Clozapine Plasma Levels Research Articles

Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia.

Investigation of peripheral gene expression patterns of transcripts within the NRG–ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG–ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini–Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG–ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG–ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.

Plasma ratio of clozapine to N-desmethylclozapine can predict cognitive performance in treatment-resistant psychotic patients

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.

Concentrations in plasma clozapine levels in schizophrenic and schizoaffective patients

IntroductionThere is great variability in plasma levels of clozapine. The objective of this study is to know the characteristics of patients treated with clozapine and the relationship between them and the variability of plasma levels. Material and methodsDescriptive, cross-sectional study of all patients currently treated with clozapine in a Psychiatric Service with a diagnosis of schizophrenic psychosis or schizoaffective disorder. The present study assessed physical situation, psychopathology and functionality of the patients and explored the associations and correlations between clinical variables and plasma levels. ResultsWe studied 39 patients, predominantly men, with negative and depressive symptoms and cardiovascular risk factors (metabolic syndrome and smoking). Significant variability in dose and even greater in clozapine levels were observed. The levels of clozapine at equal doses/kg of body weight were higher in non-smokers, they had positive correlation with BMI and negative correlation with systolic BP, disruptive behaviours and number of cigarettes consumed. ConclusionPlasma level monitoring clozapine is an important tool to avoid clozapine plasma levels monitoring and minimise undesirable clinical situations (metabolic syndrome, sedation, negative symptoms and functional impairment). It is also important to control the effects of a smoking habit for optimum drug bioavailability.

Concentrations in plasma clozapine levels in schizophrenic and schizoaffective patients.

There is great variability in plasma levels of clozapine. The objective of this study is to know the characteristics of patients treated with clozapine and the relationship between them and the variability of plasma levels. Descriptive, cross-sectional study of all patients currently treated with clozapine in a Psychiatric Service with a diagnosis of schizophrenic psychosis or schizoaffective disorder. The present study assessed physical situation, psychopathology and functionality of the patients and explored the associations and correlations between clinical variables and plasma levels. We studied 39 patients, predominantly men, with negative and depressive symptoms and cardiovascular risk factors (metabolic syndrome and smoking). Significant variability in dose and even greater in clozapine levels were observed. The levels of clozapine at equal doses/kg of body weight were higher in non-smokers, they had positive correlation with BMI and negative correlation with systolic BP, disruptive behaviors and number of cigarettes consumed. Plasma level monitoring clozapine is an important tool to avoid clozapine plasma levels monitoring and minimize undesirable clinical situations (metabolic syndrome, sedation, negative symptoms and functional impairment). It is also important to control the effects of a smoking habit for optimum drug bioavailability.

Effects of adjunctive fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia: A 12-week, randomized, double-blind, placebo-controlled study

ObjectiveNumerous studies have demonstrated that fluvoxamine has considerable pharmacokinetic and pharmacodynamic interactions with clozapine. We conducted a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia. MethodsWe recruited 85 patients who received a DSM-IV diagnosis of schizophrenia. Eligible patients were randomized to receive fluvoxamine 50mg/day plus clozapine 100mg/day or clozapine 300mg/day. We studied metabolic parameters, psychopathology, and drug levels at baseline and 4, 8, and 12weeks after the intervention. Plasma levels of clozapine, norclozapine, clozapine N-oxide, and fluvoxamine were determined using high-performance liquid chromatography with ultraviolet detection. ResultsNo significant difference was observed in baseline characteristics between the two groups. Clozapine–fluvoxamine combined treatment significantly attenuated the increments in body weight, insulin resistance, and levels of insulin, glucose, and triglycerides compared with clozapine monotherapy. Both groups exhibited significant improvements in their Positive and Negative Syndrome Scale (PANSS) total and negative scores. The combined treatment group showed significant reduction in the PANSS general psychopathology scores compared with the monotherapy group. No difference was observed in the plasma clozapine level between the two groups. The monotherapy group showed higher levels of norclozapine and clozapine N-oxide than the combined group. ConclusionsCompared with clozapine monotherapy, treatment with adjunctive fluvoxamine with clozapine for 12weeks can alleviate body weight gain and metabolic abnormalities in patients with schizophrenia, without sacrificing the clinical effect. Clinicians should interpret these findings cautiously considering the short duration of this study.The study was registered at www.clinicaltrials.gov (NCT01401491).

