Stem Cells to Treat Depression?

Fran Lowry

December 09, 2015

A stem cell–derived small molecule, NSI-189, taken orally, has demonstrated efficacy in a small number of patients with major depressive disorder (MDD).

The molecule is the first potential antidepressant agent that does not act on the monoamines but promotes the growth of new nerve cells in the hippocampus, lead investigator Maurizio Fava, MD, executive vice chair, Department of Psychiatry, and executive director, Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, Massachusetts, told Medscape Medical News.

"A compound that was selected not because of its effect on monoamines but because of its effect on actual neurogenesis has shown promising antidepressant effects," Dr Fava said.

Dr Maurizio Fava

"If this is confirmed in a larger trial, it is very exciting, because all the approved antidepressants are basically monoamine-based therapies," he said.

The phase 1B study was published online December 8 in Molecular Psychiatry.

To assess the safety and tolerability of NSI-189, Dr Fava and his team enrolled 24 patients with MDD.

The patients were divided into three equal groups and were randomly assigned in a 3:1 ratio to receive either the active drug in one of three doses (40 mg once a day, 40 mg twice a day, or 40 mg three times a day; n = 6 patients) or placebo (n = 2 patients) for 28 days.

During the treatment period, they were monitored in clinic and were then discharged and monitored in periodic follow-up visits for 8 more weeks.

The researchers found that NSI-189 was well tolerated, with no serious adverse events identified for any of the three doses tested.

Its mean half-life was 17.4 to 20.5 hours, and steady state was achieved after 96 to 120 hours.

The researchers used the following four measures to assess clinical efficacy: the Symptoms of Depression Questionnaire (SDQ), the Montgomery-Åsberg Depression Scale (MADRS), the Clinical Global Impressions–Improvement (CGI-I), and the Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ).

Treatment with NSI-189 led to a reduction in depressive and cognitive symptoms across all measures, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures.

The effect sizes for all measures were as follows:

  • CGI-I: 0.57

  • SDQ: 0.90

  • CPFQ: 0.94

  • MADRS: 0.95

These improvements persisted during the 8-week, drug-free, follow-up phase.

Hippocampal and amygdala volumes did not change. However, a post hoc analysis suggested a modest but not statistically significant increase in left hippocampal volume (P = .12) but not the right (P = .82) in the patients treated with NSI-189.

Researchers also assessed changes in quantitative electroencephalography. Analysis showed significant effects by NSI-189 but not by placebo on patients' brain activity, indicated by increased high-frequency alpha waves and amplitude change from baseline to post-dose assessment in specific locations in the left side of the brain.

Confirms How Antidepressants Work

Medscape Medical News invited Peter D. Kramer, MD, professor emeritus, Brown University, Providence, Rhode Island, to give his views on this preliminary research.

Dr Peter Kramer

"This work seems to validate an aspect of the prevailing model of how antidepressant medications work, which is by increasing neurogenesis in the hippocampus. This new chemical appears to do the same thing, but without affecting the same two or three chemicals in the brain, the norepinephrine, serotonin, monoamine oxidase, that the other antidepressants affect," Dr Kramer said.

"Our current antidepressants also increase the volume and number of cells and cell connections in the hippocampus, and this compound was apparently identified because it does that without doing the other things, so in that way, it's a confirmation of principle," he said.

"There's a lot of criticism among the more argumentative scientific essays and also in the lay press saying we don't really know how these medicines work. Well, maybe there really is a good model for how they work," he said.

Dr Kramer cautioned that the work is still very preliminary.

"Lots of things do well in early testing and don't do well over time, either because they don't test out as well or because some negative effects emerge. Still, for me, the most important aspect of this study is that it appears to validate a step in our model of how antidepressant medications work to alleviate depression," he said.

The study was funded by Neuralstem. Dr Fava reports receiving a research grant from Neuralstem. Dr Kramer has disclosed no relevant financial relationships.

Mol Psychiatry. Published online December 8, 2015. Full text.

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