Antidepressant with novel action appears safe and effective in phase 1b clinical trial

December 08, 2015

A small clinical trial of a novel antidepressant that stimulates neurogenesis - the production of new brain cells - shows that the compound appears to be safe and may be effective against depression. Results of the phase 1B trial, led by Massachusetts General Hospital (MGH) investigators, show that treatment with the drug currently identified as NSI-189 improved both depressive and cognitive symptoms in study participants and that its effects appear to persist for several months after treatment discontinuation. The study was supported by the pharmaceutical company Neuralstem.

"All currently approved antidepressant drugs modulate changes in the levels of monoamine neurotransmitters," says Maurizio Fava, MD, executive director of the Clinical Trials Network & Institute (CTNI) in the MGH Department of Psychiatry, lead author of the study published online in the journal Molecular Psychiatry. "Our study finds that this novel compound promotes neurogenesis in a specific part of the brain, is well tolerated and may have robust antidepressant effects. If its efficacy is confirmed in larger trials, this drug could be an important new option for patients not helped by currently available medications."

The study authors note that only one third of patients with major depressive disorder can be adequately treated with today's antidepressant drugs. For some, the drugs do not provide sufficient symptom relief; for others, unpleasant side effects - including gastrointestinal symptoms, weight increase, sleep disorders and sexual dysfunction - can lead them to discontinue treatment. While the primary mechanism of current antidepressants is alteration of neurotransmitters like serotonin, these drugs also induce neurogenesis in the brain structure called the hippocampus, suggesting that increasing neurogenesis could be an alternate strategy for treating depression.

Animal studies of NSI-189 conducted by Neuralstem, which is developing the drug for clinical use, showed that it stimulated hippocampal neurogenesis and improved behavioral symptoms in a mouse model of depression. A phase 1a trial in healthy volunteers was conducted in 2011, and the current phase 1b trial - designed primarily to address safety and identify the maximum safe dose - was designed and guided by investigators from the MGH CTNI. The trial enrolled 24 adult patients diagnosed with major depressive disorder, who were randomized into three treatment groups. In each group of 8 participants, 6 received the active drug and 2 received a placebo; those assigned to the active drug in the double-blinded study received 40 mg doses either once, twice or three times daily. After 28 days of treatment, which was conducted in an inpatient clinical trials unit, patients were followed for another 56 days.

Reports of adverse effects - none of them serious - were similar in both the control group and in participants receiving the active drug, even those who took the maximum daily dose. EEG readings taken prior to and at several times during treatment showed some changes, primarily an increase in high-frequency alpha waves, and MRI scans suggested the possibility of increased hippocampal volume in those taking the active drug. On four measures of depressive or cognitive symptoms, participants receiving the active drugs showed improvement after the 28-day treatment period, with significant differences from the placebo group on two measures based on participants' self-reports. Symptom improvement was maintained throughout the follow-up period, which the authors indicate is particularly notable since the effects of current antidepressants typically only last as long as they are taken. The MGH team has also helped to design and is involved in implementing the larger phase 2 trial of NSI-189 that has recently been initiated
Along with Fava, who is the Slater Family Professor of Psychiatry at Harvard Medical School, co-authors of the Molecular Psychiatry paper are Bettina Hoeppner, PhD, Martina Flynn, David Mischoulon, MD, PhD, Gustavo Kinrys, MD, and Marlene Freeman, MD, MGH Psychiatry; Bradford Dickerson, MD, and Nikolaos Makris, MD, MGH Neurology; Karl Johe, PhD, Neuralstem; Larry Ereshefsky, PharmD, FCCP, BCPP, and Brett English, PharmD, PhD, PAREXEL International; Lev Gertsik, MD, California Clinical Trials Medical Group; J.A. Bilello and L.M. Thurmond, Ridge Diagnostics; and Jack Johnstone, Q-Metrx, Inc.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $760 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Antidepressant Articles from Brightsurf:

Antidepressant may prevent severe COVID-19, trial suggests
The antidepressant fluvoxamine appears to prevent COVID-19 infections from worsening and may help keep patients out of the hospital, a trial based on research from the University of Virginia School of Medicine suggests.

Trajectories of antidepressant medication use during pregnancy
In an analysis of women who started pregnancy when taking antidepressant medications, investigators identified three trajectories of antidepressant dispensing during pregnancy: more than half stopped their treatment, a quarter maintained their treatment throughout pregnancy, and one-fifth discontinued it for a minimum of three months and then resumed it during the postpartum period.

Decades-old antidepressant may fend off prostate cancer's return
An antidepressant from the '50s, repurposed to fight prostate cancer, lowered PSA levels in men with recurrent disease, pilot study shows.

Researchers say extended antidepressant use creates physical dependence
Researchers explain symptoms associated with Antidepressant Discontinuation Syndrome and provide a schedule for tapering various classes of antidepressants.

Number of depressed over-65s unchanged but antidepressant use soars
The proportion of people aged over 65 on antidepressants has more than doubled in two decades -- according to new research led by the University of East Anglia.

Antidepressant medications appear to be generally safe
Antidepressants are generally safe, according to a new study by an international team of researchers.

Why is ketamine an antidepressant?
Delving deep inside the neural circuitry of 'depressed' mice, researchers have revealed how ketamine works in cells to achieve its fast-acting antidepressant effect.

Childhood methylphenidate treatment predicts antidepressant use during adolescence
A new, 12-year longitudinal study, which monitored 6,830 children from early childhood into adolescence, has shown that consistent treatment with MPH-based medications during childhood increases the risk of antidepressant use during adolescence.

Antidepressant could stop deadly sepsis, study suggests
An antidepressant drug used to treat obsessive-compulsive disorder could save people from deadly sepsis, new research suggests.

Overprescribing of antidepressant medications may be common in elderly patients
In a Pharmacology Research & Perspectives study of individuals living in Olmsted County, Minnesota from 2005-2012, potential overprescribing of antidepressant medications occurred in nearly one-quarter of elderly residents.

Read More: Antidepressant News and Antidepressant Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to