Side effects of clozapine and their relationship with clinical variables in patients with schizophrenia

IntroductionThe side effects of clozapine may affect the treatment process negatively, and increase the disability.AimsWe aimed to assess the side effects of clozapine, and their relationship with the clinical variables in schizophrenia patients, and study the predictors of disability.MethodsConsecutive 122 outpatients who met DSM-IV criteria for schizophrenia, and were on clozapine treatment were included in the study. Information about sociodemographic characteristics, past and current clinical status were gathered through a clinical interview and review of the medical records, and physical measures and laboratory tests, including clozapine plasma levels, were recorded. The patients were assessed with SCID-I, Positive and Negative Syndrome Scale, UKU-Side Effect Rating Scale, WHO-Disability Assessment Schedule-II.ResultsHypersalivation, weight gain, sedation and constipation were the most common side effects of clozapine. Although the mean plasma clozapine levels were high (828.11 ± 445.5 ng/mL), no significant effect of clozapine dose and plasma levels were detected on the severity of side effects, except for constipation. Metabolic syndrome prevalence was found to be 50% according to ATP IIIA criteria. Duration of clozapine treatment, clozapine dose and plasma levels were not significantly different between patients with and without metabolic syndrome. Regression analysis showed that the severity of schizophrenia psychopathology and the number of side effects predicted the severity of disability.ConclusionsSide effects of clozapine increase the disability of patients with schizophrenia and should be monitored regularly. On the other hand, clozapine dose and plasma levels do not determine the severity of most of the common side effects.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Effect of clozapine on psychiatric comorbidities in patients with schizophrenia

IntroductionClozapine has superior efficacy in treatment-resistant schizophrenia, and has various effects on psychiatric comorbidities, which may affect the illness course.AimsWe aimed to assess the past and current psychiatric comorbidities in schizophrenia patients treated with clozapine, and study their relationship with clinical variables.MethodsConsecutive 122 outpatients who met DSM-IV criteria for schizophrenia receiving clozapine were included. Information about past and current clinical status were gathered through a clinical interview and review of the medical records, along with laboratory test results. Patients were assessed with structured clinical interview for Axis-I Disorders for DSM-IV, Clinical Global Impression Scale, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Panic and Agoraphobia Scale (PAS), WHO-Disability Assessment Schedule-II.ResultsThere was a significant decrease in the diagnosis of depression, alcohol and substance use disorder, number of suicide attempts, and an increase in the diagnosis of obsessive compulsive disorder (OCD) after clozapine initiation. Clozapine related de novo OCD appeared in 48.4% of the patients, and there was a positive correlation between Y-BOCS total scores and clozapine dose and plasma levels. In the de novo OCD group, compulsion scores were higher than obsession scores with checking most prevalent among compulsions. Total PANSS, Y-BOCS, PASscores were positively correlated withtotal disability score.ConclusionsClozapine seems to decrease comorbid depression, alcohol and substance use and number of suicide attempts and increase OCD. Assessment and treatment of psychiatric comorbidities in clozapine using schizophrenia patients is vital to decrease disability.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Subjective well-being under clozapine measured with the Serbian version of GASS-C: Preliminary results

IntroductionClinical benefits of antipsychotic treatment depend on the efficacy and on the patients’ tolerability and compliance. To reduce patient initiated treatment discontinuation, timely detection of treatment emergent side effects is essential. The Glasgow Antipsychotic Side-effects scale for clozapine (GASS-C) is a recently developed instrument to measure subjectively experienced clozapine side effects.ObjectivesTimely detection of unreported clozapine related side-effects.AimDocumenting the prevalence of side-effects in schizophrenia or chronic psychotic disorder with the Serbian version of the GASS-C.MethodsThe sample included 95 in and outpatients with schizophrenia or chronic psychotic disorder. All subjects filled out the Serbian version of the GASS-C and a sociodemographic questionnaire.ResultsThe median age was 46.1 years; 53.7% of subjects were male. Clozapine doses ranged from 25 to 423 mg. Drowsiness (78%) was the most commonly reported side-effect. Overall, 16.8% of the patients added other complaints, such as headache, pain, hand or leg numbing or nightmares. According to GASS-C total score categorization [2], only 4.2. % of subjects were rated with severe side-effects, while 14% of themselves rated their symptoms as severe or distressing. More side effects were reported by female patients and by inpatients. Only a weak positive correlation was found between the severity of the side effects and clozapine dosage.ConclusionsWe found the GASS-C to be a useful instrument that elicits both unknown side-effects and patients rating of their severity. Side effects did not clearly relate to the prescribed dose. Future research should include the relation of clozapine plasma levels with side effects assessed with GASS-C.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The Porirua Protocol in the Treatment of Clozapine-Induced Gastrointestinal Hypomotility and Constipation: A Pre- and Post-Treatment Study.

