Ketamine may have transient, robust antidepressant and anti-suicidal properties, but evidence remains limited, according to a systematic review published in BJPsych Open.
Researchers searched for systemic reviews and meta-analyses of the clinical effect of ketamine, esketamine, or arketamine in treating mental health disorders in Medline and PsycINFO on October 21, 2020. Studies that focused on modeling schizophrenia and psychosis symptoms, the action or predictors of treatment response, ketamine metabolites, ketamine treatment for general health, use of ketamine as an analgesic or anesthetic agent, and treatment of problematic ketamine use were excluded.
They identified 83 reports, including 33 systematic reviews (17 with meta-analyses), 29 randomized controlled trials, 2 randomized trials without placebo, 3 non-randomized trials with controls, 6 open-label trials, and 10 retrospective reviews.
Systematic reviews regarding unipolar depression, major depressive disorder (MDD), and bipolar disorder suggested ketamine had a rapid, and short-lived effect. Case studies, open-label trials, and retrospective reviews indicated nonintravenous administration of ketamine is effective for bipolar disorder.
Systematic reviews and meta-analyses found that ketamine was associated with moderate-to-large decrease in suicidal ideation (Cohen’s d = 0.51-0.85) within 4 hours of treatment, for a few days. Individuals with remission of suicidal ideation within 24 hours of treatment tended to experience a treatment effect for up to 1 week. Adjusting for change in depression did not significantly reduce ketamine effect.
Ketamine with electroconvulsive therapy was beneficial for treatment-resistant depression but not for treatment of depressive symptoms in MDD or bipolar disorder.
In patients with social anxiety disorder or generalized anxiety disorder, ketamine showed some a reduction in symptoms. It showed benefits at 4 hours and 7 days for treatment-resistant obsessive compulsive disorder.
Open-label trials of ketamine indicated the treatment was associated with decrease of posttraumatic stress disorder and depression symptoms.
A trial regarding ketamine-assisted psychotherapy for heroin use disorders showed an association between high dose (2 mg/kg) and reduced cravings. Paired with mindfulness-based relapse prevention therapy, a 0.5 mg/kg dose of ketamine contributed better, compared with midazolam (0.025 mg/kg), to abstinence from cocaine use.
The most frequently reported adverse effects of ketamine were mild increases in blood pressure that returned to baseline within, at most, 2 hours. Other symptoms included tachycardia, bradycardia, intermittent atrial fibrillation, single salve ventricular extrasystoles, transient and dose-dependent dissociative and psychotomimetic effects, dysphoria, treatment-emergent suicidal ideation, transient mania and hypomania, increased anxiety, and mild sedation.
Most studies tended to have a substantial risk of bias. Researchers said concerns included selection bias, deviations from intended interventions, and missing data. Systematic reviews often lacked reference to registered review protocol and risk-of-bias analysis.
Limitations of the study included high risk of bias among the majority of studies and the heterogeneity of studies.
“There is also much still to determine regarding synergistic effects with psychological therapy and to better specify therapeutic modalities,” the researchers noted.
“Research on optimal dose, route and frequency of administration that foregrounds accessibility and equity will also be paramount to reduce barriers to access among the lower income and marginalized communities that are disproportionately affected by the conditions for which this promising treatment may be effective. In sum, despite important unknowns regarding means of prolonging effects and risk over time associated with long-term repeated use, interest in the psychiatric applications of ketamine has accelerated dramatically over the past decade. This [interest] is warranted given ketamine’s broad spectrum of potential applications in psychiatric treatment, with limited adverse effects.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Walsh Z, Mollaahmetoglu OM, Rootman J, et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsychOpen.8(1), E19. doi:10.1192/bjo.2021.1061