Solving Clinical Challenges in Major Depression

September 18, 2017

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


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.


Is it grief or depression?

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,1 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.2

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 colleagues3-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.4

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.

Treatment-resistant depression

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.5

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.6 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,7 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.8 Nevertheless, there are many important questions to be answered about longer-term efficacy and safety of such extended courses of intravenous ketamine therapy.9,10 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.

Managing adverse effects

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).11,12

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.13


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. J Affect Disord. 2003;73:133-146.

2. Stahl SM, Morrissette DA, Faedda G, et al. Guidelines for the recognition and management of mixed depression. CNS Spectr. 2017;22:203-219.

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. J Affect Disord. 2014;168:357-362.

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. Am J Psychiatry. 2016;173:400-407.

5. Thase ME. Adverse effects of second-generation antipsychotics as adjuncts to antidepressants: are the risks worth the benefits? Psychiatr Clin North Am. 2016;39:477-486.

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. JAMA. 2017;318:132-145.

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. Am J Psychiatry. 2015;172:950-966.

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. Am J Psychiatry. 2017;174:695-696.

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. JAMA Psychiatry. 2017;74:399-405.

10. Singh I, Morgan C, Curran V, et al. Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight. Lancet Psychiatry. 2017;4:419-426.

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. J Affect Disord. 2017;208:345-354.

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. Am J Psychiatry. May 25, 2017; Epub ahead of print.

13. Hearing CM, Chang WC, Szuhany KL, et al. Physical exercise for treatment of mood disorders: a critical review. Curr Behav Neurosci Rep. 2016;3:350-359.