Clomipramine demethylation rate is important on the outcome of obsessive–compulsive disorder treatment Tania Marcourakis a , Márcio A. Bernik b , Francisco Lotufo Neto b , Roseli Gedanke Shavitt b and Clarice Gorenstein c,d The aim of this study was to investigate the influence of demethylation rate on the outcome of obsessive–compulsive disorder patients treated with clomipramine. Eighteen patients meeting the DSM-IV criteria for obsessive–compulsive disorder received 150–300 mg of clomipramine daily in a single-blind design for 12 weeks. The patients were evaluated with the Clinical Global Impression scale and the Yale–Brown Obsessive–Compulsive Scale (YBOCS). Clinical assessment and serum measurements of clomipramine and desmethylclomipramine were carried out at baseline and after 3, 6, 8, 10, and 12 weeks. A greater improvement in Clinical Global Impression scale rating was associated with a lower desmethylclomipramine/daily dose and the total clomipramine and desmethylclomipramine/daily dose. Moreover, an improved response on the YBOCS-obsession score was associated with higher serum levels of clomipramine and the total clomipramine and desmethylclomipramine/daily dose. Patients with a greater reduction in baseline YBOCS rating had a lower desmethylclomipramine/clomipramine ratio. These data suggest that a lower demethylation rate correlates with better clinical outcome. Int Clin Psychopharmacol 30:43–48 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. International Clinical Psychopharmacology 2015, 30:43–48 Keywords: clomipramine, demethylation ratio, desmethylclomipramine, obsessive–compulsive disorder, serum levels a Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Science, b Department and Institute of Psychiatry, c Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo and d LIM-23, Laboratory of Psychopharmacology of the Clinical Hospital, Medical School of the University of São Paulo, São Paulo, Brazil Correspondence to Tania Marcourakis, PhD, Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Science, University of São Paulo, Av. Prof. Lineu Prestes, 580 Bloco 13B, CEP: 05508-900, São Paulo (SP), Brazil Tel/fax: + 55 11 3091 1504; e-mail: tmarcour@usp.br Received 27 May 2014 Accepted 4 September 2014 Introduction Clomipramine (CMI) is a tricyclic antidepressant success- fully used in the treatment of several psychiatric conditions, including depression, panic, and obsessive–compulsive dis- orders (OCDs). The relationship between levels of CMI and its active metabolite [N-desmethylclomipramine (DCMI)] in the plasma or serum and clinical outcome is a complex issue in psychiatric disorders, such as depression (Broadhurst et al., 1977; Della Corte et al., 1979; Faravelli et al. , 1984; Wargny et al., 1986; Pascalis et al., 1987) and panic disorder (Marcourakis et al. , 1999). The relationship between clinical improvement and serum levels of CMI and DCMI is similarly unclear in OCD, a condition for which CMI is one of the first- line drugs (Micallef and Blin, 2001; Fineberg and Gale, 2005; Bandelow et al., 2008; Fineberg et al., 2013). Improvement in OCD symptoms has been associated with both higher and lower levels of CMI and DCMI. The amelioration of obsessive–compulsive symptoms was associated with higher CMI (Insel et al., 1983; Mavissakalian et al., 1990) or DCMI serum levels (Kasvikis and Marks, 1988). In contrast, lower CMI (Thorén et al., 1980) and DCMI serum levels (Flament et al., 1985) were correlated with a more pronounced improvement in OCD. Symptom improvement was associated with a therapeutic window of 100–250 ng/ml for CMI and 150–450 ng/ml for DCMI (Stern et al., 1980). Alternatively, Montgomery et al. (1990) found no asso- ciation between clinical progress and serum levels of CMI and DCMI. Finally, Marazziti et al. (2012) observed a correlation between obsessive–compulsive symptom improvement and demethylation ratio only in male patients. Although the heterogeneity of these results might be considered an argument against the potential clinical usefulness of measuring CMI serum levels, it is still unknown whether there are pharmacokinetic factors underlying this variability. For instance, the rate of demethylation has not been sufficiently investigated. CMI demethylation is relevant to its therapeutic effects because CMI and its metabolite DCMI have different profiles regarding their action on monoamine reuptake inhibition: CMI preferentially acts on the serotonin sys- tem, whereas DCMI has a more pronounced action on the noradrenergic system. Considering the large body of evidence pointing to the involvement of an abnormality in serotonergic neurotransmission in the pathophysiology of OCD (Insel et al., 1990; Pigott and Seay, 1999; Micallef and Blin, 2001), we hypothesized that a lower deme- thylation rate, which maintains high levels of CMI, might Original article 43 0268-1315 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YIC.0000000000000050 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.