What effects do antidepressants have on the brain? And why do they often take several weeks to work? These questions have been controversial in science for decades. A study has now uncovered a previously unknown mechanism of action: According to this, the drugs dock on a receptor on the nerve cells that promotes neuronal plasticity. This enables patients to process positive information better again. However, the effect depends on the cholesterol level being neither too high nor too low. The findings could help develop new, more effective antidepressants.
Since the 1960s, the view was widespread in science and medicine that depression was caused by a lack of the neurotransmitter serotonin in the brain. Many antidepressants are therefore based on the idea of inhibiting the reuptake of serotonin from the synaptic gap so that the concentration remains higher. However, there have long been doubts about the serotonin hypothesis. Numerous studies could not find a connection between the serotonin concentration and depression. In addition, the hypothesis cannot explain why most antidepressants take several weeks to take effect.
Receptor increases neural plasticity
Researchers led by Plinio Casarotto from the University of Helsinki in Finland have now identified a new mechanism of action: According to this, antidepressants bind to the receptor for a growth factor in the brain, the so-called brain-derived neurotrophic factor (BDNF). This messenger substance promotes the growth of new nerve cells and synapses and thus increases neuronal plasticity. “With the BDNF receptor as the docking point, we can for the first time directly explain how antidepressants work and why it takes so long for the effect to set in,” explains co-author Claus Normann from the University of Freiburg.
In simulations and cell cultures, the researchers demonstrated that antidepressants dock on a side pocket of the receptor and thus stabilize it in such a way that more BDNF can bind to it. In addition, they ensure that the receptor is expressed more frequently on the surface of the cells, which also leads to increased binding of BDNF and thus more neuronal plasticity. This mechanism was found for different types of antidepressants, including so-called tricyclic antidepressants, selective serotonin reuptake inhibitors, and ketamine.
Effect depending on the cholesterol level
The researchers also observed the effect on mice. In a mouse model for depression, all tested antidepressants ensured that the mice showed fewer depressive symptoms. This also applied to mice that lacked an important serotonin transporter in the brain – that is, exactly the point at which the antidepressant should act according to the serotonin hypothesis. Mice, on the other hand, in which the BDNF receptor was mutated in such a way that the antidepressants could not bind there, continued to show depressive symptoms. “This fits in with our hypothesis that the effect of antidepressants is mediated by their binding to this receptor,” said the researchers.
In addition, Casarotto and colleagues showed that the effect of antidepressants depends on the cholesterol level in the brain. If they gave the mice a cholesterol-lowering drug, the antidepressants worked worse. Too high a cholesterol level also reduced the effect. “Interestingly, this binding site needs a normal cholesterol level in order to be able to be optimally active,” says Normann. At the molecular level, the researchers explain the effect in such a way that cholesterol in the cell membrane of the nerve cells influences the shape of the BDNF receptor. Too much or too little cholesterol makes it harder for the active ingredients to bind.
Approach to new therapies
Scientists had long suspected that the effects of antidepressants are related to neuronal plasticity. The current study now shows a direct link for the first time. “By stimulating the BDNF, the brain can better absorb new, positive information from the environment or during psychotherapy and recovers from its depressed state,” says Normann. Regions of the brain that have become abnormally wired due to stress, for example, and show reduced activity, can renew themselves. According to the researchers, the findings on the mechanism of action can also help develop new, more effective antidepressants with fewer side effects. They also show how drug and psychotherapeutic treatment can work together.
Source: Plinio Casarotto (University of Helsinki, Finland) et al., Cell, doi: 10.1016 / j.cell.2021.01.034