Reviews

Pathological laughter and crying— pseudobulbar affect (PBA)—is a disor­der of emotional expression character­ized by uncontrollable outbursts of laughter or crying without an environmental trigger. Persons with PBA are at an increased risk of depressive and anxiety symptoms associated with an inappropriate outburst of emotion¹; such emotional acts might be incongruent with their underlying emotional state.

When should you consider PBA?
Consider PBA in patients with new-onset emotional lability in the presence of certain neurologic conditions. PBA is most common in patients with amyotrophic lateral sclerosis and stroke, in which an incidence of >50% has been estimated.² Other conditions asso­ciated with PBA include Parkinson’s disease, multiple sclerosis, frontotemporal dementia, traumatic brain injury, Alzheimer’s disease, epilepsy, normal pressure hydrocephalus, progressive supranuclear palsy, Wilson dis­ease, and neurosyphilis.³

Avoid PBA misdiagnosis
Depression is the most common PBA mis­diagnosis (Table). However, many clinical features distinguish PBA episodes from de­pressive symptoms; the most prominent dif­ference is duration. Depressive symptoms, including depressed mood, typically last weeks to months, but a PBA episode lasts seconds or minutes. In addition, crying, as a symptom of PBA, might be unrelated or ex­aggerated relative to the patient’s mood, but crying is congruent with subjective mood in depression. Other symptoms of depres­sion—fatigue, anorexia, insomnia, anhedo­nia, and feelings of hopelessness and guilt— are not associated with pseudobulbar affect.

PBA also can be differentiated from bi­polar disorder (BD) with rapid cycling or mixed mood episodes because of PBA’s relatively brief duration of laughing or cry­ing episodes—with no mood disturbance between episodes—compared with the sustained changes in mood, cognition, and behavior seen in BD.

Options for treating PBA
Serotonergic therapies, such as amitriptyline and fluoxetine, may exert effects by increas­ing serotonin in the synapse; dextrometho­rphan may act via antiglutamatergic effects at N-methyl-d-aspartate receptors and sig­ma-1 receptors.⁴ Dextromethorphan bind­ing is most prominent in the brainstem and cerebellum, brain areas known to be rich in sigma-1 receptors and key sites implicated in the pathophysiology of PBA. Although the precise mechanisms by which dextro­methorphan ameliorates PBA are unknown, modulation of excessive glutamatergic trans­mission within corticopontine-cerebellar circuits may contribute to its benefits.

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

Pathological laughter and crying— pseudobulbar affect (PBA)—is a disor­der of emotional expression character­ized by uncontrollable outbursts of laughter or crying without an environmental trigger. Persons with PBA are at an increased risk of depressive and anxiety symptoms associated with an inappropriate outburst of emotion¹; such emotional acts might be incongruent with their underlying emotional state.

When should you consider PBA?
Consider PBA in patients with new-onset emotional lability in the presence of certain neurologic conditions. PBA is most common in patients with amyotrophic lateral sclerosis and stroke, in which an incidence of >50% has been estimated.² Other conditions asso­ciated with PBA include Parkinson’s disease, multiple sclerosis, frontotemporal dementia, traumatic brain injury, Alzheimer’s disease, epilepsy, normal pressure hydrocephalus, progressive supranuclear palsy, Wilson dis­ease, and neurosyphilis.³

Avoid PBA misdiagnosis
Depression is the most common PBA mis­diagnosis (Table). However, many clinical features distinguish PBA episodes from de­pressive symptoms; the most prominent dif­ference is duration. Depressive symptoms, including depressed mood, typically last weeks to months, but a PBA episode lasts seconds or minutes. In addition, crying, as a symptom of PBA, might be unrelated or ex­aggerated relative to the patient’s mood, but crying is congruent with subjective mood in depression. Other symptoms of depres­sion—fatigue, anorexia, insomnia, anhedo­nia, and feelings of hopelessness and guilt— are not associated with pseudobulbar affect.

PBA also can be differentiated from bi­polar disorder (BD) with rapid cycling or mixed mood episodes because of PBA’s relatively brief duration of laughing or cry­ing episodes—with no mood disturbance between episodes—compared with the sustained changes in mood, cognition, and behavior seen in BD.

Options for treating PBA
Serotonergic therapies, such as amitriptyline and fluoxetine, may exert effects by increas­ing serotonin in the synapse; dextrometho­rphan may act via antiglutamatergic effects at N-methyl-d-aspartate receptors and sig­ma-1 receptors.⁴ Dextromethorphan bind­ing is most prominent in the brainstem and cerebellum, brain areas known to be rich in sigma-1 receptors and key sites implicated in the pathophysiology of PBA. Although the precise mechanisms by which dextro­methorphan ameliorates PBA are unknown, modulation of excessive glutamatergic trans­mission within corticopontine-cerebellar circuits may contribute to its benefits.

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

Pathological laughter and crying— pseudobulbar affect (PBA)—is a disor­der of emotional expression character­ized by uncontrollable outbursts of laughter or crying without an environmental trigger. Persons with PBA are at an increased risk of depressive and anxiety symptoms associated with an inappropriate outburst of emotion¹; such emotional acts might be incongruent with their underlying emotional state.

When should you consider PBA?
Consider PBA in patients with new-onset emotional lability in the presence of certain neurologic conditions. PBA is most common in patients with amyotrophic lateral sclerosis and stroke, in which an incidence of >50% has been estimated.² Other conditions asso­ciated with PBA include Parkinson’s disease, multiple sclerosis, frontotemporal dementia, traumatic brain injury, Alzheimer’s disease, epilepsy, normal pressure hydrocephalus, progressive supranuclear palsy, Wilson dis­ease, and neurosyphilis.³

Avoid PBA misdiagnosis
Depression is the most common PBA mis­diagnosis (Table). However, many clinical features distinguish PBA episodes from de­pressive symptoms; the most prominent dif­ference is duration. Depressive symptoms, including depressed mood, typically last weeks to months, but a PBA episode lasts seconds or minutes. In addition, crying, as a symptom of PBA, might be unrelated or ex­aggerated relative to the patient’s mood, but crying is congruent with subjective mood in depression. Other symptoms of depres­sion—fatigue, anorexia, insomnia, anhedo­nia, and feelings of hopelessness and guilt— are not associated with pseudobulbar affect.

PBA also can be differentiated from bi­polar disorder (BD) with rapid cycling or mixed mood episodes because of PBA’s relatively brief duration of laughing or cry­ing episodes—with no mood disturbance between episodes—compared with the sustained changes in mood, cognition, and behavior seen in BD.

Options for treating PBA
Serotonergic therapies, such as amitriptyline and fluoxetine, may exert effects by increas­ing serotonin in the synapse; dextrometho­rphan may act via antiglutamatergic effects at N-methyl-d-aspartate receptors and sig­ma-1 receptors.⁴ Dextromethorphan bind­ing is most prominent in the brainstem and cerebellum, brain areas known to be rich in sigma-1 receptors and key sites implicated in the pathophysiology of PBA. Although the precise mechanisms by which dextro­methorphan ameliorates PBA are unknown, modulation of excessive glutamatergic trans­mission within corticopontine-cerebellar circuits may contribute to its benefits.

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

Depression carries a wide differential diagnosis. Practitioners sometimes think polarity is the fundamental distinction when they conceptualize depression as a clinical entity; in fact, many nosologic frameworks have been described for defining and subtyping clinically meaningful forms of depression, and each waxed and waned in popularity.

Kraepelin, writing in the early 20th century, linked manic-depres­sive illness with “the greater part of the morbid states termed mel­ancholia,”¹ but many features other than polarity remain important components of depression, and those features often carry implications for how individual patients respond to treatment.

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 first part of this article examines major depressive disorder (MDD), minor depression, chronic depression, depression in bipolar disorder, depression that is severe or mild, and psychotic depression. Treatments for these subtypes for which there is evidence, or a clinical rationale, are given in the Table.

The subtypes of depression that I’ll discuss in the second part of the article are listed on page 47.

Major and minor depression
MDD has been the focus of most drug tri­als seeking FDA approval. As a syndrome, MDD is defined by a constellation of fea­tures that are related not only to mood but also to sleep, energy, cognition, motiva­tion, and motor behavior, persisting for ≥2 weeks.

DSM-5 has imposed few changes to the basic definition of MDD:
   • bereavement (the aftermath of death of a loved one), formerly an exclusion cri­terion, no longer precludes making a diag­nosis of MDD when syndromal criteria are otherwise fulfilled
   • “with anxious distress” is a new course specifier that designates promi­nent anxiety features (feeling worried, restless, tense, or keyed up; fearful of losing control or something terrible happening)
   • “with mixed features” is a new course specifier pertinent when ≥3 mania or hy­pomania symptoms coexist (that is, might be a subsyndromal mania or hypomania) with a depressive syndrome; the mixed features specifier can be applied to de­pressed patients whether or not they have ever had a manic or hypomanic episode, but MDD—rather than bipolar disorder— remains the overarching diagnosis, unless criteria have ever been met for a full mania or hypomania.

More than 2 dozen medications are FDA-approved to treat MDD. Evidence-based psychotherapies (eg, cognitive-behavioral therapy [CBT] and interpersonal therapy), as adjuncts to pharmacotherapy, further improve outcomes, but with only modest additional effect.²

Minor depression. Depressive states that involve 2 to 4 associated symptoms last­ing ≥2 weeks but <2 years are sometimes described as minor depression, captured within DSM-5 as “depression not else­where defined.” The terminology of so-called “minor depression” generally is shunned, in part because it might wrongly connote low severity and therefore dis­courage treatment—even though it con­fers more than a 5-fold increase in risk of MDD.3 

Chronicity
DSM-IV-TR identified long-standing de­pression by 2 constructs:
   • chronic major depression (an episode of MDD lasting ≥2 years in adults, ≥1 year in children and adolescents)
   • dysthymic disorder (2 to 4 depressive symptoms for ≥2 years in adults and ≥1 year in children and adolescents), affecting 3% to 6% of adults and carrying a 2-fold increased risk of MDD, eventually.⁴

Depression that begins as dysthymic disorder and blossoms into syndromal MDD is described as “double depres­sion”—although it is not recognized as a unique condition in any edition of the DSM. Subsequent incomplete recovery may revert to dysthymic disorder. DSM-5 has subsumed chronic major depression and dysthymia under the unified heading of persistent depressive disorder.

There are no FDA-approved drugs for treating dysthymia. A meta-analysis of 9 controlled trials of off-label use of antide­pressants to treat dysthymia revealed an overall response rate of 52.4%, compared with 29.9% for placebo.⁵ Notably, although the active drug response rate in these stud­ies is comparable to what seen in MDD, the placebo response rate was approxi­mately 10% lower than what was seen in major depression.

Positive therapeutic findings (typically, treatment for 6 to 12 weeks) have been reported in so-called “pure” dysthymic disorder with sertraline, fluoxetine, imip­ramine, ritanserin, moclobemide (not ap­proved for use in the United States), and phenelzine; the results of additional, posi­tive placebo-controlled studies support the utility of duloxetine⁶ and paroxetine.⁷ Randomized trials have reported negative findings for desipramine,⁸ fluoxetine,⁹ and escitalopram¹⁰ escitalopram¹⁰—although the sample size in these latter studies might have been too small to detect a drug-placebo difference.

In dysthymic and minor-depressive middle-age and older adult men who have a low serum level of testosterone, hormone replacement was shown to be superior to placebo in several randomized trials.¹¹ Studies of adjunctive atypical antipsy­chotics for dysthymic disorder are scarce; a Cochrane review identified controlled data only with amisulpride (not approved for use in the United States), which yielded a modest therapeutic effect.¹²

Polarity
In recent years, depression in bipolar dis­order (BD) has been contrasted with uni­polar MDD based on a difference in:
   • duration (briefer in BD)
   • severity (worse in BD)
   • risk of suicide (higher)
   • comorbidity (more extensive)
   • family history (often present for BD and highly recurrent depression)
   • treatment outcome (generally less favorable).

DSM-5 has at least somewhat blurred the distinctions in polarity by way of the new construct of “major depression with mixed features” (see the discussion of MDD above), identifiable even when a person has never had a full manic or hypo­manic episode.

No randomized trials have been con­ducted to identify the best treatments for such presentations, which has invited ex­trapolation from the literature in regard to bipolar mixed episodes, and suggesting that 1) some mood stabilizers (eg, divalproex) might have value and 2) antidepres­sants might exacerbate manic symptoms.

Perhaps most noteworthy in regard to treating bipolar depression is the unresolved, but hotly debated, contro­versy over whether and, if so, when, an antidepressant is inappropriate (based on concerns about possible induction or exac­erbation of manic symptoms). In addition, nearly all of the large, randomized con­trolled trials of antidepressants for bipolar depression have shown that they offer no advantage over placebo.

Some authors argue that a lack of re­sponse to antidepressants might, itself, be a “soft” indicator of “bipolarity.” However, nonresponse to antidepressants should prompt a wider assessment of features other than polarity—including psychosis, anxiety, substance abuse, a personality disorder, psychiatric adverse effects from concomitant medications, medical comor­ bidity, adequacy of trials of medical ther­apy, and potential non-adherence to such trials—to account for poor antidepressant outcomes.

Severity
Severity of depression warrants consider­ation when formulating impressions about the nature and treatment of all presenta­tions of depression.

High-severity forms prompt decisions about treatment setting (inpatient or out­patient); suicide assessment; and thera­peutic modalities (eg, electroconvulsive therapy is more appropriate than psycho­therapy for catatonic depression).

Mild forms. A recent meta-analysis of 6 randomized trials (each of >6 weeks’ du­ration) of antidepressants for mild de­pression demonstrated that these agents exert only a modest effect compared with placebo, owing largely to higher placebo-responsivity in mild depressive episodes than in moderate and severe episodes.13 In contrast, another meta-analysis of sub­jects who had “mild” baseline depression severity scores found that antidepressant medication had greater efficacy than pla­cebo in 4 of 6 randomized trials.14 Higher depression severity levels typically dimin­ish the placebo response rate but also re­duce the magnitude of drug efficacy.

Psychosis
Before DSM-III, psychotic (as opposed to neurotic) depression was perhaps the key nosologic distinction when characteriz­ing forms of depression. The presence of psychosis and related components (eg, mood-congruence) is closely linked with the severity of depression (high) and prog­nosis and longitudinal outcome (poorer), and has implications for treatment (Table).

Bottom Line
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including polarity, chronicity, recurrence, psychosis, treatment resistance, comorbidity, and atypicality, among other classifications. Clinical characteristics vary across subtypes—and so do corresponding preferred treatments, which should be tailored to the needs of each of your patients.

Related Resources
• Goldberg JF, Thase ME. Monoamine oxidase inhibi­tors revisited: what you should know. J Clin Psychiatry. 2013;74(2):189-191.
• Goldberg JF. Antidepressants in bipolar disorder: 7 myths and realities. Current Psychiatry. 2010;9(5):41-49.
• Ketamine cousin rapidly lifts depression without side ef­fects. National Institute of Mental Health. http://www. nimh.nih.gov/news/science-news/2013/ketamine-cousin-rapidly-lifts-depression-without-side-effects.shtml. Published May 23, 2013. Accessed March 20, 2014.
• Research Domain Criteria (RDoC). National Institute of Mental Health. http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml?u tm_ source = govdelivery&utm_medium=email&utm_campaign= govdelivery. Accessed March 20, 2014.

Drug Brand Names
Amisulpride • Amazeo,                                  Lurasidone • Latuda
Amival, Amipride, Sulpitax                             Mirtazapine • Remeron
   Aripiprazole • Abilify                                   Moclobemide • Amira,
Armodafinil • Nuvigil                                        Aurorix, Clobemix,
Bupropion • Wellbutrin                                     Depnil, Manerix
Desipramine • Norpramin                               Modafinil • Provigil
Divalproex • Depakote,                                  Olanzapine/fluoxetine
Depakene                                                        • Symbyax
Duloxetine • Cymbalta                                    Paroxetine • Paxil
Escitalopram • Lexapro                                   Phenelzine • Nardil
Fluoxetine • Prozac                                         Pramipexole • Mirapex
Imipramine • Tofranil                                     Quetiapine • Seroquel
Ketamine • Ketalar                                         Riluzole • Rilutek
Lamotrigine • Lamictal                                    Sertraline • Zoloft
Lithium • Eskalith, Lithobid                             Vortioxetine • Brintellix

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

Editor’s note: The second part of Dr. Goldberg’s review of depression subtypes—fo­cusing on “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a sub­stance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder—will appear in the May 2014 issue of Current Psychiatry.

