clozapine and Drug-Overdose

Atypical antipsychotic medications (second-generation antipsychotics) have been increasingly used in the treatment of a number of psychotic disorders since their introduction in 1988, with the newest medication introduced in 2002. Justification for their use includes claims of equal or improved antipsychotic activity over first-generation antipsychotics, increased tolerability, and decreased side effects. However, there are still significant adverse effects and toxicities with this class of medications. Toxicologic exposures and fatalities associated with atypical antipsychotics continue to increase in the United States, with 32,422 exposures and 72 deaths in 2003. There have also been Food and Drug Administration warnings in the past year about how some atypical antipsychotics have been marketed to minimize the potentially fatal risks and claiming superior safety to other atypical antipsychotics without adequate substantiation, indicating the toxicologic potential of these agents may be underestimated.. Continued research to evaluate adverse effects and tolerability of atypical antipsychotics compared with first-generation antipsychotics and each other is reviewed. This article also reviews the pharmacodynamics, pharmacokinetics, and drug interactions with these medications. New therapeutic monitoring recommendations for this class of medications have also been proposed. Finally, clinical toxicity in overdose and management are reviewed.. While new atypical antipsychotic medications may have a safer therapeutic and overdose profile than first-generation antipsychotic medications, many adverse and toxic effects still need to be considered in therapeutic monitoring and overdose management.

Topics: Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Benzodiazepines; Cardiomyopathies; Child; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Drug Interactions; Drug Overdose; Dry Eye Syndromes; Humans; Hyperlipidemias; Hypotension; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Seizures; Thiazoles

A 40-year-old schizophrenic man was found unconscious, with constricted pupils, sinus tachycardia, and twitching of the limbs. There were signs of lung infection, which was treated with antibiotics, and mild rhabdomyolysis. He regained consciousness over 8 hours, and reported taking 3-4 g clozapine. Recovery was uneventful. Measured peak clozapine and norclozapine concentrations were 3.53 mg/L and 0.70 mg/L, respectively. The concentration-time curves were biphasic, with secondary peaks at approximately 36 hours postadmission. Terminal elimination half-lives were 16.9 hours and 22.5 hours for clozapine and norclozapine, respectively.. Clozapine and its metabolite norclozapine can show biphasic plasma concentration-time curves after overdosage.

Topics: Acute Disease; Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Drug Overdose; Half-Life; Humans; Male

One hundred patients were commenced on clozapine in the Hunter region of Australia from July 1993 to September 1995. Of these, one ingested clozapine as a self-poisoning on two occasions. Over the same period, there were four other self-poisonings with clozapine in the region. Another case from a different region is described. The cases were identified from the Hunter Area Toxicology Service Database and regional psychiatric hospitals. The severity of the poisoning is related to prior exposure and tolerance. Marked sedation at relatively low doses occurred in the absence of prior exposure. No reversible electrocardiographic changes or biochemical abnormalities were demonstrated. Anticholinergic effects were minimal. All seven cases made full recovery. A high-pressure liquid chromatography (HPLC) method for assaying clozapine and its major metabolite, norclozapine, in plasma is described. Approximate retention times were norclozapine, 3.8 minutes; clozapine, 5 minutes; and propyl-norclozapine, 7 minutes. The lower limit of analysis for this assay was 20 ng/ml for clozapine and the metabolite. Using the HPLC assay, serial clozapine and norclozapine plasma concentrations were measured in three of these cases of clozapine self-poisoning. Toxicokinetic modeling was conducted by simultaneous analysis of clozapine and norclozapine observations. A two-compartment model with a metabolite compartment attached to the central compartment was used. Clozapine metabolism to norclozapine was best described by linear elimination of norclozapine and nonlinear norclozapine formation. The Km (1918 +/- 2093 micrograms/l) relative to observed concentration (3396 +/- 962 micrograms/l) suggests that norclozapine formation was saturated at the time of the first observation.

Topics: Adult; Antipsychotic Agents; Australia; Chromatography, High Pressure Liquid; Clozapine; Drug Overdose; Female; Humans; Male; Middle Aged; Suicide, Attempted

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Overdose; Female; Humans

The neuroleptic drug clozapine is used in the treatment of schizophrenia and is characterized by not having the extrapyramidal side-effects usually shown by neuroleptics. Unfortunately clozapine has other side-effects, which limit its use. This study presents methods for the analysis of clozapine and desmethylclozapine in whole blood and tissue. Case histories and pathology findings are described for 3 autopsy cases with fatal concentrations of clozapine, 5 with toxic concentrations and 2 with therapeutic concentrations together with the concentrations found in a living person.

