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Home , Atypical depression, Melancholic depression

SECOND OF 2 PARTS A practical approach to subtyping among your patients

Improve outcomes by understanding the forms that depressive disorders can take

epression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge- Dneous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf- fering. 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 sub- groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial treatment, optimal “next-step” pharmacotherapy, after nonre- sponse or partial response, often hinges on clinical subtyping. JON KRAUSE/THE ISPOT.COM The second part of this article examines “situational,” treat- ment-resistant, melancholic, agitated, anxious, and atypical Joseph F. Goldberg, MD depression; depression occurring with a substance use disor- Clinical Professor of Icahn School of Medicine at Mount Sinai der; premenstrual dysphoric disorder; and seasonal affective New York, New York disorder. Treatments for these subtypes for which there is evi- Director, Affective Disorders Research Program dence, or a clinical rationale, are given in the Table, page 42. Silver Hill Hospital New Canaan, Connecticut

‘Situational’ depression In recent decades, the phenomenon of nonsyndromal depres- sion after a life has undergone many name changes but lit- tle conceptual revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress Disclosure Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape Current Psychiatry and WebMD. Vol. 13, No. 5 41 Table Evidence- or rationale-based somatic therapy for select subtypes of depression Premenstrual Treatment Treatment-resistant Melancholic Agitated Anxious Atypical Seasonal dysphoric disorder Atypical OFCa √ √ √ No No data No data Adjunctive aripiprazolea datab a Subtyping Adjunctive quetiapine a depression √ No data No data √ + open trials √ Inferior to SSRIs Deep brain √ No data No data No data No data No data No data stimulation Electroconvulsive √ √ √ (-) √ No data No data therapy prognostic factor Ketamine Preliminary No data No data No data No data No data No data Lamotrigine No data No data No data No data No data No data No data L-Methylfolate Adjunctive efficacy after SSRI No data No data No data No data No data No data Clinical Point non-response Lithium √ No data No data No data No data No data No data Stressful life Adjunct to events more often MAOIs √ √ √ √ √ √ No data precede first or √ √ √ √ No data No data No data early episodes N-Acetylcysteine No data No data No data No data No data No data No data Phototherapy No data No data No data No data No data √ Small effect, if any of depression Pramipexole Preliminary No data No data; No data No data No data No data than subsequent ill advised recurrences Psychostimulants Preliminary Preliminary No data; No data; No data No data No data ill-advised ill-advised Riluzole Preliminary No data No data No data No data No data No data Serotonin- √ √ √ √ Open trials Inconclusive No data norepinephrine reuptake inhibitors SSRIs √ TCAs might be √ √ √ √ √ superior Repetitive √ a (+) open trials No data (+) open trials No data No data No data transcranial magnetic stimulation Tricyclic √ √ √ √ Inferior to √ Not better than antidepressants SSRIs and placebo MAOIs Vagus nerve √ a No data No data No data No data No data No data stimulation Vortioxetine No data No data No data No data No data No data No data √ = traditional first-line intervention or recommended appropriate first-line intervention aAn FDA-approved indication; all other uses are off-label bThe effects of atypical antipsychotics on and hyperphagia associated with are not well-established MAOIs: monoamine oxidase inhibitors; OFC: olanzapine-fluoxetine combination; SSRIs: selective serotonin reuptake inhibitors; TCA:

Discuss this article at www.facebook.com/ CurrentPsychiatry response ” in DSM-5. These Paucity of guidance. There has been little names all connote presentations of depressed research to identify vulnerability variables mood after an environmental stressor, with- for adjustment disorders in the aftermath out either the full constellation of symptoms of particular stressors. Similarly, extensive that define major depression or the chronicity data are lacking on 1) the likely progression Current Psychiatry 42 May 2014 of dysthymic disorder. of such disorders to a syndromal form of depression can predispose to major depres- 1 Evidence- or rationale-based somatic therapy for select subtypes of depression sion or suicidal behaviors. Models