Current Psychiatry

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Conducting clinical research with patients in an acute inpatient psychi­atric setting raises possible ethical dif­ficulties, in part because of concern about patients’ ability to give informed consent to participate in research.

We propose the acronym CHECK (for capacity, heredity, ethics, coercion-free, and knowledge) to provide researchers with guid­ance on the process of addressing informed consent in an acute inpatient setting.

Capacity. Ensure that the patient has the decisional capacity to:

• understand disclosed information about proposed research
• appreciate the impact of participation and nonparticipation
• reason about risks and benefits of participation
• communicate a consistent choice.¹

The standards for disclosing informa­tion to a potential participant are higher for research than in clinical practice, because patients must understand and accept ran­domization, placebo control, blinding, and possible exposure to non-approved treat­ment interventions—yet there is a balance regarding how much information is neces­sary for consent in a given situation.²

Be mindful that the severity of the patient’s psychiatric illness can impair understanding and insight that might pre­clude giving informed consent (eg, major depression can produce a slowing of intel­lectual processes; mania can display dis­tractibility; schizophrenia can compromise decisional capacity because of disorga­nized thinking or delusions; and neuro­cognitive disorders can affect the ability to process information).

The MacArthur Competence Assessment Tool for Clinical Research, designed as an aid to assessing capacity, has the most empirical support, although other instru­ments might be equally or better suited to some situations.¹

Heredity. When undertaking human genetic and genomic research, create a precise, robust consent process. Genome sequencing studies can reveal information about the health of patients and their families, provoking discussion about appropriate protections for such data. Informed consent should include:

• how the data will be used now and in the future
• the extent to which patients can control future use of the data
• benefits and risks of participation, including the potential for unknown future risks
• what information, including incidental findings, will be returned to the patient
• what methods will be used to safe­guard genetic testing data.³

Ethics. Researchers are bound by a code of ethics:

• Patients have the right to decline par­ticipation in research and to withdraw at any stage without prejudice; exclusion rec­ognizes the need to protect those who may be incapable of exercising that right.² Avoid research with dissenting patients, whether or not they are considered capable.² Do not rou­tinely invite treatment-refusing patients to participate in research projects, other than in extraordinary circumstances; eg, treatment refusing patients who have been adjudicated as “incompetent,” in which case the court-appointed surrogate decision-maker could be approached for informed consent. You should routinely seek a legal opinion in such a circumstance.

• Unless the research is examining inter­ventions for acute and disabling psychiatric illness, consent should not be sought until patients are well enough to make an informed decision. However, clinical assessment is always needed (despite psychiatric illness category) because it cannot be assumed that psychiatric patients are unable to make such a decision (eg, in some cases, substance abuse should not automatically eliminate a partici­pant, as long as the patient retains adequate cognitive status for informed consent).

• Capacity for consent is not “all-or-nothing,” but is specific to the research para­digm. In cases of impaired decisional capacity, researchers can obtain informed consent by obtaining agreement of family, legal represen­tative, or caregiver; therefore, research with assenting adults, who are nonetheless incapa­ble, is unlikely to be regarded as unethical.²

Coercion-free. Avoid covert pressures:
• Ensure that consent is given freely without coercion or duress. This is impor­tant if the participant has a physician-patient relationship with a member of the research team. Exercise caution when research meth­ods involve physical contact. Such contact, in incapable patients—even those who assent— could create a medico-legal conflict (eg, tak­ing a blood sample specific for research purposes without consent could result in a charge of battery).² When in doubt, seek a legal opinion before enrolling decisionally incapable patients (and/or those adjudicated as incompetent) in research trials.

• Consider that participation be initi­ated by a third party (eg, an approach from a staff member who is not part of their care team and not involved in the research to ask if the potential participant has made a deci­sion that he wants to have communicated to the researcher⁴).

• Require that a family member, legal representative, or caregiver be present at the time of consent with decisionally incapaci­tated patients.

Knowledge. The participant must be given adequate information about the project. Understand consent as an ongoing process occurring within a specific context:

• Give participants a fair explanation of the proposed project, the risks and ben­efits that might ensue, and, when applicable, what appropriate procedures may be offered if the participant experiences discomfort. If a study is to be blinded, patients must under­stand and appreciate that they could receive no benefit at all.

• Consider the importance of using appropriate language, repeating informa­tion, ensuring adequate time for ques­tions and answers, and providing written material to the patient.² Avoid leaving the patient alone with an information sheet to avoid coercion, because this risks deny­ing patients the opportunity to participate because they lack the occasion to receive information and ask questions.⁴ Rather, go over the research consent document item by item with the patient in an iterative pro­cess, encouraging questions. Ensure private individual discussion between study team members and the patient to address ques­tions related to the study.⁴

• Reapproach patients to discuss or revisit consent as needed, because their capacity to provide informed consent may vary over time. This is especially important in CNS ill­nesses, in which the level of cognitive func­tion is variable. An item such as “consent status” for each encounter can be added to the checklist.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Conducting clinical research with patients in an acute inpatient psychi­atric setting raises possible ethical dif­ficulties, in part because of concern about patients’ ability to give informed consent to participate in research.

We propose the acronym CHECK (for capacity, heredity, ethics, coercion-free, and knowledge) to provide researchers with guid­ance on the process of addressing informed consent in an acute inpatient setting.

Capacity. Ensure that the patient has the decisional capacity to:

• understand disclosed information about proposed research
• appreciate the impact of participation and nonparticipation
• reason about risks and benefits of participation
• communicate a consistent choice.¹

The standards for disclosing informa­tion to a potential participant are higher for research than in clinical practice, because patients must understand and accept ran­domization, placebo control, blinding, and possible exposure to non-approved treat­ment interventions—yet there is a balance regarding how much information is neces­sary for consent in a given situation.²

Be mindful that the severity of the patient’s psychiatric illness can impair understanding and insight that might pre­clude giving informed consent (eg, major depression can produce a slowing of intel­lectual processes; mania can display dis­tractibility; schizophrenia can compromise decisional capacity because of disorga­nized thinking or delusions; and neuro­cognitive disorders can affect the ability to process information).

The MacArthur Competence Assessment Tool for Clinical Research, designed as an aid to assessing capacity, has the most empirical support, although other instru­ments might be equally or better suited to some situations.¹

Heredity. When undertaking human genetic and genomic research, create a precise, robust consent process. Genome sequencing studies can reveal information about the health of patients and their families, provoking discussion about appropriate protections for such data. Informed consent should include:

• how the data will be used now and in the future
• the extent to which patients can control future use of the data
• benefits and risks of participation, including the potential for unknown future risks
• what information, including incidental findings, will be returned to the patient
• what methods will be used to safe­guard genetic testing data.³

Ethics. Researchers are bound by a code of ethics:

• Patients have the right to decline par­ticipation in research and to withdraw at any stage without prejudice; exclusion rec­ognizes the need to protect those who may be incapable of exercising that right.² Avoid research with dissenting patients, whether or not they are considered capable.² Do not rou­tinely invite treatment-refusing patients to participate in research projects, other than in extraordinary circumstances; eg, treatment refusing patients who have been adjudicated as “incompetent,” in which case the court-appointed surrogate decision-maker could be approached for informed consent. You should routinely seek a legal opinion in such a circumstance.

• Unless the research is examining inter­ventions for acute and disabling psychiatric illness, consent should not be sought until patients are well enough to make an informed decision. However, clinical assessment is always needed (despite psychiatric illness category) because it cannot be assumed that psychiatric patients are unable to make such a decision (eg, in some cases, substance abuse should not automatically eliminate a partici­pant, as long as the patient retains adequate cognitive status for informed consent).

• Capacity for consent is not “all-or-nothing,” but is specific to the research para­digm. In cases of impaired decisional capacity, researchers can obtain informed consent by obtaining agreement of family, legal represen­tative, or caregiver; therefore, research with assenting adults, who are nonetheless incapa­ble, is unlikely to be regarded as unethical.²

Coercion-free. Avoid covert pressures:
• Ensure that consent is given freely without coercion or duress. This is impor­tant if the participant has a physician-patient relationship with a member of the research team. Exercise caution when research meth­ods involve physical contact. Such contact, in incapable patients—even those who assent— could create a medico-legal conflict (eg, tak­ing a blood sample specific for research purposes without consent could result in a charge of battery).² When in doubt, seek a legal opinion before enrolling decisionally incapable patients (and/or those adjudicated as incompetent) in research trials.

• Consider that participation be initi­ated by a third party (eg, an approach from a staff member who is not part of their care team and not involved in the research to ask if the potential participant has made a deci­sion that he wants to have communicated to the researcher⁴).

• Require that a family member, legal representative, or caregiver be present at the time of consent with decisionally incapaci­tated patients.

Knowledge. The participant must be given adequate information about the project. Understand consent as an ongoing process occurring within a specific context:

• Give participants a fair explanation of the proposed project, the risks and ben­efits that might ensue, and, when applicable, what appropriate procedures may be offered if the participant experiences discomfort. If a study is to be blinded, patients must under­stand and appreciate that they could receive no benefit at all.

• Consider the importance of using appropriate language, repeating informa­tion, ensuring adequate time for ques­tions and answers, and providing written material to the patient.² Avoid leaving the patient alone with an information sheet to avoid coercion, because this risks deny­ing patients the opportunity to participate because they lack the occasion to receive information and ask questions.⁴ Rather, go over the research consent document item by item with the patient in an iterative pro­cess, encouraging questions. Ensure private individual discussion between study team members and the patient to address ques­tions related to the study.⁴

• Reapproach patients to discuss or revisit consent as needed, because their capacity to provide informed consent may vary over time. This is especially important in CNS ill­nesses, in which the level of cognitive func­tion is variable. An item such as “consent status” for each encounter can be added to the checklist.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Conducting clinical research with patients in an acute inpatient psychi­atric setting raises possible ethical dif­ficulties, in part because of concern about patients’ ability to give informed consent to participate in research.

We propose the acronym CHECK (for capacity, heredity, ethics, coercion-free, and knowledge) to provide researchers with guid­ance on the process of addressing informed consent in an acute inpatient setting.

Capacity. Ensure that the patient has the decisional capacity to:

• understand disclosed information about proposed research
• appreciate the impact of participation and nonparticipation
• reason about risks and benefits of participation
• communicate a consistent choice.¹

The standards for disclosing informa­tion to a potential participant are higher for research than in clinical practice, because patients must understand and accept ran­domization, placebo control, blinding, and possible exposure to non-approved treat­ment interventions—yet there is a balance regarding how much information is neces­sary for consent in a given situation.²

Be mindful that the severity of the patient’s psychiatric illness can impair understanding and insight that might pre­clude giving informed consent (eg, major depression can produce a slowing of intel­lectual processes; mania can display dis­tractibility; schizophrenia can compromise decisional capacity because of disorga­nized thinking or delusions; and neuro­cognitive disorders can affect the ability to process information).

The MacArthur Competence Assessment Tool for Clinical Research, designed as an aid to assessing capacity, has the most empirical support, although other instru­ments might be equally or better suited to some situations.¹

Heredity. When undertaking human genetic and genomic research, create a precise, robust consent process. Genome sequencing studies can reveal information about the health of patients and their families, provoking discussion about appropriate protections for such data. Informed consent should include:

• how the data will be used now and in the future
• the extent to which patients can control future use of the data
• benefits and risks of participation, including the potential for unknown future risks
• what information, including incidental findings, will be returned to the patient
• what methods will be used to safe­guard genetic testing data.³

Ethics. Researchers are bound by a code of ethics:

• Patients have the right to decline par­ticipation in research and to withdraw at any stage without prejudice; exclusion rec­ognizes the need to protect those who may be incapable of exercising that right.² Avoid research with dissenting patients, whether or not they are considered capable.² Do not rou­tinely invite treatment-refusing patients to participate in research projects, other than in extraordinary circumstances; eg, treatment refusing patients who have been adjudicated as “incompetent,” in which case the court-appointed surrogate decision-maker could be approached for informed consent. You should routinely seek a legal opinion in such a circumstance.

• Unless the research is examining inter­ventions for acute and disabling psychiatric illness, consent should not be sought until patients are well enough to make an informed decision. However, clinical assessment is always needed (despite psychiatric illness category) because it cannot be assumed that psychiatric patients are unable to make such a decision (eg, in some cases, substance abuse should not automatically eliminate a partici­pant, as long as the patient retains adequate cognitive status for informed consent).

• Capacity for consent is not “all-or-nothing,” but is specific to the research para­digm. In cases of impaired decisional capacity, researchers can obtain informed consent by obtaining agreement of family, legal represen­tative, or caregiver; therefore, research with assenting adults, who are nonetheless incapa­ble, is unlikely to be regarded as unethical.²

Coercion-free. Avoid covert pressures:
• Ensure that consent is given freely without coercion or duress. This is impor­tant if the participant has a physician-patient relationship with a member of the research team. Exercise caution when research meth­ods involve physical contact. Such contact, in incapable patients—even those who assent— could create a medico-legal conflict (eg, tak­ing a blood sample specific for research purposes without consent could result in a charge of battery).² When in doubt, seek a legal opinion before enrolling decisionally incapable patients (and/or those adjudicated as incompetent) in research trials.

• Consider that participation be initi­ated by a third party (eg, an approach from a staff member who is not part of their care team and not involved in the research to ask if the potential participant has made a deci­sion that he wants to have communicated to the researcher⁴).

• Require that a family member, legal representative, or caregiver be present at the time of consent with decisionally incapaci­tated patients.

Knowledge. The participant must be given adequate information about the project. Understand consent as an ongoing process occurring within a specific context:

• Give participants a fair explanation of the proposed project, the risks and ben­efits that might ensue, and, when applicable, what appropriate procedures may be offered if the participant experiences discomfort. If a study is to be blinded, patients must under­stand and appreciate that they could receive no benefit at all.

• Consider the importance of using appropriate language, repeating informa­tion, ensuring adequate time for ques­tions and answers, and providing written material to the patient.² Avoid leaving the patient alone with an information sheet to avoid coercion, because this risks deny­ing patients the opportunity to participate because they lack the occasion to receive information and ask questions.⁴ Rather, go over the research consent document item by item with the patient in an iterative pro­cess, encouraging questions. Ensure private individual discussion between study team members and the patient to address ques­tions related to the study.⁴

• Reapproach patients to discuss or revisit consent as needed, because their capacity to provide informed consent may vary over time. This is especially important in CNS ill­nesses, in which the level of cognitive func­tion is variable. An item such as “consent status” for each encounter can be added to the checklist.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Patients who have epilepsy have a higher incidence of psychi­atric illness than the general population—at a prevalence of 60%.¹ Establishing a temporal association and making a psy­chiatric diagnosis can be vexing, but awareness of potential comorbidi­ties does improve the clinical outcome² (Box). As this article discusses, psychiatric presentations and ictal disorders can share com­mon pathology and exacerbate one another.³ Their coexistence often results in frequent hospitalization, higher treatment cost, and drug-resistant seizures.⁴ Risk factors for psychopathology in people who have epilepsy include psychosocial stressors, genetic factors, early age of onset of seizures, and each ictal event.⁵ Among ictal disorders, tem­poral-lobe epilepsy confers the highest rate of comorbidity.³

Mood disorders
Mood disorders are the most common psychiatric disorder comorbid with epilepsy (irrespective of age, socioeconomic status, and ethnic­ity), affecting 43% of patients who have a seizure disorder.⁵ These disorders present as an ictal aura in 1% of cases; the presence of a comorbid mood disorder implies a more severe form of epilepsy.² Most mood disorders are underdiagnosed in epilepsy, however, because of the mistaken assumption that depression is a normal reaction to hav­ing a seizure disorder.

Interictal depression is the most commonly reported complaint, although dysphoria also can present peri-ictally.6 The severity of depression and the seizure disorder often are directly proportional to each other.1 Decreased levels of serotonin and norepinephrine, or abnormalities in their transport or post­synaptic binding, have been reported in epilepsy and in affective illness.6 MRI studies have documented that patients who have a depressive disorder have more gray-matter loss compared with healthy controls.7 Depression diminishes the qual­ity of seizure remission after medical and surgical interventions for epilepsy.8

Taking a multidisciplinary approach to treating a mood disorder in a patient who has epilepsy might improve ictal and mood outcomes.⁹ Anhedonia is the most common presenting symptom, but some patients do not meet DSM-5 criteria. Depression exhib­its atypically, with fatigue, irritability, poor frustration tolerance, anxiety, and mood lability.⁶ Self-report screening scales, such as the Neurological Disorders Depression Inventory for Epilepsy, are helpful for mak­ing a diagnosis.¹⁰

Treatment. Prompt antidepressant treat­ment is indicated. Selective serotonin reuptake inhibitors (SSRIs) and sero­tonin-norepinephrine reuptake inhibitors are the most common agents in this set­ting.¹¹ Consider possible cytochrome P450 interactions between antiepileptic drugs (AEDs) and antidepressants; sertra­line, citalopram, and escitalopram have the lowest incidence of adverse effects. Because tricyclic antidepressants have proconvulsant properties, they are not commonly prescribed in these patients¹² (Table 1).¹³

AEDs can produce psychiatric effects, even in nonconvulsive epilepsies. Twenty-eight percent of cases of depression that are comorbid with epilepsy have an iatro­genic basis, and can be induced by barbi­turates, topiramate, vigabatrin, tiagabine, and levetiracetam.¹³ These adverse effects are a common reason that patients discon­tinue drug treatment and obtain psychiatric consultation.¹⁵

Neurosurgical management of epilepsy carries a low risk of depression compared with pharmacotherapy because the surgery offers better ictal control.¹⁶ Because some AEDs have mood-stabilizing properties, discontinuing one might unmask an under­lying mood disorder.¹⁷

The incidence of adjustment disorder with depressed mood in persons who have epilepsy is 10%; with dysthymia, the inci­dence is 4%. Adjustment problems with an adverse psychosocial outcome are docu­mented more often in patients who have a long-standing, chronic disorder than in those with a more recent diagnosis.¹⁸

