Atypical Depression

Abstract

The authors conducted Pubmed searches to examine the epidemiological characteristics, symptoms, association with bipolar disorder, personality and temperament features, biology, and pharmacotherapy response of atypical depression and significance of current knowledge about this subtype of depression in treatment planning. Atypical depression has a high prevalence rate, starts early in life, tends to last longer, is more likely to occur in people with bipolar disorder, has high comorbidity of anxiety disorders, carries more risk of suicidal behavior, and has distinct personality psychopathology and biological traits. Atypical depression is an important specifier with significance in terms of predicting clinical course of depression, and hence in treatment planning and service use.

Introduction

Several attempts have been made to categorize subtypes of depression that would predict response to antidepressant treatment.¹ Atypical depression as a separate diagnosis was introduced primarily because medication trials clearly showed such patients responded better to monoamine oxidase inhibitors (MAOIs) compared to tricyclic antidepressants (TCAs).^2–5

The publication of the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition in 1994 heralded the introduction of the term atypical depression in clinical psychiatry. West and Daley in 1959⁶ had initially used this term based on the unique symptom profile of reversed vegetative symptoms and hysterical personality traits in certain depressed patients.

Criteria for atypical depression. Atypical feature as a specifier can be applied to major depressive episodes, bipolar disorder when a major depressive episode is the most recent mood episode, or when atypical features predominate during the most recent two years of dysthymic disorder.

According to the DSM-IV, symptoms of depression with atypical features include the following:

1. Mood reactivity (i.e., mood brightens in response to positive events)

2. Two or more of the following features, present for most of the time, for at least two weeks:

   1. Increased appetite

   2. Increased sleep

   3. Leaden paralysis (i.e., heavy, leaden feelings in arms or legs)

   4. Interpersonal rejection sensitivity (not limited to episodes of mood disturbance) resulting in significant social or occupational impairment

3. Criteria are not met for melancholic or catatonic features of depression.

The introduction of SSRIs as antidepressants initially resulted in decrease of the interest in criteria of atypical depression, mainly because SSRIs were thought to be equally or more effective for symptoms of both atypical and nonatypical depression.⁸ But even now, very few studies, if any, have proved superior efficacy of SSRIs over MAOIs in atypical depression.⁹

Another reason for the rebirth of interest in the criteria of atypical depression is based on the observation that this specifier has significance that goes beyond different response to antidepressants.

The aim of this article is to examine the epidemiological characteristics, symptoms, association with bipolar disorder, personality and temperament features, biology, and medication response of atypical depression. We also will use current knowledge to examine the significance of this specifier with regard to management and treatment planning of depression.

Methods

MEDLINE and PsycINFO searches of literature were performed to examine the significance of atypical depression as a specifier of depression. Search terms included atypical depression and depression with atypical features.

Epidemiology

Atypical depression is the most common form of depression seen in outpatient clinics in psychiatry.⁹ The prevalence of atypical depression based on DSM-IV criteria among samples of subjects with major depressive disorder or dysthymia has been reported to be around 40 percent.^10–12 Most of the studies have shown the prevalence of atypical depression to be around four times more common in female patients.^10,13,14

Research has also supported the early age of onset of symptoms in patients with atypical depression compared to nonatypical depression. Onset of depressive symptoms in teenagers or patients in their early 20s is more likely to be in the form of atypical depression rather than nonatypical depression.^13,15,16

Symptoms of Atypical Depression

As per DSM-IV, diagnosis of atypical depression requires mood reactivity (ability to feel better temporarily in response to positive life event) plus at least two of following: Hyperphagia (gained at least 5 pounds [2kg] or reports of clear appetite increase during the current depressive illness), hypersomnia (sleep 10 hours per day or two or more hours a day than usual), leaden paralysis (feels as if limbs are weighed down or a constant fatigue), and long-standing pattern of rejection sensitivity (patient frequently has excessive response to rejection, which results in social and/or occupational impairment).

Significantly, depression with atypical feature is a chronic disorder with many subjects describing onset in childhood or adolescences^13,15,16 and indicating that they have felt this way all of their lives. Posternak and Zimmerman¹⁷ analyzed the individual symptoms of atypical depression and found the severity and chronicity of atypical depression was positively associated with specific symptoms of leaden paralysis and rejection sensitivity (Table 1).

Table 1.

Major differentiating symptoms of atypical and melancholic (part of non atypical) depression

Symptom	Atypical	Melancholic (nonatypical)
Mood reactivity	Mood reactivity present (brightens in response to positive events)	Lack of mood reactivity even temporarily, when something good happens
Weight/appetite	Significant weight gain or increase in appetite	Significant anorexia or weight loss
Sleep	Excessive sleep all through the day	Decreased sleep with early morning awakening
Psychomotor activity	Leaden paralysis (heavy feeling in arms, legs)	Psychomotor retardation or agitation
Personality/thinking	Interpersonal rejection sensitivity not limited to mood episodes	Excessive or inappropriate guilt during mood episodes
Diurnal variation	Depression likely worse in evening (not part of diagnostic criteria)	Depression regularly worse in morning

Demographic and clinical correlates have been found to differ with each of the symptoms of atypical depression. This is thought to occur because atypical depression can be part of different types of mood disorders, such as bipolar disorder, unipolar depression, or dysthymia, with comorbid conditions further influencing the presence of particular symptoms.^4,10,18

Association with Bipolar II Disorder

Atypical depression and bipolar depression, especially when the latter is bipolar disorder type II, seem to be closely associated. Many studies have found atypical depression as a common part of bipolar disorder^19–24 with some reporting it to be the case in two-thirds of the cases,^10,24,25 though some of these studies included even “soft bipolarity,” i.e., antidepressant-induced hypomania, history of <4 days of hypomania (instead of 4 days minimum specified in DSM IV)^10,24,25 as episodes of hypomania. Atypical depression with early onset (younger than age 20) has been found to be more likely associated with bipolar disorder.^.26 Genetic vulnerability to bipolar illness is supported by the presence of more positive family history of bipolar disorder in patients with atypical depression than nonatypical depression.^4,27,28

Longer duration of illness, frequent episodes, common occurrence of symptoms of leaden paralysis, and hypersomnia are some of the other features shared by people with atypical depression and those with bipolar depression.¹¹

Comorbidity and Course of Illness

Among all subtypes of depression, atypical depression seems to carry most psychiatric Axis 1 comorbidity.^{27,29,30–32} That is why individuals with atypical depression have been reported to suffer more functional impairment, exhibiting much more interpersonal sensitivity, chronic dysphoria, “double depression,” and episodes of affective instability compared to subjects with no atypical depression.^30,33,34 Benazzi¹⁰ compared the comorbidity in samples of patients with atypical (n=121) and nonatypical (n=133) depression and found the following ratios: panic disorder/agoraphobia (53.7% vs. 46.6%), obsessive-compulsive disorder (10.7% vs. 9.7%), generalized anxiety disorder (9.9% vs. 5.2%), bulimia nervosa (10.7%vs. 1.5%), and social phobia (8.2% vs. 4.5%). Angst, et al.,¹⁴ came to a similar conclusion, i.e., more comorbid nonaffective disorders in subjects with atypical (n=59) compared to nonatypical (n=52) depression as follows: panic disorder (17% vs. 8%), all phobias (37% vs. 22%), generalized anxiety (35% vs. 29%), binge eating (27% vs. 10%), social phobia (25% vs. 10%), and drug abuse and dependence (19% vs. 12%). One of the striking findings from this study was the overwhelming association of the ICD-10 diagnosis of neurasthenia (54% vs. 14%) with atypical depression. It has been acknowledged for a long time that there is a relationship between chronic fatigue syndrome and neurasthenia with depression,^35,36 but this was the first time the association was linked to a particular subtype of depression. Social phobia as comorbid diagnosis with atypical depression was also found in studies performed by Agosti and Stewart (20%),³³ Alpert, et al. (26%),³⁷ and Perugi, et al. (15%).¹⁸ Angst et al.,¹⁴ compared the suicide attempts in subjects with atypical depression versus nonatypical variants. The results showed 34.6 percent of the patients attempted suicide from the atypical group compared to 20.3 percent from the nonatypical depression group. Similar findings were reported by the national comorbidity survey²⁷ with more suicidal thoughts and attempts, greater disability and restricted activity days, history of more childhood neglect and abuse, and co-occurring psychiatric illness in the subjects with atypical depression.

