabolic risk factors, even before pharmacotherapy
• recurrent relapses lead to treatment resistance
• various degrees of fixed false beliefs (delusions)
• perceptional aberrations (various types of hallucinations)
• response to dopamine-serotonin an­­tagonists (atypical antipsychotics) as monotherapy or adjunctive therapy.

While it is fair to say that a diagnostic manual like DSM-5 should focus on the diagnosis of individual psychiatric diseases and syndromes, it is also reasonable to say that focusing primarily on clinical features does not do justice to the biologic complexities of psychiatric disorders and the importance of including biomarkers to increase the validity of psychopathological categories. The shared neurobiologic and clinical features across major psychiatric syndromes, such as schizophrenia, bipolar disorders, and depression, indicate how multifaceted psychiatric diagnosis can be. The same approach is applicable to other psychiatric syndromes, such as anxiety, personality disorders, attention-deficit/hyperactivity disorder, or dementia. Our field should move firmly and steadily toward a diagnostic schema that incorporates ongoing breakthroughs in psychiatric neuroscience as soon as they are replicated.

If psychopathology is a forest, then DSM-5 is a simplistic depiction of each tree’s structure as roots, a trunk, branches, and leaves. Psychiatry needs to move to a far more sophisticated perspective of each tree as an amazingly complex, dynamic, and evolving organism, designed genetically but continuously influenced by its environment. Psychiatry also should keep an eye on the entire forest and detect distinctive patterns as well as idiosyncratic or shared features among the trees. Major insights will ensue about the etiology, course, and management of each diagnostic tree or the mosaic of related trees.

It does not adequately inform psychiatric practitioners about the many clinical and biologic features shared across the various diagnostic categories. It does not do justice to the galloping advances in the neurobiology of psychiatric brain disorders and the wealth of potential biomarkers that will eventually endow psychiatry with an objective and ultimately more valid, not just reliable, diagnostic model that is compatible with a future of precision medicine.

The Research Domain Criteria (RDoC) Project¹ is a valiant attempt to transcend the DSM’s “Chinese menu” approach to diagnosis. It was championed by the former director of the National Institute of Mental Health (NIMH), who used his authority to encourage investigators applying for federal grants to employ the RDoC principles in their research programs. Who does not recall the awkward moment, a few weeks before the official baptism of DSM-5 as psychiatry’s latest diagnostic Bible in May 2013? The NIMH director’s unflattering portrayal of the incipient DSM-5 was a well-publicized shot across the bow. The kerfuffle was later resolved, but its effects linger among clinical researchers who relentlessly hope for neuroscience advances to translate into a more objective diagnostic approach to psychiatric diagnoses. The neurobiologic foundations of psychopathology are bound to guide us to a more valid set of diagnostic categories, yet the pace remains painfully slow.

However, the copious advances in brain research are providing other dividends beyond a better diagnostic forest. Many intriguing insights are emerging about the connectedness among major psychiatric “trees,” including schizophrenia, bipolar disorders, and major depressive disorder. The following are examples of neurobiologic, clinical, and treatment commonalities across those psychotic and mood disorders.

Shared neurobiology

Progressive brain tissue loss/neurodegeneration. Numerous studies have established that abnormal neuroplasticity is a common theme during psychotic, manic, and depressive episodes. These findings have demonstrated that the more recurrent the episodes, the more prominent the atrophy in either overall brain volume or specific brain regions, especially in the hippocampus, prefrontal cortex, and cerebellum as measured on MRI.

White matter pathology. Multiple studies have reported loss of myelin integrity in psychotic and mood disorders. Abnormalities are detected by using diffusion tensor imaging and measuring anisotropy and diffusivity of water flow in white matter traits. White matter pathology can be associated with intra- and inter-hemispheric disconnectivity and impairment of brain functional integration that may contribute to positive, negative, and cognitive symptoms.

Neuroinflammation. Acute psychotic and mood episodes have been shown to be associated with significant elevation in inflammatory cytokines in CSF and serum, including interleukins (such as interleukin-6), tumor necrosis factor-alpha, interferon gamma, and C-reactive protein. Those inflammatory biomarkers subside when the acute episodes are treated. It is believed that activation of the microglia leads to release of proinflammatory cytokines.

Mitochondrial dysfunction. Many studies document various dysfunctions of the mitochondria in schizophrenia, bipolar disorders, and major depressive disorder. The consequences include oxidative stress due to a decrease in the antioxidant glutathione, produced in the mitochondria, which is vital for neutralizing the reactive oxygen and nitrogen species referred to as free radicals. There is a substantial increase of free radicals during acute psychotic and mood episodes, which contributes to neurodegeneration.

Glutamate pathway abnormalities. A large body of literature has focused on the glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction as a key pathophysiology in schizo­phrenia and mood disorders. Interestingly, the NMDAR appears to be hypo­active in schizophrenia as evidenced by the schizophrenia-like effects of potent NMDAR antagonism by phencyclidine and hyperactive in unipolar and bipolar depression as evidenced by the remarkably rapid improvement of treatment-resistant depression with the NMDAR antagonists ketamine or nitrous oxide. Glutamate pathways may ultimately shed light on the neurochemical pathology underpinning psychotic and mood disorders. The NMDAR is also likely linked to both neuroplasticity and cognitive impairments in the major psychiatric disorders because both are related to calcium passing through the NMDAR ion channel.

Gene/environment interaction. Neurogenetic advances have demonstrated some shared genes among schizophrenia, bipolar disorders, and major depressive disorder (such as the CACNA1C gene).² Also, environmental factors, such as severe childhood maltreatment, lead to high rates of psychosis and mood disorders in adulthood. Risk genes in schizophrenia and mood disorders are likely to be over­expressed with adverse environmental factors and epigenetics.

Shortened telomeres. Patients with psychotic and mood disorders have been reported to have shorter telomeres—proteins that cap the end of chromosomes and shorten with repeated cycles of mitosis and aging—at a younger age, predicting early senescence and mortality. Telomere shortening is associated with multiple factors, including chronic stress, smoking, poor diet, obesity, infections, inflammation, and free radicals, all shared by major psychiatric disorders.

Genetic heterogeneity. Schizophrenia, bipolar disorders, and major depressive disorder are associated with complex genetics (eg, risk genes, mutations, and copy number variants) and various perinatal complications (eg, infections, gestational diabetes, vitamin D deficiency, hypoxia at delivery), which makes them highly heterogeneous syndromes, comprised of hundreds of biotypes. There are many established endophenotypes that a future diagnostic system should adopt.

Elevated cortisol levels. Increased serum cortisol levels are found in depression and schizophrenia related to HPA axis dysregulation as well as life stress. Hypercortisolemia can contribute to neurodegeneration as well as to multiple systemic medical disorders often encountered in mood and psychotic disorders.

Shared clinical features

Psychotic and mood disorders share several key clinical features, including:

• cognitive deficits
• substance use disorders (especially Cannabis and alcohol) as a common comorbidity
• increased suicide risk
• high prevalence of smoking
• premature mortality, by 10 to 20 years
• anxiety as a common comorbidity
• elevated cardiometabolic risk factors, even before pharmacotherapy
• recurrent relapses lead to treatment resistance
• various degrees of fixed false beliefs (delusions)
• perceptional aberrations (various types of hallucinations)
• response to dopamine-serotonin an­­tagonists (atypical antipsychotics) as monotherapy or adjunctive therapy.

While it is fair to say that a diagnostic manual like DSM-5 should focus on the diagnosis of individual psychiatric diseases and syndromes, it is also reasonable to say that focusing primarily on clinical features does not do justice to the biologic complexities of psychiatric disorders and the importance of including biomarkers to increase the validity of psychopathological categories. The shared neurobiologic and clinical features across major psychiatric syndromes, such as schizophrenia, bipolar disorders, and depression, indicate how multifaceted psychiatric diagnosis can be. The same approach is applicable to other psychiatric syndromes, such as anxiety, personality disorders, attention-deficit/hyperactivity disorder, or dementia. Our field should move firmly and steadily toward a diagnostic schema that incorporates ongoing breakthroughs in psychiatric neuroscience as soon as they are replicated.

If psychopathology is a forest, then DSM-5 is a simplistic depiction of each tree’s structure as roots, a trunk, branches, and leaves. Psychiatry needs to move to a far more sophisticated perspective of each tree as an amazingly complex, dynamic, and evolving organism, designed genetically but continuously influenced by its environment. Psychiatry also should keep an eye on the entire forest and detect distinctive patterns as well as idiosyncratic or shared features among the trees. Major insights will ensue about the etiology, course, and management of each diagnostic tree or the mosaic of related trees.

It does not adequately inform psychiatric practitioners about the many clinical and biologic features shared across the various diagnostic categories. It does not do justice to the galloping advances in the neurobiology of psychiatric brain disorders and the wealth of potential biomarkers that will eventually endow psychiatry with an objective and ultimately more valid, not just reliable, diagnostic model that is compatible with a future of precision medicine.

The Research Domain Criteria (RDoC) Project¹ is a valiant attempt to transcend the DSM’s “Chinese menu” approach to diagnosis. It was championed by the former director of the National Institute of Mental Health (NIMH), who used his authority to encourage investigators applying for federal grants to employ the RDoC principles in their research programs. Who does not recall the awkward moment, a few weeks before the official baptism of DSM-5 as psychiatry’s latest diagnostic Bible in May 2013? The NIMH director’s unflattering portrayal of the incipient DSM-5 was a well-publicized shot across the bow. The kerfuffle was later resolved, but its effects linger among clinical researchers who relentlessly hope for neuroscience advances to translate into a more objective diagnostic approach to psychiatric diagnoses. The neurobiologic foundations of psychopathology are bound to guide us to a more valid set of diagnostic categories, yet the pace remains painfully slow.

However, the copious advances in brain research are providing other dividends beyond a better diagnostic forest. Many intriguing insights are emerging about the connectedness among major psychiatric “trees,” including schizophrenia, bipolar disorders, and major depressive disorder. The following are examples of neurobiologic, clinical, and treatment commonalities across those psychotic and mood disorders.

Shared neurobiology

Progressive brain tissue loss/neurodegeneration. Numerous studies have established that abnormal neuroplasticity is a common theme during psychotic, manic, and depressive episodes. These findings have demonstrated that the more recurrent the episodes, the more prominent the atrophy in either overall brain volume or specific brain regions, especially in the hippocampus, prefrontal cortex, and cerebellum as measured on MRI.

White matter pathology. Multiple studies have reported loss of myelin integrity in psychotic and mood disorders. Abnormalities are detected by using diffusion tensor imaging and measuring anisotropy and diffusivity of water flow in white matter traits. White matter pathology can be associated with intra- and inter-hemispheric disconnectivity and impairment of brain functional integration that may contribute to positive, negative, and cognitive symptoms.

Neuroinflammation. Acute psychotic and mood episodes have been shown to be associated with significant elevation in inflammatory cytokines in CSF and serum, including interleukins (such as interleukin-6), tumor necrosis factor-alpha, interferon gamma, and C-reactive protein. Those inflammatory biomarkers subside when the acute episodes are treated. It is believed that activation of the microglia leads to release of proinflammatory cytokines.

Mitochondrial dysfunction. Many studies document various dysfunctions of the mitochondria in schizophrenia, bipolar disorders, and major depressive disorder. The consequences include oxidative stress due to a decrease in the antioxidant glutathione, produced in the mitochondria, which is vital for neutralizing the reactive oxygen and nitrogen species referred to as free radicals. There is a substantial increase of free radicals during acute psychotic and mood episodes, which contributes to neurodegeneration.

Glutamate pathway abnormalities. A large body of literature has focused on the glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction as a key pathophysiology in schizo­phrenia and mood disorders. Interestingly, the NMDAR appears to be hypo­active in schizophrenia as evidenced by the schizophrenia-like effects of potent NMDAR antagonism by phencyclidine and hyperactive in unipolar and bipolar depression as evidenced by the remarkably rapid improvement of treatment-resistant depression with the NMDAR antagonists ketamine or nitrous oxide. Glutamate pathways may ultimately shed light on the neurochemical pathology underpinning psychotic and mood disorders. The NMDAR is also likely linked to both neuroplasticity and cognitive impairments in the major psychiatric disorders because both are related to calcium passing through the NMDAR ion channel.

Gene/environment interaction. Neurogenetic advances have demonstrated some shared genes among schizophrenia, bipolar disorders, and major depressive disorder (such as the CACNA1C gene).² Also, environmental factors, such as severe childhood maltreatment, lead to high rates of psychosis and mood disorders in adulthood. Risk genes in schizophrenia and mood disorders are likely to be over­expressed with adverse environmental factors and epigenetics.

Shortened telomeres. Patients with psychotic and mood disorders have been reported to have shorter telomeres—proteins that cap the end of chromosomes and shorten with repeated cycles of mitosis and aging—at a younger age, predicting early senescence and mortality. Telomere shortening is associated with multiple factors, including chronic stress, smoking, poor diet, obesity, infections, inflammation, and free radicals, all shared by major psychiatric disorders.

Genetic heterogeneity. Schizophrenia, bipolar disorders, and major depressive disorder are associated with complex genetics (eg, risk genes, mutations, and copy number variants) and various perinatal complications (eg, infections, gestational diabetes, vitamin D deficiency, hypoxia at delivery), which makes them highly heterogeneous syndromes, comprised of hundreds of biotypes. There are many established endophenotypes that a future diagnostic system should adopt.

Elevated cortisol levels. Increased serum cortisol levels are found in depression and schizophrenia related to HPA axis dysregulation as well as life stress. Hypercortisolemia can contribute to neurodegeneration as well as to multiple systemic medical disorders often encountered in mood and psychotic disorders.

Shared clinical features

Psychotic and mood disorders share several key clinical features, including:

• cognitive deficits
• substance use disorders (especially Cannabis and alcohol) as a common comorbidity
• increased suicide risk
• high prevalence of smoking
• premature mortality, by 10 to 20 years
• anxiety as a common comorbidity
• elevated cardiometabolic risk factors, even before pharmacotherapy
• recurrent relapses lead to treatment resistance
• various degrees of fixed false beliefs (delusions)
• perceptional aberrations (various types of hallucinations)
• response to dopamine-serotonin an­­tagonists (atypical antipsychotics) as monotherapy or adjunctive therapy.

While it is fair to say that a diagnostic manual like DSM-5 should focus on the diagnosis of individual psychiatric diseases and syndromes, it is also reasonable to say that focusing primarily on clinical features does not do justice to the biologic complexities of psychiatric disorders and the importance of including biomarkers to increase the validity of psychopathological categories. The shared neurobiologic and clinical features across major psychiatric syndromes, such as schizophrenia, bipolar disorders, and depression, indicate how multifaceted psychiatric diagnosis can be. The same approach is applicable to other psychiatric syndromes, such as anxiety, personality disorders, attention-deficit/hyperactivity disorder, or dementia. Our field should move firmly and steadily toward a diagnostic schema that incorporates ongoing breakthroughs in psychiatric neuroscience as soon as they are replicated.

If psychopathology is a forest, then DSM-5 is a simplistic depiction of each tree’s structure as roots, a trunk, branches, and leaves. Psychiatry needs to move to a far more sophisticated perspective of each tree as an amazingly complex, dynamic, and evolving organism, designed genetically but continuously influenced by its environment. Psychiatry also should keep an eye on the entire forest and detect distinctive patterns as well as idiosyncratic or shared features among the trees. Major insights will ensue about the etiology, course, and management of each diagnostic tree or the mosaic of related trees.

