Mean Clozapine Research Articles

Antipsychotic agents used to augment clozapine during long-term inpatient hospitalizations.

Literature assessing effective clozapine augmentation strategies is limited. The aim of this retrospective evaluation was to examine antipsychotics used to augment clozapine and assess whether an augmentation antipsychotic would continue at discharge. Demographic, clinical and pharmacy data were collected retrospectively if patients had received clozapine plus an antipsychotic used for augmentation. The dose of the augmentation agent, length of augmentation therapy, and concomitant medications were collected. Of the 49 patients (mean age 45.3±12.1 years), 27 (55%) were male. The mean clozapine dose at discharge was 406.1±121.8 mg. When a first generation antipsychotic (FGA) was selected initially to augment clozapine there was a greater likelihood it would be continued until discharge compared to a second generation antipsychotic (SGA) (78 vs. 50%, OR=3.6, 95% CI 1.03-12.6). FGAs (3.2%) compared to SGAs (35%) were less likely to be discontinued due to a documented lack of benefit when first selected to augment clozapine (OR=16.2, 95% CI 2-131.3). Electroconvulsive therapy plus clozapine was found to be beneficial in several patients (n=14) who failed at least 1 augmentation strategy. This real world data suggests that adding an antipsychotic to clozapine is a reasonable approach to those who do not fully respond to clozapine monotherapy. While comparisons of all agents could not be conducted from this small retrospective study, these data suggest FGAs should be investigated in future studies as potential agents to successfully augment clozapine therapy.

Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC–MS/MS method

ObjectiveClozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP–TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography–tandem mass spectrometric method (UHPLC–MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples. Design and methodsSerum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid–liquid extraction with methyl t-butylether, analyzed using a fully validated UHPLC–MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP–TDM guidelines. ResultsFor clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350–600ng/mL, while 67.9% of the concentrations were below 350ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100–600ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range. ConclusionThis retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations.

Pulmonary Thromboembolism Associated With Clozapine

Pulmonary Thromboembolism Associated With Clozapine

Real‐world effectiveness of clozapine in patients with bipolar disorder: results from a 2‐year mirror‐image study

Clozapine remains the drug of choice for treatment-resistant schizophrenia but the evidence for its use in severe bipolar disorder (BD) remains sparse. A pharmaco-epidemiologic database study was carried out in Denmark, investigating the effectiveness of clozapine in BD patients (without a schizophrenia-spectrum disorder), between 1996 and 2007, using a two-year mirror-image design. A total of 21473 patients with a lifetime diagnosis of International Classification of Diseases-10 (ICD-10) BD were identified, of which only 326 (1.5%) were treated with clozapine and were included in the mirror-image analysis. The mean follow-up time was 544 ± 280 days, the mean clozapine dose was 307.4 mg [95% confidence interval (CI): 287.9-328.2], and 39.3% were male. During clozapine treatment, the mean number of bed-days decreased from 177.8 (95% CI: 149.4-211.6) to 34.6 (95% CI: 24.8-48.2) (p < 0.001). The mean number of admissions was reduced from 3.2 (95% CI: 2.9-3.7) to 2.0 (95% CI: 1.6-2.4) (p < 0.001). Overall, 240 patients (73.6%) had reduced bed-days and 130 (39.9%) were not admitted while treated with clozapine. Moreover, the number of psychotropic co-medications was reduced from 4.5 defined daily doses (DDD) (25-75 percentiles: 2.4-8.2) to 3.9 DDD (25-75 percentiles: 2.4-6.1) (p = 0.045). Somatic hospital visits for intentional self-harm/overdose reduced significantly from 8.3% to 3.1% (p = 0.004). However, non-psychotropic co-medication use for medical conditions did not increase; 0.7 DDD (25-75 percentiles: 0.0-2.9) to 0.8 DDD (25-75 percentiles: 0.1-2.89) (p = 0.3). Clozapine use for BD was associated with a significant and clinically relevant reduction in the number of bed-days, psychiatric admissions, psychotropic co-medications, and hospital contact for self-harm/overdose, without increased medical treatments. Clozapine seems to be an appropriate choice for treatment-resistant BD and should be investigated in randomized controlled trials.

