Understanding the delayed response to antidepressants

Published October 03 2016

Some antidepressants can accumulate in lipid rafts. IMAGE BY MOLLY HUTTNER

Depression is a mental illness that affects how a person feels, thinks and handles daily activities. Antidepressants are prescribed to alleviate the symptoms of depression and help the brain process and use certain chemicals that regulate mood or stress. Unfortunately, existing medications usually require two to four weeks of use before patients respond. In a recent Paper of the Week in the Journal of Biological Chemistry, Mark M. Rasenick and his team at the University of Illinois at Chicago describe why antidepressants have a delayed impact.

One consistent finding in brain and some peripheral cells of patients who suffer depression is depletion of cyclic adenosine monophosphate, or cAMP. cAMP is a second messenger. Regular antidepressant treatment activates signaling pathways to cause an increase in accumulation of cAMP and transcription of cAMP-regulated genes, which include genes for neurotransmitters and growth factors, to alleviate the symptoms of depression. Antidepressants work to increase the brain’s concentrations of various neurotransmitters, such as norepinephrine, dopamine, noradrenaline, adrenaline and serotonin. Researchers suggest that the antidepressants’ effects may be mediated through induction of the system that generates cAMP. But they need to understand why there is a delay in clinical efficacy of antidepressant action.

Rasenick and his team used glioma cells that lacked the monoamine transport proteins, including serotonin reuptake transport proteins, which are one of the binding sites for many antidepressants. They demonstrated that in the absence of SERT, antidepressants accumulate gradually in the plasma membrane microdomains of glioma cells. Next, Rasenick and colleagues showed that a sustained treatment with an antidepressant drug called escitalopram, better known by brand names of Lexapro and Cipralex, translocated the G-protein Gαs from lipid rafts. Lipid rafts are specialized regions of the plasma membrane that have been shown to inhibit the cAMP-generating cascade. Gαs went from lipid rafts to nonraft regions of the plasma membrane in the glioma cells, which enhanced its signaling ability.

Their observation of antidepressant association with lipid rafts led them to investigate the accumulation of representative drugs from different classes of antidepressants in the lipid rafts. Their studies showed that the accumulation of drugs in lipid rafts depended on drug class. For example, only monoamine oxidase inhibitors and selective serotonin receptor inhibitors, such as escitalopram, showed association with lipid rafts over time. This phenomenon coincides with previous evidence that drugs such as escitalopram, fluoxetine and phenelzine mediate the movement of cAMP from lipid rafts to nonraft regions of the plasma membrane, while antipsychotics and anti-anxiety drugs do not.

Rasenick and colleagues further analyzed escitalopram to investigate the properties of antidepressants that preferentially accumulate in lipid rafts. The investigators tracked the accumulation of escitalopram in lipid-raft fractions from glioma cells and discovered that escitalopram gradually accumulated in lipid rafts in a concentration and time-dependent manner while its nontherapeutic enantiomer, R-citalopram, did not.

This study demonstrates that antidepressants likely have different mechanisms of action, but they all translocate Gαs out of lipid rafts. It is a gradual process consistent with delayed therapeutic effects. Furthermore, there are certain selective serotonin receptor and monoamine oxidase inhibitors that accomplish this phenomenon by accumulating slowly in lipid rafts. This discovery by Rasenick and his team has identified a novel biochemical hallmark for antidepressant action that may provide new molecular targets for antidepressant action along an accelerated timescale.

Lee D. Gibbs Lee D. Gibbs is a doctoral candidate at the University of North Texas Health Science Center.