Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression
Le-Ben Wan, Cara F. Levitch, Andrew M. Perez, Jess W. Brallier, Dan V. Iosifescu, Lee C. Chang, Alexandra L. Foulkes, Sanjay J. Mathew, Dennis S. Charney, James W. Murrough
The Journal of Clinical Psychiatry September 2, 2014 DOI: 10.4088/jcp.13m08852 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pooled analysis of three clinical trials Peer reviewed |
|---|---|
| Sample size | 97 |
| Population | Participants with DSM-IV-defined major depressive disorder and treatment-resistant depression |
| Intervention | Ketamine |
| Dose | 0.5 mg/kg over 40 minutes |
| Measures | Montgomery-Asberg Depression Rating Scale (MADRS) |
| Topics | Depression Ketamine Esketamine |
| Keywords | Tolerability Psychotomimetic Dissociative Adverse effect Anesthesia Antidepressant |
| Citations | 232 |
| Registration | NCT00419003 NCT00548964 NCT00768430 |
| Key findings | Intravenous ketamine was safe and well tolerated in patients with treatment-resistant depression, with a 67% antidepressant response rate and low rates of discontinuation and attrition. |
Abstract
Objective: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.
Method: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.
Results: The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information.
Conclusions: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted.
Trial Registration: ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.
Comparable studies
Other non-randomized and open-label trials on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder Subjects with DSM-IV-diagnosed treatment-resistant major depressive disorder | 2010 | Open-label trial | n = 33 |
| Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression Adults (≥ 18 years) with treatment-resistant depression | 2020 | Phase 3, open-label, multicenter, long-term study | n = 802 |
| Intravenous arketamine for treatment-resistant depression: open-label pilot study Humans with treatment-resistant depression | 2020 | Open-label pilot trial | n = 7 |
| A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide. Hospitalized patients with Major Depressive Disorder and acute suicidal ideation and... | 2024 | Open label study | n = 17 |
| Neural correlates of change in major depressive disorder anhedonia following open-label ketamine Medication-free treatment-refractory patients with major depressive disorder | 2015 | Open-label investigation with exploratory re-analysis |