Clomipramine concentration as a predictor of delayed response : a naturalistic study

• Published in: European journal of clinical pharmacology 1999-02, Vol.54 (12), p.895-902
• Main Authors: GEX-FABRY, M, BALANT-GORGIA, A. E, BALANT, L. P
• Format: Article
• Language: English
• Subjects: Adult; Antidepressive Agents, Tricyclic - blood; Antidepressive Agents, Tricyclic - pharmacology; Biological and medical sciences; Chromatography, Gas; Clomipramine - blood; Clomipramine - pharmacology; Depression - metabolism; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Medical sciences; Middle Aged; Neuropharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Survival analysis; Time Factors
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s002280050572

The aim of the present study was to characterise onset of response to clomipramine treatment in a naturalistic setting and to investigate the relationship between concentration and delayed response, postulated to reflect drug-specific response to antidepressant therapy. Ninety-eight depressed patients were prescribed clomipramine in an open flexible manner and followed for depressive symptoms (Montgomery-Asberg depression scale) over a maximum 12 weeks follow-up period. All patients had at least one concentration measurement for therapeutic drug monitoring purpose. Firstly, survival analysis revealed a probability of 15.4% for patients not to show 50% improvement over baseline by week 12, and thus to be considered as non-responders. Median time to onset of response was 31 days for responders, indicating a relatively high probability of delayed response under routine treatment. Secondly, pattern analysis indicated a significant association between early and abrupt response on the one hand and delayed and gradual response on the other. A tendency towards an association between delayed and persistent response was also observed. Finally, receiver operating characteristics analysis allowed identification of a highly significant lower threshold of 230 ng x ml(-1) for the sum of clomipramine and desmethyl-clomipramine, as measured at week 3, with respect to response from week 3 onward. Predictive values were 68.8% and 81.0% for concentrations above and below this threshold to predict delayed response and non-response, respectively. Thresholds were 55 ng x ml(-1) for parent compound and 180 ng x ml(-1) for metabolite. This approach supports the hypothesis that delayed response may be concentration dependent and thus may reflect true drug effect. As a consequence, monitoring clomipramine concentration about 3 weeks after initiation of therapy may valuably contribute to help clinicians decide about the adequacy of ongoing therapy.