Brain-Structure Findings Help Explain Antidepressant Efficacy

A report in the Proceedings of the National Academy of Sciences suggests that stress-induced changes in brain metabolism, the volume of the hippocampus, and cell proliferation often associated with depressive illness are counteracted by the administration of a tricyclic antidepressant.

The study bolsters recent reports that impairments of the brain’s structural plasticity are important features of depressive illness and suggests that pharmacological treatments may be able to reverse structural changes in the brain.

Despite many preclinical and clinical investigations, the neurobiological processes leading to depressive disorders, and the mechanisms of actions of medications that effectively treat them, are still not well understood. However, recent studies have pointed to stress-induced “structural remodeling” within the hippocampus as a hallmark of depressive illness. During such remodeling, dendrites in the hippocampus have been shown to shorten and lose branches.

In addition, studies have indicated that there is also a suppression of neurogenesis in the specific structures within the hippocampus, one of the only areas in the brain that continues to generate new neurons into adulthood. These brain changes occur coincident to well-documented endocrine changes in response to stress resulting in increased cortisol levels.

In the present study, researchers at the Division of Neurobiology, German Primate Center of the Max Planck Institute for Biological Chemistry in Göttingen, Germany, studied the ability of the tricyclic antidepressant tianeptine (available in Europe, but not approved by FDA for sale in the U.S.) to modulate stress-induced changes in the brain. The study was funded by French pharmaceutical concern IRI Servier (maker of tianeptine) and by a grant of the Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie (the German equivalent of NIH).

The team of German researchers used a well-established animal model with high validity for research on the pathophysiology of major depression. To mimic a realistic situation of antidepressant therapy, animals were first exposed to a week of psychosocial stress to elicit the expected stress-induced endocrine and central nervous system changes prior to starting oral antidepressant therapy in the animals. Tianeptine therapy then continued during another four weeks of psychosocial stress.

Animals were divided into four groups: the control, control receiving tianeptine, stress, and stress receiving tianeptine. At the end of the protocol, researchers measured brain metabolite concentrations in vivo with magnetic resonance spectroscopy (MRS) and determined hippocampal volume and cell proliferation postmortem.

The team reported that MRS results confirmed that, relative to the control group, chronically stressed animals had significantly decreased levels of several markers for neuronal viability and functionality. N-acetyl-aspartate, which is normally found in healthy, adult neuronal tissue, decreased 13 percent (P<0.05), and two important markers of neuronal energy use, creatine and phosphocreatine, decreased 15 percent (P<0.05). In addition, on postmortem analysis, cell proliferation in certain regions of the hippocampus was found to have decreased 33 percent (P < 0.05) in the stressed animals.

The researchers report that all of these effects were prevented by the simultaneous administration of tianeptine. In stressed animals treated with the drug, an increase in hippocampal volume was seen, rather than the small decrease seen in animals that were exposed to stress without any drug treatment.

According to lead author Boldizsar Czeh, a professor of neurobiology at the German Primate Center, the findings indicate a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in the brain that have been associated with depressive disorders.

“Stress-Induced Changes in Cerebral Metabolites, Hippocampal Volume, and Cell Proliferation Are Prevented by Antidepressant Treatment With Tianeptine” can be accessed on the Web at www.pnas.org by searching on “tianeptine.” ▪

Proc. Natl. Acad. Sci. USA 2001 98 12796