Clozapine, an antipsychotic used in treatment-resistant schizophrenia, causes slow gastrointestinal transit in 50-80% of patients. Clozapine-induced gastrointestinal hypomotility is both common and serious, and potential complications include severe constipation, ileus, bowel obstruction and related complications, with a higher mortality rate than clozapine-related agranulocytosis. Little evidence exists on its prevention and management. Using a well-validated radiopaque marker ('Metcalf') method, we compared colonic transit times (CTTs) of clozapine-treated inpatients not receiving laxatives with their transit times when receiving laxatives, with treatment prescribed according to the Porirua Protocol for clozapine-related constipation (docusate and senna augmented by macrogol 3350 in treatment-resistant cases). The median age of participants was 35years, and median clozapine dose, plasma level and duration of treatment were 575mg/day, 506ng/mL and 2.5years, respectively. Overall, 14 participants (10 male) were enrolled and all completed the study. Transit times improved markedly with laxative treatment. Median colonic transit without laxatives was 110h (95% confidence interval [CI] 76-144h), over four times longer than normative values (p<0.0001). Median CTT with laxatives was 62h (95% CI 27-96h), a 2-day reduction in average transit time (p=0.009). The prevalence of gastrointestinal hypomotility decreased from 86% pre-treatment to 50% post-treatment (p=0.061). Severe gastrointestinal hypomotility decreased from 64 to 21% (p=0.031). Subjective reporting of constipation did not correlate well with objective hypomotility, and did not change significantly with treatment. Treating clozapine-treated patients with docusate and senna augmented by macrogol appears effective in reducing CTTs in clozapine-induced constipation. Randomised controlled trials are the next step. Australian New Zealand Clinical Trial Registry ACTRN12616001405404 (registered retrospectively).

Cigarette smoking has a differential effect on the plasma level of clozapine in Taiwanese schizophrenic patients associated with the CYP1A2 gene -163A/C single nucleotide polymorphism.

The efficacy of clozapine clearance has been shown to be associated with smoking and genetic polymorphism of CYP1A2. This study aims to investigate the effect of smoking on the plasma level of clozapine in Taiwanese schizophrenic patients and its relevance to the CYP1A2 gene -163A/C single nucleotide polymorphism. A total of 143 hospitalized schizophrenic patients who had received clozapine therapy for at least 14 days were enrolled in this study. The trough plasma concentration of clozapine was measured with LC/MS/MS. The -163A/C variant in the CYP1A2 gene was identified by DNA sequencing and restriction fragment length polymorphism analysis. The effect of smoking on the clozapine level was examined by multiple linear regression analysis and its relation to the -163A/C variant of the CYP1A2 gene was analyzed using a general linear model with Bonferroni correction. Patients with smoking habits showed a significantly lower plasma level of clozapine than those without smoking habits (P=0.022) and the difference in clozapine levels between smokers and nonsmokers appeared to be significant in the individuals carrying the homozygous -163A allele (P=0.02). It was also found that nonsmokers carrying the -163A allele tended to have higher plasma levels of clozapine. This tendency was not found in the individuals with smoking habits. Cigarette smoking has a significant impact on the plasma level of clozapine in Taiwanese schizophrenic patients carrying the homozygous -163A allele in the CYP1A2 gene. Cigarette smoking may increase the clearance of clozapine in these patients.

Quantifying intraindividual variations in plasma clozapine levels: a population pharmacokinetic approach.

