Q&A: Overcoming Challenges in the Treatment of Major Depressive Disorder

Course Director

Ian A. Cook, MD

Ian A. Cook, MD
David Geffen School of Medicine at UCLA
Semel Institute for Neuroscience and Human Behavior
UCLA Brain Research Institute
Los Angeles, California

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Part 2 of a 2-part series

Dr. Cook provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Despite the availability of several well-tested therapies for the treatment of major depressive disorder (MDD), only about 50% of patients show a clinical response (defined as a ≥50% reduction in intensity of depressive symptoms) with initial antidepressant therapy.1,2 For the many patients who do not respond adequately to initial antidepressant therapy, clinicians can resort to several strategies: dose maximization, switching to another antidepressant, or add-on therapy with other agents. In this activity, Dr. Ian A. Cook discusses strategies to improve outcomes in patients with MDD.


This activity is supported by an educational grant from Lilly USA, LLC.
Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Ian A. Cook, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Allergan, Inc.; Aspect Medical Systems, Inc./Covidien; and NeuroSigma, Inc.
Grant/Research Support from Aspect Medical Systems, Inc./Covidien and NeoSync.
Speakers Bureau participant with Neuronetics.
Shareholder in NeuroSigma, Inc.
Other Financial or Material Support from NeuroSigma, Inc. in the form of royalties/patents.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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How would you select the best augmentation strategy to improve partial response to current antidepressant therapy for a patient with major depressive disorder (MDD)?

Dr. Cook: There are many options available to convert a partial response to a more complete improvement. In the STAR*D study, augmentation was achieved by adding agents—including lithium and thyroid hormone and other psychotropics, such as bupropion and buspirone, and even the addition of cognitive behavioral therapy (CBT).3

Some atypical antipsychotic medications, such as aripiprazole, have received [US] FDA approval for use as an augmentation agent. Unfortunately, there is a dearth of head-to-head comparison data to really allow a data-driven choice among these options.

Narrator: In the few head-to-head studies that have compared different options, their efficacy has been generally comparable; therefore, it is reasonable to consider different sequences of the available drugs.4 For example, the remission rates were comparable in an eight-week randomized trial that compared paroxetine plus risperidone, paroxetine plus thyroid hormone, or paroxetine plus trazodone in 140 treatment-resistant patients.5 In the STAR*D trial, lithium augmentation was compared with thyroid hormone augmentation in patients who were not in remission after two rounds of pharmacotherapy, and efficacy was not statistically different between groups.6

Dr. Cook: So, selection is probably best made on an individual patient basis, balancing the benefits and side effects of each option to the context of a particular patient's symptom profile, their comorbid conditions, and the potential for drug-drug interactions.

Narrator: Drug-drug interactions between antidepressants and adjunctive medications such as second-generation antipsychotics, benzodiazepines, lithium, or triiodothyronine are generally not problematic. But combining an MAOI with another antidepressant—an SSRI, for example—can cause complications, including the serotonin syndrome or a hypertensive crisis.7

As examples of some other factors to consider, patients with a history of extrapyramidal side effects may wish to avoid aripiprazole, and overweight patients may wish to avoid quetiapine, risperidone, and olanzapine. Lithium is contraindicated in those with renal or thyroid disease, and the same generally goes for thyroid hormone in patients with compromised cardiovascular function. As another consideration— vis-à-vis patient burden—fewer lab tests and less monitoring may be needed with add-on therapy involving a second antidepressant than what is required with the addition of lithium or triiodothyronine.

Patients who are treated with an add-on drug and do not respond within six to twelve weeks of reaching the target dose—or do not tolerate the combination—should advance to treatment with a second medication combination.

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My patient is a 55-year-old female with MDD and comorbid anxiety (GAD, panic attacks) who has tried multiple SSRIs and SNRIs, with no response. What should be the next strategy?

Dr. Cook: This patient has both MDD and comorbid anxiety diagnoses, and we learned from the STAR*D trial that the presence of a comorbid anxiety diagnosis tended to attenuate the benefits of the interventions that were studied in that project.8 Treatment interventions clearly need to target both the anxiety and the depression symptoms, and selecting agents with data supporting FDA-approved indications for both of those conditions would be a reasonable choice.

