Ketamine May Not Be a Remedy for Depression

A non-peer-reviewed study suggests that ketamine is no more effective than a placebo at treating major depressive disorder.

A triple-masked, randomized, placebo-controlled trial included 40 adult patients with major depressive disorder. One group received a single infusion of ketamine (0.5 mg/kg), while another received a placebo (saline) during anesthesia for routine surgery.

Before the infusion and on days one, two, and three after, the researchers used the Montgomery-Åsberg Depression Rating Scale (MADRS) — a diagnostic questionnaire — to measure the severity of depressive episodes. MADRS includes questions about sadness, inner tension, sleep, appetite, and the ability to concentrate, among others.

Average MADRS scores did not differ between ketamine and placebo groups before the infusion. Clinical response rates were also similar between groups on day one after the injection. These rates were comparable to previous studies of ketamine in depressed populations.

"A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder," the study authors conclude.

After the follow-up visits, the participants were asked to guess which intervention they received. Only 36.8% of participants guessed correctly, with similar proportions in both groups. This suggests that anesthesia successfully masked the drug’s dissociative effects and minimized subject-expectancy bias.

Ketamine is a dissociative anesthetic that makes patients feel disconnected and not in control and has some hallucinogenic effects. It is a Schedule III non-narcotic substance approved for short-term sedation and anesthesia. Ketamine is also abused as a recreational drug. Because it can induce sedation and amnesia, ketamine is often used to facilitate sexual assault.

In 2019, the FDA authorized Spravato (esketamine, the active form of ketamine) as a nasal spray for treatment-resistant depression (TRD). The drug can be prescribed to people who did not respond to at least two antidepressant treatments in the same episode.

A 2020 systematic review and meta-analysis concludes that intravenous ketamine injections appear promising in the short-term treatment of TRD, but more clinical and experimental data is needed on the efficacy, tolerance, and security of long-term administration of ketamine.

Although the study indicates that a single injection of ketamine is not superior to a placebo, its findings should be interpreted cautiously because the research is yet to be peer-reviewed.