Postictal suicidal ideation is more com­mon in persons who have a preexisting mood disorder.⁶ The rate of suicide among epilepsy patients is 5%, compared with 1.4% in the general population—which is the same rate seen among patients with other psychiatric conditions, but higher than what is observed in many chronic medical conditions.¹⁹ Attempted suicide is not a direct result of epilepsy, but is sig­nificantly related to underlying psychopa­thology²⁰; anxiety comorbid with a mood disorder increases the risk of suicide.²¹

The incidence of bipolar disorder among epilepsy patients is 1.4%.²² Although some AEDs can induce mania and hypomania, valproate and lamotrigine each have mood-stabilizing properties that might prevent such episodes.²³


Anxiety disorders
Anxiety. Approximately one-third of epi­lepsy patients report anxiety. In contrast to what is seen with depression, AEDs do no alleviate anxiety.^16,19 Anxiety or fear is the most common ictal-related psychiatric symptom2 making it difficult to differenti­ate anxiety and a seizure.²⁴

Antidepressants, especially an SSRI, often are the treatment of choice; patients must be warned about the risk of an exac­erbation of anxiety precipitated by an anti­depressant. Such an adverse reaction might prompt cognitive-behavioral therapy (CBT) or limited use of a benzodiazepine.²⁵

Obsessive-compulsive disorder. The incidence of OCD in epilepsy is 14% to 22%.²⁶ Damage to the orbitofrontal cor­tex or temporal lobe epilepsy surgery can induce OCD; neurotransmitters involved are serotonin, glutamate, dopamine, and γ-aminobutyric acid (GABA).²⁷ Patients may report obsessive thoughts in the peri-ictal period as well; some AEDs, such as topiramate, have been reported to induce such behaviors.²⁸ Treatment options include CBT, an antidepressant, and, in refractory cases, neurosurgery.²⁹

Psychosis
The prevalence of psychosis is approxi­mately 10% among persons who have epilepsy, and is observed most often in patients who have complex partial sei­zures.³⁰ Risk factors include a family history of epilepsy or psychosis, temporal lobe epi­lepsy, a long seizure history, and significant neuropathology.³¹ Structural abnormalities in the limbic system, especially the hippo­campus, predispose patients to psychosis. Abnormal activity of GABA and dopamine are implicated in psychotic symptoms in these patients.³²

Depending on the type and focus of the seizure, ictal psychoses present with cog­nitive and affective symptoms or halluci­nations. Delusions can be associated with comorbid traumatic brain injury.³² Postictal psychosis is differentiated from other peri-ictal confusional states by:

• absence of confusion or autonomic dysfunction
• presence of more organized thinking
• absence of EEG changes.³³

Alteration of an AED regimen can induce post-ictal psychosis. Iatrogenic psychosis sometimes is observed after right-sided temporal lobe surgery.³⁴

Interictal psychoses probably occur as a result of aberrant nerve regeneration, with an increased concentration of dopa­mine in the brain after long-term seizure control. Epileptic psychosis is distin­guished from schizophrenia by the pre­dominance of visual hallucinations, no alteration of personality or affect, and glial proliferation.35 Some patients exhibit “forced normalization,” in which psy­chotic features appear after epilepsy has been treated successfully and EEG find­ings are normalized.³⁶

Management of psychosis in epilepsy includes ensuring the patient’s safety, rul­ing out medical causes of psychosis, and preventing relapse. Prescribe antipsychotics with caution because many of these agents have epileptogenic potential or can inter­fere with the hepatic metabolism of AEDs. Quetiapine, risperidone, and haloperi­dol have low potential for seizure induc­tion; chlorpromazine and clozapine are more likely to precipitate an ictal event.³⁷ Ziprasidone, quetiapine, and aripiprazole often are prescribed for post-ictal and inter-ictal psychoses.³⁸


Sleep disorders
Epilepsy patients often complain about dif­ficulty sleeping, namely:

• 10% to 33% exhibit restless leg syndrome or periodic limb movement disorder
• 10% to 65% have obstructive sleep apnea
• 11% to 28% report excessive daytime sleepiness.³

Convulsive activity and the rate of gen­eralization of partial seizures are increased by sleep, especially non-rapid eye move­ment sleep. Rapid eye movement (REM) sleep suppresses ictal activity, but the pat­tern of REM sleep is disrupted in epilepsy. Seizures and some sleep disorders present with similar symptoms, such as confusion and amnesia (Table 2).39

Management of comorbid sleep prob­lems includes:

• effective control of seizures
• avoidance of polypharmacy
• assuring sleep hygiene.

Disordered sleep resulting from an AED might be relieved by switching to another medication.39

Substance abuse
Abuse of substances is a significant risk factor for recurrence of seizures.

Alcohol, at a low dose, has antiepileptic properties; intoxication rarely induces a seizure, although seizures often accom­pany alcohol withdrawal.⁴⁰

Acute alcohol abuse increases the free level of AEDs by inhibiting 1) microsomal enzyme systems and 2) binding of albumin by metabolites, such as acetaldehyde. These effects can lead to the dangerous outcome of respiratory depression, especially with drugs like phenobarbital.

Chronic alcohol use induces hepatic enzymes, which augments clearance of AEDs, except benzodiazepines. Metabolism of AEDs is decreased because of reduced hepatic blood flow.

Moderate drinking does not increase the incidence of seizures in medication-adherent patients. People who have recur­rent alcohol-withdrawal seizures do not have a heightened risk of epilepsy.41

Cannabis. Animal studies have docu­mented the anticonvulsant effect of Cannabis in partial and generalized epi­lepsy and a proconvulsant effect in absence (petit mal) seizures.⁴²

Tramadol, caffeine. Patients who abuse tramadol or who have an excessive intake of caffeine have a decreased seizure threshold.⁴³

Opiates can exert a proconvulsant or anti­convulsant action, depending on the type of endorphin receptors involved.⁴⁴

Cocaine decreases the seizure threshold by 1) blocking cerebral GABA receptors and 2) inhibiting dopamine reuptake, thus elevating excitatory neurotransmitters. Cocaine can cause a generalized or focal seizure; the latter is caused by intracere­bral stroke or hemorrhage.45

The AEDs topiramate and lamotrigine tend to decrease the desire to abuse alcohol by enhancing inhibitory control by way of decreasing dopamine activity in the meso­corticolimbic system.⁴⁶


Memory deficits
The relative risk of dementia among epi­lepsy patients is greater compared with the general population. Recurrent seizures can result in cognitive deficits; epilepsy has been documented in 2% to 64% of Alzheimer’s disease patients.⁴⁷

Progressive amnesia, with an associated decline in cognition in epilepsy patients despite AED therapy, warrants a dementia workup.⁴⁸ Patients with an ictal disorder often have difficulty with memory, espe­cially if the hippocampus is affected, such as in temporal lobe epilepsy. Seizures are a common manifestation of several neu­rodegenerative conditions, and may be associated with a treatable dementia or psychosis in patients with cyanocobalamin deficiency.⁴⁹

Several memory deficits are associated with seizure disorders:

• Transient epileptic amnesia can be ictal or post-ictal, or can be a manifestation of an underlying seizure disorder. The con­dition is associated with isolated memory deficits; other cognitive functions usually are intact.
• Accelerated long-term memory deficit occurs when patients forget skills acquired over the past few days or weeks. The problem can be reduced with sleep.⁵⁰
• Remote memory impairment is characterized by inability to recall personal information from the past.⁵¹

When considering a diagnosis of a mem­ory deficit as a manifestation of dementia, keep in mind that cognitive impairment also can develop after epilepsy treat­ment—although most newer medications cause relatively few such problems.^52,53

2-pronged management. It is difficult to establish a temporal association between epilepsy and dementia. When the condi­tions coexist, appropriate treatment of both is important, because inadequate control of seizures can heighten release of amyloid toxins in the hippocampus. This results in rapidly progressive cognitive decline.⁵⁴

Neurodevelopmental disorders
The incidence of epilepsy in children who have an autism spectrum disorder is 5% to 38%; the disorder is more common in the presence of mental retardation or cere­bral palsy.⁵⁵

A significant percentage of youth who are referred for evaluation of attention-deficit/ hyperactivity disorder (ADHD) eventually are given a diagnosis of absence seizures. The incidence of ADHD in children with epi­lepsy is 20%; these patients display epilepti­form EEG changes, and require meticulous screening, which includes ictal induction by hyperventilation to differentiate ADHD from a seizure disorder.⁵⁶ Many AEDs, especially GABAergic drugs, can cause symptoms of ADHD. Methylphenidate is safe in children whose seizures are well-controlled, and has no significant interactions with AEDs.⁵⁷

Management. Adequate seizure control is the only effective means to slow regression in cases of epilepsy comorbid with autism spectrum disorder, mental retardation, and cerebral palsy.⁵⁸

BOTTOM LINE
Patients who have epilepsy have a lifetime susceptibility to psychopathology, especially depression and anxiety. Psychiatric practitioners should work collaboratively with patients' primary care provider to evaluate, diagnose, and treat both conditions. Quick action is the key to the best possible outcomes, including reducing the risk of recurrent seizures.

