clozapine and Fever

To identify the clinical determinants of fever in clozapine users and their impact on management of clozapine treatment.. Articles published in English or French identified with a MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search, from inception through February 2019, using the term "clozapine" in combination with "fever" OR "hyperthermia" OR "body temperature" OR "pyrexia" OR "febrile" OR "heat" OR "thermoregulation". Information extracted for each medical condition were frequency, time to onset after initiation of clozapine treatment, characteristics of fever, associated symptoms, laboratory tests used for diagnosis, course, lethality, discontinuation of clozapine. Data were synthesized narratively.. Our search yielded 394 unique hits published from 1993 to 2018. We included 73 articles in the review: two meta-analyses, 14 reviews, six epidemiological studies, 11 clinical studies and 40 case reports. During clozapine initiation, fever is most frequently benign and transient but should be closely monitored as it may be the first stage of potentially life-threatening adverse drug reactions (ADR) (agranulocytosis, neuroleptic malignant syndrome myocarditis, hepatitis, pancreatitis, nephritis, colitis, etc.). Other ADR associated with fever are independent of duration of exposure to clozapine (heat stroke, pneumonia, pulmonary embolism, necrotizing colitis). If fever is due to intercurrent infection, therapeutic drug monitoring is recommended to adjust clozapine daily dosage.. Benign causes of fever are much more frequent than life-threatening ADR during clozapine treatment. Discontinuation should not be considered as automatic in the event of fever, especially during the early phase of clozapine initiation.

Topics: Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Colitis; Dose-Response Relationship, Drug; Drug Monitoring; Fever; Hepatitis; Humans; Infections; Lupus Erythematosus, Systemic; Myocarditis; Nephritis; Neuroleptic Malignant Syndrome; Pancreatitis; Pneumonia; Pulmonary Embolism; Schizophrenia; Serositis

Neuroleptic malignant syndrome (NMS) is the most dangerous life-threatening complication of antipsychotic medication. It's development is connected with the blockade of dopaminergic transmission (D2 receptors) in the nigrostriatal system of the brain. Fever is one of the main symptoms of this syndrome and it's elevation is due to the activation of the immune system. Numerous studies report that treatment with clozapine (doses 37.5-600 mg) or olanzapine (doses 10-25 mg) or the use of these drugs in polytherapy cause pyrexia between 37.8-40.6 °C. Additionally, levels of proinflammatory interleukins such as IL-6, IL-1,TNF-α were increased. The aim of this article is to describe how olanzapine and clozapine influence fever development in NMS, in relation to the dose of the drug taken by schizophrenic patients including changes in immunological system.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Fever; Humans; Inflammation Mediators; Interleukins; Neuroleptic Malignant Syndrome; Olanzapine; Schizophrenia

To characterize clozapine-induced fever and suggest clinically relevant management recommendations.. Literature was accessed through MEDLINE (1966-June 2007) using the terms clozapine, fever, and adverse effects. In addition, reference citations from publications identified were reviewed.. All English-language articles about human studies of fever associated with the use of clozapine were evaluated.. Mild to high-grade fever frequently accompanies clozapine therapy. Fever usually occurs within 10-15 days after treatment initiation and has been reported to last between 2 and 4 days. The mechanism and clinical implications of clozapine-induced fever are unclear. The primary concern for clinicians, with regard to these fevers, is the possibility of 2 serious conditions: agranulocytosis with infection or neuroleptic malignant syndrome (NMS). However, the presence of fever during clozapine therapy does not appear to predict agranulocytosis, NMS, or an increased rate of drug discontinuation at 1 year.. Available data suggest that clozapine-induced fevers are benign; once infectious and other medical causes for fever are ruled out, clozapine therapy can be continued.

Topics: Acetaminophen; Animals; Clozapine; Disease Management; Fever; Humans

Clozapine-associated fever is common but the specific cytokine changes and treatment durations that may cause fever remain unknown. We investigated the association between inflammatory cytokine changes and clozapine-induced fever in patients who were treated with clozapine.. Forty-three patients with schizophrenia or schizoaffective disorder, diagnosed by using the Chinese Version of the Mini International Neuropsychiatric Interview, were treated with clozapine for the first time (first-time use group, n = 22) or for more than 6 months (long-term use group, n = 21). The Positive and Negative Syndrome Scale, tympanic temperature, and levels of tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined at baseline and weeks 1, 2, 3, 4, and 6. A multiple linear regression with generalized estimating equation methods was used to analyze the association between the changes in the cytokine levels and clozapine-induced fever in the different groups.. The IL-6 level changes were significantly different between the two groups (P = 0.04). In the first-time use group, the fever rate was increased (47.1%) compared with the long-term use group (5.6%, P = 0.005). Moreover, in these patients, the TNF-α, INF-γ, IL-2, and IL-6 levels were significantly (P < 0.001) different from patients who did not develop a fever. An interaction effect with the different treatment duration groups and fever development was only significant for IL-6 (P < 0.001).. Patients who were treated with clozapine for the first time have an increased rate of developing a fever, and IL-6 might have a specific role in the interaction effect between treatment duration and fever development.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Fever; Humans; Interferon-gamma; Interleukin-2; Interleukin-6; Male; Prospective Studies; Tumor Necrosis Factor-alpha; Young Adult

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p<0.01) higher than in those patients treated with clozapine who did not develop fever. In conclusion, increase of BMI appears to be related to clozapine's and olanzapine's similar effects on cytokine systems, whilst drug-induced fever appears to be related to clozapine's differential effects on interleukin-6.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Cytokines; Double-Blind Method; Female; Fever; Humans; Leptin; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Weight Gain

Topics: Adolescent; Antipsychotic Agents; Bipolar Disorder; C-Reactive Protein; Clozapine; Eosinophilia; Female; Fever; Humans

We recently introduced a new rat model of emotional hyperthermia in which a salient stimulus activates brown adipose tissue (BAT) thermogenesis and tail artery constriction. Antipsychotic drugs, both classical and second generation, act to reduce excessive assignment of salience to objects and events in the external environment. The close association between salient occurrences and increases in body temperature suggests that antipsychotic drugs may also reduce emotional hyperthermia.. We determined whether chlorpromazine, clozapine, and risperidone dose dependently reduce emotionally elicited increases in BAT thermogenesis, cutaneous vasoconstriction, and body temperature in rats.. Rats, chronically instrumented for measurement of BAT and body temperature and tail artery blood flow, singly housed, were confronted with an intruder rat (confined within a small wire-mesh cage) after systemic pre-treatment of the resident rat with vehicle or antipsychotic agent. BAT and body temperatures, tail blood flow, and behavioral activity were continuously measured.. Clozapine (30 μg-2 mg/kg), chlorpromazine (0.1-5 mg/kg), and risperidone (6.25 μg-1 mg/kg) robustly and dose-relatedly reduced intruder-elicited BAT thermogenesis and tail artery vasoconstriction, with consequent dose-related reduction in emotional hyperthermia.. Chlorpromazine, a first-generation antipsychotic, as well as clozapine and risperidone, second-generation agents, dose-dependently reduce emotional hyperthermia. Dopamine D

Topics: Animals; Arousal; Chlorpromazine; Clozapine; Dose-Response Relationship, Drug; Emotions; Fever; Male; Rats; Rats, Sprague-Dawley; Risperidone; Thermogenesis; Vasoconstriction

Psychomotor stimulants are frequently used by humans to intensify the subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of physiological activation and in warm humid environments could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV, and methylone, three structurally related recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how MDMA, MDPV, and methylone affect brain and body temperatures in awake freely moving rats. Here, we will discuss the role of drug-induced heat production in the brain due to metabolic brain activation and diminished heat dissipation due to peripheral vasoconstriction as two primary contributors to the hyperthermic effects of these drugs. Then, we will consider how the hyperthermic effects of these drugs are modulated under conditions that model human drug use (social interaction and warm ambient temperature). Since social interaction results in brain and body heat production, coupled with skin vasoconstriction that impairs heat loss to the external environment, these physiological changes interact with drug-induced changes in heat production and loss, resulting in distinct changes in the hyperthermic effects of each tested drug. Finally, we present our recent data, in which we compared the efficacy of different pharmacological strategies for reversing MDMA-induced hyperthermia in both the brain and body. Specifically, we demonstrate increased efficacy of the centrally acting atypical neuroleptic compound clozapine over the peripherally acting vasodilator drug, carvedilol. These data could be important for understanding the potential dangers of MDMA in humans and the development of pharmacological tools to alleviate drug-induced hyperthermia - potentially saving the lives of highly intoxicated individuals.

Topics: Animals; Antipsychotic Agents; Benzodioxoles; Body Temperature; Brain; Carbazoles; Carvedilol; Central Nervous System Stimulants; Clozapine; Environment; Fever; Humans; Interpersonal Relations; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Propanolamines; Pyrrolidines; Rats; Social Behavior; Synthetic Cathinone; Vasoconstriction; Vasodilator Agents

Clozapine is a second-generation antipsychotic drug used in treatment-resistant schizophrenia. Fever induced by clozapine is a rather frequent side-effect which usually occurs in the first 4 weeks of treatment. Despite its effectiveness, there are potentially life-threatening adverse effects, such as cardiotoxicity.. We present the case of a 31-year-old caucasian male with refractory schizophrenia who developed benign fever, increase of C-reactive protein and high troponin levels, without presenting any other signs to myocarditis, on the 13th day under clozapine treatment, which declined progressively upon discontinuation of the drug.. This case hints at the presence of initially subclinical cardiotoxicity as an underlying factor in patients developing fever.. Taking advantage of more sensitive methods for measuring troponin, clinicians would be promptly aware of this possible side-effect. This would allow for significant reduction of the risk of cardiac dysfunction, further attained by carefully monitoring the patient.

Topics: Adult; Antipsychotic Agents; Autoimmunity; Cardiotoxicity; Clozapine; Electrocardiography; Fever; Humans; Male; Schizophrenia

Topics: Antipsychotic Agents; C-Reactive Protein; Clozapine; Dose-Response Relationship, Drug; Female; Fever; Humans; Middle Aged; Psychotic Disorders

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

Topics: Animals; Antipsychotic Agents; Body Temperature; Brain; Carbazoles; Carvedilol; Clozapine; Fever; Hallucinogens; Homeostasis; Labetalol; Male; N-Methyl-3,4-methylenedioxyamphetamine; Propanolamines; Rats, Long-Evans; Skin; Social Behavior; Sympathomimetics; Vasodilator Agents

Clozapine is the gold-standard antipsychotic medication for treatment-refractory schizophrenia (TRS). However, one potentially lethal side effect of clozapine, as with other antipsychotics, is neuroleptic malignant syndrome (NMS) which could present differently in clozapine therapy. 'Atypical NMS' is a recognised variant of NMS with less rigidity and delayed elevation of creatine kinase; this variant is associated with clozapine.. A case from the author's clinical practice was reviewed.. A 67-year-old man with TRS was treated with clozapine. Unfortunately, his physical condition deteriorated and he presented with atypical NMS, which initially was treated as presumable urinary tract infection.. Atypical NMS is associated with clozapine. This case exposes the potential difficulties in diagnosis, and highlights the importance of considering less common diagnoses in acutely unwell psychiatric patients.

Topics: Acute Kidney Injury; Aged; Antipsychotic Agents; Clozapine; Confusion; Fever; Humans; Male; Neuroleptic Malignant Syndrome; Polypharmacy; Risperidone; Schizophrenia

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

Topics: Antipsychotic Agents; Child; Clozapine; Female; Fever; Humans; Leukocytosis; National Institute of Mental Health (U.S.); Schizophrenia; United States

Topics: Antipsychotic Agents; Clozapine; Female; Fever; Humans; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Female; Fever; Humans; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Fever; Humans; Male; Young Adult

Topics: Antipsychotic Agents; Clozapine; Consciousness; Diagnosis, Differential; Fever; Humans; Male; Middle Aged; Muscle Rigidity; Neuroleptic Malignant Syndrome; Schizophrenia, Paranoid; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Clozapine; Consciousness; Fever; Humans; Male; Schizophrenia, Paranoid

Topics: Abdominal Pain; Adult; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Diagnostic Errors; Dibenzothiazepines; Drug Therapy, Combination; Female; Fever; Fluid Therapy; Headache; Hemodiafiltration; Humans; Lithium; Multiple Organ Failure; Norepinephrine; Quetiapine Fumarate; Schizophrenia; Systemic Inflammatory Response Syndrome; Urinary Tract Infections; Valproic Acid; Vasoconstrictor Agents

Topics: Antipsychotic Agents; Clozapine; Female; Fever; Follow-Up Studies; Humans; Middle Aged; Movement Disorders; Severity of Illness Index

Topics: Antipsychotic Agents; Clozapine; Female; Fever; Humans; Multiple Organ Failure; Systemic Inflammatory Response Syndrome

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: Antipsychotic Agents; Catatonia; Clozapine; Delusions; Electroconvulsive Therapy; Female; Fever; Hallucinations; Humans; Recurrence; Young Adult

To report a case of recurrent clozapine-induced fever that was associated with a rise in C-reactive protein (CRP).. A 73-year-old man with Lewy Body dementia was admitted for psychosis. He was treated with clozapine (initial dose 12.5 mg/day, titrated to 75 mg/day over 15 days). On day 15 of clozapine therapy, he developed a benign fever (maximum 38.4 degrees C) that was associated with a rise in the CRP level (3.96 mg/dL). The level normalized when clozapine was discontinued. However, when the patient was rechallenged with clozapine, the CRP level became elevated (4.36 mg/dL) after 3 days of therapy, with a subsequent recurrence of fever (38.7 degrees C).. We postulate that the elevation in CRP levels and the subsequent fever were caused by the effects of clozapine on the cytokine system via interleukin-6 and tumor necrosis factor-alpha, resulting in an inflammatory response with an acute phase reaction. This case is unique, as it is the first reported in the literature associating a recurrence of clozapine-induced fever with the known immunomodulatory effects of clozapine on cytokines and CRP level. According to the Naranjo probability scale, this adverse effect is probably associated with clozapine.. Clozapine-related fever is generally benign but difficult to assess and manage, as it can be confused with much more serious conditions. Further research is needed to study whether CRP is a useful tool in predicting and managing clozapine fever.

Topics: Aged; Biomarkers; C-Reactive Protein; Clozapine; Fever; Humans; Male; Predictive Value of Tests

To determine the incidence, characteristics, and predictors of clozapine-induced fever in a sample of patients in a local psychiatric unit.. A retrospective review of case notes of 227 inpatients newly started on clozapine from March 2003 to December 2006 was conducted. Demographic characteristics, presence of fever, investigations carried out, fever characteristics, and complications of fever were recorded and analyzed. Patients with clozapine-induced fever were compared with their fever-free counterparts on demographic and clinical factors. Multivariate logistic regression was performed to identify predictors of clozapine-induced fever.. Thirty-one out of 227 patients (13.7%) developed clozapine-induced fever. The means for day of onset of clozapine-induced fever after clozapine initiation and duration of fever were 13.7 and 4.7 days, respectively. The mean highest body temperature was 38.8 degrees C. Fever resolved within 48 hours after clozapine discontinuation in 79% of the patients with clozapine-induced fever. One out of 7 patients (14.3%) had fever on re-challenge. Clozapine-induced fever was associated with rate of titration more than 50 mg/wk (OR 18.9; 95% CI 5.3 to 66.7; P < 0.01), concomitant use of valproate (OR 3.6; 95% CI 1.5 to 8.9; P = 0.01), and presence of physical illnesses (OR 3.2; 95% CI 1.2 to 8.3; P = 0.02).. Clozapine-induced fever is common. Temporary withdrawal of clozapine may result in resolution of fever, and clozapine re-challenge may be considered after fever subsides. Slower rate of clozapine titration may be helpful in patients with underlying physical illness and concomitant valproate treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fever; Hong Kong; Humans; Incidence; Male; Middle Aged; Psychiatric Department, Hospital; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Valproic Acid; Young Adult

A 74-year-old psychotic female patient who was treated with clozapine developed Sweet's syndrome followed by agranulocytosis from which she later died. A link between these two conditions seems unlikely. Sweet's syndrome is characterised by an acute onset of fever, leukocytosis and erythematous plaques with dense neutrophilic infiltrates. Frequent counting of the numbers of neutrophiles is advisable when skin disorders appear during treatment with clozapine.