Compared with first-generation antipsychotics, second-generation antipsychotics (SGAs) have a lower risk for extrapyramidal symptoms. Yet tardive dyskinesia (TD) remains a concern because of the widespread use of SGAs for multiple indications.¹ Prior to April 2017, clinicians had no FDA-approved TD treatment options. The most widely used agent worldwide, tetrabenazine, had positive efficacy data in TD trials over the past 45 years but was not available in the United States until 2008, and its sole indication was for chorea associated with Huntington’s disease.² Moreover, the use of tetrabenazine involved slow titration, multiple daily dosing, cytochrome P450 (CYP) 2D6 genotyping for doses >50 mg/d, and tolerability issues.

Tetrabenazine is an inhibitor of vesicular monoamine transport type 2 (VMAT2), a transport protein located almost exclusively in the CNS whose role is to place monoamine neurotransmitters (dopamine, serotonin, norepinephrine) into presynaptic vesicles. By decreasing dopamine transport into these presynaptic vesicles, synaptic dopamine release is lessened, thus reducing postsynaptic dopamine D2 receptor activity and the severity of dyskinetic movements.¹

In 2 pivotal 12-week clinical trials, deutetrabenazine significantly reduced TD severity as measured by Abnormal Involuntary Movement Scale (AIMS) scores (see Efficacy).^6,7

Clinical implications

TD remains a substantial public health concern due to the increasing use of antipsychotics for mood and other disorders beyond the initial indications for schizophrenia.¹ Although exposure to dopamine D2antagonism results in postsynaptic receptor upregulation and supersensitivity that underlies the development of dyskinesia, this process is often rapidly reversible in animal models.¹ The persistence of TD symptoms in up to 80% of patients after dopamine receptor blocking agents (DRBAs) are stopped has led to hypotheses that the underlying pathophysiology of TD is also a problem with neuroplasticity. Aside from DRBA exposure, environmental factors (eg, oxidative stress) and genetic predisposition might contribute to TD risk.¹

Before 2017, only 1 medication (branched-chain amino acids) had been FDA-approved for treating TD in the United States, and only a few existing medications (clonazepam, amantadine, and ginkgo biloba extract [EGb-761]) had positive results from controlled trials, most with small effect sizes.⁸ Moreover, there was only 1 controlled trial each for clonazepam and EGb-761.¹ A branched-chain amino acid preparation received FDA approval for managing TD in male patients, but is no longer commercially available, except from compounding pharmacies.⁹

Tetrabenazine was developed in the mid-1950s to avoid orthostasis and sedation associated with reserpine.¹⁰ Both reserpine and tetrabenazine proved effective for TD,¹¹ but tetrabenazine lacked reserpine’s peripheral adverse effects. However, the kinetics of tetrabenazine necessitated multiple daily doses, and CYP2D6 genotyping was required for doses >50 mg/d.²

Receptor blocking. The mechanism that distinguishes the clinical profiles of reserpine and tetrabenazine relates to their differential properties at VMAT.¹² VMAT exists in 2 forms (VMAT1 and VMAT2) that vary in distribution, with VMAT1 expressed mainly in the peripheral nervous system and VMAT2 expressed mainly in monoaminergic cells of the CNS.¹³ Tetrabenazine is a specific and reversible VMAT2 inhibitor, whereas reserpine is an irreversible and nonselective antagonist of VMAT1 and VMAT2. It is reserpine’s VMAT1 inhibition that results in peripheral adverse effects such as orthostasis. Tetrabenazine is rapidly and extensively converted into 2 isomers, alpha-dihydrotetrabenazine (α-DHTBZ) and beta-dihydrotetrabenazine (β-DHTBZ), both of which are metabolized by CYP2D6, with a role for CYP3A4 in α-DHTBZ metabolism.¹ These DHTBZ metabolites have a short half-life when generated from oral tetrabenazine, a feature that necessitates multiple daily dosing; moreover, the existence of 2D6 polymorphisms led to FDA-mandated CYP2D6 genotyping for tetrabenazine doses >50 mg/d when it was approved for Huntington’s chorea. The concern is that 2D6 poor metabolizers will have excessive exposure to the VMAT2 effects of DHTBZ, resulting in sedation, akathisia, parkinsonism, and mood symptoms.²

How deuterium impacts medication kinetics. Deuterium is a naturally occurring, stable, nontoxic isotope of hydrogen. Humans have 5 g of deuterium in their body at any time, mostly in the form of heavy water (D₂O).¹⁴ When deuterium is used to replace selected hydrogen atoms, the resulting molecule will have similar configuration and receptor-binding properties but markedly different kinetics. Because the carbon–deuterium covalent bond requires 8 times more energy to break than a carbon–hydrogen bond, the half-life is prolonged.¹⁵ Utilizing this knowledge, a deuterated form of tetrabenazine, deutetrabenazine, was synthesized with such a purpose in mind. While the active metabolites of deutetrabenazine retain the VMAT2 affinity of non-deuterated tetrabenazine, the substitution of deuterium for hydrogen at specific positions slows the breakdown of metabolites, resulting in sustained duration of action, greater active drug exposure, and less impact of 2D6 genotype on drug exposure, thus eliminating the need for genotyping, unless one wants to exceed 36 mg/d.

Deutetrabenazine was first studied in Huntington’s chorea in a 13-week, double-blind, placebo-controlled, parallel-group study (N = 90).⁴ The maximum daily deutetrabenazine dose was 48 mg, but reduced to 36 mg in those taking strong CYP2D6 inhibitors (bupropion, fluoxetine, or paroxetine). Blinded 2D6 genotyping was performed, but there was no dose modification required based on 2D6 genotype. There was a 36.4% reduction in total maximal chorea score for deutetrabenazine compared with 14.4% for placebo (P < .001).⁴ Importantly, adverse effects were comparable between both groups, with 1 drop-out in the deutetrabenazine arm vs 2 in the placebo arm. The only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo was somnolence: 11.1% for deutetrabenazine vs 4.4% for placebo.⁴ The mean deutetrabenazine daily dose at the end of the treatment period was 39.7 ± 9.3 mg, and for those with impaired CYP2D6 function (poor metabolizers or those taking strong CYP2D6 inhibiting medications), the mean daily dose was 34.8 mg ± 3.8 mg.⁴

Use in tardive dyskinesia. The recommended starting dosage for TD treatment is 6 mg, twice daily with food. The dose may be increased at weekly intervals in increments of 6 mg/d to a maximum recommended daily dosage of 48 mg.⁵ The maximum daily dose is 36 mg (18 mg, twice daily) in patients receiving strong CYP2D6 inhibitors or who are 2D6 poor metabolizers.⁵

Deutetrabenazine has not been studied in those with moderate or severe hepatic impairment, and its use is contraindicated in these patients.⁵ No clinical studies have been conducted to assess the effect of renal impairment on the pharmacokinetics of deutetrabenazine.⁵

Pharmacologic profile, adverse reactions

When the data from the two 12-week, phase 3 placebo-controlled studies were pooled, the most common adverse reactions occurring in >3% of deutetrabenazine patients and greater than placebo were nasopharyngeal symptoms (4% vs 2% placebo) and insomnia (4% vs 1% placebo).⁵ Importantly, in neither TD study were there clinically significant changes in rating scales for depression, suicidal ideation and behavior, or parkinsonism. There also were no clinically significant changes in measures of schizophrenia symptoms. The mean QT prolongation for a single 24 mg dose of deutetrabenazine in healthy volunteers was 4.5 milliseconds, with the upper bound of the double-sided 90% confidence interval reaching 6.5 milliseconds.⁵ For tetrabenazine, single 50 mg doses administered to volunteers resulted in mean QT prolongation of 8 milliseconds.⁵ In patients requiring deutetrabenazine doses >24 mg/d who are taking other medications known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications that are known to prolong QTc.⁵

How it works

Tetrabenazine is the only agent that has demonstrated significant efficacy for TD management, but its use involves slow titration, multiple daily dosing, CYP2D6 genotyping for doses >50 mg/d, and tolerability issues. For example, the most common adverse effects in the pivotal tetrabenazine Huntington’s disease trial were sedation/somnolence (tetrabenazine 31% vs 3% for placebo), insomnia (tetrabenazine 22% vs 0% for placebo), depression (tetrabenazine 19% vs 0% for placebo), fatigue (tetrabenazine 22% vs 13% for placebo), and akathisia (tetrabenazine 19% vs 0% for placebo).² For comparison, the only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo in the pivotal Huntington’s disease trial was somnolence (11.1% for deutetrabenazine vs 4.4% for placebo).⁴

Pharmacokinetics

Deutetrabenazine has 80% oral bioavailability, and is rapidly converted to its active metabolites after oral dosing (Table 2).⁵ Linear dose dependence of Cmax and area under the curve (AUC) was observed for the active metabolites following single or multiple doses of deutetrabenazine (6 to 24 mg and 7.5 to 22.5 mg, twice daily).¹⁵ Cmax of deuterated α-DHTBZ and β-DHTBZ is reached within 3 to 4 hours after dosing, with a steady state ratio of 3:1 for the α-DHTBZ vs the β-DHTBZ form. Food had no effect on AUC, but did increase Cmax by 50%.⁵

Deutetrabenazine is metabolized through carbonyl reductase enzymes to its active metabolites, and these are further metabolized through multiple CYP pathways, predominantly 2D6 and to a lesser extent 3A4. The effect of CYP2D6 inhibition on the pharma­cokinetics of deutetrabenazine and its α-DHTBZ and β-DHTBZ metabolites was studied in 24 healthy participants following a single 22.5 mg dose of deutetrabenazine given after 8 days of administration of the strong CYP2D6 inhibitor paroxetine, 20 mg/d. In the presence of paroxetine, systemic exposure (AUC) of α-DHTBZ was 1.9-fold higher and β-DHTBZ was 6.5-fold higher, resulting in an approximately 3-fold increase in AUC for total (α+β)-DHTBZ, with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively.⁵ Neither deutetrabenazine or its metabolites are inhibitors or inducers of major CYP enzymes. Aside from VMAT2, the results of in vitro studies suggest that deutetrabenazine and its active metabolites are unlikely to inhibit most major drug transporters at clinically relevant concentrations.

Efficacy

Efficacy was established in two 12-week, double-blind, placebo-controlled trials of adult patients with TD (ages 18 to 80).^6,7 Eligible participants had:

• TD diagnosis for ≥3 months before screening and a history of DRBA treatment for ≥3 months (≥1 month if age ≥60)
• Total AIMS motor score ≥6 (items 1 to 7) at both screening and baseline, verified by a blinded central rater at screening via central video rating
• Patients with an underlying psychiatric illness had to be stable. Psychoactive medication use, including antipsychotics, was allowed if stable for ≥30 days before screening (antidepressants, ≥45 days).

Exclusion criteria included treatment with tetrabenazine, reserpine, α-methyl-p-tyrosine, strong anticholinergic medications, dopamine antagonizing antiemetics (eg, metoclopramide, prochlorperazine, promethazine), dopamine agonists, levodopa, stimulants, or a monoamine oxidase inhibitor (MAOI) within 30 days of screening or baseline, or treatment with botulinum toxin within 3 months of screening; and presence of a neurologic condition that could confound TD assessments, serious untreated or undertreated psychiatric illness, or unstable medical illness. Patients with a history of or active suicidal ideation or behavior within 6 months of screening or score ≥11 on the depression subscale of the Hospital Anxiety and Depression Scale were excluded. Those participants with Fridericia-corrected QT interval values >450 milliseconds in men, >460 milliseconds in women, or >480 milli­seconds in patients with a right bundle branch block on electrocardiography at screening also were excluded.

The flexible-dose TD study was performed in 117 participants randomized in a 1:1 manner to deutetrabenazine or placebo, both administered twice daily, titrated to optimal dosage (12 to 48 mg/d) over 6 weeks, and then administered at that dose for another 6 weeks.⁷ The population demographics were: mean age, 54.6 ± 10.3 years, 52.1% female, 69.2% white, and 80.3% receiving ongoing dopamine antagonists, with a mean TD duration of 74.7 ± 81.5 months. Sixty-eight percent had schizophrenia spectrum disorders, and 30% had mood disorders. The primary outcome was change in total AIMS score (items 1 to 7) assessed by central, independent raters. The mean baseline AIMS score for items 1 to 7 was 9.6 ± 3.9, with 82.9% of participants with baseline AIMS scores ≥6. Study treatment retention was high: placebo 88.1%, deutetrabenazine 89.7%.⁷ There was a mean 3 point decrease in AIMS score for deutetrabenazine compared with 1.4 for placebo (P = .019). Among those with baseline AIMS scores ≥6, there was a 3.4 point decrease in AIMS scores for deutetrabenazine compared with a 1.9 point decrease for placebo (P = .027). The only adverse effects that occurred in ≥5% of deutetrabenazine participants and at a rate ≥2 times the rate in placebo were insomnia (deutetra­benazine 6.9% vs placebo 1.7%) and akathisia (deutetrabenazine 5.2% vs placebo 0%).

The fixed-dose TD study was performed in 293 participants randomized in 1:1:1:1 manner to 1 of 3 fixed doses of deutetrabenazine (12 mg/d, 24 mg/d, or 36 mg/d) or placebo, both administered twice daily.⁶ The starting dose of deutetrabenazine was 6 mg twice daily. During the dose escalation period (through Week 4), the dose of study drug was increased weekly in increments of 6 mg/d until the randomized dose was achieved. Patients continued to receive the dose they were assigned to over a maintenance period of 8 weeks.⁶ The population demographics were: mean age, 56.4 ± 11.3 years, 55% female, 79% white, 76% receiving ongoing dopamine antagonists, with a mean TD duration of 67.2 ± 66 months. Sixty percent had schizophrenia spectrum disorders, and 36% had mood disorders. The primary outcome was change in AIMS total score (items 1 to 7) assessed by central, independent raters. The mean AIMS score at baseline was 9.5 ± 2.7 in the placebo group, and for deutetrabenazine: 9.6 ± 2.4 in the 12 mg/d group, 9.4 ± 2.9 in the 24 mg/d group, and 10.1 ± 3.2 in the 36 mg/d group. The 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). Study treatment retention rates were high: placebo 90.5%, deutetrabenazine 88%. Across all doses, only 1 adverse effect occurred in ≥5% of deutetrabenazine participants: headache (5% deutetrabenazine vs 6% placebo). At the highest dose, 36 mg/d, the only adverse effects that occurred in ≥5% of participants were diarrhea (7% deutetrabenazine vs 3% placebo) and headache (7% deutetrabenazine vs 6% placebo).

Outcome. In the flexible-dose study (mean dose 38.8 ± 7.92 mg/d), the deutetrabenazine arm experienced a mean 30% reduction in AIMS scores from baseline at the Week 12 endpoint. Compared with placebo, the mean reduction in AIMS scores (standard error) was: −3.0 (0.45) deutetrabenazine vs −1.6 (0.46) placebo (P = .019).⁷ For the fixed-dose study, the 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). In addition to these mean changes from baseline, 35% of the 24 mg/d group and 33% of the 36 mg/d group demonstrated ≥50% reduction in AIMS scores.⁶

Tolerability

In the 2 phase 3 trials, there were no adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo.⁵ Discontinuations because of adverse events were low in both pivotal studies across all treatment groups: 3.4% for placebo vs 1.7% for deutetrabenazine in the flexible-dose trial,⁷ and 3% for placebo vs 4% for deutetrabenazine in the fixed-dose study.⁶ In neither trial were there clinically significant changes in ratings of depression, suicidality, parkinsonism, or schizophrenia symptoms. The mean QT prolongation in healthy volunteers is described above.