Depression carries a wide differential diagnosis. Practitioners sometimes think polarity is the fundamental distinction when they conceptualize depression as a clinical entity; in fact, many nosologic frameworks have been described for defining and subtyping clinically meaningful forms of depression, and each waxed and waned in popularity.

Kraepelin, writing in the early 20th century, linked manic-depres­sive illness with “the greater part of the morbid states termed mel­ancholia,”¹ but many features other than polarity remain important components of depression, and those features often carry implications for how individual patients respond to treatment.

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 first part of this article examines major depressive disorder (MDD), minor depression, chronic depression, depression in bipolar disorder, depression that is severe or mild, and psychotic depression. Treatments for these subtypes for which there is evidence, or a clinical rationale, are given in the Table.

The subtypes of depression that I’ll discuss in the second part of the article are listed on page 47.

Major and minor depression
MDD has been the focus of most drug tri­als seeking FDA approval. As a syndrome, MDD is defined by a constellation of fea­tures that are related not only to mood but also to sleep, energy, cognition, motiva­tion, and motor behavior, persisting for ≥2 weeks.

DSM-5 has imposed few changes to the basic definition of MDD:
   • bereavement (the aftermath of death of a loved one), formerly an exclusion cri­terion, no longer precludes making a diag­nosis of MDD when syndromal criteria are otherwise fulfilled
   • “with anxious distress” is a new course specifier that designates promi­nent anxiety features (feeling worried, restless, tense, or keyed up; fearful of losing control or something terrible happening)
   • “with mixed features” is a new course specifier pertinent when ≥3 mania or hy­pomania symptoms coexist (that is, might be a subsyndromal mania or hypomania) with a depressive syndrome; the mixed features specifier can be applied to de­pressed patients whether or not they have ever had a manic or hypomanic episode, but MDD—rather than bipolar disorder— remains the overarching diagnosis, unless criteria have ever been met for a full mania or hypomania.

More than 2 dozen medications are FDA-approved to treat MDD. Evidence-based psychotherapies (eg, cognitive-behavioral therapy [CBT] and interpersonal therapy), as adjuncts to pharmacotherapy, further improve outcomes, but with only modest additional effect.²

Minor depression. Depressive states that involve 2 to 4 associated symptoms last­ing ≥2 weeks but <2 years are sometimes described as minor depression, captured within DSM-5 as “depression not else­where defined.” The terminology of so-called “minor depression” generally is shunned, in part because it might wrongly connote low severity and therefore dis­courage treatment—even though it con­fers more than a 5-fold increase in risk of MDD.3 

Chronicity
DSM-IV-TR identified long-standing de­pression by 2 constructs:
   • chronic major depression (an episode of MDD lasting ≥2 years in adults, ≥1 year in children and adolescents)
   • dysthymic disorder (2 to 4 depressive symptoms for ≥2 years in adults and ≥1 year in children and adolescents), affecting 3% to 6% of adults and carrying a 2-fold increased risk of MDD, eventually.⁴

Depression that begins as dysthymic disorder and blossoms into syndromal MDD is described as “double depres­sion”—although it is not recognized as a unique condition in any edition of the DSM. Subsequent incomplete recovery may revert to dysthymic disorder. DSM-5 has subsumed chronic major depression and dysthymia under the unified heading of persistent depressive disorder.

There are no FDA-approved drugs for treating dysthymia. A meta-analysis of 9 controlled trials of off-label use of antide­pressants to treat dysthymia revealed an overall response rate of 52.4%, compared with 29.9% for placebo.⁵ Notably, although the active drug response rate in these stud­ies is comparable to what seen in MDD, the placebo response rate was approxi­mately 10% lower than what was seen in major depression.

Positive therapeutic findings (typically, treatment for 6 to 12 weeks) have been reported in so-called “pure” dysthymic disorder with sertraline, fluoxetine, imip­ramine, ritanserin, moclobemide (not ap­proved for use in the United States), and phenelzine; the results of additional, posi­tive placebo-controlled studies support the utility of duloxetine⁶ and paroxetine.⁷ Randomized trials have reported negative findings for desipramine,⁸ fluoxetine,⁹ and escitalopram¹⁰ escitalopram¹⁰—although the sample size in these latter studies might have been too small to detect a drug-placebo difference.

In dysthymic and minor-depressive middle-age and older adult men who have a low serum level of testosterone, hormone replacement was shown to be superior to placebo in several randomized trials.¹¹ Studies of adjunctive atypical antipsy­chotics for dysthymic disorder are scarce; a Cochrane review identified controlled data only with amisulpride (not approved for use in the United States), which yielded a modest therapeutic effect.¹²

Polarity
In recent years, depression in bipolar dis­order (BD) has been contrasted with uni­polar MDD based on a difference in:
   • duration (briefer in BD)
   • severity (worse in BD)
   • risk of suicide (higher)
   • comorbidity (more extensive)
   • family history (often present for BD and highly recurrent depression)
   • treatment outcome (generally less favorable).

DSM-5 has at least somewhat blurred the distinctions in polarity by way of the new construct of “major depression with mixed features” (see the discussion of MDD above), identifiable even when a person has never had a full manic or hypo­manic episode.

No randomized trials have been con­ducted to identify the best treatments for such presentations, which has invited ex­trapolation from the literature in regard to bipolar mixed episodes, and suggesting that 1) some mood stabilizers (eg, divalproex) might have value and 2) antidepres­sants might exacerbate manic symptoms.

Perhaps most noteworthy in regard to treating bipolar depression is the unresolved, but hotly debated, contro­versy over whether and, if so, when, an antidepressant is inappropriate (based on concerns about possible induction or exac­erbation of manic symptoms). In addition, nearly all of the large, randomized con­trolled trials of antidepressants for bipolar depression have shown that they offer no advantage over placebo.

Some authors argue that a lack of re­sponse to antidepressants might, itself, be a “soft” indicator of “bipolarity.” However, nonresponse to antidepressants should prompt a wider assessment of features other than polarity—including psychosis, anxiety, substance abuse, a personality disorder, psychiatric adverse effects from concomitant medications, medical comor­ bidity, adequacy of trials of medical ther­apy, and potential non-adherence to such trials—to account for poor antidepressant outcomes.

Severity
Severity of depression warrants consider­ation when formulating impressions about the nature and treatment of all presenta­tions of depression.

High-severity forms prompt decisions about treatment setting (inpatient or out­patient); suicide assessment; and thera­peutic modalities (eg, electroconvulsive therapy is more appropriate than psycho­therapy for catatonic depression).

Mild forms. A recent meta-analysis of 6 randomized trials (each of >6 weeks’ du­ration) of antidepressants for mild de­pression demonstrated that these agents exert only a modest effect compared with placebo, owing largely to higher placebo-responsivity in mild depressive episodes than in moderate and severe episodes.13 In contrast, another meta-analysis of sub­jects who had “mild” baseline depression severity scores found that antidepressant medication had greater efficacy than pla­cebo in 4 of 6 randomized trials.14 Higher depression severity levels typically dimin­ish the placebo response rate but also re­duce the magnitude of drug efficacy.

Psychosis
Before DSM-III, psychotic (as opposed to neurotic) depression was perhaps the key nosologic distinction when characteriz­ing forms of depression. The presence of psychosis and related components (eg, mood-congruence) is closely linked with the severity of depression (high) and prog­nosis and longitudinal outcome (poorer), and has implications for treatment (Table).

Bottom Line
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including polarity, chronicity, recurrence, psychosis, treatment resistance, comorbidity, and atypicality, among other classifications. Clinical characteristics vary across subtypes—and so do corresponding preferred treatments, which should be tailored to the needs of each of your patients.

Related Resources
• Goldberg JF, Thase ME. Monoamine oxidase inhibi­tors revisited: what you should know. J Clin Psychiatry. 2013;74(2):189-191.
• Goldberg JF. Antidepressants in bipolar disorder: 7 myths and realities. Current Psychiatry. 2010;9(5):41-49.
• Ketamine cousin rapidly lifts depression without side ef­fects. National Institute of Mental Health. http://www. nimh.nih.gov/news/science-news/2013/ketamine-cousin-rapidly-lifts-depression-without-side-effects.shtml. Published May 23, 2013. Accessed March 20, 2014.
• Research Domain Criteria (RDoC). National Institute of Mental Health. http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml?u tm_ source = govdelivery&utm_medium=email&utm_campaign= govdelivery. Accessed March 20, 2014.

Drug Brand Names
Amisulpride • Amazeo,                                  Lurasidone • Latuda
Amival, Amipride, Sulpitax                             Mirtazapine • Remeron
   Aripiprazole • Abilify                                   Moclobemide • Amira,
Armodafinil • Nuvigil                                        Aurorix, Clobemix,
Bupropion • Wellbutrin                                     Depnil, Manerix
Desipramine • Norpramin                               Modafinil • Provigil
Divalproex • Depakote,                                  Olanzapine/fluoxetine
Depakene                                                        • Symbyax
Duloxetine • Cymbalta                                    Paroxetine • Paxil
Escitalopram • Lexapro                                   Phenelzine • Nardil
Fluoxetine • Prozac                                         Pramipexole • Mirapex
Imipramine • Tofranil                                     Quetiapine • Seroquel
Ketamine • Ketalar                                         Riluzole • Rilutek
Lamotrigine • Lamictal                                    Sertraline • Zoloft
Lithium • Eskalith, Lithobid                             Vortioxetine • Brintellix

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

Editor’s note: The second part of Dr. Goldberg’s review of depression subtypes—fo­cusing on “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a sub­stance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder—will appear in the May 2014 issue of Current Psychiatry.

Depression carries a wide differential diagnosis. Practitioners sometimes think polarity is the fundamental distinction when they conceptualize depression as a clinical entity; in fact, many nosologic frameworks have been described for defining and subtyping clinically meaningful forms of depression, and each waxed and waned in popularity.

Kraepelin, writing in the early 20th century, linked manic-depres­sive illness with “the greater part of the morbid states termed mel­ancholia,”¹ but many features other than polarity remain important components of depression, and those features often carry implications for how individual patients respond to treatment.

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 first part of this article examines major depressive disorder (MDD), minor depression, chronic depression, depression in bipolar disorder, depression that is severe or mild, and psychotic depression. Treatments for these subtypes for which there is evidence, or a clinical rationale, are given in the Table.

The subtypes of depression that I’ll discuss in the second part of the article are listed on page 47.

Major and minor depression
MDD has been the focus of most drug tri­als seeking FDA approval. As a syndrome, MDD is defined by a constellation of fea­tures that are related not only to mood but also to sleep, energy, cognition, motiva­tion, and motor behavior, persisting for ≥2 weeks.

DSM-5 has imposed few changes to the basic definition of MDD:
   • bereavement (the aftermath of death of a loved one), formerly an exclusion cri­terion, no longer precludes making a diag­nosis of MDD when syndromal criteria are otherwise fulfilled
   • “with anxious distress” is a new course specifier that designates promi­nent anxiety features (feeling worried, restless, tense, or keyed up; fearful of losing control or something terrible happening)
   • “with mixed features” is a new course specifier pertinent when ≥3 mania or hy­pomania symptoms coexist (that is, might be a subsyndromal mania or hypomania) with a depressive syndrome; the mixed features specifier can be applied to de­pressed patients whether or not they have ever had a manic or hypomanic episode, but MDD—rather than bipolar disorder— remains the overarching diagnosis, unless criteria have ever been met for a full mania or hypomania.

More than 2 dozen medications are FDA-approved to treat MDD. Evidence-based psychotherapies (eg, cognitive-behavioral therapy [CBT] and interpersonal therapy), as adjuncts to pharmacotherapy, further improve outcomes, but with only modest additional effect.²

Minor depression. Depressive states that involve 2 to 4 associated symptoms last­ing ≥2 weeks but <2 years are sometimes described as minor depression, captured within DSM-5 as “depression not else­where defined.” The terminology of so-called “minor depression” generally is shunned, in part because it might wrongly connote low severity and therefore dis­courage treatment—even though it con­fers more than a 5-fold increase in risk of MDD.3 

Chronicity
DSM-IV-TR identified long-standing de­pression by 2 constructs:
   • chronic major depression (an episode of MDD lasting ≥2 years in adults, ≥1 year in children and adolescents)
   • dysthymic disorder (2 to 4 depressive symptoms for ≥2 years in adults and ≥1 year in children and adolescents), affecting 3% to 6% of adults and carrying a 2-fold increased risk of MDD, eventually.⁴

Depression that begins as dysthymic disorder and blossoms into syndromal MDD is described as “double depres­sion”—although it is not recognized as a unique condition in any edition of the DSM. Subsequent incomplete recovery may revert to dysthymic disorder. DSM-5 has subsumed chronic major depression and dysthymia under the unified heading of persistent depressive disorder.

There are no FDA-approved drugs for treating dysthymia. A meta-analysis of 9 controlled trials of off-label use of antide­pressants to treat dysthymia revealed an overall response rate of 52.4%, compared with 29.9% for placebo.⁵ Notably, although the active drug response rate in these stud­ies is comparable to what seen in MDD, the placebo response rate was approxi­mately 10% lower than what was seen in major depression.

Positive therapeutic findings (typically, treatment for 6 to 12 weeks) have been reported in so-called “pure” dysthymic disorder with sertraline, fluoxetine, imip­ramine, ritanserin, moclobemide (not ap­proved for use in the United States), and phenelzine; the results of additional, posi­tive placebo-controlled studies support the utility of duloxetine⁶ and paroxetine.⁷ Randomized trials have reported negative findings for desipramine,⁸ fluoxetine,⁹ and escitalopram¹⁰ escitalopram¹⁰—although the sample size in these latter studies might have been too small to detect a drug-placebo difference.

In dysthymic and minor-depressive middle-age and older adult men who have a low serum level of testosterone, hormone replacement was shown to be superior to placebo in several randomized trials.¹¹ Studies of adjunctive atypical antipsy­chotics for dysthymic disorder are scarce; a Cochrane review identified controlled data only with amisulpride (not approved for use in the United States), which yielded a modest therapeutic effect.¹²

Polarity
In recent years, depression in bipolar dis­order (BD) has been contrasted with uni­polar MDD based on a difference in:
   • duration (briefer in BD)
   • severity (worse in BD)
   • risk of suicide (higher)
   • comorbidity (more extensive)
   • family history (often present for BD and highly recurrent depression)
   • treatment outcome (generally less favorable).

DSM-5 has at least somewhat blurred the distinctions in polarity by way of the new construct of “major depression with mixed features” (see the discussion of MDD above), identifiable even when a person has never had a full manic or hypo­manic episode.

No randomized trials have been con­ducted to identify the best treatments for such presentations, which has invited ex­trapolation from the literature in regard to bipolar mixed episodes, and suggesting that 1) some mood stabilizers (eg, divalproex) might have value and 2) antidepres­sants might exacerbate manic symptoms.

Perhaps most noteworthy in regard to treating bipolar depression is the unresolved, but hotly debated, contro­versy over whether and, if so, when, an antidepressant is inappropriate (based on concerns about possible induction or exac­erbation of manic symptoms). In addition, nearly all of the large, randomized con­trolled trials of antidepressants for bipolar depression have shown that they offer no advantage over placebo.

Some authors argue that a lack of re­sponse to antidepressants might, itself, be a “soft” indicator of “bipolarity.” However, nonresponse to antidepressants should prompt a wider assessment of features other than polarity—including psychosis, anxiety, substance abuse, a personality disorder, psychiatric adverse effects from concomitant medications, medical comor­ bidity, adequacy of trials of medical ther­apy, and potential non-adherence to such trials—to account for poor antidepressant outcomes.

Severity
Severity of depression warrants consider­ation when formulating impressions about the nature and treatment of all presenta­tions of depression.

High-severity forms prompt decisions about treatment setting (inpatient or out­patient); suicide assessment; and thera­peutic modalities (eg, electroconvulsive therapy is more appropriate than psycho­therapy for catatonic depression).

Mild forms. A recent meta-analysis of 6 randomized trials (each of >6 weeks’ du­ration) of antidepressants for mild de­pression demonstrated that these agents exert only a modest effect compared with placebo, owing largely to higher placebo-responsivity in mild depressive episodes than in moderate and severe episodes.13 In contrast, another meta-analysis of sub­jects who had “mild” baseline depression severity scores found that antidepressant medication had greater efficacy than pla­cebo in 4 of 6 randomized trials.14 Higher depression severity levels typically dimin­ish the placebo response rate but also re­duce the magnitude of drug efficacy.

Psychosis
Before DSM-III, psychotic (as opposed to neurotic) depression was perhaps the key nosologic distinction when characteriz­ing forms of depression. The presence of psychosis and related components (eg, mood-congruence) is closely linked with the severity of depression (high) and prog­nosis and longitudinal outcome (poorer), and has implications for treatment (Table).

Bottom Line
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including polarity, chronicity, recurrence, psychosis, treatment resistance, comorbidity, and atypicality, among other classifications. Clinical characteristics vary across subtypes—and so do corresponding preferred treatments, which should be tailored to the needs of each of your patients.

Related Resources
• Goldberg JF, Thase ME. Monoamine oxidase inhibi­tors revisited: what you should know. J Clin Psychiatry. 2013;74(2):189-191.
• Goldberg JF. Antidepressants in bipolar disorder: 7 myths and realities. Current Psychiatry. 2010;9(5):41-49.
• Ketamine cousin rapidly lifts depression without side ef­fects. National Institute of Mental Health. http://www. nimh.nih.gov/news/science-news/2013/ketamine-cousin-rapidly-lifts-depression-without-side-effects.shtml. Published May 23, 2013. Accessed March 20, 2014.
• Research Domain Criteria (RDoC). National Institute of Mental Health. http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml?u tm_ source = govdelivery&utm_medium=email&utm_campaign= govdelivery. Accessed March 20, 2014.

Drug Brand Names
Amisulpride • Amazeo,                                  Lurasidone • Latuda
Amival, Amipride, Sulpitax                             Mirtazapine • Remeron
   Aripiprazole • Abilify                                   Moclobemide • Amira,
Armodafinil • Nuvigil                                        Aurorix, Clobemix,
Bupropion • Wellbutrin                                     Depnil, Manerix
Desipramine • Norpramin                               Modafinil • Provigil
Divalproex • Depakote,                                  Olanzapine/fluoxetine
Depakene                                                        • Symbyax
Duloxetine • Cymbalta                                    Paroxetine • Paxil
Escitalopram • Lexapro                                   Phenelzine • Nardil
Fluoxetine • Prozac                                         Pramipexole • Mirapex
Imipramine • Tofranil                                     Quetiapine • Seroquel
Ketamine • Ketalar                                         Riluzole • Rilutek
Lamotrigine • Lamictal                                    Sertraline • Zoloft
Lithium • Eskalith, Lithobid                             Vortioxetine • Brintellix

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

Editor’s note: The second part of Dr. Goldberg’s review of depression subtypes—fo­cusing on “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a sub­stance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder—will appear in the May 2014 issue of Current Psychiatry.

Major depressive disorder (MDD) frequently is recur­rent, with new episodes causing substantial social and economic impairment¹ and increasing the like­lihood of future episodes.² For this reason, contemporary psychiatric practitioners think of depression treatment as long-term and plan thoughtfully for maintenance therapy.

Recognizing the importance of engaging depressed indi­viduals beyond the initial response,³ American Psychiatric Association practice guidelines conceptualize depression treatment as 3 phases:
   • acute treatment, with the aim of remission (symptom removal)
   • continuation treatment, with the aim of preventing re­lapse (symptom return)
   • maintenance treatment, with the aim of preventing re­currence (new episodes).⁴
Interpersonal psychotherapy (IPT) is an evidence-based psychosocial treatment that adheres to this model.⁵ As a time-limited, manual-driven^6,7 approach, IPT focuses on interpersonal distresses as precipitating and perpetuating factors of depression.⁸

Acute IPT’s efficacy is well-established across >200 empirical studies—making it an evidence-based, first-line treatment for adult depression.^4,9,10 Meta-analyses show that acute IPT is superior to placebo and no-treatment con­trols, and largely comparable to antidepressant medication and other active, first-line psychotherapies, such as cogni­tive-behavioral therapy (CBT).^11,12

Although this review, as well as the liter­ature, focuses largely on adult outpatients with depression, evidence of IPT’s general efficacy exists for adolescents,¹³ chronically depressed patients,¹¹ and depressed inpa­tients.¹⁴ This article presents a case study to describe the structure of IPT when used to treat depressed adults. We also present evidence of IPT’s acute and long-term ef­ficacy in preventing depression recurrence and data to guide its use in practice.

CASE REPORT

‘Safe’ but depressed
Timothy, age 18, is a first-year college student who presents for outpatient psychotherapy to address recurrent depression. He reports general unhappiness, loss of interest in things, low energy, sleep problems, poor academic and work functioning, and low self-esteem. He experienced at least 3 similar depressive episodes while in high school.

The therapist’s diagnostic and interper­sonal assessment suggests that Timothy’s depression is interpersonally driven. Timothy longs for relational intimacy but fears he will fail or burden people with his needs. He has difficulty gauging appropriate lev­els of enmeshment with others and either becomes overdependent or stays at a dis­tance. This “safe” approach to relationships contributes to boredom, loneliness, and isolation. His recent transition to college away from home and the failure of a roman­tic relationship have compounded these experiences.

Interpersonal model of IPT
IPT conceptualizes depression as involving predisposing, precipitating, and perpetu­ating biopsychosocial factors, including:
   • underlying biological and social vul­nerability, such as insecure attach­ ment (ie, tenuous and often negative views of self and others)
   • current interpersonal life stressors
   • inadequate social supports.^15,16

For example, poor early attachment to caregivers can give rise to despair, isolation, and low mood. In turn, this can be exacerbated by poor social and commu­nication skills that promote further rejec­tion and withdrawal of social support and thus, intensified despair, isolation, and low mood. As in Timothy’s case, this vicious cycle underscores psychosocial stressors as a causal factor, maintaining factor, and result of depression. Specifically, IPT con­ceptualizes 4 main biopsychosocial problem domains:
   • grief and loss
   • interpersonal disputes
   • role transitions
   • interpersonal/communication deficits (often connected to isolation).

Working within 1 or 2 of the most salient problem domains, IPT centers on strategies for helping patients solve interpersonal problems based on the notion that modi­fied relationships, revised interpersonal expectations, improved communications, and increased social support will lead to symptom reduction.^15-17

Many techniques are utilized in IPT (Table 1) to help patients modify their interpersonal relationships as a mechanism for decreasing their distress. IPT is prob­lem-focused, aiming to improve patients’ relationships by drawing on their assets and helping to build skills around short­comings. Therefore, IPT focuses on observ­able interpersonal patterns, as opposed to latent personality dynamics.

CASE CONTINUED

Setting goals
When the clinical explains in the non-technical terms the data supporting IPT’s efficacy for depression, including with young adults, Timothy agrees to teeatment with acute IPT. The therapist behins with consciousness-raising techniques to help Timothy adopt the “sick role” by viewing depressing as an illness to be cured. Collaboratively, they establish treatment goals that fit the IPT formulation of depression— ie, revising current relationships and expectations of them, increasing social support, improving communication skills, and solving problems within 1 or 2 of the IPT prob­lem domains.

For Timothy, the most pressing psy­chosocial problems seem to be interper­sonal deficits and role transitions. He ap­pears to be insecurely attached to others, which is a risk factor for poor facilitation of, and boundaries around, good relation­ships. A transition to a new and intimidat­ing interpersonal context—living on a college campus—compounded his vulnerabilities and increased his depression.

Acute treatment. The acute phase of IPT is time-limited—often, 12 to 16 sessions with gradual tapering toward the end (akin to a continuation phase). The time limit’s pur­pose is to focus both patient and therapist on the specific goal of removing the acute “illness” of depression. The IPT clinician takes an interpersonal inventory to learn about the patient’s most important rela­tionships and hones in on the IPT domain foci. Working collaboratively, the thera­pist might help the patient mourn a loss, reconstruct a narrative with a deceased loved one, consider ways to increase social contact, develop assertiveness, label feel­ings and needs, resolve an impasse with a significant other, and so forth.

The IPT therapist is an advocate for the patient and adopts an active stance laced with empathy and warmth. However, the therapist is more than unconditionally ac­cepting as depression is viewed as a prob­lem to be actively resolved.

CASE CONTINUED

Creating new patterns
The therapist uses various IPT strategies to work collaboratively with Timothy. She at­tempts to develop a strong working alliance by building interpersonal safety and trust— which take time with an insecurely attached patient. She tries to provide a new model for how close relationships can develop, while also focusing on current relationships. She and Timothy address his romantic desire for a coworker and work on developing realistic ex­pectations and effective methods for convey­ing his interest.

When Timothy approaches his coworker, she does not reject him—as he expected— but wants to pursue friendship before pos­sibly dating. The therapist then works with Timothy’s emotional reaction and explores ways to effectively convey his emotions to this young woman. Drawing on communica­tion analysis and problem-solving strategies, Timothy is able to sustain this friendship—a shift from his typical retreat when relation­ships have not gone as hoped or expected.

Timothy develops confidence to take more risks in initiating social encounters and starts to confide in his roommates when he feels upset. After 3 months of treatment, his expanded social network and improved in­terpersonal skills result in decreased depres­sion. When Timothy suggests termination, he and the therapist agree to end acute IPT but—given his history of depression—to continue maintenance sessions.

Limited data exist on variables that relate to IPT’s acute success or conditions under which it works best. Although process re­search lags behind acute IPT outcome re­search, some findings can help guide the IPT practitioner. For example, variables shown to predict outcomes of acute IPT for depression include a positive therapeutic alliance, therapist warmth, and psycho­ psycho­therapist use of exploratory techniques (Table 2).

Similarly, IPT has been shown to be more effective in some patients than oth­ers, depending on various moderators of depression. For example:
   • For patients with high cognitive dys­function, IPT outperforms CBT.
   • For patients with higher need for medical reassurance, IPT outperforms selective serotonin reuptake inhibitor (SSRI) pharmacotherapy.
   • For patients with severe depression, CBT outperforms IPT.
   • For patients with low psychomotor activation, response is more rapid with an SSRI than with IPT (Table 3).¹⁸

Durability of acute IPT
One way to understand recurrence pre­vention is to examine the durability of a treatment’s acute effect in the absence of a specific maintenance plan. In theory, patients will continue to apply the skills learned in acute IPT to maintain gains and prevent recurrences, even after they stop seeing the psychotherapist.

Initial findings.  Some research speaks to IPT’s acute-phase durability. The inaugural clinical trial of IPT by Weissman et al¹⁹ included 4 months of acute treatment and a 1-year uncontrolled naturalistic follow-up assessment. At follow-up, depression and global clinical symptoms were the same, whether patients had been acutely treated with IPT alone, pharmacotherapy alone (amitriptyline), combined IPT and pharmacotherapy, or nonscheduled treat­ment with a psychiatrist.

Some patients continued to function well, whereas others did not fully main­tain acute treatment gains. Patients who received IPT acutely, either singly or with medication, showed better social function­ing at follow-up compared with patients who did not receive IPT. This long-term durability of social improvements was an obvious target of IPT.

Support from TDCRP. In the National Institute of Mental Health Treatment of Depression Collaborative Research Project (TDCRP),²⁰ patients in the acute phase of depression were assigned to 16 weeks of IPT, CBT, pharmacotherapy (imipramine) and clinical management (CM), or placebo plus CM. Among those who recovered by acute treatment’s end, MDD relapse rates at 18-month naturalistic follow-up were 33% for IPT, 36% for CBT, 50% for imipramine, and 33% for placebo. Between-group differ­ences were not statistically significant.

Because acute responders to different types of treatment might have different inherent relapse tendencies, these data do not support causal attributions about the enduring effects of acute-phase treatment. The relapse rates do suggest, however, that 16 weeks of acute treatment, irrespec­tive of kind, was insufficient for some pa­tients to achieve full recovery and lasting remission. Consistent with the initial IPT trial,¹⁹ IPT (and CBT) outperformed medi cation and placebo in maintaining rela­tionship quality.²¹

Long-term benefits. A more recent trial by Zobel et al²² examined the durabil­ity of benefits from 5 weeks of acute IPT plus pharmacotherapy and pharmaco­therapy plus CM for inpatients with MDD. Although caution is required in interpret­ing naturalistic follow-up studies, patients in both groups showed decreased depres­sion from baseline to 5-year follow-up. Early symptom reduction was more rapid for patients in the IPT plus pharmacother­apy group, but no significant difference ex­isted at 5 years. More IPT patients than CM patients showed sustained remission (28% vs 11%, respectively). These rates demon­strate a need for longer-term potency of acute treatments and more targeted main­tenance treatments.

IPT-M for preventing recurrence
A second way to understand recurrence prevention is to examine the efficacy of a treatment’s maintenance protocol add­ed to an acute treatment phase. IPT has been adapted as a maintenance treatment (IPT-M), with emphasis on keeping pa­tients well. With this revised focus, IPT-M differs somewhat from acute IPT. Although treatment continues to center on interper­sonal functioning, IPT-M favors:
   • vigilance for possible triggers of new depressive episodes
   • longer-term contact with a therapist
   • reinforcing skills learned
   • addressing an expanded number of interpersonal problem areas (given that such problems can be addressed more ef­ficiently relative to acute treatment).

Efficacy of IPT-M. In the initial trial, Frank et al²³ compared the efficacy of IPT-M with that of pharmacotherapy (imipramine) in preventing depressive relapse among pa­tients with recurrent depression who had responded to ≥16 sessions of acute IPT and imipramine and remained well during a 17- week continuation phase. For maintenance, patients were assigned to IPT-M alone, imipramine alone, placebo alone, IPT-M plus imipramine, or IPT-M plus placebo. Maintenance imipramine was continued at the acute dosage (target 200 mg/d; up to 400 mg/d was allowed). Maintenance IPT was monthly sessions. Patients remained in the trial for 3 years or until depression recurred.

On its own, IPT-M showed some efficacy in preventing recurrence, as the mean time to recurrence was 82 weeks for IPT-M alone and 74 weeks for IPT-M plus placebo. The prophylactic effect of imipramine was stron­ger, however. The mean time to recurrence for imipramine with IPT was 131 weeks, and the mean time to recurrence for imipra­mine without IPT was 124 weeks. Therefore, whereas monthly IPT-M can certainly help prolong wellness and delay recurrence, IPT maintenance treatment with acute doses of imipramine might be even more effective— if the patient is willing to take medication. These findings must be considered with caution because of the inherent inequity be­tween imipramine and IPT-M in regard to maintenance dosage strength.

Frequency of treatment. In another trial, Frank et al²⁴ examined whether the fre­quency of maintenance IPT sessions played a role in its prophylactic effect. Adult wom­en who had achieved depression remission with acute IPT (alone or in combination with SSRI pharmacotherapy) were ran­domized to weekly, bi-weekly, or monthly IPT-M alone for 2 years or until recurrence. Depression recurred during IPT-M in:
   • 26% of patients who had received acute IPT alone
   • 50% of those who had received acute IPT plus an SSRI.

Frequency of IPT-M sessions did not af­fect time to recurrence. Thus, for women who can achieve remission with IPT alone, varied frequencies of IPT-M can be good prophylaxis. For women who need an SSRI to augment acute IPT, IPT-M alone at varied dosages is less effective in pre­venting depression recurrence. Therefore, acute treatment response patterns can in­form maintenance plans, with the most prudent maintenance strategy being to maintain the acute treatment strategy over a longer period.

IPT-M for late-life depression. A trial by Reynolds et al25 examined the efficacy of maintenance nortriptyline and IPT-M in preventing depression recurrence in pa­tients age ≥59 who initially recovered after combined acute and continuation IPT plus nortriptyline. The 4 conditions (with their recurrence rates) were:
   • monthly IPT-M with nortriptyline (20%)
   • monthly IPT-M with placebo (64%)
   • nortriptyline plus medication visits (43%)
   • placebo plus medication visits (90%).

Clearly, the combined active treat­ments outperformed placebo and anti­depressant alone in terms of delaying or preventing recurrence, which suggests an optimal maintenance strategy with this population.

IPT-M for later life. Another trial by the same group²⁶ enrolled patients age ≥70 with MDD that responded to acute IPT plus paroxetine. The maintenance treat­ments to which they were randomly as­signed (and recurrence rates within 2 years) were:
   • paroxetine plus IPT-M (35%)
   • placebo plus IPT-M (68%)
   • paroxetine plus clinical management (37%)
   • placebo plus clinical management (58%).

Recurrence rates were the same for pa­tients receiving medication plus IPT-M and medication plus clinical management, and depression was 2.4 times more likely to recur in patients receiving placebo vs active medication. Therefore, for later life depression, the optimal maintenance strat­egy was the SSRI.

Secondary analyses of data from these seminal trials of IPT-M point to other predictors of how and for whom mainte­nance IPT may work (Table 4). For example:
   • Greater variability of depression symptoms during all forms of mainte­nance treatment is related to a greater risk of recurrence.
   • Persistent insomnia is related to greater risk of recurrent depression.
   • High interpersonal focus in IPT-M sessions is related to longer time to recurrence.

