clozapine and Tachycardia

This article reviews four of the milder but still bothersome side effects of clozapine that are fairly frequent and may have a negative impact on patients' compliance with the treatment regime. We reviewed the available literature on the rate and management of four non-life-threatening side effects of clozapine, including hypersalivation, constipation, tachycardia, and nocturnal enuresis. We found a variety of pharmacological and behavioral strategies to manage these four side effects. There is, however, no consensus on a preferred strategy to control these distressing side effects and there are no guidelines. Psychiatrists should be aware of the relatively high rate of hypersalivation, constipation, tachycardia, and nocturnal enuresis in clozapine-treated patients, of the impact that these side effects may have on patients' quality of life, and should be able to suggest management strategies to the patients.

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans; Nocturnal Enuresis; Sialorrhea; Tachycardia

Compliance with conventional antipsychotic medication is often poor, with many patients discontinuing treatment only a few months after commencing therapy. The side effects of treatment, which are not necessarily restricted solely to motor symptoms, are often considered to be responsible for this noncompliance. In contrast to conventional antipsychotics, clozapine is associated with only minimal extrapyramidal symptoms, and in most patients, its use results in significant improvements in compliance. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. Clozapine therapy is associated with a beneficial risk/benefit ratio in the majority of treatment-resistant schizophrenic patients. With careful hematologic control, the risk of agranulocytosis can be minimized. The marked increase in the well-being of patients receiving clozapine should stimulate psychiatrists to broaden its use and not limit it to severely treatment-resistant individuals.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Electroencephalography; Fatigue; Humans; Patient Compliance; Risk Assessment; Schizophrenia; Schizophrenic Psychology; Seizures; Sialorrhea; Tachycardia; Treatment Outcome

Since its introduction to the United States in 1990, the benefits of clozapine use have been repeatedly validated. Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia. Because clozapine has been part of the psychiatric pharmacopeia for considerably less time than neuroleptics, which have dominated the field for over 4 decades, its underutilization may be partly attributed to a lack of experience in managing associated side effects. Most side effects associated with clozapine are typical of antipsychotics in general, and with clozapine, these side effects are typically benign, tolerable, and manageable. It is conceivable that there remains a concern over the risk of agranulocytosis. However, the mandatory blood monitoring carried out through the Clozaril National Registry has considerably reduced the incidence of fully developed cases of agranulocytosis from premarketing values of approximately 1% to 2% to current values of 0.38% and virtually prevented mortalities. These values are likely to decrease further with the application of cytokine augmentation therapy among patients developing blood dyscrasias. Many side effects of clozapine are observed early after treatment onset and are greatly reduced by dose adjustments. Appropriate management of side effects will facilitate a maximization of the benefits of clozapine treatment. Clearly, the benefits of clozapine therapy far outweigh its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Drug Administration Schedule; Drug Monitoring; Humans; Incidence; Risk Factors; Schizophrenia; Sleep Wake Disorders; Tachycardia; Urinary Incontinence; Weight Gain

Clozapine is an atypical neuroleptic with superior efficacy in severely ill, treatment-resistant inpatients with schizophrenia. To determine if clozapine's differential efficacy generalizes to less ill, outpatients populations, the authors examined the effects of clozapine on positive and negative symptoms in outpatients with schizophrenia.. Outpatients with schizophrenia who had histories of partial response to conventional neuroleptics and who had not responded to a prospective 6-week trial of fluphenazine participated in a 10-week, double-blind, parallel-groups comparison of clozapine and haloperidol. Thirteen men and six women were given clozapine, and 15 men and five women were given haloperidol. Clinical response rates were determined and effects on primary versus secondary negative symptoms were addressed. Doses of clozapine and haloperidol at the end of the 10-week trial were 410.5 mg/day (SD = 45.8) and 24.8 mg/day (SD = 5.5), respectively.. Clozapine was superior to haloperidol for treating positive symptoms. In addition, eight of the patients given clozapine and only one of the patients given haloperidol fulfilled clinical responder criteria. Clozapine was also superior to haloperidol for treating negative symptoms, although these effects were relatively minor. Negative symptoms were significantly affected in the subgroup of patients with nondeficit schizophrenia but not in the subgroup with deficit schizophrenia. Overall, clozapine was well tolerated.. Clozapine has superior efficacy for treating positive symptoms in partially responsive outpatients with chronic schizophrenia, suggesting that it has utility for a broad spectrum of patients with schizophrenia beyond the most severely ill.

Topics: Adult; Ambulatory Care; Chronic Disease; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Sialorrhea; Tachycardia

Clozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences.. To examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects.. A retrospective analysis of the record database for 247 621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined.. Of 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation.. Suspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The 'critical period' for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.

Topics: Antipsychotic Agents; Biomarkers; Clozapine; Drug-Related Side Effects and Adverse Reactions; Electronics; Humans; Incidence; Myocarditis; Retrospective Studies; Tachycardia; Troponin

Tachycardia is associated with cardiovascular mortality. Tachycardia is also a known clozapine adverse effect. However, whether clozapine-associated tachycardia is persistent is not known. Thirty clozapine-treated patients with clinical tachycardia were investigated with 24-hour ambulatory electrocardiography (ECG). Baseline peripheral heart rate (HR) was 106.7±7.8. The ambulatory ECG 24-hour-HR was 98.7±9.7. Baseline HR and 24-hour-HR correlated strongly (r=0.74, p=0.000003). Daytime HR was 106.4±9.9 and nighttime HR 89.2±12.0. Low dose bisoprolol reduced HR significantly. The high 24-hour-HR indicates a persistent tachycardia. Tachycardia should not discourage from clozapine use but the findings indicate a need of guidelines for detection and treatment of clozapine-associated tachycardia.

Topics: Adult; Antipsychotic Agents; Bisoprolol; Cardiovascular Agents; Clozapine; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Male; Photoperiod; Tachycardia; Time Factors

Topics: Adolescent; Age of Onset; Antipsychotic Agents; Clozapine; Female; Humans; Schizophrenia; Tachycardia

People with schizophrenia are 3-4 times more likely to die from cardiovascular disease than the general population. Clozapine (CLZ) is the gold standard of treatment for refractory schizophrenia. It has been associated with tachycardia and recent evidence shows individuals prescribed CLZ may develop blood pressure (BP) elevation and hypertension. The purpose of this study was to examine the effects of CLZ on BP and heart rate (HR). This was a retrospective chart review of patients 18-75 years old with a DSM IV diagnosis of Schizophrenia or Schizoaffective disorder. Primary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measured 12 weeks before and 24 weeks during CLZ treatment. Eighteen patient records were included in this study. The mean stabilized CLZ dose was 441.7 ± 171.8 mg/day. DBP (t = 1.02, df = 79.5, = 2.00, 0.049) and HR (t = 1.32, df = 355  = -4.61, < 0.0001) were significantly higher after CLZ initiation. A trend was noted for increase in SBP (p = 0.071). 22 % of patients met criteria for hypertension before CLZ and 67 % during CLZ treatment (Chi Square = 6.25, df = 1, p = 0.0124). No significant changes in weight or renal function occured during CLZ treatment. No patients had evidence of cardiomyopathy. The data suggest CLZ may be associated with a rise in BP and HR. The results of this study support previous literature that found an increase in SBP/DBP regardless of CLZ dose, occurring early in treatment. Due to high risk of cardiovascular morbidity and mortality, more work is needed to determine risk factors and understand the mechanism of action that may cause this side effect.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Pressure; Clozapine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Retrospective Studies; Schizophrenia; Tachycardia; Young Adult

Tachycardia is a known adverse effect during clozapine treatment. However, prevalence reported differs widely between studies and hitherto there are no studies comparing clozapine-treated patients with a similar control group. The present study was carried out to assess the prevalence of tachycardia in patients treated with clozapine and antipsychotic long-acting injections (LAI). Data on heart rate (HR), concomitant medication, and relevant anthropometric and laboratory measurements were collected for all clozapine-treated patients (n=174) in a defined catchment area and compared with data on patients treated with LAI (n=87). In total, 33% of patients on long-term clozapine treatment had tachycardia (HR>100) compared with 16% in the LAI group (P<0.001). The mean HR was 91 in the clozapine group and 82 in the LAI group (P<0.001). Clozapine dose correlated with HR. The majority of patients with HR more than 100 received no specific treatment for tachycardia. In conclusion, the prevalence of tachycardia was twice as high in patients treated with clozapine as in a similar patient group with severe schizophrenia spectrum disorder. The tachycardia was in many cases clinically unnoticed. Tachycardia during antipsychotic treatment is a common phenomenon that must be monitored for actively and, when noticed, further investigated and treated.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Delayed-Action Preparations; Female; Humans; Injections; Male; Middle Aged; Sweden; Tachycardia; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Biomarkers; Clozapine; Electrocardiography; Fever; Humans; Leukocytosis; Male; Myocarditis; Schizophrenia, Paranoid; Tachycardia; Ultrasonography

Although many patients with schizophrenia fail to respond adequately to trials of 2 or more antipsychotics, utilization of clozapine for these patients remains low, despite recommendations for its use by accepted treatment guidelines. Some experts estimate that 5-10 times more patients could benefit from clozapine than who are now receiving it. Learning how to manage the unique side effect profile of clozapine can potentially remove barriers to prescribing this agent and thus unlock its unique therapeutic efficacy for more patients.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Constipation; Diabetes Mellitus; Eosinophilia; Humans; Myocarditis; Neuroleptic Malignant Syndrome; Neutropenia; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia; Sialorrhea; Tachycardia; Weight Gain

A 25-year-old male developed sinus tachycardia after given clozapine for treatment-resistant psychosis in schizophrenia. The tachycardia was treated successfully with propranolol for several weeks. The patient developed skin eruptions, later diagnosed as psoriasis. Propranolol is known to be capable of causing, evoking or aggravating psoriasis. Several other drugs commonly used in psychiatric practice are also known to cause psoriasis. Doctors need to be aware to the possible side effects of such drugs because they can jeopardise the patient's wellbeing and reduce the efficacy of psychiatric treatment.

Topics: Adrenergic beta-Antagonists; Adult; Antipsychotic Agents; Clozapine; Humans; Male; Propranolol; Psoriasis; Psychotic Disorders; Schizophrenia; Tachycardia

Topics: Adrenal Gland Neoplasms; Antipsychotic Agents; Catecholamines; Clozapine; Female; Humans; Hypertension; Middle Aged; Pheochromocytoma; Syndrome; Tachycardia

To analyze cases of clozapine-induced myocarditis for clinical and diagnostic trends.. A case definition was developed by a multidisciplinary group using reports of myocarditis with clozapine submitted to the Australian Therapeutic Goods Administration. The definition uses for diagnosis either histology or the combination of new signs of cardiac dysfunction combined with a cardiac-specific diagnostic parameter occurring within 45 days of starting clozapine. Potential cases of clozapine-related myocarditis occurring between January 1993 and September 2008 and a comparative group of long-term clozapine users were documented from the patients' medical records.. Thirty-eight of 59 reviewed cases met the case definition. Three patients died, and the diagnosis for these was confirmed on cardiac histology. Nearly all of the remaining patients had persistent tachycardia and elevated troponin level. The time to onset was 14-22 days in all except 2 patients. Of the patients who survived, 66% (23 cases) had eosinophilia occurring 0-7 days (mean, 4.0) after the peak in troponin. C-reactive protein (CRP) level was elevated to above 100 mg/L (952 nmol/L) in 79% (23 cases), and some had elevated levels of CRP when troponin level was still normal. None of the control group (47 patients) met the case definition.. Eosinophil counts should not be relied on for diagnosis of clozapine-related myocarditis, but elevated CRP may be an early indicator of developing myocarditis. Patients starting clozapine should be actively monitored for myocarditis during the first 4 weeks, with extra care taken during week 3.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Australia; C-Reactive Protein; Case-Control Studies; Clozapine; Echocardiography; Eosinophilia; Female; Fever; Gated Blood-Pool Imaging; Humans; Male; Middle Aged; Myocarditis; Tachycardia; Troponin

Topics: Adult; Antipsychotic Agents; Clozapine; Creatine Kinase; Electrocardiography; Female; Follow-Up Studies; Humans; Myocarditis; Schizophrenia; Tachycardia

To report a case of severe and sustained tachycardia that developed asymptomatically on a low dose of clozapine (150 mg daily).. Case report.. Serially monitored 24 h heart rate after the introduction of clozapine showed an increase in the 24 h mean from 87 to 126 bpm, a reduction of pulse variability and anomalies in sleep-wake regulation. Cessation of clozapine was followed by a rapid return to preclozapine activity. Application of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship between clozapine and the sustained tachycardia.. Severe and sustained tachycardia can develop asymptomatically with a relatively low dose of clozapine and a slow titration rate. The severity of the tachycardia may not be revealed in isolated pulse measurements and may escape clinical detection without closer monitoring of heart rate.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Electrocardiography; Humans; Psychotic Disorders; Severity of Illness Index; Sleep Disorders, Circadian Rhythm; Tachycardia

A 31-year-old white man was referred for investigation of a persistent sinus tachycardia. His only significant past medical history was of chronic schizophrenia for which he had been taking clozapine for six years. An electrocardiogram demonstrated sinus tachycardia, voltage criteria for left ventricular hypertrophy, and a prolonged QTc. Echocardiographic findings were consistent with a dilated cardiomyopathy. Serious cardiac complications of clozapine use are rare but have been reported previously. It is important to note that sinus tachycardia may be the only obvious clinical sign, and that complications can manifest months or even years (as in this case) after starting the drug. Patients on clozapine should be informed of potential cardiac symptoms and doctors should maintain a high degree of clinical suspicion throughout the duration of treatment.

Topics: Adult; Antipsychotic Agents; Cardiomyopathy, Dilated; Clozapine; Humans; Male; Schizophrenia; Tachycardia

Topics: Adrenal Gland Neoplasms; Adult; Antipsychotic Agents; Catecholamines; Clozapine; Female; Humans; Hypertension; Male; Obesity; Pheochromocytoma; Schizophrenia; Sweating; Syndrome; Tachycardia; Time Factors

Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial.. The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics.. Forty-five patients, 35 males and ten females, aged 19-65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less.. Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472+/-220 versus 328+/-128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201+/-104 versus 156+/-64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r(s)=0.371, P<0.02), but not for norclozapine (r(s)=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%).. These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350-400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations.

Topics: Adult; Aged; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Conscious Sedation; Constipation; Dizziness; Dose-Response Relationship, Drug; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Sialorrhea; Tachycardia; Treatment Outcome; Weight Gain

Cardiovascular side effects of clozapine are not uncommon, but few systematic studies of these effects have been performed. In this study, we reviewed data on the electrocardiographic (ECG) abnormalities in patients treated with clozapine.. Sixty-one patients treated with clozapine were selected from the Seoul National University Hospital Treatment-Resistant Schizophrenia Clinic. A retrospective chart review was conducted to identify ECG abnormalities and cardiovascular side effects.. The prevalence of ECG abnormalities in patients who had been using antipsychotics other than clozapine was 13.6% at baseline, which increased significantly to 31.1% after commencement of clozapine treatment. Among the 53 patients without baseline ECG abnormalities, 13 showed new-onset ECG abnormalities after using clozapine. Normal ECG under previous antipsychotic medication reduced the risk of new-onset ECG abnormalities, whereas increased age was found to increase the risk. The occurrence of orthostatic hypotension or tachycardia was not related to the development of ECG abnormalities. Most of the newly developed abnormalities had little clinical significance, and they tended to occur during the initial phase of treatment. In 10 patients, ECGs normalized despite the continued use of clozapine. Clozapine increased corrected QT interval (QTc) in a dose-dependent fashion; however, the clinical significance of this observation is uncertain. Pathologic prolongation of QTc was found to be rare.. Although a substantial portion of patients treated with clozapine developed ECG abnormalities, most of the abnormalities were benign and did not hinder further treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Arrhythmias, Cardiac; Clozapine; Comorbidity; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Diseases; Humans; Hypotension, Orthostatic; Male; Middle Aged; Prevalence; Regression Analysis; Retrospective Studies; Sex Factors; Tachycardia

Although the new atypical antipsychotic, quetiapine fumarate, is growing in popularity over its progenitor, clozapine, clinical experience with overdose of this agent remains limited. Observation of an overdose situation provided a unique opportunity to define the safety, clinical effects, and pharmacokinetics of this medication more clearly.. A patient admitted immediately after ingesting an overdose of 30 tablets of 100 mg of quetiapine was observed carefully to document effects of the medication. These observations were compared with the only two other published cases of overdose, to the known pharmacology of the drug, and to serial measurements of serum drug concentrations obtained to document the time course of elimination of the drug.. Consistent with the two previously published cases, the main clinical effects of overdose were hypotension, tachycardia, and somnolence as predicted by its known alpha-adrenergic receptor and histamine receptor blockade. These effects were managed with fluid resuscitation and supportive measures. No cardiac arrhythmias other than tachycardia have been reported, but the tachycardia was of an unexpectedly long duration in this case. Decline in serum quetiapine concentration followed a biexponential pattern with a terminal elimination half-life of 22 hours. Unexpectedly low peak serum concentrations in three patients with overdose suggest that absorption is highly reduced, either by the effects of the overdose or by the activated charcoal administered.. Quetiapine appears to have greater safety in overdose than traditional antipsychotic agents. Its toxicity is consistent with its receptor pharmacology. Elevated serum concentrations associated with this overdose remained above the limit of detection long enough to document a terminal elimination half-life of 22 hours in this patient. This is much more consistent with previously noted duration of clinical effects and detectable serum concentrations after overdose than the published half-life of 6 hours. Physicians should be aware that any new drug that is active at low concentrations may have had its half-life underestimated during preclinical development because of the difficulty in detecting the drug after the distribution phase has ended.

Topics: Adrenergic alpha-Antagonists; Adult; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Drug Overdose; Female; Half-Life; Humans; Hypotension; Quetiapine Fumarate; Sleep Stages; Tachycardia

Topics: Agranulocytosis; Clozapine; Emergencies; Humans; Status Epilepticus; Tachycardia; Unconsciousness

Topics: Clozapine; Coma; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Middle Aged; Propranolol; Psychotic Disorders; Tachycardia