Conference Coverage

IV ketamine proves superior to active placebo in low, high doses



– Intravenous ketamine in a range of doses is superior to active placebo, according to analyses from a study of the drug for treatment-resistant depression.

Most of the effect was attributable to differences recorded at Day 1 of the 3-day study, according to George I. Papakostas, MD, scientific director of the Massachusetts General Hospital Clinical Trials Network and Institute and coinvestigator of the study, who presented these findings at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation meeting.

The 99 adults with treatment-resistant depression – primarily white women in their mid-40s – were randomly assigned either to an active placebo group given 0.045 mg/kg of midazolam or to one of four treatment arms given a single infusion of intravenous ketamine at either 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, or 1.0 mg/kg.

Baseline scores on the 6-item Hamilton Depression Rating Scale (HAMD-6) ranged between 12.6 and 13.1 across the study.

To determine the efficacy of intravenous ketamine at different doses over the course of 72 hours, Dr. Papakostas, who also directs treatment-resistant depression studies at Massachusetts General, and his colleagues used multiple statistical models. The first analysis was a comparison of the effects of the active placebo and all ketamine groups combined at Day 1 and at Day 3.

At Day 1, the change in baseline HAMD-6 scores for all the ketamine arms combined, compared with the active placebo group, was statistically significant (P = .0278). At Day 3, the change in baseline HAMD-6 scores for the combined ketamine groups, compared with the active placebo arm, also was statistically significant (P = .0391).

A secondary analysis of the patient-reported Symptoms of Depression Questionnaire also showed a statistically significant improvement (P = .09) from baseline in the combined ketamine groups, compared with the active placebo group.

At Day 1, the combined ketamine groups’ changes from baseline HAMD-6 were –3.25 with an effect size of 0.86, a statistically significant finding. However, by the Day 3, the combined ketamine groups’ effects size fell away. “There is no longer a statistically significant difference, so it’s a rapid effect – like we’ve seen in the other studies for the combined doses – but it is not an effect that is sustained,” said Dr. Papakostas, also an associate professor of psychiatry at Harvard Medical School, Boston.

For the individual doses, compared with active placebo, the ketamine 0.1 mg/kg arm had an overall –0.35 change in baseline HAMD-6 scores, which Dr. Papakostas said had “a large effect size of 0.82.”

Dr. Papakostas also said the ketamine 0.2 mg/kg arm “did not really seem to move things around at all.” Meanwhile, the 0.5 mg/kg and 1.0 mg/kg arms each had “big differences” in baseline HAMD-6 scores, compared with active placebo, of –4.79 and –3.76, respectively. They also exhibited statistically significant effect sizes of 1.21 and 0.95 at Day 1, respectively. However, at Day 3, there were neither numerical nor statistical differences, indicating the effect is not sustained.

Changes in the Symptoms of Depression Questionnaire for the combined drug arms at Day 1 were statistically significant with an unadjusted P value of .07 and an adjusted P value of .13.

Results for the Clinician Administered Dissociative States Scale showed that neither the ketamine 0.1 mg/kg arm nor the ketamine 0.2 mg/kg arm separated from active placebo, while the ketamine 0.5 mg/kg arm and the ketamine 1.0 mg/kg arm were each different from active placebo to numerically and statistically significant degrees. Each of the 0.5 mg/kg and the 1.0 mg/kg ketamine arms were associated with rises in blood pressure, according to Dr. Papakostas.

“So, it seems as though the doses that caused a dissociation seemed to cause a clinical effect that is equivalent, whereas in the lower doses, there didn’t seem to be any dissociative effects or blood pressure effects,” Dr. Papakostas said. “If you combine the findings, in my opinion, there is a signal in the 0.1 mg/kg treatment arm, even though it just misses it on the P value.”

Dr. Papakostas said that, although more data are needed to determine optimal dosing and a clearer risk-benefit ratio, the results suggested that intravenous ketamine could offer transient, beneficial effects for patients with treatment-resistant depression.

Dr. Papakostas is the scientific director of the MGH Clinical Trials Network and Institute. This study’s coinvestigator, Maurizio Fava, MD, has numerous relevant financial ties to industry. This trial was part of the National Institute of Mental Health’s Rapidly-Acting Treatments for Treatment-Resistant Depression research program.

On Twitter @whitneymcknight

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