of behavioral sensitization posit Premenstrual that stressful life events more often precede Treatment Treatment-resistant Melancholic Agitated Anxious Atypical Seasonal dysphoric disorder first or early episodes of depression than sub- Atypical OFCa √ √ √ No No data No data sequent recurrences.2 At the same time, non- antipsychotics Adjunctive aripiprazolea datab melancholic depressions that are preceded by Adjunctive quetiapinea “situational stresses” tend to recur in similar Bupropion √ No data No data √ + open trials √a Inferior to SSRIs fashion.3 Deep brain √ No data No data No data No data No data No data stimulation Electroconvulsive √ √ √ (-) √ No data No data Medical therapy of value? therapy prognostic without medication—apart from occa- factor sional sedative−hypnotic drugs as needed Ketamine Preliminary No data No data No data No data No data No data for , anxiety, or distress—is con- Lamotrigine No data No data No data No data No data No data No data sidered the standard of care for treating an L-Methylfolate Adjunctive efficacy after SSRI No data No data No data No data No data No data . No drug has demon- non-response strated superiority to placebo for alleviating Clinical Point Lithium √ No data No data No data No data No data No data symptoms of an adjustment disorder, but For treatment- Adjunct to antidepressants some clinicians nonetheless sometimes feel MAOIs √ √ √ √ √ √ No data compelled to “up-code” the diagnosis of an resistant depression, Mirtazapine √ √ √ √ No data No data No data adjustment disorder to the status of a major repetitive N-Acetylcysteine No data No data No data No data No data No data No data affective disorder, even when syndromal cri- transcranial Phototherapy No data No data No data No data No data √ Small effect, if any teria for major depressive disorder (MDD) or magnetic stimulation Pramipexole Preliminary No data No data; No data No data No data No data are absent. ill advised appears to be Psychostimulants Preliminary Preliminary No data; No data; No data No data No data inferior to ECT ill-advised ill-advised Riluzole Preliminary No data No data No data No data No data No data Treatment-resistant depression Serotonin- √ √ √ √ Open trials Inconclusive No data Disease staging models for depression and norepinephrine other psychiatric disordersa make note that, reuptake inhibitors elsewhere in medicine, distinct clinical SSRIs √ TCAs might be √ √ √ √ √ entities often are identified based on their superior responsivity to treatment (eg, classifying Repetitive √ a (+) open trials No data (+) open trials No data No data No data infections as antibiotic-sensitive or -resis- transcranial magnetic tant). Within the study and management stimulation of mood disorders, “treatment resistance” Tricyclic √ √ √ √ Inferior to √ Not better than sometimes is a catch-all description of situ- antidepressants SSRIs and placebo ations in which past treatment 1) yielded MAOIs no improvement or partial improvement Vagus nerve √ a No data No data No data No data No data No data stimulation or 2) was marked by intolerance. Poor out- Vortioxetine No data No data No data No data No data No data No data comes due to past medication intolerance or √ = traditional first-line intervention or recommended appropriate first-line intervention an aborted trial often are commingled with aAn FDA-approved indication; all other uses are off-label cases of true lack of improvement after an b The effects of atypical antipsychotics on hypersomnia and hyperphagia associated with atypical depression are not well-established adequate treatment trial. MAOIs: monoamine oxidase inhibitors; OFC: olanzapine-fluoxetine combination; SSRIs: selective serotonin reuptake inhibitors; TCA: tricyclic antidepressant It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres- sion.” True past nonresponse to appropriate depression or 2) protective factors against treatment often carries prognostic importance developing clinically significant depres- and bears on future treatment decisions. sion after a life stress. The extent to which Few interventions are FDA approved adjustment disorders lie on a continuum for treatment-resistant depression (Table). with major mood disorders is not well- aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry established, although subthreshold levels of Current Psychiatry, May 2013, at CurrentPsychiatry.com. Vol. 13, No. 5 43 continued Neuromodulation techniques are attract- Anxious depression ing interest in this area, although repetitive Anxiety symptoms or