Can the antidysphoric and anxiolytic profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain 3α, 5α- tetrahydroprogesterone (allopregnanolone) availability?

Neurosteroids synthesized in the nervous system are potent modulators of synaptic activity. Allopregnanolone (ALLO) is of great significance for neuropsychiatric research because it binds with high affinity at nanomolar concentration to various gamma-aminobutyric acid (GABA)A receptor subtypes and potently facilitates GABA action at these receptors. Fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats increase brain ALLO content without altering the brain content of other steroids, including ALLO’s precursor 5α dihydroprogesterone. Moreover the improvement in depression symptomatology following administration of fluoxetine or fluvoxamine to unipolar depressed patients for 8–10 weeks is related to the increase of ALLO content in cerebrospinal fluid. Because ALLO via its action at GABAA receptors may relieve anxiety and dysphoria, the increase in ALLO brain content elicited by fluoxetine or other SSRIs may participate in the beneficial anxiolytic and antidysphoric clinical action of this class of drugs. Preliminary experiments suggest that the effect of SSRIs on ALLO biosynthesis is independent from serotonin reuptake inhibition and may be due to a specific SSRI action on the enzymes that synthesize ALLO from its precursor.