1 Boring Old Man

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

by Ewgeni Jakubovski, M.A., Anjali L. Varigonda, M.D., Nicholas Freemantle, Ph.D., Matthew J. Taylor, Ph.D., Michael H. Bloch, M.D., M.S.

American Journal of Psychiatry. Published online: November 10, 2015.

Objective: Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors [SSRIs] in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.

Method: The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.

Results: Forty studies involving 10,039 participants were included. Longitudinal modeling [dose-by-time interaction=0.0007, 95% CI=0.0001–0.0013] and endpoint analysis [meta-regression: β=0.00053, 95% CI=0.00018–0.00088, z=2.98] demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects [meta-regression: β=0.00207, 95% CI=0.00071–0.00342, z=2.98] and decreased likelihood of all-cause dropout [meta-regression: β=–0.00093, 95% CI=–0.00165 to −0.00021, z=−2.54].

Conclusions: Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents [50 mg of fluoxetine] The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

This study uses some fancy statistical manipulation to conclude that higher doses of antidepressants might be a little more likely to be effective in treating depression. The psychiatric literature is filled with articles about schemes to get more mileage out of the antidepressant treatment. There was the pharmaceutical pipeline that regularly released a new molecule every couple of years. There were several different classes of drugs [TCAs, MAOIs, SSRIs, SNRIs, Buproprion]. We studied sequencing [STAR*D, TMAP], combining [CO-MED], and augmenting [thyroxin, Atypical Antipsychotics]. Here we have the suggestion to try a higher dose. The group a UT Southwestern [Rush, Trivedi] insisted that if we pushed the doses and treated to remission, we would up our odds back when they designed STAR*D, and Dr. Rush is still talking about it [Isn’t It About Time to Employ Measurement-Based Care in Practice? AJP October 2015]. So far, the notion that genetic testing would refine our prescribing remains just that – a notion. Along the way, we’ve had Vagus Nerve, Transcranial Magnetic, and Deep Brain Stimulators. One would think that with such a heavily studied toolkit literally dominating twenty-five years of our journal literature, offering so many combinations and permutations, we would’ve arrived in the promised land. The inconvenient truth is that we haven’t – we haven’t even come close.

Skeptics like me would say it’s because most depression arises in response to psychological, biographical, and social forces that don’t fit the current DSM model of Major Depressive Disorder – that instead of Treatment-Resistant-Depression, we’d be best advised to turn our attention back to Non-Biomedical-Responsive-Depression with a bigger toolkit than simply Cognitive Behavior Therapy – a direction strongly opposed by the Managed Care/Collaborative Care/Integrative Care models. But even Biomedical Devotees like Dr. Insel aren’t satisfied with the current state of play and he has prattled on endlessly about his disappointment with our lack of progress.

Another facet of this inconvenient truth is that the therapeutic zeal accompanying the attempts to expand the effectiveness of the medications has fueled an epidemic of iatragenic illness [illnesses caused by treatment] – overmedication, adverse effects, dysinhibition, violence, withdrawal syndromes, etc. Which brings me back to my starting place. After I saw that abstract suggesting higher antidepressant doses before I headed off to the clinic, I recall thinking about how much time I spend dealing with patients who have iatragenic illnesses from their medications or who show up seeking a change in their medications. I mentioned a mega-overmedicated case recently [blitzed…, some truths are self-evident…] and this man I saw later in the day [it just is what it is…], but that’s just the tip of an iceberg of how many such cases I see. We’re beginning to see Obamacare and Medicaid patients now in the clinic, and I think the local doctors and contract mental health center are beginning to send those cases my way [for me to try to get straightened out]. That obviously can’t go on forever, even at the moment it’s barely manageable. But the point is, the inconvenient truth for me is that I appear to be developing a sub-specialty I would never have imagined – medication untangler.

"Let’s take another look at your story. Maybe there’s something going on in you or your life that needs much more attention, something contributing to your depression that medication can’t possibly change."