Atypical Depression in the 21st Century: Diagnostic and Treatment Issues

The existence of different subtypes of depressive episodes (ie, endogenous and nonendogenous) was initially postulated at least 80 years ago.^1,2 In the early formulations, the term “endogenous depression” was used to describe a more severe biologically mediated illness, whereas “nonendogenous depression” or “exogenous depression” referred to a less severe and environmentally mediated condition characterized by mood reactivity.³ It was not until the introduction of the first monoamine oxidase inhibitor (MAOI)—iproniazid—that the term “atypical depression” began to emerge to describe a particular variant of nonendogenous depression.

Originally, endogenous, or melancholic, depression was thought to be the prototypical form of depression.⁴ Endogenous depression manifested with neurovegetative symptoms and nonreactive mood and regularly responded to the tricyclic antidepressant (TCA) imipramine(Drug information on imipramine) and/or electroconvulsive therapy (ECT). A different subgroup of patients was found to be responsive to iproniazid (the first commercially available MAOI, but currently off the market because of significant toxicity) and nonresponsive to well-established treatments for depression (ie, imipramine and ECT).⁵ Furthermore, those patients presented an unusual constellation of symptoms characterized by the absence of endogenous-type neurovegetative symptoms and the presence of emotional reactivity.⁴

On the basis of these early observations, the existence of a unique subtype of nonendogenous depressive episodes characterized by mood reactivity with reversed neurovegetative symptoms (ie, hypersomnia and hyperphagia) and a predictable response to certain antidepressants was proposed and termed “atypical depression.” The hypothesis that such depressions were relatively nonresponsive to TCAs and more responsive to MAOIs was further supported by studies in the 1970s and 1980s.^6-9 Atypical depression was formally recognized in 1994, when it was included as an “episode specifier” in DSM-IV.¹⁰

DIAGNOSIS

The DSM-IV specifier “with atypical features” can be used to characterize the current or most recent depressive episode in patients with either unipolar or bipolar type mood disorder and in patients with dysthymic disorder.¹⁰ As described in the Table, the DSM-IV specifier requires the presence of mood reactivity (criterion A) and at least 2 of 4 criterion B features (significant weight gain or hyperphagia, hypersomnia, leaden paralysis, and interpersonal rejection sensitivity resulting in social or occupational impairment). If the patient meets criteria for either melancholic or catatonic features during the same major depressive episode, a diagnosis of atypical depression cannot be made (criterion C).¹⁰

To avoid overdiagnosis or underdiagnosis, bear in mind definitional aspects of the clinical features that constitute the criteria for atypical depression. Mood reactivity means that clinically depressed patients have the capacity to feel at least 50% better and even become transiently euthymic when exposed to positive events (eg, an invitation for a date, a compliment).^10,11 Although never studied in a rigorous prospective manner, it has been reported that patients with atypical depression can remain euthymic for extended periods if the external circumstances remain positive.¹⁰ With respect to hyperphagia, a clear and sustained increase in appetite or a 5-lb weight gain during the depressive episode would satisfy criterion B1 (see Table).^10,12

Table

DSM-IV criteria for atypical depression features specifier

Hypersomnia refers to either a total of at least 10 hours of sleep per day, including nighttime sleep and daytime naps, or at least 2 hours more than when not depressed.¹⁰ Leaden paralysis is defined as a sensation of heaviness in the arms or legs as if they were made of lead; it is generally present for at least an hour a day but can last for many hours at a time.^10,11

Interpersonal rejection sensitivity in the context of atypical depression implies a lifelong trait (during both periods of depression and periods of euthymia) that is typically exacerbated during depressive episodes. It is characterized by an excessive or pathological sensitivity to rejection and/or criticism leading to functional impairment (eg, stormy relationships, inability to sustain long-term relationships, problems at work, avoidance of relationships because of fear of rejection, avoidance and fear of embarrassment) or maladaptive behavioral responses such as substance abuse.^3,10,11 Rejection sensitivity seems to be the most common clinical feature in atypical depression, as demonstrated by a study of 332 patients, of whom 71% reported rejection sensitivity, 47% hyperphagia, 47% leaden paralysis, and 35% oversleeping.¹³