syndromes occur in at transcranial magnetic stimulation appears least one-half of outpatients who have major inferior to electroconvulsive therapy (ECT) depression, and might account for a substan- for this indication.4 tial percentage of nonresponse to first-line antidepressant therapies.13 The construct of a mixed anxiety−depressive disorder is, in fact, Subtyping well-represented in the literature, particu- depression involves the cardinal symptoms larly in primary care medicine, but its poor of and lack of mood reactivity, inter-rater reliability in DSM-5 field trials led alongside such features as distinct quality of to its exclusion there as a formal diagnosis.14 mood, diurnal variation, excessive guilt, and Serotonergic antidepressants remain the severe weight loss. It most closely approxi- mainstay of treatment for depression with mates pre-DSM-III “endogenous depres- anxiety, although (contrary to popular percep- sion” and can involve 1) greater genetic tion) bupropion exerts an anxiolytic effect that loading5 and 2) structural and functional is comparable to the effect of SSRIs.15 Notably, Clinical Point abnormalities in frontostriatal pathways.6,7 high somatic anxiety during depression might 16 High somatic anxiety Melancholic features do not necessarily predict a poor outcome from ECT. recur across successive episodes8 but carry during depression an increased risk of psychosis9 and high- might predict a poor lethality suicidal behavior.10 Melancholia Atypical depression outcome from ECT implies necessity for pharmacotherapy or Often closely linked with early onset and ECT rather than psychosocial treatment chronicity, the construct of atypical depres- alone; some researchers have suggested that sion has been defined in the literature by the tricyclic antidepressants (TCAs) might yield symptom constellation of: better results than selective serotonin reup- • mood reactiveness to environmental take inhibitors (SSRIs).11 circumstances (unlike melancholia) • heightened interpersonal sensitivity • hypersomnia Agitated depression • hyperphagia The Research Diagnostic Criteria (a forerun- • profound or a sense of physical ner in the 1970s to DSM-III) described agi- heaviness. tated depression, but the disorder was not Some authorities regard atypical fea- included in any DSM editions—although it tures as being especially common in bipolar is a “clinical modification” for MDD in the depression, or in depression among people 10th revision of the International Statistical who have borderline . Classification of Diseases and Related Particular interest in this construct grew Health Problems. from studies that suggested that atypical Agitated depression refers to a major depression is more responsive to a monoamine depressive episode involving motor or psy- oxidase inhibitor (MAOI) than to a TCA, but chic agitation, intense inner tension, and rac- also that SSRIs are not clearly superior to ing or “crowded” thoughts. Some experts MAOIs.17 Response to ECT might also be bet- believe that it represents a variant of psy- ter in atypical than in typical depression.18 chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist. Depression with a substance Recovery from agitated depression tends use disorder to be slower than in non-agitated depression. Although not a distinct diagnostic entity, Treatment usually entails an antidepressant depression with a coexisting substance plus an , although some believe use disorder poses special challenges with that antidepressants can exacerbate, not alle- regard to the source of symptom emergence viate, symptoms and, instead, favor antipsy- (that is, when does depression lead to drug Current Psychiatry 44 May 2014 chotics, mood stabilizers, or ECT.12 or alcohol use to “self-medicate,” and when does drug use cause depression?) and treat- feron) are viewed as distinct from MDD in ment. Debate continues about whether 1) regard to risk of recurrence, genetic under- medicines that treat depression are effec- pinnings, and possible neurodegenerative tive and worthwhile in the setting of active pathophysiology.b Unlike MDD, patient- substance use or 2) aggressive treatment of specific risk factors are poorly defined for substance misuse is a prerequisite for sub- anticipating that a secondary depression is sequent pharmacotherapy for depression more or less likely to develop in the context that is “uncontaminated” by the psychotoxic of an exogenous substance or medical illness. effects of concurrent substances of abuse. Treating secondary depression involves Meta-analysis