Michael E. Thase, MD

Dr. Thase is with the Department of Psychiatry, Perelman School of Medicine of the University of Pennsylvania and the Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104

Editor’s Note: We are pleased to present this brief summary, based on Dr Thase’s presentation, “Solving Clinical Challenges in Major Depression” at the 2017 Psychiatric Congress. That presentation focused on answering attendees' questions about challenging patients and on thorny clinical issues that arise during the case of depressed patients. A summary of key points of the Q&A follows.

A number of cases are presented that illustrate changes in diagnosis and practice ushered in following the publication of DSM-5 in 2013. The first describes a 60-year-old African American woman who was brought in for treatment by her adult children about 7 months after the death of her husband of more than 30 years. The patient had a history of 2 major depressive episodes (MDEs) and had responded to a trial of paroxetine some years ago, but stated “this [depressive episode] feels different-I don’t want to be medicated-why won’t my kids just let me alone to grieve?”

Of course, the relevant change in DSM-5 reflects the fact that it is neither justified nor helpful to try to differentiate grief from depression when the individual presents with a full depressive syndrome (a recurrent episode of MDD in this case). Specifically, studies have shown that depressive episodes of bereaved individuals are very similar to those experiencing other kinds of stressful life events.

In this case, what was helpful was to accept our patient’s sustained, unresolved grief as the primary initial focus of treatment utilizing interpersonal psychotherapy (IPT) as the first-line intervention. That said, clinical features that were not evident in this case that might have “pushed” the decision to recommend pharmacotherapy at the outset of the treatment episode include suicidality, psychosis, and disability/incapacity. Our challenging patient appreciated the chance to do grief work, although her depressive episode, which included fairly pervasive anhedonia, did not remit with IPT. She benefitted from the addition of escitalopram (final dose: 20 mg/d) and is now recovered, with the focus of IPT eventually shifting from grief to role transition.

Distinguishing between MDD and depressive episodes

Other cases highlighted our daily challenges distinguishing between “unipolar” depression (ie, MDD) and depressive episodes that more accurately are conceptualized falling with a spectrum of bipolarity. It is now clear that the actual incidence of bipolar II disorder is quite fluid based on the number of signs/symptoms and the duration of symptoms that are required as the threshold for diagnosis. For example, in the classic study of Angst and colleagues,

 the proportion of depressive episodes that met threshold for diagnosis for bipolar II varied more than 5-fold (ie, from as low as 2% to as high as 11%) based on the criteria. There are thus a lot of people-perhaps up to one-half of all those who seek treatment for MDD-who technically do not meet relatively strict criteria for bipolar II disorder who have a number of subthreshold features of the disorder.

Arguably the most intriguing change for the depressive disorders ushered in by DSM-5 was the addition of the “. . . with mixed features” specifier for MDEs, which can be applied to describe “unipolar” as well as bipolar depressive episodes. Defined by both negative (ie, does not meet criteria for hypomania) and positive (at least 3 symptoms of the other “pole” of illness) features, use of the mixed features specifier is hoped to help clinicians identify patients who are at greater risk to switch from MDD to bipolar disorder over time, as well as patients who may benefit from use of mood stabilizers-either alone or in combination with antidepressants.

Although DSM-5 criteria for the “with mixed features” specifier can be used verbatim to make the diagnosis, practice may be facilitated by the use of self-report scales for both diagnosis and monitoring of outcomes. In this regard, the scale by Zimmerman and colleagues

-CUDOS-M-appears to be “shelf-ready” and preliminary studies show sound psychometric characteristics. It does, however, remain to be seen if the routine screening for and monitoring of mixed features can reliably improve outcomes in everyday practice. Results of the first prospective study of treatment of MDD with mixed features, a placebo-controlled study of lurasidone 20 to 60 mg daily, showed that substantial clinical benefits could be achieved without the use of antidepressants.

With respect to pharmacotherapy of depressive disorders, there were several questions about differentiating the role(s) of the more recently introduced antidepressants from the generically available first-line therapies, as well as questions reflecting abiding concerns about the widespread use of second generation antipsychotics (SGAs) relatively early in treatment algorithms. I think it is fair to say that vilazodone and vortioxetine are not simply “me too” drugs and both offer some potentially unique properties compared with FDA-approved SSRIs.

This is also true for levomilnacipran, as its racemic ancestor (milnacipran) was not approved for treatment of depression in the US. However, their potential value as first-line medications is largely blocked by formulary pricing decisions that tend to place these medications in second, third, or even lower tiers.

