After an MDMA therapy for post-traumatic stress disorder dramatically 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 a therapy for treatment-resistant depression.
In a mid-stage, randomized, placebo-controlled clinical trial, researchers tested slow-release ketamine pills, taken twice weekly. The trial, sponsored by New Zealand-based Douglas Pharmaceuticals, found ketamine to be safe compared with placebo. At the trial's highest dose, the treatment showed some efficacy against depression in patients who had previously tried an average of nearly five antidepressants without success, according to the results published Monday in Nature Medicine.
But the Phase II trial, which started with 231 participants, indicated that the pool of patients who may benefit from the treatment could be quite limited. The researchers behind the trial chose an unusual "enrichment" design to test the depression treatment. This was intended to thwart the high failure rates generally seen in trials for depression treatments, even in patients without treatment-resistant cases. But even after selecting patients who initially responded to ketamine, 59.5 percent of the enriched participants still dropped out of the trial before its completion, largely due to a lack of efficacy.
Enriched design
In the trial's initial enrichment phase, all 231 participants were given a 120-milligram ketamine pill every day for five days. All the participants knew they were getting ketamine, which could introduce bias if participants expected the drug to work. A few days after 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, in which each item is scored 0 to 6 points for a maximum score of 60. The higher the score, the more severe the depression. All 231 participants started the trial with scores of 20 or higher, indicating at least moderate depression. The average score was around 30. The researchers considered a patient to have achieved remission of their depressive symptoms if their score fell to 10 or lower during the trial.