Bottom Line
Interpersonal psychotherapy (IPT) is efficacious for acute depression and for preventing recurrences. Patients treated successfully with acute IPT alone benefit from varied doses of maintenance IPT. Combining IPT-M with antidepressant medication can be more potent than IPT-M alone. For late-life depression, medication appears to be most effective for maintenance treatment.

Related Resources

Media
• Video demonstration, role-play transcripts, lesson plans, and quizzes. In: Appendices in and DVD companion to Ravitz P, Watson P, Grigoriadas S. Interpersonal psychother­apy for depression. New York, NY: Norton; 2013.
• Video demonstration of IPT sessions. In: DVD companion to Dewan, M, Steenbarger, B, Greenberg, R, eds. The art and science of brief psychotherapies: An illustrated guide. 2nd ed. Arlington, VA: American Psychiatric Publishing; 2012.

Text
• Stuart S, Robertson M. Interpersonal psychotherapy: a cli­nician’s guide. London, United Kingdom: Taylor & Francis; 2012.
• Weissman MM, Markowitz JC, Klerman GL. Comprehensive guide to interpersonal psychotherapy. New York, NY: Basic Books; 2000.
• Weissman M, Markowitz J, Klerman GL. Clinician’s quick guide to interpersonal psychotherapy. New York, NY: Oxford University Press; 2007.

Websites
• Interpersonal Psychotherapy Institute. http://iptinstitute.com.
• International Society for Interpersonal Psychotherapy. http://interpersonalpsychotherapy.org.

Drug Brand Names
Amitriptyline • Elavil       Nortriptyline • Pamelor
Imipramine • Tofranil     Paroxetine • Paxil

Acknowledgments
The authors are grateful to Samantha L. Bernecker, MS, and Nicholas R. Morrison for their assistance with the research review.

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

Major depressive disorder (MDD) frequently is recur­rent, with new episodes causing substantial social and economic impairment¹ and increasing the like­lihood of future episodes.² For this reason, contemporary psychiatric practitioners think of depression treatment as long-term and plan thoughtfully for maintenance therapy.

Recognizing the importance of engaging depressed indi­viduals beyond the initial response,³ American Psychiatric Association practice guidelines conceptualize depression treatment as 3 phases:
   • acute treatment, with the aim of remission (symptom removal)
   • continuation treatment, with the aim of preventing re­lapse (symptom return)
   • maintenance treatment, with the aim of preventing re­currence (new episodes).⁴
Interpersonal psychotherapy (IPT) is an evidence-based psychosocial treatment that adheres to this model.⁵ As a time-limited, manual-driven^6,7 approach, IPT focuses on interpersonal distresses as precipitating and perpetuating factors of depression.⁸

Acute IPT’s efficacy is well-established across >200 empirical studies—making it an evidence-based, first-line treatment for adult depression.^4,9,10 Meta-analyses show that acute IPT is superior to placebo and no-treatment con­trols, and largely comparable to antidepressant medication and other active, first-line psychotherapies, such as cogni­tive-behavioral therapy (CBT).^11,12

Although this review, as well as the liter­ature, focuses largely on adult outpatients with depression, evidence of IPT’s general efficacy exists for adolescents,¹³ chronically depressed patients,¹¹ and depressed inpa­tients.¹⁴ This article presents a case study to describe the structure of IPT when used to treat depressed adults. We also present evidence of IPT’s acute and long-term ef­ficacy in preventing depression recurrence and data to guide its use in practice.

CASE REPORT

‘Safe’ but depressed
Timothy, age 18, is a first-year college student who presents for outpatient psychotherapy to address recurrent depression. He reports general unhappiness, loss of interest in things, low energy, sleep problems, poor academic and work functioning, and low self-esteem. He experienced at least 3 similar depressive episodes while in high school.

The therapist’s diagnostic and interper­sonal assessment suggests that Timothy’s depression is interpersonally driven. Timothy longs for relational intimacy but fears he will fail or burden people with his needs. He has difficulty gauging appropriate lev­els of enmeshment with others and either becomes overdependent or stays at a dis­tance. This “safe” approach to relationships contributes to boredom, loneliness, and isolation. His recent transition to college away from home and the failure of a roman­tic relationship have compounded these experiences.

Interpersonal model of IPT
IPT conceptualizes depression as involving predisposing, precipitating, and perpetu­ating biopsychosocial factors, including:
   • underlying biological and social vul­nerability, such as insecure attach­ ment (ie, tenuous and often negative views of self and others)
   • current interpersonal life stressors
   • inadequate social supports.^15,16

For example, poor early attachment to caregivers can give rise to despair, isolation, and low mood. In turn, this can be exacerbated by poor social and commu­nication skills that promote further rejec­tion and withdrawal of social support and thus, intensified despair, isolation, and low mood. As in Timothy’s case, this vicious cycle underscores psychosocial stressors as a causal factor, maintaining factor, and result of depression. Specifically, IPT con­ceptualizes 4 main biopsychosocial problem domains:
   • grief and loss
   • interpersonal disputes
   • role transitions
   • interpersonal/communication deficits (often connected to isolation).

Working within 1 or 2 of the most salient problem domains, IPT centers on strategies for helping patients solve interpersonal problems based on the notion that modi­fied relationships, revised interpersonal expectations, improved communications, and increased social support will lead to symptom reduction.^15-17

Many techniques are utilized in IPT (Table 1) to help patients modify their interpersonal relationships as a mechanism for decreasing their distress. IPT is prob­lem-focused, aiming to improve patients’ relationships by drawing on their assets and helping to build skills around short­comings. Therefore, IPT focuses on observ­able interpersonal patterns, as opposed to latent personality dynamics.

CASE CONTINUED

Setting goals
When the clinical explains in the non-technical terms the data supporting IPT’s efficacy for depression, including with young adults, Timothy agrees to teeatment with acute IPT. The therapist behins with consciousness-raising techniques to help Timothy adopt the “sick role” by viewing depressing as an illness to be cured. Collaboratively, they establish treatment goals that fit the IPT formulation of depression— ie, revising current relationships and expectations of them, increasing social support, improving communication skills, and solving problems within 1 or 2 of the IPT prob­lem domains.

For Timothy, the most pressing psy­chosocial problems seem to be interper­sonal deficits and role transitions. He ap­pears to be insecurely attached to others, which is a risk factor for poor facilitation of, and boundaries around, good relation­ships. A transition to a new and intimidat­ing interpersonal context—living on a college campus—compounded his vulnerabilities and increased his depression.

Acute treatment. The acute phase of IPT is time-limited—often, 12 to 16 sessions with gradual tapering toward the end (akin to a continuation phase). The time limit’s pur­pose is to focus both patient and therapist on the specific goal of removing the acute “illness” of depression. The IPT clinician takes an interpersonal inventory to learn about the patient’s most important rela­tionships and hones in on the IPT domain foci. Working collaboratively, the thera­pist might help the patient mourn a loss, reconstruct a narrative with a deceased loved one, consider ways to increase social contact, develop assertiveness, label feel­ings and needs, resolve an impasse with a significant other, and so forth.

The IPT therapist is an advocate for the patient and adopts an active stance laced with empathy and warmth. However, the therapist is more than unconditionally ac­cepting as depression is viewed as a prob­lem to be actively resolved.

CASE CONTINUED

Creating new patterns
The therapist uses various IPT strategies to work collaboratively with Timothy. She at­tempts to develop a strong working alliance by building interpersonal safety and trust— which take time with an insecurely attached patient. She tries to provide a new model for how close relationships can develop, while also focusing on current relationships. She and Timothy address his romantic desire for a coworker and work on developing realistic ex­pectations and effective methods for convey­ing his interest.

When Timothy approaches his coworker, she does not reject him—as he expected— but wants to pursue friendship before pos­sibly dating. The therapist then works with Timothy’s emotional reaction and explores ways to effectively convey his emotions to this young woman. Drawing on communica­tion analysis and problem-solving strategies, Timothy is able to sustain this friendship—a shift from his typical retreat when relation­ships have not gone as hoped or expected.

Timothy develops confidence to take more risks in initiating social encounters and starts to confide in his roommates when he feels upset. After 3 months of treatment, his expanded social network and improved in­terpersonal skills result in decreased depres­sion. When Timothy suggests termination, he and the therapist agree to end acute IPT but—given his history of depression—to continue maintenance sessions.

Limited data exist on variables that relate to IPT’s acute success or conditions under which it works best. Although process re­search lags behind acute IPT outcome re­search, some findings can help guide the IPT practitioner. For example, variables shown to predict outcomes of acute IPT for depression include a positive therapeutic alliance, therapist warmth, and psycho­ psycho­therapist use of exploratory techniques (Table 2).

Similarly, IPT has been shown to be more effective in some patients than oth­ers, depending on various moderators of depression. For example:
   • For patients with high cognitive dys­function, IPT outperforms CBT.
   • For patients with higher need for medical reassurance, IPT outperforms selective serotonin reuptake inhibitor (SSRI) pharmacotherapy.
   • For patients with severe depression, CBT outperforms IPT.
   • For patients with low psychomotor activation, response is more rapid with an SSRI than with IPT (Table 3).¹⁸

Durability of acute IPT
One way to understand recurrence pre­vention is to examine the durability of a treatment’s acute effect in the absence of a specific maintenance plan. In theory, patients will continue to apply the skills learned in acute IPT to maintain gains and prevent recurrences, even after they stop seeing the psychotherapist.

Initial findings.  Some research speaks to IPT’s acute-phase durability. The inaugural clinical trial of IPT by Weissman et al¹⁹ included 4 months of acute treatment and a 1-year uncontrolled naturalistic follow-up assessment. At follow-up, depression and global clinical symptoms were the same, whether patients had been acutely treated with IPT alone, pharmacotherapy alone (amitriptyline), combined IPT and pharmacotherapy, or nonscheduled treat­ment with a psychiatrist.

Some patients continued to function well, whereas others did not fully main­tain acute treatment gains. Patients who received IPT acutely, either singly or with medication, showed better social function­ing at follow-up compared with patients who did not receive IPT. This long-term durability of social improvements was an obvious target of IPT.

Support from TDCRP. In the National Institute of Mental Health Treatment of Depression Collaborative Research Project (TDCRP),²⁰ patients in the acute phase of depression were assigned to 16 weeks of IPT, CBT, pharmacotherapy (imipramine) and clinical management (CM), or placebo plus CM. Among those who recovered by acute treatment’s end, MDD relapse rates at 18-month naturalistic follow-up were 33% for IPT, 36% for CBT, 50% for imipramine, and 33% for placebo. Between-group differ­ences were not statistically significant.

Because acute responders to different types of treatment might have different inherent relapse tendencies, these data do not support causal attributions about the enduring effects of acute-phase treatment. The relapse rates do suggest, however, that 16 weeks of acute treatment, irrespec­tive of kind, was insufficient for some pa­tients to achieve full recovery and lasting remission. Consistent with the initial IPT trial,¹⁹ IPT (and CBT) outperformed medi cation and placebo in maintaining rela­tionship quality.²¹

Long-term benefits. A more recent trial by Zobel et al²² examined the durabil­ity of benefits from 5 weeks of acute IPT plus pharmacotherapy and pharmaco­therapy plus CM for inpatients with MDD. Although caution is required in interpret­ing naturalistic follow-up studies, patients in both groups showed decreased depres­sion from baseline to 5-year follow-up. Early symptom reduction was more rapid for patients in the IPT plus pharmacother­apy group, but no significant difference ex­isted at 5 years. More IPT patients than CM patients showed sustained remission (28% vs 11%, respectively). These rates demon­strate a need for longer-term potency of acute treatments and more targeted main­tenance treatments.

IPT-M for preventing recurrence
A second way to understand recurrence prevention is to examine the efficacy of a treatment’s maintenance protocol add­ed to an acute treatment phase. IPT has been adapted as a maintenance treatment (IPT-M), with emphasis on keeping pa­tients well. With this revised focus, IPT-M differs somewhat from acute IPT. Although treatment continues to center on interper­sonal functioning, IPT-M favors:
   • vigilance for possible triggers of new depressive episodes
   • longer-term contact with a therapist
   • reinforcing skills learned
   • addressing an expanded number of interpersonal problem areas (given that such problems can be addressed more ef­ficiently relative to acute treatment).

Efficacy of IPT-M. In the initial trial, Frank et al²³ compared the efficacy of IPT-M with that of pharmacotherapy (imipramine) in preventing depressive relapse among pa­tients with recurrent depression who had responded to ≥16 sessions of acute IPT and imipramine and remained well during a 17- week continuation phase. For maintenance, patients were assigned to IPT-M alone, imipramine alone, placebo alone, IPT-M plus imipramine, or IPT-M plus placebo. Maintenance imipramine was continued at the acute dosage (target 200 mg/d; up to 400 mg/d was allowed). Maintenance IPT was monthly sessions. Patients remained in the trial for 3 years or until depression recurred.

On its own, IPT-M showed some efficacy in preventing recurrence, as the mean time to recurrence was 82 weeks for IPT-M alone and 74 weeks for IPT-M plus placebo. The prophylactic effect of imipramine was stron­ger, however. The mean time to recurrence for imipramine with IPT was 131 weeks, and the mean time to recurrence for imipra­mine without IPT was 124 weeks. Therefore, whereas monthly IPT-M can certainly help prolong wellness and delay recurrence, IPT maintenance treatment with acute doses of imipramine might be even more effective— if the patient is willing to take medication. These findings must be considered with caution because of the inherent inequity be­tween imipramine and IPT-M in regard to maintenance dosage strength.

Frequency of treatment. In another trial, Frank et al²⁴ examined whether the fre­quency of maintenance IPT sessions played a role in its prophylactic effect. Adult wom­en who had achieved depression remission with acute IPT (alone or in combination with SSRI pharmacotherapy) were ran­domized to weekly, bi-weekly, or monthly IPT-M alone for 2 years or until recurrence. Depression recurred during IPT-M in:
   • 26% of patients who had received acute IPT alone
   • 50% of those who had received acute IPT plus an SSRI.

Frequency of IPT-M sessions did not af­fect time to recurrence. Thus, for women who can achieve remission with IPT alone, varied frequencies of IPT-M can be good prophylaxis. For women who need an SSRI to augment acute IPT, IPT-M alone at varied dosages is less effective in pre­venting depression recurrence. Therefore, acute treatment response patterns can in­form maintenance plans, with the most prudent maintenance strategy being to maintain the acute treatment strategy over a longer period.

IPT-M for late-life depression. A trial by Reynolds et al25 examined the efficacy of maintenance nortriptyline and IPT-M in preventing depression recurrence in pa­tients age ≥59 who initially recovered after combined acute and continuation IPT plus nortriptyline. The 4 conditions (with their recurrence rates) were:
   • monthly IPT-M with nortriptyline (20%)
   • monthly IPT-M with placebo (64%)
   • nortriptyline plus medication visits (43%)
   • placebo plus medication visits (90%).

Clearly, the combined active treat­ments outperformed placebo and anti­depressant alone in terms of delaying or preventing recurrence, which suggests an optimal maintenance strategy with this population.

IPT-M for later life. Another trial by the same group²⁶ enrolled patients age ≥70 with MDD that responded to acute IPT plus paroxetine. The maintenance treat­ments to which they were randomly as­signed (and recurrence rates within 2 years) were:
   • paroxetine plus IPT-M (35%)
   • placebo plus IPT-M (68%)
   • paroxetine plus clinical management (37%)
   • placebo plus clinical management (58%).

Recurrence rates were the same for pa­tients receiving medication plus IPT-M and medication plus clinical management, and depression was 2.4 times more likely to recur in patients receiving placebo vs active medication. Therefore, for later life depression, the optimal maintenance strat­egy was the SSRI.

Secondary analyses of data from these seminal trials of IPT-M point to other predictors of how and for whom mainte­nance IPT may work (Table 4). For example:
   • Greater variability of depression symptoms during all forms of mainte­nance treatment is related to a greater risk of recurrence.
   • Persistent insomnia is related to greater risk of recurrent depression.
   • High interpersonal focus in IPT-M sessions is related to longer time to recurrence.

Bottom Line
Interpersonal psychotherapy (IPT) is efficacious for acute depression and for preventing recurrences. Patients treated successfully with acute IPT alone benefit from varied doses of maintenance IPT. Combining IPT-M with antidepressant medication can be more potent than IPT-M alone. For late-life depression, medication appears to be most effective for maintenance treatment.

