desmethylclomipramine and Depressive-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

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

Two different initial dosing regimens with clomipramine (CMI) were compared with particular attention to early response indicators. Thirty-two inpatients with major depressive disorder were randomized in a double-blind protocol. The pulse-loading (P-L) group received 150 and 200 mg of CMI on two consecutive evenings, then placebo for 8 days; the traditional group began at 50 mg, followed by gradual increases every second day until 200 mg was reached. Both groups were then placed on an adjustable dosing schedule of CMI, initially set at 200 mg for an additional 2 weeks. After the completion of P-L, the improvement in scores on the Hamilton Rating Scale for Depression across protocol days 7 to 13 (the P-L placebo period) was equivalent for both dosage regimens and was significantly associated with therapeutic response at the end of the study (p = 0.0186). Desmethylclomipramine levels were significantly greater in P-L nonresponders (p = 0.0039), and a ratio of desmethylclomipramine/CMI of 2 or more after P-L was strongly associated with failure to respond to CMI (p = 0.02). Early, acute responses and assessments of metabolism observed with targeted doses of CMI may be predictive of later successful treatment.

Topics: Adult; Clomipramine; Depressive Disorder; Double-Blind Method; Electroencephalography; Female; Humans; Male; Psychiatric Status Rating Scales

A double-blind, randomized trial of oral vs intravenous clomipramine hydrochloride pulse-loading dosing regimens was conducted. After a two-week drug-free assessment period, 22 inpatients with a diagnosis of major depressive disorder were given either an evening infusion of 150 mg of clomipramine hydrochloride and placebo tablets or 150 mg of oral clomipramine hydrochloride and an isotonic saline infusion. Twenty-four hours later, this procedure was repeated using a dose of 200 mg of clomipramine hydrochloride. Patients received no further medication over the next five days. The mean Hamilton Depression Rating Scale score for all patients, five days after pulse loading, had dropped by 35% (range, 13.3% to -82.4%). This improvement was significant, as was the amelioration in the Raskin Severity for Depression Scale and the Beck Depression Inventory scores. Although the bioavailability of parenteral clomipramine was greater, there were no significant differences in either efficacy or side effects between the two groups. Pronounced early improvements in severe depressive symptoms may be achieved via loading dose regimens with clomipramine in the absence of continuous treatment.

Topics: Administration, Oral; Adult; Biological Availability; Clinical Trials as Topic; Clomipramine; Depressive Disorder; Double-Blind Method; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Personality Inventory; Psychiatric Status Rating Scales; Random Allocation

Thirty one in-patients suffering from depression were treated orally with clomipramine (C1) at various dosage, for 28 days, after a "wash-out" period of three days. In 17 patients receiving 75 mg per day of C1, steady state plasma levels of C1 were reached at Day 14, and steady state plasma levels of its active metabolite, desmethylclomipramine (DMC1), were reached at Day 21. In contrast, in 7 other patients receiving a dosage increasing to 150 mg per day at Day 7, mean plasma levels of C1 and DMC1 continued to rise during the entire treatment period. At the steady state, a correlation was found between C1 dosage expressed as mg kg body weight and the plasma concentration of C1 and DMC1. Factors such as tobacco and alcohol consumption seem to modify the C1/DMC1 ratio. A comparison of clinical response with plasma levels of C1, DMC1 and C1 + DMC1 showed a significant negative linear correlation.

Topics: Adult; Aged; Biotransformation; Clomipramine; Depressive Disorder; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Time Factors

The aim of this paper is to describe two cases of clomipramine-induced delirium. One 61-year-old and one 67-year-old female depressive patients became delirious after beginning intravenous clomipramine injections in addition to their oral clomipramine administrations. Their plasma levels of both clomipramine and its metabolite, desmethylclomipramine, were acutely increased about twofold during delirium. The intravenous clomipramine administrations were discontinued. Their delirious state was gradually improved after stopping the intravenous clomipramine administrations. These findings suggest that acute increases of plasma levels of clomipramine and desmethylclomipramine after intravenous clomipramine injections might be related to the appearance of the delirious episodes.

Topics: Aged; Clomipramine; Delirium; Depressive Disorder; Female; Humans; Injections, Intravenous; Middle Aged

We measured the plasma concentrations of clomipramine and its metabolites, N-desmethylclompiramine, 8-hydroxy-N-desmethylclomipramine, 8-hydroxyclomipramine in 65 depressed patients with subtypes of DSM-III-R mood disorders receiving clomipramine hydrochloride. There were large interindividual variations in the concentrations of the parent and each of the metabolic compounds, though the overall correlations between drug concentrations and daily doses of clomipramine were highly significant. Metabolic ratios for both desmethylation and hydroxylation varied by 15-35-fold interindividually. Discriminant analysis of the data from drug concentrations and scores of Global Assessment of Functioning revealed that it is useful to monitor the concentrations of both desmethylated and hydroxylated metabolites in order to predict the clinical effects of clomipramine.

