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With limited medication options for treatment-resistant depression, patients often turn to transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), or even intravenous ketamine, which is available at for-profit clinics despite the absence of long-term safety and efficacy data. These researchers conducted a manufacturer-funded, phase II trial of intranasal esketamine (a ketamine enantiomer).
The 67 antidepressant-treated patients with treatment-resistant depression (no psychosis or bipolar illness; 39% with history of adjunctive antipsychotics) were randomized to esketamine (28 mg, 56 mg, or 84 mg) or placebo. Treatment occurred twice in week 1. Placebo recipients with continuing moderate-to-severe depression (n=28) were rerandomized and received treatment twice in week 2, along with the original esketamine patients. Open treatment followed, tapering eventually to biweekly.
At week 1, all three esketamine doses produced significantly greater improvement in depression than placebo, with greater effects at higher doses. Day-14 response rates were 38%, 36%, and 50% at increasing esketamine doses and 10% with placebo; remission rates were 13%, 27%, and 40% with esketamine and 10% with placebo. Esketamine effects persisted through day 74 of administration and 8-week follow-up. Adverse events leading to study discontinuation occurred in 5% of esketamine patients in week 1 and 2% thereafter. Mild-to-moderate dizziness, nausea, headache, dissociation, and blood pressure elevations occurred transiently in 10% to 47%.
Daly EJ et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry 2017 Dec 27; [e-pub]. (http://dx.doi.org/10.1001/jamapsychiatry.2017.3739)
Comment
Despite the small study population, this non–FDA-approved intranasal drug had longer-lasting effects than intravenous ketamine, reasonable tolerability, and a route of administration usable in ambulatory settings. Drug–placebo differences in response and remission rates were greater than those seen with antidepressants in nonresistant depression and with adjunctive antipsychotics in treatment-resistant illness. Because many patients were not at the highest stages of treatment resistance, we don't know whether efficacy extends to the population in greatest need or whether continued intermittent treatment is required, as is sometimes the case with ECT or TMS.