Topics: Aged; Agranulocytosis; Clozapine; Fatal Outcome; Female; Fever; Humans; Sweet Syndrome

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Drug Resistance; Eosinophilia; Exanthema; Female; Fever; Humans; Middle Aged; Schizophrenia

Topics: Antipsychotic Agents; Blood Sedimentation; Clozapine; Colitis; Diarrhea; Eosinophilia; Fever; Humans; Male; Middle Aged; Schizophrenia

Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1-5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 +/- 0.5 degrees C in 5 mg/kg clozapine-treated rabbits and 39.0 +/- 0.2 degrees C in olanzapine-treated rabbits, less than untreated animals (41.5 +/- 0.3 degrees C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 +/- 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 +/- 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 +/- 0.5 degrees C, <38.6 +/- 0.3 degrees C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 +/- 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 +/- 1 cm/sec) and the pre-MDMA level (17 +/- 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.

Topics: Anesthesia; Animals; Antipsychotic Agents; Benzodiazepines; Body Temperature; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Ear; Fever; N-Methyl-3,4-methylenedioxyamphetamine; Olanzapine; Pirenzepine; Rabbits; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Skin; Sympathetic Nervous System; Tail; Treatment Outcome; Vasoconstriction; Wakefulness

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Disease Models, Animal; Fever; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Olanzapine; Serotonin Antagonists

Clozapine-induced fever is a known side effect that can occur during clozapine initiation. This study aims to characterize patients who experience clozapine-induced fever, the nature of the fevers, and rates of clozapine continuation at 1 year in patients who develop fever versus those who do not.. A retrospective chart review of 93 consecutive clozapine initiations (1991-1999) was conducted. Fever was defined as any 1 temperature at or above 38.0 degrees C (100.4 degrees F). Demographic information, presence or absence of clozapine-induced fevers, and continuation of clozapine treatment at 1 year were extracted from the charts. These variables were analyzed for significance, and subsample analysis was conducted for those with more severe fevers (at or above 38.5 degrees C [101.3 degrees F]).. Of the 93 patients, 20.4% (N = 19) developed clozapine-induced fevers. At 1 year, there was no significant difference in clozapine discontinuation rate between those patients who experienced fever and those who did not. Patients who experienced higher fevers (> or = 38.5 degrees C [101.3 degrees F]) tended to be significantly older than those who did not (p < .027). The mean fever duration was 3.8 days (range, 1-9 days), with a mean temperature of 39.1 degrees C (102.4 degrees F) (range, 38.0-41.0 degrees C [100.4-105.8 degrees F]). At 1 year, the patients who experienced fever showed no increased risk of severe reactions such as agranulocytosis. All patients with fevers continued clozapine treatment with good 1-year continuation rate on treatment with this medication.. Clozapine-induced fever is not an indication for discontinuing this effective medication. It is a benign, self-limited phenomenon not predictive of drug discontinuation at 1 year. Older age at time of treatment may be a risk factor for developing clozapine-induced fever.

Topics: Adolescent; Adult; Age Factors; Body Temperature; Clozapine; Drug Administration Schedule; Female; Fever; Follow-Up Studies; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Severity of Illness Index; Treatment Outcome

Topics: Adult; Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Body Temperature Regulation; Clozapine; Cross-Sectional Studies; Female; Fever; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Risk; Schizophrenia

The study objectives were to examine the effects of the atypical antipsychotic drugs olanzapine, risperidone, and quetiapine on core temperature in the rat in relation to such effects produced by clozapine and to compare possible in vivo intrinsic efficacy of olanzapine, risperidone, and quetiapine at dopamine (DA) D(1) receptors with such effects previously shown for clozapine. Core temperature measurements were made in adult male Wistar rats maintained under standard laboratory conditions using a reversed 12-h daylight cycle. Clozapine (0-32 micromol/kg s.c.), olanzapine (0-32 micromol/kg s.c.), and risperidone (0-4 micromol/kg s.c.) all produced a dose-dependent hypothermia. Except for slight nondose-dependent hyperthermia, there were no effects of quetiapine (0-16 micromol/kg s.c. or i.p.) on the core temperature. The hypothermia produced by clozapine, but not that produced by equipotent doses of olanzapine or risperidone, was fully antagonized by pretreatment with the DA D(1) receptor antagonist SCH-23,390 (0.1 micromol/kg s.c.). On the other hand, quinpirole-induced hypothermia (4 micromol/kg s.c.) was partially antagonized by olanzapine (2 micromol/kg s.c.), risperidone (4 micromol/kg s.c.), and quetiapine (16 micromol/kg s.c.) but not by clozapine (1 micromol/kg s.c.). Clozapine preferentially stimulates DA D(1) receptors in comparison with olanzapine and risperidone, whereas olanzapine, risperidone, and quetiapine preferentially block DA D(2) receptors compared with clozapine. It is suggested that stimulation of DA D(1) receptors, presumably in the prefrontal cortex, is a distinguishing feature of clozapine responsible for its favorable profile on cognitive functioning in schizophrenia.

Topics: Animals; Antipsychotic Agents; Benzazepines; Benzodiazepines; Clozapine; Dibenzothiazepines; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Interactions; Fever; Hypothermia; Male; Olanzapine; Pirenzepine; Quetiapine Fumarate; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine; Risperidone; Time Factors

Topics: Adolescent; Antipsychotic Agents; Clozapine; Drug Interactions; Erythromycin; Fever; Humans; Male; Neutropenia; Pharyngitis; Schizophrenia

Topics: Agranulocytosis; Antithyroid Agents; Clozapine; Female; Fever; Humans; Incidence; Leukocyte Count; Male

Topics: Antipsychotic Agents; Clozapine; Drug Hypersensitivity; Exanthema; Fever; Humans; Pleural Effusion

Clozapine often causes low-grade fever and less frequently spiking fever. We describe three cases of spiking fever that occurred in the first 3 weeks of clozapine therapy. A new set of side effects of clozapine is identified, which includes spiking fever, respiratory and gastrointestinal symptoms, and neutrophilia. Possible mechanisms are discussed.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Fever; Gastrointestinal Diseases; Humans; Leukocyte Count; Lung Diseases; Male; Neutrophils; Psychotic Disorders; Schizophrenia, Paranoid

The antipsychotic drug clozapine frequently induces fever during the first weeks of administration. In addition, it has been shown that clozapine increases plasma soluble interleukin-2 receptor (sIL-2r) levels as early as 1 week after treatment is started. These findings suggest that clozapine has immunomodulatory effects. To investigate this issue in more detail, we assessed the time course of rectal temperature, blood cell counts, and cytokine and soluble cytokine receptor plasma levels during 6 weeks of clozapine treatment in 27 schizophrenic patients. Clozapine increased the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, and sIL-2r. These increases were independent of prior or concurrent medication and did also occur in patients who did not experience clozapine-induced fever. However, increases in TNF-alpha and sIL-2r levels were more pronounced in patients with clozapine-induced fever who showed in addition increased plasma IL-6 levels and granulocyte counts. Plasma IL-1 receptor antagonist levels and monocyte and lymphocyte counts were not affected by clozapine treatment. It is concluded that clozapine has consistent in vivo immunomodulatory effects. The results presented suggest that clozapine-induced fever is mediated by pyrogenic cytokines.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cytokines; Female; Fever; Humans; Male; Receptors, Cytokine; Schizophrenia

In 27 schizophrenic patients we investigated plasma levels of cytokines before the initiation of treatment and after the first, second and sixth week of treatment with the atypical antipsychotic agent clozapine. In addition, we did polysomnographic recordings in one schizophrenic patient prior to, during and following clozapine-induced fever. We found that independently of fever clozapine significantly increased the plasma levels of tumor-necrosis-factor a (TNFa) and soluble interleukin-2-receptor (sIL-2r) which were further increased by fever. Interleukin-6 (IL-6) was increased only together with fever and showed a significant positive correlation with clozapine-induced fever. The sleep recording of the fever night revealed severely disturbed sleep. Possible links between the clozapine-induced release of cytokines and clozapine's effect on night sleep are discussed.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cytokines; Female; Fever; Humans; Interleukin-5; Male; Receptors, Interleukin-2; Schizophrenia; Schizophrenic Psychology; Sleep Stages; Tumor Necrosis Factor-alpha

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Clozapine; Diagnosis, Differential; Female; Fever; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome

Topics: Adult; Antipsychotic Agents; Clozapine; Electroencephalography; Female; Fever; Humans; Longitudinal Studies; Schizophrenia; Sleep; Sleep, REM

Clozapine is an atypical neuroleptic drug that was initially thought not to cause neuroleptic malignant syndrome (NMS). We report a case of NMS associated with clozapine as a single agent that developed in a patient with no prior history of NMS. In contrast to other reported cases of NMS with clozapine monotherapy in which rigidity was reported to be absent, our patient had classic NMS with lead-pipe rigidity. NMS should be included in the differential diagnosis of a febrile patient with a history of any neuroleptic treatment, including clozapine.

Topics: Adult; Antipsychotic Agents; Bromocriptine; Clozapine; Dantrolene; Diagnosis, Differential; Fever; Humans; Male; Muscle Rigidity; Neuroleptic Malignant Syndrome; Schizophrenia

Topics: Adult; Clozapine; Diarrhea; Fever; Humans; Male; Psychotic Disorders

Topics: Adult; Aged; Clozapine; Diagnosis, Differential; Female; Fever; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Research Design

Topics: Cataplexy; Clozapine; Dibenzazepines; Fever; Humans; Sleep Wake Disorders; Sleep, REM

In addition to the low risk of agranulocytosis, several more frequent side effects are associated with clozapine therapy. We tried to estimate the incidence of these side effects. We analysed 391 treatments in 315 inpatients, who received clozapine alone or combined with other neuroleptic and antidepressant drugs. Two thirds were combined treatments, one third were treatments with clozapine alone (i.e., no other neuroleptic, antidepressant or anticonvulsive drugs were allowed). The numbers in brackets show the incidence based on the analysis of the treatments with clozapine alone. In 49% (61%) of the treatments a rise in the liver enzyme values was observed. However, counting only the cases in which a two-fold increase over the normal values was observed, the incidence was reduced to 20% (31%). Increase in temperature was observed in 4% (6%) and leukopenia (leukocyte count under 3500/microliters) was recorded in 2% (2%). Hypotensive dysregulation (systolic blood pressure under 90 mm Hg) was observed in 25% of all treatments and pharmacogenic delirium in 8%. No cases of agranulocytosis were observed. Mean treatment duration was 56 days, mean daily dosage 257 mg. The mean age of the patients was 34 years. In the overall evaluation 71% of the treatments were classified as successful; clozapine therapy was continued after discharge in 68% of the treatments. Adverse reactions (delirium, rise in temperature, hypotension, fatigue, rise in liver enzymes) necessitated a change of medication in 17% of the treatments. Changeover to another neuroleptic drug due to ineffectiveness of clozapine was necessary in 7% of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Clozapine; Dibenzazepines; Female; Fever; Humans; Hypotension; Leukocyte Count; Liver; Male; Psychoses, Substance-Induced

Topics: Adult; Anti-Anxiety Agents; Benzodiazepines; Blood Pressure; Clozapine; Dibenzazepines; Fever; Humans; Hypnotics and Sedatives; Leukocyte Count; Liver Function Tests; Male; Psychoses, Substance-Induced; Risk Factors

Topics: Basal Ganglia Diseases; Clozapine; Dibenzazepines; Fever; Headache; Humans