Why is it so hard to get rid of some antidepressants?


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Researchers at the University of Illinois, Chicago, are one step closer to discovering why it is so difficult for people to withdraw from some antidepressant medications.

The document “Antidepressants produce signaling changes associated with persistent Gαs in ponds following withdrawal, “published in the journal Molecular pharmacology, deals with the molecular and cellular mechanisms that cause antidepressant withdrawal syndrome.

The study’s authors, Mark Rasenick, a distinguished professor of physiology and biophysics and psychiatry at the UIC and a research career scientist at Jesse Brown VA Medical Center, and Nicholas Senese, a UIC postdoctoral fellow, explained that current antidepressants it can take about two months to take effect in patients who then continue to take these medications for years. Weaning patients from these medications can cause unpleasant symptoms that can range from flu-like feelings, persistent pain or itching to Parkinson’s conditions that can last for weeks.

One in six Americans has or will have depression; for veterans, the estimated rate is double.

Previous research has shown that antidepressant drugs are gradually collected in cholesterol-rich membrane structures called lipid ponds. When a neurotransmitter (such as serotonin, which participates in mood) binds to a receptor located outside a cell, a lipid protein –— called Gs alpha –— transmits the signal inside the cell where it can cause various actions. One of these actions is the production of an intracellular signaling molecule called cyclic AMP. In the brains of people with depression, cyclic AMP is low; but with effective antidepressant treatment, cyclic AMP returns to normal.

For their new study, Rasenick and Senese examined the activity of Gs alpha molecules by using fluorescent light to determine how they moved in and out of lipid ponds. They found that while the withdrawal of some antidepressant drugs balances the alpha action of Gs in and out of lipid ponds, other drugs suppress the return of Gs alpha to ponds. Researchers believe that this suppression is what causes persistent and unwanted effects of some antidepressants.

Lipid puddles appear to be relevant both for the delayed therapeutic effects of antidepressants and for the difficulty of weaning these drugs. It takes a long time for these drugs to be classified into ponds and a long time for the drugs to come out, some more than others. Interestingly, fast-acting antidepressants such as ketamine have similar effects on Gs alpha and , but without delay, Rasenick said.

“This validates the notion that intracellular molecules resulting from an active alpha Gs protein are a very good biomarker for the functioning of antidepressants,” Rasenick said. “We believe we have achieved some clarity on this issue and we would like to move towards the use of technology to create a personalized treatment for depression.”

Rasenick explained that by observing how an individual patient’s cells metabolize alpha Gs proteins, they can better predict which antidepressant drugs might work for them. This can be achieved in days and not in weeks and months of trial and error to find the right medication. A company that uses this technology developed by the UIC, Pax Neuroscience, has been created to develop the technology for the market.

Ketamine acts quickly to treat depression and its effects last, but how?

More information:
Nicolas B. Senese et al, Antidepressants produce persistent Gα-associated signaling changes in lipid ponds after drug withdrawal, Molecular pharmacology (2021). DOI: 10.1124 / molpharm.120.000226

Citation: Why is it so hard to get rid of some antidepressants? (2021, May 27), retrieved May 27, 2021 at https://medicalxpress.com/news/2021-05-hard-antidepressants.html

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