Neurogenesis-Stimulating Compounds Show Promise in the Treatment of Major Depression

Deborah Brauser

September 21, 2009

September 21, 2009 — A neurogenesis-based platform may be leading the way in helping to identify new treatments for depression, including major depressive disorder (MDD), according to new research.

In a clinical proof-of-concept study first presented at the 49th Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, patients treated with a compound named BCI-952 (BrainCells, Inc), which combined buspirone and melatonin, showed improvements in depression symptoms via multiple depression scales.

"Our study results provide the first prospective clinical validation of neurogenesis as a target for the treatment of mood disorders like depression, in contrast to the traditional focus on affecting serotonin function for antidepressant drug development," lead investigator Maurizio Fava, MD, executive vice chair of the department of psychiatry at Massachusetts General Hospital in Boston, told Medscape Psychiatry.

"We now know that we can stimulate the natural process of neurogenesis with a positive clinical impact on depression symptoms," added Dr. Fava.

Treating Depression by Stimulating Neuron Growth

Neurogenesis is the process by which preexisiting stem cells in the hippocampus of the adult brain produce new brain cells, including neurons, explained Dr. Fava. "Researchers have speculated that the brain's ability to grow new brain cells may have an impact on depression," he added.

In this trial, the investigators sought to evaluate the efficacy of BCI-952 for the treatment of MDD. The BCI-952 compound was selected for this trial because of its neurogenic properties.

"Buspirone and melatonin are 2 compounds not known to have antidepressant efficacy by themselves," said Dr. Fava. "But in combination, they have shown a robust effect in stimulating neuron growth and were identified as potentially having an antidepressant effect when taken together."

A total of 134 patients with MDD were randomly assigned to receive the BCI-952 combination (n = 67), buspirone alone (n = 34), or placebo (n = 33) during a 6-week period.

Efficacy measures included the Clinical Global Impressions Scale for improvement (CGI-I), the Inventory of Depressive Symptoms (IDSC30), the Hamilton Anxiety Scale, and the patient-rated Quick Inventory of Depressive Symptomatology (QIDS SR-16).

Depression Symptoms Reduced

Results at the end of the study showed that the mean CGI-I scores were statistically significant for those treated with BCI-952 compared with those treated with placebo (P = .046).

In addition, the responders' analysis for CGI-I (score ≤ 2) demonstrated a higher response rate for BCI-952, at 58% vs 38% for buspirone alone (P = .063) and 36% for placebo (P = .055).

The patients treated with BCI-952 also showed statistically significant improvements on the IDSC30 (P = .034) and Hamilton (P = .041) scales.

Although the QIDS SR16 also demonstrated improvements for BCI-952 compared with placebo, they were not statistically significant.

"We believe that this pilot study represents the first demonstration that rational drug discovery utilizing a preclinical neurogenesis platform can be applied to the treatment of [MDD]," said Dr. Fava. "It also showed that when 2 fairly benign compounds are used together, they can have an antidepressant effect."

"The results were a nice surprise and suggest that there may be new ways of identifying antidepressant compounds," he added.

The next steps for the investigators include another trial to confirm the effectiveness of BCI-952, as well as concluding the phase 2 trial of BCI-540, another compound in BrainCells neurogenesis platform, for the treatment of depression with anxiety.

Early Days

"These findings are exciting," said Rene Hen, PhD, professor of neuroscience and psychiatry at Columbia University in New York, who was credited with discovering the link between neurogenesis and depression, to Medscape Psychiatry. Dr. Hen was not involved with this study, but he is a cofounder of BrainCells.

"In preclinical mouse models, my team found that neurogenesis was required for some of the effects of antidepressants. However, we had not been able to show whether that was sufficient in humans. In other words, if you can isolate a compound that stimulates neurogenesis, can you then produce an antidepressant effect in humans? The BCI study suggests that that is possible, which I think is very exciting."

Dr. Hen said that he looks forward to seeing replication studies with the BCI-952 compound, including comparisons with known antidepressants such as fluoxetine.

"From the point of view of basic science, this study suggests that by studying and looking for compounds that stimulate neurogenesis, we may gain access to novel antidepressants," said Dr. Hen. "But from the clinicians' point of view, it's too early because whether these novel compounds are going to be better than other antidepressants currently on the market is something we really don't know yet.

"What this study really encourages me to do now is to look further at strategies for stimulating neurogenesis and to look at their impact in all sorts of behaviors such as anxiety and even cognition. It's just an exciting time for the study of neurogenesis as a whole," he said.

This study was supported by BrainCells, Inc. Dr. Fava is on the Clinical Advisory Board for BrainCells, and Dr. Hen is a cofounder of the company.

49th Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting. Presented July 1, 2009.

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