Personality and Temperament

Atypical depression is a unique variant of depression that has the personality trait, rejection sensitivity, as part of its diagnostic criteria. DSM-IV requires rejection sensitivity to be present prior to the current depressive episode. Liebowitz and Klien³⁸ thought that personality traits formed the core symptom for atypical depression. Recent literature has associated histrionic, borderline, and avoidant personality disorders with atypical depression.^20,39,37,40 Posternak and Zimmerman⁴⁰ suggested that the overlap between personality disorders and atypical depression could be an artifact of shared criteria in the diagnoses (Table 2).

Table 2.

Shared criteria (DSM-IV) for atypical depression and avoidant personality disorder

Atypical Depression	Avoidant Personality Disorder
Long-standing pattern of interpersonal rejection sensitivity (not limited to mood disorder episodes) resulting in significant functional impairment	Avoidance of activities that involve significant interpersonal contact because of fears of criticism and rejection

Chopre, et al.,⁴¹ used a dimensional approach to clarify the association. Results from this study showed high neuroticism, impulsivity, anger, hostility, and low deliberation as traits common to both atypical depression and cluster B and C personality disorders.

Atypical depression has also been associated with distinct temperament. Cloninger, et al.,⁴² found interesting temperamental differences in subjects with atypical depression. This study reported specific temperament traits in people with atypical depression, which included the tendency to anticipate failure, rumination with high anticipatory worry, difficulty getting over humiliation and embarrassment, giving up easily in frustration, extreme sensitivity to criticism, underachievement (low persistence), and tendency to discuss feelings and experiences (high attachment).

Biological Aspects

Atypical depression as a biologically distinct subtype of depression has been suggested by its superior response to MAOIs compared to TCAs and from cerebral laterality, as well from genetic and neuroendocrine studies.⁴³ Atypical depression has been shown to be associated with exaggerated negative feedback regulation of HPA axis.^44–46 Though nonatypical cases of depression have also been found to be associated with malfunction of hypothalamic pituitary adrenal (HPA) axis, corticotrophin releasing factor (CRF) levels are high rather than low as in subjects with atypical depression.^47,48 Bruder, et al.,⁴⁹ reported that patients with atypical depression showed right hemisphere dominance for perceiving chimeric faces. This finding was reported to be unrelated to the subject's gender or any comorbidity and is opposite to left-sided cerebral laterality seen in nonatypical depression.⁴⁹

Genetic predisposition has been found to be different in atypical depression with more family members having chronic atypical depression (many times part of bipolar disorder), less having nonatypical depression, and a comparatively higher concordance in monozygotic twin pairs.^50,51

Pharmacotherapy Response

Patients with atypical depression have been shown to have less or no response to TCAs and better response to MAOIs (Table 3).^2–5,52

Table 3.

Atypical depression patient response to medication

Study	No. of Subjects	Positive Response	Limitations
Lonnqvist, et al.53 (meclobemide vs fluoxetine)	n=52	67% with meclobemide and 55% with fluoxetine	Columbia14 criteria,* small sample
Pande, et al.8 (fluoxetine vs phenelzine)	n=42	80–85% with both	Columbia criteria, small sample
Sogaard, et al.54 (meclobemide vs sertraline)	n=197	77% with sertraline and 67% with moclebemide	Columbia criteria
McGrath, et al.3 (fluoxetine vs imipramine)	n=154	Around 55% in fluoxetine and imipramine	Columbia criteria
McGrath, et al.56 (gepirone)	n=60	62%	Columbia criteria, small sample
Roose, et al.58 (venlafaxine)	n=17	65–70%	Small sample, mean age 65 yr, open trial
Docherty, et al.55 (chromium picolinate)	n=113	65%	Subjects mostly obese, main effect on appetite

^*Columbia criteria require mood reactivity and one of the following symptoms: Increased appetite, hypersomnia, leaden paralysis or rejection sensitivity (unlike DSM- IV which requires mood reactivity and two of four symptoms).