Related Resources
• Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;14:75.
• Centers for Disease Control and Prevention. Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep. 2013;62(43):849-853.
• Kui C, Yingfu P, Chenling X, et al. What are the predictors of major depression in adult patients with epilepsy? Epileptic Disord. 2014;16(1):74-79.
• Lunde ME, Rasmussen KG. Electroconvulsive therapy in patients with epilepsy. Epilepsy Behav. 2006;9(2):355-359.


Drug Brand Names

Aripiprazole • Abilify                               Risperidone • Risperdal
Chlorpromazine •  Thorazine                   Quetlapine • Seroquel
Citalopram •  Celexa                               Sertraline • Zoloft
Clozapine •  Clozaril, FazaClo                   Tiagabine • Gabitril
Escitalopram • Lexapro                            Topiramate • Topamax
Haloperidol • Haldol                                 Tramadol • Ryzolt, Ultram, ConZip
Lamotrigine • Lamictal                             Valproate • Depokate
Levetiracetam • Keppra                            Vigabatrin • Sabril
Methylphenidate • Methylin, Ritalin            Ziprasidone • Geodon


Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Patients who have epilepsy have a higher incidence of psychi­atric illness than the general population—at a prevalence of 60%.¹ Establishing a temporal association and making a psy­chiatric diagnosis can be vexing, but awareness of potential comorbidi­ties does improve the clinical outcome² (Box). As this article discusses, psychiatric presentations and ictal disorders can share com­mon pathology and exacerbate one another.³ Their coexistence often results in frequent hospitalization, higher treatment cost, and drug-resistant seizures.⁴ Risk factors for psychopathology in people who have epilepsy include psychosocial stressors, genetic factors, early age of onset of seizures, and each ictal event.⁵ Among ictal disorders, tem­poral-lobe epilepsy confers the highest rate of comorbidity.³

Mood disorders
Mood disorders are the most common psychiatric disorder comorbid with epilepsy (irrespective of age, socioeconomic status, and ethnic­ity), affecting 43% of patients who have a seizure disorder.⁵ These disorders present as an ictal aura in 1% of cases; the presence of a comorbid mood disorder implies a more severe form of epilepsy.² Most mood disorders are underdiagnosed in epilepsy, however, because of the mistaken assumption that depression is a normal reaction to hav­ing a seizure disorder.

Interictal depression is the most commonly reported complaint, although dysphoria also can present peri-ictally.6 The severity of depression and the seizure disorder often are directly proportional to each other.1 Decreased levels of serotonin and norepinephrine, or abnormalities in their transport or post­synaptic binding, have been reported in epilepsy and in affective illness.6 MRI studies have documented that patients who have a depressive disorder have more gray-matter loss compared with healthy controls.7 Depression diminishes the qual­ity of seizure remission after medical and surgical interventions for epilepsy.8

Taking a multidisciplinary approach to treating a mood disorder in a patient who has epilepsy might improve ictal and mood outcomes.⁹ Anhedonia is the most common presenting symptom, but some patients do not meet DSM-5 criteria. Depression exhib­its atypically, with fatigue, irritability, poor frustration tolerance, anxiety, and mood lability.⁶ Self-report screening scales, such as the Neurological Disorders Depression Inventory for Epilepsy, are helpful for mak­ing a diagnosis.¹⁰

Treatment. Prompt antidepressant treat­ment is indicated. Selective serotonin reuptake inhibitors (SSRIs) and sero­tonin-norepinephrine reuptake inhibitors are the most common agents in this set­ting.¹¹ Consider possible cytochrome P450 interactions between antiepileptic drugs (AEDs) and antidepressants; sertra­line, citalopram, and escitalopram have the lowest incidence of adverse effects. Because tricyclic antidepressants have proconvulsant properties, they are not commonly prescribed in these patients¹² (Table 1).¹³

AEDs can produce psychiatric effects, even in nonconvulsive epilepsies. Twenty-eight percent of cases of depression that are comorbid with epilepsy have an iatro­genic basis, and can be induced by barbi­turates, topiramate, vigabatrin, tiagabine, and levetiracetam.¹³ These adverse effects are a common reason that patients discon­tinue drug treatment and obtain psychiatric consultation.¹⁵

Neurosurgical management of epilepsy carries a low risk of depression compared with pharmacotherapy because the surgery offers better ictal control.¹⁶ Because some AEDs have mood-stabilizing properties, discontinuing one might unmask an under­lying mood disorder.¹⁷

The incidence of adjustment disorder with depressed mood in persons who have epilepsy is 10%; with dysthymia, the inci­dence is 4%. Adjustment problems with an adverse psychosocial outcome are docu­mented more often in patients who have a long-standing, chronic disorder than in those with a more recent diagnosis.¹⁸

Postictal suicidal ideation is more com­mon in persons who have a preexisting mood disorder.⁶ The rate of suicide among epilepsy patients is 5%, compared with 1.4% in the general population—which is the same rate seen among patients with other psychiatric conditions, but higher than what is observed in many chronic medical conditions.¹⁹ Attempted suicide is not a direct result of epilepsy, but is sig­nificantly related to underlying psychopa­thology²⁰; anxiety comorbid with a mood disorder increases the risk of suicide.²¹

The incidence of bipolar disorder among epilepsy patients is 1.4%.²² Although some AEDs can induce mania and hypomania, valproate and lamotrigine each have mood-stabilizing properties that might prevent such episodes.²³


Anxiety disorders
Anxiety. Approximately one-third of epi­lepsy patients report anxiety. In contrast to what is seen with depression, AEDs do no alleviate anxiety.^16,19 Anxiety or fear is the most common ictal-related psychiatric symptom2 making it difficult to differenti­ate anxiety and a seizure.²⁴

Antidepressants, especially an SSRI, often are the treatment of choice; patients must be warned about the risk of an exac­erbation of anxiety precipitated by an anti­depressant. Such an adverse reaction might prompt cognitive-behavioral therapy (CBT) or limited use of a benzodiazepine.²⁵

Obsessive-compulsive disorder. The incidence of OCD in epilepsy is 14% to 22%.²⁶ Damage to the orbitofrontal cor­tex or temporal lobe epilepsy surgery can induce OCD; neurotransmitters involved are serotonin, glutamate, dopamine, and γ-aminobutyric acid (GABA).²⁷ Patients may report obsessive thoughts in the peri-ictal period as well; some AEDs, such as topiramate, have been reported to induce such behaviors.²⁸ Treatment options include CBT, an antidepressant, and, in refractory cases, neurosurgery.²⁹

Psychosis
The prevalence of psychosis is approxi­mately 10% among persons who have epilepsy, and is observed most often in patients who have complex partial sei­zures.³⁰ Risk factors include a family history of epilepsy or psychosis, temporal lobe epi­lepsy, a long seizure history, and significant neuropathology.³¹ Structural abnormalities in the limbic system, especially the hippo­campus, predispose patients to psychosis. Abnormal activity of GABA and dopamine are implicated in psychotic symptoms in these patients.³²

Depending on the type and focus of the seizure, ictal psychoses present with cog­nitive and affective symptoms or halluci­nations. Delusions can be associated with comorbid traumatic brain injury.³² Postictal psychosis is differentiated from other peri-ictal confusional states by:

• absence of confusion or autonomic dysfunction
• presence of more organized thinking
• absence of EEG changes.³³

Alteration of an AED regimen can induce post-ictal psychosis. Iatrogenic psychosis sometimes is observed after right-sided temporal lobe surgery.³⁴

Interictal psychoses probably occur as a result of aberrant nerve regeneration, with an increased concentration of dopa­mine in the brain after long-term seizure control. Epileptic psychosis is distin­guished from schizophrenia by the pre­dominance of visual hallucinations, no alteration of personality or affect, and glial proliferation.35 Some patients exhibit “forced normalization,” in which psy­chotic features appear after epilepsy has been treated successfully and EEG find­ings are normalized.³⁶

Management of psychosis in epilepsy includes ensuring the patient’s safety, rul­ing out medical causes of psychosis, and preventing relapse. Prescribe antipsychotics with caution because many of these agents have epileptogenic potential or can inter­fere with the hepatic metabolism of AEDs. Quetiapine, risperidone, and haloperi­dol have low potential for seizure induc­tion; chlorpromazine and clozapine are more likely to precipitate an ictal event.³⁷ Ziprasidone, quetiapine, and aripiprazole often are prescribed for post-ictal and inter-ictal psychoses.³⁸


Sleep disorders
Epilepsy patients often complain about dif­ficulty sleeping, namely:

• 10% to 33% exhibit restless leg syndrome or periodic limb movement disorder
• 10% to 65% have obstructive sleep apnea
• 11% to 28% report excessive daytime sleepiness.³

Convulsive activity and the rate of gen­eralization of partial seizures are increased by sleep, especially non-rapid eye move­ment sleep. Rapid eye movement (REM) sleep suppresses ictal activity, but the pat­tern of REM sleep is disrupted in epilepsy. Seizures and some sleep disorders present with similar symptoms, such as confusion and amnesia (Table 2).39

Management of comorbid sleep prob­lems includes:

• effective control of seizures
• avoidance of polypharmacy
• assuring sleep hygiene.

Disordered sleep resulting from an AED might be relieved by switching to another medication.39

Substance abuse
Abuse of substances is a significant risk factor for recurrence of seizures.

