Plasma levels of chlorimipramine and its demethyl metabolite during treatment of depression

Abstract

The biochemical and antidepressant effects of chlorimipramine (Cl) were studied in depressed patients after 3 wk of treatment. In vitro studies performed with rat brain slices incubated in human plasma showed that chlorimipramine and its demethyl metabolite (DMCI) are fairly specific blockers of serotonin and norepinephrine uptake. The uptake inhibition of serotonin and norepinephrine in plasma drawn from patients during treatment correlated with the plasma levels of parent drug and metabolite. Treatment with Cl caused a decrease of the main serotonin (5‐HIAA) and norepinephrine metabolites (HMPG) but had no significant mean effect on the major dopamine metabolite (HVA) or on tryptophan in cerebrospinal fluid (CSF). The 5‐HIAA decrease in CSF correlated with the plasma concentration of Cl within the range 80 to 360 nmole/l. The HMPG decrease in CSF correlated with plasma DMCI concentration. The patients were subdivided into two groups, those with “low” and those with “high” CSF 5‐HIAA. In patients with a “high” pretreatment CSF 5‐HIAA, there was a positive correlation between amelioration of depression and plasma level of DMCI. In this patient group there also was a correlation between HMPG alteration and amelioration of depression. This finding supports the hypothesis that patients with “high” CSF 5‐HIAA levels benefit from treatment with norepinephrine uptake blockers. In the patient group with “low” CSF 5‐HIAA, correlations between plasma levels of Cl and DMCI and amelioration were consistently negative, albeit not significant, supporting the idea that these patients are a biochemical subgroup within the depressive illness with a different reaction to antidepressant drugs than those with “high” CSF 5‐HIAA levels.