Ketamine May Help Teens With Resistant Depression

Fran Lowry

June 03, 2019

SCOTTSDALE, Arizona — The first randomized controlled clinical trial of ketamine suggests the drug may help teens with treatment-resistant depression (TRD), but experts caution that the findings are preliminary.

Investigators at Yale University, New Haven, Connecticut, found that use of the drug led to significantly improved depression scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) the day after treatment.

Dr Jennifer Dwyer

However, study investigator Jennifer Dwyer, MD, PhD, Yale Child Study Center, Yale University, said that while promising, this signal of efficacy needs further exploration in carefully conducted clinical trials to ensure the drug does not adversely affect the developing brain or cause other problems related to safety in this population.

"Adolescent depression is a serious problem, and treatment-resistant adolescent depression is extremely serious, so we need new treatments," Dwyer told Medscape Medical News.

"This study is just one of the first steps towards trying to establish a novel treatment. This research in adolescents is still very much in preliminary stages, and I want to emphasize this, because people get very excited to see an efficacy signal and that people are getting better. But there is still a lot of testing that needs to be done, especially on the safety side, when you think about repeat dosing," she said.

Dwyer presented the findings here at the American Society of Clinical Psychopharmacology (ASCP) 2019 annual meeting.

Impact on the Developing Brain

The adolescent brain is a unique pharmacologic substrate, and the proposed sites of ketamine's action, the prefrontal cortex and the hippocampus, are actively maturing during this time.

"The prefrontal cortex is one of the last brain areas to mature. That's one of the reasons why you can't rent a car until you're 25, because the prefrontal cortex, which is critical for executive control and decision making, continues to mature into early adulthood to be as mature as possible. I think the car companies had caught on before scientists did," Dwyer said.

"There is a pruning back of glutamate synapses and changes in the relative distribution of GABAergic cells. Both of these are important potential targets of ketamine. In addition, there are glutamate and GABA receptors themselves, and animal studies suggest that those also change in the type of subunits that make up each receptor. That is important when you think about how those compounds act. The subunits are very important in determining how well the receptor gets turned on or off and what the downstream effects are. So it's very complicated," Dwyer said.

Nearly 1 in 5 adolescents will experience major depressive disorder (MDD), and suicide is the second leading cause of death in this age group. Forty percent of adolescents with MDD fail to respond to initial treatment with selective serotonin reuptake inhibitors.

Ketamine has rapid antidepressant and antisuicidal effects in adults with TRD. Dwyer and her team wanted to study its efficacy in teens by comparing the effects of a single dose of ketamine to that of a single dose of an active control medication, which in this case was midazolam (multiple brands).

The 4-week study included 17 adolescents aged 13 to 17 years (average age, 15.4 years; 72% female) whose depression had failed to improve after at least one adequate trial of a standard antidepressant. The average number of prior failed medication trials was 4.7 (±3.3).

Patients continued to take their psychiatric medications; dosing was stable for the 4 weeks prior to the study and for the duration of the study.

On day 1 and day 14, patients received either ketamine (0.5 mg/kg over 40 min) or midazolam (0.045 mg/kg over 40 min) per IV infusion.

"Midazolam is an active control. It's a benzodiazepine, and the idea was to try to mimic some of the experiential side effects of ketamine. We think it's a better blind than using saline," Dwyer said.

On day 1, MADRS scores were significantly improved for the patients who took ketamine compared to those who took midazolam. This separation between the ketamine group and midazolam-placebo group persisted to day 14, the last time point studied.

Dwyer and her group will soon be starting a second study of longer duration.

"This second study will look at a limited amount of repeat dosing and will be a parallel design, where different people get different treatments, and it will compare six infusions of ketamine over 3 weeks to six infusions of midazolam over 3 weeks. The teens will be followed for 7 months, and we will be doing very detailed neurocognitive testing," Dwyer said.

"Animal data suggest that younger ages are more sensitive to the potential neurotoxic effects of ketamine. If you study adults that have abused ketamine or used ketamine chronically for recreational purposes, you see neurocognitive problems, you see chronic bladder problems.

"These studies suggest that there's a dose that's too much, but we don't know where that threshold is, so we're trying to tread very carefully. We are only extending this kind of experimental treatment to kids who have failed all of the available options, often cases where we are considering ECT [electroconvulsive therapy], and then following them very carefully with safety measures," said Dwyer

Proceed, but With Caution

Commenting on the study for Medscape Medical News, Carlos A. Zarate Jr, MD, chief, Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, who was the session's discussant, said caution should be exercised when extrapolating findings from adults to younger patients.

Dr Carlos Zarate Jr

Just because a "treatment works or does not work in adults, it doesn't necessarily mean that it will work or not work in children and teens," he said.

It is not just a matter of efficacy but also of side effects, he added.

"It's very important to have these unique studies in children and adolescents to establish safety and efficacy, and also studies on the neurobiology that is unique to children," Zarate said.

"Extrapolating our knowledge from adults to children is nonsense. For example, imipramine is an effective antidepressant for adults but does not do much in children.

We need specific trials in kids. We need to know what happens to those young developing brains. The other thing we need to keep in mind is abuse potential.

"I think that this study by Dwyer and her team was a very nice, elegant study. It's very preliminary, subjects crossed over, the dissociative side effects were comparable to what you see in adults, and the blinding with midazolam is not perfect, but it's an attempt to get there, and the medication appears to be well tolerated. Now, about the repeat dosage study, we have to see what happens, but I would encourage caution," Zarate said.

Dwyer reports no relevant financial relationships. Zarate is a coinventor on a patent for the use of ketamine and its metabolites in major depression. He has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. The study was funded by an American Academy of Child and Adolescent Psychiatry pilot award, the Thrasher Research Fund, and the Yale Child Study Center.

American Society of Clinical Psychopharmacology (ASCP) 2019: Abstract 3001727. Presented May 28, 2019.

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