Clozapine has strong recommendations for therapeutic drug monitoring. While factors that influence interindividual variation in plasma clozapine levels have been extensively reported, intraindividual variation remains poorly studied. We employed a population pharmacokinetic approach to assess intraindividual variations in plasma levels of both clozapine and N-desmethylclozapine, as well as the impact of smoking on this variability. Patients who were initiated on clozapine from January 2009 to December 2010 and who provided at least 2 plasma samples were included in this study. The observed concentrations of clozapine and N-desmethylclozapine were applied in a Bayesian pharmacokinetic modeling approach by using a previously published pharmacokinetic model from an independent sample to compute a predicted concentration. The predicted concentrations of clozapine and N-desmethylclozapine were then compared with the observed concentrations in the form of a ratio: predicted-to-observed concentration ratio (Cpred/Cobs). The coefficient of variation of the Cpred/Cobs ratios was taken as a measure of intraindividual variation. A total of 723 plasma levels from 61 patients were included in this analysis. The coefficient of variation of Cpred/Cobs ratios for clozapine and N-desmethylclozapine were 29.8% (SD = 17.2%) and 27.4% (SD = 16.4%), respectively. Though values were higher, smoking did not have a significant effect on coefficients of variation of clozapine (33.5% vs 26.3%, P = .184) or N-desmethylclozapine (30.7% vs 24.2%, P = .100). Clinicians need to be aware of intraindividual variability and not assume that plasma levels are static. If plasma levels are used to guide dosing of clozapine, serial measurements rather than a single level might be necessary to make an informed clinical decision. The clinical implications of intraindividual variability in plasma clozapine levels need further study.

Clozapine-treated Patients Have Marked Gastrointestinal Hypomotility, the Probable Basis of Life-threatening Gastrointestinal Complications: A Cross Sectional Study

BackgroundGastrointestinal side effects are particularly common with clozapine and occur with other antipsychotics, ranging from mild constipation to fatal bowel obstruction and/or ischemia. While this adverse-effect spectrum has been attributed to ‘gastrointestinal hypomotility’, gastrointestinal transit times in antipsychotic-treated patients have not previously been measured, making this mechanism speculative. MethodsUsing standardized radiopaque marker (‘Metcalf’) methods we established colonic transit times of antipsychotic-treated psychiatric inpatients and compared them with population normative values. We analyzed results by antipsychotic type, antipsychotic dose equivalent, anticholinergic load, duration of treatment, gender, ethnicity, and age. OutcomesFor patients not prescribed clozapine, median colonic transit time was 23h. For patients prescribed clozapine, median transit time was 104.5h, over four times longer than those on other antipsychotics or normative values (p<0.0001). Eighty percent of clozapine-treated patients had colonic hypomotility, compared with none of those prescribed other antipsychotics (olanzapine, risperidone, paliperidone aripiprazole, zuclopenthixol or haloperidol). In the clozapine group, right colon, left colon and rectosigmoid transit times were all markedly abnormal suggesting pan-colonic pathology. Hypomotility occurred irrespective of gender, age, ethnicity, or length of clozapine treatment. Transit times were positively correlated with clozapine plasma level (rho=0.451, p=0.045), but not with duration of treatment, total antipsychotic load or demographic factors. InterpretationClozapine, unlike the other antipsychotics examined, causes marked gastrointestinal hypomotility, as previously hypothesized. Pre-emptive laxative treatment is recommended when starting clozapine.

Ciprofloxacin and Clozapine: A Potentially Fatal but Underappreciated Interaction.

Objective. Clozapine provides a 50%–60% response rate in refractory schizophrenia but has a narrow therapeutic index and is susceptible to pharmacokinetic interactions, particularly with strong inhibitors or inducers of cytochrome P450 (CYP) 1A2. Case Report. We report the case of a 28-year-old nonsmoking female with intellectual disability who was maintained for 3 years on clozapine 100 mg orally twice daily. The patient was treated for presumptive urinary tract infection with ciprofloxacin 500 mg orally twice daily and two days later collapsed and died despite resuscitation efforts. The postmortem femoral clozapine plasma level was dramatically elevated at 2900 ng/mL, and the cause of death was listed as acute clozapine toxicity. Conclusion. Given the potentially fatal pharmacokinetic interaction between clozapine and ciprofloxacin, clinicians are advised to monitor baseline clozapine levels prior to adding strong CYP450 1A2 inhibitors, reduce the clozapine dose by at least two-thirds if adding a 1A2 inhibitor such as ciprofloxacin, check subsequent steady state clozapine levels, and adjust the clozapine dose to maintain levels close to those obtained at baseline.

The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review.

New clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC). This study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine. MEDLINE, Embase, and the Cochrane Library were searched with the search terms "clozapine" and "fluvoxamine" without any time limit. Language was restricted to English, Scandinavian, Polish, and German. Studies were sorted for relevance based on title and abstract. Clinical recommendations of potential indications/effects were graded as level A, B, C, or D depending on studies of high, moderate, low, or very low quality, respectively. Based on data from 24 case reports/series, seven cohort studies, and two randomized controlled trials, 241 patients were studied. Evidence (A) supported that adjunctive fluvoxamine increased clozapine plasma levels. This may increase the probability of response in patients, where sufficient clozapine plasma levels cannot be achieved. Adjunctive fluvoxamine reduced metabolic adverse effects of clozapine (B) but not agranulocytosis risk (B). Although depressive or obsessive-compulsive symptoms may improve, a SSRI with no CYP1A2 inhibition should rather be used (C). No studies investigated the effect of adjunctive fluvoxamine to minimize clozapine rebound psychosis (D) or to reduce the effects of smoking on clozapine plasma levels (D). Adjunctive fluvoxamine may have clinical potentials for optimizing clozapine treatment but further clinical studies are warranted to explore the clinical implications.

Clozapine toxicity due to a multiple drug interaction: a case report

IntroductionWe report the case of a multiple drug interaction involving clozapine, antifungals and oral contraceptives, which resulted in an increased clozapine plasma level, pericarditis with pericardial effusion and eosinophilia in a young Caucasian woman. These symptoms and signs disappeared a few days after discontinuation of clozapine. At present, we are not aware of reports of clozapine–antifungals interaction, whereas there is only one other case report on the interaction between oral contraceptives and clozapine. The purpose of this case report is to show the risk of potentially serious adverse effects stemming from drug interactions involving medications routinely used in clinical practice.Case presentationA 29-year-old Caucasian woman diagnosed with a schizoaffective disorder was admitted to a psychiatric unit for acute psychosis (hallucinations, delusions and catatonic behavior). She denied smoking tobacco products and was on long-term oral contraceptives. During the first month of hospitalization she was treated with antipsychotics and for 1 week she took simultaneously fluconazole and miconazole gel, after being diagnosed with oral candidiasis. On the last day of antifungals treatment, 29 days after admission, clozapine was started with resolution of psychotic symptoms. After 3 weeks, her clozapine plasma level had increased to 542ng/mL and eosinophilia was observed. She complained of nausea, vomiting and palpitations; echocardiography showed echocardiographic abnormalities and pericardial effusion. Oral contraceptives were discontinued and after 1 week clozapine was interrupted, with a complete resolution of side effects and pericardial effusion within 4 days.ConclusionsClozapine is metabolized by cytochrome P450. The use of inhibitors or other substrates of cytochrome P450, such as antifungals and oral contraceptives, can cause long-lasting interactions and clozapine toxicity. The Naranjo algorithm shows clozapine is a definite cause of pericarditis (score 9) and both clozapine–antifungals and clozapine–contraceptives interactions resulted probable (score 5) in Drug Interaction Probability Scale. A good knowledge on drugs that act as substrates, inhibitors or inducers of cytochrome P450 is mandatory. When those drugs are used in patients taking clozapine, blood level monitoring of clozapine should be recommended, since a lower dose of clozapine might be required to prevent clozapine toxicity.

Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

To assess (1) the variance of plasma clozapine levels; (2) the relative importance of sex, smoking habits, weight, age, and specific genetic variants of cytochrome P450 1A2 (CYP1A2), uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4), and multidrug resistance protein 1 (MDR1) on plasma levels of clozapine; and (3) the relation between plasma clozapine levels, fasting glucose levels, and waist circumference. There were 113 patients on clozapine treatment recruited from psychosis outpatient clinics in Stockholm County, Sweden. Patients had genotype testing for single nucleotide polymorphisms: 2 in MDR1, 3 in CYP1A2, and 1 in UGT1A4. Multiple and logistic regression were used to analyze the relations. There was a wide variation in plasma concentrations of clozapine (mean = 1,615 nmol/L, SD = 1,354 nmol/L), with 37% of the samples within therapeutic range (1,100-2,100 nmol/L). Smokers had significantly lower plasma clozapine concentrations than nonsmokers (P ≤ .03). There was a significant association between the rs762551 A allele of CYP1A2 and lower plasma clozapine concentration (P ≤ .05). Increased fasting glucose level was 3.7-fold more frequent in CC and CA genotypes than AA genotype (odds ratio = 0.27; 95% confidence interval, 0.10-0.72). There was no significant relation between higher fasting glucose levels, larger waist circumference, and higher clozapine levels. It is difficult to predict plasma clozapine concentration, even when known individual and genetic factors are considered. Therefore, therapeutic drug monitoring is recommended in patients who are treated with clozapine.

