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CATEGORY
SPONSORED BY CME LLC • PSYCHIATRIC TIMES • JANUARY 2011
Atypical Depression in the 21st Century:
Diagnostic and Treatment Issues
by Mario A. Cristancho, MD,
John P. O’Reardon, MD,
and Michael E. Thase, MD
he 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 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 wellestablished treatments for depression (ie, imipramine and ECT).5 Furthermore, those patients
presented an unusual constellation of symptoms
characterized by the absence of endogenoustype neurovege­tative symptoms and the pres-
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accordance with the Essential Areas and Policies of the
RELEASE DATE: January 20, 2011
This activity has been independently reviewed for balance.
T
EXPIRATION DATE: January 20, 2012
TARGET AUDIENCE
FACULTY
This continuing medical education activity is intended for
Mario A. Cristancho, MD
psychiatrists, psychologists, primary care physicians,
Research Associate–Psychiatry Resident
nurse practitioners, and other health care professionals
John P. O’Reardon, MD, Associate Professor of Psychiatry
who seek to improve their care for patients with mental
Michael E. Thase, MD, Professor of Psychiatry
Department of Psychiatry, University of Pennsylvania
Philadelphia
health disorders.
GOAL STATEMENT
This activity will provide participants with education on the
unique characteristics and treatment needs associated with
FACULTY DISCLOSURES
atypical depression.
Dr Cristancho reports that he has no conflicts of interest
concerning the subject matter of this article.
ESTIMATED TIME TO COMPLETE
The activity in its entirety should take approximately 90
Dr O’Reardon reports that he is a member of Lilly’s speaker
bureau and receives research support from Medtronic.
Dr Thase reports that during the past 2 years he has been a
consultant or advisory board member for Adolar, Astra­
Zeneca, Bristol-Myers Squibb Company, Dey Pharma, Eli
Lilly and Company, Forest Laboratories, GlaxoSmithKline,
Janssen (Johnson and Johnson), MedAvante, Inc, Merck (for­
merly Schering-Plough), Neuronetics, Novartis, Otsuka, Pam­
Lab, Pfizer (formerly Wyeth Pharmaceuticals), Shire US,
Supernus Pharmaceuticals, Takeda, and Transcept Pharma­
ceuticals; he has received grant support from Eli Lilly and
Company, Forest, GlaxoSmithKline, National Institute of
Mental Health, and Otsuka; he is or has been a member of
the speakers’ bureaus of AstraZeneca, Bristol-Myers Squibb
Company, Eli Lilly and Company, Merck, and Pfizer (Wyeth);
he has equity holding in MedAvante, Inc; he received royal­
minutes to complete.
LEARNING OBJECTIVES
After completing this activity, participants should be able to:
• Identify the unique symptomatology of atypical depression
• Identify the importance of accurately diagnosing atypical
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The opinions and recommendations expressed by faculty
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depression
mary references or full prescribing information resources.
• Understand treatment options for atypical depression
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JANUARY 2011
ence 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
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,
CATEGORY 1
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 pre­
sent 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 following3,4,22,28,30:
• 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.
PSYCHIATRIC TIMES
43
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-pituitaryadrenal (HPA) axis activity
• Polysomnographic findings
• Asymmetry of hemispheric processing on
psychophysiological testing
• Distinct regional cerebral blood flow patterns
on single photon emission CT (SPECT)
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).
(Please see Atypical Depression, page 44)
44
PSYCHIATRIC TIMES
Atypical Depression
Continued from page 43
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.
TREATMENT
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
MAOIs
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—over TCAs. For example, Liebowitz and
colleagues54 randomized 119 patients with atypical depression to phenelzine, 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,
Table
CATEGORY 1
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 transdermal
delivery system), only the label for phenelzine
includes a clear indication for atypical features.
SSRIs
Although MAOIs are clearly effective in patients
with atypical depression, they are not considered
DSM-IV criteria for atypical depression features specifier
A. Mood reactivity (ie, mood brightens in response to actual or potential positive events)
B. Two or more of the following features:
1. Significant weight gain or increase in appetite
2. Hypersomnia
3. Leaden paralysis (ie, heavy, leaden feeling in arms or legs)
4. Long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance)
that results in significant social or occupational impairment
C. Criteria are not met for “with melancholic features” or “with catatonic features” during the same episode
Note: The “with atypical features” specifier can be applied when these features predominate during the most recent 2 weeks of a current major
depressive episode in major depressive disorder or in bipolar I or bipolar II disorder when a current major depressive episode is the most recent
type of mood episode, or when these features predominate during the most recent 2 years of dysthymic disorder. If the major depressive episode
is not current, it applies if the feature predominates during any 2-week period.
Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994.10
JANUARY 2011
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/nonTCA 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 (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)
versus the reversible MAOI drug 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 20week, 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.
JANUARY 2011
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
CONCLUSIONS
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 depressionspecific psychotherapy, CBT, has also been found
to be efficacious and should be included in the
treatment plan for atypical depression.
CATEGORY 1
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.
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Category 1 Posttest
1. Atypical depression is a unique subtype of depression
characterized by which of the following:
A. Relative unresponsiveness to monoamine oxidase
inhibitors
4. What estimated percentage of patients in clinical and
community settings have atypical depression?
A. 1.3% to 5.7%
8. On the basis of the available evidence, it is widely
accepted that the most effective treatment option for
atypical depression is a:
B. 15.7% to 36.6%
A. Serotonin reuptake inhibitor
B. Good response to treatment with tricyclic antidepressants
C. 68.3% to 84.6%
B. Monoamine oxidase inhibitor
C. Mood reactivity with reversed neurovegetative symptoms
D. None of the above
C. Tricyclic antidepressant
D. All of the above
E. None of the above
D. Course of electroconvulsive therapy
5. Atypical depression is often associated with an earlier onset
of symptoms and a chronic course.
9. On the basis of the available evidence and considering
2. To make a diagnosis of atypical depression, the
A. True
the risk-benefit profile of uncomplicated cases, which of
DSM-IV requires mood reactivity as well as an
B. False
the following represents a good initial treatment for atypical
depression?
additional 2 of 4 criteria be met.
A. True
6. Patients with atypical depression seem to have higher rates
A. Serotonin reuptake inhibitor
B. False
of comorbid conditions, including anxiety, cluster B and C
B. Monoamine oxidase inhibitor
personality disorders, substance abuse, and somatization
C. Tricyclic antidepressant
disorders.
D. Course of electroconvulsive therapy
3. Criterion B features of atypical depression include:
A. Significant weight gain or hyperphagia
A. True
B. Hypersomnia
B. False
10. Cognitive-behavioral therapy has been found to be effective
in treating atypical depression.
C. Leaden paralysis
D. Rejection sensitivity
E. All of the above
7. Mood reactivity is unanimously accepted as a clear indicator
of atypical depression.
A. True
B. False
A. True
B. False
A11001011