Two out of three participants in clinical studies with previously untreatable depression experience a fast and long-lasting end to their depressive symptoms after receiving ketamine intravenously. The effects of ketamine generally last about a week — much longer than would be expected with ketamine’s six-hour half-life in the body.

But the exact mechanism behind ketamine’s success has remained unclear.

Now, in a new rodent study, researchers from the University of Illinois at Chicago College of Medicine describe the molecular mechanisms behind ketamine’s ability to halt depression in its tracks and keep it at bay.

They reported their findings in the journal Molecular Psychiatry.

In previous studies, the research team showed that selective serotonin reuptake inhibitors (SSRIs) — the most commonly prescribed class of antidepressants, which includes Prozac and Zoloft — work in the brain by moving molecules called G proteins off of “lipid rafts” on the cell membrane, where the G proteins are held inactive.

These G proteins produce a chemical messenger called cyclic AMP, which nerve cells need to signal properly.

People with depression tend to have a greater proportion of their G proteins packed into these membrane patches, along with poor brain cell signaling, which may contribute to symptoms of depression, including a feeling of overall numbness.

In the previous study, when the research team exposed rat brain cells to SSRIs, the drug accumulated in the lipid rafts, and G proteins moved out of the rafts. The movement was gradual, over the span of several days, which may be the reason why SSRIs and most other antidepressants can take a long time to begin working.

In the new study, the researchers conducted a similar experiment with ketamine and noticed that the G proteins left the rafts much faster. G proteins began migrating out of the lipid rafts within 15 minutes.

And the long-lasting effects of ketamine may be due to the fact that the G proteins were very slow to move back into the lipid rafts.

“When G proteins move out of the lipid rafts, it allows for better communication among brain cells, which is known to help alleviate some of the symptoms of depression,” said Dr. Mark Rasenick, distinguished professor of physiology and psychiatry in the University of Illinois at Chicago College of Medicine.

“Whether they are moved out by traditional antidepressants or ketamine, it doesn’t matter, although with ketamine, the G proteins are very slow to move back into the lipid rafts, which would explain the drugs’ long-term effects on depressive symptoms.”

“This further illustrates that the movement of G proteins out of lipid rafts is a true biomarker of the efficacy of antidepressants, regardless of how they work,” Rasenick explained. “It confirms that our cell model is a useful tool for showing the effect of potential new antidepressant drug candidates on the movement of G proteins and the possible efficacy of these drugs in treating depression.”

Source: University of Illinois at Chicago

Rat Study Shows How Ketamine Combats Depression