Evidence-Based Reviews

Atypical depression Puzzled? How to piece together symptoms and treatments

Current Psychiatry. 2003 April;2(4):12-19

When do depressive symptoms become ‘atypical,’ and which antidepressants are most effective? Though evidence is incomplete, these authors recommend a clinical approach.

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References

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4. Posternak MA, Zimmerman M. Partial validation of the atypical features subtype of major depressive disorder. Arch Gen Psychiatry 2002;59(1):70-6.

5. Perugi G, Akiskal HS, Lattanzi L, et al. The high prevalence of “soft” bipolar (II) features in atypical depression. Compr Psychiatry 1998;39(2):63-71.

6. Levitan RD, Kaplan AS, Brown GM, et al. Low plasma cortisol in bulimia nervosa patients with reversed neurovegetative symptoms of depression. Biol Psychiatry 1997;41(3):366-8.

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8. Kendler KS, Eaves LJ, Walters EE, Neale MC, Heath AC, Kessler RC. The identification and validation of distinct depressive syndromes in a population-based sample of female twins. Arch Gen Psychiatry 1996;53(5):391-9.

9. Ebert D, Barocka A. The early course of atypical depression. Eur Arch Psychiatry Clin Neurosci 1991;241(2):131-2.

10. Zubieta JK, Pande AC, Demitrack MA. Two-year follow-up of atypical depression. J Psychiatr Res 1999;33(1):23-9.

11. Nierenberg AA, Pava JA, Clancy K, Rosenbaum JF, Fava M. Are neurovegetative symptoms stable in relapsing or recurrent atypical depressive episodes? Biol Psychiatry 1996;40(8):691-6.

12. Quitkin FM, McGrath PJ, Stewart JW, et al. Phenelzine and imipramine in mood reactive depressives. Further delineation of the syndrome of atypical depression. Arch Gen Psychiatry 1989;46(9):787-93.

13. Pande AC, Birkett M, Fechner-Bates S, Haskett RF, Greden JF. Fluoxetine versus phenelzine in atypical depression. Biol Psychiatry 1996;40(10):1017-20.

14. Sogaard J, Lane R, Latimer P, et al. A 12-week study comparing moclobemide and sertraline in the treatment of outpatients with atypical depression. J Psychopharmacol 1999;13(4):406-14.

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Deciding if a patient’s depressive episodes are “atypical” can be difficult because key pieces of the diagnostic puzzle are missing. Notwithstanding DSM-IV criteria, atypical depression’s definition remains unclear. This creates a therapeutic dilemma because we know that patients with atypical depression respond differently to antidepressants:

Monoamine oxidase inhibitors (MAOIs) may be most effective, but their side effects can be troublesome.
Tricyclics are clearly less effective than MAOIs, but the newer antidepressants’ role in treating atypical depressive symptoms has not been adequately explored.

We offer recommendations for diagnosing and treating atypical depression and address issues that may affect your clinical approach. These include possible overemphasis on mood reactivity in DSM-IV, shortcomings in studies defining the atypical depressive syndrome, and the potential role of biological markers in clarifying this challenging diagnosis.

Features of atypical depression

Atypical depression, as defined in DSM-IV,¹ is characterized by mood reactivity and two or more of the following criteria:

hypersomnia
increased appetite or weight gain
leaden paralysis (heavy, leaden feeling in arms or legs)
longstanding sensitivity to interpersonal rejection that results in significant social or occupational impairment (Table 1 ).

An estimated 16 to 23% of patients with unipolar depression present with atypical features.² These rates are higher among patients with bipolar disorder.^2,3

Distinctive features. Studies comparing atypical depression with typical or melancholic depression suggest that atypical depression may be distinct in epidemiology, family history, comorbidity, and course of illness (Table 2). Specifically, atypical depression has a higher female-to-male ratio and earlier age of onset.⁴ Patients with atypical depression have higher rates of comorbid panic disorder,^4,5 social phobia,^4,5 bipolar II disorder,⁵ and bulimia⁶ than do those with typical depression.

Family members of patients with atypical depression are more likely to have atypical features during a depressive episode than are family members of patients with melancholic depression.⁷ These findings suggest a genetic component to atypical depression. Atypical depressive episodes also may be more likely to become chronic.^4,8

Not all patients are alike. Studies of the diagnostic stability of atypical depression over time suggest that patients exhibiting atypical features are heterogeneous.⁹ Some longitudinal studies report reasonable diagnostic stability, with 59% to 100% of patients with an index episode of atypical depression exhibiting atypical features 12 to 24 months later.^9,10 In a follow-up study of patients in remission from an episode of atypical depression, 64% of patients suffering a relapse were again found to have atypical features.¹¹

Table 1

MOOD EPISODES: DSM-IV CRITERIA FOR ATYPICAL FEATURES SPECIFIER

The following criteria must be present in the last 2 weeks of the episode
Criterion A. Mood reactivity (ie, mood brightens in response to positive events)
Criterion B. Two or more of the following: Increased appetite or weight gain Hypersomnia Leaden paralysis Longstanding sensitivity to interpersonal rejection

Although numerous studies have failed to replicate one or more of these findings,^4,8 several investigators have concluded that atypical depression is a distinct and valid sub-type of major depression.^4,7,8

Antidepressant dilemmas

Unlike typical or melancholic depression, atypical depression responds more robustly to MAOIs than to tricyclic antidepressants (TCAs).¹² MAOIs are roughly twice as effective as TCAs (response rate 72% vs. 44%, respectively), according to a meta-analysis of six studies comparing MAOIs and TCAs in patients with atypical depression.¹³

Clinicians rarely use MAOIs as first-line antidepressants, however, because of side effects and potential dietary and drug interactions. A depressed patient is thus unlikely to receive MAOIs unless the clinician strongly suspects that the presentation is atypical.

SSRIs. Few studies have evaluated how patients with atypical depression respond to newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). This lack of evidence creates a dilemma when treating atypical depression, as SSRIs are widely used in depressed patients, including those with atypical features.

One study found fluoxetine and phenelzine comparably effective in atypical depression,¹⁴ while another found sertraline works as well as moclobe-mide.¹⁵ However, the fluoxetine study was limited by a relatively small sample size (n=42), and both studies lacked placebo controls.

Some studies have suggested that SSRIs are less effective than MAOIs¹⁶ or as effective as TCAs in depressed patients with atypical features.^17,18 However, one of these trials was limited by a small sample size (n=28),¹⁸ and only one was placebo-controlled.¹⁷

Bupropion. Studies of other antidepressants in atypical depression also are limited. In two separate trials, depressed patients with atypical features showed a greater response to bupropion than did depressed patients with typical features.^19,²⁰

Bupropion—a combined dopaminergic-noradrenergic antidepressant—appears to have stimulating properties that may help patients with hypersomnia and hyperphagia. Like MAOIs, bupropion also appears to have a greater effect on dopaminergic systems than either TCAs or SSRIs.