Clinical considerations

Unique properties. Deutetrabenazine utilizes the greater bond strength of the carbon–deuterium bond to slow CYP metabolism, resulting in prolonged duration of action that is well tolerated, and provides significant efficacy.

Why Rx? The reasons to prescribe deutetrabenazine for TD patients include:

• only 1 of 2 agents with FDA approval for TD
• fewer tolerability issues than with tetrabenazine
• lower sedation rates in TD trials than with valbenazine
• no signal for effects on mood para­meters or rates of parkinsonism when used for TD.

Dosing

The recommended starting dosage of deutetrabenazine is 6 mg twice daily taken with food, increasing by 6 mg/d weekly as needed, with a maximum dose of 48 mg/d or 36 mg/d in those taking strong CYP2D6 inhibitors or who are 2D6 poor metabolizers. Deutetrabenazine is contraindicated in patients with hepatic impairment (as determined by Child-Pugh criteria¹⁶). There are no data in patients with renal impairment. The combined efficacy and tolerability of dosages >48 mg/d has not been evaluated. Overdoses of tetrabenazine ranging from 100 to 1,000 mg have been reported in the literature and were associated with acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.⁵

Contraindications

When used for TD, deutetrabenazine is contraindicated for patients taking reserpine, tetrabenazine, valbenazine, or MAOIs, and for patients with hepatic impairment. As with most medications, there are no data on deutetrabenazine use in pregnant women; however, oral administration of deutetrabenazine (5, 10, or 30 mg/kg/d) or tetrabenazine (30 mg/kg/d) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/d on a body surface area (mg/m²) basis. There are no data on the presence of deutetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

Compared with first-generation antipsychotics, second-generation antipsychotics (SGAs) have a lower risk for extrapyramidal symptoms. Yet tardive dyskinesia (TD) remains a concern because of the widespread use of SGAs for multiple indications.¹ Prior to April 2017, clinicians had no FDA-approved TD treatment options. The most widely used agent worldwide, tetrabenazine, had positive efficacy data in TD trials over the past 45 years but was not available in the United States until 2008, and its sole indication was for chorea associated with Huntington’s disease.² Moreover, the use of tetrabenazine involved slow titration, multiple daily dosing, cytochrome P450 (CYP) 2D6 genotyping for doses >50 mg/d, and tolerability issues.

Tetrabenazine is an inhibitor of vesicular monoamine transport type 2 (VMAT2), a transport protein located almost exclusively in the CNS whose role is to place monoamine neurotransmitters (dopamine, serotonin, norepinephrine) into presynaptic vesicles. By decreasing dopamine transport into these presynaptic vesicles, synaptic dopamine release is lessened, thus reducing postsynaptic dopamine D2 receptor activity and the severity of dyskinetic movements.¹

In 2 pivotal 12-week clinical trials, deutetrabenazine significantly reduced TD severity as measured by Abnormal Involuntary Movement Scale (AIMS) scores (see Efficacy).^6,7

Clinical implications

TD remains a substantial public health concern due to the increasing use of antipsychotics for mood and other disorders beyond the initial indications for schizophrenia.¹ Although exposure to dopamine D2antagonism results in postsynaptic receptor upregulation and supersensitivity that underlies the development of dyskinesia, this process is often rapidly reversible in animal models.¹ The persistence of TD symptoms in up to 80% of patients after dopamine receptor blocking agents (DRBAs) are stopped has led to hypotheses that the underlying pathophysiology of TD is also a problem with neuroplasticity. Aside from DRBA exposure, environmental factors (eg, oxidative stress) and genetic predisposition might contribute to TD risk.¹

Before 2017, only 1 medication (branched-chain amino acids) had been FDA-approved for treating TD in the United States, and only a few existing medications (clonazepam, amantadine, and ginkgo biloba extract [EGb-761]) had positive results from controlled trials, most with small effect sizes.⁸ Moreover, there was only 1 controlled trial each for clonazepam and EGb-761.¹ A branched-chain amino acid preparation received FDA approval for managing TD in male patients, but is no longer commercially available, except from compounding pharmacies.⁹

Tetrabenazine was developed in the mid-1950s to avoid orthostasis and sedation associated with reserpine.¹⁰ Both reserpine and tetrabenazine proved effective for TD,¹¹ but tetrabenazine lacked reserpine’s peripheral adverse effects. However, the kinetics of tetrabenazine necessitated multiple daily doses, and CYP2D6 genotyping was required for doses >50 mg/d.²

Receptor blocking. The mechanism that distinguishes the clinical profiles of reserpine and tetrabenazine relates to their differential properties at VMAT.¹² VMAT exists in 2 forms (VMAT1 and VMAT2) that vary in distribution, with VMAT1 expressed mainly in the peripheral nervous system and VMAT2 expressed mainly in monoaminergic cells of the CNS.¹³ Tetrabenazine is a specific and reversible VMAT2 inhibitor, whereas reserpine is an irreversible and nonselective antagonist of VMAT1 and VMAT2. It is reserpine’s VMAT1 inhibition that results in peripheral adverse effects such as orthostasis. Tetrabenazine is rapidly and extensively converted into 2 isomers, alpha-dihydrotetrabenazine (α-DHTBZ) and beta-dihydrotetrabenazine (β-DHTBZ), both of which are metabolized by CYP2D6, with a role for CYP3A4 in α-DHTBZ metabolism.¹ These DHTBZ metabolites have a short half-life when generated from oral tetrabenazine, a feature that necessitates multiple daily dosing; moreover, the existence of 2D6 polymorphisms led to FDA-mandated CYP2D6 genotyping for tetrabenazine doses >50 mg/d when it was approved for Huntington’s chorea. The concern is that 2D6 poor metabolizers will have excessive exposure to the VMAT2 effects of DHTBZ, resulting in sedation, akathisia, parkinsonism, and mood symptoms.²

How deuterium impacts medication kinetics. Deuterium is a naturally occurring, stable, nontoxic isotope of hydrogen. Humans have 5 g of deuterium in their body at any time, mostly in the form of heavy water (D₂O).¹⁴ When deuterium is used to replace selected hydrogen atoms, the resulting molecule will have similar configuration and receptor-binding properties but markedly different kinetics. Because the carbon–deuterium covalent bond requires 8 times more energy to break than a carbon–hydrogen bond, the half-life is prolonged.¹⁵ Utilizing this knowledge, a deuterated form of tetrabenazine, deutetrabenazine, was synthesized with such a purpose in mind. While the active metabolites of deutetrabenazine retain the VMAT2 affinity of non-deuterated tetrabenazine, the substitution of deuterium for hydrogen at specific positions slows the breakdown of metabolites, resulting in sustained duration of action, greater active drug exposure, and less impact of 2D6 genotype on drug exposure, thus eliminating the need for genotyping, unless one wants to exceed 36 mg/d.

Deutetrabenazine was first studied in Huntington’s chorea in a 13-week, double-blind, placebo-controlled, parallel-group study (N = 90).⁴ The maximum daily deutetrabenazine dose was 48 mg, but reduced to 36 mg in those taking strong CYP2D6 inhibitors (bupropion, fluoxetine, or paroxetine). Blinded 2D6 genotyping was performed, but there was no dose modification required based on 2D6 genotype. There was a 36.4% reduction in total maximal chorea score for deutetrabenazine compared with 14.4% for placebo (P < .001).⁴ Importantly, adverse effects were comparable between both groups, with 1 drop-out in the deutetrabenazine arm vs 2 in the placebo arm. The only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo was somnolence: 11.1% for deutetrabenazine vs 4.4% for placebo.⁴ The mean deutetrabenazine daily dose at the end of the treatment period was 39.7 ± 9.3 mg, and for those with impaired CYP2D6 function (poor metabolizers or those taking strong CYP2D6 inhibiting medications), the mean daily dose was 34.8 mg ± 3.8 mg.⁴

Use in tardive dyskinesia. The recommended starting dosage for TD treatment is 6 mg, twice daily with food. The dose may be increased at weekly intervals in increments of 6 mg/d to a maximum recommended daily dosage of 48 mg.⁵ The maximum daily dose is 36 mg (18 mg, twice daily) in patients receiving strong CYP2D6 inhibitors or who are 2D6 poor metabolizers.⁵

Deutetrabenazine has not been studied in those with moderate or severe hepatic impairment, and its use is contraindicated in these patients.⁵ No clinical studies have been conducted to assess the effect of renal impairment on the pharmacokinetics of deutetrabenazine.⁵

Pharmacologic profile, adverse reactions

When the data from the two 12-week, phase 3 placebo-controlled studies were pooled, the most common adverse reactions occurring in >3% of deutetrabenazine patients and greater than placebo were nasopharyngeal symptoms (4% vs 2% placebo) and insomnia (4% vs 1% placebo).⁵ Importantly, in neither TD study were there clinically significant changes in rating scales for depression, suicidal ideation and behavior, or parkinsonism. There also were no clinically significant changes in measures of schizophrenia symptoms. The mean QT prolongation for a single 24 mg dose of deutetrabenazine in healthy volunteers was 4.5 milliseconds, with the upper bound of the double-sided 90% confidence interval reaching 6.5 milliseconds.⁵ For tetrabenazine, single 50 mg doses administered to volunteers resulted in mean QT prolongation of 8 milliseconds.⁵ In patients requiring deutetrabenazine doses >24 mg/d who are taking other medications known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications that are known to prolong QTc.⁵

How it works

Tetrabenazine is the only agent that has demonstrated significant efficacy for TD management, but its use involves slow titration, multiple daily dosing, CYP2D6 genotyping for doses >50 mg/d, and tolerability issues. For example, the most common adverse effects in the pivotal tetrabenazine Huntington’s disease trial were sedation/somnolence (tetrabenazine 31% vs 3% for placebo), insomnia (tetrabenazine 22% vs 0% for placebo), depression (tetrabenazine 19% vs 0% for placebo), fatigue (tetrabenazine 22% vs 13% for placebo), and akathisia (tetrabenazine 19% vs 0% for placebo).² For comparison, the only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo in the pivotal Huntington’s disease trial was somnolence (11.1% for deutetrabenazine vs 4.4% for placebo).⁴

Pharmacokinetics

Deutetrabenazine has 80% oral bioavailability, and is rapidly converted to its active metabolites after oral dosing (Table 2).⁵ Linear dose dependence of Cmax and area under the curve (AUC) was observed for the active metabolites following single or multiple doses of deutetrabenazine (6 to 24 mg and 7.5 to 22.5 mg, twice daily).¹⁵ Cmax of deuterated α-DHTBZ and β-DHTBZ is reached within 3 to 4 hours after dosing, with a steady state ratio of 3:1 for the α-DHTBZ vs the β-DHTBZ form. Food had no effect on AUC, but did increase Cmax by 50%.⁵

Deutetrabenazine is metabolized through carbonyl reductase enzymes to its active metabolites, and these are further metabolized through multiple CYP pathways, predominantly 2D6 and to a lesser extent 3A4. The effect of CYP2D6 inhibition on the pharma­cokinetics of deutetrabenazine and its α-DHTBZ and β-DHTBZ metabolites was studied in 24 healthy participants following a single 22.5 mg dose of deutetrabenazine given after 8 days of administration of the strong CYP2D6 inhibitor paroxetine, 20 mg/d. In the presence of paroxetine, systemic exposure (AUC) of α-DHTBZ was 1.9-fold higher and β-DHTBZ was 6.5-fold higher, resulting in an approximately 3-fold increase in AUC for total (α+β)-DHTBZ, with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively.⁵ Neither deutetrabenazine or its metabolites are inhibitors or inducers of major CYP enzymes. Aside from VMAT2, the results of in vitro studies suggest that deutetrabenazine and its active metabolites are unlikely to inhibit most major drug transporters at clinically relevant concentrations.

Efficacy

Efficacy was established in two 12-week, double-blind, placebo-controlled trials of adult patients with TD (ages 18 to 80).^6,7 Eligible participants had:

• TD diagnosis for ≥3 months before screening and a history of DRBA treatment for ≥3 months (≥1 month if age ≥60)
• Total AIMS motor score ≥6 (items 1 to 7) at both screening and baseline, verified by a blinded central rater at screening via central video rating
• Patients with an underlying psychiatric illness had to be stable. Psychoactive medication use, including antipsychotics, was allowed if stable for ≥30 days before screening (antidepressants, ≥45 days).

Exclusion criteria included treatment with tetrabenazine, reserpine, α-methyl-p-tyrosine, strong anticholinergic medications, dopamine antagonizing antiemetics (eg, metoclopramide, prochlorperazine, promethazine), dopamine agonists, levodopa, stimulants, or a monoamine oxidase inhibitor (MAOI) within 30 days of screening or baseline, or treatment with botulinum toxin within 3 months of screening; and presence of a neurologic condition that could confound TD assessments, serious untreated or undertreated psychiatric illness, or unstable medical illness. Patients with a history of or active suicidal ideation or behavior within 6 months of screening or score ≥11 on the depression subscale of the Hospital Anxiety and Depression Scale were excluded. Those participants with Fridericia-corrected QT interval values >450 milliseconds in men, >460 milliseconds in women, or >480 milli­seconds in patients with a right bundle branch block on electrocardiography at screening also were excluded.

The flexible-dose TD study was performed in 117 participants randomized in a 1:1 manner to deutetrabenazine or placebo, both administered twice daily, titrated to optimal dosage (12 to 48 mg/d) over 6 weeks, and then administered at that dose for another 6 weeks.⁷ The population demographics were: mean age, 54.6 ± 10.3 years, 52.1% female, 69.2% white, and 80.3% receiving ongoing dopamine antagonists, with a mean TD duration of 74.7 ± 81.5 months. Sixty-eight percent had schizophrenia spectrum disorders, and 30% had mood disorders. The primary outcome was change in total AIMS score (items 1 to 7) assessed by central, independent raters. The mean baseline AIMS score for items 1 to 7 was 9.6 ± 3.9, with 82.9% of participants with baseline AIMS scores ≥6. Study treatment retention was high: placebo 88.1%, deutetrabenazine 89.7%.⁷ There was a mean 3 point decrease in AIMS score for deutetrabenazine compared with 1.4 for placebo (P = .019). Among those with baseline AIMS scores ≥6, there was a 3.4 point decrease in AIMS scores for deutetrabenazine compared with a 1.9 point decrease for placebo (P = .027). The only adverse effects that occurred in ≥5% of deutetrabenazine participants and at a rate ≥2 times the rate in placebo were insomnia (deutetra­benazine 6.9% vs placebo 1.7%) and akathisia (deutetrabenazine 5.2% vs placebo 0%).

