• Research Highlights
Depression symptoms can be difficult to manage, especially for people with treatment-resistant depression, a persistent and severe form of the disorder. Fortunately, new treatments are emerging for such difficult conditions. One of these is the drug ketamine, which numerous NIMH-funded studies have shown to have real action and lasting effects in people with mood disorders such as depression.
The discovery of ketamine was a game-changer for people with severe depression, who often need rapid relief from life-threatening symptoms. While most antidepressants take weeks or months to work, ketamine works within hours to significantly reduce symptoms of depression in people for whom other treatments have not worked.
Despite ketamine’s effectiveness as an antidepressant, serious concerns limit its use, including problematic side effects and a high risk of misuse. To address these concerns, the National Institutes of Health (NIH) is investing in finding drugs that capitalize on ketamine’s therapeutic effects while avoiding its negatives.
What did the researchers look at in the study?
New research funded through NIH Blueprint Neurotherapeutics Network for Small Molecules Program tested a new drug related to ketamine known as RR– HNK. RR-HNK is a metabolite or byproduct, of ketamine that remains as the body breaks it down. RR-HNK showed antidepressant effects in preclinical animal studies but it had not yet been tested on humans.
The study involved a broad collaboration of researchers in the intramural programs of the NIH’s National Institute of Mental Health, the National Center for Advancing Translational Sciences, and the National Institute on Aging. Duke University and the University of Maryland School of Medicine. and other national and international bodies.
What did the researchers do in the study?
This study looked at safety, tolerability, pharmacokinetics (how the drug moves through the body) and pharmacodynamics (how the drug affects the body) RR-HNK for the first time in humans.
Participants were healthy adults between 18-65 years of age. A total of 74 people participated in three randomized trials: 55 received RR-HNK and 19 received an inactive placebo. Both the drug and the placebo were given intravenously, with participants and researchers unaware of which group the participants belonged to.
- In Trial 1, participants received one of six dose levels RR-HNK only once.
- In Trial 2, participants received one of two dose levels RR-HNK four times in 2 weeks.
- In Trial 3, participants received a single dose RR-HNK, and their cerebrospinal fluid (a fluid that surrounds the brain and spinal cord) was collected.
The primary goal of the study was to determine whether the drug is safe by first testing it in healthy adults without a diagnosed mental health condition. Throughout the study, the researchers watched closely for adverse effects, such as negative side effects. The comprehensive safety profile included physical examinations. lab results; vital signs; electrocardiograms of cardiac activity. and assessments of mood, suicidal risk, and dissociative and depressive symptoms. In addition, participants were asked to inform study staff if they experienced any concerns or side effects at any point.
The researchers also collected blood and urine samples from all participants before, during and after taking the drug. These samples and the cerebrospinal fluid collected in Trial 3 were used to test whether the drug entered the body and brain.
As a final exploratory step, the researchers used brain imaging to examine the participants’ gamma oscillations (a type of brain wave) before and after taking the drug. This measure of the brain’s response to stimuli is one of the few available biomarkers of a drug’s effects on the brain.
What did the study find?
RR-HNK has proven to be extremely safe, with no serious side effects and only mild side effects that resolve quickly without care. Participants also reported no symptoms of depression or dissociation. The positive safety profile was maintained at all doses tested and after multiple doses. Together, the results show it RR-HNK is safe and tolerable, with limited potential for abuse or misuse.
The cerebrospinal fluid confirmed it RR-HNK entered the brain and remained at detectable levels several hours after administration. The results further showed a dose-dependent response to the drug, meaning that at higher levels RR-HNK, the amount of the substance in the body also increased at the same rate. A predictable relationship between the amount of RR-HNK is given and the amount of RR-HNK in the bloodstream is important to the drug’s clinical effectiveness, allowing doctors and researchers to precisely calibrate doses to a person’s specific level and type of symptoms.
In the brain activity test, some participants who received low to moderate doses RR-HNK, but not those given high doses or the placebo, showed an increase in the power of gamma oscillations. Preliminary evidence that RR-HNK causing a change in brain activity strengthens the case for its use as an antidepressant and provides a clinical biomarker to measure if it works in future research. However, there was a lot of variability in the results, and given the small number of participants, the researchers caution against drawing firm conclusions from these findings.
What do the results mean?
This study offers critical insight into its safety, tolerability, and effects RR-HNK in a diverse population of healthy adults. Findings from this early-stage study show that the ketamine metabolite does not cause the negative side effects of ketamine and is safe for use in humans. The results also help define dosing parameters for its use in future research and therapy.
These data, particularly a strong safety profile, support progress to the next phase of research aimed at developing new treatments for people with difficult-to-treat mental disorders. Despite the small size of each trial, making some of the results difficult to interpret, the findings hold promise for the future of mental health treatment. This study is a critical early step in NIMH’s mission to improve the treatment of mental illness through research, setting the stage for clinical trials testing whether RR-HNK effectively treats depression and other disorders.
Reference
Raja, SM, Guptill, JT, Mack, M., Peterson, M., Byard, S., Twieg, R., Jordan, L., Rich, N., Castledine, R., Bourne, S., Wilmshurst, M., Oxendine, S., Avula, SGC, Zuleta, H., Quigley, P., Lawson, S., McQuaker, SJ, Ahmadkhaniha, R., Appelbaum, LG … & Thomas, CJ (2024). Phase 1 evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of (2R,6R)-hydroxynorketamine in healthy volunteers. Clinical Pharmacology & Therapeutics, 116(5), 1314–1324. https://www.doi.org/10.1002/cpt.3391
Grants
R01MH107615 , ZIAMH002857 , ZIATR000042 , ZIAAG000297
