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Antidepressants make the brain receptive to new experiences again

Selective serotonin reuptake inhibitors (SSRIs) increase neuroplasticity
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(Vienna, 31 May 2021) Around 15% of the global population will suffer from depression at least once in their lives. Antidepressants from the group of so-called selective serotonin reuptake inhibitors (SSRIs) are highly effective in one third of patients, while another third shows significant improvement. A Viennese research team has investigated whether these antidepressants improve learning ability and receptivity. The results of a double-blind study show that SSRIs increase neuroplasticity. Knowledge about this starting point in the brain might help in the development of alternative or faster-acting antidepressants.

Babies soak up environmental influences and use them to learn. Never again in our lives is our brain so receptive and ready to create new neural networks. Neuroplasticity is the name given to this ability of the brain to adapt, to process new information and reassign tasks, for example in the event of a physical or sensory impairment. At the other end of this scale of receptivity are people with clinical depression, which occurs in around 15% of the total population at least once in their lives. "They are dejected, lethargic, emotionally numb, and some become weary of life as a consequence," says Rupert Lanzenberger, Head of the Neuroimaging Lab at the Medical University of Vienna's Department of Psychiatry and Psychotherapy, describing the symptoms.

So-called SSRIs, short for Selective Serotonin Reuptake Inhibitors, are among the most commonly prescribed antidepressants. They usually take effect after a few weeks and have few side-effects. So far, there has been limited research into exactly how the drugs alter the neurotransmitter regime and neuronal networks in the human brain. A double-blind study on healthy volunteers has now been conducted at the Medical University of Vienna, backed by funding from the Austrian Science Fund (FWF). Using imaging techniques, a team led by project leader Lanzenberger has now shown that SSRIs boost neuroplasticity, thereby facilitating certain learning processes in the brain. This opens up new possibilities for developing alternative or faster-acting drugs.

Lowering the relearning threshold
The neurotransmitter serotonin co-determines what needs to be stored or modified in the brain over the course of a person's lifetime. Various animal studies support the theory that SSRIs lower the threshold for this and therefore increase neuroplasticity: "In principle, every conversation can alter the microstructure of our brain and serotonin modulates the neuroplastic response of the brain to these environmental stimuli. Adult brains are no longer able to store every experience as easily and, consequently, the neuronal microstructures of the brain are not as adaptive as they were in childhood or adolescence. However, if you can no longer take your usual route to work because of roadworks, you have to respond to this. We relearn, in that we imprint a new route," explains the project leader.

In order to investigate whether antidepressants facilitate the relearning process relative to a placebo, the team led by Rupert Lanzenberger conducted a six-week double-blind study with 80 healthy volunteers. Using magnetic resonance imaging, they measured the microstructure, the functional and structural connectivity and the interaction and activity of brain regions that are particularly significant in memory processes, such as the hippocampus and insula. In addition, they used magnetic resonance spectroscopy to quantify the concentration of the major excitatory neurotransmitter, glutamate, and the major inhibitory neurotransmitter, gamma aminobutyric acid (GABA), in various regions of the brain.

Essential mode of action confirmed
In an initial examination, the researchers first of all measured the base-line networking and activity of the relevant brain regions in all volunteers, as well as the levels of neurotransmitters. Subsequently, as part of a concentrated daily task, one group learned to pair up unfamiliar faces and the other group learned to associate Chinese symbols with words. After a comparative measurement, they started to take SSRIs or placebo for a period of three weeks in parallel to the concomitant relearning programme with new pairs of faces and symbol-word pairs. A third measurement was then taken.

The researchers' hypothesis was confirmed: SSRIs make it easier to store the new associations, as is confirmed by the visible changes in the brain. "The increase in neuroplasticity is an important mode of action of SSRIs," stresses Rupert Lanzenberger. So, you could say that they make the brain more receptive to new associations again, and to letting go of old ones. "At the end of the day, it appears that the treatment of depression also involves letting go of learned associations and adopting a new outlook on the world," describes the brain researcher, adding: "We see that medication is often only the first step in treating depression. Just as important are concomitant psychotherapy and different environmental experiences and this process can also be regarded as a sort of relearning process with increased plasticity."

The study clearly showed the increase in neuroplasticity in the group taking SSRIs compared to the control group: "The imaging data pointed to a change in the balance. Some regions are more strongly inhibited than others, the balance between different regions of the brain changes, as does the intensity of communication between the brain regions." SSRIs do not therefore have a direct acute impact on mood but alter the receptivity for relearning processes, thereby creating favourable conditions to help people out of their depression. This knowledge can be used to develop other substances that could increase neuroplasticity and have a faster antidepressant effect.

Rupert Lanzenberger is Associate Professor of Neurosciences and a doctor at the Medical University of Vienna's Department of Psychiatry and Psychotherapy, where he has headed up the Neuroimaging Lab since 2005. He works with imaging techniques to visualise molecular and functional processes in the brain, particularly in psychiatric illnesses and in the area of psychopharmacology. The clinical study "Antidepressants in combination with learning promote neuroplasticity" was funded by the Austrian Science Fund (FWF) to the tune of around €300,000. Lanzenberger has won numerous international research prizes and is a member of the European Academy of Sciences and Arts (EASA).

 

Publications
Reed MB, Vanicek T, Seiger R, et al.: Neuroplastic effects of a selective serotonin reuptake inhibitor in relearning and retrieval, in: NeuroImage 2021

Spurny B, Vanicek T, Seiger R, et al.: Effects of SSRI treatment on GABA and glutamate levels in an associative relearning paradigm, in: NeuroImage 2021

Spurny B, Seiger R, Moser P, et al.: Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm, in: NeuroImage 2020