A recent systematic review and network meta-analysis published in the Journal of Affective Disorders compared the efficacy, tolerability, and acceptability of four augmentative treatments for treatment-resistant depression (TRD): intravenous racemic ketamine, intranasal esketamine, aripiprazole, and lithium.

The study included 22 randomized controlled trials focusing on acute antidepressant effects as the primary outcome. The participants were aged 18-65 years, and had TRD. The study defined TRD as “MDD diagnosed using standard diagnostic criteria with no improvement after using one or more antidepressants at a sufficient dose for a sufficient period of time”.

The primary outcome measure was response rate, defined as the proportion of participants who achieved a specified reduction in depression scale scores. Secondary endpoints included discontinuation rates, which assessed treatment tolerability (due to adverse events only) and acceptability (for any reason). Treatment effects across outcomes were quantified using odds ratios. For the primary outcome analysis, response was evaluated sequentially based on the Montgomery-Åsberg Depression Rating Scale score first, followed by the Hamilton Rating Scale for Depression score if the first measure did not show statistically significant differences, and finally the Beck Depression Inventory score.

Key findings:

All four augmentation treatments were more effective than placebo in improving depression symptoms.

Intravenous racemic ketamine was significantly more effective than intranasal esketamine and aripiprazole. There was no significant difference in efficacy between racemic ketamine and lithium.

Racemic ketamine and lithium were similarly tolerated as placebo, whereas esketamine and aripiprazole had significantly higher drop-out rates due to side effects compared to placebo.

Racemic ketamine was significantly more acceptable, with lower overall discontinuation rates, than esketamine, aripiprazole, and placebo.

The authors conclude that intravenous racemic ketamine may be superior to esketamine and aripiprazole as an augmentative treatment for TRD given its better efficacy, tolerability, and acceptability in this analysis. However, they note some limitations around small sample sizes and conceptual heterogeneity between trials. More robust head-to-head comparisons are still needed to clarify the place of ketamine among established augmentation strategies for difficult-to-treat depression.

Reference:
Terao I et al. Journal of Affective Disorders. 2024;346:49-56. Abstract.