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Studies by researchers at the University of Illinois Chicago (UIC) offer up new insights into the molecular and cellular mechanisms that underpin the unpleasant symptoms associated with withdrawing from antidepressant therapy. The team’s studies linked prolonged suppression of signaling in membrane lipid rafts with what they call the “constellation of symptoms known as antidepressant discontinuation syndrome.”

The discoveries could ultimately aid in the development of new antidepressant treatments, and also point to strategies that could help reduce the symptoms of withdrawal. Reporting on their in vitro studies in Molecular Pharmacology, Mark Rasenick, PhD, who is distinguished professor of physiology and biophysics and psychiatry at UIC and research career scientist at the Jesse Brown VA Medical Center, and Nicholas Senese, PhD, a postdoctoral fellow at UIC, concluded, “The ability to model antidepressant discontinuation in vitro may facilitate the development of effective antidepressant compounds without the risk of discontinuation syndromes.” Their paper is titled, “Antidepressants produce persistent Gαs associated signaling changes in lipid rafts following drug withdrawal.”

Major depressive disorder (MDD) is the leading cause of disability worldwide, the authors wrote, citing WHO estimates. One in six Americans have, or will, suffer from depression, and for veterans the estimated rate is twice that, they continued. There is no single treatment for depression that is fully effective for everyone, and two thirds of individuals may not respond to initial therapy. Many patients will also fail to remit after even second and third-line treatment options have been exhausted. And with long lag times between starting treatment and antidepressant responses—the beneficial effects of some antidepressant drugs may not be evident for two months after treatment begins—individuals can undergo many months or even years of failed therapy before finding effective treatment, and some patients may drop out of therapy altogether. “These challenges necessitate a deeper understanding of the processes leading to a positive antidepressant response, and the specific factors that distinguish individuals who will not respond to antidepressant treatment,” the team noted.

Patients who do continue with antidepressant therapy may take their drugs for years, and weaning off treatment can then result in unpleasant symptoms that range from flu-like feelings and persistent pain or itch, to Parkinson’s-like conditions that can last for weeks. “These symptoms may include sleep disturbances, anxiety, flu-like symptoms, and sensory abnormalities, including electric shock-like experiences,” the authors added.

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 believed to be involved in regulating mood and anxiety) binds to a receptor on the outside of a cell, a protein in the lipid raft called Gs alpha (Gαs) conveys the signal into the cell’s interior, where it can then trigger a variety of actions. “A wide variety of antidepressant drugs are known to cause translocation of Gαs out of lipid rafts, the team explained. “This action is specific to Gαs, as other Gα proteins are not similarly affected.”

One of the actions elicited by (Gαs) signaling is the production of the signaling molecule cyclic AMP. In the brains of people with depression, cyclic AMP is low; but with effective antidepressant treatment, cyclic AMP may be returned to normal. “The cAMP signaling cascade has been linked to depression and antidepressant action in various contexts,” the author wrote.

For their newly reported study, Rasenick and Senese used a cell-based model to investigate whether the previously observed effects of antidepressants on Gαs signaling persisted after drug withdrawal. To do this they looked at the activity of Gs alpha molecules by using fluorescent light to determine how the molecules moved in and out of the lipid rafts. “… we differentiated antidepressant-induced signaling changes in lipid rafts and non-raft regions using fluorescent cAMP sensors.”

The results showed that while withdrawal of some antidepressant drugs balanced Gs alpha action in and out of the lipid rafts, other drugs suppressed the return of Gs alpha to rafts. The team found that in their cell model system, the cellular hallmarks of antidepressant action, including translocation of Gαs from lipid rafts, persisted after drug withdrawal. “Further, we demonstrated that in contrast to antidepressant-induced increases in whole cell cAMP, lipid raft cAMP signaling was suppressed following antidepressant withdrawal,” they continued. This suppression, the researchers believe, is what causes the persistent and undesired effects of some antidepressants. “Results from this study suggest that, for some antidepressants, effects on Gαs signaling and localization persist following drug withdrawal,” they wrote. “The reduction in lipid raft cAMP observed here is consistent with predictions from earlier work showing that many antidepressants reduce Gαs distribution in lipid rafts without altering cellular content of this protein.” Moreover, the team pointed out, this process is specific to antidepressants, as non-antidepressant drugs, including olanzapine, haloperidol, lithium and diazepam, lack the same effects.

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 validates the notion that intracellular molecules that result from an active Gs alpha protein are a very good biomarker for the functioning of antidepressants,” he noted. “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.”

The authors further commented, that their results “ … validate Gαs translocation from lipid rafts and the sequelae of cAMP signaling events accompanying this, as consistent biomarkers of antidepressant action.” They suggested that the residual depression of lipid raft cAMP signaling may represent “ … an as of yet unrecognized cellular mechanism underlying antidepressant discontinuation syndromes.” They hope that future studies will help to determine how different antidepressants affect lipid raft signaling, and whether this action correlates with severity of discontinuation symptoms.

Rasenick suggested that looking at how an individual patient’s cells metabolize Gs alpha proteins may help to better predict which antidepressant medication would work for that patient. This could be accomplished in days, rather than through weeks and months of trial and error to find the right medication. Additionally, the cellular fluorescent indicators allow testing at a cellular level to develop new antidepressant medications.

A company using this UIC-developed technology, Pax Neuroscience, has been established to develop the technology.

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