Topics: Adult; Chromatography, Gas; Chromatography, High Pressure Liquid; Clozapine; Drug Overdose; Fatal Outcome; Female; Forensic Medicine; Humans; Liver; Male; Middle Aged; Muscles; Suicide

Antipsychotics (APs), during treatment or overdose, may be associated with respiratory aspiration.. A PubMed search on 30 September 2022, provided 3 cases of respiratory aspiration during clozapine therapy and 1 case during an AP overdose. VigiBase records of respiratory aspiration associated with APs from inception until 5 September 2021, were reviewed. VigiBase, the World Health Organization's global pharmacovigilance database, uses a statistical signal for associations called the information component (IC).

Topics: Aged; Antidepressive Agents; Antipsychotic Agents; Clozapine; Drug Overdose; Humans; Pharmacovigilance; Respiratory Aspiration; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Overdose; Humans

Topics: Antipsychotic Agents; Clozapine; Drug Overdose; Humans; Male; Middle Aged

Comorbid mental illness is common in patients with intellectual disability. Antipsychotics are widely used for these conditions, but the effect of clozapine remains largely unknown.. We aimed to investigate the effectiveness of clozapine on naturalistic outcomes in patients with intellectual disability.. By combining the national health registers, we identified all patients in Denmark with intellectual disability initiating clozapine treatment during the period 1996-2012. We used a mirror-image model to test whether initiation of clozapine treatment was associated with reduction in psychiatric admissions and inpatient days, reduction in the number of individuals performing intentional self-harm or overdose, and less frequent use of concomitant psychopharmacological treatment. Similar outcome measures were used in a reverse mirror-image model to investigate the effects of clozapine termination.. A total of 405 patients with intellectual disability redeemed clozapine. After initiation of clozapine the number of psychiatric admissions were reduced by 0.65 admissions (95% CI: 0.31-1.00) and the inpatient days were reduced by 67.2 days (95% CI: 51.2-83.3), with a similar decrease for patients with intellectual disability without psychiatric comorbidity. Clozapine treatment was not found to reduce the number of individuals with intentional self-harm, incidents of overdose, or the use of concomitant psychotropics. In cases where clozapine treatment was terminated, the number of psychiatric admissions increased by 0.57 admissions (95% CI: 0.01-1.12).. This nationwide study, which is the largest to date, suggests that treatment with clozapine is associated with a reduction in psychiatric admissions and inpatient days in patients with intellectual disability. Further studies evaluating the effects of clozapine in patients with intellectual disability are warranted.

Topics: Adult; Antipsychotic Agents; Clozapine; Denmark; Drug Overdose; Female; Follow-Up Studies; Hospitalization; Humans; Intellectual Disability; Male; Outcome Assessment, Health Care; Registries; Self-Injurious Behavior; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Drug Overdose; Humans; Male; Medication Errors; Middle Aged; Pulmonary Embolism; Schizophrenia

The prescribing of clozapine in China is common because of its outstanding efficacy and low price. There have been many cases of clozapine overdose in China. However, studies about the pharmacokinetics after overdose in the Chinese have rarely been reported. Population pharmacokinetics (PopPK) can analyze sparse data, and it is appropriate to compute clozapine pharmacokinetics after overdose.. There were 47 clozapine overdose cases. We constructed a single-compartment first-order elimination PopPK model. We also considered some covariates that can influence the pharmacokinetics parameters.. 21 cases were included in the analysis. When the reported toxic dosage was 3,740 mg, the elimination rate constant of the population was 0.0258(h(-1)). The elimination half-life was 26.9 h. The coefficient of random variation was 17%.. PopPK can solve the problem of sparse data after overdose. The area under the concentration-time curve after clozapine overdose exhibited the "two peaks phenomenon." The reported toxic dosage could impact clozapine elimination after overdose. Delayed absorption of clozapine is the best explanation for this finding.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Asian People; China; Clozapine; Drug Overdose; Female; Half-Life; Humans; Male; Middle Aged; Models, Biological; Schizophrenia; Young Adult