The fixed-dose TD study was performed in 293 participants randomized in 1:1:1:1 manner to 1 of 3 fixed doses of deutetrabenazine (12 mg/d, 24 mg/d, or 36 mg/d) or placebo, both administered twice daily.⁶ The starting dose of deutetrabenazine was 6 mg twice daily. During the dose escalation period (through Week 4), the dose of study drug was increased weekly in increments of 6 mg/d until the randomized dose was achieved. Patients continued to receive the dose they were assigned to over a maintenance period of 8 weeks.⁶ The population demographics were: mean age, 56.4 ± 11.3 years, 55% female, 79% white, 76% receiving ongoing dopamine antagonists, with a mean TD duration of 67.2 ± 66 months. Sixty percent had schizophrenia spectrum disorders, and 36% had mood disorders. The primary outcome was change in AIMS total score (items 1 to 7) assessed by central, independent raters. The mean AIMS score at baseline was 9.5 ± 2.7 in the placebo group, and for deutetrabenazine: 9.6 ± 2.4 in the 12 mg/d group, 9.4 ± 2.9 in the 24 mg/d group, and 10.1 ± 3.2 in the 36 mg/d group. The 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). Study treatment retention rates were high: placebo 90.5%, deutetrabenazine 88%. Across all doses, only 1 adverse effect occurred in ≥5% of deutetrabenazine participants: headache (5% deutetrabenazine vs 6% placebo). At the highest dose, 36 mg/d, the only adverse effects that occurred in ≥5% of participants were diarrhea (7% deutetrabenazine vs 3% placebo) and headache (7% deutetrabenazine vs 6% placebo).

Outcome. In the flexible-dose study (mean dose 38.8 ± 7.92 mg/d), the deutetrabenazine arm experienced a mean 30% reduction in AIMS scores from baseline at the Week 12 endpoint. Compared with placebo, the mean reduction in AIMS scores (standard error) was: −3.0 (0.45) deutetrabenazine vs −1.6 (0.46) placebo (P = .019).⁷ For the fixed-dose study, the 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). In addition to these mean changes from baseline, 35% of the 24 mg/d group and 33% of the 36 mg/d group demonstrated ≥50% reduction in AIMS scores.⁶

Tolerability

In the 2 phase 3 trials, there were no adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo.⁵ Discontinuations because of adverse events were low in both pivotal studies across all treatment groups: 3.4% for placebo vs 1.7% for deutetrabenazine in the flexible-dose trial,⁷ and 3% for placebo vs 4% for deutetrabenazine in the fixed-dose study.⁶ In neither trial were there clinically significant changes in ratings of depression, suicidality, parkinsonism, or schizophrenia symptoms. The mean QT prolongation in healthy volunteers is described above.

Clinical considerations

Unique properties. Deutetrabenazine utilizes the greater bond strength of the carbon–deuterium bond to slow CYP metabolism, resulting in prolonged duration of action that is well tolerated, and provides significant efficacy.

Why Rx? The reasons to prescribe deutetrabenazine for TD patients include:

• only 1 of 2 agents with FDA approval for TD
• fewer tolerability issues than with tetrabenazine
• lower sedation rates in TD trials than with valbenazine
• no signal for effects on mood para­meters or rates of parkinsonism when used for TD.

Dosing

The recommended starting dosage of deutetrabenazine is 6 mg twice daily taken with food, increasing by 6 mg/d weekly as needed, with a maximum dose of 48 mg/d or 36 mg/d in those taking strong CYP2D6 inhibitors or who are 2D6 poor metabolizers. Deutetrabenazine is contraindicated in patients with hepatic impairment (as determined by Child-Pugh criteria¹⁶). There are no data in patients with renal impairment. The combined efficacy and tolerability of dosages >48 mg/d has not been evaluated. Overdoses of tetrabenazine ranging from 100 to 1,000 mg have been reported in the literature and were associated with acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.⁵

Contraindications

When used for TD, deutetrabenazine is contraindicated for patients taking reserpine, tetrabenazine, valbenazine, or MAOIs, and for patients with hepatic impairment. As with most medications, there are no data on deutetrabenazine use in pregnant women; however, oral administration of deutetrabenazine (5, 10, or 30 mg/kg/d) or tetrabenazine (30 mg/kg/d) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/d on a body surface area (mg/m²) basis. There are no data on the presence of deutetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

Compared with first-generation antipsychotics, second-generation antipsychotics (SGAs) have a lower risk for extrapyramidal symptoms. Yet tardive dyskinesia (TD) remains a concern because of the widespread use of SGAs for multiple indications.¹ Prior to April 2017, clinicians had no FDA-approved TD treatment options. The most widely used agent worldwide, tetrabenazine, had positive efficacy data in TD trials over the past 45 years but was not available in the United States until 2008, and its sole indication was for chorea associated with Huntington’s disease.² Moreover, the use of tetrabenazine involved slow titration, multiple daily dosing, cytochrome P450 (CYP) 2D6 genotyping for doses >50 mg/d, and tolerability issues.

Tetrabenazine is an inhibitor of vesicular monoamine transport type 2 (VMAT2), a transport protein located almost exclusively in the CNS whose role is to place monoamine neurotransmitters (dopamine, serotonin, norepinephrine) into presynaptic vesicles. By decreasing dopamine transport into these presynaptic vesicles, synaptic dopamine release is lessened, thus reducing postsynaptic dopamine D2 receptor activity and the severity of dyskinetic movements.¹

In 2 pivotal 12-week clinical trials, deutetrabenazine significantly reduced TD severity as measured by Abnormal Involuntary Movement Scale (AIMS) scores (see Efficacy).^6,7

Clinical implications

TD remains a substantial public health concern due to the increasing use of antipsychotics for mood and other disorders beyond the initial indications for schizophrenia.¹ Although exposure to dopamine D2antagonism results in postsynaptic receptor upregulation and supersensitivity that underlies the development of dyskinesia, this process is often rapidly reversible in animal models.¹ The persistence of TD symptoms in up to 80% of patients after dopamine receptor blocking agents (DRBAs) are stopped has led to hypotheses that the underlying pathophysiology of TD is also a problem with neuroplasticity. Aside from DRBA exposure, environmental factors (eg, oxidative stress) and genetic predisposition might contribute to TD risk.¹

Before 2017, only 1 medication (branched-chain amino acids) had been FDA-approved for treating TD in the United States, and only a few existing medications (clonazepam, amantadine, and ginkgo biloba extract [EGb-761]) had positive results from controlled trials, most with small effect sizes.⁸ Moreover, there was only 1 controlled trial each for clonazepam and EGb-761.¹ A branched-chain amino acid preparation received FDA approval for managing TD in male patients, but is no longer commercially available, except from compounding pharmacies.⁹

Tetrabenazine was developed in the mid-1950s to avoid orthostasis and sedation associated with reserpine.¹⁰ Both reserpine and tetrabenazine proved effective for TD,¹¹ but tetrabenazine lacked reserpine’s peripheral adverse effects. However, the kinetics of tetrabenazine necessitated multiple daily doses, and CYP2D6 genotyping was required for doses >50 mg/d.²

Receptor blocking. The mechanism that distinguishes the clinical profiles of reserpine and tetrabenazine relates to their differential properties at VMAT.¹² VMAT exists in 2 forms (VMAT1 and VMAT2) that vary in distribution, with VMAT1 expressed mainly in the peripheral nervous system and VMAT2 expressed mainly in monoaminergic cells of the CNS.¹³ Tetrabenazine is a specific and reversible VMAT2 inhibitor, whereas reserpine is an irreversible and nonselective antagonist of VMAT1 and VMAT2. It is reserpine’s VMAT1 inhibition that results in peripheral adverse effects such as orthostasis. Tetrabenazine is rapidly and extensively converted into 2 isomers, alpha-dihydrotetrabenazine (α-DHTBZ) and beta-dihydrotetrabenazine (β-DHTBZ), both of which are metabolized by CYP2D6, with a role for CYP3A4 in α-DHTBZ metabolism.¹ These DHTBZ metabolites have a short half-life when generated from oral tetrabenazine, a feature that necessitates multiple daily dosing; moreover, the existence of 2D6 polymorphisms led to FDA-mandated CYP2D6 genotyping for tetrabenazine doses >50 mg/d when it was approved for Huntington’s chorea. The concern is that 2D6 poor metabolizers will have excessive exposure to the VMAT2 effects of DHTBZ, resulting in sedation, akathisia, parkinsonism, and mood symptoms.²

How deuterium impacts medication kinetics. Deuterium is a naturally occurring, stable, nontoxic isotope of hydrogen. Humans have 5 g of deuterium in their body at any time, mostly in the form of heavy water (D₂O).¹⁴ When deuterium is used to replace selected hydrogen atoms, the resulting molecule will have similar configuration and receptor-binding properties but markedly different kinetics. Because the carbon–deuterium covalent bond requires 8 times more energy to break than a carbon–hydrogen bond, the half-life is prolonged.¹⁵ Utilizing this knowledge, a deuterated form of tetrabenazine, deutetrabenazine, was synthesized with such a purpose in mind. While the active metabolites of deutetrabenazine retain the VMAT2 affinity of non-deuterated tetrabenazine, the substitution of deuterium for hydrogen at specific positions slows the breakdown of metabolites, resulting in sustained duration of action, greater active drug exposure, and less impact of 2D6 genotype on drug exposure, thus eliminating the need for genotyping, unless one wants to exceed 36 mg/d.

Deutetrabenazine was first studied in Huntington’s chorea in a 13-week, double-blind, placebo-controlled, parallel-group study (N = 90).⁴ The maximum daily deutetrabenazine dose was 48 mg, but reduced to 36 mg in those taking strong CYP2D6 inhibitors (bupropion, fluoxetine, or paroxetine). Blinded 2D6 genotyping was performed, but there was no dose modification required based on 2D6 genotype. There was a 36.4% reduction in total maximal chorea score for deutetrabenazine compared with 14.4% for placebo (P < .001).⁴ Importantly, adverse effects were comparable between both groups, with 1 drop-out in the deutetrabenazine arm vs 2 in the placebo arm. The only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo was somnolence: 11.1% for deutetrabenazine vs 4.4% for placebo.⁴ The mean deutetrabenazine daily dose at the end of the treatment period was 39.7 ± 9.3 mg, and for those with impaired CYP2D6 function (poor metabolizers or those taking strong CYP2D6 inhibiting medications), the mean daily dose was 34.8 mg ± 3.8 mg.⁴

Use in tardive dyskinesia. The recommended starting dosage for TD treatment is 6 mg, twice daily with food. The dose may be increased at weekly intervals in increments of 6 mg/d to a maximum recommended daily dosage of 48 mg.⁵ The maximum daily dose is 36 mg (18 mg, twice daily) in patients receiving strong CYP2D6 inhibitors or who are 2D6 poor metabolizers.⁵

Deutetrabenazine has not been studied in those with moderate or severe hepatic impairment, and its use is contraindicated in these patients.⁵ No clinical studies have been conducted to assess the effect of renal impairment on the pharmacokinetics of deutetrabenazine.⁵

Pharmacologic profile, adverse reactions

When the data from the two 12-week, phase 3 placebo-controlled studies were pooled, the most common adverse reactions occurring in >3% of deutetrabenazine patients and greater than placebo were nasopharyngeal symptoms (4% vs 2% placebo) and insomnia (4% vs 1% placebo).⁵ Importantly, in neither TD study were there clinically significant changes in rating scales for depression, suicidal ideation and behavior, or parkinsonism. There also were no clinically significant changes in measures of schizophrenia symptoms. The mean QT prolongation for a single 24 mg dose of deutetrabenazine in healthy volunteers was 4.5 milliseconds, with the upper bound of the double-sided 90% confidence interval reaching 6.5 milliseconds.⁵ For tetrabenazine, single 50 mg doses administered to volunteers resulted in mean QT prolongation of 8 milliseconds.⁵ In patients requiring deutetrabenazine doses >24 mg/d who are taking other medications known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications that are known to prolong QTc.⁵

How it works

Tetrabenazine is the only agent that has demonstrated significant efficacy for TD management, but its use involves slow titration, multiple daily dosing, CYP2D6 genotyping for doses >50 mg/d, and tolerability issues. For example, the most common adverse effects in the pivotal tetrabenazine Huntington’s disease trial were sedation/somnolence (tetrabenazine 31% vs 3% for placebo), insomnia (tetrabenazine 22% vs 0% for placebo), depression (tetrabenazine 19% vs 0% for placebo), fatigue (tetrabenazine 22% vs 13% for placebo), and akathisia (tetrabenazine 19% vs 0% for placebo).² For comparison, the only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo in the pivotal Huntington’s disease trial was somnolence (11.1% for deutetrabenazine vs 4.4% for placebo).⁴

Pharmacokinetics

Deutetrabenazine has 80% oral bioavailability, and is rapidly converted to its active metabolites after oral dosing (Table 2).⁵ Linear dose dependence of Cmax and area under the curve (AUC) was observed for the active metabolites following single or multiple doses of deutetrabenazine (6 to 24 mg and 7.5 to 22.5 mg, twice daily).¹⁵ Cmax of deuterated α-DHTBZ and β-DHTBZ is reached within 3 to 4 hours after dosing, with a steady state ratio of 3:1 for the α-DHTBZ vs the β-DHTBZ form. Food had no effect on AUC, but did increase Cmax by 50%.⁵

Deutetrabenazine is metabolized through carbonyl reductase enzymes to its active metabolites, and these are further metabolized through multiple CYP pathways, predominantly 2D6 and to a lesser extent 3A4. The effect of CYP2D6 inhibition on the pharma­cokinetics of deutetrabenazine and its α-DHTBZ and β-DHTBZ metabolites was studied in 24 healthy participants following a single 22.5 mg dose of deutetrabenazine given after 8 days of administration of the strong CYP2D6 inhibitor paroxetine, 20 mg/d. In the presence of paroxetine, systemic exposure (AUC) of α-DHTBZ was 1.9-fold higher and β-DHTBZ was 6.5-fold higher, resulting in an approximately 3-fold increase in AUC for total (α+β)-DHTBZ, with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively.⁵ Neither deutetrabenazine or its metabolites are inhibitors or inducers of major CYP enzymes. Aside from VMAT2, the results of in vitro studies suggest that deutetrabenazine and its active metabolites are unlikely to inhibit most major drug transporters at clinically relevant concentrations.

Efficacy

Efficacy was established in two 12-week, double-blind, placebo-controlled trials of adult patients with TD (ages 18 to 80).^6,7 Eligible participants had:

• TD diagnosis for ≥3 months before screening and a history of DRBA treatment for ≥3 months (≥1 month if age ≥60)
• Total AIMS motor score ≥6 (items 1 to 7) at both screening and baseline, verified by a blinded central rater at screening via central video rating
• Patients with an underlying psychiatric illness had to be stable. Psychoactive medication use, including antipsychotics, was allowed if stable for ≥30 days before screening (antidepressants, ≥45 days).

Exclusion criteria included treatment with tetrabenazine, reserpine, α-methyl-p-tyrosine, strong anticholinergic medications, dopamine antagonizing antiemetics (eg, metoclopramide, prochlorperazine, promethazine), dopamine agonists, levodopa, stimulants, or a monoamine oxidase inhibitor (MAOI) within 30 days of screening or baseline, or treatment with botulinum toxin within 3 months of screening; and presence of a neurologic condition that could confound TD assessments, serious untreated or undertreated psychiatric illness, or unstable medical illness. Patients with a history of or active suicidal ideation or behavior within 6 months of screening or score ≥11 on the depression subscale of the Hospital Anxiety and Depression Scale were excluded. Those participants with Fridericia-corrected QT interval values >450 milliseconds in men, >460 milliseconds in women, or >480 milli­seconds in patients with a right bundle branch block on electrocardiography at screening also were excluded.

