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We're a little crazy, about science!

Why do antidepressants take so long to work?

depression

Medication roulette, if you have ever had to deal with depression or other types of mental illness you know what I’m talking about. You take a pill that could help or could cause all sorts of horrid side effects. You cross your fingers as you take that first pill and in the 4-6 weeks it takes to start working you cross your fingers, hope, wish and probably even dread the outcome. But why does it take so long for antidepressants to start working in the first place and what could be done to change that?

Researchers have (finally) discovered one reason the drugs take so long to work, and their finding could help scientists develop faster-acting drugs in the future.

Neuroscientists have identified a previously unknown mechanism of action for selective serotonin reuptake inhibitors, or SSRIs, the most commonly prescribed type of antidepressant. Big surprise, science doesn’t quite know what causes depression, or how to treat it effectively. However, SSRI’s have long been thought to work by preventing the reabsorption of serotonin back into nerve cells, hence the name SSRI.

They also accumulate in patches of the cell membrane called lipid rafts and the buildup was associated with diminished levels of an important signal molecule in the rafts. This lead researchers to have another method of action for how SSRIs might affect the brain.

“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 Mark Rasenick.

“We thought that maybe these drugs have an alternate binding site that is important in the action of the drugs to reduce depressive symptoms.”

Serotonin is thought to be in short supply in people with depression. SSRIs bind to serotonin transporters – structures embedded within nerve-cell membranes that allow serotonin to pass in and out of the nerve cells as they communicate with one another. SSRIs block the transporter from ferrying serotonin that has been released into the space between neurons – the synapse – back into the neurons, keeping more of the neurotransmitter available in the synapse, amplifying its effects and reducing symptoms of depression.

Researchers suspected that the delayed drug response involved certain signaling molecules in nerve-cell membranes called G proteins.

Previous research by the team showed that in people with depression, G proteins tended to congregate in lipid rafts, areas of the membrane rich in cholesterol. Stranded on the rafts, the G proteins lacked access to a molecule called cyclic AMP, which they need in order to function. The dampened signaling could be why people with depression are “numb” to their environment.

The team bathed rat glial cells, a type of brain cell, with different SSRIs and located the G proteins within the cell membrane. They found that they accumulated in the lipid rafts over time — and as they did so, G proteins in the rafts decreased.

“The process showed a time-lag consistent with other cellular actions of antidepressants,” 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 finding suggests how these drugs could be improved.

“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.”

Rasenick already knows a little about the lipid raft binding site. When he doused rat neurons with an SSRI called escitalopram and a molecule that was its mirror image, only the right-handed form bound to the lipid raft.

“This very minor change in the molecule prevents it from binding, so that helps narrow down some of the characteristics of the binding site,” Rasenick said.

And from someone who suffers from depression and mental illness personally, if you are too, I’m sorry.

Sources:
Erb, S., Schappi, J., & Rasenick, M. (2016). Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G protein, Gαs Journal of Biological Chemistry DOI: 10.1074/jbc.M116.727263

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