What Causes Time-Lag in Antidepressants?

A new study revealed the reason why antidepressants can take weeks or months to become effective, which could lead to faster-acting drugs.

Researchers were able to identify a mechanism for selective serotonin reuptake inhibitors (SSRIs), which are a common antidepressant, in a study published by the Journal of Biological Chemistry. It has been thought that SSRIs prevented reabsorption of seratonin into nerve cells.

SSRIs also collect in the area of the cell membrane called lipid rafts, which is associated with decreased levels of a signal molecule in the raft, G proteins.

“It's been a puzzle for quite a long time why SSRI antidepressants can take up to two months to start reducing symptoms, especially because we know that they bind to their targets within minutes,” said researcher Mark Rasenick, PhD. “We thought that maybe these drugs have an alternate binding site that is important in the action of the drugs to reduce depressive symptoms.”

SSRIs bind to serotonin transporters in the nerve-cell membranes to allow serotonin in and out of the cell during communication, according to the study. Since serotonin is generally thought to be limited in patients with depression, the SSRIs stop transporters from taking serotonin to the synapse back into the neurons.

This allows more neurotransmitters into the synapse and reduces depression, the researchers wrote. Previous studies found that patients with depression had G proteins stranded on the lipid rafts without access to cyclic AMP that they need to function.

Researchers believe that limited signaling from G proteins can lead to a feeling of numbness in patients with depression. In the current study, researchers tested different SSRIs in rat glial cells, and found that SSRIs collect in the lipid rafts over time and decrease the amount of G proteins.

“The process showed a time-lag consistent with other cellular actions of antidepressants,” Dr Rasenick said. “It's likely that this effect on the movement of G proteins out of the lipid rafts towards regions of the cell membrane where they are better able to function is the reason these antidepressants take so long to work.”

The researchers believe their findings suggest a way to create faster-acting antidepressants.

“Determining the exact binding site could contribute to the design of novel antidepressants that speed the migration of G proteins out of the lipid rafts, so that the antidepressant effects might start to be felt sooner.”