No session on MDD is complete without a number of cases and a slew of questions about treatment-resistant depression. There is little uncertainty about the efficacy of SGAs when used as adjuncts to otherwise ineffective antidepressants: multiple positive placebo-controlled studies have established the efficacy of risperidone, aripiprazole, olanzapine, quetiapine, and brexpiprazole for this indication. However, real questions persist about cost-effectiveness and the best practices to mitigate risks of weight gain and other adverse metabolic effects and to help ensure patient safety during longer-term use of SGAs.

In my own practice, I tend to use adjunctive SGAs earlier in treatment only when there are high levels of symptom severity or clinical urgency. The results of a recently published study that compared therapies for veterans with treatment-resistant depression are generally consistent with this approach: adjunctive aripiprazole was only nominally more effective than adjunctive bupropion. The results were not statistically significant on most measures, and treatment with the SGA carried a significantly greater risk of weight gain.

 Vigilant monitoring of weight during SGA therapy and assertive intervention when patients continue to gain weight despite sound clinical management are essential strategies to keep the benefit to risk ratio on the favorable side.

For patients with more advanced degrees of treatment resistance, questions abound about the use-and potential limitations-of ketamine infusions. Ketamine is of course an “old” anesthetic drug that has long been known to have abuse liability because of its euphorigenic and dissociative properties.

As reported by a Task Force of the American psychiatric Association,

 there is ample evidence that an infusion of a sub-anesthetic dose of ketamine (typically 0.4-0.5 mg/kg infused over 40 minutes) can have rapid and dramatic effects for people who have not responded to multiple trials of standard antidepressants. Antidepressant effects generally persist for 4 to 7 days after a single infusion and typically are not linked to psychotomimetic or dissociative adverse effects. Response rates typically range from 40% to 60% after one week of therapy and preliminary results suggest that the benefits may be sustained by once or twice weekly infusions on an ongoing basis.

Such evidence has led to a brisk proliferation of clinics specializing in ketamine infusions.

 Nevertheless, there are many important questions to be answered about longer-term efficacy and safety of such extended courses of intravenous ketamine therapy.

 That said, the remarkably rapid efficacy of a treatment that does not directly target monoaminergic neurotransmission has had a revitalizing effect on drug development and it is possible that other medications with less “baggage” than ketamine will be identified that exert antidepressant effects via modulation of glutamatergic neurotransmission.

With respect to managing the adverse effects of our more and less commonly used treatments for depression, the large number of questions that were submitted suggest that there are many, many depressed patients who would benefit from having better-tolerated therapies, yet remarkably few controlled studies of potential remedies. Beyond weight gain, which is more strongly associated with use of adjunctive SGAs than antidepressant monotherapy, treatment-emergent sexual dysfunction is an endemic problem with the SSRIs and SNRIs.

My preferred approach to treatment-emergent sexual dysfunction is to switch to a potentially less “offensive” antidepressant, such as bupropion, mirtazapine, or vilazodone. This may not be a desirable strategy in some clinical scenarios, such as when a patient has only (finally) responded to a particular medication after a long list of drug failures. Nevertheless, there are no certain answers when one considers the various “antidotes” (eg, bupropion, buspirone, psychostimulants, or sildenafil and related drugs) that might be used as adjuncts to ongoing antidepressant therapy and sometimes simpler strategies, such as “23 hour drug holidays” on days that intercourse is anticipated and behavioral interventions drawn from sex therapy to vary or intensify the sexual experience, can lead to more gratifying results.

Asking about our patients’ sex lives from the outset of therapy is important to establish a baseline and the willingness to try to address a potentially “deal-breaking” adverse effect on an ongoing and iterative basis can do wonders to maintain a strong therapeutic alliance. For most patients, it is not necessary to trade a satisfying sex life for an effective antidepressant medication.

For patients who experience significant sexual dysfunction on multiple antidepressant medications the best course of treatment may be to avoid antidepressants entirely, emphasizing instead one of the time-limited models of psychotherapy that have been developed for and tested in patients with MDD. The final section of my presentation addresses questions pertaining to the “old favorite” depression-focused psychotherapies (eg, cognitive behavior therapy and interpersonal therapy) and more recently researched alternatives (eg, behavioral activation and short-term dynamic psychotherapy).

One potential public health advantage of behavioral activation is that it can be delivered in large group settings and does not require an advance level of psychotherapeutic expertise. Perhaps foremost among the behavioral activation strategies is aerobic exercise, which also has been shown to have antidepressant effects even when uncoupled from more comprehensive programs.

