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

Objective: To evaluate the efficacy and tolerability of dose increase compared to dose continuation of the initially prescribed antidepressant in antidepressant treatment failure (ATF).

Data Sources: We searched CENTRAL, PubMed, Embase, and PsycINFO using generic terms for depression, dose increase, and randomized controlled trials (RCTs), without date or language restrictions.

Study Selection: Of 1,780 studies screened, 9 studies reporting on 1,273 patients were included for meta-analysis (PROSPERO Registration: CRD42017058389). Studies met the following predetermined inclusion criteria: randomized controlled trial, patients diagnosed with unipolar depression according to a standardized diagnostic instrument, ATF after a standard antidepressant trial (duration of ≥ 3 weeks at a standard dose), dose increase regimen, and control group of dose continuation.

Data Extraction: Two authors extracted data independently according to the Cochrane Handbook for Systematic Reviews. Analyses are based on random effects models.

Results: All studies reported on selective serotonin reuptake inhibitors (SSRIs); 1 study also reported on maprotiline. Meta-analyses resulted in a statistically nonsignificant summary effect size of 0.053 standardized mean difference (95% CI, −0.143 to 0.248) in favor of antidepressant dose increase. Subgroup and sensitivity analyses and secondary outcome analyses resulted in similar effect estimates and supported the robustness of the results.

Conclusions: With clinically and statistically nonsignificant effect estimates, there is evidence from RCTs against increasing the dose of SSRIs (with the possible exception of citalopram) in adult patients with major depression and ATF. Dose increase with other antidepressants (eg, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors) and in other patient groups (minor depression, children and adolescents) or after long periods of first-line antidepressant therapy (ie, 8 weeks) have not been or not been sufficiently studied and, at this time, cannot be recommended in clinical practice.