Alcohol, at a low dose, has antiepileptic properties; intoxication rarely induces a seizure, although seizures often accom­pany alcohol withdrawal.⁴⁰

Acute alcohol abuse increases the free level of AEDs by inhibiting 1) microsomal enzyme systems and 2) binding of albumin by metabolites, such as acetaldehyde. These effects can lead to the dangerous outcome of respiratory depression, especially with drugs like phenobarbital.

Chronic alcohol use induces hepatic enzymes, which augments clearance of AEDs, except benzodiazepines. Metabolism of AEDs is decreased because of reduced hepatic blood flow.

Moderate drinking does not increase the incidence of seizures in medication-adherent patients. People who have recur­rent alcohol-withdrawal seizures do not have a heightened risk of epilepsy.41

Cannabis. Animal studies have docu­mented the anticonvulsant effect of Cannabis in partial and generalized epi­lepsy and a proconvulsant effect in absence (petit mal) seizures.⁴²

Tramadol, caffeine. Patients who abuse tramadol or who have an excessive intake of caffeine have a decreased seizure threshold.⁴³

Opiates can exert a proconvulsant or anti­convulsant action, depending on the type of endorphin receptors involved.⁴⁴

Cocaine decreases the seizure threshold by 1) blocking cerebral GABA receptors and 2) inhibiting dopamine reuptake, thus elevating excitatory neurotransmitters. Cocaine can cause a generalized or focal seizure; the latter is caused by intracere­bral stroke or hemorrhage.45

The AEDs topiramate and lamotrigine tend to decrease the desire to abuse alcohol by enhancing inhibitory control by way of decreasing dopamine activity in the meso­corticolimbic system.⁴⁶


Memory deficits
The relative risk of dementia among epi­lepsy patients is greater compared with the general population. Recurrent seizures can result in cognitive deficits; epilepsy has been documented in 2% to 64% of Alzheimer’s disease patients.⁴⁷

Progressive amnesia, with an associated decline in cognition in epilepsy patients despite AED therapy, warrants a dementia workup.⁴⁸ Patients with an ictal disorder often have difficulty with memory, espe­cially if the hippocampus is affected, such as in temporal lobe epilepsy. Seizures are a common manifestation of several neu­rodegenerative conditions, and may be associated with a treatable dementia or psychosis in patients with cyanocobalamin deficiency.⁴⁹

Several memory deficits are associated with seizure disorders:

• Transient epileptic amnesia can be ictal or post-ictal, or can be a manifestation of an underlying seizure disorder. The con­dition is associated with isolated memory deficits; other cognitive functions usually are intact.
• Accelerated long-term memory deficit occurs when patients forget skills acquired over the past few days or weeks. The problem can be reduced with sleep.⁵⁰
• Remote memory impairment is characterized by inability to recall personal information from the past.⁵¹

When considering a diagnosis of a mem­ory deficit as a manifestation of dementia, keep in mind that cognitive impairment also can develop after epilepsy treat­ment—although most newer medications cause relatively few such problems.^52,53

2-pronged management. It is difficult to establish a temporal association between epilepsy and dementia. When the condi­tions coexist, appropriate treatment of both is important, because inadequate control of seizures can heighten release of amyloid toxins in the hippocampus. This results in rapidly progressive cognitive decline.⁵⁴

Neurodevelopmental disorders
The incidence of epilepsy in children who have an autism spectrum disorder is 5% to 38%; the disorder is more common in the presence of mental retardation or cere­bral palsy.⁵⁵

A significant percentage of youth who are referred for evaluation of attention-deficit/ hyperactivity disorder (ADHD) eventually are given a diagnosis of absence seizures. The incidence of ADHD in children with epi­lepsy is 20%; these patients display epilepti­form EEG changes, and require meticulous screening, which includes ictal induction by hyperventilation to differentiate ADHD from a seizure disorder.⁵⁶ Many AEDs, especially GABAergic drugs, can cause symptoms of ADHD. Methylphenidate is safe in children whose seizures are well-controlled, and has no significant interactions with AEDs.⁵⁷

Management. Adequate seizure control is the only effective means to slow regression in cases of epilepsy comorbid with autism spectrum disorder, mental retardation, and cerebral palsy.⁵⁸

BOTTOM LINE
Patients who have epilepsy have a lifetime susceptibility to psychopathology, especially depression and anxiety. Psychiatric practitioners should work collaboratively with patients' primary care provider to evaluate, diagnose, and treat both conditions. Quick action is the key to the best possible outcomes, including reducing the risk of recurrent seizures.

Related Resources
• Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;14:75.
• Centers for Disease Control and Prevention. Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep. 2013;62(43):849-853.
• Kui C, Yingfu P, Chenling X, et al. What are the predictors of major depression in adult patients with epilepsy? Epileptic Disord. 2014;16(1):74-79.
• Lunde ME, Rasmussen KG. Electroconvulsive therapy in patients with epilepsy. Epilepsy Behav. 2006;9(2):355-359.


Drug Brand Names

Aripiprazole • Abilify                               Risperidone • Risperdal
Chlorpromazine •  Thorazine                   Quetlapine • Seroquel
Citalopram •  Celexa                               Sertraline • Zoloft
Clozapine •  Clozaril, FazaClo                   Tiagabine • Gabitril
Escitalopram • Lexapro                            Topiramate • Topamax
Haloperidol • Haldol                                 Tramadol • Ryzolt, Ultram, ConZip
Lamotrigine • Lamictal                             Valproate • Depokate
Levetiracetam • Keppra                            Vigabatrin • Sabril
Methylphenidate • Methylin, Ritalin            Ziprasidone • Geodon


Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Patients who have epilepsy have a higher incidence of psychi­atric illness than the general population—at a prevalence of 60%.¹ Establishing a temporal association and making a psy­chiatric diagnosis can be vexing, but awareness of potential comorbidi­ties does improve the clinical outcome² (Box). As this article discusses, psychiatric presentations and ictal disorders can share com­mon pathology and exacerbate one another.³ Their coexistence often results in frequent hospitalization, higher treatment cost, and drug-resistant seizures.⁴ Risk factors for psychopathology in people who have epilepsy include psychosocial stressors, genetic factors, early age of onset of seizures, and each ictal event.⁵ Among ictal disorders, tem­poral-lobe epilepsy confers the highest rate of comorbidity.³

Mood disorders
Mood disorders are the most common psychiatric disorder comorbid with epilepsy (irrespective of age, socioeconomic status, and ethnic­ity), affecting 43% of patients who have a seizure disorder.⁵ These disorders present as an ictal aura in 1% of cases; the presence of a comorbid mood disorder implies a more severe form of epilepsy.² Most mood disorders are underdiagnosed in epilepsy, however, because of the mistaken assumption that depression is a normal reaction to hav­ing a seizure disorder.

Interictal depression is the most commonly reported complaint, although dysphoria also can present peri-ictally.6 The severity of depression and the seizure disorder often are directly proportional to each other.1 Decreased levels of serotonin and norepinephrine, or abnormalities in their transport or post­synaptic binding, have been reported in epilepsy and in affective illness.6 MRI studies have documented that patients who have a depressive disorder have more gray-matter loss compared with healthy controls.7 Depression diminishes the qual­ity of seizure remission after medical and surgical interventions for epilepsy.8

Taking a multidisciplinary approach to treating a mood disorder in a patient who has epilepsy might improve ictal and mood outcomes.⁹ Anhedonia is the most common presenting symptom, but some patients do not meet DSM-5 criteria. Depression exhib­its atypically, with fatigue, irritability, poor frustration tolerance, anxiety, and mood lability.⁶ Self-report screening scales, such as the Neurological Disorders Depression Inventory for Epilepsy, are helpful for mak­ing a diagnosis.¹⁰

Treatment. Prompt antidepressant treat­ment is indicated. Selective serotonin reuptake inhibitors (SSRIs) and sero­tonin-norepinephrine reuptake inhibitors are the most common agents in this set­ting.¹¹ Consider possible cytochrome P450 interactions between antiepileptic drugs (AEDs) and antidepressants; sertra­line, citalopram, and escitalopram have the lowest incidence of adverse effects. Because tricyclic antidepressants have proconvulsant properties, they are not commonly prescribed in these patients¹² (Table 1).¹³

AEDs can produce psychiatric effects, even in nonconvulsive epilepsies. Twenty-eight percent of cases of depression that are comorbid with epilepsy have an iatro­genic basis, and can be induced by barbi­turates, topiramate, vigabatrin, tiagabine, and levetiracetam.¹³ These adverse effects are a common reason that patients discon­tinue drug treatment and obtain psychiatric consultation.¹⁵

Neurosurgical management of epilepsy carries a low risk of depression compared with pharmacotherapy because the surgery offers better ictal control.¹⁶ Because some AEDs have mood-stabilizing properties, discontinuing one might unmask an under­lying mood disorder.¹⁷

The incidence of adjustment disorder with depressed mood in persons who have epilepsy is 10%; with dysthymia, the inci­dence is 4%. Adjustment problems with an adverse psychosocial outcome are docu­mented more often in patients who have a long-standing, chronic disorder than in those with a more recent diagnosis.¹⁸