The number of interesting cases and scores of questions submitted to inform this year’s talk underscore the ongoing challenges that we face treating people suffering from MDD. Hopefully, this approach to continuing education helps to fill a void and, even more so, will be helpful for at least some of our most challenging patients.

1. Angst J, Gamma A, Benazzi F, et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. 

2. Stahl SM, Morrissette DA, Faedda G, et al. Guidelines for the recognition and management of mixed depression. 

3. Zimmerman M, Chelminski I, Young D, et al. A clinically useful self-report measure of the DSM-5 mixed features specifier of major depressive disorder. 

4. Suppes T, Silva R, Cucchiaro J, Mao Y, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo-controlled study. 

5. Thase ME. Adverse effects of second-generation antipsychotics as adjuncts to antidepressants: are the risks worth the benefits? 

6. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D Randomized Clinical Trial. 

7. Newport DJ, Carpenter LL, McDonald WM, et al, for the APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. 

8. Wilkinson ST, Toprak M, Turner MS, et al. A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. 

9. Sanacora G, Frye MA, McDonald W, et al, for the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A consensus statement on the use of ketamine in the treatment of mood disorders. 

10. Singh I, Morgan C, Curran V, et al. Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight. 

11. Chan AT, Sun GY, Tam WW, et al.The effectiveness of group-based behavioral activation in the treatment of depression: an updated meta-analysis of randomized controlled trial. 

12. Steinert C, Munder T, Rabung S, et al. Psychodynamic therapy: as efficacious as other empirically supported treatments? A meta-analysis testing equivalence of outcomes. 

13. Hearing CM, Chang WC, Szuhany KL, et al. Physical exercise for treatment of mood disorders: a critical review. 

Articles

Grief vs depression? MDD vs depressive episodes? SGAs in treatment-resistant depression? Treatment-emergent sexual dysfunction? Insights in this Q&A.

Solving Clinical Challenges in Major Depression

[Editor's Note: Originally presented as an independent educational activity under the direction of CME LLC, this article was published by 

). The ability to receive CME credits has expired. The article is presented here for informational purposes.]

The existence of different subtypes of depressive episodes (ie, endogenous and nonendogenous) was initially postulated at least 80 years ago.

 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.

 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.

 Endogenous depression manifested with neurovegetative symptoms and nonreactive mood and regularly responded to the tricyclic antidepressant (TCA) imipramine and/or 

 (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).

 Furthermore, those patients presented an unusual constellation of symptoms characterized by the absence of endogenous-type neurovegetative symptoms and the presence of emotional reactivity.

On the basis of these early observations, the existence of a unique subtype of nonendogenous depressive episodes characterized by mood reactivity with 

 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.

 Atypical depression was formally recognized in 1994, when it was included as an “episode specifier” in DSM-IV.

” 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.

, 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).

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).

 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.

 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 (

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.

 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.

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.

 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.

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.

 Estimates in both community and clinical settings suggest that 15.7% to 36.6% of patients with depression present with atypical features.

 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.

 The presence of atypical features is even higher (up to 50%) in patients with bipolar II disorder and dysthymic disorder.

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.

 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.

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.

 Pertinent sources of controversy include the following

• 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

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.

 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 

s or MAOIs has been challenged by a number of pharmacological studies.

 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.

 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.

 In a more recent analysis, Angst and colleagues

 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 

• 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)

The characteristic biological profile of atypical depression includes either normal or abnormally 

; a relatively normal polysomnographic sleep profile; increased frontal, temporal, and parietal perfusion; and abnormally increased right hemispheric processing when performing psychophysiological tasks.

 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.

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.

 These specific biological characteristics imply that atypical depression is in fact a distinct entity and, as such, requires a distinct treatment approach.

 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.

 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.

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 colleagues

 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, 

 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.

Similar findings were obtained by Quitkin and colleagues

 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 (

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).

 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.

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.

 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.

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, 

 years) and chronic atypical depression (ie, duration of at least 2 years with well periods of no longer than 2 months).

 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.

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.

 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 colleagues

 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 

 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.

 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.

 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.

 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.

 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 (

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 colleagues

). 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 colleagues

 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.

 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.

The irreversible MAOI selegiline, which is selective for monoamine oxidase B at low oral doses, and 

 (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.

 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.

 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.

 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.

 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.

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 

 has been thought to be ineffective for atypical depression, recent reports suggest that it, too, may be effective in well-selected cases.

 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.

 Gillespie RD. The clinical differentiation of types of depression. 