Topics: Adolescent; Adult; Aged; Biotransformation; Bipolar Disorder; Clomipramine; Depressive Disorder; Drug Monitoring; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Psychiatric Status Rating Scales; Structure-Activity Relationship; Treatment Outcome

A 75 mg/day clomipramine treatment was prescribed for 4 weeks to 92 outpatients with major depression at the Neuropsychiatric Clinic of the National University Hospital of Cotonou in Benin, West Africa. Among them, only 42 followed the treatment during the 4 weeks and had a clomipramine and desmethylclomipramine plasma level measure (gas chromatography technique). The rate of noncompliance appeared high: 10 patients had no trace and another 2 had only traces of antidepressant in their plasma. For the remaining 29, a comparison with 29 Caucasian patients treated by clomipramine (the two samples are matched for sex and age, and the variables of weight, dosage and drug association are controlled) shows no significantly higher plasma levels in the Beninese sample.

Topics: Ambulatory Care; Benin; Black People; Clomipramine; Depressive Disorder; Humans; Patient Compliance; White People

In an open study of 12 inpatients who met the DSM-III criteria for a major depressive episode, the effects of clomipramine (CI) on the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured simultaneously with the effects on 3H-imipramine binding, serotonin (5-HT) uptake and 5-HT concentration in platelets after 3 and 6 weeks of treatment. Drug (CI and desmethylclomipramine) plasma concentrations were determined. The concentrations of 5-HIAA and HMPG decreased substantially, and the concentration of HVA remained unchanged. There was also a large and significant reduction of the number of imipramine binding sites (Bmax) and of the platelet 5-HT concentration. The 5-HT uptake was not measurable after 3 weeks of treatment. None of the parameters changed significantly between weeks 3 and 6. There were no significant correlations between antidepressant effect (measured by the Montgomery-Asberg Depression Rating Scale) and plasma drug concentrations, although a tendency to a significant correlation between antidepressant effect and CI was observed at 3 weeks. There were no significant intercorrelations between the different 5-HT parameters and no other significant correlations between the biochemical measures and clinical outcome.

Topics: Adult; Blood Platelets; Carrier Proteins; Clomipramine; Depressive Disorder; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neurotransmitter Agents; Psychiatric Status Rating Scales; Receptors, Drug; Receptors, Neurotransmitter; Receptors, Serotonin; Serotonin

A patient showed excessive concentrations of desmethylclomipramine after receiving normal daily doses of clomipramine (Anafranil) and the elimination kinetics of the desmethylated metabolite was zero-order/saturable. Investigation showed that she was a poor metabolizer of debrisoquine and that, in addition, she had been treated with allopurinol, an inhibitor of hepatic drug metabolism.

Topics: Allopurinol; Clomipramine; Debrisoquin; Depressive Disorder; Female; Humans; Hydroxylation; Kinetics; Middle Aged

Twenty four in-patients with an endogenous or non endogenous depressive syndrome (9 and 15, respectively) were treated in hospital for 21 days with various dosages regimens of clomipramine. Plasma concentrations of clomipramine and demethylclomipramine were determined once a week in blood samples. Therapeutic effects were assessed with Hamilton Rating Scale. At day 21, optimal therapeutic effect was observed when the sum of clomipramine and demethylclomipramine plasma levels was situated between 200-400 ng/ml.

Topics: Adolescent; Adult; Aged; Clomipramine; Depressive Disorder; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Tranquilizing Agents

Release of human neurophysin I (hNp I) and neurophysin II (hNp II) during insulin-induced hypoglycemia was studied in 10 unipolar depressed women before and after 4-5 weeks of standard antidepressant drug treatment with daily intravenous infusions of clomipramine. Before treatment, a significant increase of hNp I but not of hNp II serum levels in response to hypoglycemia was observed. At retest during clomipramine administration, a marked clinical amelioration occurred in all patients as determined with the Hamilton Rating Scale for Depression; the hNp I response to insulin was abolished, but no effect on hNp II concentration could be demonstrated. No correlation was found between the degree of the depression score decrease and the amplitude of the inhibition of hNp I release or serum levels of clomipramine or its metabolite, desmethylclomipramine. The meaning of this difference in reactivity of the neurohypophyseal system in the course of depressive illness, based on the pharmacological and biochemical profiles of clomipramine action, is discussed.

Topics: Blood Glucose; Clomipramine; Depressive Disorder; Female; Humans; Insulin; Middle Aged; Neurophysins; Pituitary Gland, Posterior

The plasma levels of clomipramine (CI) and its major metabolite desmethylclomipramine (DMCI) may be related to clinical response during treatment of depression. Not all workers have been able to demonstrate such a relationship. The many factors which may affect clinical response include sample selection, assessment and its quantification and kinetic factors. A further investigation into the relationship between plasma levels and response was, therefore, carried out taking these into account and attempting to control them. Sixty-two patients with depressive illness were included. The plasma levels of CI + DMCI as measured on the 28th day of treatment were correlated against clinical response at the time. Patients with the highest combined plasma levels showed the best response. Patients with intermediate plasma levels showed more modest response, whilst lowest plasma levels tended to be shown by patients who exhibited an inadequate response or who relapsed during subsequent outpatient follow-up. The threshold value for satisfactory antidepressant effect appeared to be a combined CI + DMCI plasma level of 160-200 mg/ml.