Postictal suicidal ideation is more com­mon in persons who have a preexisting mood disorder.⁶ The rate of suicide among epilepsy patients is 5%, compared with 1.4% in the general population—which is the same rate seen among patients with other psychiatric conditions, but higher than what is observed in many chronic medical conditions.¹⁹ Attempted suicide is not a direct result of epilepsy, but is sig­nificantly related to underlying psychopa­thology²⁰; anxiety comorbid with a mood disorder increases the risk of suicide.²¹

The incidence of bipolar disorder among epilepsy patients is 1.4%.²² Although some AEDs can induce mania and hypomania, valproate and lamotrigine each have mood-stabilizing properties that might prevent such episodes.²³


Anxiety disorders
Anxiety. Approximately one-third of epi­lepsy patients report anxiety. In contrast to what is seen with depression, AEDs do no alleviate anxiety.^16,19 Anxiety or fear is the most common ictal-related psychiatric symptom2 making it difficult to differenti­ate anxiety and a seizure.²⁴

Antidepressants, especially an SSRI, often are the treatment of choice; patients must be warned about the risk of an exac­erbation of anxiety precipitated by an anti­depressant. Such an adverse reaction might prompt cognitive-behavioral therapy (CBT) or limited use of a benzodiazepine.²⁵

Obsessive-compulsive disorder. The incidence of OCD in epilepsy is 14% to 22%.²⁶ Damage to the orbitofrontal cor­tex or temporal lobe epilepsy surgery can induce OCD; neurotransmitters involved are serotonin, glutamate, dopamine, and γ-aminobutyric acid (GABA).²⁷ Patients may report obsessive thoughts in the peri-ictal period as well; some AEDs, such as topiramate, have been reported to induce such behaviors.²⁸ Treatment options include CBT, an antidepressant, and, in refractory cases, neurosurgery.²⁹

Psychosis
The prevalence of psychosis is approxi­mately 10% among persons who have epilepsy, and is observed most often in patients who have complex partial sei­zures.³⁰ Risk factors include a family history of epilepsy or psychosis, temporal lobe epi­lepsy, a long seizure history, and significant neuropathology.³¹ Structural abnormalities in the limbic system, especially the hippo­campus, predispose patients to psychosis. Abnormal activity of GABA and dopamine are implicated in psychotic symptoms in these patients.³²

Depending on the type and focus of the seizure, ictal psychoses present with cog­nitive and affective symptoms or halluci­nations. Delusions can be associated with comorbid traumatic brain injury.³² Postictal psychosis is differentiated from other peri-ictal confusional states by:

• absence of confusion or autonomic dysfunction
• presence of more organized thinking
• absence of EEG changes.³³

Alteration of an AED regimen can induce post-ictal psychosis. Iatrogenic psychosis sometimes is observed after right-sided temporal lobe surgery.³⁴

Interictal psychoses probably occur as a result of aberrant nerve regeneration, with an increased concentration of dopa­mine in the brain after long-term seizure control. Epileptic psychosis is distin­guished from schizophrenia by the pre­dominance of visual hallucinations, no alteration of personality or affect, and glial proliferation.35 Some patients exhibit “forced normalization,” in which psy­chotic features appear after epilepsy has been treated successfully and EEG find­ings are normalized.³⁶

Management of psychosis in epilepsy includes ensuring the patient’s safety, rul­ing out medical causes of psychosis, and preventing relapse. Prescribe antipsychotics with caution because many of these agents have epileptogenic potential or can inter­fere with the hepatic metabolism of AEDs. Quetiapine, risperidone, and haloperi­dol have low potential for seizure induc­tion; chlorpromazine and clozapine are more likely to precipitate an ictal event.³⁷ Ziprasidone, quetiapine, and aripiprazole often are prescribed for post-ictal and inter-ictal psychoses.³⁸


Sleep disorders
Epilepsy patients often complain about dif­ficulty sleeping, namely:

• 10% to 33% exhibit restless leg syndrome or periodic limb movement disorder
• 10% to 65% have obstructive sleep apnea
• 11% to 28% report excessive daytime sleepiness.³

Convulsive activity and the rate of gen­eralization of partial seizures are increased by sleep, especially non-rapid eye move­ment sleep. Rapid eye movement (REM) sleep suppresses ictal activity, but the pat­tern of REM sleep is disrupted in epilepsy. Seizures and some sleep disorders present with similar symptoms, such as confusion and amnesia (Table 2).39

Management of comorbid sleep prob­lems includes:

• effective control of seizures
• avoidance of polypharmacy
• assuring sleep hygiene.

Disordered sleep resulting from an AED might be relieved by switching to another medication.39

Substance abuse
Abuse of substances is a significant risk factor for recurrence of seizures.

Alcohol, at a low dose, has antiepileptic properties; intoxication rarely induces a seizure, although seizures often accom­pany alcohol withdrawal.⁴⁰

Acute alcohol abuse increases the free level of AEDs by inhibiting 1) microsomal enzyme systems and 2) binding of albumin by metabolites, such as acetaldehyde. These effects can lead to the dangerous outcome of respiratory depression, especially with drugs like phenobarbital.

Chronic alcohol use induces hepatic enzymes, which augments clearance of AEDs, except benzodiazepines. Metabolism of AEDs is decreased because of reduced hepatic blood flow.

Moderate drinking does not increase the incidence of seizures in medication-adherent patients. People who have recur­rent alcohol-withdrawal seizures do not have a heightened risk of epilepsy.41

Cannabis. Animal studies have docu­mented the anticonvulsant effect of Cannabis in partial and generalized epi­lepsy and a proconvulsant effect in absence (petit mal) seizures.⁴²

Tramadol, caffeine. Patients who abuse tramadol or who have an excessive intake of caffeine have a decreased seizure threshold.⁴³

Opiates can exert a proconvulsant or anti­convulsant action, depending on the type of endorphin receptors involved.⁴⁴

Cocaine decreases the seizure threshold by 1) blocking cerebral GABA receptors and 2) inhibiting dopamine reuptake, thus elevating excitatory neurotransmitters. Cocaine can cause a generalized or focal seizure; the latter is caused by intracere­bral stroke or hemorrhage.45

The AEDs topiramate and lamotrigine tend to decrease the desire to abuse alcohol by enhancing inhibitory control by way of decreasing dopamine activity in the meso­corticolimbic system.⁴⁶


Memory deficits
The relative risk of dementia among epi­lepsy patients is greater compared with the general population. Recurrent seizures can result in cognitive deficits; epilepsy has been documented in 2% to 64% of Alzheimer’s disease patients.⁴⁷

Progressive amnesia, with an associated decline in cognition in epilepsy patients despite AED therapy, warrants a dementia workup.⁴⁸ Patients with an ictal disorder often have difficulty with memory, espe­cially if the hippocampus is affected, such as in temporal lobe epilepsy. Seizures are a common manifestation of several neu­rodegenerative conditions, and may be associated with a treatable dementia or psychosis in patients with cyanocobalamin deficiency.⁴⁹

Several memory deficits are associated with seizure disorders:

• Transient epileptic amnesia can be ictal or post-ictal, or can be a manifestation of an underlying seizure disorder. The con­dition is associated with isolated memory deficits; other cognitive functions usually are intact.
• Accelerated long-term memory deficit occurs when patients forget skills acquired over the past few days or weeks. The problem can be reduced with sleep.⁵⁰
• Remote memory impairment is characterized by inability to recall personal information from the past.⁵¹

When considering a diagnosis of a mem­ory deficit as a manifestation of dementia, keep in mind that cognitive impairment also can develop after epilepsy treat­ment—although most newer medications cause relatively few such problems.^52,53

2-pronged management. It is difficult to establish a temporal association between epilepsy and dementia. When the condi­tions coexist, appropriate treatment of both is important, because inadequate control of seizures can heighten release of amyloid toxins in the hippocampus. This results in rapidly progressive cognitive decline.⁵⁴

Neurodevelopmental disorders
The incidence of epilepsy in children who have an autism spectrum disorder is 5% to 38%; the disorder is more common in the presence of mental retardation or cere­bral palsy.⁵⁵

A significant percentage of youth who are referred for evaluation of attention-deficit/ hyperactivity disorder (ADHD) eventually are given a diagnosis of absence seizures. The incidence of ADHD in children with epi­lepsy is 20%; these patients display epilepti­form EEG changes, and require meticulous screening, which includes ictal induction by hyperventilation to differentiate ADHD from a seizure disorder.⁵⁶ Many AEDs, especially GABAergic drugs, can cause symptoms of ADHD. Methylphenidate is safe in children whose seizures are well-controlled, and has no significant interactions with AEDs.⁵⁷

Management. Adequate seizure control is the only effective means to slow regression in cases of epilepsy comorbid with autism spectrum disorder, mental retardation, and cerebral palsy.⁵⁸

BOTTOM LINE
Patients who have epilepsy have a lifetime susceptibility to psychopathology, especially depression and anxiety. Psychiatric practitioners should work collaboratively with patients' primary care provider to evaluate, diagnose, and treat both conditions. Quick action is the key to the best possible outcomes, including reducing the risk of recurrent seizures.

