Is there a therapeutic window for plasma concentration of mianserin plus desmethylmianserin?

Abstract

The relationship between clinical effects and plasma concentrations of mianserin and desmethylmianserin was studied in 29 cases of major depression during 3 weeks of mianserin treatment. The daily dose of mianserin was 30 mg in 27 cases and 20 mg in two cases. There was a significant U-shaped relationship between the final Montgomery Asberg Depression Rating Scale (MADRS) score and the steady-state plasma concentration of mianserin (p < 0.05) or desmethylmianserin (p < 0.05). A much stronger relationship was observed for mianserin plus desmethylmianserin @<0.001). A theoretical therapeutic window (where a final MADRS score was expected to be 10 or less) was 71-128 nmol/l for mianserin, 34-61 nmol/l for desmethylmianserin, and 101-183 nmol/l for mianserin plus desmethylmianserin. The proportion of responders was significantly higher inside than outside the window for mianserin plus desmethylmianserin (p =0,0033), but not for mianserin (p =0.063) or for desmethylmianserin (p =0.077). The occurrence of subjective side-effects was not dependent on the plasma concentrations of these compounds. The present study suggests that desmethylmianserin contributes substantially to the overall antidepressant effects of mianserin treatment, and that the therapeutic response is most dependent on the combined plasma concentration of mianserin and desmethylmianserin, with an optimal therapeutic response occurring in the intermediate range.

Relationship between clinical effects of fluvoxamine and the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients

“…These results suggest that not only FLV but also FLA contributes to the antidepressant effect during FLV treatment, and the combined Css best correlates with the therapeutic outcome. Similar phenomena have been suggested for nortriptyline and 10-hydroxynortriptyline (Nordin and Bertilsson 1995), desipramine and 2-hydroxydesipramine (Nelson et al 1988), and mianserin and desmethylmianserin (Otani et al 1991).…”

“…The percent improvement in the MADRS score was calculated as amelioration score/pretreatment score100. A patient with a final MADRS score of 10 was defined as a responder according to previous studies (Otani et al 1991(Otani et al , 1996Mihara et al 1997Mihara et al , 2002. A corrected UKU score was calculated by subtracting the pretreatment score from the score during treatment.…”

“…These findings, together with the large interindividual variations in the pharmacokinetics of these drugs, have made plasma concentration monitoring a useful measure to improve the therapeutic effects and decrease the side effects of these drugs (Task Force on the Use of Laboratory Tests in Psychiatry 1985). The presence of therapeutic plasma concentrations has also been suggested for non-tricyclic antidepressants such as mianserin (Montgomery et al 1978;Otani et al 1991;Mihara et al 1997) and trazodone (Monteleone et al 1989;Mihara et al 2002).…”

“…Furthermore, although involvement of metabolites in the antidepressant effect has been suggested for some antidepressants, e.g. nortriptyline (Nordin and Bertilsson 1995), desipramine (Nelson et al 1988), and mianserin (Otani et al 1991), none of these studies has considered the metabolites of FLV.…”

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

“…In the case of mianserin, an antidepressant, it has been suggested that the overall effectiveness of the agent is better explained by the consideration of the pharmacological activity of the parent and its main metabolite, desmethylmianserin, in totality (Otani et al, 1991). Since the stereoselective disposition of both mianserin and its metabolite, desmethylmianserin, is controlled by CYP2D6, some noteworthy differences have been observed in the pharmacokinetics of mianserin enantiomers and its metabolite (Dahl et al, 1994).…”