Related Resources

Media
• Video demonstration, role-play transcripts, lesson plans, and quizzes. In: Appendices in and DVD companion to Ravitz P, Watson P, Grigoriadas S. Interpersonal psychother­apy for depression. New York, NY: Norton; 2013.
• Video demonstration of IPT sessions. In: DVD companion to Dewan, M, Steenbarger, B, Greenberg, R, eds. The art and science of brief psychotherapies: An illustrated guide. 2nd ed. Arlington, VA: American Psychiatric Publishing; 2012.

Text
• Stuart S, Robertson M. Interpersonal psychotherapy: a cli­nician’s guide. London, United Kingdom: Taylor & Francis; 2012.
• Weissman MM, Markowitz JC, Klerman GL. Comprehensive guide to interpersonal psychotherapy. New York, NY: Basic Books; 2000.
• Weissman M, Markowitz J, Klerman GL. Clinician’s quick guide to interpersonal psychotherapy. New York, NY: Oxford University Press; 2007.

Websites
• Interpersonal Psychotherapy Institute. http://iptinstitute.com.
• International Society for Interpersonal Psychotherapy. http://interpersonalpsychotherapy.org.

Drug Brand Names
Amitriptyline • Elavil       Nortriptyline • Pamelor
Imipramine • Tofranil     Paroxetine • Paxil

Acknowledgments
The authors are grateful to Samantha L. Bernecker, MS, and Nicholas R. Morrison for their assistance with the research review.

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

Major depressive disorder (MDD) frequently is recur­rent, with new episodes causing substantial social and economic impairment¹ and increasing the like­lihood of future episodes.² For this reason, contemporary psychiatric practitioners think of depression treatment as long-term and plan thoughtfully for maintenance therapy.

Recognizing the importance of engaging depressed indi­viduals beyond the initial response,³ American Psychiatric Association practice guidelines conceptualize depression treatment as 3 phases:
   • acute treatment, with the aim of remission (symptom removal)
   • continuation treatment, with the aim of preventing re­lapse (symptom return)
   • maintenance treatment, with the aim of preventing re­currence (new episodes).⁴
Interpersonal psychotherapy (IPT) is an evidence-based psychosocial treatment that adheres to this model.⁵ As a time-limited, manual-driven^6,7 approach, IPT focuses on interpersonal distresses as precipitating and perpetuating factors of depression.⁸

Acute IPT’s efficacy is well-established across >200 empirical studies—making it an evidence-based, first-line treatment for adult depression.^4,9,10 Meta-analyses show that acute IPT is superior to placebo and no-treatment con­trols, and largely comparable to antidepressant medication and other active, first-line psychotherapies, such as cogni­tive-behavioral therapy (CBT).^11,12

Although this review, as well as the liter­ature, focuses largely on adult outpatients with depression, evidence of IPT’s general efficacy exists for adolescents,¹³ chronically depressed patients,¹¹ and depressed inpa­tients.¹⁴ This article presents a case study to describe the structure of IPT when used to treat depressed adults. We also present evidence of IPT’s acute and long-term ef­ficacy in preventing depression recurrence and data to guide its use in practice.

CASE REPORT

‘Safe’ but depressed
Timothy, age 18, is a first-year college student who presents for outpatient psychotherapy to address recurrent depression. He reports general unhappiness, loss of interest in things, low energy, sleep problems, poor academic and work functioning, and low self-esteem. He experienced at least 3 similar depressive episodes while in high school.

The therapist’s diagnostic and interper­sonal assessment suggests that Timothy’s depression is interpersonally driven. Timothy longs for relational intimacy but fears he will fail or burden people with his needs. He has difficulty gauging appropriate lev­els of enmeshment with others and either becomes overdependent or stays at a dis­tance. This “safe” approach to relationships contributes to boredom, loneliness, and isolation. His recent transition to college away from home and the failure of a roman­tic relationship have compounded these experiences.

Interpersonal model of IPT
IPT conceptualizes depression as involving predisposing, precipitating, and perpetu­ating biopsychosocial factors, including:
   • underlying biological and social vul­nerability, such as insecure attach­ ment (ie, tenuous and often negative views of self and others)
   • current interpersonal life stressors
   • inadequate social supports.^15,16

For example, poor early attachment to caregivers can give rise to despair, isolation, and low mood. In turn, this can be exacerbated by poor social and commu­nication skills that promote further rejec­tion and withdrawal of social support and thus, intensified despair, isolation, and low mood. As in Timothy’s case, this vicious cycle underscores psychosocial stressors as a causal factor, maintaining factor, and result of depression. Specifically, IPT con­ceptualizes 4 main biopsychosocial problem domains:
   • grief and loss
   • interpersonal disputes
   • role transitions
   • interpersonal/communication deficits (often connected to isolation).

Working within 1 or 2 of the most salient problem domains, IPT centers on strategies for helping patients solve interpersonal problems based on the notion that modi­fied relationships, revised interpersonal expectations, improved communications, and increased social support will lead to symptom reduction.^15-17

Many techniques are utilized in IPT (Table 1) to help patients modify their interpersonal relationships as a mechanism for decreasing their distress. IPT is prob­lem-focused, aiming to improve patients’ relationships by drawing on their assets and helping to build skills around short­comings. Therefore, IPT focuses on observ­able interpersonal patterns, as opposed to latent personality dynamics.

CASE CONTINUED

Setting goals
When the clinical explains in the non-technical terms the data supporting IPT’s efficacy for depression, including with young adults, Timothy agrees to teeatment with acute IPT. The therapist behins with consciousness-raising techniques to help Timothy adopt the “sick role” by viewing depressing as an illness to be cured. Collaboratively, they establish treatment goals that fit the IPT formulation of depression— ie, revising current relationships and expectations of them, increasing social support, improving communication skills, and solving problems within 1 or 2 of the IPT prob­lem domains.

For Timothy, the most pressing psy­chosocial problems seem to be interper­sonal deficits and role transitions. He ap­pears to be insecurely attached to others, which is a risk factor for poor facilitation of, and boundaries around, good relation­ships. A transition to a new and intimidat­ing interpersonal context—living on a college campus—compounded his vulnerabilities and increased his depression.

Acute treatment. The acute phase of IPT is time-limited—often, 12 to 16 sessions with gradual tapering toward the end (akin to a continuation phase). The time limit’s pur­pose is to focus both patient and therapist on the specific goal of removing the acute “illness” of depression. The IPT clinician takes an interpersonal inventory to learn about the patient’s most important rela­tionships and hones in on the IPT domain foci. Working collaboratively, the thera­pist might help the patient mourn a loss, reconstruct a narrative with a deceased loved one, consider ways to increase social contact, develop assertiveness, label feel­ings and needs, resolve an impasse with a significant other, and so forth.

The IPT therapist is an advocate for the patient and adopts an active stance laced with empathy and warmth. However, the therapist is more than unconditionally ac­cepting as depression is viewed as a prob­lem to be actively resolved.

CASE CONTINUED

Creating new patterns
The therapist uses various IPT strategies to work collaboratively with Timothy. She at­tempts to develop a strong working alliance by building interpersonal safety and trust— which take time with an insecurely attached patient. She tries to provide a new model for how close relationships can develop, while also focusing on current relationships. She and Timothy address his romantic desire for a coworker and work on developing realistic ex­pectations and effective methods for convey­ing his interest.

When Timothy approaches his coworker, she does not reject him—as he expected— but wants to pursue friendship before pos­sibly dating. The therapist then works with Timothy’s emotional reaction and explores ways to effectively convey his emotions to this young woman. Drawing on communica­tion analysis and problem-solving strategies, Timothy is able to sustain this friendship—a shift from his typical retreat when relation­ships have not gone as hoped or expected.

Timothy develops confidence to take more risks in initiating social encounters and starts to confide in his roommates when he feels upset. After 3 months of treatment, his expanded social network and improved in­terpersonal skills result in decreased depres­sion. When Timothy suggests termination, he and the therapist agree to end acute IPT but—given his history of depression—to continue maintenance sessions.

Limited data exist on variables that relate to IPT’s acute success or conditions under which it works best. Although process re­search lags behind acute IPT outcome re­search, some findings can help guide the IPT practitioner. For example, variables shown to predict outcomes of acute IPT for depression include a positive therapeutic alliance, therapist warmth, and psycho­ psycho­therapist use of exploratory techniques (Table 2).

Similarly, IPT has been shown to be more effective in some patients than oth­ers, depending on various moderators of depression. For example:
   • For patients with high cognitive dys­function, IPT outperforms CBT.
   • For patients with higher need for medical reassurance, IPT outperforms selective serotonin reuptake inhibitor (SSRI) pharmacotherapy.
   • For patients with severe depression, CBT outperforms IPT.
   • For patients with low psychomotor activation, response is more rapid with an SSRI than with IPT (Table 3).¹⁸

Durability of acute IPT
One way to understand recurrence pre­vention is to examine the durability of a treatment’s acute effect in the absence of a specific maintenance plan. In theory, patients will continue to apply the skills learned in acute IPT to maintain gains and prevent recurrences, even after they stop seeing the psychotherapist.

Initial findings.  Some research speaks to IPT’s acute-phase durability. The inaugural clinical trial of IPT by Weissman et al¹⁹ included 4 months of acute treatment and a 1-year uncontrolled naturalistic follow-up assessment. At follow-up, depression and global clinical symptoms were the same, whether patients had been acutely treated with IPT alone, pharmacotherapy alone (amitriptyline), combined IPT and pharmacotherapy, or nonscheduled treat­ment with a psychiatrist.

Some patients continued to function well, whereas others did not fully main­tain acute treatment gains. Patients who received IPT acutely, either singly or with medication, showed better social function­ing at follow-up compared with patients who did not receive IPT. This long-term durability of social improvements was an obvious target of IPT.

Support from TDCRP. In the National Institute of Mental Health Treatment of Depression Collaborative Research Project (TDCRP),²⁰ patients in the acute phase of depression were assigned to 16 weeks of IPT, CBT, pharmacotherapy (imipramine) and clinical management (CM), or placebo plus CM. Among those who recovered by acute treatment’s end, MDD relapse rates at 18-month naturalistic follow-up were 33% for IPT, 36% for CBT, 50% for imipramine, and 33% for placebo. Between-group differ­ences were not statistically significant.

Because acute responders to different types of treatment might have different inherent relapse tendencies, these data do not support causal attributions about the enduring effects of acute-phase treatment. The relapse rates do suggest, however, that 16 weeks of acute treatment, irrespec­tive of kind, was insufficient for some pa­tients to achieve full recovery and lasting remission. Consistent with the initial IPT trial,¹⁹ IPT (and CBT) outperformed medi cation and placebo in maintaining rela­tionship quality.²¹

Long-term benefits. A more recent trial by Zobel et al²² examined the durabil­ity of benefits from 5 weeks of acute IPT plus pharmacotherapy and pharmaco­therapy plus CM for inpatients with MDD. Although caution is required in interpret­ing naturalistic follow-up studies, patients in both groups showed decreased depres­sion from baseline to 5-year follow-up. Early symptom reduction was more rapid for patients in the IPT plus pharmacother­apy group, but no significant difference ex­isted at 5 years. More IPT patients than CM patients showed sustained remission (28% vs 11%, respectively). These rates demon­strate a need for longer-term potency of acute treatments and more targeted main­tenance treatments.

IPT-M for preventing recurrence
A second way to understand recurrence prevention is to examine the efficacy of a treatment’s maintenance protocol add­ed to an acute treatment phase. IPT has been adapted as a maintenance treatment (IPT-M), with emphasis on keeping pa­tients well. With this revised focus, IPT-M differs somewhat from acute IPT. Although treatment continues to center on interper­sonal functioning, IPT-M favors:
   • vigilance for possible triggers of new depressive episodes
   • longer-term contact with a therapist
   • reinforcing skills learned
   • addressing an expanded number of interpersonal problem areas (given that such problems can be addressed more ef­ficiently relative to acute treatment).

Efficacy of IPT-M. In the initial trial, Frank et al²³ compared the efficacy of IPT-M with that of pharmacotherapy (imipramine) in preventing depressive relapse among pa­tients with recurrent depression who had responded to ≥16 sessions of acute IPT and imipramine and remained well during a 17- week continuation phase. For maintenance, patients were assigned to IPT-M alone, imipramine alone, placebo alone, IPT-M plus imipramine, or IPT-M plus placebo. Maintenance imipramine was continued at the acute dosage (target 200 mg/d; up to 400 mg/d was allowed). Maintenance IPT was monthly sessions. Patients remained in the trial for 3 years or until depression recurred.

On its own, IPT-M showed some efficacy in preventing recurrence, as the mean time to recurrence was 82 weeks for IPT-M alone and 74 weeks for IPT-M plus placebo. The prophylactic effect of imipramine was stron­ger, however. The mean time to recurrence for imipramine with IPT was 131 weeks, and the mean time to recurrence for imipra­mine without IPT was 124 weeks. Therefore, whereas monthly IPT-M can certainly help prolong wellness and delay recurrence, IPT maintenance treatment with acute doses of imipramine might be even more effective— if the patient is willing to take medication. These findings must be considered with caution because of the inherent inequity be­tween imipramine and IPT-M in regard to maintenance dosage strength.

Frequency of treatment. In another trial, Frank et al²⁴ examined whether the fre­quency of maintenance IPT sessions played a role in its prophylactic effect. Adult wom­en who had achieved depression remission with acute IPT (alone or in combination with SSRI pharmacotherapy) were ran­domized to weekly, bi-weekly, or monthly IPT-M alone for 2 years or until recurrence. Depression recurred during IPT-M in:
   • 26% of patients who had received acute IPT alone
   • 50% of those who had received acute IPT plus an SSRI.

Frequency of IPT-M sessions did not af­fect time to recurrence. Thus, for women who can achieve remission with IPT alone, varied frequencies of IPT-M can be good prophylaxis. For women who need an SSRI to augment acute IPT, IPT-M alone at varied dosages is less effective in pre­venting depression recurrence. Therefore, acute treatment response patterns can in­form maintenance plans, with the most prudent maintenance strategy being to maintain the acute treatment strategy over a longer period.

IPT-M for late-life depression. A trial by Reynolds et al25 examined the efficacy of maintenance nortriptyline and IPT-M in preventing depression recurrence in pa­tients age ≥59 who initially recovered after combined acute and continuation IPT plus nortriptyline. The 4 conditions (with their recurrence rates) were:
   • monthly IPT-M with nortriptyline (20%)
   • monthly IPT-M with placebo (64%)
   • nortriptyline plus medication visits (43%)
   • placebo plus medication visits (90%).

Clearly, the combined active treat­ments outperformed placebo and anti­depressant alone in terms of delaying or preventing recurrence, which suggests an optimal maintenance strategy with this population.

IPT-M for later life. Another trial by the same group²⁶ enrolled patients age ≥70 with MDD that responded to acute IPT plus paroxetine. The maintenance treat­ments to which they were randomly as­signed (and recurrence rates within 2 years) were:
   • paroxetine plus IPT-M (35%)
   • placebo plus IPT-M (68%)
   • paroxetine plus clinical management (37%)
   • placebo plus clinical management (58%).

Recurrence rates were the same for pa­tients receiving medication plus IPT-M and medication plus clinical management, and depression was 2.4 times more likely to recur in patients receiving placebo vs active medication. Therefore, for later life depression, the optimal maintenance strat­egy was the SSRI.

Secondary analyses of data from these seminal trials of IPT-M point to other predictors of how and for whom mainte­nance IPT may work (Table 4). For example:
   • Greater variability of depression symptoms during all forms of mainte­nance treatment is related to a greater risk of recurrence.
   • Persistent insomnia is related to greater risk of recurrent depression.
   • High interpersonal focus in IPT-M sessions is related to longer time to recurrence.

Bottom Line
Interpersonal psychotherapy (IPT) is efficacious for acute depression and for preventing recurrences. Patients treated successfully with acute IPT alone benefit from varied doses of maintenance IPT. Combining IPT-M with antidepressant medication can be more potent than IPT-M alone. For late-life depression, medication appears to be most effective for maintenance treatment.

Related Resources

Media
• Video demonstration, role-play transcripts, lesson plans, and quizzes. In: Appendices in and DVD companion to Ravitz P, Watson P, Grigoriadas S. Interpersonal psychother­apy for depression. New York, NY: Norton; 2013.
• Video demonstration of IPT sessions. In: DVD companion to Dewan, M, Steenbarger, B, Greenberg, R, eds. The art and science of brief psychotherapies: An illustrated guide. 2nd ed. Arlington, VA: American Psychiatric Publishing; 2012.

