Antidepressants Grow New Brain Cells

Neurons under the microscope.

Research funded by the National Institute of Mental Health strongly suggests that some antidepressants work by growing new neurons (brain cells). One 2003 study, for example, found that blocking the formation of neurons in the hippocampus blocked the behavioral effects of the antidepressant fluoxetine (marketed as Prozac and Sarafem) in mice.

Studies had already demonstrated that depression and anxiety can cause loss of neurons.

Other studies have shown that antidepressants can trigger neuron growth, termed neurogenesis, in the hippocampus; but the significance of this was unclear. Here's how an NIMH press release summarized the research:

The researchers first showed that mice become less anxious – they begin eating sooner in a novel environment – after four weeks of antidepressant treatment, but not after just 5 days of such treatment. Paralleling the delay in onset of antidepressant efficacy in humans, the chronically-treated mice, but not the briefly-treated ones, showed a 60 percent boost in a telltale marker of neurogenesis in a key area of the hippocampus.

To find out if the observed neurogenesis is involved in antidepressants’ mechanism-of-action, Rene Hen, Ph.D and colleagues selectively targeted the hippocampus with x-rays to kill proliferating cells. This reduced neurogenesis by 85 percent. Antidepressants had no effect on anxiety and depression-related behaviors in the irradiated mice.

For example, fluoxetine failed to improve grooming behavior, as it normally does, in animals whose behavior had deteriorated following chronic unpredictable stress. Evidence suggested that this could not be attributed to other effects of x-rays.

Neurons communicate with each other by secreting messenger chemicals, or neurotransmitters, such as serotonin, which cross the synaptic gulf between cells and bind to receptors on neighboring cell membranes.

Medications that enhance such binding of serotonin to its receptors (serotonin selective reuptake inhibitors, or SSRIs) are widely prescribed to treat anxiety and depression, suggesting that these receptors play an important role in regulating emotions.

By knocking out the gene that codes for a key subtype of serotonin receptor (5-HT1A), the researchers created a strain of "knockout"mice that as adults show anxiety-related traits, such as a reluctance to begin eating in a novel environment. While unaffected by chronic treatment with the SSRI fluoxetine, the knockout mice became less anxious after chronic treatment with tricyclic antidepressants, which act via another neurotransmitter, norepinephrine, suggesting an independent molecular pathway.

While chronic fluoxetine treatment doubled the number of new hippocampal neurons in normal mice, it had no effect in the knockout mice. The tricyclic imipramine boosted neurogenesis in both types of mice, indicating that the serotonin 1A receptor is required for neurogenesis induced by fluoxetine, but not imipramine.

Chronic treatment with a serotonin 1A-selective drug confirmed that activating the serotonin 1A receptor is sufficient to spur cell proliferation.

What is the significance of this research? We always assumed that antidepressants worked by affecting neurotransmitters, the chemicals that pass nerve signals between neurons; but this did not explain why they often take several weeks to work. This research provides a possible explanation. This is the first research to demonstrate that antidepressant-induced growth of new nerve cells produces positive behavior changes.

“This is an important new insight into how antidepressants work,”according to NIMH director Thomas Insel, M.D. “We have known that antidepressants influence the birth of neurons in the hippocampus. Now it appears that this effect may be important for the clinical response.”

Lead researcher Rene Hen, Ph.D., of Columbia University,is reported by NIMH to comment that "If antidepressants work by stimulating the production of new neurons, there’s a built-in delay. Stem cells must divide, differentiate, migrate and establish connections with post-synaptic targets – a process that takes a few weeks. Our results suggest that strategies aimed at stimulating hippocampal neurogenesis could provide novel avenues for the treatment of anxiety and depressive disorders."

Source: ASHER, j. Creation of New Neurons Critical to Antidepressant Action in Mice National Institute of Mental Health, August 7, 2003

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