Ziprasidone as adjunctive therapy in severe bipolar patients treated with clozapine.

Aim. To confirm the efficacy and tolerability of ziprasidone as adjunctive therapy in bipolar patients partially responding to clozapine or with persisting negative symptoms, overweight, or with metabolic syndrome. Methods. Eight patients with psychotic bipolar disorder were tested with the BPRS, the HAM-D, and the CGI at T0 and retested after 2 weeks (T1). Plasma clozapine and norclozapine levels and BMI were tested at T0 and T1. Results. Ziprasidone was well tolerated by all the patients. BPRS and HAM-D scores were reduced in all patients. BMI was reduced in patients with a BMI at T0 higher than 25. Plasma levels of clozapine and norclozapine showed an irregular course.

Increasing the clozapine: Norclozapine ratio with co-administration of fluvoxamine to enhance efficacy and minimize side effects of clozapine therapy

Although clozapine is the only antipsychotic agent to have demonstrated superior efficacy in treatment-refractory schizophrenia, one- to two-thirds of patients do not respond adequately despite acceptable dosages and plasma levels. Moreover, a significant number of patients stop the therapy for various reasons, including its side effects, many of which are thought to be related to its active metabolite, norclozapine. However, combining clozapine with the SSRI antidepressant fluvoxamine decreases norclozapine formation by inhibiting the CYP450 1A2 isoenzyme. Lowering norclozapine levels in this way while maintaining therapeutic clozapine levels increases the clozapine: norclozapine ratio; the potential benefits include both a reduction of such side effects as sedation, weight gain, metabolic disturbances, and neutropenia, and an increase in efficacy. The optimal ratio of clozapine to norclozapine has not yet been defined, but a ratio of two or more implies that saturation of clozapine metabolism has been reached. We hypothesize that co-administration of clozapine and fluvoxamine at dosages that will produce therapeutic plasma levels of clozapine and a clozapine: norclozapine ratio of two or more will increase efficacy and tolerability of clozapine therapy in treatment-resistant schizophrenic patients.

Interaction of St John’s wort (Hypericum perforatum) with clozapine

St John's wort (Hypericum perforatum) is notorious for its ability to induce the enzymes of the P450 system. Especially, it induces CYP1A2 and CYP3A4, enzymes that are closely involved in the metabolism of clozapine. We present a patient with schizophrenia, who was stable on a fixed dose with stable plasma level of clozapine, and who deteriorated after she started self-medicating with St John's wort. The reduced plasma clozapine level and the psychiatric condition normalized after the withdrawal of St John's wort. It is possible that, beside the induction of P450-enzymes, the induction of P-glycoprotein by St John's wort aggravated psychiatric deterioration of the patient. Physicians should be alert to patients self-medicating with over-the-counter medicines, especially when these medicines can lower clozapine concentrations below the therapeutic range.

A review of the use of clozapine levels to guide treatment and determine cause of death

To review the literature to examine the use of clozapine levels to (i) guide therapy and prevent toxicity in clinical care and (ii) determine cause of death in post-mortem examination of patients who were treated with clozapine. MEDLINE was searched in December 2010 using the following keywords: 'clozapine levels', 'clozapine and toxicity', 'clozapine and death', 'clozapine and mortality' and 'post-mortem redistribution'. Data was also collected from the 2010 MIMS Annual. The literature reported significant variation in clozapine levels attained with any given dose, and considerable variability in the clinical response achieved at any given clozapine level. The lowest effective clozapine levels ranged from 250 to 550 µg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 µg/L. There was minimal correlation between clozapine levels and side effects, with the exception of sedation, hypotension and seizure activity. The risk of seizures increased with plasma clozapine levels greater than 600 µg/L or rapid upward titration. In addition to prescribed dose, there are many factors that influence plasma clozapine levels. After death, the process of post-mortem drug redistribution resulted in 3.00 to 4.89 times increases in clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels. The exact range of clozapine levels that corresponds to toxicity remains unclear. However, levels between 350 µg/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity. Ongoing clozapine level monitoring is indicated, especially when (i) prescribing higher doses (> 600 mg/day) of clozapine, (ii) there has been a change in a patient's concomitant pharmacotherapy or cigarette use and (iii) there has been a suboptimal response to treatment. The use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable.