A new of its kind study published in the journal Molecular Psychiatry reports two subanesthetic dosage levels of the anesthetic drug ketamine that appear to provide significant symptom relief to patients with treatment-resistant depression. The study finds that single intravenous doses of 0.5 mg/kg and 1.0 mg/kg were more effective than an active placebo in reducing depression symptoms over a three-day period.
Previous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min) but the optimal antidepressant dosage was unclear.
Maurizio Fava and associates conducted a study to compare active placebo to the rapid-acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). The investigators compared a range of IV ketamine doses to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min.
“Treatment resistance in depression is a major issue, with more than half of patients not responding adequately to standard, appropriate antidepressant treatment,” says Maurizio Fava, senior author of the Molecular Psychiatry paper. “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.”
The outpatient study was conducted in six US sites which included patients aged 18-70 years with TRD. TRD was defined as defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode.
Five study groups were created including 99 eligible participants.The subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion as follows:
- A single intravenous dose of ketamine 0.1 mg/kg (n = 18)
- A single dose of ketamine 0.2 mg/kg (n = 20)
- A single dose of ketamine 0.5 mg/kg (n = 22)
- A single dose of ketamine 1.0 mg/kg (n = 20) and
- A single dose of midazolam 0.045 mg/kg (active placebo) (n = 19).
The study assessments were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy.
Key study findings:
- On the standard depression scale, participants receiving ketamine had significantly greater symptom improvement during the three days after infusion than did those in the active control group.
- Comparison of dosage levels, after adjusting for multiple comparisons, found statistically significant improvement compared to the control group only for participants receiving 0.5 mg/kg and 1.0 mg/kg doses.
- The low 0.1 mg/kg dose produced significant relief only prior to adjustment, and the 0.2 mg/kg dose did not show any significant benefits.
- For most participants in the higher-dose groups, the benefits of ketamine treatment began to decrease on the third day after treatment and were no longer detectable after five days.
- There were no significant differences in the occurrence of adverse events among all study participants.
“Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for the clinically meaningful efficacy of lower doses of IV ketamine, ”write the authors.
For reference log on to 10.1038/s41380-018-0256-5
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