Why Is It so Hard to Withdraw From Some Antidepressants?

Summary: A new study reveals the molecular and cellular mechanisms behind why some people find it harder to stop using antidepressants than others with depression.

Source: University of Illinois

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

The paper “Antidepressants produce persistent Gαs associated signaling changes in lipid rafts following drug withdrawal,” published in the journal Molecular Pharmacology, addresses the molecular and cellular mechanisms that cause antidepressant withdrawal syndrome.

The study’s authors, Mark Rasenick, distinguished professor of physiology and biophysics and psychiatry at UIC and research career scientist at the Jesse Brown VA Medical Center, and Nicholas Senese, a postdoctoral fellow at UIC, explained that current antidepressants can take approximately two months to take effect in patients who then continue taking these drugs for years.

Weaning patients from these drugs can result in unpleasant symptoms that can range from flu-like feelings and persistent pain or itch to Parkinson’s-like conditions that can last for weeks.

One in six Americans have, or will, suffer from depression; for veterans, the estimated rate is twice that.

Previous research has demonstrated that antidepressant drugs collect gradually in cholesterol-rich membrane structures called lipid rafts. When a neurotransmitter (such as serotonin, which is involved with mood) binds to a receptor on the outside of a cell, a protein in the lipid raft — called Gs alpha — conveys the signal into the cell’s interior where it can elicit a variety of actions.

One of those 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 is returned to normal.

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

Lipid rafts appear to be relevant for both the delayed therapeutic effects of antidepressants as well as the difficulty in weaning off from these drugs. It takes a long time for these drugs to sort into rafts and a long time for the drugs to exit — some more than others. Curiously, rapid-acting antidepressants like ketamine have similar effects on Gs alpha and lipid rafts, but without the delay, Rasenick said.

This shows different colored pills and scrabble tiles spelling out "help"
One in six Americans have, or will, suffer from depression; for veterans, the estimated rate is twice that. Image is in the public domain

“This validates the notion that intracellular molecules that result from an active Gs alpha protein are a very good biomarker for the functioning of antidepressants,” Rasenick said. “We think we have achieved some clarity on this issue and we’d like to move forward toward using technology to create a personalized treatment for depression.”

Rasenick explained that by looking at how an individual patient’s cells metabolize Gs alpha proteins, they can better predict what antidepressant medication could work for them. This can be accomplished in days and not weeks and months of trial and error to find the right medication. A company using this UIC-developed technology, Pax Neuroscience, has been formed to develop the technology for the market.

Additionally, the cellular fluorescent indicators allow testing at a cellular level to develop new antidepressant medications.

Funding: This study was funded by the Veterans Administration (VA Merit BX001149) and the National Institutes of Health (T32 MH067631 and R01 AT009169).

About this psychopharmacology research news

Source: University of Illinois
Contact: Lori Botterman – University of Illinois
Image: The image is in the public domain

Original Research: Closed access.
Antidepressants produce persistent Gαs associated signaling changes in lipid rafts following drug withdrawal” by Nicolas B. Senese and Mark M. Rasenick. Molecular Pharmacology


Antidepressants produce persistent Gαs associated signaling changes in lipid rafts following drug withdrawal

Termination of antidepressant therapy often has negative consequences. While symptoms of antidepressant withdrawal are widely recognized, the molecular processes that underlie them are not well characterized.

We show that certain aspects of Gαs signaling remain suppressed following antidepressant withdrawal, even after others have reverted to baseline. Antidepressant treatment causes translocation of Gαs protein from lipid rafts, to non-raft membrane regions.

This results in augmented Gαs signaling, including facilitated activation of adenylyl cyclase (AC) and increased cAMP accumulation. Using c6 or SK-N-SH cells and a lipid raft localized cAMP sensor, we show that Gαs signaling is reduced in lipid rafts, even while signaling is enhanced elsewhere in the cell.

These signaling changes mirror the changes in Gαs localization observed following antidepressant treatment. Furthermore, we show that suppression of Gαs signaling in lipid rafts persists at least 24 hr after cessation of antidepressant treatment. Gαs localization was quantified following membrane isolation and sequential detergent extraction.

We show that suppression of lipid raft Gαs signaling persists for an extended time period after antidepressant withdrawal, while increased non-raft membrane Gαs signaling reverts partially or fully upon cessation of antidepressant treatment. Translocation of Gαs out of lipid rafts is also persistent.

These events may reflect cellular adaptations to antidepressant treatment which contribute to antidepressant withdrawal syndromes, and may aid in the discovery of new treatments and strategies to mitigate these side effects.

Significance Statement 

This work explores, for the first time, the effects of antidepressants on Gαs signaling following drug withdrawal.

This provides novel insight into the cellular and molecular processes affected by antidepressant drugs, and their persistence after discontinuation of treatment.

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