Increase in the Cerebrospinal Fluid Content of Neurosteroids in Patients with Unipolar Major Depression who are Receiving Fluoxetine or Fluvoxamine

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 6; pp. 3239 - 3244
• Main Authors: Uzunova, V., Sheline, Y., Davis, J. M., Rasmusson, A., Uzunov, D. P., Costa, E., Guidotti, A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 17.03.1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Adult; Biological Sciences; Body fluids; Brain; Cerebrospinal fluid; Depressive Disorder, Major - cerebrospinal fluid; Depressive Disorder, Major - diagnosis; Depressive Disorder, Major - drug therapy; Dosage; Drug therapy; Enzymes; Female; Fluoxetine - therapeutic use; Fluvoxamine - therapeutic use; Humans; Major depressive disorder; Male; Mental depression; Middle Aged; Neurology; Pregnanolone - cerebrospinal fluid; Protein isoforms; Psychometrics; Receptors; Reuptake; Serotonin agents; Serotonin Uptake Inhibitors - therapeutic use; Spinal cord; Stereoisomerism; Steroids
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.6.3239

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3α -hydroxy-5α -pregnane-20-one (3α 5α -ALLO) without altering the brain content of other neurosteroids. ALLO (3α 5α and 3α 5β isomers) binds with high affinity to various γ -aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO (≈ 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.