The flexible-dose TD study was performed in 117 participants randomized in a 1:1 manner to deutetrabenazine or placebo, both administered twice daily, titrated to optimal dosage (12 to 48 mg/d) over 6 weeks, and then administered at that dose for another 6 weeks.⁷ The population demographics were: mean age, 54.6 ± 10.3 years, 52.1% female, 69.2% white, and 80.3% receiving ongoing dopamine antagonists, with a mean TD duration of 74.7 ± 81.5 months. Sixty-eight percent had schizophrenia spectrum disorders, and 30% had mood disorders. The primary outcome was change in total AIMS score (items 1 to 7) assessed by central, independent raters. The mean baseline AIMS score for items 1 to 7 was 9.6 ± 3.9, with 82.9% of participants with baseline AIMS scores ≥6. Study treatment retention was high: placebo 88.1%, deutetrabenazine 89.7%.⁷ There was a mean 3 point decrease in AIMS score for deutetrabenazine compared with 1.4 for placebo (P = .019). Among those with baseline AIMS scores ≥6, there was a 3.4 point decrease in AIMS scores for deutetrabenazine compared with a 1.9 point decrease for placebo (P = .027). The only adverse effects that occurred in ≥5% of deutetrabenazine participants and at a rate ≥2 times the rate in placebo were insomnia (deutetra­benazine 6.9% vs placebo 1.7%) and akathisia (deutetrabenazine 5.2% vs placebo 0%).

The fixed-dose TD study was performed in 293 participants randomized in 1:1:1:1 manner to 1 of 3 fixed doses of deutetrabenazine (12 mg/d, 24 mg/d, or 36 mg/d) or placebo, both administered twice daily.⁶ The starting dose of deutetrabenazine was 6 mg twice daily. During the dose escalation period (through Week 4), the dose of study drug was increased weekly in increments of 6 mg/d until the randomized dose was achieved. Patients continued to receive the dose they were assigned to over a maintenance period of 8 weeks.⁶ The population demographics were: mean age, 56.4 ± 11.3 years, 55% female, 79% white, 76% receiving ongoing dopamine antagonists, with a mean TD duration of 67.2 ± 66 months. Sixty percent had schizophrenia spectrum disorders, and 36% had mood disorders. The primary outcome was change in AIMS total score (items 1 to 7) assessed by central, independent raters. The mean AIMS score at baseline was 9.5 ± 2.7 in the placebo group, and for deutetrabenazine: 9.6 ± 2.4 in the 12 mg/d group, 9.4 ± 2.9 in the 24 mg/d group, and 10.1 ± 3.2 in the 36 mg/d group. The 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). Study treatment retention rates were high: placebo 90.5%, deutetrabenazine 88%. Across all doses, only 1 adverse effect occurred in ≥5% of deutetrabenazine participants: headache (5% deutetrabenazine vs 6% placebo). At the highest dose, 36 mg/d, the only adverse effects that occurred in ≥5% of participants were diarrhea (7% deutetrabenazine vs 3% placebo) and headache (7% deutetrabenazine vs 6% placebo).

Outcome. In the flexible-dose study (mean dose 38.8 ± 7.92 mg/d), the deutetrabenazine arm experienced a mean 30% reduction in AIMS scores from baseline at the Week 12 endpoint. Compared with placebo, the mean reduction in AIMS scores (standard error) was: −3.0 (0.45) deutetrabenazine vs −1.6 (0.46) placebo (P = .019).⁷ For the fixed-dose study, the 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). In addition to these mean changes from baseline, 35% of the 24 mg/d group and 33% of the 36 mg/d group demonstrated ≥50% reduction in AIMS scores.⁶

Tolerability

In the 2 phase 3 trials, there were no adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo.⁵ Discontinuations because of adverse events were low in both pivotal studies across all treatment groups: 3.4% for placebo vs 1.7% for deutetrabenazine in the flexible-dose trial,⁷ and 3% for placebo vs 4% for deutetrabenazine in the fixed-dose study.⁶ In neither trial were there clinically significant changes in ratings of depression, suicidality, parkinsonism, or schizophrenia symptoms. The mean QT prolongation in healthy volunteers is described above.

Clinical considerations

Unique properties. Deutetrabenazine utilizes the greater bond strength of the carbon–deuterium bond to slow CYP metabolism, resulting in prolonged duration of action that is well tolerated, and provides significant efficacy.

Why Rx? The reasons to prescribe deutetrabenazine for TD patients include:

• only 1 of 2 agents with FDA approval for TD
• fewer tolerability issues than with tetrabenazine
• lower sedation rates in TD trials than with valbenazine
• no signal for effects on mood para­meters or rates of parkinsonism when used for TD.

Dosing

The recommended starting dosage of deutetrabenazine is 6 mg twice daily taken with food, increasing by 6 mg/d weekly as needed, with a maximum dose of 48 mg/d or 36 mg/d in those taking strong CYP2D6 inhibitors or who are 2D6 poor metabolizers. Deutetrabenazine is contraindicated in patients with hepatic impairment (as determined by Child-Pugh criteria¹⁶). There are no data in patients with renal impairment. The combined efficacy and tolerability of dosages >48 mg/d has not been evaluated. Overdoses of tetrabenazine ranging from 100 to 1,000 mg have been reported in the literature and were associated with acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.⁵

Contraindications

When used for TD, deutetrabenazine is contraindicated for patients taking reserpine, tetrabenazine, valbenazine, or MAOIs, and for patients with hepatic impairment. As with most medications, there are no data on deutetrabenazine use in pregnant women; however, oral administration of deutetrabenazine (5, 10, or 30 mg/kg/d) or tetrabenazine (30 mg/kg/d) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/d on a body surface area (mg/m²) basis. There are no data on the presence of deutetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

Ms. S, age 39, with a 15-year history of schizophrenia and severe paranoid delusions, is admitted after physically assaulting a staff member at a group home. She is receiving paliperidone palmitate, 234 mg every 4 weeks. This has reduced the severity of her symptoms, but she continues to have persistent delusions that affect her ability to accept redirection from staff. Ms. S frequently accuses staff and peers of sexual assault, says that she is pregnant, and does not adhere to treatment recommendations for laboratory monitoring because the “staff uses her blood for experiments.”

Ms. S frequently requires administration of oral and IM haloperidol, as needed, when she becomes aggressive with the staff. She has poor insight into her mental illness and does not believe that she needs medication. Ms. S has a long history of stopping her oral antipsychotic after a few days, reporting that it is “harming her baby.” Monotherapy has been tried with various long-acting injectable antipsychotics (LAIAs), but she still exhibits persistent delusions. The treatment team decides to add a second LAIA, haloperidol decanoate, 200 mg every 4 weeks, to her regimen.

Ross and Fabian.¹¹ An African American man, age 44, was receiving haloperidol decanoate, 400 mg every 2 weeks, and oral haloperidol, 20 mg/d.¹¹ Because of residual symptoms, a history of nonadherence, and concerns about increasing the haloperidol decanoate dose or frequency, oral haloperidol was discontinued and paliperidone palmitate, 156 mg every 4 weeks, was started. The patient was able to transition into a step-down unit, and no adverse effects were reported.

What to consider before initiating dual LAIA treatment

Evaluate the frequency of administration, flexibility of dosing, administration site, adverse effects, and monitoring requirements of each LAIA (Table 2^12-19) to ensure the patient’s optimal tolerability of the regimen. Previous tolerability of each medication must be confirmed by evaluating the patient’s medication history or oral or IM administration of each agent prior to initiating the LAIA.

When choosing 2 agents that are each administered once every 4 weeks, consider administering the medications together every 4 weeks or alternating administration so that the patient receives an injection every 2 weeks. Receiving an injection once every 2 weeks might be beneficial for patients who need close follow-up or are more sensitive to injection site reactions, whereas a regimen of once every 4 weeks might be beneficial for patients who are more resistant to receiving the injections, so there is potentially less time spent agitated or anxious leading up to the date of the injection.

Use the lowest effective dose of each LAIA to limit adverse effects and improve tolerability of the regimen. Monitor patients closely for adverse reactions and discontinue the regimen as soon as possible if a severe adverse reaction occurs.

Cost may influence the decision to use 2 LAIAs. The majority of LAIAs in the United States are available only as branded formulations. Insurance companies may require prior authorization for the use of 2 LAIAs.

Although there are no treatment guidelines for combining 2 LAIAs, this practice has been used. A few case reports have described successful use of dual LAIA treatment, but one should consider the risk of the publication’s bias. Overall, the decision to use 2 LAIAs is difficult because there is lack of a large evidence base supporting the practice or direction from treatment guidelines. Because of this, dual LAIA treatment should not be used for most patients. In cases of treatment-resistant schizophrenia where clozapine is not an option and adherence is a concern, it is reasonable to consider this strategy on a case-by-case basis.

Ms. S, age 39, with a 15-year history of schizophrenia and severe paranoid delusions, is admitted after physically assaulting a staff member at a group home. She is receiving paliperidone palmitate, 234 mg every 4 weeks. This has reduced the severity of her symptoms, but she continues to have persistent delusions that affect her ability to accept redirection from staff. Ms. S frequently accuses staff and peers of sexual assault, says that she is pregnant, and does not adhere to treatment recommendations for laboratory monitoring because the “staff uses her blood for experiments.”

Ms. S frequently requires administration of oral and IM haloperidol, as needed, when she becomes aggressive with the staff. She has poor insight into her mental illness and does not believe that she needs medication. Ms. S has a long history of stopping her oral antipsychotic after a few days, reporting that it is “harming her baby.” Monotherapy has been tried with various long-acting injectable antipsychotics (LAIAs), but she still exhibits persistent delusions. The treatment team decides to add a second LAIA, haloperidol decanoate, 200 mg every 4 weeks, to her regimen.

Ross and Fabian.¹¹ An African American man, age 44, was receiving haloperidol decanoate, 400 mg every 2 weeks, and oral haloperidol, 20 mg/d.¹¹ Because of residual symptoms, a history of nonadherence, and concerns about increasing the haloperidol decanoate dose or frequency, oral haloperidol was discontinued and paliperidone palmitate, 156 mg every 4 weeks, was started. The patient was able to transition into a step-down unit, and no adverse effects were reported.

What to consider before initiating dual LAIA treatment

Evaluate the frequency of administration, flexibility of dosing, administration site, adverse effects, and monitoring requirements of each LAIA (Table 2^12-19) to ensure the patient’s optimal tolerability of the regimen. Previous tolerability of each medication must be confirmed by evaluating the patient’s medication history or oral or IM administration of each agent prior to initiating the LAIA.

When choosing 2 agents that are each administered once every 4 weeks, consider administering the medications together every 4 weeks or alternating administration so that the patient receives an injection every 2 weeks. Receiving an injection once every 2 weeks might be beneficial for patients who need close follow-up or are more sensitive to injection site reactions, whereas a regimen of once every 4 weeks might be beneficial for patients who are more resistant to receiving the injections, so there is potentially less time spent agitated or anxious leading up to the date of the injection.

Use the lowest effective dose of each LAIA to limit adverse effects and improve tolerability of the regimen. Monitor patients closely for adverse reactions and discontinue the regimen as soon as possible if a severe adverse reaction occurs.

Cost may influence the decision to use 2 LAIAs. The majority of LAIAs in the United States are available only as branded formulations. Insurance companies may require prior authorization for the use of 2 LAIAs.

Although there are no treatment guidelines for combining 2 LAIAs, this practice has been used. A few case reports have described successful use of dual LAIA treatment, but one should consider the risk of the publication’s bias. Overall, the decision to use 2 LAIAs is difficult because there is lack of a large evidence base supporting the practice or direction from treatment guidelines. Because of this, dual LAIA treatment should not be used for most patients. In cases of treatment-resistant schizophrenia where clozapine is not an option and adherence is a concern, it is reasonable to consider this strategy on a case-by-case basis.

Ms. S, age 39, with a 15-year history of schizophrenia and severe paranoid delusions, is admitted after physically assaulting a staff member at a group home. She is receiving paliperidone palmitate, 234 mg every 4 weeks. This has reduced the severity of her symptoms, but she continues to have persistent delusions that affect her ability to accept redirection from staff. Ms. S frequently accuses staff and peers of sexual assault, says that she is pregnant, and does not adhere to treatment recommendations for laboratory monitoring because the “staff uses her blood for experiments.”

Ms. S frequently requires administration of oral and IM haloperidol, as needed, when she becomes aggressive with the staff. She has poor insight into her mental illness and does not believe that she needs medication. Ms. S has a long history of stopping her oral antipsychotic after a few days, reporting that it is “harming her baby.” Monotherapy has been tried with various long-acting injectable antipsychotics (LAIAs), but she still exhibits persistent delusions. The treatment team decides to add a second LAIA, haloperidol decanoate, 200 mg every 4 weeks, to her regimen.

Ross and Fabian.¹¹ An African American man, age 44, was receiving haloperidol decanoate, 400 mg every 2 weeks, and oral haloperidol, 20 mg/d.¹¹ Because of residual symptoms, a history of nonadherence, and concerns about increasing the haloperidol decanoate dose or frequency, oral haloperidol was discontinued and paliperidone palmitate, 156 mg every 4 weeks, was started. The patient was able to transition into a step-down unit, and no adverse effects were reported.

What to consider before initiating dual LAIA treatment

Evaluate the frequency of administration, flexibility of dosing, administration site, adverse effects, and monitoring requirements of each LAIA (Table 2^12-19) to ensure the patient’s optimal tolerability of the regimen. Previous tolerability of each medication must be confirmed by evaluating the patient’s medication history or oral or IM administration of each agent prior to initiating the LAIA.

When choosing 2 agents that are each administered once every 4 weeks, consider administering the medications together every 4 weeks or alternating administration so that the patient receives an injection every 2 weeks. Receiving an injection once every 2 weeks might be beneficial for patients who need close follow-up or are more sensitive to injection site reactions, whereas a regimen of once every 4 weeks might be beneficial for patients who are more resistant to receiving the injections, so there is potentially less time spent agitated or anxious leading up to the date of the injection.

Use the lowest effective dose of each LAIA to limit adverse effects and improve tolerability of the regimen. Monitor patients closely for adverse reactions and discontinue the regimen as soon as possible if a severe adverse reaction occurs.

Cost may influence the decision to use 2 LAIAs. The majority of LAIAs in the United States are available only as branded formulations. Insurance companies may require prior authorization for the use of 2 LAIAs.

Although there are no treatment guidelines for combining 2 LAIAs, this practice has been used. A few case reports have described successful use of dual LAIA treatment, but one should consider the risk of the publication’s bias. Overall, the decision to use 2 LAIAs is difficult because there is lack of a large evidence base supporting the practice or direction from treatment guidelines. Because of this, dual LAIA treatment should not be used for most patients. In cases of treatment-resistant schizophrenia where clozapine is not an option and adherence is a concern, it is reasonable to consider this strategy on a case-by-case basis.

CASE A lifelong habit

Ms. B, age 14, has diagnoses of attention-deficit/hyperactive disorder (ADHD) and oppositional defiant disorder, and is taking extended-release (ER) methylphenidate, 36 mg/d. Her mother brings her to the hospital with concerns that Ms. B has been stealing small objects, such as money, toys, and pencils from home, school, and her peers, even though she does not need them and her family can afford to buy them for her. Ms. B’s mother routinely searches her daughter when she leaves the house and when she returns and frequently finds things in Ms. B’s possession that do not belong to her.

The mother reports that Ms. B’s stealing has been a lifelong habit that worsened after Ms. B’s father died in a car accident last year.

Ms. B does not volunteer any information about her stealing. She is admitted to a partial hospitalization program for further evaluation and treatment.

[polldaddy:9837962]

EVALUATION Continued stealing

A week later, Ms. B remains reluctant to talk about her stealing habit. However, once a therapeutic alliance is established, she reveals that she experiences increased anxiety before stealing and feels pleasure during the theft. Her methylphenidate ER dosage is increased to 54 mg/d in an attempt to address poor impulse control and sub­sequent stealing behavior. Her ADHD symptoms are controlled, and she does not exhibit poor impulse control in any situation other than stealing.

However, Ms. B continues to have poor insight and impaired judgment about her behavior. During treatment, Ms. B steals markers from the psychiatrist’s office, which later are found in her bag. When the staff convinces Ms. B to return the markers to the psychiatrist, she denies knowing how they got there. Behavioral interventions, including covert sensitization, systemic desensitization, positive reinforcement, body and bag search, and reminders, occur consistently as part of treatment, but have little effect on her symptoms.

The author’s observations

Risk-taking and novelty-seeking behaviors are common in adolescent patients. Impulsivity, instant reward-seeking behavior, and poor judgment can lead to stealing in this population, but this behavior is not necessarily indicative of kleptomania.

Kleptomania is the recurrent failure to resist impulses to steal objects.² It differs from other forms of stealing in that the objects stolen by a patient with kleptomania are not needed for personal use or for their monetary value. Kleptomania usually begins in early adolescence, is found in about 0.5% of the general population, and is more common among females.³

• The psychoanalytical theory explains kleptomania as an immature defense against unconscious impulses, conflicts, and desires of destruction. By stealing, the individual protects the self from narcissistic injury and disintegration. The frantic search for objects helps to divert self-destructive aggressiveness and allows for the preservation of the self.⁴
• The biological model indicates that individuals with kleptomania have a significant deficit of white matter in inferior frontal regions and poor integrity of the tracts connecting the limbic system to the thalamus and to the prefrontal cortex.⁵ Reward system circuitry (ventral tegmental area–nucleus accumbens–orbital frontal cortex) is likely to be involved in impulse control disorders including kleptomania.⁶

Comorbidity. Kleptomania often is comorbid with substance use disorder (SUD), obsessive-compulsive disorder (OCD), and compulsive shopping, as well as depression, anxiety disorders, bulimia nervosa, and impulse control and conduct disorders.^3,6

Kleptomania shares many characteristics with SUD, including continued engagement in a behavior despite negative consequences and the temporary reduction in urges after the behavior’s completion, followed by a return of the urge to steal. There also is a bidirectional relationship between OCD and kleptomania. Individuals with both disorders frequently engage in excessive and unnecessary rituals even when it is ego-dystonic. First-degree relatives of kleptomania patients have high rates of SUD and OCD.³

Serotonin, dopamine, and opioid pathways play a role in both kleptomania and other behavioral addictions.⁶ Clinicians should be cautious in treating comorbid disorders with stimulants. These agents may help patients with high impulsivity, but lead to disinhibition and worsen impulse control in patients with low impulsivity.⁷

TREATMENT Naltrexone

The psychiatrist discusses pharmacologic options to treat kleptomania with Ms. B and her mother. After considering the risks, benefits, adverse effects, and alternative treatments (including the option of no pharma­cologic treatment), the mother consents and Ms. B assents to treatment with naltrexone, 25 mg/d. Before starting this medication, both the mother and Ms. B receive detailed psychoeducation describing naltrexone’s interactions with opioids. They are told that if Ms. B has a traumatic injury, they should inform the treatment team that she is taking naltrexone, which can acutely precipitate opiate withdrawal.

Before initiating pharmacotherapy, a comprehensive metabolic profile is obtained, and all values are within the normal range. After 1 week, naltrexone is increased to 50 mg/d. The medication is well tolerated, without any adverse effects.

[polldaddy:9837976]

The author’s observations

Behavioral interventions, such as covert sensitization and systemic desensitization, often are used to treat kleptomania.⁸ There are no FDA-approved medications for this condition. Opioid antagonists have been considered for the treatment of kleptomania.⁷

Mu-opioid receptors exist in highest concentrations in presynaptic neurons in the periaqueductal gray region and spinal cord and have high affinity for enkephalins and beta-endorphins. They also are involved in the reward and pleasure pathway. This neurocircuit is implicated in behavioral addiction.⁹

Naltrexone is an antagonist at μ-opioid receptors. It blocks the binding of endogenous and exogenous opioids at the receptors, particularly at the ventral tegmental area. By blocking the μ-receptor, naltrexone inhibits the processing of the reward and pleasure pathway involved in kleptomania. Naltrexone binds to these receptors, preventing the euphoric effects of behavioral addictions.¹⁰ This medication works best in conjunction with behavioral interventions.⁸

Naltrexone is a Schedule II drug. Use of naltrexone to treat kleptomania or other impulse control disorders is an off-label use of the medication. Naltrexone should not be prescribed to patients who are receiving opiates because it can cause acute opiate withdrawal.

Liver function tests should be monitored in all patients taking naltrexone. If liver function levels begin to rise, naltrexone should be discontinued. Naltrexone should be used with caution in patients with pre­existing liver disease.¹¹

OUTCOME Marked improvement

Ms. B’s K-SAS scores are evaluated 2 weeks after starting naltrexone. The results show a marked reduction in the urge to steal and in stealing behavior, and Ms. B’s mother reports no incidents of stealing in the previous week.

Ms. B is maintained on naltrexone, 50 mg/d, for 2 months. On repeated K-SAS scores, her mother rates Ms. B’s symptoms “very much improved” with “occasional” stealing. Ms. B is discharged from the intensive outpatient program.

CASE A lifelong habit

Ms. B, age 14, has diagnoses of attention-deficit/hyperactive disorder (ADHD) and oppositional defiant disorder, and is taking extended-release (ER) methylphenidate, 36 mg/d. Her mother brings her to the hospital with concerns that Ms. B has been stealing small objects, such as money, toys, and pencils from home, school, and her peers, even though she does not need them and her family can afford to buy them for her. Ms. B’s mother routinely searches her daughter when she leaves the house and when she returns and frequently finds things in Ms. B’s possession that do not belong to her.

The mother reports that Ms. B’s stealing has been a lifelong habit that worsened after Ms. B’s father died in a car accident last year.

Ms. B does not volunteer any information about her stealing. She is admitted to a partial hospitalization program for further evaluation and treatment.

[polldaddy:9837962]

EVALUATION Continued stealing

A week later, Ms. B remains reluctant to talk about her stealing habit. However, once a therapeutic alliance is established, she reveals that she experiences increased anxiety before stealing and feels pleasure during the theft. Her methylphenidate ER dosage is increased to 54 mg/d in an attempt to address poor impulse control and sub­sequent stealing behavior. Her ADHD symptoms are controlled, and she does not exhibit poor impulse control in any situation other than stealing.

However, Ms. B continues to have poor insight and impaired judgment about her behavior. During treatment, Ms. B steals markers from the psychiatrist’s office, which later are found in her bag. When the staff convinces Ms. B to return the markers to the psychiatrist, she denies knowing how they got there. Behavioral interventions, including covert sensitization, systemic desensitization, positive reinforcement, body and bag search, and reminders, occur consistently as part of treatment, but have little effect on her symptoms.

The author’s observations

Risk-taking and novelty-seeking behaviors are common in adolescent patients. Impulsivity, instant reward-seeking behavior, and poor judgment can lead to stealing in this population, but this behavior is not necessarily indicative of kleptomania.

Kleptomania is the recurrent failure to resist impulses to steal objects.² It differs from other forms of stealing in that the objects stolen by a patient with kleptomania are not needed for personal use or for their monetary value. Kleptomania usually begins in early adolescence, is found in about 0.5% of the general population, and is more common among females.³

• The psychoanalytical theory explains kleptomania as an immature defense against unconscious impulses, conflicts, and desires of destruction. By stealing, the individual protects the self from narcissistic injury and disintegration. The frantic search for objects helps to divert self-destructive aggressiveness and allows for the preservation of the self.⁴
• The biological model indicates that individuals with kleptomania have a significant deficit of white matter in inferior frontal regions and poor integrity of the tracts connecting the limbic system to the thalamus and to the prefrontal cortex.⁵ Reward system circuitry (ventral tegmental area–nucleus accumbens–orbital frontal cortex) is likely to be involved in impulse control disorders including kleptomania.⁶

Comorbidity. Kleptomania often is comorbid with substance use disorder (SUD), obsessive-compulsive disorder (OCD), and compulsive shopping, as well as depression, anxiety disorders, bulimia nervosa, and impulse control and conduct disorders.^3,6

Kleptomania shares many characteristics with SUD, including continued engagement in a behavior despite negative consequences and the temporary reduction in urges after the behavior’s completion, followed by a return of the urge to steal. There also is a bidirectional relationship between OCD and kleptomania. Individuals with both disorders frequently engage in excessive and unnecessary rituals even when it is ego-dystonic. First-degree relatives of kleptomania patients have high rates of SUD and OCD.³

Serotonin, dopamine, and opioid pathways play a role in both kleptomania and other behavioral addictions.⁶ Clinicians should be cautious in treating comorbid disorders with stimulants. These agents may help patients with high impulsivity, but lead to disinhibition and worsen impulse control in patients with low impulsivity.⁷

TREATMENT Naltrexone

The psychiatrist discusses pharmacologic options to treat kleptomania with Ms. B and her mother. After considering the risks, benefits, adverse effects, and alternative treatments (including the option of no pharma­cologic treatment), the mother consents and Ms. B assents to treatment with naltrexone, 25 mg/d. Before starting this medication, both the mother and Ms. B receive detailed psychoeducation describing naltrexone’s interactions with opioids. They are told that if Ms. B has a traumatic injury, they should inform the treatment team that she is taking naltrexone, which can acutely precipitate opiate withdrawal.

Before initiating pharmacotherapy, a comprehensive metabolic profile is obtained, and all values are within the normal range. After 1 week, naltrexone is increased to 50 mg/d. The medication is well tolerated, without any adverse effects.

[polldaddy:9837976]

The author’s observations

Behavioral interventions, such as covert sensitization and systemic desensitization, often are used to treat kleptomania.⁸ There are no FDA-approved medications for this condition. Opioid antagonists have been considered for the treatment of kleptomania.⁷

Mu-opioid receptors exist in highest concentrations in presynaptic neurons in the periaqueductal gray region and spinal cord and have high affinity for enkephalins and beta-endorphins. They also are involved in the reward and pleasure pathway. This neurocircuit is implicated in behavioral addiction.⁹

Naltrexone is an antagonist at μ-opioid receptors. It blocks the binding of endogenous and exogenous opioids at the receptors, particularly at the ventral tegmental area. By blocking the μ-receptor, naltrexone inhibits the processing of the reward and pleasure pathway involved in kleptomania. Naltrexone binds to these receptors, preventing the euphoric effects of behavioral addictions.¹⁰ This medication works best in conjunction with behavioral interventions.⁸

Naltrexone is a Schedule II drug. Use of naltrexone to treat kleptomania or other impulse control disorders is an off-label use of the medication. Naltrexone should not be prescribed to patients who are receiving opiates because it can cause acute opiate withdrawal.

Liver function tests should be monitored in all patients taking naltrexone. If liver function levels begin to rise, naltrexone should be discontinued. Naltrexone should be used with caution in patients with pre­existing liver disease.¹¹

OUTCOME Marked improvement

Ms. B’s K-SAS scores are evaluated 2 weeks after starting naltrexone. The results show a marked reduction in the urge to steal and in stealing behavior, and Ms. B’s mother reports no incidents of stealing in the previous week.

Ms. B is maintained on naltrexone, 50 mg/d, for 2 months. On repeated K-SAS scores, her mother rates Ms. B’s symptoms “very much improved” with “occasional” stealing. Ms. B is discharged from the intensive outpatient program.

CASE A lifelong habit

Ms. B, age 14, has diagnoses of attention-deficit/hyperactive disorder (ADHD) and oppositional defiant disorder, and is taking extended-release (ER) methylphenidate, 36 mg/d. Her mother brings her to the hospital with concerns that Ms. B has been stealing small objects, such as money, toys, and pencils from home, school, and her peers, even though she does not need them and her family can afford to buy them for her. Ms. B’s mother routinely searches her daughter when she leaves the house and when she returns and frequently finds things in Ms. B’s possession that do not belong to her.

The mother reports that Ms. B’s stealing has been a lifelong habit that worsened after Ms. B’s father died in a car accident last year.

Ms. B does not volunteer any information about her stealing. She is admitted to a partial hospitalization program for further evaluation and treatment.

[polldaddy:9837962]

EVALUATION Continued stealing

A week later, Ms. B remains reluctant to talk about her stealing habit. However, once a therapeutic alliance is established, she reveals that she experiences increased anxiety before stealing and feels pleasure during the theft. Her methylphenidate ER dosage is increased to 54 mg/d in an attempt to address poor impulse control and sub­sequent stealing behavior. Her ADHD symptoms are controlled, and she does not exhibit poor impulse control in any situation other than stealing.

However, Ms. B continues to have poor insight and impaired judgment about her behavior. During treatment, Ms. B steals markers from the psychiatrist’s office, which later are found in her bag. When the staff convinces Ms. B to return the markers to the psychiatrist, she denies knowing how they got there. Behavioral interventions, including covert sensitization, systemic desensitization, positive reinforcement, body and bag search, and reminders, occur consistently as part of treatment, but have little effect on her symptoms.

The author’s observations

Risk-taking and novelty-seeking behaviors are common in adolescent patients. Impulsivity, instant reward-seeking behavior, and poor judgment can lead to stealing in this population, but this behavior is not necessarily indicative of kleptomania.

Kleptomania is the recurrent failure to resist impulses to steal objects.² It differs from other forms of stealing in that the objects stolen by a patient with kleptomania are not needed for personal use or for their monetary value. Kleptomania usually begins in early adolescence, is found in about 0.5% of the general population, and is more common among females.³

• The psychoanalytical theory explains kleptomania as an immature defense against unconscious impulses, conflicts, and desires of destruction. By stealing, the individual protects the self from narcissistic injury and disintegration. The frantic search for objects helps to divert self-destructive aggressiveness and allows for the preservation of the self.⁴
• The biological model indicates that individuals with kleptomania have a significant deficit of white matter in inferior frontal regions and poor integrity of the tracts connecting the limbic system to the thalamus and to the prefrontal cortex.⁵ Reward system circuitry (ventral tegmental area–nucleus accumbens–orbital frontal cortex) is likely to be involved in impulse control disorders including kleptomania.⁶

Comorbidity. Kleptomania often is comorbid with substance use disorder (SUD), obsessive-compulsive disorder (OCD), and compulsive shopping, as well as depression, anxiety disorders, bulimia nervosa, and impulse control and conduct disorders.^3,6

Kleptomania shares many characteristics with SUD, including continued engagement in a behavior despite negative consequences and the temporary reduction in urges after the behavior’s completion, followed by a return of the urge to steal. There also is a bidirectional relationship between OCD and kleptomania. Individuals with both disorders frequently engage in excessive and unnecessary rituals even when it is ego-dystonic. First-degree relatives of kleptomania patients have high rates of SUD and OCD.³

Serotonin, dopamine, and opioid pathways play a role in both kleptomania and other behavioral addictions.⁶ Clinicians should be cautious in treating comorbid disorders with stimulants. These agents may help patients with high impulsivity, but lead to disinhibition and worsen impulse control in patients with low impulsivity.⁷

TREATMENT Naltrexone

The psychiatrist discusses pharmacologic options to treat kleptomania with Ms. B and her mother. After considering the risks, benefits, adverse effects, and alternative treatments (including the option of no pharma­cologic treatment), the mother consents and Ms. B assents to treatment with naltrexone, 25 mg/d. Before starting this medication, both the mother and Ms. B receive detailed psychoeducation describing naltrexone’s interactions with opioids. They are told that if Ms. B has a traumatic injury, they should inform the treatment team that she is taking naltrexone, which can acutely precipitate opiate withdrawal.

