By Zenobia Morrill

A team of researchers in Germany investigated the common clinical practice of increasing the antidepressant dose when patients do not respond to the initial treatment. The results of their systematic review of the literature, recently published in the Journal of Clinical Psychiatry,found no support for this practice.

“Despite its frequent use in clinical practice, we found no sufficient evidence for the efficacy of antidepressant dose increase after failure of an antidepressant treatment in patients with major depressive disorder,” the authors write.

Rates of nonresponse to antidepressant drugs are reported to occur in as many as 30-40% of patients. Current guidelines recommend “antidepressant switch, augmentation with a second-generation antipsychotic or lithium, a combination of antidepressants, and a dose increase of the initially prescribed antidepressant,” when initial treatment fails.

Current studies demonstrate that increasing the dose of the initially prescribed antidepressant is one of the most popular strategies. Yet, clinicians need evidenced-based recommendations. The current research regarding the decision to increase the dose is varied and inconclusive.

In response, Rink and colleagues conducted a systematic review of the literature and meta-analysis on the dose increase of antidepressants strategy when “antidepressant treatment failure” occurs. They included studies that met the following criteria: (1) RCTs with randomization of patients with “antidepressant treatment failure” to either a dose increase regimen or unchanged continuation, (2) patients diagnosed with unipolar depression, (3) standardized diagnosis of “antidepressant treatment failure.”

Their literature search results retrieved 1,780 articles after the removal of duplicates. Nine studies met the inclusion criteria and featured a total of 1,273 patients (635 women). About half of the participants (628) received dose increase when they experienced failure to respond to antidepressants.

In the analyses, the researchers examined the “efficacy of dose increase compared with continuation of initially prescribed dose of antidepressants, expressed as the standardized mean difference (SMD).” Additionally, they looked at the response, remission, and dropout rates, assessed publication bias, and conducted a post-hoc analysis that focused on different definitions of “antidepressant treatment failure.” Their results did not support the dose increase of SSRIs when patients are nonresponsive. The researchers write:

“This systematic literature review and meta-analysis yielded 2 main results, as follows. (1) There is no clinically or statistically significant effect of SSRI dose increase after failure in antidepressant pharmacotherapy. (2) Studies on dose increase of antidepressants other than SSRIs (and of citalopram) are needed.”

This research is particularly relevant in light of studies of adverse effects of antidepressants that are dose-dependent, such as hypertension, QT prolongation, sexual dysfunction, fracture risk, and liver injury. Additionally, high doses of SSRIs increase the risk of withdrawal symptoms. The researchers conclude:

“Clinically, and pending studies in children, with other antidepressants, and with longer initial treatment durations, we recommend not increasing the dose of antidepressants after initial treatment failure in antidepressant pharmacotherapy.”

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Rink, L., Braun, C., Bschor, T., Hennsler, J., Franklin, J., & Baethge, C. (2018). Dose Increase Versus Unchanged Continuation of Antidepressants After Initial Antidepressant Treatment Failure in Patients With Major Depressive Disorder: A Systematic Review and Meta-Analysis of Randomized, Double-Blind Trials. Journal of Clinical Psychiatry. (Link)