Journal of affective disordersOct 12, 2026

Ways to improve IV ketamine treatment in hard-to-treat depression: A review and combined analysis

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 13, 2026

Abstract

Seven randomized controlled trials involving 346 adults were analyzed to evaluate the effects of intravenous ketamine augmentation in treatment-resistant depression.

Intravenous ketamine was associated with improvement in depressive symptoms for individuals with treatment-resistant depression.
Augmentation strategies, including various pharmacological and therapeutic approaches, generally did not show additional benefit over placebo or control conditions.
Cognitive behavioral therapy and automated self-association training showed preliminary signals of improved maintenance of antidepressant effects, but were only evaluated in single studies.
An exploratory meta-analysis indicated no statistically significant difference in depressive symptoms between augmentation and control groups.
No new safety concerns were identified, although adverse-event reporting varied across the studies.
The evidence from these trials is low-certainty, suggesting a need for more comprehensive studies to assess the effectiveness of specific augmentation strategies.

Simplified

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.

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Ways to improve IV ketamine treatment in hard-to-treat depression: A review and combined analysis

Abstract

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