of controlled trials of addressing the underlying condition and antidepressants for patients who have might include antidepressant medication. MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to Seasonal affective disorder placebo unless a patient is actively drink- DSM-5 identifies “with seasonal pattern” as ing.19 Of the various classes of antidepres- a specifier for recurrent major depression. sants, TCAs and nefazodone were found Phototherapy remains a standard treatment, Clinical Point to be superior to placebo but, surprisingly, although a Cochrane Review identified In a meta-analysis SSRIs were not. Another meta-analysis of comparable outcomes with fluoxetine, but adjunctive antidepressant outcomes for inconclusive data for other, newer antide- of depressed opiate-dependent, depressed patients who pressants.24 Small open trials have suggested patients who abuse are receiving methadone maintenance that MAOIs and TCAs can be efficacious. alcohol, TCAs and therapy found no difference between anti- Note: Phototherapy lacks demonstrated nefazodone were depressants and placebo in their effect on efficacy in non-seasonal forms of depression.25 superior to placebo, depression symptom outcomes.20 but SSRIs were not What does the future hold for Premenstrual dysphoric disorder classifying depressive disorders? A new category in DSM-5, premenstrual Recent initiatives have attempted to classify dysphoric disorder (PMDD) represents depression less by traditional clinical signs a variant of premenstrual and more by focusing on possible underly- that arises during the luteal phase and ing neurobiological substrates.c In the future, ends with menstruation. Symptoms subtyping of mood disorders might focus on include several of those identified with such constructs as: MDD (without duration criteria), as well • positive and negative valence systems as mood swings, panic attacks, and physi- and attentional domains cal complaints. • treatment-responsivity relative to SSRIs—but not bupropion21 or TCAs22— genotypic variants (for example, the sero- and, sometimes, low-estrogen oral contra- tonin transporter gene locus [SLC6A4] or ceptives are mainstays of treatment; so is prediction of L-methylfolate-responsive cognitive-behavioral therapy, as well as life- depression based on the genotype of style modifications (eg, exercise and changes the methylenetetrahydrofolate reductase to diet). Phototherapy has not shown robust [MTHFR] polymorphism) efficacy for PMDD.23 • disrupted neural plasticity in brain cir- cuits believed to regulate emotion. Until robust biomarkers for depression Secondary depression are identified and validated, however, In DSM-5, depressive episodes that arise such advances in nosology remain experi- secondary to a general medical condition mental and speculative.

(eg, hypothyroidism and other endocrinopa- bFor further discussion, see “Is a medical illness causing thies, cerebrovascular accidents, malignan- your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com. cies) or iatrogenically from medications (eg, cAn example is the Research Domain Criteria [RDoC],www. Current Psychiatry corticosteroids, some anticonvulsants, inter- nimh.nih.gov/research-priorities/rdoc/index.shtml. Vol. 13, No. 5 45 continued 9. Caldieraro MA, Baeza FL, Pinheiro DO, et al. Prevalence of psychotic symptoms in those with melancholic Related Resources and nonmelancholic depression. J Nerv Ment Dis. • Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: 2013;201(10):855-859. Forgotten treatment for depression. Current Psychiatry. 10. Grunebaum MF, Galfalvy HC, Oquendo MA, et al. 2012;11(12):20-26. Melancholia and the probability and lethality of attempts. Br J Psychiatry. 2004;184:534-535. • Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom- 11. Roose SP, Glassman AH, Attia E, et al. Comparative based subtypes of depression and their psychosocial cor- efficacy of selective serotonin reuptake inhibitors and relates: a person-centered approach focusing on the influ- tricyclics in the treatment of melancholia. Am J Psychiatry. ence of sex. J Affect Disord. 2014;156:92-103. 1994;151(12):1735-1739. Subtyping 12. Koukopoulos A, Sani G, Koukopoulos AE, et al. Melancholia Drug Brand Names agitata and mixed depression. Acta Psychiatr Scand Suppl. depression • Abilify Mirtazapine • Remeron 2007;(433):50-57. Bupropion • Wellbutrin Nefazodone • Serzone 13. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment Fluoxetine • Prozac Olanzapine/fluoxetine • outcome in outpatients with anxious versus nonanxious Ketamine • Ketalar Symbyax depression: a STAR*D report. Am J Psychiatry. 