PREVALENCE, COURSE, AND COMORBIDITY

Although the term “atypical” implies an unusual or uncommon condition, depression with atypical features is in fact a common clinical presentation and is one of the most common forms of depression in outpatient settings.¹¹ Estimates in both community and clinical settings suggest that 15.7% to 36.6% of patients with depression present with atypical features.^14-21 This estimate is in harmony with the 18% prevalence of atypical depression detected in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study series and with the 42% prevalence in a sample of 396 patients with depression.^11,22 The presence of atypical features is even higher (up to 50%) in patients with bipolar II disorder and dysthymic disorder.^8,23-25

Studies have suggested that patients with atypical depression tend to have an earlier onset of symptoms and a more chronic course than their melancholic counterparts.^24,26,27 Atypical depression is more common in younger women. Also, rates of comorbid conditions, such as anxiety, cluster B and C personality disorders, substance abuse, and somatization disorder, seem to be higher in patients with atypical depression than in those with other forms of depression.^{16,17,21,25,27-29}

Validity of atypical depression and its DSM-IV criteria

Although atypical depression appears to be clinically and diagnostically well characterized, the DSM-IV criteria for diagnosing atypical depression and its validity as a subtype of depression have been questioned recently.^3,4 Pertinent sources of controversy include the following^3,4,22,28,30:

• The inconsistency between reactive mood and the presence or absence of criterion B features
• Both the sex bias and the definition of rejection sensitivity
• The exclusion of state-dependent anxiety

Reactive mood

The validity of mood reactivity as a mandatory feature for diagnosing atypical depression has been challenged. Findings from 4 studies showed that mood reactivity does not significantly correlate with the presence of criterion B features, which suggests that mood reactivity should not be considered an obligatory feature for the diagnosis of atypical depression.^22,28,30,31 Furthermore, regarding melancholia (which requires the loss of mood reactivity) as exclusionary of the diagnosis of atypical depression subtype makes the presence of reactive mood largely redundant. The inclusion of mood reactivity as an essential feature also neglects the fact that some depressive episodes, when quite severe, manifest with a nonreactive mood, even in the presence of reversed neurovegetative symptoms. The term “anergic depression” is sometimes used to describe depressive episodes that take this form.

One established characteristic of atypical depression is its differential response to MAOIs. The correlation between the presence or absence of reactive mood and a differential response to either TCAs or MAOIs has been challenged by a number of pharmacological studies.^29,32-38 Findings from those studies suggest that the effectiveness of MAOIs in depression is not necessarily associated with mood reactivity, implying that the presence of this specific feature may not be essential for diagnosing this syndrome.

The hypothesis that reactive mood as a mandatory criterion is not indispensable for the diagnosis of atypical depression was supported by the community study by Angst and colleagues.²¹ Although mood reactivity was the most common symptom reported by their sample of patients with atypical depression (89% to 90%), other symptoms (ie, rejection sensitivity, leaden paralysis, and hypersomnia) were also quite commonly present (78% to 89%). This suggests that atypical depression could also be effectively diagnosed when mood reactivity is not considered a mandatory criterion.²¹ In a more recent analysis, Angst and colleagues²⁴ reported that diagnosis of atypical depression could be made with equal validity if 3 of 5 criteria (including mood reactivity) or 2 of 4 criteria (excluding mood reactivity) were used.

Clearly, the inclusion of mood reactivity as a mandatory or hierarchical criterion for the diagnosis of atypical depression should be reassessed. This could be done using the available literature or, ideally, through more specific studies (ie, compare subjects with 2 or more criterion B symptoms and reactive mood with subjects with 2 or more criterion B symptoms without reactive mood).

Biological features of atypical depression

Evidence for the validity of atypical depression as a distinct subtype of depression includes distinct biological correlates, such as the following:

• Abnormalities of hypothalamic-pituitary-adrenal (HPA) axis activity
• Polysomnographic findings
• Asymmetry of hemispheric processing on psychophysiological testing
• Distinct regional cerebral blood flow patterns on single photon emission CT (SPECT)