Topics: Adult; Clomipramine; Depressive Disorder; Female; Humans; Male; Middle Aged; Time Factors

A simultaneous analytical method was reported for measuring the plasma levels of amitriptyline, imipramine, clomipramine, maprotiline, nortriptyline, desipramine, desmethylclomipramine, desmethylmaprotiline and amoxapine by high performance liquid chromatography (HPLC). The total plasma levels of each parent drug plus its desmethyl metabolite were monitored in 29 depressed patients administered with amitriptyline, maprotiline or amoxapine using the present analytical method. There were significant linear correlations between the dose per kg body weight and the total plasma levels with amitriptyline and maprotiline, but no such correlation was found with amoxapine. The ratios of total plasma levels to dose per kg body weight of these three drugs were lower in outpatients than in inpatients. These results indicate that the monitoring of plasma levels of antidepressants is useful in treating depression.

Topics: Adult; Amitriptyline; Amoxapine; Antidepressive Agents; Chromatography, High Pressure Liquid; Clomipramine; Depressive Disorder; Desipramine; Dose-Response Relationship, Drug; Female; Humans; Imipramine; Male; Maprotiline; Middle Aged; Nortriptyline

Intravenous clomipramine and oral clomipramine at a daily dose of 2 mg/kg body weight were compared in a double-blind study of 40 inpatients with primary depressive illness. No significant differences between the two routes of clomipramine administration were found, either in response or in side effects. Steady state was not attained at the 4th week of treatment in 30% of patients. However, combined plasma levels of clomipramine (CI) plus desmethylclomipramine (DMCI) were similar in the two groups at all stages of treatment. The only significant pharmacokinetic difference that was found was in the ratio of DMCI to CI, which was higher among the patients who received the drug orally, but this did not correlate with clinical response. Conversely, Day 28 plasma concentrations of CI, DMCI, and the sum CI + DMCI were significantly related to clinical outcome in the patients treated orally. Among the patients who received the drug intravenously only CI was significantly associated with the percentage reduction of symptoms. By pooling the two groups, CI, DMCI, and their sum all bore relationships to clinical response significant at the 0.01 level.

Topics: Administration, Oral; Clomipramine; Depressive Disorder; Double-Blind Method; Humans; Injections, Intravenous; Middle Aged

Clomipramine (CMI) was administered to eight patients, either as an antidepressive drug or, in two patients, as an antalgic drug (average age: 54 y.; average body surface area: 1,71 m2). These patients were treated with 20 to 150 mg, every day, for various lengths of time: min.; one week: max.; 7 years, till the day before the determination of plasma levels. The samples were drawn on patients, fasting, in the morning. Plasma levels of CMI, Desmethylclomipramine (DCMI) and Cortisol were dosed by means of High Performance Liquid Chromatography with U. V. detection.

Topics: Adult; Aged; Circadian Rhythm; Clomipramine; Depressive Disorder; Female; Humans; Hydrocortisone; Male; Middle Aged

Topics: Clomipramine; Depressive Disorder; Dose-Response Relationship, Drug; Humans; Kinetics

Topics: Adult; Clomipramine; Depressive Disorder; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Male; Pregnancy; Pregnancy Complications; Seizures; Substance Withdrawal Syndrome

Ten patients with a vital depressive syndrome were treated for 4 weeks with clomipramine (CI), five receiving the drug by mouth and five receiving it first intramuscularly and then by mouth. Plasma concentrations of CI and desmethylclomipramine (DCI) were measured daily. Both concentrations showed marked interindividual differences, especially after oral administration of the drug. The mean relative CI clearance after repeated i.m. injections was 0.441 kg-1 hour-1. The route of administration proved to exert a marked influence on the plasma concentration ratio CI/DCI. In this small population, no significant relationship could be demonstrated between plasma CI and DCI concentrations, or the sum of both, and the clinical effect.

Topics: Administration, Oral; Adult; Clomipramine; Depressive Disorder; Female; Humans; Injections, Intramuscular; Male; Middle Aged

Pharmacokinetic can perhaps explain that about 30% of depressed patients do not respond to tricyclic antidepressants. Studies of the relationship between the pharmacokinetic and pharmacological effects of the tricyclic antidepressants are particularly important. Clomipramine is a tricyclic antidepressant widely used. But there are disparities in various findings on relationship between plasma levels of this drug and clinical effect. Forty in-patients, with an endogenous or exogenous depressive syndrome, received clomipramine orally. In 19 patients treated by 75 mg per day of clomipramine, there was a great interindividual variability of the plasma levels at the 28 day treatment. A comparison of clinical response with plasma levels of clomipramine and desmethylclomipramine, showed a significant negative linear correlation at day 28.

Topics: Adjustment Disorders; Adult; Aged; Clomipramine; Depressive Disorder; Female; Humans; Kinetics; Male; Middle Aged