Higher-Dose SSRIs for Major Depression May Improve Response

Nancy A. Melville

February 18, 2016

Increased dosing of selective serotonin reuptake inhibitors (SSRI) is associated with modest improvement of major depressive disorder (MDD). However, the benefits are offset at the highest doses by reduced tolerability, according to a new meta-analysis.

"Our results suggest it would be worthwhile to try higher doses in patient who tolerate lower doses well," first author Ewgeni Jakubovski told Medscape Medical News.

The study was published in the February issue of the American Journal of Psychiatry.

Optimal Dosing Unclear

Only about 60% of patients respond to SSRIs, said Jakubovski, yet optimal dosing for the drugs remains unclear, and clinicians are often reluctant to try higher doses because of concerns about poor tolerability.

To investigate, the researchers evaluated 40 randomized, placebo-controlled trials that examined the efficacy of SSRIs in MDD. The studies included 10,039 participants.

The SSRIs used in the studies included fluoxetine (multiple brands), fluvoxamine (Luvox, Jazz Pharmaceuticals, Inc), paroxetine (multiple brands), sertraline (Zoloft, Pfizer Inc), citalopram (multiple brands), and escitalopram (Lexapro, Forest Laboratories, Inc).

The researchers found a small but statistically significant relationship between SSRI dose and efficacy using longitudinal modeling (P = .019) and an endpoint analysis (P = .002).

The higher doses (200 mg to 250 mg) showed improvement over lower doses (100 mg to 200 mg range), with odds ratios of approximately 1.3 and numbers needed to treat in the 14 to 16 range, the authors report.

"This benefit appears to plateau at approximately 250 mg of imipramine equivalents (50 mg of fluoxetine)," they write.

Dropouts due to side effects were higher with higher doses of SSRIs (P = .002), although the higher doses were also associated with a lower rate of all-cause dropouts (P = .011).

Although the findings are consistent with a previous meta-analysis, which also showed reduced tolerability at higher doses, the new analysis differs by finding a flattening of the improved efficacy only at the higher end of the recommended dosing range (>250-mg imipramine equivalents).

The authors note several likely explanations for the differences, including the fact that the new analysis was restricted to SSRI trials and did not include trials of other antidepressants that may have different dose-response and dose-tolerability curves.

In addition, symptom improvement was evaluated as a continuous measure rather than with respect to whether clinical improvement was achieved or not as a primary outcome.

"This decision likely increased power of the meta-analysis by increasing sensitivity of the primary outcome measure and reducing heterogeneity by eliminating differences in definition of therapeutic response," the authors write.

The analysis included some trials that were published after the previous analysis, adding power to the new findings.

Although the SSRIs paroxetine and escitalopram showed some small benefit over the other SSRIs, Jakubovski noted that the nature of the data prevented identifying benefits of any drugs over the others.

"We did not choose to single out any particular SSRI because there was not too much of a difference [between drugs], and we did not want to convey the message that [the effects] were only true for selected antidepressants," said Jakubovski, who is currently with Hannover Medical School MHH, in Germany. He was a postgraduate research associate at the Child Study Center at Yale University, New Haven, Connecticut, at the time of the study.

Likewise, the study did not have data as to which patients may be the best candidates for dose escalation.

"We don't say that most patients should be put on particularly high doses of SSRIs, but we believe that this is a viable strategy to see if a patient could possibly benefit more from the current medication," Jakubovski said.

"This being said, it is very important to keep an eye on side effects. The dose increase should always be accompanied by a close monitoring for potential side effects and should only be considered if the side effects are minimal or manageable."

Need for Biomarkers?

In an accompanying editorial, Madhukar H. Trivedi, MD, of the Department of Psychiatry/Mood Disorders at the University of Texas Southwestern Medical Center, in Dallas, said the results underscore how group findings in studies may hide individual responses.

"The results point to the likelihood of important individual differences that are masked by group effects in traditional efficacy trials," Dr Trivedi writes. "[The] results may also argue for a need to assess specific biomarkers to carefully identify those who are likely to need higher doses to achieve the best benefit with the least side-effect burden."

In looking at the big picture of antidepressants and long-term benefits, however, the magic number for benefits appears to be in the 200-mg range, as was described in a 20-year longitudinal study published in the American Journal of Psychiatry in 2003, said Peter D. Kramer, MD, professor of psychiatry at Brown University, in Providence, Rhode Island.

"For all antidepressants, in serious, long-term usage, it looks as if only doses equivalent to 200 mg of imipramine offer real treatment or protection," he told Medscape Medical News.

Low doses have been shown to benefit many patients, "but in the longer term, and especially for more severe and chronic, recurrent depression, either higher doses or combination treatment, [which is] many psychiatrists' choice, may be more protective," Dr Kramer said.

He added that a key reason for continued debate on the issue is that research into dosing effects is often clouded by patient samples that do not accurately reflect real-world populations.

"Overview research is tainted by the low quality of many industry-sponsored studies. We might be able to discern effects at lower doses if the patient samples were more reliable, if enrollment recruited more representative patient groups," Dr Kramer said.

"That is to say, the apparent superior efficacy of higher doses may result from the difficulty created by the 'noise' from 'baseline score inflation' — the distortions created by poor diagnosis at the start of trials — so that only the 'big guns show through."

The authors have disclosed no relevant financial relationships. Dr Kramer is the author of the book, Ordinarily Well, which scheduled to be published in June by Farrar, Straus and Giroux. Dr Trivedi has a number of relationships with industry, which are listed with his editorial.

Am J Psychiatry. 2016;173:174-183. Abstract, Editorial

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