Dec. 15, 2000 New Haven, Conn. – Continued use of anti-depressants leads to new cell growth in an area of the brain known to suffer cell death and atrophy as a result of depression and stress, a study by Yale researchers shows.
Depression affects an estimated 12 percent to 17 percent of the population at some point during their lifetime. Anti-depressants are commonly prescribed for depression and other affective disorders, but the drugs’ therapeutic effects on the molecular and cellular level are not clearly understood.
"The findings of our study are that chronic administration of anti-depressants increases the number of neurons in the adult hippocampal ," said Ronald Duman, M.D.., professor of psychiatry and pharmacology. "This could explain in part how anti-depressants produce their therapeutic response." Duman was senior author of the study published Dec. 15 in The Journal of Neuroscience.
The hippocampus is part of the limbic brain that is involved in learning, memory, mood and emotion. It is one of only a few regions of the brain where production of neurons occurs in the adult brain of animals, including humans. Several studies have demonstrated that stressful experiences, both physical and psychological, lead to neuronal loss or atrophy in the hippocampus. Other studies show that anti-depressants can block this cell loss.
"In humans, brain imaging studies demonstrate that in patients with depression or post traumatic stress syndrome there is a decrease in volume of the hippocampus that is thought to be related to the neuronal atrophy and loss," Duman said. "The results of our study demonstrate that anti-depressants can reverse or block further loss of neurons in the hippocampus by increasing neurogenesis (new cell growth)."
Duman’s laboratory has been studying the mechanism of action of anti-depressants in rodents for over 15 years. The researchers have focused on cellular actions of anti-depressants, looking at the role of the intracellular signal transduction pathways that control neuronal function. They have identified several actions of anti-depressants which indicate that anti-depressants influence the survival or the number of neurons in the hippocampus.
This study was intended to look at whether the anti-depressants increased the birth of neurons in the hippocampus. The researchers tested several different classes of anti-depressant drugs, as well as electroconvulsive seizure therapy (ECS), and an anti-psychotic medication.
ECS is clinically the most effective treatment for cases of depression that are resistant to available drug treatments. As expected, chronic, or repeated, administration of ECS increased the number of neurons in the hippocampus of the brain by 50 percent. The chemical anti-depressants tested increased the number of neurons in the same area by 20 percent to 40 percent.
The anti-depressants that were administered included a monoamineoxidase inhibitor (tranlcypromine), a serotonin-selective reuptake inhibitor (fluoxetine), and a norepinephrine-selective reuptake inhibitor (reboxetine).
However, brief or "acute" (one to five days) administration of the anti-depressants did not lead to any significant cell change. Results were seen after 14 to 28 days of administration, which is consistent with treatment regimens for the therapeutic response to anti-depressants.
Administration of the anti-psychotic drug haloperidol, which is a non-antidepressant psychotropic drug, also did not produce any significant cell change in this area of the brain. In addition, the researchers recently have demonstrated that morphine, another non-antidepressant psychotropic drug, decreases the number of cells in the hippocampal area.
Co-authors of the study were Jessica Malberg and Amelia Eisch, both postdoctoral fellows in psychiatry, and Eric Nestler, formerly a professor of psychology, pharmacology and neurobiology at Yale.
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