Genetic Determinants of Antidepressant Response

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

NCT00088699 Early Genetic Studies At the start of this project, our researchers looked at specific genes to see if they were linked to how people respond to antidepressants or experience side effects. Later, we joined a large study that combined data from three major genetic studies. Even with this bigger dataset, we didn’t find any strong links between common genes and antidepressant outcomes. This suggested that common genetic differences probably don’t have a big impact on how well antidepressants work. Searching for Rare Genetic Variants More recently, our research team began using advanced DNA sequencing to look for rare genetic changes that might have a stronger effect—especially in people whose depression doesn’t improve with standard treatments (called treatment-resistant depression, or TRD). TRD is a serious condition that can deeply disrupt people’s lives. We sequenced the protein-coding parts of the genome (called the exome) in over 250 people with TRD or regular depression. We also used data from about 200 depressed patients without TRD and nearly 2,000 healthy individuals for comparison. We found five genes with a significant increase of rare variants in people with TRD. One gene, ZDHHC3, stood out—it helps control how brain cells communicate using GABA and glutamate, two key neurotransmitters. These findings suggest that rare genetic changes may play a role in TRD and could lead to new treatment targets. Studying Antidepressants in Lab-Grown Brain Cells Working with other scientists, our team has also studied how antidepressants affect human brain cells grown from stem cells. These cells were created from adult cells that were reprogrammed to act like early-stage brain cells. Initial experiments with a form of ketamine, a fast-acting antidepressant, have shown that the drug changes the activity of many genes involved in cell growth and development. These findings are consistent with the idea that antidepressants act, in part, by stimulating growth in brain cells. We now are trying to find out how ketamine does this and whether other novel antidepressants, like psilocin, show a similar mechanism of action. Exploring Psilocin’s Effects Psilocin is the active metabolite of psilocybin, a “psychedelic” drug that may also have a role in treating some patients with TRD. Animal studies have shown that psilocin can help brain cells grow and form new connections, but this hasn’t been much studied in human cells. Using lab-grown human brain cells, we are finding that psilocin: Increased the number and length of neurites (branches of neurons that connect to other neurons), boosted the number of branch points in neurites, and raised electrical activity in brain cell networks. These effects lasted up to two days and suggest that psilocin helps brain cells grow and communicate better—which may play a role in psilocin’s antidepressant effects. Future Plans In the coming year, our research team plans to test other new antidepressants using the same methods. We hope to find out whether these drugs work through similar biological pathways or whether other pathways are also important in TRD. If successful, this research could uncover key genes and processes involved in how antidepressants work—leading to better, more targeted treatments for depression.