norclozapine and Psychotic-Disorders

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.

Topics: Adult; Aged; Antipsychotic Agents; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Psychotic Disorders; Reference Values; Schizophrenia; Smoking

Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoxetine; Humans; Male; Psychotic Disorders; Schizophrenia; Stimulation, Chemical; Valproic Acid

Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation. Clozapine's main metabolite, N-desmethylclozapine (NDMC), has potent 5-HT2C antagonist properties which may explain this metabolic dysfunction, thus the CLZ:NDMC ratio is of particular interest. High insulin resistance states could be associated with CYP1A2 induction and lower CLZ:NDMC ratios. Additionally, lower CLZ:NDMC ratios have been associated with better cognitive, but worse metabolic functioning. This study investigated associations between metabolic and cognitive parameters with the CLZ/NDMC ratio. Primary outcomes included relationships between the CLZ:NDMC ratio to the homeostatic model assessment for insulin resistance (HOMA-IR) and Brief Assessment of Cognition in Schizophrenia (BACS) composite z-scores. Secondary outcomes assessed relationships between CLZ:NDMC ratios to fasting insulin, BMI, weight, fasting glucose, and BACS digit sequencing z-scores. 38 patients who were overweight or obese with schizophrenia or schizoaffective disorder completed fasting bloodwork, anthropometric, psychopathological, and cognitive assessments. Multivariate regressions found a statistically significant inverse association between the CLZ/NDMC ratio and HOMA-IR (B = - 1.028, SE B = .473, β = - 0.348 p = 0.037), which may have been driven by fasting insulin levels (B = - 27.124, SE B = 12.081, β = - 0.351 p = 0.031). The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cognition; Female; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Psychotic Disorders; Schizophrenia; Young Adult

Topics: Adult; Aggression; Clozapine; Fatal Outcome; Female; Heart Failure; Humans; Psychiatric Department, Hospital; Psychomotor Agitation; Psychotic Disorders; Restraint, Physical

Valproic acid and clozapine are drugs commonly used in the treatment of schizophrenic and schizoaffective disorders. Pharmacokinetic interactions of valproic acid with several drugs are well known, yet results concerning the interaction with clozapine are inconsistent.. Steady-state dose-corrected serum concentrations of clozapine and its main metabolite norclozapine were retrospectively analyzed in 45 patients receiving both clozapine and valproic acid. Controls were matched for sex, age, smoking, comedication, and inflammatory response.. The group receiving comedication with valproic acid showed significantly lower median dose-corrected serum concentrations of norclozapine (0.44 [0.27-0.58] (ng/mL)/(mg/d) vs 0.78 [0.60-1.07] (ng/mL)/(mg/d)) as well as metabolite to parent compound ratios (0.40 [0.36-0.47] vs 0.71 [0.58-0.84]) by approximately 44%. Dose-corrected serum concentrations of clozapine were not significantly lower. The effect of valproic acid was independent of sex and smoking.. Comedication with valproic acid accelerated metabolism of clozapine with predominant effects on the degradation of norclozapine. Therapeutic drug monitoring should be applied to guide individual patient responses upon initiation of comedication.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Monitoring; Female; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Valproic Acid

Cognitive symptoms play a central role in schizophrenia and are strongly associated with social functioning. Treatment with clozapine presents controversial results regarding its effects on cognition. The opposite effects of clozapine and n-desmethylclozapine (NDMC) on cholinergic system have been suggested to underlie these inconclusive findings. The aim of this study is to determine whether clozapine/NDMC ratio can predict cognitive performance in patients with treatment-resistant psychosis. Nineteen clinically stable patients with schizophrenia or schizoaffective disorder treated with clozapine monotherapy completed demographic and clinical interviews. For the purpose of the study, patients were assessed with a neuropsychological battery and on the same day a blood sampling was obtained from each patient to measure plasma levels of clozapine and NDMC. Our results showed that clozapine/NDMC ratio, but not clozapine or NDMC plasma levels separately, was a predictive factor of cognitive performance, specifically of executive functioning. Our results showed that lower clozapine/NDMC ratios are associated with better executive functioning in clinically stable patients. These findings could be interpreted by the different pharmacodynamic properties on cholinergic, dopaminergic and serotonergic systems of NDMC compared to clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Choline; Clozapine; Cognition; Cross-Sectional Studies; Dopamine; Female; Humans; Male; Middle Aged; Prognosis; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Serotonin