Topics: Antipsychotic Agents; Clozapine; Drug Overdose; Emergency Service, Hospital; Female; Humans; Hypotension; Vasoconstrictor Agents; Vasopressins; Young Adult

Topics: Aged; Clozapine; Drug Overdose; Humans; Male

No systematic study has focused on the characteristics and outcome of acute clozapine intoxication, although clozapine is the most widely used antipsychotic agent in China. The study reported herein examined the features of clozapine intoxication and the therapeutic effect of hemoperfusion (HP).. In a retrospective chart review, the notes of 47 patients who attempted suicide by ingesting large amounts of clozapine and were treated at the only psychiatric emergency service in Beijing were analyzed. Of the 20 unconscious patients with plasma clozapine concentrations of more than 2000 ng/mL, 14 received a combination of HP and symptomatic treatment, whereas the other 6 and the remaining 27 patients received only symptomatic treatment. Patients' psychiatric conditions and both plasma clozapine and norclozapine concentrations were closely monitored and registered.. One patient died of pulmonary edema and subsequent heart failure, but the rest of the patients recovered without any sequelae. Patients who received HP regained consciousness significantly faster than their counterparts with the same level of clozapine plasma concentration (>2000 ng/mL) who did not receive HP.. A combination of HP and symptomatic treatment is the best therapeutic option when plasma clozapine concentration is high.

Topics: Acute Disease; Adult; Alprazolam; Antipsychotic Agents; China; Clonazepam; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Drug Overdose; Emergency Service, Hospital; Hemoperfusion; Humans; Medical History Taking; Middle Aged; Pulmonary Edema; Retrospective Studies; Schizophrenia; Stress Disorders, Post-Traumatic; Suicide, Attempted; Sulpiride; Unconsciousness; Wine

Toxicological analyses are often performed to investigate suspected poisoning, but the interpretation of results may not be straightforward. We studied suspected poisoning cases 1992-2003 where blood clozapine and N-desmethylclozapine (norclozapine) were measured in order to assess the relationship of these parameters to outcome.. Samples were referred from clinicians, pathologists/coroners, or via the Clozaril Patient Monitoring Service (CPMS, Novartis). Information was gathered from clinical, post-mortem, or coroners' reports.. There were seven fatal [five male, two female; median (range) age 28 (24-41) year] and five non-fatal [four male, one female; median age 35 (26-41) year] clozapine overdoses. The median post-mortem blood clozapine and norclozapine concentrations were 8.2 (3.7-12) and 1.9 (1.4-2.4)mg/L, respectively [median clozapine:norclozapine ratio 4.4 (2.9-5.1)]. The median plasma clozapine and norclozapine concentrations (first or only sample) were 3.9 (1.7-7.0) and 0.40 (0.30-0.70)mg/L, respectively [median clozapine:norclozapine ratio 7.6 (5.3-18)] in the remainder. These overdoses were in patients who were poorly or non-adherent to clozapine, or who had taken tablets prescribed for someone else. In 54 further people who died whilst receiving clozapine [38 male, 16 female; median age 41 (22-70) year], the median post-mortem blood clozapine and norclozapine concentrations were 1.9 (0-7.7, n = 43) and 1.4 (0-6.0, n = 39)mg/L, respectively [median clozapine:norclozapine ratio 1.5 (0.4-7.6, n = 38)]. The median post-mortem increase in blood clozapine and norclozapine as compared to the most recent ante-mortem measurement was 489 (98-5,350)% and 371 (139-831)%, respectively [median sample time before death 14 (0-30, n = 21) days].. Clozapine poisoning cannot be diagnosed on the basis of blood clozapine and norclozapine concentrations alone. The analysis of ante-mortem blood specimens collected originally for white cell count monitoring and the blood clozapine:norclozapine ratio may provide additional interpretative information.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Drug Overdose; Female; Forensic Medicine; Humans; Leukocyte Count; Male; Middle Aged; Poisoning; Postmortem Changes; Suicide; Treatment Refusal; United Kingdom

