desmethylclomipramine and Obsessive-Compulsive-Disorder

Pharmacogenetics within psychiatry has the potential to aid in the dose and selection of medications. A substantial number of psychiatric medications are metabolized through either of the highly polymorphic drug-metabolizing enzymes CYP2D6 and CYP2C19. Of these, clomipramine is subject to metabolism by both CYP2C19 and CYP2D6, leaving individuals with deficiencies of these drug-metabolizing enzymes at risk of higher concentrations of the parent molecule. Herein, we present the case of a 29-year-old male with diagnoses of depression and obsessive compulsive disorder who had trialed and failed a dozen psychiatric medications, many of which are subject to metabolism by CYP2D6 and/or CYP2C19, and had most recently been taking clomipramine for approximately 2.5 years. Pharmacogenetic testing revealed this patient to be an intermediate metabolizer for both CYP2C19 (*1/*2) and CYP2D6 (*4/*41), which resulted in considerably elevated serum trough concentrations of clomipramine and its active metabolite desmethylclomipramine. This case provides a retrospective view of how the knowledge of an individual's pharmacogenetic test results can aid in their clinical care.

Topics: Adult; Antidepressive Agents, Tricyclic; Clomipramine; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Depressive Disorder; Humans; Male; Obsessive-Compulsive Disorder; Retrospective Studies

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.

Topics: Adult; Antidepressive Agents, Tricyclic; Biotransformation; Brazil; Clomipramine; Dealkylation; Drug Monitoring; Female; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Single-Blind Method; Treatment Outcome

Combination treatment with tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors (SSRIs) is an increasingly employed strategy especially in depressed patients unresponsive to monotherapy. Comedications with SSRIs, however, may be hazardous owing to pharmacokinetic interactions that can result in elevated serum TCA levels. For the combinations, safety and tolerability data are lacking.. We report tolerability and safety of combined treatment with fluvoxamine and clomipramine (CMI) in 22 patients. Most patients suffered from depression and obsessive-compulsive symptoms. Diagnoses were made according to DSM-III-R criteria. Serum levels of CMI, N-desmethylclomipramine (DCMI), and 8-hydroxylated metabolites were determined. EEG, ECG, and laboratory parameters and adverse effects reported by the patients, as well as global clinical improvement, were assessed.. Generally, fluvoxamine/clomipramine comedication was well tolerated. Serum CMI levels reached 500 to 1200 ng/mL in half of the patients, while corresponding levels for DCMI and 8-hydroxylated metabolites were low. Moreover, the ratios of N-demethylation DCMI:CMI calculated from the ratios of drug concentrations in serum were markedly lower under comedication than under CMI monotherapy. Alterations in EEG, ECG, and laboratory parameters that had clinical relevance were rarely observed and were reversible after dose reduction of CMI. However, 2 patients developed myoclonic jerks. A majority of patients improved clinically during combination treatment. Clinically relevant side effects were absent in patients with serum CMI and DCMI levels below 450 ng/mL and ratios of N-demethylation below 0.3.. Our results suggest that comedication of fluvoxamine and clomipramine will result in markedly elevated serum clomipramine levels. Therefore, combination treatment with fluvoxamine and clomipramine should be carefully monitored by determination of serum levels of the TCA. Clinically, the pharmacokinetic interactions between fluvoxamine and clomipramine may be well tolerated in a majority of patients. However, in a few patients, higher serum levels may be associated with an increased risk of EEG changes and changes of intracardiac conductance. EEG and ECG should be used regularly to monitor comedicated patients.

Topics: Adult; Aged; Antidepressive Agents, Tricyclic; Clomipramine; Depressive Disorder; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Electroencephalography; Female; Fluvoxamine; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Selective Serotonin Reuptake Inhibitors

A pharmacokinetic interaction between the selective serotonin reuptake inhibitor citalopram and a tricyclic antidepressant, clomipramine, was noted in a patient treated for major depression and obsessive-compulsive disorder. After the addition of citalopram, a desmethylclomipramine plasma level increase and an 8-hydroacy-desmethylclomipramine plasma level decrease were observed. The CYP2D6 phenotype, determined when the patient received the antidepressant comedication, characterized a poor metabolizer status (dextromethorphan metabolic ratio >0.3), despite a heterozygous genotype containing a wild-type allele with extensive metabolic capacity and a mutant non-functional allele (CYP2D6*1A/CYP2D6*4A). This case seems to be one of the first descriptions of the clinical relevance of a CYP2D6 heterozygous genotype in a patient treated with antidepressant.

Topics: Adult; Antidepressive Agents; Antidepressive Agents, Tricyclic; Citalopram; Clomipramine; Cytochrome P-450 CYP2D6; Drug Interactions; Drug Therapy, Combination; Female; Genotype; Humans; Obsessive-Compulsive Disorder; Phenotype

Women with postpartum-onset obsessive compulsive disorder may elect treatment with clomipramine. There is minimal information to guide the clinician who must advise breastfeeding women about clomipramine therapy.. Four clomipramine-treated breastfeeding mother-infant pairs were assessed for serum concentrations of clomipramine, N-desmethylclomipramine, and corresponding 8-hydroxymetabolites.. Although the mothers exhibited a wide range of serum concentrations, the parent drug and metabolites were either nondetectable or below the quantifiable limit in the sera of all infants. No adverse clinical effects were observed.. This report adds to the growing literature that suggests that tricyclic use during breastfeeding rarely results in measurable drug levels in infant sera.

Topics: Adult; Breast Feeding; Clomipramine; Female; Half-Life; Humans; Infant; Infant, Newborn; Male; Obsessive-Compulsive Disorder; Pregnancy; Pregnancy Complications

A 62 year old woman presented with a long history of obsessive-compulsive disorder, the symptoms of which were not adequately controlled by oral clomipramine. The patient was started on intravenous clomipramine. Drug levels of both clomipramine and its active metabolite desmethylclomipramine were measured. Symptoms were controlled during her hospital stay. A three year follow-up report indicated the patient is doing well with no evidence of obsessive-compulsive or depressive symptoms. A discussion of the blood levels obtained and the caution to be exercised during intravenous administration is presented.

Topics: Clomipramine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Middle Aged; Obsessive-Compulsive Disorder

The clinical significance of the effects of pharmacotherapy and the relationship between plasma tricyclic concentrations and outcome in 33 obsessive-compulsive disorder (OCD) patients who completed 10 weeks of treatment with clomipramine (239.4 +/- 57.0 mg/day) were analyzed. Results revealed that at the end of treatment, OCD symptoms had decreased to a subclinical level in 15 (47%) patients and that nearly 33 percent of the sample was virtually symptom free. However, 1 out of 4 patients failed to improve. Analysis of plasma levels (clomipramine 169.9 +/- 102.1 ng/ml; N-desmethylclomipramine 379.0 +/- 160.6 ng/ml) revealed that responders had significantly higher clomipramine levels and a trend toward lower desmethylclomipramine/clomipramine ratios. A significant degree of correlation was also obtained between plasma levels of clomipramine, but not N-desmethylclomipramine, and post-treatment outcome measures.

Topics: Adult; Clomipramine; Female; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder