Serotonin and noradrenaline uptake inhibitors in the treatment of depression--relationship to 5-HIAA in spinal fluid.

Abstract

Evidence is accumulating that endogenous depression, in spite of its relatively uniform clinical picture, may have different pathophysiological correlates, and that these may predict the outcome of treatment. The distribution of the serotonin (5‐HT) metabolite, 5‐hydroxyindoleacetic acid (5‐HIAA) in the spinal fluid (CSF) from depressed patients has repeatedly been shown to be bimodal, provided that sufficiently sensitive biochemical methods (mass fragmentography) are used for the analysis.A study of nortriptyline revealed a poor antidepressant effect of this typical noradrenaline (NA) uptake blocker in patients with low pretreatment CSF 5‐HIAA. Chlorimipramine (CI), which is a potent 5‐HT uptake blocker in vitro and in animals was therefore given to depressed patients. The serotonin effects were borne out by a profound decrease in CSF 5‐HIAA. This effect, which is presumably mediated by feed‐back inhibition of 5‐HT synthesis was correlated to the plasma concentration of CI, but only up to a certain plasma level. Above this, there was little effect on 5‐HIAA, suggesting that high concentrations of CI may block 5‐HT receptors. The concentration of the NA metabolite, 4‐hydroxy‐3‐methoxyphenyl glycol (HMPG) in CSF decreased in proportion to the demethyl metabolite (DMCI) concentration in plasma. DMCI is a potent NA uptake blocker in vitro. Patients with low pretreatment CSF 5‐HIAA reacted equally well to treatment with CI as those with high levels, but only in the latter group was there a correlation to plasma levels (between DMCI and antidepressant effect). The antidepressant effect was also correlated to HMPG reduction in CSF, suggesting that these patients recover in proportion to drug effect on NA