International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators
Rebecca B Price, Nicholas Kissel, Andrew Baumeister, Rebecca Rohac, Mary L Woody, Elizabeth D. Ballard, Carlos A. Zarate, William Deakin, Chadi G. Abdallah, Adriana Feder, Dennis S. Charney, Michael F Grunebaum, J John Mann, Sanjay J. Mathew, Bronagh Gallagher, Declan M. Mcloughlin, James W. Murrough, Suresh Muthukumaraswamy, Rebecca McMillan, Rachael Sumner, George I. Papakostas, Maurizio Fava, Rebecca S. Hock, Jennifer L Phillips, Pierre Blier, Paulo R Shiroma, Peter Šóš, Tung-Ping Su, Mu-Hong Chen, Mikael Tiger, Johan Lundberg, Samuel T. Wilkinson, Meredith L Wallace
Molecular Psychiatry September 7, 2022 DOI: 10.1038/s41380-022-01757-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Individual patient-level data meta-analysis of randomized controlled trials Peer reviewed |
|---|---|
| Sample size | 809 |
| Population | Individuals with unipolar or bipolar depression or post-traumatic stress disorder enrolled in randomized controlled trials of intravenous ketamine |
| Intervention | Intravenous (IV) ketamine |
| Duration | Acute (~24 hours) and post-acute (~7 days) |
| Topics | Depression Esketamine Ketamine |
| Keywords | Depression treatment Ketamine therapy Mental health research Clinical trials |
| Citations | 80 |
| Key findings | Ketamine robustly reduces depressive symptoms across a heterogeneous patient population, with larger effects relative to placebo in those with greater prior treatment resistance, but no patient-level features could guide personalized treatment decisions. |
Abstract
Abstract Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β *(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; β *(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions. Review Registration: PROSPERO Identifier: CRD42021235630
Comparable studies
Other systematic reviews and meta-analyses on ketamine for depression, most cited first.