Immunosuppressant May Extend Ketamine's Antidepressant Effects

Nancy A. Melville

April 02, 2019

CHICAGO — While exploring the immunosuppressant rapamycin and its potential to block the antidepressant effects of ketamine, researchers serendipitously discovered the drug may actually prolong ketamine's efficacy.

In a small, double-blind crossover study, patients with major depressive disorder (MDD) were treated with either rapamycin or placebo, followed 2 hours later with an infusion of ketamine.

"It was purely a scientific paper to understand the mechanism of action of ketamine in humans," study investigator Samuel T. Wilkinson, MD, assistant professor and assistant director of the Yale Depression Research Program, West Haven, Connecticut, told Medscape Medical News.

However, "unexpectedly, pre-treatment with rapamycin prolonged the acute antidepressant effects of ketamine, demonstrating a large effect size and a significantly increased response rate 2 weeks post-treatment," co-investigator Chadi G. Abdallah, MD, psychiatrist at the Yale School of Medicine, said during his presentation here at the Anxiety and Depression Association of America's (ADAA) 2019 39th Annual Conference.

Abdallah noted that the novel findings, while exciting, need to be replicated.

"We definitely have a lot of good news in this study and I'm optimistic about the results, but this is not phase 3 confirmatory evidence by any definition," he said. "It is a pilot study, and replication is critical."

Rapid, But Short-Acting Effect

Ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, has been shown to rapidly reduce suicidal ideation in MDD.

As reported by Medscape Medical News, the US Food and Drug Administration recently approved esketamine, an intranasal formulation of the drug, for treatment-resistant depression.

While ketamine's effects are rapid, they are also short acting. Efforts to extend the drug's effects, ranging from multiple infusions to intensive cognitive behavioral therapy, are ongoing.

However, Abdallah and his team were not originally examining rapamycin's potential to extend ketamine's effects. They were only seeking to confirm that rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR), blocks the antidepressant effects of ketamine.

"In rodents, it seems that ketamine works through the mTOR pathway and rapamycin will block this pathway," Wilkinson said. Their study was created "just to confirm if by blocking mTOR pathway, rapamycin would block ketamine's antidepressant effects" in humans.

In the study, 23 patients with MDD were randomly assigned to treatment with either rapamycin 6 mg or placebo, each of which was followed 2 hours later by an infusion of ketamine 0.5 mg/kg.

The reverse treatment was provided at least 2 weeks later, a time point chosen because most patients with depression relapse within 2 weeks of a single infusion of ketamine, the researchers note.

No Relapse

Remarkably, instead of the expected blocking of ketamine's effects, the results showed the opposite effect. At 2 weeks post-treatment, the primary outcome of depression scores on the Montgomery-Åsberg Depression Rating Scale improved when ketamine was preceded by rapamycin (P = .04).

The response rate at 2 weeks was significantly greater for the rapamycin group, with as much as a 41% response compared with a 13% response in the placebo group (P = .04). In addition, the remission rate at 2 weeks was 29% vs 7%, respectively (P = .003).

"We hypothesized that rapamycin would be statistically significant in blocking the effect of ketamine, but instead the effect was prolonged and people didn't relapse at 2 weeks, as we'd expected," Abdallah said.

Post-hoc analyses showed significantly lower depression scores in the rapamycin/ketamine group compared with the placebo/ketamine group at day 3 (P = .04) and day 5 (P = .02), and it was trending at week 2 (P = .12).

Mirroring a common occurrence with ketamine infusions, the study participants experienced significant increases in dissociative and other psychotomimetic symptoms during their infusions, as assessed by Clinician Administered Dissociative States Scale (CADSS) and Positive and Negative Syndrome Scale (PANSS) scores (all, P < .0001).

At 2 hours post-infusion, CADSS scores were back to baseline, while there were significant reductions in PANSS Positive (P = .02) and Negative scores (P = .0002).

The researchers speculate that perhaps the dissociated side effects were more intense with rapamycin. However, there were no differences between the groups.

They also speculated that anxiolytic effects may have played a role in prolonging the antidepressant effects; but again, there were no differences between the rapamycin and placebo groups in scores on the Hamilton Anxiety Rating Scale (P = .87).

There were also no differences between the groups in ketamine levels, and no effects were observed in inflammatory measures of C-reactive protein or erythrocyte sedimentation rate in the combination-treatment group. All rapamycin levels reached a therapeutic value.

Third Case of Serendipity?

Abdallah noted that there was an important difference in administration of rapamycin in the preclinical studies compared with clinical studies. In preclinical studies, rapamycin is applied directly to the prefrontal cortex in rats. In humans, rapamycin is given systemically.

"Our main hypothesis is that perhaps you have to apply rapamycin directly to the brain intra-cortically to have the blocking effect on ketamine," Abdallah said.

In terms of the mechanisms behind the prolonged effects, he speculated that rapamycin may provide the additional anti-inflammatory action needed to boost ketamine's synaptic effects.

"This is the most important question. Our hypothesis right now is when you treat with ketamine, you do reverse this [depression] pathology by increasing synaptic plasticity. But maybe you're not addressing the underlying mechanism; maybe neuroinflammation is bringing it back down to pre-treatment levels," Abdallah said.

"By giving this immunosuppressant, we may have delayed or stabilized these synaptic changes for a longer period of time," he added.

Another possibility is the potential role of autophagy, which was linked to rapamycin in recent research and suggests the drug has antiaging properties.

"The theory is that that autophagy is regulated by mTORC1, and the main function of autophagy is to remove the component of cells that are not necessary, which is critical for neuroplasticity," Abdallah explained.

"So it's possible that by enhancing autophagy, we are prolonging the synaptic effect that we see post-ketamine," he said.

Either way, Abdallah noted that the unexpected nature of the findings appears to be a trend in depression treatments.

"We saw that with tricyclic antidepressants; and then with ketamine itself, researchers were in fact looking for something else. So perhaps this is a third case of serendipity," he said.

However, Wilkinson remains cautious, as many questions remain about long-term use of ketamine.

"The rapamycin results are very preliminary so it's important to interpret them cautiously," he said. "The concerns about long-term use of ketamine are very real and mainly include abuse liability, worries of cognitive impairment, and bladder toxicity."

"Exciting, Promising Findings"

Commenting on the findings for Medscape Medical News, Rebecca B. Price, PhD, assistant professor of psychiatry at the University of Pittsburgh, Pennsylvania, noted that this research on rapamycin offers important new information.

"This is a very exciting finding as it is the clearest and most promising finding I have seen in terms of a pharmacological strategy that might work synergistically with ketamine to enhance and extend ketamine's rapid effect," she said.

Although not involved with the current study, Price is involved in ongoing research to extend ketamine's effects through cognitive training to boost neuroplasticity.

"I believe the future of rapid-acting antidepressant treatment will be to find strategies that both retain the rapidity of ketamine's effect, but also make longer-term maintenance of this effect more feasible," she said.

Abdallah reported being a consultant to or on the advisory board of FSV7, Lundbeck, Janssen, and Genentech and is an editor for Sage Publication's Chronic Stress. Wilkinson receives funding from the National Institute of Mental Health, Agency for Healthcare Research and Quality, Janssen, and Sage Therapeutics. Price has disclosed no relevant financial relationships.

Anxiety and Depression Association of America (ADAA) Conference 2019: Abstract 1189. Presented March 30, 2019.

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