Clozapine is associated with subjectively unpleasant or clinically serious side-effects, which may affect treatment adherence. The aims of the study were to explore the association of clozapine+ norclozapine serum concentration and other factors with subjective side-effects in schizophrenia patients.. In this cross-sectional study, 237 patients with a diagnosis of schizophrenia, schizo-affective or other non-organic psychoses completed the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), a self-report scale measuring side-effects of antipsychotics and a clinical questionnaire. Clozapine+ norclozapine serum concentration of 190 patients was measured. Of the patients 80 (33.7%) were on antipsychotic combination therapy.. Higher clozapine+ norclozapine concentrations were associated with the depression-anxiety factor of LUNSERS and antipsychotic combination treatments were associated with sympatichotonia-tension factor. Younger patients reported sedation more often than older patients.. According to the present results, high clozapine concentrations were associated with depression-anxiety symptoms, but the causality remains unknown.

Topics: Adult; Aged; Antipsychotic Agents; Anxiety; Causality; Clozapine; Cross-Sectional Studies; Depression; Female; Humans; Male; Medication Adherence; Middle Aged; Psychotic Disorders; Risk Factors; Schizophrenia; Self Report; Sleep Stages; Surveys and Questionnaires; Young Adult

Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia.. Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity.. The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains.. This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Psychometrics; Psychotic Disorders; Schizophrenia; Treatment Outcome; Young Adult

The purpose of this study was to estimate the effect sizes of drug interactions on plasma clozapine concentrations, adjusting for potentially confounding factors such as smoking.. The estimation was performed by using a mixed model, and a combination of unpublished (N=83) and published (N=172) data that included patients taking phenobarbital, valproic acid, fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram and reboxetine, and patients not taking co-medications.. The 255 patients provided a total of 415 steady-state trough plasma clozapine concentrations. Each patient provided 1 to 15 measures of plasma clozapine concentrations. Total plasma clozapine concentration, defined as the sum of plasma clozapine and norclozapine concentrations, was also investigated. A random intercept linear model of the natural log of plasma clozapine concentration with the natural log of dose and other variables as independent variables was built. The model confirmed that phenobarbital induces clozapine metabolism (effect size, E=-28%), and that fluoxetine (E=+42%), fluvoxamine (E=+263%) and paroxetine (E=+30%) inhibit it. Valproic acid appeared to inhibit clozapine metabolism in non-smokers (effect size, E=+16%), whereas it appeared to induce clozapine metabolism in smokers (E=-22%). The effect sizes of smoking on plasma clozapine concentration were -20% in patients not taking valproic acid, and -46% in patients taking valproic acid. Thus, smoking induces clozapine metabolism, and this induction may be stronger when the patient is taking valproic acid. The effect sizes allowed the computation of clozapine dose-correction factors for phenobarbital, 1.4 [95% confidence interval, CI, (1.1, 1.7)]; paroxetine, 0.77 (0.67, 0.89); fluoxetine, 0.70 (0.64, 0.78); fluvoxamine, 0.28 (0.22, 0.35); and valproic acid [0.86 (0.75, 1.0) in non-smokers, and 1.3 (0.96, 1.73) in smokers]. Sertraline, reboxetine and citalopram had no obvious effects.. The results for total plasma clozapine concentrations are similar to those for plasma clozapine concentrations. The main limitations of this study were that the computed effect sizes reflect only the doses and treatment-durations of the co-medications studied, and that the substantial "noise" of the clinical environment may make it difficult to detect the effects of some variables, particularly those with small effect sizes. Gender was not significant probably due to its relatively small effect size in the studied population, and age was not significant probably due to the limited age variability.. This article contributes to the clozapine literature by describing a possible interaction between taking valproic acid and smoking, which modifies plasma clozapine concentrations, by estimating the effect sizes of other compounds on plasma clozapine concentrations after correcting for confounders, and by providing dose-correction factors for clinicians.

Topics: Antipsychotic Agents; Clozapine; Confounding Factors, Epidemiologic; Female; Humans; Linear Models; Male; Psychotic Disorders; Reference Values; Weights and Measures

There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT(2) antagonist and as a partial agonist to dopamine D(2) and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D(2) and 5-HT(2) receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT(2) (64-79%), but minimal D(2) occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Avoidance Learning; Biomarkers; Brain; Brain Chemistry; Catalepsy; Clozapine; Dopamine Agonists; Drug Evaluation, Preclinical; Haloperidol; Male; Piperazines; Prolactin; Proto-Oncogene Proteins c-fos; Psychotic Disorders; Quinolones; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Serotonin Antagonists; Treatment Outcome