Case Report: The clinical implications of clozapine and cigarette smoking

INTRODUCTION Cigarette smoking is prevalent among psychiatric patients, with rates several times higher than the general population. As an example, up to 80% of schizophrenic patients smoke cigarettes. Clozapine is extensively metabolized by cytochrome P450 isoenzyme 1A2 and polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke are thought to induce CYP 1A2. Therefore concurrent smoking with clozapine can potentially lead to decreased clozapine levels and decreased efficacy, while smoking cessation can potentially lead to increased levels and toxicity. Enzyme induction has been reported to result in a 20 to 40% lower mean clozapine concentration in smokers compared to nonsmokers. We present a case of altered serum drug concentrations in association with changes in smoking status in a patient upon admission to a nonsmoking inpatient psychiatric facility.

Salivary Flow Rate in Patients With Schizophrenia on Clozapine

To assess the change in salivary flow rate in patients with schizophrenia on clozapine and whether the change in salivary flow rate was dose related. Twenty male inpatients with a diagnosis of schizophrenia according to the International Statistical Classification of Diseases, 10th Revision diagnostic criteria for research who were started on clozapine were recruited for the study. Unstimulated salivary flow rate was assessed at baseline and then weekly for 4 weeks using cotton swab method in 17 patients. Repeated-measures analysis of variance showed a significant increase in salivary flow rate over time (F [2.37/37.94] = 3.134, P = 0.047, Greenhouse-Geisser correction, eta = 0.16). Also, there was a significant increase in salivary flow rate between weeks 2 and 3 (P < 0.05). There was no correlation between salivary flow rate and mean clozapine dose. There was a significant increase in salivary flow rate from baseline after starting clozapine, with a significant increase from the second to the third week followed by a "plateau."

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Metabolic differences between Asian and Caucasian patients on clozapine treatment

To establish if there are ethnic differences in the various metabolic disturbances that are common with clozapine treatment. Forty subjects (20 Asians and 20 Caucasians) with a diagnosis of schizophrenia were recruited for the study. Clozapine blood levels as well as fasting blood glucose, lipid levels, and liver function tests were established. Other clinical parameters such as blood pressure and Body Mass Index (BMI) were recorded for each patient. The mean clozapine dose was significantly higher in the Caucasian subjects (432.5+/-194.7 mg) as compared to the Asian subjects (175.6+/-106.9 mg) (p<0.001) while the mean weight-corrected dose for Asian patients was lower (3.0+/-1.9 and 5.0+/-2.1 mg/kg, respectively, p=0.005). There were, however, no ethnic differences in the mean plasma clozapine concentration (415.3+/-185.8 ng/ml in Caucasians and 417.1+/-290.8 ng/ml in Asians). BMI were significantly higher in Caucasians, as were the number of subjects with hypertension; levels of hepatic enzymes were higher in the Asian group. Not only are there pharmacokinetic differences between Asian and Caucasian patients receiving clozapine, but there may also be differential emergence of certain metabolic abnormalities like hypertension and weight gain in these two ethnic groups. However, the effects of life style including diet and exercise cannot be excluded.

High clozapine concentrations in leukocytes in a patient who developed leukocytopenia

Up to now direct toxic effects or immunological processes have been said to explain clozapine-induced agranulocytosis. However, more recent studies may suggest that not yet metabolized clozapine is taken up by leukocytes and transformed by oxidative processes to apoptosis-inducing metabolites. To verify this hypothesis the concentrations of clozapine were measured in the plasma and the leukocytes of a patient receiving clozapine who developed clozapine-induced leukocytopenia and in 10 patients receiving clozapine who did not show any serious adverse side effects. The patient who developed leukocytopenia showed clozapine concentrations in the leukocytes that were about 8 times higher than the mean clozapine concentrations in the leukocytes in the group of 10 patients receiving clozapine with no changes in the leukocyte count in the history. However, no major difference was found in the clozapine plasma concentrations. The results may suggest that patients at risk of developing clozapine-induced leukocytopenia show increased clozapine concentrations in the leukocytes although the clozapine plasma concentration is in the therapeutic range. It is assumed that changes or abnormalities of clozapine uptake at the cell membrane might play a role in the development of clozapine-induced leukocytopenia and/or agranulocytosis.

Influence of clozapine on platelet serotonin, monoamine oxidase and plasma serotonin levels

The purpose of this study was to investigate the influence of clozapine on plasma serotonin, platelet serotonin and monoamine oxidase (MAO) levels in schizophrenic patients and to compare their results with those of unmedicated healthy controls. Groups of 20 outpatients with schizophrenia and 20 healthy controls matched for age, sex and smoking status were recruited for the study. Psychopathology, neurocognitive functioning, plasma serotonin, platelet serotonin and MAO levels were assessed after 1-week drug free interval, and 8 weeks after initiation of clozapine treatment in an open design. The mean clozapine dose at week 8 was 382.5 ± 96.4 (range: 250–600) mg/day. In the patient group, at baseline, plasma serotonin and platelet MAO levels were significantly lower, and platelet serotonin levels were significantly higher than in controls. After 8 weeks of clozapine treatment, plasma serotonin and platelet MAO levels increased significantly, while a significant decrease in platelet serotonin levels was detected compared with baseline values. Baseline platelet MAO levels explained 22% of the variance in Clinical Global Impression–Improvement (CGI–I) and improvement in attention, while baseline platelet serotonin predicted 23% of the variance in the improvement in positive symptoms during clozapine treatment. Our data indicate that clozapine may be reversing or compensating for a pre-existing alteration in serotonergic neurotransmission in schizophrenic patients. The prediction of response to clozapine through peripheral biochemical markers may have important clinical implications if repeated in larger samples.

Risperidone augmentation of clozapine

Atypical antipsychotics are frequently used as augmentation agents in clozapine-resistant schizophrenic patients. Risperidone (RIS) is the one most studied as a clozapine (CLZ) adjunct. The aim of this study is to critically review all published studies regarding the efficacy and safety of RIS as an adjunctive agent in CLZ-resistant schizophrenic or schizoaffective patients. A MEDLINE search from January 1988 to June 2005 was conducted. Identified papers were examined against several clinical, pharmacological and methodological parameters. A total of 15 studies were found (2 randomized controlled trials, 3 open-label trials (OTs) and 8 case-studies (CSs)) comprising 86 schizophrenic or schizoaffective patients (mean age 38.4 years). Mean CLZ dosage during the combined treatment was 474.2 mg/day. Plasma CLZ levels were assessed in 62 patients (72.1%). RIS was added at a mean dosage of 4.6 mg/day for a mean of 7.9 weeks. Significant improvement in psychopathology was reported for 37 patients (43%). A lower RIS dosage and a longer duration of the trial seemed to be associated with a better outcome. Main side effects reported were: extrapyramidal symptoms or akathisia (9.3%), sedation (7%) and hypersalivation (5.8%). Existing evidence encourages the use of RIS as an adjunctive agent in CLZ-resistant schizophrenic or schizoaffective patients.

An exploratory open‐label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia

We conducted this 6-week open-label trial to examine the effects of adjunctive aripiprazole in clozapine-treated subjects on weight, lipid and glucose metabolism, as well as positive and negative symptoms of schizophrenia. Ten clozapine-treated subjects received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. Eighty percent were male, the mean age was 38.7 +/- 8.9 years and the mean clozapine dose was 455 +/- 83 mg daily. There was a significant decrease in weight (P = 0.003), body mass index (P = 0.004), fasting total serum cholesterol (P = 0.002) and total triglycerides (P = 0.04) comparing baseline to study endpoint. There was no significant change in total Positive and Negative Syndrome Scale scores. This combination may be useful for clozapine-associated medical morbidity and must be studied in placebo-controlled double-blind randomized trials to determine efficacy and safety.

An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels

The present study investigated clozapine dosage, plasma clozapine and metabolite levels, clinical and side-effect profiles in Asian versus Caucasian patients with chronic schizophrenia who were on stable maintenance treatment. Twenty Asian patients from Singapore and 20 Caucasian patients from Australia were systematically evaluated with the following rating scales: Positive and Negative Syndrome Scale for Schizophrenia, drug attitude scale (DAI-10), drug adverse reaction profile (Liverpool University Neuroleptic Side-effect Rating Scale), extrapyramidal side-effects scales (Abnormal Involuntary Movement Scale, Simpson and Angus Scale). Cigarette and caffeine consumption were recorded and steady-state plasma clozapine and metabolites levels were measured. Although Asian patients received a significantly lower mean clozapine dose (176 mg/day) than the Caucasian group (433 mg/day, P<0.001), plasma clozapine levels were similar between the groups. As a result, Asian patients had more than twice the effective clozapine concentration to dose ratio (P<0.001). The findings remained significant even after controlling for gender, body mass index, cigarette, alcohol and caffeine use. Conversely, the plasma metabolites (desmethylclozapine and clozapine N-oxide) to clozapine ratios were higher in the Caucasian patients (P<0.01). Compared to Caucasian patients, Asian patients appeared to have a lower dosage requirement for clinical efficacy. Hence, appropriate dose adjustment should be considered in Asian patients receiving maintenance clozapine therapy in clinical practice.