We reviewed the available published data on intentional or unintentional secondgeneration antipsychotic overdoses in children and adolescents. The prescribing of secondgeneration antipsychotics has continued to increase over the past decade for children, adolescents, and adults. The authors reviewed the existing literature to determine the circumstances, presenting problems, treatment, and outcomes of youths who were exposed to nontherapeutic doses of these medications.. A systematic English-language Medline search of all reports (1989-2005) and a review of the bibliographies of all articles obtained was done to identify papers reporting an overdose or ingestion of a second-generation antipsychotic. Data were reviewed on clozapine, risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole. The annual reports of the American Association of Poison Control Centers National Data Collection System were reviewed from 1990 to 2003, the most recent report currently available. All fatalities in children and youths under 18 years of age were included.. The literature review identified 40 reports that included 63 patients, ranging in age from 1 day to 17 years of age. The clinical presentations included drowsiness, lethargy, agitation, irritability, combativeness, and tachycardia. There were 11 fatalities in the cases reviewed, 1 from clozapine overdose, 3 from risperidone overdose, 2 from olanzapine overdose, and 5 from quetiapine overdose. All other cases reported no significant sequelae and resolved without any reported clinical consequences. Duration of overdose symptoms ranged from 24 hours to 7 days. One case of clozapine intoxication showed resolution of symptoms in 6 hours and, in another case of olanzapine overdose, symptoms resolved in 13 days. The most frequently employed treatments included intubation, gastric lavage, activated charcoal, intravenous fluids, artificial respiration, and restraints or sedatives.. There is a need for future case reports to include serum medication level, weight of patient, coingestants, the health of the patient at baseline, relevant laboratory and toxicology studies and a standardized scale to rate the level of consciousness, such as the Glasgow Coma Scale. The existing pharmacovigilance data reports indicate these medications are relatively safe when taken in overdose, particularly when coingestants are not involved.

Topics: Adolescent; Antipsychotic Agents; Cause of Death; Child; Clozapine; Drug Overdose; Female; Humans; Male; Neurologic Examination; Risperidone; Survival Rate

Massive drug overdoses provide a unique opportunity to observe human pharmacokinetic data not otherwise ethically available. They can also provide practical examples for teaching thoughtful application of the principles of clinical pharmacology. Following a case of clozapine overdose in which onset of toxicity was delayed by 72 hours, a probable explanation was found in an exploration of three cases with unusual concentration-time profiles and revealed unexpected implications for the management of clozapine overdoses. The authors systematically addressed the possible mechanisms proposed in the literature for an unusual plateau in concentrations observed in three clozapine overdoses. The effects that the most commonly suggested explanations (i.e., delayed absorption and saturated or impaired metabolism) would have on both clozapine and norclozapine concentrations were then modeled using the data available from those three cases to provide an objective illustration for comparison. This exercise was then used as a teaching seminar, leading students through the steps required to reach a logical explanation for the observed delayed toxicity and to consider the implications for therapy. Delayed absorption best predicted the sustained serum clozapine and norclozapine concentrations observed in three cases, and modeling suggests that much of the drug remains in the gut, available for absorption for days following an overdose. As a seminar, the exercise provides students with a practical example of the value of systematically ruling out possible explanations by considering what effects various pharmacokinetic alterations would have on observed data. Absorption following massive clozapine overdose appears fundamentally different from that with conventional dosing. This suggests a potential for delayed or prolonged toxicity, extending well beyond the time frame predicted by its half-life, unless aggressive and sustained efforts are applied to remove clozapine from the gut. Data from drug overdoses provide opportunities to explore unusual aspects of pharmacokinetics, better understand future overdoses of the same agent, and present excellent material for teaching. A seminar illustrating the role that thoughtful application of pharmacologic principles had in addressing this case is now used to introduce the clinical aspects of pharmacology to students at our institutions.

Topics: Adult; Aged; Clozapine; Drug Overdose; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Pharmacology, Clinical; Problem-Based Learning; Serotonin Antagonists; Teaching

Experience with managing overdoses of the atypical antipsychotic agent, clozapine, has been limited. A 20-year-old woman, who presented 6 h after ingesting 3500 mg of clozapine, had an unexpectedly prolonged duration of tachycardia and somnolence. Successful recovery followed management with supportive measures for several days in the intensive care unit. However, the duration of symptoms greatly exceeded that predicted by the published 12-h half-life of clozapine and was associated with an unexplained persistence of serum clozapine concentrations. Recovery with normalization of autonomic function occurred only after serum clozapine began to decline again after a 4-day plateau, as revealed by serum monitoring. Similar observations have been reported in two other cases. In overdose, clozapine may not behave as predicted by its published pharmacokinetics. Persistent serum drug concentrations may prolong the period of intensive care, suggesting that aggressive measures to remove clozapine from the gut at the time of overdose may be warranted.