Text
• Stuart S, Robertson M. Interpersonal psychotherapy: a cli­nician’s guide. London, United Kingdom: Taylor & Francis; 2012.
• Weissman MM, Markowitz JC, Klerman GL. Comprehensive guide to interpersonal psychotherapy. New York, NY: Basic Books; 2000.
• Weissman M, Markowitz J, Klerman GL. Clinician’s quick guide to interpersonal psychotherapy. New York, NY: Oxford University Press; 2007.

Websites
• Interpersonal Psychotherapy Institute. http://iptinstitute.com.
• International Society for Interpersonal Psychotherapy. http://interpersonalpsychotherapy.org.

Drug Brand Names
Amitriptyline • Elavil       Nortriptyline • Pamelor
Imipramine • Tofranil     Paroxetine • Paxil

Acknowledgments
The authors are grateful to Samantha L. Bernecker, MS, and Nicholas R. Morrison for their assistance with the research review.

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Voluntary psychiatric admission has become more problematic because of managed care authorization policies, restrictive inpatient entry criteria, uninsured
patients, and a decline in hospital beds.

In addition, patients often are ambivalent or resistant to hospitalization. It can be challenging to persuade a patient, as well as his (her) family, of the need for psychiatric admission, even when he acknowledges emotional suffering and impaired functioning.

The strategies offered here can enhance the probability that your patient, and his family, will agree to voluntary admission.

Provide a compelling rationale. Stress the need for immediate, specialized, and intensive services. If the patient is receiving outpatient mental health care, advise him that these services have been unsuccessful in achieving safety and clinical stability, and that it is not possible to quickly establish a modified outpatient plan or a day hospital placement that would meet his needs. For a patient who is not receiving outpatient care, explain that it is not feasible to implement a workable plan “from the ground up” in a timely manner.

Reset the clock. Redefine admission as a way to interrupt a downward spiral and offer a new start with a treatment team that has “fresh eyes.”

Use language of the medical model. Explain to the patient that a person who has a dangerously high, poorly controlled body temperature unquestionably needs to be hospitalized and that, by analogy, he—your patient—is running a “high emotional temperature” that warrants inpatient care.

Consider having the patient complete a brief, self-report rating scale, such as the Beck Depression Inventory-II or the Generalized Anxiety Disorder 7-item scale.¹ Review findings with him and his family to show the frequency, duration, and severity of symptoms.

Dispel misconceptions and myths. These include catastrophic fears—often based on stereotypes—about coercive treatment and indefinite confinement. Clarifying what a patient can expect with voluntary admission with regard to probable length of stay, participation in the milieu, visitation, and discharge planning is helpful for allaying such fears.

Build bridges with significant others. Ally with parties who support voluntary admission, including the patient’s primary care or mental health provider, if appropriate. Getting family members and significant others on board; having them talk with the patient can go a long way toward reaching an agreement to proceed with hospitalization.

Maintain an empathic stance. For many patients, psychiatric admission evokes considerable distress. Remain sensitive to the situational concerns that typically arise, such as disruption to family and job responsibilities, insurance coverage, and whether there will be an outpatient plan in place at discharge.

A psychiatric admission often triggers long-standing psychological vulnerabilities— such as feelings of humiliation or failure, fear of separation and abandonment, worry about being a burden to family, stigma, and anxiety about having a serious mental illness—all of which might require exploration to allay upset and enhance compliance.


Disclosure
Dr. Pollak reports no financial relationships with any company whose products are mentioned with this article or with manufacturers of competing products.

Voluntary psychiatric admission has become more problematic because of managed care authorization policies, restrictive inpatient entry criteria, uninsured
patients, and a decline in hospital beds.

In addition, patients often are ambivalent or resistant to hospitalization. It can be challenging to persuade a patient, as well as his (her) family, of the need for psychiatric admission, even when he acknowledges emotional suffering and impaired functioning.

The strategies offered here can enhance the probability that your patient, and his family, will agree to voluntary admission.

Provide a compelling rationale. Stress the need for immediate, specialized, and intensive services. If the patient is receiving outpatient mental health care, advise him that these services have been unsuccessful in achieving safety and clinical stability, and that it is not possible to quickly establish a modified outpatient plan or a day hospital placement that would meet his needs. For a patient who is not receiving outpatient care, explain that it is not feasible to implement a workable plan “from the ground up” in a timely manner.

Reset the clock. Redefine admission as a way to interrupt a downward spiral and offer a new start with a treatment team that has “fresh eyes.”

Use language of the medical model. Explain to the patient that a person who has a dangerously high, poorly controlled body temperature unquestionably needs to be hospitalized and that, by analogy, he—your patient—is running a “high emotional temperature” that warrants inpatient care.

Consider having the patient complete a brief, self-report rating scale, such as the Beck Depression Inventory-II or the Generalized Anxiety Disorder 7-item scale.¹ Review findings with him and his family to show the frequency, duration, and severity of symptoms.

Dispel misconceptions and myths. These include catastrophic fears—often based on stereotypes—about coercive treatment and indefinite confinement. Clarifying what a patient can expect with voluntary admission with regard to probable length of stay, participation in the milieu, visitation, and discharge planning is helpful for allaying such fears.

Build bridges with significant others. Ally with parties who support voluntary admission, including the patient’s primary care or mental health provider, if appropriate. Getting family members and significant others on board; having them talk with the patient can go a long way toward reaching an agreement to proceed with hospitalization.

Maintain an empathic stance. For many patients, psychiatric admission evokes considerable distress. Remain sensitive to the situational concerns that typically arise, such as disruption to family and job responsibilities, insurance coverage, and whether there will be an outpatient plan in place at discharge.

A psychiatric admission often triggers long-standing psychological vulnerabilities— such as feelings of humiliation or failure, fear of separation and abandonment, worry about being a burden to family, stigma, and anxiety about having a serious mental illness—all of which might require exploration to allay upset and enhance compliance.


Disclosure
Dr. Pollak reports no financial relationships with any company whose products are mentioned with this article or with manufacturers of competing products.

Voluntary psychiatric admission has become more problematic because of managed care authorization policies, restrictive inpatient entry criteria, uninsured
patients, and a decline in hospital beds.

In addition, patients often are ambivalent or resistant to hospitalization. It can be challenging to persuade a patient, as well as his (her) family, of the need for psychiatric admission, even when he acknowledges emotional suffering and impaired functioning.

The strategies offered here can enhance the probability that your patient, and his family, will agree to voluntary admission.

Provide a compelling rationale. Stress the need for immediate, specialized, and intensive services. If the patient is receiving outpatient mental health care, advise him that these services have been unsuccessful in achieving safety and clinical stability, and that it is not possible to quickly establish a modified outpatient plan or a day hospital placement that would meet his needs. For a patient who is not receiving outpatient care, explain that it is not feasible to implement a workable plan “from the ground up” in a timely manner.

Reset the clock. Redefine admission as a way to interrupt a downward spiral and offer a new start with a treatment team that has “fresh eyes.”

Use language of the medical model. Explain to the patient that a person who has a dangerously high, poorly controlled body temperature unquestionably needs to be hospitalized and that, by analogy, he—your patient—is running a “high emotional temperature” that warrants inpatient care.

Consider having the patient complete a brief, self-report rating scale, such as the Beck Depression Inventory-II or the Generalized Anxiety Disorder 7-item scale.¹ Review findings with him and his family to show the frequency, duration, and severity of symptoms.

Dispel misconceptions and myths. These include catastrophic fears—often based on stereotypes—about coercive treatment and indefinite confinement. Clarifying what a patient can expect with voluntary admission with regard to probable length of stay, participation in the milieu, visitation, and discharge planning is helpful for allaying such fears.

Build bridges with significant others. Ally with parties who support voluntary admission, including the patient’s primary care or mental health provider, if appropriate. Getting family members and significant others on board; having them talk with the patient can go a long way toward reaching an agreement to proceed with hospitalization.

Maintain an empathic stance. For many patients, psychiatric admission evokes considerable distress. Remain sensitive to the situational concerns that typically arise, such as disruption to family and job responsibilities, insurance coverage, and whether there will be an outpatient plan in place at discharge.

A psychiatric admission often triggers long-standing psychological vulnerabilities— such as feelings of humiliation or failure, fear of separation and abandonment, worry about being a burden to family, stigma, and anxiety about having a serious mental illness—all of which might require exploration to allay upset and enhance compliance.


Disclosure
Dr. Pollak reports no financial relationships with any company whose products are mentioned with this article or with manufacturers of competing products.

For mentally ill young men, especially, abruptly stopping a psychotropic medication can be lethal.¹ Under such circumstances, excited delirium syndrome (EDS), also known as sudden in-custody death syndrome and Bell’s mania, can occur, warranting your careful observation.

Approximately 10% of EDS cases are fatal²; >95% of fatalities occur in men
(mean age, 36 years).³ Most cases involve stimulant abuse—usually cocaine, although cases associated with methamphetamine, phencyclidine, and LSD have been reported. Patients who present with EDS experience a characteristic loss of
the dopamine transporter in the striatum and excessive dopamine stimulation in
the striatum.


What should you watch for?

Other syndromes and disorders can mimic EDS (Table), but there are certain specific symptoms to look for. Patients who have EDS can present with delirium and an excited or agitated state. Other common symptoms include:
   • altered sensorium
   • aggressive, agitated behavior
   • “superhuman” strength (including a tendency to break glass or unwillingness
      to yield to overwhelming force)
   • diaphoresis
   • hyperthermia
   • attraction to light.

Patients who have EDS often exhibit constant physical movement. They are likely to be naked or inadequately clothed; to sweat profusely; and to make unintelligible, animal-like noises. They are insensitive to extreme pain. In a small percentage of cases, EDS progresses to sudden cardiopulmonary arrestand death.³

Medication or restraints?
Many clinicians consider aggressive chemical sedation the first-line intervention for
EDS^2,3; choice of medication varies from practice to practice. Restraints often are
necessary to ensure the safety of patient and staff, but use them only in conjunction with aggressive chemical sedation. Physical struggle is a greater contributor to catecholamine surge and metabolic acidosis than other types of exertion; methods of physical control should therefore minimize the time a patient spends struggling while safely achieving physical control.

What is the treatment for EDS?

Begin treatment while you are evaluating the patient for precipitating causes or additional pathology. There are cases of death from EDS even with minimal restraint (such as handcuffs),^1,2 without the use of an electronic control device or so-called hog-tie restraint.

When providing pharmacotherapy for EDS, consider a benzodiazepine (midazolam, lorazepam, diazepam), an antipsychotic (haloperidol, droperidol, ziprasidone, olanzapine), or ketamine.⁴ Because these agents can have depressive respiratory and cardiovascular effects, continuously monitor heart and lungs.

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

For mentally ill young men, especially, abruptly stopping a psychotropic medication can be lethal.¹ Under such circumstances, excited delirium syndrome (EDS), also known as sudden in-custody death syndrome and Bell’s mania, can occur, warranting your careful observation.

Approximately 10% of EDS cases are fatal²; >95% of fatalities occur in men
(mean age, 36 years).³ Most cases involve stimulant abuse—usually cocaine, although cases associated with methamphetamine, phencyclidine, and LSD have been reported. Patients who present with EDS experience a characteristic loss of
the dopamine transporter in the striatum and excessive dopamine stimulation in
the striatum.


What should you watch for?

Other syndromes and disorders can mimic EDS (Table), but there are certain specific symptoms to look for. Patients who have EDS can present with delirium and an excited or agitated state. Other common symptoms include:
   • altered sensorium
   • aggressive, agitated behavior
   • “superhuman” strength (including a tendency to break glass or unwillingness
      to yield to overwhelming force)
   • diaphoresis
   • hyperthermia
   • attraction to light.

Patients who have EDS often exhibit constant physical movement. They are likely to be naked or inadequately clothed; to sweat profusely; and to make unintelligible, animal-like noises. They are insensitive to extreme pain. In a small percentage of cases, EDS progresses to sudden cardiopulmonary arrestand death.³

Medication or restraints?
Many clinicians consider aggressive chemical sedation the first-line intervention for
EDS^2,3; choice of medication varies from practice to practice. Restraints often are
necessary to ensure the safety of patient and staff, but use them only in conjunction with aggressive chemical sedation. Physical struggle is a greater contributor to catecholamine surge and metabolic acidosis than other types of exertion; methods of physical control should therefore minimize the time a patient spends struggling while safely achieving physical control.

What is the treatment for EDS?

Begin treatment while you are evaluating the patient for precipitating causes or additional pathology. There are cases of death from EDS even with minimal restraint (such as handcuffs),^1,2 without the use of an electronic control device or so-called hog-tie restraint.

When providing pharmacotherapy for EDS, consider a benzodiazepine (midazolam, lorazepam, diazepam), an antipsychotic (haloperidol, droperidol, ziprasidone, olanzapine), or ketamine.⁴ Because these agents can have depressive respiratory and cardiovascular effects, continuously monitor heart and lungs.

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

For mentally ill young men, especially, abruptly stopping a psychotropic medication can be lethal.¹ Under such circumstances, excited delirium syndrome (EDS), also known as sudden in-custody death syndrome and Bell’s mania, can occur, warranting your careful observation.

Approximately 10% of EDS cases are fatal²; >95% of fatalities occur in men
(mean age, 36 years).³ Most cases involve stimulant abuse—usually cocaine, although cases associated with methamphetamine, phencyclidine, and LSD have been reported. Patients who present with EDS experience a characteristic loss of
the dopamine transporter in the striatum and excessive dopamine stimulation in
the striatum.


What should you watch for?

Other syndromes and disorders can mimic EDS (Table), but there are certain specific symptoms to look for. Patients who have EDS can present with delirium and an excited or agitated state. Other common symptoms include:
   • altered sensorium
   • aggressive, agitated behavior
   • “superhuman” strength (including a tendency to break glass or unwillingness
      to yield to overwhelming force)
   • diaphoresis
   • hyperthermia
   • attraction to light.

Patients who have EDS often exhibit constant physical movement. They are likely to be naked or inadequately clothed; to sweat profusely; and to make unintelligible, animal-like noises. They are insensitive to extreme pain. In a small percentage of cases, EDS progresses to sudden cardiopulmonary arrestand death.³

Medication or restraints?
Many clinicians consider aggressive chemical sedation the first-line intervention for
EDS^2,3; choice of medication varies from practice to practice. Restraints often are
necessary to ensure the safety of patient and staff, but use them only in conjunction with aggressive chemical sedation. Physical struggle is a greater contributor to catecholamine surge and metabolic acidosis than other types of exertion; methods of physical control should therefore minimize the time a patient spends struggling while safely achieving physical control.

What is the treatment for EDS?

Begin treatment while you are evaluating the patient for precipitating causes or additional pathology. There are cases of death from EDS even with minimal restraint (such as handcuffs),^1,2 without the use of an electronic control device or so-called hog-tie restraint.

When providing pharmacotherapy for EDS, consider a benzodiazepine (midazolam, lorazepam, diazepam), an antipsychotic (haloperidol, droperidol, ziprasidone, olanzapine), or ketamine.⁴ Because these agents can have depressive respiratory and cardiovascular effects, continuously monitor heart and lungs.

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

Zolpidem, an imidazopyridine hypnotic, has been used as an alternative to benzodiazepines for treating short-term insomnia because it has a relatively favorable side effect profile and less potential for abuse.¹

However, several cases of zolpidemrelated psychotic symptoms have been reported,² including a report of an association between zolpidem and hallucinations.¹ The case illustrated here describes distortion of visual perception that can occur after ingestion of more than the recommended dosage of zolpidem.

CASE: Terrified and paranoid with distorted vision

Ms. K, age 33, an English-speaking woman from Portugal with a history of schizoaffective disorder, is brought to the emergency department in a terrified state. She describes visual distortion and paranoia because she fears losing her vision. She complains of suicidal ideation, depressed mood, insomnia, auditory
hallucinations, and distortion of visual perception. She reports seeing shadows, recurring movements of the ceiling bearing down on her, and molding or melting walls.

Ms. K reports that the visual distortions began when she started zolpidem, 10 mg/d, 2 months earlier, after her mother in Portugal gave it to her.

Ms. K describes feeling disoriented and disconnected from reality. She reports taking extra doses of zolpidem (40 mg)—recommended maximum dosage is 10 mg³—and clonazepam (1 mg) to address her insomnia.

On examination, Ms. K appears shaky and tremulous, and we note that her eyeballs roll upward. Vital signs are within normal limits, and she is awake, alert, and oriented to person, place, and time.

We diagnose exacerbation of schizoaffective disorder.