Comparison of Clozapine Use in Maryland and in Victoria, Australia

Studies of how differences in systems of care, including cultural differences, affect prescribing practice and patient outcomes are important and can help answer questions such as the effectiveness of clozapine in routine practice. This study examined the use of clozapine in Maryland and in Victoria, Australia. This study used medical record data to examine the use of clozapine in January 2000 for people with schizophrenia in two different countries. Data were gathered from all six public inpatient facilities in Maryland and from the two main community outpatient centers in Victoria. Outpatients were studied in Victoria because Australia's inpatient mental health facilities have closed and people with treatment-resistant schizophrenia are managed exclusively as outpatients. In Maryland 591 inpatients with schizophrenia were given a prescription for second-generation antipsychotics; in Victoria 356 outpatients with schizophrenia were given such a prescription. Among second-generation antipsychotics, clozapine was used significantly more frequently in Australia than in Maryland for the treatment of schizophrenia (173 prescriptions, or 49 percent, compared with 144 prescriptions, or 19 percent). Both systems used clozapine mostly for the treatment of schizophrenia (94 percent in Victoria compared with 88 percent in Maryland). The mean clozapine dosages that were used for the treatment of schizophrenia were significantly higher in Maryland than in Australia (522 mg per day compared with 431 mg per day). Significant differences in use and dosages of clozapine were found in two populations that were similar in diagnoses and demographic characteristics.

Low doses of clozapine may stabilize treatment?resistant bipolar patients

Open, uncontrolled studies suggest clozapine can have mood-stabilizing effects in treatment-resistant bipolar disorder. Unfortunately, the side effect profile limits clozapine's use at high doses. We report a series of nine bipolar I disorder patients who improved on relatively low doses of clozapine add-on therapy (250 mg or lower). Retrospectively abstracted clinical data identified nine patients with bipolar I disorder, as defined by DSMIV criteria, treated with low-dose clozapine at inpatient and outpatient settings. Monthly symptom evaluations were collected prospectively using standard assessments. Symptoms of mania and mood lability improved in all patients. Three patients demonstrated striking mood stabilization and returned to previous levels of functioning; five patients evidenced moderate improvement in mood stabilization and functioning; and one patient showed a minimal response. Overall, clozapine did not have a significant antidepressant effect. The mean clozapine dose at the end of the study was 156.3 +/- 77.6 mg/day, and duration of treatment was 12 months. Residual side effects were mild. The symptomatic improvement in these prospectively evaluated patients is consistent with our clinical impression in the majority of patients with bipolar disorder taking clozapine.

February 10 Highlight and Commentary

Durif et al. studied the effect of clozapine on levodopa-induced dyskinesias (LID) in 50 parkinsonian patients in a 10-week randomized placebo-controlled study. The duration of LID was reduced by 2 hours and their intensities by 50%. The mean clozapine dose was 40 mg. Three patients in the clozapine group developed hypereosinophilia, which resolved rapidly after stopping the drug. see page 381 Commentary by Robert L. Rodnitzky, MD Levodopa-induced dyskinesia (LID) is a source of motoric or social disability in a significant percentage of patients undergoing treatment for …

The safety of clozapine in the treatment of first- and multiple-episode patients with treatment-resistant schizophrenia.

The importance of antipsychotics in the treatment of schizophrenia has been documented in numerous clinical trials. In addition to its established superiority over other antipsychotics in treatment-resistant patients, clozapine has been consistently shown to improve psychopathology and other psychosocial outcome variables in patients with schizophrenia. To determine whether the course of the illness has an influence on response and side-effects to clozapine, we directly contrasted first- and multiple-episode patients with schizophrenia, who had histories of failing response to traditional antipsychotics, during the acute treatment phase. Thirty-nine first-episode patients with schizophrenia and 56 patients who had suffered from at least two episodes of this illness were investigated. Severity of illness and clinical improvement were rated by means of the CGI Scale. Vital signs were recorded weekly. Side-effects were regularly assessed with the UKU Side Effect Rating Scale. Compliance was regularly assessed by clinical interviews and plasma level monitoring. By using comparable mean clozapine doses, the number of treatment responders was similar in both groups (first-episode patients, 51.3%; multiple-episode patients, 46.4%). However, we found a negative association between age and response rate. With regard to side-effects, we could not find any significant difference between groups. Altogether, response and side-effects to clozapine treatment do not seem to be determined by the chronicity of the disorder.

Association Analysis of the Genetic Variants of the N-Methyl D-Aspartate Receptor Subunit 2b (NR2b) and Treatment-Refractory Schizophrenia in the Chinese

Several pieces of evidence showed that N-methyl D-aspartate (NMDA)-receptor-mediated decreases in function may be a causative factor for schizophrenia. The NMDA receptors are composed of a common glutamate receptor, an ionotropic NMDA 1 (GRIN1) subunit and one of four GRIN2 subunits (GRIN2A–GRIN2D), combined in an undetermined ratio to make up the receptor complex. In this study, we tested the hypothesis of whether the GRIN2B 366C/G and 2664C/T genetic polymorphisms are related to Chinese treatment-refractory schizophrenic patients. 193 treatment-refractory schizophrenic patients and 176 normal subjects were recruited for this study. The results demonstrated that the genotype distribution was similar between schizophrenic patients and control subjects in 366C/G (p = 0.88) and 2664C/T (p = 0.336), but we found a higher mean clozapine dosage in 2664C/C genotype patients. These results show that GRIN2B genetic variations were not a major risk factor for treatment-refractory schizophrenic patients, but may influence the effect of clozapine during treatment.

Is the Time Course of Clozapine Response Correlated to the Time Course of Clozapine Plasma Levels? A One-Year Prospective Study in Drug-Resistant Patients with Schizophrenia

The relationship between the time course of clinical response to clozapine and the time course of clozapine plasma levels has never been investigated. In the present study, we assessed prospectively the clinical response to clozapine and the plasma levels of the drug and its major metabolites in 32 drug-resistant patients with schizophrenia kept on a fixed dose of 600 mg/day for 1 year Four of the patients met response criteria at week 4 of treatment. At weeks 8, 12, and 24, new responders were 7, 6, and 6, respectively. Nine patients never achieved clinical response. In responders at week 4, clozapine and clozapine-N-oxide plasma levels were significantly higher than in both new responders at weeks 8, 12, and 24 and nonresponders. In new responders at weeks 8, 12, and 24, in spite of a fixed clozapine daily dose, mean drug plasma levels progressively rose up to when clinical response occurred; then, the levels remained stable over time. Nonresponders exhibited mean clozapine plasma levels constantly below the value of 260 ng/ml, with N-demethylation as the preferred metabolic route.The present findings show, for the first time, that the time course of the clinical response to clozapine may be linked to the time course of plasma levels of clozapine and its major metabolites.

Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine?

Drug monitoring in psychiatry usually serves psychoactive drug plasma concentration measurement. Anticholinergic properties offer a faster approach to monitoring pharmacodynamic intraindividual effects of the drug by measuring their effects on heart rate variability (HRV), which is sympathetically and parasympathetically controlled via cholinergic synapses. The plasma concentrations of the atypical antipsychotics clozapine and olanzapine correlated with parameters of HRV in 59 patients suffering from schizophrenia or schizoaffective disorder. HRV during 4 minutes at rest was extracted from the ECG trace of a routine digital EEG registration in addition to blood sampling for plasma concentration measurement (HPLC method). We calculated sympathetically and parasympathetically controlled heart frequency bands (low, medium and high frequency) and other HRV parameters, coefficient of variation (CV), and root mean square of successive differences (RMSSD). All HRV parameters were significantly more impaired in clozapine patients (n = 33, mean clozapine plasma concentration 331 +/- 294 ng/ml) than in olanzapine patients (n = 26, mean olanzapine plasma concentration 42 +/- 32 ng/ml) and demonstrated 1.7 - 4.8 times the cardiac anticholinergic properties of clozapine in vivo. 14 out of 14 patients with a CV beyond 3.2 % had clozapine plasma concentrations below the proposed optimal therapeutic concentration of 350 ng/ml. All HRV parameters were inversely and significantly correlated with the clozapine plasma concentrations (such as lgCV: r = - 0.73, p < 0.001) and, to a lesser extent, with the olanzapine plasma concentrations (lgCV r = - 0.44, p < 0.05). These results underline the potential clinical value of HRV parameter extraction from routine ECGs in predicting plasma concentrations and objective individual neurocardiac effects of drugs with anticholinergic properties.