A team of scientists from Taiwan and the United States have uncovered the first evidence that ketamine has dose-related antidepressant effects. The researchers also found evidence that the drug is effective in a Chinese population.

Ketamine, which is used in both human and veterinary medicine as an anesthetic, is increasingly being used off-label to treat severe and treatment-resistant depression.

“There were several reasons why this study, led by Dr. Tom Su, was important,” explained study co-author John H. Krystal, the chairman of the Department of Psychiatry at Yale University School of Medicine and chief of psychiatry at Yale-New Haven Hospital.

“Firstly, it was the first study of ketamine to evaluate the dose-related effects of ketamine. Ketamine has been predominantly tested at a single dose (0.5 mg/kg iv over 40 minutes). This study was the first to compare saline placebo and 0.2 mg/kg to 0.5 mg/kg.”

“Secondly, it was the first study conducted in an Asian population where the patients were genotyped,” Krystal said. “This genotyping confirmed the expectation that the less functional variant (Met Allele) of the gene coding for brain-derived neurotrophic factor (BDNF) was the predominant allele in this population, the opposite pattern seen in people of European descent.”

“BDNF is thought to be a critical mediator of the antidepressant effects of ketamine and so we wished to see whether ketamine would still be effective in this population.

“Thirdly, although all of the patients had treatment-resistant symptoms despite prior and current episodes of treatment, they varied in the severity of their symptoms,” Krystal added. “We wondered whether symptom severity was related to treatment efficacy.”

The double-blind placebo-controlled study of 71 patients confirmed the rapid antidepressant effects of ketamine. The findings were published in the journal Neuropsychopharmacology.

“Ketamine was effective in the Taiwanese population even though they predominantly had at least one copy of the less functional allele of the Val/Met allele of BDNF,” Krystal told PsyPost.

The findings from the study also indicated that lower doses of ketamine are ineffective. The dose of 0.2 mg/kg was not significantly better than placebo.

“The dose of ketamine is very important: only the highest dose was effective. This validates the most commonly used dose,” Krystal said.

The researchers also found that the antidepressant effects of ketamine were moderated by the severity of depression.

“Ketamine was more effective than placebo in patients with moderate-to-severe symptoms, but not in patients with mild symptoms,” Krystal noted. “This suggests that ketamine may be helpful for most patients with treatment-resistant symptoms, but it is not for everyone.”

But the study still leaves some important questions unanswered.

“We cannot conclude on the basis of this study whether the BDNF gene variants modify ketamine response, since the Met allele was present in so many of the patients we studied,” Krystal explained to PsyPost. “Adequately sized studies comparing people with and without the Met allele would be needed to see whether the Met allele blunts ketamine response, whether it leads to the need to be treated with higher ketamine dose, and whether it prevents patients with mild depression symptoms from benefitting from ketamine.”

The study, “Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression“, was also co-authored by Tung-Ping Su, Mu-Hong Chen, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ralitza Gueorguieva, Pei-Chi Tu, Ya-Mei Bai, and Chih-Ming Cheng.