Evidence-Based Reviews

Atypical depression Puzzled? How to piece together symptoms and treatments

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

References

1. American Psychiatric Association. Diagnostic and statistical manual of mentab disorders (4th ed). Washington DC: American Psychiatric Association, 2000.

2. Benazzi F. Prevalence and clinical features of atypical depression in depressed outpatients: a 467-case study. Psychiatry Res 1999;86(3):259-65.

3. Benazzi F. Is atypical depression a moderate severity depression? A 536-case study. J Psychiatry Neurosci 1999;24(3):244-7.

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.

7. Stewart JW, McGrath PJ, Rabkin JG, Quitkin FM. Atypical depression. A valid clinical entity? Psychiatr Clin North Am 1993;16(3):479-95.

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.

15. Lonnqvist J, Sihvo S, Syvalahti E, Kiviruusu O. Moclobemide and fluoxetine in atypical depression: a double-blind trial. J Affect Disord 1994;32(3):169-77.

16. McGrath PJ, Stewart JW, Janal MN, Petkova E, Quitkin FM, Klein DF. A placebo-controlled study of fluoxetine versus imipramine in the acute treatment of atypical depression. Am J Psychiatry 2000;157(3):344-50.

17. Stratta P, Bolino F, Cupillari M, Casacchia M. A double-blind parallel study comparing fluoxetine with imipramine in the treatment of atypical depression. Int Clin Psychopharmacol 1991;6(3):193-6.

18. Goodnick PJ, Dominguez RA, DeVane CL, Bowden CL. Bupropion slow-release response in depression: diagnosis and biochemistry. Biol Psychiatry 1998;44(7):629-32.

19. Goodnick PJ, Extein I. Bupropion and fluoxetine in depressive subtypes. Ann Clin Psychiatry 1989;1:119-22.

20. Rye DB, Dihenia B, Bliwise DL. Reversal of atypical depression, sleepiness, and REM-sleep propensity in narcolepsy with bupropion. Depress Anxiety 1998;7(2):92-5.

21. Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002;159(9):1470-9.

22. Liebowitz MR, Quitkin FM, Stewart JW, et al. Phenelzine v imipramine in atypical depression. A preliminary report. Arch Gen Psychiatry 1984;41(7):669-77.

23. Thase ME, Carpenter L, Kupfer DJ, Frank E. Clinical significance of reversed vegetative subtypes of recurrent major depression. Psychopharmacol Bull 1991;27(1):17-22.

24. Angst J, Gamma A, Sellaro R, Zhang H, Merikangas K. Toward validation of atypical depression in the community: results of the Zurich cohort study. J Affect Disord 2002;72(2):125-38.

25. Gold PW, Chrousos GP. The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Physicians 1999;111(1):22-34.

26. Garvey MJ, Schaffer C, Schaffer L, Perry PJ. Is DST status associated with depression characteristics? J Affect Disord 1989;16(2-3):159-65.

27. Geracioti TD, Jr, Loosen PT, Orth DN. Low cerebrospinal fluid corticotropin-releasing hormone concentrations in eucortisolemic depression. Biol Psychiatry 1997;42(3):165-74.

28. Casper RC, Kocsis J, Dysken M, et al. Cortisol measures in primary major depressive disorder with hypersomnia or appetite increase. J Affect Disord 1988;15(2):131-40.

29. Sullivan PF, Kessler RC, Kendler KS. Latent class analysis of lifetime depressive symptoms in the national comorbidity survey. Am J Psychiatry 1998;155(10):1398-406.

30. Levitan RD, Lesage A, Parikh SV, Goering P, Kennedy SH. Reversed neurovegetative symptoms of depression: a community study of Ontario. Am J Psychiatry 1997;154(7):934-40.

31. McElroy SL, Suppes T, Keck PE, Jr, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry 2000;47(12):1025-33.

32. Shapira NA, Goldsmith TD, McElroy SL. Treatment of binge-eating disorder with topiramate: a clinical case series. J Clin Psychiatry 2000;61(5):368-72.

Recommendation. The most prudent approach appears to be using SSRIs or bupropion as first-line treatment for atypical depression and reserving MAOIs for patients who do not respond.

Attempts to define atypical depression

Although atypical depression responds differently to MAOIs than to TCAs, it is unclear which patients will respond preferentially to MAOIs. Early attempts to classify this subgroup recognized that these patients display symptom clusters, including:

anxious depression (prominent anxiety symptoms)
anergic depression (prominent fatigue and/or psychomotor retardation)
and depression with reversed vegetative symptoms (hypersomnia and increased weight/appetite).^7,21

Researchers have focused on patients with different combinations of these symptom profiles when defining the atypical depressive syndrome. Some have defined atypical depression as anxious temperament and reactive mood; others, as depression with reversed vegetative symptoms and severe fatigue; still others employ aspects of both profiles, as does DSM-IV.²¹ As a result of this confusion, investigators have demonstrated the preferential response to MAOIs in groups that exhibit different “atypical” symptoms.

