After MDMA therapy for post-traumatic stress disorder failed to impress advisers to the U.S. Food and Drug Administration earlier this month, researchers are now developing a slow-release, oral version of another psychedelic drug, the hallucinogen ketamine, to treat treatment-resistant depression.
In a mid-term randomized, placebo-controlled clinical trial, researchers tested a sustained-release ketamine tablet taken twice weekly. The study, sponsored by New Zealand’s Douglas Pharmaceuticals, found ketamine to be safe compared with a placebo. At the highest dose in the study, it was shown to be effective in treating depression in patients who had tried an average of five antidepressants without success. According to a study published Monday in the journal Nature Medicine,.
However, a Phase II trial that began with 231 participants indicated that the pool of patients who could benefit from the treatment may be rather limited. The researchers behind the trial chose an unusual “enrichment” design to test the depression treatment, which was intended to thwart the high failure rate typically seen in trials of depression treatments, even in patients who are not treatment-resistant. However, even after selecting patients who initially responded to ketamine, 59.5% of the enriched participants dropped out of the study before it was completed, mainly due to a lack of efficacy.
Extensive design
In the initial consolidation phase of the trial, all 231 participants were given 120 milligrams of ketamine tablets daily for five days. All participants knew they were receiving ketamine, which could introduce bias if participants were expecting the drug to work. On the eighth day, several days after the five-day treatment, the researchers assessed participants’ depressive symptoms using a common standardized scale called the Montgomery-Asberg Depression Rating Scale (MADRS). This is a 10-item questionnaire, with each item scored from 0 to 6, with a maximum score of 60. The higher the score, the greater the severity of depression. All 231 participants began the trial with a score of 20 or higher, indicating at least moderate depression. The average score was about 30. The researchers considered patients to have remitted their depressive symptoms if their scores dropped to 10 or lower during the trial.
On day 8 of the consolidation phase, 132 of the 231 participants (57%) had achieved remission, and an additional 36 participants had achieved at least a 50% reduction in their MADRS score. Therefore, 168 of the original study participants (72%) continued on to the next phase of the study. Participants who did not respond to the drug did not continue in the study.
The next phase was a randomized, double-blind, placebo-controlled portion of the study, where different doses of ketamine were also tested. 168 patients who responded to ketamine were randomly assigned to one of five groups: a placebo group or a ketamine group, with doses of 30 mg, 60 mg, 120 mg, or 180 mg. The number of participants in each group ranged from 31 to 37. Each group was administered the drug twice a week for 12 weeks.
At the end of the study, on Day 92, the researchers were able to see a dose response; that is, there appeared to be a gradual improvement in depression symptoms between groups as the dose was increased to the highest level of 180 mg. However, only the 180 mg dose showed a statistically significant improvement. On Day 92, the MADRS scores of the remaining participants in the 180 mg group were, on average, 6.1 points lower than the scores of participants who remained in the placebo group. In other words, the final scores of participants in the 180 mg group were an average of 14 points lower than their starting MADRS scores, compared to an average of 8 points lower for the placebo group.
The researchers reported that these results showed “statistically significant and clinically meaningful improvements in depressive symptoms.”
Drop out
However, it should be noted that by day 92, only 68 of the 168 participants who responded to ketamine remained in the study. The remaining 100 participants (59.5% of 168) had dropped out at that point. Of the 100 who dropped out, 94 dropped out due to lack of efficacy (defined as a MADRS score of 22 or higher during the study). Of the other six, four dropped out for unknown reasons, one dropped out due to an adverse event, and a 65-year-old man receiving 180 mg committed suicide on day 42 of the study. The investigators conducting the study determined that the cause was depression.
By day 92, only 11 of 37 participants remained in the placebo group and 18 of 32 remained in the 180 mg group. Thus, the final statistically significant difference of 6.1 points between the placebo and 180 mg groups was based on scores from only 29 of 168 participants.
The authors acknowledge that the study design “is likely to overestimate the population level of treatment response” and that “future, more detailed clinical trials are needed to address this issue.”
On the other hand, the researchers reported that oral ketamine appears to be safe. The study did not report any cardiovascular side effects, particularly the increase in blood pressure previously seen with ketamine. The researchers also noted a low incidence of dissociation and a very low incidence of sedation. Other common side effects included mild to moderate headache, dizziness, anxiety, depressed mood, and dissociation.
The study did not collect specific data on potential abuse or diversion. Most of the dosing in the second phase of the trial was administered at home, potentially raising concerns among clinicians. Researchers anecdotally reported that they had not heard of participants craving pills. They also noted that ketamine pills are difficult to open. One participant was removed from the trial for “lack of compliance.”
