The characteristic biological profile of atypical depression includes either normal or abnormally decreased HPA axis function; a relatively normal polysomnographic sleep profile; increased frontal, temporal, and parietal perfusion; and abnormally increased right hemispheric processing when performing psychophysiological tasks.39-45 Thus, the neurobiological profile of patients with atypical depression is both distinct from melancholia and, on select measures, abnormal compared with that of healthy controls. Interestingly, the most abnormal profiles appear to be evident in patients whose atypical depression has an early onset and a chronic course.40,45
A SPECT brain perfusion study in patients with atypical depression showed increased frontal, temporal, and parietal perfusion coupled with decreased occipital perfusion relative to that seen in patients with melancholic and undifferentiated depression (ie, neither atypical nor melancholic). A SPECT study also showed increased right frontal perfusion relative to that seen in individuals in the control group.46 These specific biological characteristics imply that atypical depression is in fact a distinct entity and, as such, requires a distinct treatment approach.
Differential response to standard treatments is historically the strongest determinant of atypical depression as a distinct subtype; patients with atypical depression have a preferential response to MAOIs compared with TCAs and less robust therapeutic responses to ECT.5,47-49 Although some studies have failed to demonstrate the relationship between atypical features and preferential response to certain medications, the therapeutic benefit of MAOIs in atypical depression is widely accepted in practice guidelines and has been confirmed by meta-analyses.50-52
The first reports of preferential response to MAOIs were based on uncontrolled case series; early attempts to replicate these findings in larger-scale randomized controlled trials (RCTs) met with only limited success (see Thase and colleagues53 for detailed review). Subsequent prospective trials using specific diagnostic criteria for atypical depression have generally supported the superiority of MAOIs—particularly phenelzine(Drug information on phenelzine)—over TCAs. For example, Liebowitz and colleagues54 randomized 119 patients with atypical depression to phenelzine, imipramine(Drug information on imipramine), or placebo. Improvement in both active groups was significantly superior to that in the placebo group; response rates were 71%, 50%, and 28% for phenelzine, imipramine, and placebo, respectively. Although the 21% difference in response rate between the phenelzine and imipramine groups was not statistically significant, the overall trend favored the MAOI.54
Similar findings were obtained by Quitkin and colleagues55 in an RCT of 90 outpatients with atypical depression. They observed response rates of 83%, 50%, and 19% for phenelzine, imipramine, and placebo, respectively. In this study, the difference in response rate between phenelzine and imipramine was both clinically and statistically significant (P = .005).55
The utility of phenelzine was also supported in a 2-stage, double-blind study of patients with atypical depression. During the first stage, response rates were significantly higher for phenelzine at both 6- and 12-week assessments (63% at 6 weeks and 51% at 12 weeks) than for imipramine (35% at 6 weeks and 24% at 12 weeks).56 During the second phase, nonresponders to imipramine were switched to phenelzine; a response rate of 67% was observed. Only 41% of the phenelzine nonresponders responded to imipramine.57
Interestingly, another placebo-controlled RCT conducted by the same group of investigators compared phenelzine and imipramine in outpatients with a depressive episode characterized by reactive mood but none of the other criteria for atypical depression.32,56,57 In this trial, response rates to the MAOI and to the TCA were essentially identical (75% for phenelzine and 74% for imipramine); both drugs were superior to placebo. When taken together, these findings suggest that mood reactivity per se is not related to drug response, but rather it is the presence of criterion B features that predicts response to MAOIs.32
It is also worth noting that results of a re-analysis suggest that the overall advantage of the MAOI over the TCA in the aforementioned studies may well be the result of the relative inferiority of imipramine in patients with early onset of illness (ie, before age 21 years) and chronic atypical depression (ie, duration of at least 2 years with well periods of no longer than 2 months).26 In fact, among the patients with a later illness onset and a less chronic course, the imipramine response rate was about 65% (approximating that with phenelzine). Although 4 different MAOIs are licensed by the FDA for the treatment of major depression (ie, tranylcypromine, phenelzine, isocarboxazid, and selegiline(Drug information on selegiline) transdermal delivery system), only the label for phenelzine includes a clear indication for atypical features.
Although MAOIs are clearly effective in patients with atypical depression, they are not considered first-line choices because of the required dietary restrictions and potential adverse effects.12 In light of this, researchers have switched their focus to the potential role of non-MAOI/non-TCA medications in the treatment of atypical depression.
In the first study to directly compare an SSRI with an MAOI, Pande and colleagues58 randomized 40 patients with atypical depression to a 6-week course of either fluoxetine(Drug information on fluoxetine) (20 to 60 mg/d) or phenelzine (15 to 90 mg/d). Response rates (defined as a decrease of 50% or more in Hamilton Rating Scale for Depression-17 [HAMD-17] or a Clinical Global Impressions Improvement [CGI-I] score of 1 or 2) for fluoxetine and phenelzine were reported as 80% to 85% and 85%, respectively.58 Remission rates (HAMD-17 less than 5 and a CGI-I score of 1 or 2) were 80% for fluoxetine and 70% for phenelzine. No statistically significant differences were found between the groups, but the frequency of adverse effects was lower with fluoxetine.58 This study suggests that fluoxetine may be as effective as phenelzine in the treatment of atypical depression, with the SSRI having a better tolerability profile.
