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Scientists at the Medical Center - University of Freiburg have discovered a second mechanism by which common antidepressants work and make the brain more stress-resistant

How common antidepressants work has been known for 60 years. Now researchers at the Medical Center - University of Freiburg have discovered a second, completely independent mechanism of action in mice. Until now, it was only known that antidepressants slow down the breakdown of the neurotransmitter serotonin. Low serotonin levels have long been considered the main cause of depression. The scientists have now shown that antidepressants also block calcium transport in nerve cells in the brain. This makes it easier for the cells to form new connections to other nerve cells. This interconnectivity is essential in order to be able to adapt to new stimuli and stress. In depression, this ability is reduced, as has been shown in recent years. The new findings, published on October 19, 2017 in the journal Biological Psychiatry, could help to develop new therapeutic approaches.

More than four million people in Germany suffer from depression. One in ten experience a severe depressive episode once in their lives. "Almost all the drugs for depression that have come onto the market in recent decades were merely minor modifications of the original substances. Our findings can help to develop drugs that specifically target the newly discovered mechanism of action. This could help people for whom previous medications have had little or no effect," says study leader Prof. Dr. Claus Normann, Managing Senior Physician at the Department of Psychiatry and Psychotherapy at the Medical Center - University of Freiburg.

Effect even without actual site of action

It has been known since the 1960s that too little of the neurotransmitter serotonin is produced in the brains of depressed people. This is why almost all antidepressants inhibit its recycling process in order to increase the amount of serotonin available. These drugs are known as selective serotonin reuptake inhibitors, or SSRIs for short. However, the researchers from the Medical Center - University of Freiburg, the University of Freiburg and the University of Basel already suspected from preliminary studies that this is not the only mechanism of action.

They therefore examined mice in an animal model that had no serotonin uptake mechanism. They should not have reacted to the SSRI administration. "To our great surprise, there was also an antidepressant effect in animals without a serotonin transporter," says Prof. Normann.

Drug facilitates adaptation and learning

The Freiburg researchers showed that the antidepressants intervene in a central learning and adaptation mechanism of the brain known as synaptic plasticity. In order to process new stimuli and adapt to stress, new neural connections must be formed in the brain. This ability is weaker in people with depression than in healthy people. "We have discovered that the SSRI drugs normalize this adaptation process by blocking the calcium channels of the nerve cells. This prevents stress-induced depression and helps animals that already show depression-like symptoms," says Prof. Normann. "Our study clearly shows that this blockade is an essential mechanism of action of antidepressants."

Occurrence and treatment of depression

Depression can occur at any age, but is most common for the first time between the ages of 20 and 30. Those affected feel depressed, listless and uninterested. They usually sleep poorly, tire quickly and are often unable to feel emotions. Severely affected patients can be suicidal. Treatment is psychotherapeutic in accordance with guidelines, with additional medication in the case of a severe depressive episode. Rapid professional help is necessary, particularly due to the frequent occurrence of thoughts of death. The disease is thought to be triggered by a combination of hereditary, life history and current stress factors such as stress.

Original title of the paper: Antidepressants rescue stress-induced disruption of synaptic plasticity via serotonin transporter-independent inhibition of L-type calcium channels

DOI: 10.1016/j.biopsych.2017.10.008

Link to the study: https://www.ncbi.nlm.nih.gov/pubmed/29174591

Further information:

Research group Prof. Normann "Mechanisms of Depression"

Contact:
Prof. Dr. Claus Normann
Managing Senior Physician
Department of Psychiatry and Psychotherapy
Medical Center - University of Freiburg
Phone: 0761 270-66340
claus.normann@uniklinik-freiburg.de