Augmentation strategies for intravenous ketamine in treatment-resistant depression: A systematic review and meta-analysis

Treatment-resistant depression (TRD) affects 30–60% of individuals with major depressive disorder and carries substantial morbidity and healthcare costs. Intravenous (IV) ketamine (KET) is a rapid-acting antidepressant, but benefits are often transient, prompting augmentation to sustain efficacy or improve tolerability. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of IV KET augmentation in adults with TRD. MEDLINE, Embase, and PsycINFO were searched through October 29, 2025. Eligible studies compared KET plus augmentation with KET plus placebo/sham or active control. Seven RCTs (N = 346) met inclusion criteria. Strategies included glutathione, riluzole, lamotrigine, lithium, D-cycloserine and ketamine combined with psychotherapy (KCP) approaches involving cognitive behavioral therapy (CBT) and automated self-association training (ASAT). Across the included trials, IV KET was associated with antidepressant improvement, although augmentation strategies generally did not demonstrate additional benefit over their respective control conditions. Pharmacological augmentation strategies did not demonstrate additional benefit at primary endpoints. KCP approaches using CBT and ASAT yielded preliminary signals of improved maintenance of antidepressant effects, although each was evaluated in a single study. An exploratory random-effects meta-analysis of seven heterogeneous comparisons found no statistically significant overall difference in depressive symptoms between augmentation and control conditions (SMD = −0.12; 95% CI, −0.37 to 0.12; p = 0.323; I2 = 0.0%). No clear new safety signal emerged in the trials, although adverse-event reporting was heterogeneous across studies. Overall, low-certainty randomized evidence is insufficient to support routine augmentation of IV ketamine for TRD, highlighting the need for larger, rigorously designed trials to determine whether specific strategies can meaningfully extend ketamine's antidepressant effects.