Ketamine formulation study is ‘groundbreaking’


It is remarkable to consider that we now have more than 30 medications approved by the Food and Drug Administration as monotherapy or augmentation for the treatment of major depressive disorder. And yet, we know very little about how these medications perform for patients at high risk for suicide.

Historically, suicidal patients have been excluded from phase 3 antidepressant trials, which provide the basis for regulatory approval. Even studies in treatment-resistant depression (TRD) have tended to exclude patients with the highest risk of suicide. Further, the FDA does not mandate that a new antidepressant medication demonstrate any benefit for suicidal ideation.

Dr. Sanjay Mathew

Dr. Sanjay J. Mathew

An important milestone for antidepressant drug development was, therefore, achieved in 2016 – when an intranasal spray formulation of esketamine, the S(+)-enantiomer of racemic ketamine – was granted FDA “breakthrough therapy” designation for the indication of major depressive disorder (MDD) with “imminent risk for suicide.” Several years earlier, the drug manufacturer Janssen had initiated studies of esketamine for TRD, which have reported rapid antidepressant effects similar to ketamine1,2. Esketamine has been used in Europe as an anesthetic agent since the 1990s but was never marketed in the United States. Compared with R-(–) ketamine, it has a three- to fourfold higher affinity for N-methyl-D-aspartate receptors.

Focus on high-risk patients

The recent report by Canuso et al.3 in the American Journal of Psychiatry is a groundbreaking study: To my knowledge, it marks the first published randomized, placebo-controlled, repeated-dose trial of any ketamine formulation in depressed patients at high risk for suicide. Previous placebo-controlled trials of intravenous ketamine in depressed patients with clinically significant suicidal ideation have used only one-time dose administrations4,5,6.

This phase 2, proof-of-concept trial randomized 68 adults with MDD at 11 U.S. sites, which were primarily academic medical centers. In contrast to previous ketamine studies, which recruited patients via advertisement or clinician referral, patients were identified and screened in an emergency department or an inpatient psychiatric unit. Participants had to voluntarily agree to hospitalization for 5 days following randomization, with the remainder of the study conducted on an outpatient basis. Intranasal esketamine (84 mg) or placebo was administered twice per week over 4 weeks, in addition to standard-of-care antidepressant treatment. The primary outcome was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) score from baseline to 4 hours after first dose of study medication.

For the primary MADRS outcome, esketamine statistically separated from placebo at 4 hours and 24 hours, with moderate effect sizes (0.61 to 0.65). There were no significant differences at the end of the double-blind period at day 25 and at posttreatment follow-up at day 81. For the suicidal thoughts item of the MADRS, esketamine’s efficacy was greater than placebo at 4 hours, but not at 24 hours or at day 25. Clinician global judgment of suicide risk was not statistically different between groups at any time point, although the esketamine group had numerically greater improvements at 4 hours and 24 hours. There were no group differences in self-report measures (Beck Scale for Suicidal Ideation or Beck Hopelessness Scale) at any time point.

Regarding safety and tolerability, adverse events led to early termination for 5 patients in the esketamine group, compared with one in the placebo group. The most common adverse events were nausea, dizziness, dissociation, unpleasant taste, and headache, which were more frequent in the esketamine group. Transient elevations in blood pressure and dissociative symptoms generally peaked at 40 minutes after dosing and returned to baseline by 2 hours.

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