Mood reactivity. The importance of mood reactivity in the diagnosis of atypical depression has been debated. DSM-IV requires mood reactivity for the diagnosis, perhaps to clearly differentiate melancholia from atypical depression.⁷ Yet some studies have demonstrated the preferential MAOI response in patients without this symptom.

Table 2

HOW ATYPICAL DEPRESSION COMPARES WITH MELANCHOLIC OR ‘TYPICAL’ DEPRESSION

Feature	Atypical depression	Melancholic (MEL)/typical (TYP) depression
Symptom
Sleep	Increased	Decreased
Appetite	Increased	Decreased
Age of onset	Late teens to early 20s	Mid to late 30s
Female:male ratio	> 2:1	Between 1:1 and 2:1
Frequency of bipolar II disorder	Increased compared with MEL/TYP
Duration of episodes	Increased compared with MEL/TYP
Biology
HPA axis activity	Low to normal	High
Comorbidity
Panic disorder, social phobia, bulimia	Frequency increased compared with MEL/TYP

The Columbia group, from whose work the DSM-IV definition was adopted, performed several convincing studies showing clear superiority of MAOIs in patients who had reactive mood and displayed at least two additional atypical features, such as reversed vegetative symptoms and anergia.²² Patients with reactive mood and only one additional atypical symptom (classified as “probable” atypical depression) also displayed the preferential response to MAOIs, whereas patients who displayed mood reactivity alone did not.¹²

Thase et al,²³ however, reported that reversed vegetative symptoms were more common with nonreactive mood (48%) than with reactive mood (16%) in patients with highly recurrent depression. Moreover, patients who displayed reversed vegetative symptoms without mood reactivity showed the same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Table 3

HOW ANTIDEPRESSANTS COMPARE IN CLINICAL TRIALS OF ATYPICAL DEPRESSION

MAOIs	8 controlled trials found MAOI > placebo 6 controlled trials found MAOI > TCA
TCAs	6 controlled trials found MAOI > TCA
SSRIs	2 controlled trials found SSRI = MAOI 1 trial found MAOI > SSRI 2 trials found SSRI = TCA
Bupropion	1 open-label trial found bupropion more effective in atypical depression than in typical depression 1 open-label trial found bupropion effective in depression with hypersomnia 1 retrospective study found bupropion > fluoxetine in atypical depression
> more effective than
= as effective as

More evidence suggests that mood reactivity should not be given the hierarchical importance it holds in the DSM-IV definition of atypical depression. In studies using latent class and cluster analyses, mood reactivity did not correlate with any other atypical feature,⁴^,21 whereas hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity appear to be associated with one another.

Recommendation. Mood reactivity’s uncertain status in atypical depression’s definition makes it difficult to predict which patients may respond preferentially to MAOIs, as many patients present with other atypical features and nonreactive mood. Most recently, it has been suggested that atypical depression’s diagnostic criteria should be modified so that mood reactivity is not required but is one of five atypical features, of which three must be present for the diagnosis.²⁴

Biological markers of depression

Atypical depression’s definition might be clarified if specific depressive symptoms could be linked to any biological markers. One proposed marker is decreased HPA axis activity, possibly caused by a central deficiency of corticotropin-releasing hormone (CRH),²⁵ a potent HPA axis stimulator.

HPA axis hyperactivity—presumably caused by increased CRH activity in the central nervous system—has been linked to melancholic depressive symptoms—particularly insomnia and reduced appetite.²⁶
Normal or diminished HPA axis activity—suggested by normal cortisol levels, low levels of CRH in cerebrospinal fluid, and increased frequency of dexamethasone suppression—has been associated with some atypical depressive features—specifically reversed vegetative symptoms.^27-29

However, no studies have examined whether low HPA axis activity is associated with other atypical symptoms listed in DSM-IV. Research is needed to determine whether HPA axis hypoactivity is associated only with reversed vegetative symptoms or with atypical depression per se.

Obesity and eating disorders. Depressed patients who are obese or present with eating disorders may overlap with the atypical subtype and may respond better to some drug interventions than to others. Evidence suggests that depression—particularly the atypical subtype—is associated with increased rates of obesity^8,29 and eating disorders.^8,30