Ketamine pills for depression show positive results in trial, but with caveats

After an MDMA therapy for post-traumatic stress disorder failed to impress Food and Drug Administration advisers earlier this month, researchers are moving forward with another psychedelic — a slow-release oral dose of the hallucinogenic drug ketamine) as therapy for treatment-resistant patients. depression.

In a mid-stage, randomized, placebo-controlled clinical trial, researchers tested slow-release ketamine pills, taken twice a week. The trial, sponsored by New Zealand-based Douglas Pharmaceuticals, found ketamine to be safe compared to placebo. At the highest dose in the trial, the treatment showed some effectiveness against depression in patients who had previously tried an average of nearly five antidepressants without success, according to results published Monday in Nature Medicine.

But the phase II trial, which began with 231 participants, indicated that the group of patients who could benefit from the treatment could be quite limited. The researchers behind the trial chose an unusual “enrichment” design to test the treatment of depression. This was intended to thwart the high failure rates typically seen in trials of depression treatments, even in patients without treatment-resistant cases. But even after selecting patients who initially responded to ketamine, 59.5 percent of enriched participants left the trial before its completion, largely due to a lack of efficacy.

Rich design

In the initial enrichment phase of the trial, the 231 participants received a 120-milligram ketamine pill every day for five days. All participants knew they were taking ketamine, which could introduce bias if participants expected the drug to work. A few days into their five-day treatment, on day eight, researchers assessed their depression symptoms using a common standardized scale called the Montgomery-Asberg Depression Rating Scale (MADRS). This is a 10-item questionnaire, with each item given a score of 0 to 6 points for a maximum score of 60. The higher the score, the more severe the depression. All 231 participants began the trial with scores of 20 or higher, indicating at least moderate depression. The average score was around 30. Researchers considered a patient to have achieved remission of their depressive symptoms if their score dropped to 10 or below during the trial.

On the eighth day of the enrichment phase, 132 of the 231 participants (57 percent) achieved remission, and another 36 participants achieved at least a 50 percent reduction in their MADRS score. Therefore, 168 (72 percent) of the initial trial participants advanced to the next phase of the trial. Those who did not respond to the drug did not continue.

The next phase was the randomized, double-blind, placebo-controlled portion of the trial, which also tested different dosage levels of ketamine. The 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. Group sizes ranged from 31 to 37 participants. Each group received their dose twice a week for 12 weeks.

At the end, on day 92 of the trial, the researchers were able to see a dose response, meaning there appeared to be gradual improvements in depressive symptoms between the groups as the dose increased to the highest level, 180 mg. However, only that 180 mg dose had statistically significant improvements. At day 92, the remaining participants in the 180 mg group had MADRS scores that were, on average, 6.1 points lower than the scores of participants who remained in the placebo group. In other words, participants in the 180 mg group had final scores that averaged a 14-point drop from their baseline MADRS score, while the placebo group showed, on average, an 8-point drop.

The researchers reported that these results showed “a statistically and clinically significant improvement in depressive symptoms.”


However, it is important to note that by day 92 of the trial, only 68 of the 168 participants responding to ketamine remained in the trial. The other 100 participants (59.5 percent of the 168) had already dropped out of the study. Of the 100 who dropped out, 94 did so due to lack of efficacy (defined as a MADRS score of 22 or higher during the trial). For the other six, four dropped out for unspecified reasons, one dropped out due to an adverse event, and a 65-year-old man receiving the 180 mg dose committed suicide on day 42 of the trial. The researchers who conducted the trial determined that it was due to depression.

At day 92, only 11 of 37 participants remained in the placebo group and 18 of 32 remained in the 180 mg dose group. Therefore, the final statistically significant difference of 6.1 points calculated between the placebo group and the 180 mg dose group was based on the scores of only 29 of the 168 participants.

The authors acknowledge that their trial design “is likely to overestimate population treatment response levels” and that “future unenriched clinical trials are needed to address this issue.”

Meanwhile, researchers reported that oral doses of ketamine appeared safe. In the trial, no cardiovascular side effects were observed, particularly no increase in blood pressure readings as previously seen with ketamine. There were also low rates of dissociation and very low rates of sedation, the researchers wrote. Otherwise, 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 dosing in the trial’s second phase was done at home, which may raise concerns among physicians. Researchers only reported anecdotally that they were not aware of any participants wanting to take the pills. They also noted that ketamine tablets are difficult to open. One participant was removed from the trial due to “noncompliance.”

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