The first of 2 parts: A practical approach to subtyping depression among your patients

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.