Most antidepressant drugs increase the synaptic content of serotonin and/or norepinephrine by preventing breakdown or reuptake of these neurotransmitters. Yet most of these drugs require 6-8 weeks before any clinical improvement is noted. This suggests a multi-site mechanism for antidepressant action.

Dr. Rasenick and colleagues sought to determine identify those additional sites. What they discovered is that the antidepressants accumulate in the lipid rafts of the cell membrane but do not cause improvement unless, and until, the Gsα protein is induced to move out of the lipid rafts, so that it can bind with the enzyme adenylyl cyclase to begin a chemical cascade that supports improved neurotransmitter activity.

Gsα resides in cell membranes and is responsible for conveying information from neurotransmitters as serotonin or norepinephrine to the cell interior. One effect of depression is to diminish this action of Gsα, by shuttling Gsα to a cholesterol-rich region of the cell membrane, known as a lipid raft.

Antidepressants have the opposite effect, moving Gsα from lipid rafts and increasing responsiveness to certain neurotransmitters. Thus, the association of Gsα with lipid rafts serves as a biomarker to indicate both depression and the extent of response to antidepressant drugs. Most importantly, this is seen after just a few days of antidepressant treatment (which may be weeks before a change in symptoms is evident).