After their introduction, SSRIs, because of their better efficacy and tolerance and serotonergically mediated effects on mood and appetite, were considered potentially better alternatives then the TCAs or MAOIs. But in 1994, Lonnquist, et al.,⁵³ found meclobemide (an MAOI not available in the US) more effective than fluoxetine (SSRI) in atypical depression, though later, in 1996, Pande, et al.,⁸ found fluoxetine equally effective to phenelzine, an MAOI, in atypical depression. Further, Sogaard, et al.,⁵⁴ in 1999 found meclobemide less effective than sertraline (SSRI). Another study compared fluoxetine, imipramine, and placebo in atypical depression and found fluoxetine and imipramine similarly effective and both superior to placebo.³ One large pharmaceutical study that compared sertraline and imipramine in atypical depression was never published, raising doubts about the results.¹⁶

The influence of serotonin in atypical depression has been seen with the positive therapeutic effects of chromium picolinate (5HT2A downregulation), especially on carbohydrate craving and appetite regulation⁵⁵ and, in some cases, with the use of gepirone⁵⁶ (5HTIA agonist, not available in US). With other newer antidepressants, Rye, et al.,⁵⁷ have reported a single case of late onset atypical depression responsive to bupropion. An open trial of venlafaxine (n=17) in late life atypical depression has also yielded positive results.⁵⁸ Unfortunately, few trials have compared efficacy of MAOIs with SSRIs or other newer antidepressants, and most of the ones performed (Table 3) had either small patient samples and high risk of significant Type 2 error or used Columbia criteria (not DSM-IV) for atypical depression.^9,14

Discussion

The term atypical is usually associated with something rare. But atypical depression, though unique in its presentation, is certainly not rare in depressive disorders. Current literature supports atypical depression as a subtype of depression with high prevalence, early onset in life, and tendency to persist longer. Early onset of atypical depression might explain the reason TCAs have been relatively ineffective in children.⁵⁹

Patients of atypical depression with chronic course, pattern of long-standing rejection sensitivity, and the always present fatigue can easily end up with primary diagnosis of personality disorder or simply neurosis. This can have profound adverse effects if it results in denial of a trial of antidepressants, which have been found to be very effective.¹²

The chief complaint of fatigue as part of the symptom of leaden paralysis in people with atypical depression can also result in misdiagnosis of chronic fatigue syndrome. That is why patients with no physical signs and symptoms (like tender lymph nodes, sore throat) but with history of long-standing fatigue should be carefully screened for presence of atypical depression.

Atypical depression might not be the absolute marker of bipolar depression. But it does call for using more comprehensive screening tools to rule out bipolar illness. It can help with early diagnosis and prevent prolonged suffering of patients with bipolar disorder who are initially misdiagnosed. In a recent survey, the National Depressive and Manic Depressive Association found 69 percent of patients with bipolar disorder were initially misdiagnosed, with more than one third of cases remaining misdiagnosed for more than 10 years.⁶⁰

It has been acknowledged that patients with atypical depression have shown good response to antidepressants.¹² Though there do not appear to be any large-scale studies that endorse the use of SSRIs over MAOIs as first-line treatment of atypical depression, the potential for serious adverse effects with MAOIs (hypertensive crisis) makes SSRIs an attractive and relatively safe option. But patients unresponsive to SSRIs or other second generation antidepressants should be provided the option of treatment with MAOIs. Unfortunately, the utility of MAOI in this subtype of depression continues to be not as widely accepted as it should be.

To conclude, it is imperative that the symptoms of atypical depression be recognized so that appropriate treatment can be initiated and patient suffering minimized.