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Searching for New Antidepressants in the Brain’s Neurochemistry

Searching for New Antidepressants in the Brain's NeurochemistryProzac and a host of other common antidepressants are believed to lessen symptoms  by increasing levels of of the neurotransmitter serotonin. New research seeks to improve the understanding of how serotonin enables brain cells to communicate. That is, how does increased serotonin act to reduce symptoms of anxiety and depression?

Integral to the investigation is an improved recognition of how another molecule, termed brain-derived neurotropic factor (BDNF) nourishes nerve cells and also aids connectivity.

Investigators say connecting the dots between the two molecules — whose levels are decreased in depression and increased by current antidepressants — could lead to development of new medical therapies. Antidepressants such as Prozac have recently been found to also increase BDNF levels, said Anilkumar Pillai, Ph.D., a neuroscientist at the Medical College of Georgia.

“We don’t know how the molecule, serotonin, which is well-studied in depression, regulates BDNF signaling,” Pillai said.

Pillai has received a five year, $1.5 million grant from the National Institute of Mental Health to help him explore the connection. Investigators believe a critical piece of the puzzle is a protein called transglutaminase 2, or TG2. This protein is found in brain cells and most other cell types.

TG2 plays a role in natural serotonin recycling and potentially is a factor in the serotonin deficiency associated with depression. It also may help explain why levels of serotonin and BDNF seem to rise and fall in sync, Pillai said.

TG2 converts serotonin to Rac1, a protein that helps rejuvenate BDNF receptors, which typically sit on the surface of brain cells but must periodically move inside to reinvigorate. Depression appears to upset the balance of these complex, critical inner workings.

Pillai hypothesizes that the high levels he has found in depression likely result in too much serotonin conversion, leaving too little of the neurotransmitter to properly support brain cell communication. That is, although more serotonin of Rac1 is produced, the cells increasing degrade ultimately decreasing BDNF signaling as well.

Pillai has seen the unfortunate chain of events play out in an animal model with increased levels of TG2 and clear signs of depression.

“If you can fix problems with the receptor, you should be able to reverse depressive symptoms in these mice,” he said.

In the study, Pillai plans to investigate whether existing antidepressants impact TG2. To help clarify the role of the impaired BDNF receptors, Pillai also wants to know whether giving BDNF to the depressed animal model improves depression.

To do this, he plans to use a viral particle to directly activate the BDNF receptor. And he’s also giving the TG2 inhibitor cysteamine to an animal model developed by administering stress hormones.

He recently published in the journal PLoS ONE findings that the inhibitor appears effective in normalizing depressive behavior and BDNF levels in that model.

Mental stress is a major factor in numerous psychiatric disorders including depression, schizophrenia and anxiety, he noted.

Some antidepressants, such as Prozac, were designed to interfere with a natural recycling of serotonin called reuptake so more serotonin is available where needed to enable cell communication. Pillai said it’s not yet clear if serotonin reuptake is the same thing as its conversion to Rac-1.

“We need to learn more about how all these pieces fit to ultimately design new therapies for depression and related psychiatric disorders,” he said.

Major depressive disorder is the leading cause of disability in Americans age 15-44, affecting about 14.8 million adults.

Source: Georgia Health Sciences University

Searching for New Antidepressants in the Brain’s Neurochemistry

Rick Nauert PhD

Rick Nauert, PhDDr. Rick Nauert has over 25 years experience in clinical, administrative and academic healthcare. He is currently an associate professor for Rocky Mountain University of Health Professionals doctoral program in health promotion and wellness. Dr. Nauert began his career as a clinical physical therapist and served as a regional manager for a publicly traded multidisciplinary rehabilitation agency for 12 years. He has masters degrees in health-fitness management and healthcare administration and a doctoral degree from The University of Texas at Austin focused on health care informatics, health administration, health education and health policy. His research efforts included the area of telehealth with a specialty in disease management.

APA Reference
Nauert PhD, R. (2018). Searching for New Antidepressants in the Brain’s Neurochemistry. Psych Central. Retrieved on December 2, 2020, from
Scientifically Reviewed
Last updated: 8 Aug 2018 (Originally: 15 Aug 2012)
Last reviewed: By a member of our scientific advisory board on 8 Aug 2018
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