Comparative Benefits and Harms of Antidepressant, Psychological, Complementary, and Exercise Treatments for Major Depression

In a systematic review done by Gartlehner and colleagues, benefits and safety of second-generation antidepressants were compared with psychological, complementary and alternative medicine (CAM) and exercise treatments as first and second-step interventions in adults with acute major depressive disorder (MDD). They searched many data sources like MEDLINE and the Cochrane Library from 1990 to September 2015 for patients who were treated with second-generation antidepressants, psychological interventions, CAM interventions, exercise, or a combination of any of these treatments. Overall, they found that there was no significant differences in the efficacy of second-generation antidepressants and other types of treatments as first-step treatments. Also, second-generation antidepressants in general had higher risk of adverse events compared to the other interventions. The intervention with the strongest evidence was cognitive behavioral therapy (CBT).

I found the results of this systematic review to be very interesting because I would not have guessed that the effectiveness of CBT would be comparable to that of antidepressant medications. I feel that both interventions are very valid in treating acute MDD, and that choosing between the two will be choosing which risks are most manageable. Seeing how CBT can be effective, I wonder how other interventions, like exercise, will compare. These options may seem a lot more appealing to patients as they would not have to use a medication to treat their condition. I hope that in the future more studies will take a closer look at comparing the efficacy and safety of antidepressants and other non-medication based therapies.

Ann Intern Med. 2016;164:331-341.

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial

The association has been that Major Depressive Disorder dysregulates the natural opioid system in our bodies. This study was conducted by administering a combination opioid to test the effect it had on depression symptoms. The combination opioid used was buprenorphine/samidorphan sublingual tablets, and the outcomes were determined by measurements of the Hamilton Depression Rating Scale, the Montgomery-Åsberg Depression Rating Scale, and the Clinical Global Impressions severity score against a placebo.

The study was a randomized, double blind, two stage, placebo controlled comparison study which compared two doses of buprenorphine/samidorphan (2mg/2mg and 8mg/8mg) to a placebo. The total study looked at 142 patients over the course of two stages. The results showed that the 2mg/2mg dose gave statistically significant improvement of depression while the 8mg/8mg dose showed improvement, but it did not reach statistical significance. All of the groups had no changes in vital signs including low suicidal ideation.

These results showed that using the combination opioid can help treat people with Major Depressive Disorder who do not respond to SSRIs or SNRIs. Given the major side effects of these classes of medications, the opioid combination may even be preferred to SSRI or SNRI treatment. Of course, when dealing with opioids the risk of addiction is high. I wonder how these results will effect the prescribing of opioids, especially in the indication of Major Depressive Disorder. Considering the side effects and risk of increased suicidal ideation, I wonder if opioids may become the new gold standard in the treatment of Major Depressive Disorder.

AJP. 2016;173:1-10.

Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

Selective serotonin reuptake inhibitors are generally accepted as a class of drugs that should be prescribed to those with major depressive disorder, especially in the most severe cases. There is really not much debate about this fact, however, there is still question and uncertainty about how to dose these medications. The APA guidelines today call for optimizing the dose as long as the side effects can be tolerated because it has been shown that the there is a flat dose-response curve within the therapeutic range for antidepressant medications in major depressive disorder. The authors of this meta-analysis believe that this statement may be flawed for two reasons. One, the data that supports this statement includes all antidepressants not just SSRIs, and the researchers from the previous meta-analysis that produced this guideline looked at dose as a categorical outcome instead of continuous which could have reduced their power to determine what the dose-response relationship is really like. This meta-analysis set out to determine whether higher doses of SSRIs really improved outcomes or not.

The authors of this paper only included very specific studies to ensure that they came to the most accurate conclusion. The inclusion criteria were data for both SSRI and placebo treated patients and used standardized, validated outcome measurements for depression. The exclusion criteria included patients less than 19 or older than 60, use of a cross-over design, dual diagnoses, non-SSRIs, not randomized, not placebo-controlled, and psychotherapy was given to either the control or active group. In the end, the team of authors concluded that SSRIs show a significant increase in efficacy when higher doses were administered. The analysis also found that the higher doses are associated with reduced tolerability because more people dropped out of the trials due to side effects at high doses of SSRIs. These results differed from the previous meta-analysis, showing that the dose response curve did not level-off until the very end of the dosing range. This new finding could possibly affect how doctors prescribe SSRIs because there could be evidence to indicate prescribing higher doses than the minimum therapeutic range could be more effective for patients but also more harmful.


Jakubovski E, Varigonda AL, Freemantie N, et al. Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder. Am J Psychiatry. 2016; 173: 174-83.


After reading this article, it makes me wonder how physicians in charge of treating a patient’s major depressive disorder would react. Would more physicians start their patients off at a dose in the middle of the dose response curve, or would they start off higher? If they started in the middle and their patient did not see any improvement, would they feel more comfortable increasing the dose or would the potential side effects still keep them from doing this?

Cognitive Based Therapy versus Pharmacologic Treatment of Adult Patients with Major Depressive Disorder. A Clinical Guideline

Major depressive disorder (MDD) is characterized by a depressed mood, loss of pleasure and interest, significant changes in weight or appetite, trouble sleeping or sleeping too much, fatigue and loss of energy, inability to concentrate, feelings of worthlessness, or thoughts of death or suicide that last for at least two weeks and affect the normal functioning of the individual. Major depression disorder effects 16% of American people and the healthcare costs surrounding it totaled around 83.1 billion dollars in the year 2000, and is probably higher today. Various treatment options exist for MDD, including cognitive behavior therapy such as psychotherapy, exercise, alternative medicine, and pharmacotherapy. This study sought to create a clinical guideline that compared the effectiveness and safety of nonpharmacologic treatments, such as cognitive behavioral therapy (CBT) and pharmacotherapy, alone and in combination for the treatment of MDD. The American College of Physicians recommends that the clinician select between either cognitive behavior therapy or second-generation antidepressants to treat individuals diagnosed with MDD. Using them in combination did not prove to be more effective in the treatment of MDD.

Question: As a pharmacist, how do you feel about individuals that forgo prescription medication and choose to go an alternative route such as cognitive behavior therapy. Do you think pharmacist should be able to recognize when prescription medication is unneeded and when behavior therapy would work better for the patient, or should that be up to the MD to recognize?


Qaseem A, Barry MJ, Kansagara D. Nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. Epub ahead of print 9 February 2016.