Kiloh LG, Garside RF. Depression: a multivariate study of Sir Aubrey Lewis’s data on melancholia. 

Thase ME. Atypical depression: useful concept, but it’s time to revise the DSM-IV criteria. 

 Thase ME. Recognition and diagnosis of atypical depression.

West ED, Dally PJ. Effect of iproniazid in depressive syndromes. 

Robinson DS, Nies A, Ravaris CL, Lamborn KR. The monoamine oxidase inhibitor, phenelzine, in the treatment of depressive-anxiety states. A controlled clinical trial. 

 Quitkin F, Rifkin A, Klein DF. Monoamine oxidase inhibitors. A review of antidepressant effectiveness. 

Davidson JR, Miller RD, Turnbull CD, Sullivan JL. Atypical depression. 

Quitkin FM, Stewart JW, McGrath PJ, et al. Phenelzine versus imipramine in the treatment of probable atypical depression: defining syndrome boundaries of selective MAOI responders. 

Diagnostic and Statistical Manual of Mental Disorders. 

4th ed. Washington, DC: American Psychiatric Association; 1994.


Nierenberg AA, Alpert JE, Pava J, et al. Course and treatment of atypical depression.

 Quitkin FM. Depression with atypical features: diagnostic validity, prevalence, and treatment. 

 McGrath PJ, Stewart JW, Harrison WM, et al. Predictive value of symptoms of atypical depression for differential drug treatment outcome. 

 Kendler KS, Eaves LJ, Walters EE, et al. The identification and validation of distinct depressive syndromes in a population-based sample of female twins. 

Sullivan PF, Kessler RC, Kendler KS. Latent class analysis of lifetime depressive symptoms in the national comorbidity survey. 

 Horwath E, Johnson J, Weissman MM, Hornig CD. The validity of major depression with atypical features based on a community study. 

 Levitan RD, Lesage A, Parikh SV, et al. Reversed neurovegetative symptoms of depression: a community study of Ontario.

Asnis GM, McGinn LK, Sanderson WC. Atypical depression: clinical aspects and noradrenergic function. 

Robertson HA, Lam RW, Stewart JN, et al. Atypical depressive symptoms and clusters in unipolar and bipolar depression. 

 Zisook S, Shuchter SR, Gallagher T, Sledge P. Atypical depression in an outpatient psychiatric population. 

 Angst J, Gamma A, Sellaro R, et al. Toward validation of atypical depression in the community: results of the Zurich cohort study.


 Novick JS, Stewart JW, Wisniewski SR, et al; STAR*D Investigators. Clinical and demographic features of atypical depression in outpatients with major depressive disorder: preliminary findings from STARD*D. 

. Benazzi F. Testing DSM-IV definition of atypical depression. 

Angst J, Gamma A, Benazzi F, et al. Atypical depressive syndromes in varying definitions.

Perugi G, Akiskal HS, Lattanzi L, et al. The high prevalence of “soft” bipolar (II) features in atypical depression. 

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.

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

There  are many rapidly effective treatments for mania in bipolar disorder but there  are relatively few and no rapidly effective treatments for bipolar depression,  even though bipolar depression constitutes what may be 20% to 50% of all  depressive disorders.

In this podcast, Dr Michael Thase of the Perelman  School of Medicine at the University of Pennsylvania discusses the first,  second, and third lines of treatment available for treatment of bipolar  depression.

Update on the Treatment of Bipolar Depression

Podcasts

There are many rapidly effective treatments for mania in bipolar disorder. However, there are relatively few options for bipolar depression, and none that are rapidly effective-even though bipolar depression constitutes between 20% to 50% of all depressive disorders.

Michael Thase, MD, of the University of Pennsylvania, Perelman School of Medicine, returns once again to the 

Annual Meeting of the American Psychiatric Association

. He and his colleagues will be presenting a course on cognitive behavior therapy for severe mental illness. The focus will be on newer applications of cognitive therapy for disorders such as schizophrenia and bipolar disorder.

He and his colleagues are also involved in a miniworkshop that will focus on computer-assisted applications of cognitive behavioral therapy that range from bibliotherapy to computer-assisted models of psychotherapy.

Dr Michael Thase touches on an APA presentation about newer applications of cognitive therapy for disorders such as schizophrenia and bipolar disorder. 

Podcast: Cognitive Behavior Therapy for Severe Mental Illness

As psychiatric practice moves increasingly to brief treatment sessions, fewer psychiatric office visits are being devoted to providing traditional-length psychotherapy.

