Novel Compound Found to Be Safe, Effective at Reducing Symptoms of MDD

The results of a clinical trial published last week in Molecular Psychiatry suggest that a novel compound found to increase the production of new brain cells may help to relieve symptoms of major depressive disorder (MDD).

Massachusetts General Hospital

The phase 1B clinical trial evaluated the effectiveness, safety, and tolerability of the pharmacoagent NSI-189, a benzylpiperizine-aminopyridine previously found to stimulate neurogenesis in the hippocampus and reduce depressive behaviors in a mouse model.

Maurizio Fava, M.D., director of the Clinical Research Program at Massachusetts General Hospital, and colleagues wrote in the report, “Currently available antidepressants generally share a mechanism of action focused on the monoamine neurotransmitter system, suggesting that the most robust potential advances in the field may be most achievable by the utilization of mechanisms of action different from those of currently available medications.”

Although the mechanism of action for NSI-189 is independent of that for more commonly used SSRIs, the primary mechanism of action is unknown.

To test the effectiveness and safety of NSI-189, the researchers recruited 24 patients with recurring symptoms of MDD. Patients were randomly divided into three cohorts, with six patients in each cohort receiving active drug (a 40 mg dose once, twice, or three times daily) while the remaining two patients received placebo for 28 days in an inpatient setting. After the end of treatment, the participants were followed for an additional eight weeks.

The Symptoms of Depression Questionnaire (SDQ), Montgomery–Åsberg Depression Rating Scale (MADRS), Cognitive Global Impression-Improvement (CGI-I), and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) were used to assess the depressive symptoms of participants throughout the trial.

The researchers found NSI-189 to be well tolerated with significantly greater antidepressant effects than placebo in two (SDQ and CPFQ) of four depression outcome measures. The most common adverse events associated with NSI-189 use included headache, dizziness, and somnolence.

“The significant benefits on the SDQ and the trends for improvement on the MADRS and CGI-I were maintained steadily beyond the acute phase of the double-blind administration and were still present at day 84, with the exception perhaps of the 40 mg [once-daily] regimen,” the study authors noted. “This finding is in sharp contrast to the rapid return of symptoms typically observed following discontinuation of standard antidepressants.”

The researchers added that while the sample size of the study was small, “each cohort [treated with NSI-189] seemed to have consistently shown an antidepressant effect, and the overall effect sizes were quite robust.”

“The effect size—at first blush—looks like what we would see from current antidepressants,” said J. Raymond DePaulo Jr., M.D., the Henry Phipps professor and director of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, who was not involved with the study. Additionally, he noted that previous studies have suggested that the stimulant-like compound benzylpiperizine may reduce symptoms of depression.

“Not a major breakthrough by any means, but definitely another approach,” he told Psychiatric News.

DePaulo emphasized that more studies of NSI-189 are needed to determine how the medication stacks up against other antidepressants and stimulant-like compounds that have been used in treating depression.

A phase 2 clinical trial for NS-189 is in progress by the Massachusetts General Hospital researchers.

The study was funded by Neuralstem Inc. ■