Ms. K is admitted to the inpatient psychiatric unit for observation and treatment. Quetiapine, 100 mg at bedtime, and sertraline, 100 mg/d, are started and zolpidem is discontinued.

The morning after admission, Ms. K reports that her vision has improved and that she no longer sees shadows or colored spots. All visual distortions resolve within 1 day after discontinuing zolpidem.

Discussion

Ms. K had no history of ophthalmologic or neurologic disease or alcohol or substance use. Physical and neurologic examination and laboratory testing failed to reveal any abnormality that accounts for her clinical presentation. Also, she reported visual distortions in the absence of drowsiness,⁴ thereby ruling out hypnagogic hallucination.⁵

Visual hallucinations are uncommon in schizoaffective disorder, but have been shown to occur with zolpidem use.^1,4 The clinical manifestations in Ms. K’s case are
consistent with those of 3 reports, in which patients reported visual symptoms shortly after an initial dose of zolpidem, 10 mg.^1,6 In those cases, symptoms resolved soon after zolpidem was discontinued.

Ms. K’s case is similar to other reports in regard to time of onset and manifestations of visual distortions. Iruela and colleagues documented that hallucinations could be reproduced with a lower challenge dose of zolpidem (5 or 2.5 mg), and that, with such a challenge, symptoms should be less severe.⁷ How zolpidem induces visual hallucinations remains unknown. Several studies have looked at variables that might predispose a patient taking zolpidem to visual
perceptual distortions.¹

Sex might play an important role.^1,7 After administering the same dosage of zolpidem, women age 20 to 40 had a blood concentration of the drug that was, on average, 45% higher than those measured in men.⁶ This difference in serum concentration is more remarkable in older women; the blood concentration of the drug in women age >60 was 63% higher than that of men.

Influence of hormones. Pharmacokinetics of zolpidem seem to be related to endocrine factors associated with cytochrome P450 (CYP) 3A4 metabolism. A low plasma concentration of free testosterone may contribute to lower CYP3A activity, with women achieving as much as a 50% higher plasma level of zolpidem, whereas exposure to testosterone activates biotransformation via CYP3A.⁸

Body weight is important when dosing zolpidem. Zolpidem-induced macropsia
has been reported in women with anorexia.⁷ The protein-binding capacity of zolpidem is approximately 92%, mainly to albumin (66%) and α1-acid glycoprotein (56.6%).⁴ In malnourished patients with anorexia nervosa, hypoalbuminemia is common and, therefore, unbound drug concentration is higher. This effect could account for, or contribute to, zolpidem toxicity.⁷

Ms. K did not have anorexia nervosa and was not underweight, and her liver function and kidney function were within normal limits. However, prescribing guidelines call for an initial dosage of 5 mg/d for women (10 mg/d for men)3; Ms. K ingested 8 times the recommended daily dosage.

The lesson for practitioners? When you encounter a patient who has a psychiatric disorder with psychotic features, explore causes unrelated to their primary disorder—such as taking a hypnotic or multiple psychoactive medications—as a possible source of the presenting symptoms (Box). In Ms. K’s case, her unusual symptoms resolved after a change in pharmacotherapy, leading us to conclude that her visual distortions likely were secondary to zolpidem and not to her schizoaffective disorder—a confounding factor.

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

Zolpidem, an imidazopyridine hypnotic, has been used as an alternative to benzodiazepines for treating short-term insomnia because it has a relatively favorable side effect profile and less potential for abuse.¹

However, several cases of zolpidemrelated psychotic symptoms have been reported,² including a report of an association between zolpidem and hallucinations.¹ The case illustrated here describes distortion of visual perception that can occur after ingestion of more than the recommended dosage of zolpidem.

CASE: Terrified and paranoid with distorted vision

Ms. K, age 33, an English-speaking woman from Portugal with a history of schizoaffective disorder, is brought to the emergency department in a terrified state. She describes visual distortion and paranoia because she fears losing her vision. She complains of suicidal ideation, depressed mood, insomnia, auditory
hallucinations, and distortion of visual perception. She reports seeing shadows, recurring movements of the ceiling bearing down on her, and molding or melting walls.

Ms. K reports that the visual distortions began when she started zolpidem, 10 mg/d, 2 months earlier, after her mother in Portugal gave it to her.

Ms. K describes feeling disoriented and disconnected from reality. She reports taking extra doses of zolpidem (40 mg)—recommended maximum dosage is 10 mg³—and clonazepam (1 mg) to address her insomnia.

On examination, Ms. K appears shaky and tremulous, and we note that her eyeballs roll upward. Vital signs are within normal limits, and she is awake, alert, and oriented to person, place, and time.

We diagnose exacerbation of schizoaffective disorder.

Ms. K is admitted to the inpatient psychiatric unit for observation and treatment. Quetiapine, 100 mg at bedtime, and sertraline, 100 mg/d, are started and zolpidem is discontinued.

The morning after admission, Ms. K reports that her vision has improved and that she no longer sees shadows or colored spots. All visual distortions resolve within 1 day after discontinuing zolpidem.

Discussion

Ms. K had no history of ophthalmologic or neurologic disease or alcohol or substance use. Physical and neurologic examination and laboratory testing failed to reveal any abnormality that accounts for her clinical presentation. Also, she reported visual distortions in the absence of drowsiness,⁴ thereby ruling out hypnagogic hallucination.⁵

Visual hallucinations are uncommon in schizoaffective disorder, but have been shown to occur with zolpidem use.^1,4 The clinical manifestations in Ms. K’s case are
consistent with those of 3 reports, in which patients reported visual symptoms shortly after an initial dose of zolpidem, 10 mg.^1,6 In those cases, symptoms resolved soon after zolpidem was discontinued.

Ms. K’s case is similar to other reports in regard to time of onset and manifestations of visual distortions. Iruela and colleagues documented that hallucinations could be reproduced with a lower challenge dose of zolpidem (5 or 2.5 mg), and that, with such a challenge, symptoms should be less severe.⁷ How zolpidem induces visual hallucinations remains unknown. Several studies have looked at variables that might predispose a patient taking zolpidem to visual
perceptual distortions.¹

Sex might play an important role.^1,7 After administering the same dosage of zolpidem, women age 20 to 40 had a blood concentration of the drug that was, on average, 45% higher than those measured in men.⁶ This difference in serum concentration is more remarkable in older women; the blood concentration of the drug in women age >60 was 63% higher than that of men.

Influence of hormones. Pharmacokinetics of zolpidem seem to be related to endocrine factors associated with cytochrome P450 (CYP) 3A4 metabolism. A low plasma concentration of free testosterone may contribute to lower CYP3A activity, with women achieving as much as a 50% higher plasma level of zolpidem, whereas exposure to testosterone activates biotransformation via CYP3A.⁸

Body weight is important when dosing zolpidem. Zolpidem-induced macropsia
has been reported in women with anorexia.⁷ The protein-binding capacity of zolpidem is approximately 92%, mainly to albumin (66%) and α1-acid glycoprotein (56.6%).⁴ In malnourished patients with anorexia nervosa, hypoalbuminemia is common and, therefore, unbound drug concentration is higher. This effect could account for, or contribute to, zolpidem toxicity.⁷

Ms. K did not have anorexia nervosa and was not underweight, and her liver function and kidney function were within normal limits. However, prescribing guidelines call for an initial dosage of 5 mg/d for women (10 mg/d for men)3; Ms. K ingested 8 times the recommended daily dosage.

The lesson for practitioners? When you encounter a patient who has a psychiatric disorder with psychotic features, explore causes unrelated to their primary disorder—such as taking a hypnotic or multiple psychoactive medications—as a possible source of the presenting symptoms (Box). In Ms. K’s case, her unusual symptoms resolved after a change in pharmacotherapy, leading us to conclude that her visual distortions likely were secondary to zolpidem and not to her schizoaffective disorder—a confounding factor.

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

Zolpidem, an imidazopyridine hypnotic, has been used as an alternative to benzodiazepines for treating short-term insomnia because it has a relatively favorable side effect profile and less potential for abuse.¹

However, several cases of zolpidemrelated psychotic symptoms have been reported,² including a report of an association between zolpidem and hallucinations.¹ The case illustrated here describes distortion of visual perception that can occur after ingestion of more than the recommended dosage of zolpidem.

CASE: Terrified and paranoid with distorted vision

Ms. K, age 33, an English-speaking woman from Portugal with a history of schizoaffective disorder, is brought to the emergency department in a terrified state. She describes visual distortion and paranoia because she fears losing her vision. She complains of suicidal ideation, depressed mood, insomnia, auditory
hallucinations, and distortion of visual perception. She reports seeing shadows, recurring movements of the ceiling bearing down on her, and molding or melting walls.

Ms. K reports that the visual distortions began when she started zolpidem, 10 mg/d, 2 months earlier, after her mother in Portugal gave it to her.

Ms. K describes feeling disoriented and disconnected from reality. She reports taking extra doses of zolpidem (40 mg)—recommended maximum dosage is 10 mg³—and clonazepam (1 mg) to address her insomnia.

On examination, Ms. K appears shaky and tremulous, and we note that her eyeballs roll upward. Vital signs are within normal limits, and she is awake, alert, and oriented to person, place, and time.

We diagnose exacerbation of schizoaffective disorder.

Ms. K is admitted to the inpatient psychiatric unit for observation and treatment. Quetiapine, 100 mg at bedtime, and sertraline, 100 mg/d, are started and zolpidem is discontinued.

The morning after admission, Ms. K reports that her vision has improved and that she no longer sees shadows or colored spots. All visual distortions resolve within 1 day after discontinuing zolpidem.

Discussion

Ms. K had no history of ophthalmologic or neurologic disease or alcohol or substance use. Physical and neurologic examination and laboratory testing failed to reveal any abnormality that accounts for her clinical presentation. Also, she reported visual distortions in the absence of drowsiness,⁴ thereby ruling out hypnagogic hallucination.⁵

Visual hallucinations are uncommon in schizoaffective disorder, but have been shown to occur with zolpidem use.^1,4 The clinical manifestations in Ms. K’s case are
consistent with those of 3 reports, in which patients reported visual symptoms shortly after an initial dose of zolpidem, 10 mg.^1,6 In those cases, symptoms resolved soon after zolpidem was discontinued.

Ms. K’s case is similar to other reports in regard to time of onset and manifestations of visual distortions. Iruela and colleagues documented that hallucinations could be reproduced with a lower challenge dose of zolpidem (5 or 2.5 mg), and that, with such a challenge, symptoms should be less severe.⁷ How zolpidem induces visual hallucinations remains unknown. Several studies have looked at variables that might predispose a patient taking zolpidem to visual
perceptual distortions.¹

Sex might play an important role.^1,7 After administering the same dosage of zolpidem, women age 20 to 40 had a blood concentration of the drug that was, on average, 45% higher than those measured in men.⁶ This difference in serum concentration is more remarkable in older women; the blood concentration of the drug in women age >60 was 63% higher than that of men.

Influence of hormones. Pharmacokinetics of zolpidem seem to be related to endocrine factors associated with cytochrome P450 (CYP) 3A4 metabolism. A low plasma concentration of free testosterone may contribute to lower CYP3A activity, with women achieving as much as a 50% higher plasma level of zolpidem, whereas exposure to testosterone activates biotransformation via CYP3A.⁸

Body weight is important when dosing zolpidem. Zolpidem-induced macropsia
has been reported in women with anorexia.⁷ The protein-binding capacity of zolpidem is approximately 92%, mainly to albumin (66%) and α1-acid glycoprotein (56.6%).⁴ In malnourished patients with anorexia nervosa, hypoalbuminemia is common and, therefore, unbound drug concentration is higher. This effect could account for, or contribute to, zolpidem toxicity.⁷

Ms. K did not have anorexia nervosa and was not underweight, and her liver function and kidney function were within normal limits. However, prescribing guidelines call for an initial dosage of 5 mg/d for women (10 mg/d for men)3; Ms. K ingested 8 times the recommended daily dosage.

The lesson for practitioners? When you encounter a patient who has a psychiatric disorder with psychotic features, explore causes unrelated to their primary disorder—such as taking a hypnotic or multiple psychoactive medications—as a possible source of the presenting symptoms (Box). In Ms. K’s case, her unusual symptoms resolved after a change in pharmacotherapy, leading us to conclude that her visual distortions likely were secondary to zolpidem and not to her schizoaffective disorder—a confounding factor.

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

In studies of schizophrenia, one of the more striking findings is the delay in the initiation of treatment. That delay ranges from 1 to 2 years for patients experiencing psychotic symptoms to several years if the prodromal phase is taken into account.¹ Yet duration of untreated psychosis has been found to be a critical factor in prognosis, including psychosocial functioning, in patients with schizophrenia.^2,3 Identification of individuals in the prodromal phase not only offers an opportunity to intervene at an earlier symptomatic stage, but might be associated with a better response to antipsychotics and a better overall treatment outcome as well.

What’s in a name?

Several terms, including ultra high risk, clinical high risk, at-risk mental state, psychosis risk syndrome, and schizophrenia/psychosis prodrome, have been used to describe the prodromal phase of schizophrenia. The proposal to include attenuated psychosis syndrome (APS) in the DSM-5—originally intended to capture those with subthreshold delusions, hallucinations, or disorganized behavior, occurring at least once a week for the past month and worsening over the past year—generated a debate about the validity of such a diagnostic category^4,5 that culminated in the inclusion of APS as a condition for further study but not as a term for clinical use.⁶ Its presence in the DSM-5 brings to the forefront the importance of early clinical intervention in patients at risk of developing psychotic illness.

Schizophrenia is not inevitable

The prodromal phase can be viewed as a sequence of evolving symptoms⁷ (Box 1^8,9), starting with subtle differences evident only to the person experiencing them and often progressing to brief limited intermittent psychosis (BLIPS) or attenuated psychosis.⁸

In fact, prodrome is a retrospective diagnosis. The predictive power of conversion to psychosis has been found to fluctuate from as low as 9% to as high as 76%,¹⁰ prompting ethical concerns about a high false-positive rate, the assumption of inevitability associated with the term “schizophrenia prodrome,”⁹ and the potential for overdiagnosis and misdiagnosis. Concerns about psychosocial stigma and exposure to antipsychotic medications have been expressed as well.¹¹

A case for early engagement

In retrospect, patients who eventually progress to psychotic illness are commonly found to have been in the prodromal phase for several years. Yet many patients’ first contact with psychiatric services occurs during a florid episode of acute psychosis. Identifying patients in the early prodromal period offers the opportunity to more effectively engage them and form a therapeutic alliance.¹² Any young adult who presents with a decline in academic or occupational function, social withdrawal, perplexity, and apparent distress or agitation (Table 1^13-16) without a clear precipitating factor should therefore be closely monitored, particularly if he (she) has a family history of psychosis.

Screening tools. A variety of interviews and rating scales (Table 28) have been developed to assess and monitor at-risk persons, a number of which have been designed to detect basic symptoms in the early phase of prodrome. In addition to the structured scales, several self-report tools—including the Prodromal Questionnaire-Brief (PQ-B), Youth Psychosis At Risk Questionnaire-Brief (YPARQ-B), Prime Screen-Revised, and PROD-screen (Screen for prodromal symptoms of psychosis)—have been found to be useful in screening a large sample to identify those who might need further evaluation.¹⁷

Increased risk of conversion. Several clinical factors are associated with an increased risk of conversion to psychotic illness.9 In addition to family history, these include:

  • greater severity and longer duration of attenuated positive symptoms
  • presence of bizarre thoughts and behavior
  • paranoia
  • decline in global assessment of functioning score over the previous year
  • use of either Cannabis or amphetamines.

A history of childhood trauma, increased sensitivity to psychosocial stressors, and dysregulation of the hypothalamicpituitary axis also have been associated with progression to psychosis.¹⁸

Recent evidence suggests that the prodromal phase is a predictor not only for psychosis but also for other disabling psychiatric illnesses, such as bipolar disorder and obsessive-compulsive disorder.¹⁹

From a phenomenological standpoint, disturbance of the sense of self—characterized by features such as depersonalization, derealization, decreased reactivity to other people and the environment, and intense reflectivity to oneself or others—has been proposed as a critical marker for progression to psychosis.²⁰ Another predictor is the perception of negativity of others toward oneself. Examples include heightened sensitivity to rejection or shame, which seems to emerge from a pattern of insecure attachment, and the outsider status experienced by immigrants faced with multiple social, cultural, and language barriers.²¹ The presence of obsessivecompulsive symptoms during the prodromal phase has been linked to significant impairment in functioning, an acute switch to psychosis, and an increased risk of suicide.²²

Monitor or treat? An optimal approach

A key dilemma in the management of patients who exhibit signs and symptoms of schizophrenia prodrome is whether to simply monitor closely or to initiate treatment.

International clinical practice guidelines recommend several practical steps in the monitoring of patients in a prepsychotic state (Table 3),²³ but caution against the use of antipsychotic agents unless the patient meets diagnostic criteria for a psychotic disorder.

CBT. Some evidence supports the initiation of cognitive-behavioral therapy (CBT) during the initial prodromal phase and the addition of alow-dose atypical antipsychotic if the patient progresses to a later phase, characterized by BLIPS/APS.24,25 Evidence also suggests that a combination of CBT and antipsychotic medication might delay, but not prevent, the progression to a psychotic episode.9 Any risk of adverse metabolic complications precludes use ofan atypical antipsychotic.One potential alternative is the use of omega-3 polyunsaturated fatty acids (Box 2).^26,27

A clinically useful approach would be to view schizophrenia/psychosis prodrome not as a distinct diagnostic category but as a cluster of signs and symptoms associated with an increased risk of psychosis, with persons in this phase in need of close follow-up and, possibly, early initiation of an antipsychotic agent. It is important to engage the patient and his family at an early stage to educate them about the diagnostic uncertainty; to help them deal with the stigma; to manage risk factors; and, collaboratively, to decide on an intervention strategy.^23,28

Bottom Line

Despite several drawbacks, the concept of schizophrenia/psychosis prodrome may
be viewed as a cluster of signs and symptoms (rather than a distinct diagnostic category) associated with increased risk for psychosis that need close follow up. Follow up may involve psychoeducational and psychotherapeutic interventions and, need be, early initiation of antipsychotics. In addition, such symptoms may be associated with other psychiatric disorders such as bipolar disorder and obsessive- compulsive disorder. Timely attention and early intervention may alter the course
and improve overall prognosis.

Related Resources
• Early intervention in psychosis. WPA Education Committee’s recommended roles of the psychiatrist. www.wpanet.org/uploads/Education/Educational_Resources/earlyintervention-psychosis.pdf.
• Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. http://eppic.org.au/psychosis.
• International Early Psychosis Association Writing Group. International clinical practice guidelines for early psychosis. Br J Psychiatry. 2005;187:s120-124. http://bjp.rcpsych.org/content/187/48/s120.full.

Disclosures
Dr. Madaan is an employee of University of Virginia Health System. As an employee with the University of Virginia, Dr. Madaan has received research support from Eli Lilly and Company, Forest, Merck, Otsuka, Pfizer, Shire, and Sunovion. He also has served as a consultant for the NOW Coalition for Bipolar Disorder, and on the American Psychiatric Association’s Focus Self-Assessment editorial board. Drs. Bestha and Kolli report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

In studies of schizophrenia, one of the more striking findings is the delay in the initiation of treatment. That delay ranges from 1 to 2 years for patients experiencing psychotic symptoms to several years if the prodromal phase is taken into account.¹ Yet duration of untreated psychosis has been found to be a critical factor in prognosis, including psychosocial functioning, in patients with schizophrenia.^2,3 Identification of individuals in the prodromal phase not only offers an opportunity to intervene at an earlier symptomatic stage, but might be associated with a better response to antipsychotics and a better overall treatment outcome as well.

What’s in a name?

Several terms, including ultra high risk, clinical high risk, at-risk mental state, psychosis risk syndrome, and schizophrenia/psychosis prodrome, have been used to describe the prodromal phase of schizophrenia. The proposal to include attenuated psychosis syndrome (APS) in the DSM-5—originally intended to capture those with subthreshold delusions, hallucinations, or disorganized behavior, occurring at least once a week for the past month and worsening over the past year—generated a debate about the validity of such a diagnostic category^4,5 that culminated in the inclusion of APS as a condition for further study but not as a term for clinical use.⁶ Its presence in the DSM-5 brings to the forefront the importance of early clinical intervention in patients at risk of developing psychotic illness.

Schizophrenia is not inevitable

The prodromal phase can be viewed as a sequence of evolving symptoms⁷ (Box 1^8,9), starting with subtle differences evident only to the person experiencing them and often progressing to brief limited intermittent psychosis (BLIPS) or attenuated psychosis.⁸

In fact, prodrome is a retrospective diagnosis. The predictive power of conversion to psychosis has been found to fluctuate from as low as 9% to as high as 76%,¹⁰ prompting ethical concerns about a high false-positive rate, the assumption of inevitability associated with the term “schizophrenia prodrome,”⁹ and the potential for overdiagnosis and misdiagnosis. Concerns about psychosocial stigma and exposure to antipsychotic medications have been expressed as well.¹¹

A case for early engagement

In retrospect, patients who eventually progress to psychotic illness are commonly found to have been in the prodromal phase for several years. Yet many patients’ first contact with psychiatric services occurs during a florid episode of acute psychosis. Identifying patients in the early prodromal period offers the opportunity to more effectively engage them and form a therapeutic alliance.¹² Any young adult who presents with a decline in academic or occupational function, social withdrawal, perplexity, and apparent distress or agitation (Table 1^13-16) without a clear precipitating factor should therefore be closely monitored, particularly if he (she) has a family history of psychosis.

Screening tools. A variety of interviews and rating scales (Table 28) have been developed to assess and monitor at-risk persons, a number of which have been designed to detect basic symptoms in the early phase of prodrome. In addition to the structured scales, several self-report tools—including the Prodromal Questionnaire-Brief (PQ-B), Youth Psychosis At Risk Questionnaire-Brief (YPARQ-B), Prime Screen-Revised, and PROD-screen (Screen for prodromal symptoms of psychosis)—have been found to be useful in screening a large sample to identify those who might need further evaluation.¹⁷

Increased risk of conversion. Several clinical factors are associated with an increased risk of conversion to psychotic illness.9 In addition to family history, these include:

  • greater severity and longer duration of attenuated positive symptoms
  • presence of bizarre thoughts and behavior
  • paranoia
  • decline in global assessment of functioning score over the previous year
  • use of either Cannabis or amphetamines.

A history of childhood trauma, increased sensitivity to psychosocial stressors, and dysregulation of the hypothalamicpituitary axis also have been associated with progression to psychosis.¹⁸

Recent evidence suggests that the prodromal phase is a predictor not only for psychosis but also for other disabling psychiatric illnesses, such as bipolar disorder and obsessive-compulsive disorder.¹⁹

From a phenomenological standpoint, disturbance of the sense of self—characterized by features such as depersonalization, derealization, decreased reactivity to other people and the environment, and intense reflectivity to oneself or others—has been proposed as a critical marker for progression to psychosis.²⁰ Another predictor is the perception of negativity of others toward oneself. Examples include heightened sensitivity to rejection or shame, which seems to emerge from a pattern of insecure attachment, and the outsider status experienced by immigrants faced with multiple social, cultural, and language barriers.²¹ The presence of obsessivecompulsive symptoms during the prodromal phase has been linked to significant impairment in functioning, an acute switch to psychosis, and an increased risk of suicide.²²

Monitor or treat? An optimal approach

A key dilemma in the management of patients who exhibit signs and symptoms of schizophrenia prodrome is whether to simply monitor closely or to initiate treatment.

International clinical practice guidelines recommend several practical steps in the monitoring of patients in a prepsychotic state (Table 3),²³ but caution against the use of antipsychotic agents unless the patient meets diagnostic criteria for a psychotic disorder.

CBT. Some evidence supports the initiation of cognitive-behavioral therapy (CBT) during the initial prodromal phase and the addition of alow-dose atypical antipsychotic if the patient progresses to a later phase, characterized by BLIPS/APS.24,25 Evidence also suggests that a combination of CBT and antipsychotic medication might delay, but not prevent, the progression to a psychotic episode.9 Any risk of adverse metabolic complications precludes use ofan atypical antipsychotic.One potential alternative is the use of omega-3 polyunsaturated fatty acids (Box 2).^26,27

A clinically useful approach would be to view schizophrenia/psychosis prodrome not as a distinct diagnostic category but as a cluster of signs and symptoms associated with an increased risk of psychosis, with persons in this phase in need of close follow-up and, possibly, early initiation of an antipsychotic agent. It is important to engage the patient and his family at an early stage to educate them about the diagnostic uncertainty; to help them deal with the stigma; to manage risk factors; and, collaboratively, to decide on an intervention strategy.^23,28

Bottom Line

Despite several drawbacks, the concept of schizophrenia/psychosis prodrome may
be viewed as a cluster of signs and symptoms (rather than a distinct diagnostic category) associated with increased risk for psychosis that need close follow up. Follow up may involve psychoeducational and psychotherapeutic interventions and, need be, early initiation of antipsychotics. In addition, such symptoms may be associated with other psychiatric disorders such as bipolar disorder and obsessive- compulsive disorder. Timely attention and early intervention may alter the course
and improve overall prognosis.

Related Resources
• Early intervention in psychosis. WPA Education Committee’s recommended roles of the psychiatrist. www.wpanet.org/uploads/Education/Educational_Resources/earlyintervention-psychosis.pdf.
• Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. http://eppic.org.au/psychosis.
• International Early Psychosis Association Writing Group. International clinical practice guidelines for early psychosis. Br J Psychiatry. 2005;187:s120-124. http://bjp.rcpsych.org/content/187/48/s120.full.

Disclosures
Dr. Madaan is an employee of University of Virginia Health System. As an employee with the University of Virginia, Dr. Madaan has received research support from Eli Lilly and Company, Forest, Merck, Otsuka, Pfizer, Shire, and Sunovion. He also has served as a consultant for the NOW Coalition for Bipolar Disorder, and on the American Psychiatric Association’s Focus Self-Assessment editorial board. Drs. Bestha and Kolli report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

In studies of schizophrenia, one of the more striking findings is the delay in the initiation of treatment. That delay ranges from 1 to 2 years for patients experiencing psychotic symptoms to several years if the prodromal phase is taken into account.¹ Yet duration of untreated psychosis has been found to be a critical factor in prognosis, including psychosocial functioning, in patients with schizophrenia.^2,3 Identification of individuals in the prodromal phase not only offers an opportunity to intervene at an earlier symptomatic stage, but might be associated with a better response to antipsychotics and a better overall treatment outcome as well.

What’s in a name?

Several terms, including ultra high risk, clinical high risk, at-risk mental state, psychosis risk syndrome, and schizophrenia/psychosis prodrome, have been used to describe the prodromal phase of schizophrenia. The proposal to include attenuated psychosis syndrome (APS) in the DSM-5—originally intended to capture those with subthreshold delusions, hallucinations, or disorganized behavior, occurring at least once a week for the past month and worsening over the past year—generated a debate about the validity of such a diagnostic category^4,5 that culminated in the inclusion of APS as a condition for further study but not as a term for clinical use.⁶ Its presence in the DSM-5 brings to the forefront the importance of early clinical intervention in patients at risk of developing psychotic illness.

Schizophrenia is not inevitable

The prodromal phase can be viewed as a sequence of evolving symptoms⁷ (Box 1^8,9), starting with subtle differences evident only to the person experiencing them and often progressing to brief limited intermittent psychosis (BLIPS) or attenuated psychosis.⁸

In fact, prodrome is a retrospective diagnosis. The predictive power of conversion to psychosis has been found to fluctuate from as low as 9% to as high as 76%,¹⁰ prompting ethical concerns about a high false-positive rate, the assumption of inevitability associated with the term “schizophrenia prodrome,”⁹ and the potential for overdiagnosis and misdiagnosis. Concerns about psychosocial stigma and exposure to antipsychotic medications have been expressed as well.¹¹

A case for early engagement

In retrospect, patients who eventually progress to psychotic illness are commonly found to have been in the prodromal phase for several years. Yet many patients’ first contact with psychiatric services occurs during a florid episode of acute psychosis. Identifying patients in the early prodromal period offers the opportunity to more effectively engage them and form a therapeutic alliance.¹² Any young adult who presents with a decline in academic or occupational function, social withdrawal, perplexity, and apparent distress or agitation (Table 1^13-16) without a clear precipitating factor should therefore be closely monitored, particularly if he (she) has a family history of psychosis.

Screening tools. A variety of interviews and rating scales (Table 28) have been developed to assess and monitor at-risk persons, a number of which have been designed to detect basic symptoms in the early phase of prodrome. In addition to the structured scales, several self-report tools—including the Prodromal Questionnaire-Brief (PQ-B), Youth Psychosis At Risk Questionnaire-Brief (YPARQ-B), Prime Screen-Revised, and PROD-screen (Screen for prodromal symptoms of psychosis)—have been found to be useful in screening a large sample to identify those who might need further evaluation.¹⁷

Increased risk of conversion. Several clinical factors are associated with an increased risk of conversion to psychotic illness.9 In addition to family history, these include:

  • greater severity and longer duration of attenuated positive symptoms
  • presence of bizarre thoughts and behavior
  • paranoia
  • decline in global assessment of functioning score over the previous year
  • use of either Cannabis or amphetamines.

A history of childhood trauma, increased sensitivity to psychosocial stressors, and dysregulation of the hypothalamicpituitary axis also have been associated with progression to psychosis.¹⁸

Recent evidence suggests that the prodromal phase is a predictor not only for psychosis but also for other disabling psychiatric illnesses, such as bipolar disorder and obsessive-compulsive disorder.¹⁹

From a phenomenological standpoint, disturbance of the sense of self—characterized by features such as depersonalization, derealization, decreased reactivity to other people and the environment, and intense reflectivity to oneself or others—has been proposed as a critical marker for progression to psychosis.²⁰ Another predictor is the perception of negativity of others toward oneself. Examples include heightened sensitivity to rejection or shame, which seems to emerge from a pattern of insecure attachment, and the outsider status experienced by immigrants faced with multiple social, cultural, and language barriers.²¹ The presence of obsessivecompulsive symptoms during the prodromal phase has been linked to significant impairment in functioning, an acute switch to psychosis, and an increased risk of suicide.²²

Monitor or treat? An optimal approach

A key dilemma in the management of patients who exhibit signs and symptoms of schizophrenia prodrome is whether to simply monitor closely or to initiate treatment.

International clinical practice guidelines recommend several practical steps in the monitoring of patients in a prepsychotic state (Table 3),²³ but caution against the use of antipsychotic agents unless the patient meets diagnostic criteria for a psychotic disorder.

CBT. Some evidence supports the initiation of cognitive-behavioral therapy (CBT) during the initial prodromal phase and the addition of alow-dose atypical antipsychotic if the patient progresses to a later phase, characterized by BLIPS/APS.24,25 Evidence also suggests that a combination of CBT and antipsychotic medication might delay, but not prevent, the progression to a psychotic episode.9 Any risk of adverse metabolic complications precludes use ofan atypical antipsychotic.One potential alternative is the use of omega-3 polyunsaturated fatty acids (Box 2).^26,27

A clinically useful approach would be to view schizophrenia/psychosis prodrome not as a distinct diagnostic category but as a cluster of signs and symptoms associated with an increased risk of psychosis, with persons in this phase in need of close follow-up and, possibly, early initiation of an antipsychotic agent. It is important to engage the patient and his family at an early stage to educate them about the diagnostic uncertainty; to help them deal with the stigma; to manage risk factors; and, collaboratively, to decide on an intervention strategy.^23,28

Bottom Line

Despite several drawbacks, the concept of schizophrenia/psychosis prodrome may
be viewed as a cluster of signs and symptoms (rather than a distinct diagnostic category) associated with increased risk for psychosis that need close follow up. Follow up may involve psychoeducational and psychotherapeutic interventions and, need be, early initiation of antipsychotics. In addition, such symptoms may be associated with other psychiatric disorders such as bipolar disorder and obsessive- compulsive disorder. Timely attention and early intervention may alter the course
and improve overall prognosis.

Related Resources
• Early intervention in psychosis. WPA Education Committee’s recommended roles of the psychiatrist. www.wpanet.org/uploads/Education/Educational_Resources/earlyintervention-psychosis.pdf.
• Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. http://eppic.org.au/psychosis.
• International Early Psychosis Association Writing Group. International clinical practice guidelines for early psychosis. Br J Psychiatry. 2005;187:s120-124. http://bjp.rcpsych.org/content/187/48/s120.full.

Disclosures
Dr. Madaan is an employee of University of Virginia Health System. As an employee with the University of Virginia, Dr. Madaan has received research support from Eli Lilly and Company, Forest, Merck, Otsuka, Pfizer, Shire, and Sunovion. He also has served as a consultant for the NOW Coalition for Bipolar Disorder, and on the American Psychiatric Association’s Focus Self-Assessment editorial board. Drs. Bestha and Kolli report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.