Before initiating pharmacotherapy, a comprehensive metabolic profile is obtained, and all values are within the normal range. After 1 week, naltrexone is increased to 50 mg/d. The medication is well tolerated, without any adverse effects.

[polldaddy:9837976]

The author’s observations

Behavioral interventions, such as covert sensitization and systemic desensitization, often are used to treat kleptomania.⁸ There are no FDA-approved medications for this condition. Opioid antagonists have been considered for the treatment of kleptomania.⁷

Mu-opioid receptors exist in highest concentrations in presynaptic neurons in the periaqueductal gray region and spinal cord and have high affinity for enkephalins and beta-endorphins. They also are involved in the reward and pleasure pathway. This neurocircuit is implicated in behavioral addiction.⁹

Naltrexone is an antagonist at μ-opioid receptors. It blocks the binding of endogenous and exogenous opioids at the receptors, particularly at the ventral tegmental area. By blocking the μ-receptor, naltrexone inhibits the processing of the reward and pleasure pathway involved in kleptomania. Naltrexone binds to these receptors, preventing the euphoric effects of behavioral addictions.¹⁰ This medication works best in conjunction with behavioral interventions.⁸

Naltrexone is a Schedule II drug. Use of naltrexone to treat kleptomania or other impulse control disorders is an off-label use of the medication. Naltrexone should not be prescribed to patients who are receiving opiates because it can cause acute opiate withdrawal.

Liver function tests should be monitored in all patients taking naltrexone. If liver function levels begin to rise, naltrexone should be discontinued. Naltrexone should be used with caution in patients with pre­existing liver disease.¹¹

OUTCOME Marked improvement

Ms. B’s K-SAS scores are evaluated 2 weeks after starting naltrexone. The results show a marked reduction in the urge to steal and in stealing behavior, and Ms. B’s mother reports no incidents of stealing in the previous week.

Ms. B is maintained on naltrexone, 50 mg/d, for 2 months. On repeated K-SAS scores, her mother rates Ms. B’s symptoms “very much improved” with “occasional” stealing. Ms. B is discharged from the intensive outpatient program.

Most physicians are likely familiar with guidelines relating to physician impairment, but they may not be aware that these guidelines typically conflict with the Americans with Disabilities Act (ADA), which protects all employees against unwarranted requests for mental health information or evaluations.

Under the ADA, employers cannot request mental health information from their employees or refer them for mental health evaluations without objective evidence showing that either the employee:

• is unable to perform essential job functions because of a mental health condition
• poses a high risk of substantial, imminent harm to himself (herself) or others in the workplace because of a mental health condition.¹

Employers cannot rely on speculative evidence or generalizations about these conditions when making these determinations,¹ and common mental disorders (eg, depressive disorders, anxiety disorders, attention-­deficit/hyperactivity disorder, specific learning disorders, etc.) should almost never form the basis of such requests.²

In contrast, the American Medical Association (AMA) does not distinguish between the presence of a mental health condition and physician impairment,^3,4 which may result in unwarranted requests and referrals for mental health evaluations. Some state laws on impairment, which all derive from AMA policies,⁵ even state outright that, “‘Impaired’ or ‘impairment’ means the presence of the diseases of alcoholism, drug abuse, or mental illness”⁶ and directly discriminate against physicians with these conditions.

State physician health programs (PHPs) also may describe impairment in problematic ways (eg, “Involvement in litigation against hospital”).⁷ Their descriptions also are overly inclusive in that they could be used to describe most physicians (N.D.L., J.W.B., unpublished data, 2017), and they rarely represent sufficient legal indications for a mental health evaluation under the ADA (N.D.L., J.W.B., unpublished data, 2017). Even the APA’s Clinical Guide to Psychiatric Ethics describes physician impairment as synonymous with mental illness.⁸

Requests for mental health information or evaluations not only can include referrals to state PHPs but also “suggestions” to see a psychologist, professional job coach, or any provider who may ask for mental health information. Under the ADA's guidelines, obtaining “voluntary” consent from an employee who could be fired for not cooperating does not change the involuntary nature of these requests.^2,9

Employers who hire psychiatrists, physicians, and medical residents should comply with the ADA and disregard the AMA’s policies, state laws, PHPs, other institutional guidelines,¹⁰ and guidance from some articles published in Current Psychiatry^11,12 when requesting mental health information, evaluations, and referrals for their employees.

Most physicians are likely familiar with guidelines relating to physician impairment, but they may not be aware that these guidelines typically conflict with the Americans with Disabilities Act (ADA), which protects all employees against unwarranted requests for mental health information or evaluations.

Under the ADA, employers cannot request mental health information from their employees or refer them for mental health evaluations without objective evidence showing that either the employee:

• is unable to perform essential job functions because of a mental health condition
• poses a high risk of substantial, imminent harm to himself (herself) or others in the workplace because of a mental health condition.¹

Employers cannot rely on speculative evidence or generalizations about these conditions when making these determinations,¹ and common mental disorders (eg, depressive disorders, anxiety disorders, attention-­deficit/hyperactivity disorder, specific learning disorders, etc.) should almost never form the basis of such requests.²

In contrast, the American Medical Association (AMA) does not distinguish between the presence of a mental health condition and physician impairment,^3,4 which may result in unwarranted requests and referrals for mental health evaluations. Some state laws on impairment, which all derive from AMA policies,⁵ even state outright that, “‘Impaired’ or ‘impairment’ means the presence of the diseases of alcoholism, drug abuse, or mental illness”⁶ and directly discriminate against physicians with these conditions.

State physician health programs (PHPs) also may describe impairment in problematic ways (eg, “Involvement in litigation against hospital”).⁷ Their descriptions also are overly inclusive in that they could be used to describe most physicians (N.D.L., J.W.B., unpublished data, 2017), and they rarely represent sufficient legal indications for a mental health evaluation under the ADA (N.D.L., J.W.B., unpublished data, 2017). Even the APA’s Clinical Guide to Psychiatric Ethics describes physician impairment as synonymous with mental illness.⁸

Requests for mental health information or evaluations not only can include referrals to state PHPs but also “suggestions” to see a psychologist, professional job coach, or any provider who may ask for mental health information. Under the ADA's guidelines, obtaining “voluntary” consent from an employee who could be fired for not cooperating does not change the involuntary nature of these requests.^2,9

Employers who hire psychiatrists, physicians, and medical residents should comply with the ADA and disregard the AMA’s policies, state laws, PHPs, other institutional guidelines,¹⁰ and guidance from some articles published in Current Psychiatry^11,12 when requesting mental health information, evaluations, and referrals for their employees.

Most physicians are likely familiar with guidelines relating to physician impairment, but they may not be aware that these guidelines typically conflict with the Americans with Disabilities Act (ADA), which protects all employees against unwarranted requests for mental health information or evaluations.

Under the ADA, employers cannot request mental health information from their employees or refer them for mental health evaluations without objective evidence showing that either the employee:

• is unable to perform essential job functions because of a mental health condition
• poses a high risk of substantial, imminent harm to himself (herself) or others in the workplace because of a mental health condition.¹

Employers cannot rely on speculative evidence or generalizations about these conditions when making these determinations,¹ and common mental disorders (eg, depressive disorders, anxiety disorders, attention-­deficit/hyperactivity disorder, specific learning disorders, etc.) should almost never form the basis of such requests.²

In contrast, the American Medical Association (AMA) does not distinguish between the presence of a mental health condition and physician impairment,^3,4 which may result in unwarranted requests and referrals for mental health evaluations. Some state laws on impairment, which all derive from AMA policies,⁵ even state outright that, “‘Impaired’ or ‘impairment’ means the presence of the diseases of alcoholism, drug abuse, or mental illness”⁶ and directly discriminate against physicians with these conditions.

State physician health programs (PHPs) also may describe impairment in problematic ways (eg, “Involvement in litigation against hospital”).⁷ Their descriptions also are overly inclusive in that they could be used to describe most physicians (N.D.L., J.W.B., unpublished data, 2017), and they rarely represent sufficient legal indications for a mental health evaluation under the ADA (N.D.L., J.W.B., unpublished data, 2017). Even the APA’s Clinical Guide to Psychiatric Ethics describes physician impairment as synonymous with mental illness.⁸

Requests for mental health information or evaluations not only can include referrals to state PHPs but also “suggestions” to see a psychologist, professional job coach, or any provider who may ask for mental health information. Under the ADA's guidelines, obtaining “voluntary” consent from an employee who could be fired for not cooperating does not change the involuntary nature of these requests.^2,9

Employers who hire psychiatrists, physicians, and medical residents should comply with the ADA and disregard the AMA’s policies, state laws, PHPs, other institutional guidelines,¹⁰ and guidance from some articles published in Current Psychiatry^11,12 when requesting mental health information, evaluations, and referrals for their employees.

As psychiatrists, we often provide our patients with a prescription in the hope that the medication will alleviate their symptoms. Perhaps we engage our patients in psychotherapy, encouraging them to reflect on their thoughts, behaviors, and emotions to alter their cognitions. We may remark that our goal is for the patient to “become their own therapist.” What if we encouraged our patients to express themselves in a less structured manner and become their own therapists through writing?

Benefits of expressive writing

Writing about an experienced traumatic event—specifically, to express emotions related to the event—has been associated with improved health outcomes.^1,2 Many of these improvements are related to somatic health and basic function, including decreased use of health services, improved immune functioning, and a boost in grades or occupational performance.¹ Patients who participate in expressive writing also have demonstrated improvements in distress, negative affect, depression, and posttraumatic stress disorder (PTSD) symptoms.^1,2 Although improvement in PTSD symptoms with expressive writing has varied across studies, it appears that patients with PTSD who score high in trait negative emotion may receive the most benefit from the practice.³

Why does it work?

There are several theories regarding why expressive writing is an effective therapy. Originally, it was believed that the active inhibition of not talking about traumatic events was a form of physiological work and a long-term, low-lying stressor, and that writing about such events could reduce this stress. However, newer studies offer various explanations for its efficacy, including:

• repeat exposure to stressful or traumatic memories and consequent self-distancing
• creation of a narrative around the stressful event
• labeling of emotions
• self-affirmation and meaning-making related to the negative event.⁴

Rx writing

Encouraging your patients to use expressive writing is simple. You might ask a patient struggling with distress and negative affect following a traumatic experience to write about his (her) thoughts and feelings regarding the incident. For example:

Spend about 15 minutes writing your deepest thoughts and feelings about going through this traumatic experience. Discuss the ways it affected different areas of your life, including relationships with family and friends, school or work, or self-confidence and self-esteem. Don’t worry about spelling, grammar, or sentence structure.

Assure patients that you do not need to review their writing, but would like to hear about their experience writing. Many studies on expressive writing instructed participants to write for 3 to 5 consecutive days, 15 to 30 minutes each day.^1,2 Patients may disclose a dramatic spectrum and intensity of experience and often are willing to do so.

Expressive writing is a simple, low-risk exercise that benefits many people. Perhaps by prescribing a course of writing, you will find your patients can benefit as well.

As psychiatrists, we often provide our patients with a prescription in the hope that the medication will alleviate their symptoms. Perhaps we engage our patients in psychotherapy, encouraging them to reflect on their thoughts, behaviors, and emotions to alter their cognitions. We may remark that our goal is for the patient to “become their own therapist.” What if we encouraged our patients to express themselves in a less structured manner and become their own therapists through writing?

Benefits of expressive writing

Writing about an experienced traumatic event—specifically, to express emotions related to the event—has been associated with improved health outcomes.^1,2 Many of these improvements are related to somatic health and basic function, including decreased use of health services, improved immune functioning, and a boost in grades or occupational performance.¹ Patients who participate in expressive writing also have demonstrated improvements in distress, negative affect, depression, and posttraumatic stress disorder (PTSD) symptoms.^1,2 Although improvement in PTSD symptoms with expressive writing has varied across studies, it appears that patients with PTSD who score high in trait negative emotion may receive the most benefit from the practice.³

Why does it work?

There are several theories regarding why expressive writing is an effective therapy. Originally, it was believed that the active inhibition of not talking about traumatic events was a form of physiological work and a long-term, low-lying stressor, and that writing about such events could reduce this stress. However, newer studies offer various explanations for its efficacy, including:

• repeat exposure to stressful or traumatic memories and consequent self-distancing
• creation of a narrative around the stressful event
• labeling of emotions
• self-affirmation and meaning-making related to the negative event.⁴

Rx writing

Encouraging your patients to use expressive writing is simple. You might ask a patient struggling with distress and negative affect following a traumatic experience to write about his (her) thoughts and feelings regarding the incident. For example:

Spend about 15 minutes writing your deepest thoughts and feelings about going through this traumatic experience. Discuss the ways it affected different areas of your life, including relationships with family and friends, school or work, or self-confidence and self-esteem. Don’t worry about spelling, grammar, or sentence structure.

Assure patients that you do not need to review their writing, but would like to hear about their experience writing. Many studies on expressive writing instructed participants to write for 3 to 5 consecutive days, 15 to 30 minutes each day.^1,2 Patients may disclose a dramatic spectrum and intensity of experience and often are willing to do so.

Expressive writing is a simple, low-risk exercise that benefits many people. Perhaps by prescribing a course of writing, you will find your patients can benefit as well.

As psychiatrists, we often provide our patients with a prescription in the hope that the medication will alleviate their symptoms. Perhaps we engage our patients in psychotherapy, encouraging them to reflect on their thoughts, behaviors, and emotions to alter their cognitions. We may remark that our goal is for the patient to “become their own therapist.” What if we encouraged our patients to express themselves in a less structured manner and become their own therapists through writing?

Benefits of expressive writing

Writing about an experienced traumatic event—specifically, to express emotions related to the event—has been associated with improved health outcomes.^1,2 Many of these improvements are related to somatic health and basic function, including decreased use of health services, improved immune functioning, and a boost in grades or occupational performance.¹ Patients who participate in expressive writing also have demonstrated improvements in distress, negative affect, depression, and posttraumatic stress disorder (PTSD) symptoms.^1,2 Although improvement in PTSD symptoms with expressive writing has varied across studies, it appears that patients with PTSD who score high in trait negative emotion may receive the most benefit from the practice.³

Why does it work?

There are several theories regarding why expressive writing is an effective therapy. Originally, it was believed that the active inhibition of not talking about traumatic events was a form of physiological work and a long-term, low-lying stressor, and that writing about such events could reduce this stress. However, newer studies offer various explanations for its efficacy, including:

• repeat exposure to stressful or traumatic memories and consequent self-distancing
• creation of a narrative around the stressful event
• labeling of emotions
• self-affirmation and meaning-making related to the negative event.⁴

Rx writing

Encouraging your patients to use expressive writing is simple. You might ask a patient struggling with distress and negative affect following a traumatic experience to write about his (her) thoughts and feelings regarding the incident. For example:

Spend about 15 minutes writing your deepest thoughts and feelings about going through this traumatic experience. Discuss the ways it affected different areas of your life, including relationships with family and friends, school or work, or self-confidence and self-esteem. Don’t worry about spelling, grammar, or sentence structure.

