News on the Antidepressant Actions of Ketamine

 In the print edition of Biological Psychiatry of August 15th, 2013, two original articles and an accompanying editorial are published on the antidepressant effects of ketamine and other NMDA receptor antagonists, which are worth to be discussed further.James Murrough of the Mount Sinai School of Medicine in New York and colleagues report on their treatment of 24 patients with treatment-resistant depression with six intravenous infusions of ketamine over a period of 12 days (21 of the patients received all six treatments, three only one or two, respectively) (Murrough et al., Biol Psychiatry, 2013; 74: 250-256). Although a drawback of the study is that the treatment was open and uncontrolled, it is nevertheless the study with the largest number of patients treated with ketamine. The patients were 48 years old on average. Their disease had begun at a mean age of 23 years, the current episode had been treated with an average of six antidepressants. At baseline, patients had a Montgomery-Asberg Depression Rating Scale (MADRS) score of 32 points. Within two hours after the first infusion, the score fell dramatically by 19 to an average of 13 points. 17 of the 24 patients were responders (70.8%), with response defined as a reduction of MADRS score of at least 50%. After four hours, responders (MADRS score 10.35) clearly separated from non-responders (MADRS score 19.0). However, the non-responders showed a significant reduction of sadness, inner tension and pessimistic and suicidal thoughts. In responders, the improvement of psychopathology was maintained over the entire treatment period of 12 days.

The responders were followed up for a period of up to 83 days. The median time to relapse was 18 days (24th and 75th percentiles 11 and 27 days, respectively). Four of the patients were relapse-free after 83 days.

Ketamine led to a mild increase of psychotic and dissociative symptoms, which had disappeared again four hours after the end of infusion.

In the second study Carlos Zarate of the National Institute of Mental Health, Bethesda, Maryland, USA, and colleagues report on their study with the experimental compound AZD6765 that was conducted in cooperation with AstraZeneca (Zarate et al., Biol Psychiatry, 2013; 15; 74: 257-264). While ketamine binds with high affinity to the NMDA receptor, AZD6765 has only moderate affinity. This is expected to decrease the incidence of psychotic and dissociative symptoms. In Phase I clinical trials with AZD6765 no psychotic symptoms were observed after administration of the compound.

22 patients with depression were included in the study. They were administered  a single infusion of AZD6765 (150 mg) and placebo at an interval of one week in a double-blind randomized crossover design. The mean MADRS score at baseline was approximately 34 points (exact numbers are not specified in the paper, therefore, they were determined graphically). The patients had undergone an average of seven treatment trials with antidepressants, 45% had not responded to ECT treatment. 80 minutes after infusion of AZD6765, the score dropped to an average of about 25 points and to an average of 30 points after placebo. This difference was statistically significant (p < 0.01). After 110 minutes of AZD6765, patients still had a significantly lower score on the MADRS (approximately 26 vs. approximately 30 points, p < 0.05). 230 minutes after the infusion, the two groups were no longer significantly different from each other. Seven of 22 patients (32%) showed a response to AZD6765, three on placebo (15%). AZD6765 thus had a rapid antidepressant effect, but it lasted only briefly. Adverse effects with the experimental substance were not more common than with placebo. Overall, the effects of AZD6765 were much less pronounced and lasted much shorter in comparison to ketamine. Studies with higher doses and repeated infusions are needed to further explore the value of the compound in the treatment of depressive disorders.

The two studies show that the development of drugs that modulate glutamatergic function gives rise to hopes for a better and faster treatment of (refractory) depression.



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