Clozapine is associated with non-neurological side effects that can be subjectively unpleasant and/or clinically serious. We sought to: (i) assess the nature and prevalence of side effects experienced by patients receiving maintenance treatment with clozapine and (ii) explore the relationship between clozapine plasma concentration and side effect burden. Patients were receiving clozapine maintenance treatment. Open questioning followed by systematic enquiry using the Antipsychotic Non-neurological Side Effects Rating Scale were used to assess side effects. Trough plasma clozapine and norclozapine concentrations were measured. One hundred and three patients participated. On open questioning, 61 patients reported a total of 117 side effects, whereas systematic enquiry identified an additional 649 side effects, with each patient reporting at least one. Clozapine plasma concentrations were significantly but weakly correlated with total Antipsychotic Non-neurological Side Effects Rating Scale score (Pearson correlation=0.29, P<0.004). Patients with a plasma clozapine concentration >0.25 mg/l were significantly more likely to have moderate/severe side effects than patients with lower plasma concentrations (63/76 vs. 12/23, chi=9.07, d.f.=1, P<0.01). The side-effect burden associated with maintenance clozapine treatment is high and the true extent can only be ascertained by systematic inquiry. The use of target plasma concentrations below those used for acute treatment should be explored as a strategy for minimizing side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Schizophrenia; Sexual Dysfunction, Physiological; Sialorrhea

Steady-state plasma concentrations of clozapine and norclozapine, its major metabolite, as well as their sum and ratio (norclozapine/clozapine), were evaluated in 50 in- and outpatients taking clozapine and naturalistically recruited. Drug plasma concentrations were measured by means of a reversed-phase high-performance liquid chromatography (RPLC) method with an ultraviolet detection. Daily doses (milligrams per kilogram of body weight) of clozapine correlated positively with clozapine plasma parameters, except with the norclozapine/clozapine ratio, in all patients. When the patients were divided in subgroups with respect to gender, the corresponding plasma concentrations were no longer dose-related in men. A lack of significant correlation was observed also in patients (n=23) co-treated with typical neuroleptics. Conversely, dose-concentration correlations were significant in either smoker or nonsmoker patients. No significant relationship between body weight and clozapine plasma parameters was reported. Further, we observed (1) a trend towards higher medians of clozapine or total analytes in women than those reported in men (P=.09 and .07); (2) no significant difference in plasma levels obtained in subjects younger than 34 years and subjects 34 years old or older; (3) a trend towards higher norclozapine and clozapine plus norclozapine levels (P=.05 and .08) in nonsmoker than smoker patients; (4) no significant difference between clozapine plasma parameters measured in patients co-medicated with typical neuroleptics and in patients receiving clozapine alone.

Topics: Adolescent; Adult; Aged; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Patients; Psychotic Disorders; Sex Factors; Smoking; Statistics, Nonparametric

The goal of this study was to identify adverse effects of the atypical neuroleptic clozapine on liver function and lipid metabolism.. Data which included serum levels of clozapine and its hepatic metabolite N-desmethyl clozapine were collected from medical records of patients treated with clozapine and controls.. We identified a clozapine-associated marked elevation of plasma cholinesterase (ChE) with unchanged levels of AST, ALT or g-GT. ChE was correlated to the serum level of clozapine and even closer to N-desmethyl clozapine. For the total patient group we observed significant correlations of ChE with the body-mass index and body weight. However, clozapine-treated patients and controls did not differ with regard to body-mass index, triglycerides, and cholesterol.. We report for the first time a clozapine-associated and dose-dependent elevation of plasma ChE, which may be related to clozapine-associated effects on hepatic lipid metabolism or ChE enzyme induction.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Body Weight; Cholesterol; Cholinesterases; Clozapine; Female; Humans; Lipid Metabolism; Liver Function Tests; Male; Middle Aged; Outpatients; Psychotic Disorders; Retrospective Studies; Triglycerides

Topics: Adult; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Female; Humans; Mixed Function Oxygenases; Oxidoreductases; Psychotic Disorders

This study was done to test the hypothesis that serum concentration of norclozapine is a risk factor for leukopenia during treatment with clozapine.. Maximum decreases in leukocyte counts in 44 unselected patients treated with clozapine were determined and then correlated with drug doses and serum concentrations of clozapine, norclozapine, and clozapine-N-oxide.. White cell and granulocyte counts decreased by up to 60%-73%, but there were no positive correlations between these decrements and drug dose, drug level, ratio of drug level to drug dose, or ratio of norclozapine level to clozapine level, nor were the decreases related to age or gender.. While these results do not suggest in vivo hemotoxicity of norclozapine, further study of patients with clinically significant leukopenia is required.

Topics: Clozapine; Female; Follow-Up Studies; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Psychotic Disorders; Risk Factors