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Promising Results for a New Rapidly-Acting Antidepressant

A new drug shows substantial antidepressant action within seven days.

Key points

  • A new drug derived from methadone influences a glutamate receptor rather than an opiate receptor.
  • Preclinical studies suggested that this drug has antidepressant properties.
  • An earlier safety study suggested that this drug is safe for humans.
  • An antidepressant effect was observed in a small phase study. Larger phase studies are ongoing.

A phase 2a study of a new potential antidepressant suggests that it has rapid and strong antidepressant effects. The results of this study were recently published in the American Journal of Psychiatry by Maurizio Fava and colleagues.

A phase 2a study examines the safety, dosing, and metabolism of a drug in individuals with the specific illness of interest. Phase 2a studies establish parameters that then can be used in much larger phase 3 studies. Although the drug’s effects on symptom severity are assessed in phase 2a studies and trends of effectiveness may be seen, clearly significant results are not anticipated due to the small sample size.

The new potential antidepressant is esmethadone. How is it related to methadone? Many drugs are actually a mixture of two chemicals with exactly the same composition that are mirror images of each other. The mirror image molecules can have different biological properties and can be separated from each other. Methadone is an example of such a mixture in which the two mirror image chemicals — called “enantiomers” — have different properties. One enantiomer, levomethadone, is responsible for methadone’s activity as an opioid. The other, esmethadone (also called dextromethadone), is far less active on the opioid system; it interacts with receptors of the neurotransmitter glutamate. In fact, esmethadone inhibits the same glutamate receptors thought to be responsible for the antidepressant actions of ketamine. Like ketamine (and its more active enantiomer, esketamine), esmethadone has antidepressant-like properties in animal models of depression. One important difference between esmethadone and ketamine is that esmethadone does not appear to have the dissociative/hallucinatory effects that can occur in individuals treated with ketamine.

This multi-center, randomized, double-blind phase 2a study examined the effects of esmethadone in 62 adults who met the criteria for major depressive disorder but had failed to respond to 1-3 courses of standard antidepressants. These individuals were maintained on their current antidepressant during the study. Individuals with a history of bipolar disorder, psychotic disorder, posttraumatic stress disorder (PTSD), or certain personality disorders were excluded from the study as were individuals using antipsychotics, anticonvulsants, or mood stabilizers within the previous three months. Persons with recent opiate use were also excluded.

Study participants were admitted to an inpatient clinical trial unit. They were randomized to one of three arms of the study: placebo; 25 mg esmethadone per day for 7 days; or 50 mg esmethadone per day for 7 days. They were observed as inpatients for two days after the last day of treatment, and returned for follow-up evaluations 7 days after stopping esmethadone.

The investigators found that side effects were as common in the placebo group as in the two esmethadone groups and mostly consisted of headache, constipation, nausea, and somnolence. There was no evidence of dissociative symptoms as measured by the Clinician-Administered Dissociative States Scale (CADSS) and no indication of opiate withdrawal after esmethadone was discontinued as measured by the Clinical Opiate Withdrawal Scale.

The research team used the Montgomery-Asberg Depression Scale (MADRS) to assess depressive symptoms. By day 4 of treatment, both esmethadone groups showed significant improvement when compared to the placebo group. The degree of improvement increased during the remaining three days of esmethadone treatment and continued for at least seven days after treatment was discontinued.

The mean initial MADRS scores were above 30 for each treatment group, indicating moderate depression. Remission of symptoms was defined as MADRS scores of 10 or less. On day 14 (i.e., 7 days after treatment was stopped), 5% of those receiving placebo improved to the extent that they were in remission. For the esmethadone groups, 31% and 39% of those receiving 25 mg/day and 50 mg/day, respectively, were in remission.

The results of this phase 2a study indicate that esmethadone is safe and may have rapid antidepressant effects that remain after the drug has been discontinued. The next step involves larger and longer phase 3 studies. These studies are specifically designed to determine how well the drug works. The authors report that such studies are ongoing. If these trials are successful in confirming efficacy and safety for esmethadone, it is likely that another potent, rapidly acting antidepressant will become available.

The field of psychiatry is in the midst of a psychopharmacological revolution. New agents appear to work via different mechanisms than earlier medications. Advances in evidence-based psychotherapies are also occurring. More treatments are becoming available to help the large number of individuals suffering from psychiatric disorders.

This post was written by Eugene Rubin MD, PhD and Charles Zorumski MD. Neither of us has any relationship (financial or otherwise) with the company developing the drug discussed in this column.

References

Fava, M., Stahl, S., Pani, L., De Martin, S., Pappagallo, M., Guidetti, C., Alimonti A., et al. (2022). REL-1017 (esmethadone) as adjunctive treatment in patients with major depressive disorder: a phase 2a randomized double-blind trial. Am J Psychiatry. 179:122–131.

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