In addition, the use of cognitive behavioral therapy has support [and] was mentioned in the CANMAT guidelines.9

Still, if these approaches have not yielded sufficient improvement, then off-label combinations are frequently used. Some research studies have suggested that, in addition to the use of benzodiazepines along with antidepressants, there may be benefits of anticonvulsant augmentation with agents such as pregabalin.10,11  

The CANMAT guidelines have [also] raised the consideration of neurostimulation,12 and of complementary and alternative medicine approaches.13 But they also note that the number and size of controlled clinical trials is not nearly as extensive as desired to make firm recommendations in an evidence-based practice model for these other kinds of interventions.

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I have many patients who have good responses to antidepressants, but have one SIGNIFICANT side effect (weight gain or sexual dysfunction). I am in a dilemma about what to do for them. Should I reduce the dose or switch to another agent (which may not be effective), or should I continue with the treatment knowing that the patient is quite unhappy about the side effect?

Dr. Cook: Here, I think the overarching concern is adherence to treatment. And of course, this should be a significant concern to all practitioners. Patients who have a significant side effect burden—and here, the side effect is in the eye of the beholder—these people appear to be at an elevated risk for not adhering to prescribed treatment; and sometimes without quite telling the prescribing physician that they're sufficiently unhappy with treatment side effects to discontinue treatment. Yet, that's what they sometimes do.

Here, building a close alliance with one's patient is an important part of this, and to help support this, we really should help our patients to understand the risk of return of symptoms if a treatment is discontinued prematurely, and then we work with them to get the right balance.

So in this particular situation, it's important to remember that a number of side effects may be proportional to dose, and so a trial of an incrementally lower dose with close monitoring is something that merits consideration. This is what I often do in my own practice.

On the other hand, some clinicians might consider adding an agent to target a side effect. But this so-called “antidote approach” has generally been researched without the head-to-head trials that would support a systematic approach for selecting among the different possible agents. And here, again, patients and physicians may then have to undertake a sequential set of trials of an antidote to identify a useful agent to address the side effects, much like the search for the initial clinically efficacious treatment.

I think the bottom line is that we don't have nearly as much data to help guide this in a regular, systematic way as we would like to, and customizing the treatment for each individual patient is probably still the best practice that we can offer to our patients. So when they have to decide—and you have to decide—about either reducing a dose or switching, or pressing onwards with a patient who's quite unhappy. Patients tend to vote with their feet, and I think it can't be ignored that a side-effect burden can be a significant reason for discontinuing a medication.

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  1. Rush AJ et al. Am J Psychiatry. 2006;163:1905-1917.
  2. Trivedi MH et al. Am J Psychiatry. 2006;163:28-40.
  3. Rush AJ. Depress Anxiety. 2011;28:521-524. doi:10.1002/da.20841.
  4. Rush AJ, Trivedi MH. Am J Psychiatry. 2006;163:1905-1917.
  5. Fang Y et al. J Clin Psychopharmacol. 2011;31:638-642.
  6. Nierenberg AA et al. Am J Psychiatry. 2006;163:1519-1530. doi:10.1176/appi.ajp.163.9.1519.
  7. Preskorn SH. J Psychiatr Pract. 2009;15:202-210.
  8. Fava M et al. Am J Psychiatry. 2008;165:342-351. doi:10.1176/appi.ajp.2007.06111868.
  9. Schaffer A et al. Ann Clin Psychiatry. 2012;24:6-22.
  10. Vitali M et al. J Clin Psychopharmacol. 2013;33:95-98. doi:10.1097/JCP.0b013e31827b9351.
  11. Rickels K et al. Int Clin Psychopharmacol. 2012;27:142-150. doi:10.1097/YIC.0b013e328350b133.
  12. Kennedy SH et al. J Affect Disord. 2009;117(Suppl 1):S44-S53. doi:10.1016/j.jad.2009.06.039.
  13. Ravindran AV et al. J Affect Disord. 2009;117(Suppl 1):S54-S64. doi:10.1016/j.jad.2009.06.040.

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This activity is supported by an educational grant from Lilly USA, LLC.
Additional support provided by Penn State College of Medicine and Answers in CME.

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Expert Insights on Managing Major Depressive Disorder: The Role of Novel and Emerging Strategies

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