Distribution pattern of mirtazapine and normirtazapine in blood and CSF.

The aim of this study was to investigate the distribution pattern of mirtazapine and its metabolite normirtazapine (N-desmethylmirtazapine) in blood and cerebrospinal fluid (CSF). Concentrations of mirtazapine were measured in blood serum and CSF of 16 patients treated with daily doses of 7.5-60 mg. Daily doses were correlated with serum and CSF concentrations as well as serum levels with those in CSF. Serum levels of mirtazapine and normirtazapine showed a strong relation to the daily dose of mirtazapine of r = +0.631 and r = +0.732, respectively (p < 0.01). Between the daily doses and the CSF levels of both mirtazapine and normirtazapine, we only found a trend-wise correlation (r = +0.535, p = 0.060). The correlation between mirtazapine and normirtazapine in serum and CSF was highly significant (r = +0.664, p = 0.005 and r = +0.885, p < 0.001, respectively). High discrepancies between (total) mirtazapine levels in serum and CSF indicate a low penetration into CSF with regard to the total serum concentration as the mean of the calculated penetration ratio was 0.16 (SD = 0.11). By correcting the penetration ratio for the plasma protein binding, the mean CSF/serum ratio for the unbound fraction was 1.05 (SD 0.72, range 0.56-3.19) indicating a high passage into CSF. Findings indicate a good ability of mirtazapine and normirtazapine to overcome the blood-cerebrospinal fluid barrier and suggest a high ability to enter the brain with sufficient drug levels at the target sites within the brain contributing to clinical efficacy.