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Identifying individual response factors to antidepressants may help tailor MDD treatment

Patient response to antidepressants in major depressive disorder may be systematically associated with individual differences beyond placebo effects or statistical factors, according to results of a meta-analysis published in JAMA Psychiatry.

“The higher variability in response to antidepressants compared with placebo supports other data showing that the response to antidepressants goes beyond a generic ‘placebo effect’ and is impacted differences between patients that are yet to be determined,” Benoit H. Mulsant, MD, MS, FRCPC, of the Centre for Addiction and Mental Health at University of Toronto, told Healio Psychiatry.

According to Mulsant and colleagues, although many individuals experience depression remission because of psychiatric medications, more than 50% of patients see little improvement or worsened depression. The substantial variation observed in response to these medications has prompted attempts to personalize treatments to match antidepressants with the unique characteristics of individual patients and to identify moderators of treatment response.

To achieve these ends, the researchers collected data from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with MDD. They restricted analysis to double-blind, randomized, placebo-controlled trials with available data of the end point of the study. They derived coefficients of variation for antidepressants and placebo using validated methods, calculated ratios to compare outcome variability between the two, and then entered these ratios into a random-effects model. They repeated analysis after stratifying by antidepressant class, publication year and severity of depression.

Among 87 eligible trials with 17,540 unique participants, Mulsant and colleagues found significantly more variability in response to antidepressants than to placebo, with a coefficients of variation ratio of 1.14 (95% CI, 1.11-1.17). They noted that baseline severity of depression did not moderate variability in antidepressant response. Further, variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents, with a coefficients of variation ratio of 0.88 (95% CI, 0.8-0.97). More recent studies tended to have lower variability, with coefficients changing by a value of 0.005 (95% CI, 0.002-0.008) for every year a study was more recent.

“If we can identify the individual factors that affect response variability, we should be able to individualize antidepressant treatment (ie, by selecting a specific antidepressant for a specific patient, as opposed to the current ‘trial and error’ approach),” Mulsant said.

In a related editorial, Gerard Sanacora, MD, PhD, of the department of psychiatry at Yale University School of Medicine, highlighted the potential impact of these findings on future MDD research.

“While it is not surprising that the study would find evidence to support the idea that MDD is a heterogeneous disorder, it is nice to see actual evidence presented in this format,” Sanacora wrote. “Hopefully, it will help inspire the continued search for meaningful genotypes, endophenotypes and clinical subtypes that can one day lead to a more rational and personalized approach to the treatment of MDD.” – by Joe Gramigna

Disclosures: Mulsant reports research support from Brain Canada, the Canada Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute, the NIH, Capital Solution Design LLC and HAPPYneuron, as well as owning stock in General Electric and additional research support from Eli Lilly and Pfizer. Please see the study for all other authors’ relevant financial disclosures. Sanacora reports consulting fees from numerous pharmaceutical companies, free medication provided by Sanofi Aventis for an NIH-sponsored study, shares held in BioHaven Pharmaceuticals Holding Company and having been a coinventor on a patent with royalties paid by Yale University Office of Cooperative Research.