Assure patients that you do not need to review their writing, but would like to hear about their experience writing. Many studies on expressive writing instructed participants to write for 3 to 5 consecutive days, 15 to 30 minutes each day.^1,2 Patients may disclose a dramatic spectrum and intensity of experience and often are willing to do so.

Expressive writing is a simple, low-risk exercise that benefits many people. Perhaps by prescribing a course of writing, you will find your patients can benefit as well.

Patients may ask their psychiatrist to prescribe gluten-, lactose-, or animal-free medications because of concerns about allergies, disease states, religious beliefs, or dietary preferences. Determining the source of non-active medication ingredients can be challenging and time-consuming, because ingredients vary across dosages and formulations of the same medication. We review how to address requests for gluten-, lactose-, and animal-free medications.

Gluten-free

Although the risk of a medication containing gluten is low,¹ patients with Celiac disease must avoid gluten to prevent disease exacerbation. Therefore, physicians should thoroughly evaluate medication ingredients to prevent inadvertent gluten consumption.

Medication excipients that may contain gluten include:

• starch
• pregelatinized starch
• sodium starch glycolate.¹

These starches can come from various sources, including corn, wheat, potato, and tapioca. Wheat-derived starch contains gluten and should be avoided by patients with Celiac disease. Advise patients to avoid any starch if its source cannot be determined.

Some sources may list sugar alcohols, such as mannitol and xylitol, as gluten–containing excipients because they may be extracted from starch sources, such as wheat; however, all gluten is removed during refinement and these products are safe.²

Lactose-free

How to respond to a patient’s request for lactose-free medication depends on whether the patient is lactose intolerant or has a milk allergy. The amount of lactose that patients with lactase deficiency can tolerate varies.³ Most medications are thought to contain minimal amounts of lactose. Case reports have described patients experiencing lactose intolerance symptoms after taking 1 or 2 medications, but this is rare.³ Therefore, it is reasonable to use lactose–containing products in patients with lactose intolerance. If such a patient develops symptoms after taking a medication that contains lactose, suggest that he (she):

• take the medication with food, if appropriate, to slow absorption and reduce symptoms
• take it with a lactase enzyme product
• substitute it with a medication that does not contain lactose (switch to a different product or formulation, as appropriate).

Compared with patients who are lactose intolerant, those with a milk allergy experience an immunoglobulin E–mediated reaction when they consume milk protein. Milk proteins typically are filtered out during manufacturing, but a small amount can remain. Although it has not been determined if oral medications containing milk protein can cause an allergic reaction, some researchers have hypothesized that these medications may be tolerated because acid and digestive enzymes break down the milk protein. However, because the respiratory tract lacks this protection, inhaled products that contain lactose may be more likely to cause an allergic reaction and should be avoided if possible. Because oral medications do not usually contain milk proteins, it may be reasonable to prescribe lactose–containing oral products to a patient with a milk allergy. If the patient experiences a reaction or wishes to avoid lactose, an alternative non-lactose–containing product or formulation may be prescribed.

Animal-free

Individuals who are members of certain religions, including Judaism, Islam, Orthodox Christianity, and the Seventh Day Adventist Church, typically avoid pork, and those who are Hindu or Buddhist may avoid beef products.⁴ Gelatin and stearic acid, which can be found in the gelatin shell of capsules and within extended-release (ER) tablets, frequently are derived from porcine or bovine sources. The source of gelatin and stearic acid may change from lot to lot, and manu­facturers should be contacted to assist with identifying the source for a specific medication. Consider these options to reduce a patient’s exposure to animal-containing products:

• change from an ER to an immediate-release (IR) product (confirm that IR is gelatin- and stearic acid–free)
• use a non-capsule formulation
• remove the content of a capsule before ingestion, if appropriate
• try an alternative route of administration, such as transdermal.

How to best help patients

Before taking steps to accommodate a request for a gluten-, lactose-, or animal-free medication, which can be time-consuming, verify the reason for your patient’s request. It may be sufficient to explain to your patient that typically exposure to excipients within oral medications is small and does not cause problems for a patient with lactose intolerance or a milk allergy. The resources listed in the Table can help provide further education on these concerns; however, due to potential delays in updating a Web site, it may be necessary to contact the medication manufacturer directly to verify ingredients.

If your patient still has concerns about ingredients, consider the following steps:

• Use the National Library of Medicine’s Pillbox Web site (https://pillbox.nlm.nih.gov) to search for a medication, dose, or formulation that does not contain the concerning ingredients
• If the concerning ingredient is not listed, either prescribe the medication or contact the manufacturer for further information, depending on the patient’s reason for the request
• If the concerning ingredient is listed, work with the pharmacist to contact the manufacturer.

There are 2 additional points to consider regarding medication excipients. Be aware that generic medications are produced by multiple manufacturers, and each may use different excipients. Also, a manufacturer may not guarantee that a medication is gluten-free because of the potential for cross-contamination during manufacturing, although the risk is extremely low.

Patients may ask their psychiatrist to prescribe gluten-, lactose-, or animal-free medications because of concerns about allergies, disease states, religious beliefs, or dietary preferences. Determining the source of non-active medication ingredients can be challenging and time-consuming, because ingredients vary across dosages and formulations of the same medication. We review how to address requests for gluten-, lactose-, and animal-free medications.

Gluten-free

Although the risk of a medication containing gluten is low,¹ patients with Celiac disease must avoid gluten to prevent disease exacerbation. Therefore, physicians should thoroughly evaluate medication ingredients to prevent inadvertent gluten consumption.

Medication excipients that may contain gluten include:

• starch
• pregelatinized starch
• sodium starch glycolate.¹

These starches can come from various sources, including corn, wheat, potato, and tapioca. Wheat-derived starch contains gluten and should be avoided by patients with Celiac disease. Advise patients to avoid any starch if its source cannot be determined.

Some sources may list sugar alcohols, such as mannitol and xylitol, as gluten–containing excipients because they may be extracted from starch sources, such as wheat; however, all gluten is removed during refinement and these products are safe.²

Lactose-free

How to respond to a patient’s request for lactose-free medication depends on whether the patient is lactose intolerant or has a milk allergy. The amount of lactose that patients with lactase deficiency can tolerate varies.³ Most medications are thought to contain minimal amounts of lactose. Case reports have described patients experiencing lactose intolerance symptoms after taking 1 or 2 medications, but this is rare.³ Therefore, it is reasonable to use lactose–containing products in patients with lactose intolerance. If such a patient develops symptoms after taking a medication that contains lactose, suggest that he (she):

• take the medication with food, if appropriate, to slow absorption and reduce symptoms
• take it with a lactase enzyme product
• substitute it with a medication that does not contain lactose (switch to a different product or formulation, as appropriate).

Compared with patients who are lactose intolerant, those with a milk allergy experience an immunoglobulin E–mediated reaction when they consume milk protein. Milk proteins typically are filtered out during manufacturing, but a small amount can remain. Although it has not been determined if oral medications containing milk protein can cause an allergic reaction, some researchers have hypothesized that these medications may be tolerated because acid and digestive enzymes break down the milk protein. However, because the respiratory tract lacks this protection, inhaled products that contain lactose may be more likely to cause an allergic reaction and should be avoided if possible. Because oral medications do not usually contain milk proteins, it may be reasonable to prescribe lactose–containing oral products to a patient with a milk allergy. If the patient experiences a reaction or wishes to avoid lactose, an alternative non-lactose–containing product or formulation may be prescribed.

Animal-free

Individuals who are members of certain religions, including Judaism, Islam, Orthodox Christianity, and the Seventh Day Adventist Church, typically avoid pork, and those who are Hindu or Buddhist may avoid beef products.⁴ Gelatin and stearic acid, which can be found in the gelatin shell of capsules and within extended-release (ER) tablets, frequently are derived from porcine or bovine sources. The source of gelatin and stearic acid may change from lot to lot, and manu­facturers should be contacted to assist with identifying the source for a specific medication. Consider these options to reduce a patient’s exposure to animal-containing products:

• change from an ER to an immediate-release (IR) product (confirm that IR is gelatin- and stearic acid–free)
• use a non-capsule formulation
• remove the content of a capsule before ingestion, if appropriate
• try an alternative route of administration, such as transdermal.

How to best help patients

Before taking steps to accommodate a request for a gluten-, lactose-, or animal-free medication, which can be time-consuming, verify the reason for your patient’s request. It may be sufficient to explain to your patient that typically exposure to excipients within oral medications is small and does not cause problems for a patient with lactose intolerance or a milk allergy. The resources listed in the Table can help provide further education on these concerns; however, due to potential delays in updating a Web site, it may be necessary to contact the medication manufacturer directly to verify ingredients.

If your patient still has concerns about ingredients, consider the following steps:

• Use the National Library of Medicine’s Pillbox Web site (https://pillbox.nlm.nih.gov) to search for a medication, dose, or formulation that does not contain the concerning ingredients
• If the concerning ingredient is not listed, either prescribe the medication or contact the manufacturer for further information, depending on the patient’s reason for the request
• If the concerning ingredient is listed, work with the pharmacist to contact the manufacturer.

There are 2 additional points to consider regarding medication excipients. Be aware that generic medications are produced by multiple manufacturers, and each may use different excipients. Also, a manufacturer may not guarantee that a medication is gluten-free because of the potential for cross-contamination during manufacturing, although the risk is extremely low.

Patients may ask their psychiatrist to prescribe gluten-, lactose-, or animal-free medications because of concerns about allergies, disease states, religious beliefs, or dietary preferences. Determining the source of non-active medication ingredients can be challenging and time-consuming, because ingredients vary across dosages and formulations of the same medication. We review how to address requests for gluten-, lactose-, and animal-free medications.

Gluten-free

Although the risk of a medication containing gluten is low,¹ patients with Celiac disease must avoid gluten to prevent disease exacerbation. Therefore, physicians should thoroughly evaluate medication ingredients to prevent inadvertent gluten consumption.

Medication excipients that may contain gluten include:

• starch
• pregelatinized starch
• sodium starch glycolate.¹

These starches can come from various sources, including corn, wheat, potato, and tapioca. Wheat-derived starch contains gluten and should be avoided by patients with Celiac disease. Advise patients to avoid any starch if its source cannot be determined.

Some sources may list sugar alcohols, such as mannitol and xylitol, as gluten–containing excipients because they may be extracted from starch sources, such as wheat; however, all gluten is removed during refinement and these products are safe.²

Lactose-free

How to respond to a patient’s request for lactose-free medication depends on whether the patient is lactose intolerant or has a milk allergy. The amount of lactose that patients with lactase deficiency can tolerate varies.³ Most medications are thought to contain minimal amounts of lactose. Case reports have described patients experiencing lactose intolerance symptoms after taking 1 or 2 medications, but this is rare.³ Therefore, it is reasonable to use lactose–containing products in patients with lactose intolerance. If such a patient develops symptoms after taking a medication that contains lactose, suggest that he (she):

• take the medication with food, if appropriate, to slow absorption and reduce symptoms
• take it with a lactase enzyme product
• substitute it with a medication that does not contain lactose (switch to a different product or formulation, as appropriate).

Compared with patients who are lactose intolerant, those with a milk allergy experience an immunoglobulin E–mediated reaction when they consume milk protein. Milk proteins typically are filtered out during manufacturing, but a small amount can remain. Although it has not been determined if oral medications containing milk protein can cause an allergic reaction, some researchers have hypothesized that these medications may be tolerated because acid and digestive enzymes break down the milk protein. However, because the respiratory tract lacks this protection, inhaled products that contain lactose may be more likely to cause an allergic reaction and should be avoided if possible. Because oral medications do not usually contain milk proteins, it may be reasonable to prescribe lactose–containing oral products to a patient with a milk allergy. If the patient experiences a reaction or wishes to avoid lactose, an alternative non-lactose–containing product or formulation may be prescribed.

Animal-free

Individuals who are members of certain religions, including Judaism, Islam, Orthodox Christianity, and the Seventh Day Adventist Church, typically avoid pork, and those who are Hindu or Buddhist may avoid beef products.⁴ Gelatin and stearic acid, which can be found in the gelatin shell of capsules and within extended-release (ER) tablets, frequently are derived from porcine or bovine sources. The source of gelatin and stearic acid may change from lot to lot, and manu­facturers should be contacted to assist with identifying the source for a specific medication. Consider these options to reduce a patient’s exposure to animal-containing products:

• change from an ER to an immediate-release (IR) product (confirm that IR is gelatin- and stearic acid–free)
• use a non-capsule formulation
• remove the content of a capsule before ingestion, if appropriate
• try an alternative route of administration, such as transdermal.

How to best help patients

Before taking steps to accommodate a request for a gluten-, lactose-, or animal-free medication, which can be time-consuming, verify the reason for your patient’s request. It may be sufficient to explain to your patient that typically exposure to excipients within oral medications is small and does not cause problems for a patient with lactose intolerance or a milk allergy. The resources listed in the Table can help provide further education on these concerns; however, due to potential delays in updating a Web site, it may be necessary to contact the medication manufacturer directly to verify ingredients.

If your patient still has concerns about ingredients, consider the following steps:

• Use the National Library of Medicine’s Pillbox Web site (https://pillbox.nlm.nih.gov) to search for a medication, dose, or formulation that does not contain the concerning ingredients
• If the concerning ingredient is not listed, either prescribe the medication or contact the manufacturer for further information, depending on the patient’s reason for the request
• If the concerning ingredient is listed, work with the pharmacist to contact the manufacturer.

There are 2 additional points to consider regarding medication excipients. Be aware that generic medications are produced by multiple manufacturers, and each may use different excipients. Also, a manufacturer may not guarantee that a medication is gluten-free because of the potential for cross-contamination during manufacturing, although the risk is extremely low.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

Since finishing up the initial planning phase of our project, my mentors and I have continued with even more planning as we head into the fall. Coming up with a good plan is the first step in making sure everything goes smoothly later on in a project. The same goes for coming up with a well-thought-out discharge plan when sending a patient to the next level of care.

Monisha Bhatia, a native of Nashville, Tenn., is a fourth-year medical student at Vanderbilt University in Nashville. She is hoping to pursue either a residency in internal medicine or a combined internal medicine/emergency medicine program. Prior to medical school, she completed a JD/MPH program at Boston University, and she hopes to use her legal training in working with regulatory authorities to improve access to health care for all Americans.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

Since finishing up the initial planning phase of our project, my mentors and I have continued with even more planning as we head into the fall. Coming up with a good plan is the first step in making sure everything goes smoothly later on in a project. The same goes for coming up with a well-thought-out discharge plan when sending a patient to the next level of care.

Monisha Bhatia, a native of Nashville, Tenn., is a fourth-year medical student at Vanderbilt University in Nashville. She is hoping to pursue either a residency in internal medicine or a combined internal medicine/emergency medicine program. Prior to medical school, she completed a JD/MPH program at Boston University, and she hopes to use her legal training in working with regulatory authorities to improve access to health care for all Americans.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

Since finishing up the initial planning phase of our project, my mentors and I have continued with even more planning as we head into the fall. Coming up with a good plan is the first step in making sure everything goes smoothly later on in a project. The same goes for coming up with a well-thought-out discharge plan when sending a patient to the next level of care.

Monisha Bhatia, a native of Nashville, Tenn., is a fourth-year medical student at Vanderbilt University in Nashville. She is hoping to pursue either a residency in internal medicine or a combined internal medicine/emergency medicine program. Prior to medical school, she completed a JD/MPH program at Boston University, and she hopes to use her legal training in working with regulatory authorities to improve access to health care for all Americans.