 Yet, there are many reasons to consider using psychotherapeutic methods in the briefer sessions that dominate contemporary clinical practice.

 A primary reason is the lack of full symptom control from psychopharmacological treatment for a large number of patients.

There is evidence that the combination of medication and psychotherapy improves outcomes for many psychiatric illnesses, including depression, bipolar disorder, and schizophrenia. Among the several forms of psychotherapy that might be considered, cognitive-behavioral therapy (CBT) is the most extensively studied. A meta-analysis of combined treatment for depression has shown that using medication plus CBT has an advantage over monotherapy.

 Several trials have also shown superiority for adding CBT to antipsychotic medication for schizophrenia.

Other reasons for psychiatrists to use psychotherapy, even in relatively brief sessions, when they are also providing medication management, include:

• Findings that the majority of patients come to treatment with psychosocial issues and stresses that lead them to prefer psychotherapeutic interventions over a treatment plan that uses medication management alone

• The value of conceptualizing and treating psychiatric illnesses with a biopsychosocial treatment model

• Possible advantages, such as cost-effectiveness, of delivering pharmacotherapy and psychotherapy as an integrated method

• Evidence that psychotherapy can complement the effects of medication via biologically mediated mechanisms

Recognizing the importance of psychotherapy skills in psychiatric practice, the Accreditation Counsel for Graduate Medical Education psychiatry residency program requirements (

http://acgme.org/acWebsite/RRC_400/400_prIndex.asp

) mandate that residents must achieve competency in cognitive-behavioral, psychodynamic, and supportive therapy approaches. But what happens when residents enter practice and must face the reality of demands to treat patients in efficient ways that de-emphasize the use of longer psychotherapeutic interventions? And how can practicing psychiatrists respond to the challenge of incorporating psychotherapeutic methods into brief sessions when the primary focus may be on providing effective pharmacotherapy?

Surprisingly little has been written about specific methods for using psychotherapy in brief sessions. Our literature review found a limited number of citations that described the use of CBT in brief sessions.

Clearly more research is needed, but sufficient clinical experience has been accumulated to develop a guide for psychiatrists who wish to use CBT principles and techniques in their brief treatment sessions.

CBT is an ideal psychotherapy method to consider for use in brief sessions with pharmacotherapy because of the following:

• It is fully compatible with an integrated biopsychosocial treatment approach

• Many psychotherapeutic interventions can be delivered within a short time frame

• The structured techniques of CBT can help clinicians and patients make the best use of available time

• Psychoeducation is a central element of therapy

• The CBT skills that are taught in brief sessions can be practiced as self-help exercises during regular homework assignments

High-Yield Cognitive-Behavior Therapy for Brief Sessions: An Illustrated Guide,

17 includes video illustrations of a variety of CBT applications that last from about 5 to 15 minutes. Examples of methods that can be delivered in a short time frame are listed in 

To illustrate the use of CBT in brief sessions, the applications for 3 common psychiatric disorders are described below.


Exposure therapy in brief sessions along with an SSRI were used to treat a patient with obsessive-compulsive disorder (OCD) who had counting rituals. After the patient was educated about the CBT model for OCD, she agreed to a plan of setting targets for exposure therapy and carrying out the assignments between sessions. During 15 brief sessions that lasted about 20 minutes each, the psychiatrist checked for effects of the medication, reviewed the patient’s homework, assisted her with setting targets for progressing with exposure therapy, and helped her troubleshoot any problems with completing exposure tasks.

CHECKPOINTS 
? The majority of patients who come for treatment of psychosocial issues and stresses prefer psychotherapeutic interventions over a treatment plan that uses medication management alone.

? Although brief cognitive-behavioral therapy (CBT) sessions can provide a useful treatment alternative, longer sessions are recommended when patients have symptoms that require intensive psychotherapy, psychosocial problems that need to be addressed in 50-minute sessions, a desire to have intensive therapy in long sessions, or a failed response to combined brief CBT and medication.

There is evidence that the combination of medication and psychotherapy improves outcomes for many psychiatric illnesses. Among the several forms of psychotherapy that might be considered, cognitive-behavioral therapy (CBT) is the most extensively studied.

Michael E. Thase, MD

Articles

Solving Clinical Challenges in Major Depression

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

Update on the Treatment of Bipolar Depression

Podcast: Cognitive Behavior Therapy for Severe Mental Illness

Combining High-Yield CBT Methods and Pharmacotherapy in Brief Sessions

Book Review: Cognitive Behavioral Therapy for Clinicians

Small Effects Are Not Trivial From a Public Health Perspective