Further attempts to establish the utility of SSRIs in the treatment of atypical depression include trials of SSRIs (fluoxetine and sertraline(Drug information on sertraline)) versus the reversible MAOI drug moclobemide(Drug information on moclobemide).59,60 In the first trial, moclobemide (an investigational drug that is not commercially available in the United States) at a median dose of 379 mg displayed superiority as evidenced by response rates ranging from 71% to 91% (HAMD and CGI-I) over the 60% to 65% for fluoxetine at a median dose of 27 mg in the sample of 40 patients with atypical depression.59 In the second trial, there was a trend toward superiority for sertraline at 50 to 100 mg/d over moclobemide at 300 to 450 mg/d, as reflected by remission rates (CGI-I = 1) of 77.5% and 67.5% for sertraline and moclobemide, respectively, after 12 weeks of treatment (P > .05; n = 172).60
Interpretation of these studies is limited by the absence of a placebo arm and also by concerns about the limited clinical efficacy of moclobemide at the dosages studied (see, for example, Lotufo-Neto and colleagues61). This work, nevertheless, provides some further support for the clinical impression that the SSRIs are more useful for treatment of patients with atypical depression than the TCAs.
The efficacy of fluoxetine was also demonstrated by McGrath and colleagues62 in their 20-week, double-blind, placebo-controlled study of atypical depression (N = 154), which used imipramine and placebo control groups. A significant advantage for both active groups compared with the placebo group was reported; however, no significant difference was found between the SSRI and TCA groups. Both active groups achieved comparable response rates (ie, 51% for fluoxetine and 53% for imipramine); fluoxetine had a better tolerability profile.62 Although both response rates are lower than the ones that have been reported for studies conducted by this group with phenelzine, they are still clinically significant and support the usefulness of SSRIs in the treatment of atypical depression.
Other treatment options
The irreversible MAOI selegiline, which is selective for monoamine oxidase B at low oral doses, and cognitive-behavioral therapy (CBT) both appear to be promising treatment options for patients with atypical depression. Initial studies of selegiline in atypical depression date back to 1984 and suggested a beneficial role with response rates of 59% at doses greater than 20 mg/d and up to 40 mg/d.63 Later, a placebo-controlled trial of selegiline (N = 98) also showed positive results, as evidenced by a response rate of 50% in the selegiline arm compared with 28% in the placebo arm.64 It is noteworthy that the doses of selegiline used in these studies were high enough to inhibit monoamine oxidase A. However, to date, no studies of atypical depression have been completed using the transdermal formulation of selegiline.
A 10-week, double-blind, placebo-controlled study found efficacy for CBT in the acute-phase treatment of atypical depression.65 A total of 108 subjects were randomly assigned to twice-weekly CBT, phenelzine, or placebo. A significant reduction in HAMD scores was reported with both active interventions. Response rates were 58% for both active modalities compared with 28% for placebo. There was no statistically significant difference between the active groups.65 CBT also fared relatively well in the subset of patients with atypical depression in secondary analyses of the NIMH Treatment of Depression Collaborative Research Program, which also studied interpersonal psychotherapy and clinical management with double-blind placebo or imipramine.66,67
Identification of atypical features is important in the treatment of depression for both treatment selection and prognosis, especially when initial measures prove ineffective. The concept of atypical depression has evolved over many years, and now it appears timely for a further revision. Our review of the current literature suggests a need for optimizing the precision and reliability of the current DSM criteria for atypical features. This could be achieved by the elimination of reactive mood as mandatory for diagnosis, by a more specific definition of criterion B features, and by the inclusion of chronicity and early age at onset as criteria.
Findings from the literature on the treatment of atypical depression show that phenelzine, and by implication the MAOIs as an antidepressant class, is the most effective pharmacological agent for atypical depression. Imipramine, and by implication the TCAs, is not as effective but still represents a treatment option for patients with atypical depression, particularly those with later onset of illness and less chronic courses. Given that neither MAOIs nor TCAs are widely prescribed now, other important treatment options include the SSRIs, notably fluoxetine and sertraline. Unfortunately, other antidepressants that may be useful in atypical depression, including bupropion and venlafaxine, have not been systematically studied. One form of depression-specific psychotherapy, CBT, has also been found to be efficacious and should be included in the treatment plan for atypical depression.
There is still a clear need for medication trials to better characterize the initial steps (before consideration of MAOIs or TCAs) in the treatment algorithm for atypical depression. Although historically ECT has been thought to be ineffective for atypical depression, recent reports suggest that it, too, may be effective in well-selected cases.68,69 The role of newer neuromodulation techniques, such as transcranial magnetic stimulation and, for patients with more advanced degrees of treatment resistance, vagus nerve stimulation and deep brain stimulation, still needs to be explored.
[Editor's Note: Originally presented as an independent educational activity under the direction of CME LLC, this article was published by Psychiatric Times (2011;28:42-47; click here for a pdf of the article and authors' financial disclosures). The ability to receive CME credits has expired. The article is presented here for your reference.]