2008; 165(3):342-351. L-Methylfolate • Deplin Pramipexole • Mirapex Lamotrigine • Lamictal Quetiapine • Seroquel 14. Regier DA, Narrow WE, Clarke DE, et al. DSM-5 field trials in the United States and Canada, Part II: test-retest Lithium • Eskalith, Lithobid Riluzole • Rilutek reliability of selected categorical diagnoses. Am J Psychiatry. Methadone • Dolophine Vortioxetine • Brintellix 2013;170(1):59-70. 15. Rush AJ, Trivedi MH, Carmody TJ, et al. Response in relation to baseline anxiety levels in major depressive disorder treated with bupropion sustained release or . Clinical Point Editor’s note: The first part of Dr. Goldberg’s Neuropsychopharmacology. 2001;25(1):131-138. 16. Rasmussen KG, Snyder KA, Knapp RG, et al. Relationship Treating secondary review of depression subtypes—focusing on between somatization and remission with ECT. Psychiatry major and minor depression, chronicity, polar- Res. 2004;129(3):293-295. depression involves 17. Henkel V, Mergl R, Allgaier AK, et al. Treatment of ity, severity, and —appeared in the depression with atypical features: a meta-analytic approach. addressing the April 2014 issue. Psychiatry Res. 2006;141(1):89-101. 18. Husain MM, McClintock SM, Rush AJ, et al. The efficacy underlying medical of acute electroconvulsive therapy in atypical depression. J References Clin Psychiatry. 2008;69(3):406-411. condition and 1. Fergusson DM, Horwood LJ, Ridder EM, et al. Subthreshold 19. Iovieno N, Tedeschini E, Bentley KH, et al. Antidepressants depression in adolescence and outcomes in for major depressive disorder and dysthymic disorder might include adulthood. Arch Gen Psychiatry. 2005;62(1):66-72. in patients with comorbid alcohol use disorders: a meta- 2. Mitchell PB, Parker GB, Gladstone GL, et al. Severity of analysis of placebo-controlled randomized trials. J Clin antidepressants stressful life events in first and subsequent episodes of Psychiatry. 2011;72(8):1144-1151. depression: the relevance of depressive subtypes. J Affect 20. Pedrelli P, Iovieno N, Vitali M, et al. Treatment of major Disord. 2003;73(3):245-252. depressive disorder and dysthymic disorder with 3. Coryell W, Winokur G, Maser JD, et al. Recurrently antidepressants in patients with comorbid opiate use situational (reactive) depression: a study of course, disorders enrolled in methadone maintenance therapy: a phenomenology and familial . J Affect meta-analysis. J Clin Psychopharmacol. 2011;31(5):582-586. Disord. 1994;31(3):203-210. 21. Pearlstein TB, Stone AB, Lund SA, et al. Comparison of 4. Slotema CW, Blom JD, Hoek HW, et al. Should we expand fluoxetine, bupropion, and placebo in the treatment of the toolbox of psychiatric treatment methods to include premenstrual dysphoric disorder. J Clin Psychopharmacol. Repetitive Transcranial Magnetic Stimulation (rTMS)? 1997;17(4):261-266. A meta-analysis of the efficacy of rTMS in psychiatric 22. Freeman EW, Rickels K, Sondheimer SJ, et al. Differential disorders. J Clin Psychiatry. 2010;71(7):873-884. response to antidepressants in women with premenstrual 5. Kendler KS. The diagnostic validity of melancholic major syndrome/premenstrual dysphoric disorder: a randomized depression in a population-based sample of female twins. controlled trial. Arch Gen Psychiatry. 1999;56(10):932-939. Arch Gen Psychiatry. 1997;54(4):299-304. 23. Krasnik C, Montori VM, Guyatt GH, et al. The effect of bright 6. Bracht T, Horn H, Strik W, et al. White matter microstructure on depression associated with premenstrual alterations of the medial forebrain bundle in melancholic dysphoric disorder. Am J Obstet Gynecol. 2005;193(3, pt depression. J Affect Disord. 2014;155:186-193. 1):658-661. 7. Pizzagalli DA, Oakes TR, Fox AS, et al. Functional but not 24. Thaler K, Delivuk M, Chapman A, et al. Second-generation structural subgenual prefrontal cortex abnormalities in antidepressants for seasonal affective disorder. Cochrane melancholia. Mol Psychiatry. 2004;9(4):325, 393-405. Database Syst Rev. 2011;7(12):CD008591. 8. Melartin T, Leskelä U, Rytsälä H, et al. Co-morbidity and 25. Thalén BE, Kjellman BF, Mørkid L, et al. Light treatment in stability of melancholic features in DSM-IV major depressive seasonal and nonseasonal depression. Acta Psychiatr Scand. disorder. Psychol Med. 2004;34(8):1443-1452. 1995;91(5):352-360.

Bottom Line Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding Current Psychiatry 46 May 2014 preferred treatments, which should be tailored to the needs of your patients.