October 18, 2018
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Standard-, high-dose ketamine outperform placebo in treatment-resistant depression

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Maurizio Fava, MD
Maurizio Fava

Single IV ketamine doses of 0.5 mg/kg and 1 mg/kg were more effective than an active placebo in reducing symptoms over a 3-day period in patients with treatment-resistant depression, according to study data.

However, the findings, published in Molecular Psychiatry, revealed not enough clinical evidence supported the efficacy of lower doses of IV ketamine.

"Treatment resistance in depression is a major issue, with more than half of patients not responding adequately to standard, appropriate antidepressant treatment," Maurizio Fava, MD, director of the division of clinical research at Massachusetts General Hospital Research Institute, and executive vice chair of the department of psychiatry at Massachusetts General Hospital, said in a press release. "There are only a few approved therapies that can help some patients with treatment-resistant depression, so we critically need more options to choose from."

To determine the optimal antidepressant dose, the researchers compared a range of subanesthetic IV ketamine doses to active placebo for adult outpatients with treatment-resistant depression over a 3-day period following a single infusion over 40 minutes.

After a washout period, 99 participants were randomized to receive a single IV dose of ketamine 0.1 mg/kg (n = 18), ketamine 0.2 mg/kg (n = 20), ketamine 0.5 mg/kg (n = 22), ketamine 1 mg/kg (n = 20) or active placebo (midazolam 0.045 mg/kg; n = 19). To examine safety and efficacy, investigators assessed participants’ scores on the Hamilton Depression Scale-6, the Montgomery-Asberg Depression Rating Scale, Strengths and Difficulties Questionnaire, The Clinical Global Impressions Scale and Psychogeriatric Assessment Scales at days 0, 1, 3 (endpoint), 5, 7, 14 and 30.

The results showed that participants receiving IV ketamine had significantly greater symptom improvement as measured on the Hamilton Depression Scale over the 3 days post-infusion compared with participants receiving active placebo.

However, post hoc analysis, which controlled for multiple comparisons, revealed that only standard-dose (0.5mg/kg) and high-dose (1mg/kg) IV ketamine were superior to active placebo. A low dose (0.1mg/kg) of IV ketamine produced significant symptom relief only before adjustment (P=.02 at day 1), according to the findings. In addition, the 0.2 mg/kg dose did not show any significant benefits compared with placebo.

The benefits from the IV ketamine treatment began to wane on the third day after treatment and were no longer detectable after 5 days among participants in the higher-dose groups, according to the press release. Fava and colleagues observed that most of the interaction effect was caused by differences at day 1, with no significant adjusted differences at day 3.

Ketamine was relatively well-tolerated, with no significant differences in adverse events among all study participants, the release said. However, the researchers noted some participants taking the higher doses had greater dissociative symptoms and transient blood pressure elevations.

"These results support the clinical observation that one size — in this case the most studied dose of 0.5 mg/kg — does not fit all, as some patients may require a lower-than-average dose; and each patient needs a tailored treatment plan that may include ketamine, together with other medications, and talk therapy,” Cristina Cusin, MD, from the department of psychiatry at Massachusetts General Hospital, said in the press release.

“Further investigation should examine the efficacy of repeat doses of ketamine, as well as whether higher doses may require less frequent administration,” Fava added. – by Savannah Demko

Disclosure: Fava reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.