Related Resources
• Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;14:75.
• Centers for Disease Control and Prevention. Comorbidity in adults with epilepsy—United States, 2010. MMWR Morb Mortal Wkly Rep. 2013;62(43):849-853.
• Kui C, Yingfu P, Chenling X, et al. What are the predictors of major depression in adult patients with epilepsy? Epileptic Disord. 2014;16(1):74-79.
• Lunde ME, Rasmussen KG. Electroconvulsive therapy in patients with epilepsy. Epilepsy Behav. 2006;9(2):355-359.


Drug Brand Names

Aripiprazole • Abilify                               Risperidone • Risperdal
Chlorpromazine •  Thorazine                   Quetlapine • Seroquel
Citalopram •  Celexa                               Sertraline • Zoloft
Clozapine •  Clozaril, FazaClo                   Tiagabine • Gabitril
Escitalopram • Lexapro                            Topiramate • Topamax
Haloperidol • Haldol                                 Tramadol • Ryzolt, Ultram, ConZip
Lamotrigine • Lamictal                             Valproate • Depokate
Levetiracetam • Keppra                            Vigabatrin • Sabril
Methylphenidate • Methylin, Ritalin            Ziprasidone • Geodon


Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In the February 2014 issue (Psychiatry’s future shock, Current Psychiatry, February 2014, p. 19-20, 32 [http://bit.ly/1bvrp3t]) Dr. Nasrallah tells us that psychiatrists who are not speaking the new language of the “neuroscientifica­tion” of psychiatry will soon be ren­dered obsolete. He says that we are at the “tipping point” in psychiatry, giving up the “primitive notions that have guided the profession for the past century,” and moving toward explaining our successes and fail­ures in terms of microglial activation, inflammatory markers, apoptosis, S100B, and NOTCH 3. Those who talk about ego strengths, defense mecha­nisms, resilience, the unconscious mind, and the human spirit are “clini­cal dinosaurs.”

Sadly, Dr. Nasrallah speaks for many psychiatric academicians today, who believe the best way to understand the complexity of the human condition is to explain it in terms of neurotrans­mitters, genomics, and MRIs. But the truth is, no matter how much we know about the brain, the mind will always have a mind of its own. The language of science cannot adequately explain the mystery that is an essential part of the human experience.

The brain is hardwired for mystical experiences. We are biologically pro­grammed to experience transcendent states that allow us to see the familiar from a new perspective, and to expe­rience the awesome. It matters less how we explain the mechanics of the mysterious than it does to know it is important. To all my academic col­leagues who herald in the “neurosci­entification” of psychiatry, and the obsolescence of clinicians who still explore the unconscious mind, I say let’s not take ourselves too seriously. Awe is the mechanism by which we tame the ego.

Carl Hammerschlag, MD
Arizona Health Services Center
University of Arizona
Phoenix, Arizona

In the February 2014 issue (Psychiatry’s future shock, Current Psychiatry, February 2014, p. 19-20, 32 [http://bit.ly/1bvrp3t]) Dr. Nasrallah tells us that psychiatrists who are not speaking the new language of the “neuroscientifica­tion” of psychiatry will soon be ren­dered obsolete. He says that we are at the “tipping point” in psychiatry, giving up the “primitive notions that have guided the profession for the past century,” and moving toward explaining our successes and fail­ures in terms of microglial activation, inflammatory markers, apoptosis, S100B, and NOTCH 3. Those who talk about ego strengths, defense mecha­nisms, resilience, the unconscious mind, and the human spirit are “clini­cal dinosaurs.”

Sadly, Dr. Nasrallah speaks for many psychiatric academicians today, who believe the best way to understand the complexity of the human condition is to explain it in terms of neurotrans­mitters, genomics, and MRIs. But the truth is, no matter how much we know about the brain, the mind will always have a mind of its own. The language of science cannot adequately explain the mystery that is an essential part of the human experience.

The brain is hardwired for mystical experiences. We are biologically pro­grammed to experience transcendent states that allow us to see the familiar from a new perspective, and to expe­rience the awesome. It matters less how we explain the mechanics of the mysterious than it does to know it is important. To all my academic col­leagues who herald in the “neurosci­entification” of psychiatry, and the obsolescence of clinicians who still explore the unconscious mind, I say let’s not take ourselves too seriously. Awe is the mechanism by which we tame the ego.

Carl Hammerschlag, MD
Arizona Health Services Center
University of Arizona
Phoenix, Arizona

In the February 2014 issue (Psychiatry’s future shock, Current Psychiatry, February 2014, p. 19-20, 32 [http://bit.ly/1bvrp3t]) Dr. Nasrallah tells us that psychiatrists who are not speaking the new language of the “neuroscientifica­tion” of psychiatry will soon be ren­dered obsolete. He says that we are at the “tipping point” in psychiatry, giving up the “primitive notions that have guided the profession for the past century,” and moving toward explaining our successes and fail­ures in terms of microglial activation, inflammatory markers, apoptosis, S100B, and NOTCH 3. Those who talk about ego strengths, defense mecha­nisms, resilience, the unconscious mind, and the human spirit are “clini­cal dinosaurs.”

Sadly, Dr. Nasrallah speaks for many psychiatric academicians today, who believe the best way to understand the complexity of the human condition is to explain it in terms of neurotrans­mitters, genomics, and MRIs. But the truth is, no matter how much we know about the brain, the mind will always have a mind of its own. The language of science cannot adequately explain the mystery that is an essential part of the human experience.

The brain is hardwired for mystical experiences. We are biologically pro­grammed to experience transcendent states that allow us to see the familiar from a new perspective, and to expe­rience the awesome. It matters less how we explain the mechanics of the mysterious than it does to know it is important. To all my academic col­leagues who herald in the “neurosci­entification” of psychiatry, and the obsolescence of clinicians who still explore the unconscious mind, I say let’s not take ourselves too seriously. Awe is the mechanism by which we tame the ego.

Carl Hammerschlag, MD
Arizona Health Services Center
University of Arizona
Phoenix, Arizona

In the interesting March 2014 Savvy Psychopharmacology article (Strategies for managing drug-induced tar­dive dyskinesia, Current Psychiatry, March 2014, p. 44-46; [http://bit. ly/1gNALYi]), the authors did not mention a medical food made from the branched-chain amino acids L-Leucine, L-Valine, and L-Isoleucine, which was reviewed by the FDA for the dietary management of tardive dyskinesia (TD) in males.^1,2 Although this product, “Tarvil,” is no longer being manufactured, compounding pharmacies can make it using the same ratio of ingredients that was tested in the clinical trial.¹ It may be worth con­sidering before using tetrabenazine, a medication approved in the United States under the Orphan Drug Act, and launched at $34.25 for a 12.5 mg tablet and $68.50 for a 25 mg tablet.³

Leslie Citrome, MD, MPH
Clinical Professor of Psychiatry & Behavioral Sciences
New York Medical College
Valhalla, NY

 
Dr. Ellingrod responds
On behalf of Dr. Kaspar and myself, we thank Dr. Citrome for his interest and clarification. Because of the brevity of Savvy Psychopharmacology in the pages of Current Psychiatry, we decided to include only information on therapies that are readily available for TD.  We also agree with Dr. Citrome that other treat­ment modalities, which often cost less, should be tried before tetrabenazine is utilized. Most important, judicious use of antipsychotics should be considered before any additional medications are added to the patient’s regimen. 

Vicki L. Ellingrod, PharmD, FCCP
John Gideon Searle Professor of Clinical and Translational Pharmacy
University of Michigan College of Pharmacy and School of Medicine
Ann Arbor, Michigan

In the interesting March 2014 Savvy Psychopharmacology article (Strategies for managing drug-induced tar­dive dyskinesia, Current Psychiatry, March 2014, p. 44-46; [http://bit. ly/1gNALYi]), the authors did not mention a medical food made from the branched-chain amino acids L-Leucine, L-Valine, and L-Isoleucine, which was reviewed by the FDA for the dietary management of tardive dyskinesia (TD) in males.^1,2 Although this product, “Tarvil,” is no longer being manufactured, compounding pharmacies can make it using the same ratio of ingredients that was tested in the clinical trial.¹ It may be worth con­sidering before using tetrabenazine, a medication approved in the United States under the Orphan Drug Act, and launched at $34.25 for a 12.5 mg tablet and $68.50 for a 25 mg tablet.³

Leslie Citrome, MD, MPH
Clinical Professor of Psychiatry & Behavioral Sciences
New York Medical College
Valhalla, NY

 
Dr. Ellingrod responds
On behalf of Dr. Kaspar and myself, we thank Dr. Citrome for his interest and clarification. Because of the brevity of Savvy Psychopharmacology in the pages of Current Psychiatry, we decided to include only information on therapies that are readily available for TD.  We also agree with Dr. Citrome that other treat­ment modalities, which often cost less, should be tried before tetrabenazine is utilized. Most important, judicious use of antipsychotics should be considered before any additional medications are added to the patient’s regimen. 

