New Antidepressant Stimulates Neuron Growth

Peter Forster Treatments of Depression

The results of a clinical trial published in December in Molecular Psychiatry suggest that a new medication (NSI-189) which has been shown to increase the production of cells in the hippocampus and the amygdala in pre-clinical studies may help treat major depression.

The results highlight the evidence that has been accumulating that stimulating the production of new cells in the hippocampus (neurogenesis) may be a key factor in the antidepressant effects of many, if not all, medications currently used to treat depression (see Malberg, et al). NSI-189 was specifically developed to target neurogenesis and its success in this trial might support this new theory of how antidepressants work.

Maurizio Fava, MD, who is the director of the Clinical Research Program at Massachusetts General Hospital, led a team of researchers who evaluated the effectiveness, safety, and tolerability of NSI-189 in a phase 1B clinical trial that included 24 patients with recurring symptoms of MDD.

This is a very small study that was intended to generate hypotheses that can be tested in larger studies.

The results showed that on two of the four scales (the Symptoms of Depression Questionnaire (SDQ) and Cognitive, and the
Physical Functioning Questionnaire (CPFQ)) the medication significantly improved symptoms of depression.

On the two clinician administered scales (the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Cognitive Global Impression-Improvement (CGI-I) scale) there was a trend towards improvement in those receiving the active medication which did not reach clinical significance.

The researchers also found that the benefits in this study lasted for at least an additional month after the initial 28 day study, which may make this medication unique. Other antidepressants generally lose their effectiveness after discontinuation.

The most common adverse events associated with NSI-189 use included headache, dizziness, and somnolence.

Commenting on the significance of the study in the American Psychiatric Association’s Psychiatric News, Dr. Fava wrote:
“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… This finding is in sharp contrast to the rapid return of symptoms typically observed following discontinuation of standard antidepressants.”

Although this was a small study, the authors added that, “each cohort [treated with NSI-189] seemed to have consistently shown an antidepressant effect and the overall effect sizes were quite robust.”


“A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.”M Fava 1,2, K Johe 3, L Ereshefsky 4, L G Gertsik 5, B A English 4, J A Bilello 6, L M Thurmond 6, J Johnstone 7, B C Dickerson 8, N Makris 8, B B Hoeppner 1,2, M Flynn 1, D Mischoulon 1,2, G Kinrys 1,2 and M P Freeman 1,2 Molecular Psychiatry advance online publication 8 December 2015; doi: 10.1038/mp.2015.178

Malberg JE, Schechter LE. Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs. Curr Pharm Des. 2005;11(2):145-55. Review. PubMed PMID: 15638755.