Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine

Abstract

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-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 ( approximately 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.

Figures

Figure 1

Biosynthesis of neurosteroids. 5α-DHP, 5α-dehydroprogesterone; ALLO, 3α-hydroxy, 5α-pregnane-20-one; 3α5α20α-HHP, 3α,5α,20α-hexahydroprogesterone; P450scc, cytochrome P450 side chain cleavage; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 3α-HSORC, 3α-hydroxysteroid oxidoreductase cytosolic (Km for 5αDHP, 80 nM; Km for ALLO, 2 μM; NADPH/NADP+ linked); 3α-HSORP, 3α-hydroxysteroid oxidoreductase particulate (Km for 5α-DHP, 230 nM; Km for ALLO, 58 nM; NADH/NAD+-linked); 20α-HSOR, 20α-hydroxysteroidoxydoreductase. The kinetic properties of 3α-HSORC and 3α-HSORP are from Karavolas and Hodges (8).

Figure 2

Gas chromographic retention times of ALLO stereoisomers. Peaks: A, HFBA derivative of 3α5α-ALLO; B, HFBA derivatives of 3α5β-ALLO; C, HFBA derivative of 3β5α- and 3β5β-ALLO. The ion current generated by ≈3 pmol of each derivatized steroid is recorded.

Figure 3

ALLO levels in four cisternal–lumbar gradient fractions of CSF before and 8–10 weeks after fluoxetine or fluvoxamine treatment. Each value is the mean ± SEM of data from 15 depressed patients (see Table 1 for details). ALLO (fmol/ml) includes the level of 3α5α-ALLO (solid bars) and of 3α5β-ALLO (shaded bars).

Figure 4

Negative correlation exists between the severity of depression (HAM-D) and ALLO levels in CSF at base line [r = 0.081; P = 0.01; Pearson’s Product Moment Correlation (18)]. •, ALLO levels in CSF of depressed patients; ▴, ALLO level in CSF of control subjects. Each point is the mean of determinations of ALLO in four CSF fractions (see Fig. 2).

Figure 5

Fluoxetine- or fluvoxamine-elicited increase in the ALLO content of CSF correlates with the improvement in the HAM-D score [r = 0.58; P < 0.023; Pearson’s Product Moment Correlation (18)]. The percent changes in HAM-D scores before and after fluoxetine and fluvoxamine treatment (abscissa) were plotted against changes in corresponding ALLO levels in the CSF (ordinate). For each patient the change in ALLO levels in the CSF before and after treatment reflects the mean of the difference between ALLO level before and after SSRI treatment in the four cisternal–lumbar CSF fractions.