Vicki L. Ellingrod, PharmD, FCCP
John Gideon Searle Professor of Clinical and Translational Pharmacy
University of Michigan College of Pharmacy and School of Medicine
Ann Arbor, Michigan

In the interesting March 2014 Savvy Psychopharmacology article (Strategies for managing drug-induced tar­dive dyskinesia, Current Psychiatry, March 2014, p. 44-46; [http://bit. ly/1gNALYi]), the authors did not mention a medical food made from the branched-chain amino acids L-Leucine, L-Valine, and L-Isoleucine, which was reviewed by the FDA for the dietary management of tardive dyskinesia (TD) in males.^1,2 Although this product, “Tarvil,” is no longer being manufactured, compounding pharmacies can make it using the same ratio of ingredients that was tested in the clinical trial.¹ It may be worth con­sidering before using tetrabenazine, a medication approved in the United States under the Orphan Drug Act, and launched at $34.25 for a 12.5 mg tablet and $68.50 for a 25 mg tablet.³

Leslie Citrome, MD, MPH
Clinical Professor of Psychiatry & Behavioral Sciences
New York Medical College
Valhalla, NY

 
Dr. Ellingrod responds
On behalf of Dr. Kaspar and myself, we thank Dr. Citrome for his interest and clarification. Because of the brevity of Savvy Psychopharmacology in the pages of Current Psychiatry, we decided to include only information on therapies that are readily available for TD.  We also agree with Dr. Citrome that other treat­ment modalities, which often cost less, should be tried before tetrabenazine is utilized. Most important, judicious use of antipsychotics should be considered before any additional medications are added to the patient’s regimen. 

Vicki L. Ellingrod, PharmD, FCCP
John Gideon Searle Professor of Clinical and Translational Pharmacy
University of Michigan College of Pharmacy and School of Medicine
Ann Arbor, Michigan

Hematologic abnormalities, such as leukopenia, agranulocytosis, and thrombocytopenia, can be life-threatening adverse reactions to atypical antipsychotics. Although clozapine has the highest risk of leukopenia and neutropenia, these side effects also have been associated with other atypical antipsychotics, including risperidone, olanzapine, ziprasidone, paliperdione, and quetiapine. Risperdone-induced leukopenia has been reported,^1,2 but risperidone-
induced bicytopenia— that is, leukopenia/ thrombocytopenia—is rare.

Case
Mr. A, age 25, is an African American man admitted to an inpatient psychiatric unit for management of acute psychotic symptoms. He has been taking risperidone, 4 mg/d, for the past 6 months, although his adherence to the regimen is questionable. Baseline blood count shows a white blood cell (WBC) count of 4,400/μL with an absolute neutrophil count (ANC) of 1,900/μL and a platelet count
160×103/μL. A few days after restarting risperidone, repeat blood count shows a drop in the WBC count to 2,900/μL, with an ANC of 900/μL and a platelet count of 130×103/μL.

Mr. A’s physical examination is normal, he does not have any signs or symptoms of infection, and additional lab tests are negative. Risperidone is considered as a possible cause of bicytopenia and is discontinued. Mr. A agrees to start treatment with aripiprazole, 10 mg/d. In next 10 days, the WBC count increases to 6,000/μL. The ANC at 3,100/μL and platelets at 150×103/μL remain stable throughout hospitalization. The slowly increasing WBC count after stopping risperidone is highly suggestive that this agent caused Mr. A’s bicytopenia.

Differential diagnosis
Bone-marrow suppression is associated with first- and second-generation antipsychotics. Blood dyscrasia is a concern in clinical psychiatry because hematologic abnormalities can be life-threatening, requiring close monitoring of the blood count for patients taking an antipsychotic. It is important, therefore, to consider medication side effects in the differential diagnosis of >1 hematologic abnormalities in these patients.

Precise pathophysiologic understanding of the hematologic side effects of antipsychotics is lacking, although different mechanisms of action have been proposed.³ Possible mechanisms when a patient is taking clozapine or olanzapine include:
   • direct toxic effect of the drug on bone marrow
   • increased peripheral destruction
   • oxidative stress induced by unstable metabolites.

There is not enough evidence, however, to identify risperidone’s mechanism of action on blood cells.

Aripiprazole might be a useful alternative when another antipsychotic causes leukopenia and neutropenia. In addition to regularly monitoring the blood cell count during antipsychotic treatment, the neutrophil and platelet counts should be monitored.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Hematologic abnormalities, such as leukopenia, agranulocytosis, and thrombocytopenia, can be life-threatening adverse reactions to atypical antipsychotics. Although clozapine has the highest risk of leukopenia and neutropenia, these side effects also have been associated with other atypical antipsychotics, including risperidone, olanzapine, ziprasidone, paliperdione, and quetiapine. Risperdone-induced leukopenia has been reported,^1,2 but risperidone-
induced bicytopenia— that is, leukopenia/ thrombocytopenia—is rare.

Case
Mr. A, age 25, is an African American man admitted to an inpatient psychiatric unit for management of acute psychotic symptoms. He has been taking risperidone, 4 mg/d, for the past 6 months, although his adherence to the regimen is questionable. Baseline blood count shows a white blood cell (WBC) count of 4,400/μL with an absolute neutrophil count (ANC) of 1,900/μL and a platelet count
160×103/μL. A few days after restarting risperidone, repeat blood count shows a drop in the WBC count to 2,900/μL, with an ANC of 900/μL and a platelet count of 130×103/μL.

Mr. A’s physical examination is normal, he does not have any signs or symptoms of infection, and additional lab tests are negative. Risperidone is considered as a possible cause of bicytopenia and is discontinued. Mr. A agrees to start treatment with aripiprazole, 10 mg/d. In next 10 days, the WBC count increases to 6,000/μL. The ANC at 3,100/μL and platelets at 150×103/μL remain stable throughout hospitalization. The slowly increasing WBC count after stopping risperidone is highly suggestive that this agent caused Mr. A’s bicytopenia.

Differential diagnosis
Bone-marrow suppression is associated with first- and second-generation antipsychotics. Blood dyscrasia is a concern in clinical psychiatry because hematologic abnormalities can be life-threatening, requiring close monitoring of the blood count for patients taking an antipsychotic. It is important, therefore, to consider medication side effects in the differential diagnosis of >1 hematologic abnormalities in these patients.

Precise pathophysiologic understanding of the hematologic side effects of antipsychotics is lacking, although different mechanisms of action have been proposed.³ Possible mechanisms when a patient is taking clozapine or olanzapine include:
   • direct toxic effect of the drug on bone marrow
   • increased peripheral destruction
   • oxidative stress induced by unstable metabolites.

There is not enough evidence, however, to identify risperidone’s mechanism of action on blood cells.

Aripiprazole might be a useful alternative when another antipsychotic causes leukopenia and neutropenia. In addition to regularly monitoring the blood cell count during antipsychotic treatment, the neutrophil and platelet counts should be monitored.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Hematologic abnormalities, such as leukopenia, agranulocytosis, and thrombocytopenia, can be life-threatening adverse reactions to atypical antipsychotics. Although clozapine has the highest risk of leukopenia and neutropenia, these side effects also have been associated with other atypical antipsychotics, including risperidone, olanzapine, ziprasidone, paliperdione, and quetiapine. Risperdone-induced leukopenia has been reported,^1,2 but risperidone-
induced bicytopenia— that is, leukopenia/ thrombocytopenia—is rare.

Case
Mr. A, age 25, is an African American man admitted to an inpatient psychiatric unit for management of acute psychotic symptoms. He has been taking risperidone, 4 mg/d, for the past 6 months, although his adherence to the regimen is questionable. Baseline blood count shows a white blood cell (WBC) count of 4,400/μL with an absolute neutrophil count (ANC) of 1,900/μL and a platelet count
160×103/μL. A few days after restarting risperidone, repeat blood count shows a drop in the WBC count to 2,900/μL, with an ANC of 900/μL and a platelet count of 130×103/μL.

Mr. A’s physical examination is normal, he does not have any signs or symptoms of infection, and additional lab tests are negative. Risperidone is considered as a possible cause of bicytopenia and is discontinued. Mr. A agrees to start treatment with aripiprazole, 10 mg/d. In next 10 days, the WBC count increases to 6,000/μL. The ANC at 3,100/μL and platelets at 150×103/μL remain stable throughout hospitalization. The slowly increasing WBC count after stopping risperidone is highly suggestive that this agent caused Mr. A’s bicytopenia.

Differential diagnosis
Bone-marrow suppression is associated with first- and second-generation antipsychotics. Blood dyscrasia is a concern in clinical psychiatry because hematologic abnormalities can be life-threatening, requiring close monitoring of the blood count for patients taking an antipsychotic. It is important, therefore, to consider medication side effects in the differential diagnosis of >1 hematologic abnormalities in these patients.

Precise pathophysiologic understanding of the hematologic side effects of antipsychotics is lacking, although different mechanisms of action have been proposed.³ Possible mechanisms when a patient is taking clozapine or olanzapine include:
   • direct toxic effect of the drug on bone marrow
   • increased peripheral destruction
   • oxidative stress induced by unstable metabolites.

There is not enough evidence, however, to identify risperidone’s mechanism of action on blood cells.

Aripiprazole might be a useful alternative when another antipsychotic causes leukopenia and neutropenia. In addition to regularly monitoring the blood cell count during antipsychotic treatment, the neutrophil and platelet counts should be monitored.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.