Topics: Adult; Anti-Bacterial Agents; Clozapine; Drug Overdose; Female; Humans; Intubation, Intratracheal; Pneumonia, Aspiration; Pneumonia, Staphylococcal; Staphylococcus aureus; Treatment Outcome

Clozapine is a tricyclic dibenzodiazepine derivative used commonly in the treatment of schizophrenia. Severe side effects of overdose have been described in children. This report describes the unintentional ingestion of clozapine by a 10-y-o girl, presenting dramatic changes of mental status and progressive alteration of consciousness with a Glasgow Coma Scale drop from 12 to 7. Urine analysis revealed 500 microg clozapine/L 24 h after ingestion. Full resolution of symptoms occurred after approximately 55 h with no sequels or alterations at follow-up. Awareness must be taken when administering atypical antipsychotics such as clozapine to children because of the severe intoxication effects cases reported.

Topics: Antipsychotic Agents; Child; Clozapine; Coma; Diagnosis, Differential; Drug Overdose; Emergency Treatment; Female; Glasgow Coma Scale; Humans; Neurologic Examination

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

Clozapine (Clozaril) is an atypical antipsychotic agent used to treat schizophrenia refractory to other pharmacological agents. This report describes an accidental clozapine overdose. The half-life of clozapine in this patient was determined from two blood levels, one obtained on admission and the second 10.5 hours later. The calculated half-life of 8.11 hours is consistent with published levels for single doses and suggests an apparent stability in clozapine elimination half-life in the face of overdose. The maximum clozapine blood level attained was probably among the highest nonfatal levels reported. The patient recovered fully following hospital admission for monitoring and supportive care. This case report illustrates the usefulness of following the time course of the changes in blood level at selected time intervals, as well as the importance of entertaining a diagnosis of drug overdose in patients presenting with acute mental status changes.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Overdose; Half-Life; Humans; Male; Schizophrenia

Topics: Aged; Antipsychotic Agents; Clozapine; Conscious Sedation; Drug Overdose; Female; Humans; Pneumonia, Aspiration; Seizures

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Overdose; Humans; Imidazoles; Indoles; Male; Schizophrenia; Schizophrenic Psychology

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Drug Overdose; Fatal Outcome; Fluoxetine; Humans; Male; Middle Aged; Selective Serotonin Reuptake Inhibitors

An ingestion of an unknown quantity of Leponex (clozapine) tablets in a suicide is described. Although clozapine is known for over 30 years now, relatively few cases of intoxications due to clozapine overdose have been reported. The authors report a new and quick method to analyze and determine the clozapine and N-desmethylclozapine concentration in body fluids. The analytes and an internal standard (zolpidem) were extracted from alkalinized samples into ethyl acetate before GC/NPD analysis. The proposed method resulted in a rapid procedure most useful in cases of deliberate poisoning with the neuroleptic drug Leponex.

Topics: Adolescent; Antipsychotic Agents; Chromatography, Gas; Clozapine; Drug Overdose; Female; Forensic Medicine; Humans; Suicide

Twenty patients suffering from schizophrenia and 36 patients suffering from endogenous depression underwent a standardized heart rate analysis before drug therapy. The patient's parameters of heart rate variability (HRV), which are controlled by the parasympathetic nervous system and which are independent of heart rate, did not significantly differ from the HRV parameters of normal control subjects. Ten of the patients with schizophrenia were treated with 200-400 mg of clozapine/day as monotherapy, while the other ten patients received a combination of different psychotropic drugs. The depressed patients were either treated with 150 mg of amitriptyline/d (n = 24) or 20 mg of paroxetine/d (n = 12) as monotherapy, respectively. After treatment with an average of 300 mg of clozapine/d for 4 weeks or with 150 mg of amitriptyline/day for 2 weeks, all of the patients HRV parameters had significantly decreased (P < 0.001). At this time, about 90% of these patients fulfilled the criteria of cardiovascular autonomic neuropathy. However, treatment with 20 mg of paroxetine/day for 2 weeks had no impact on any of the heart rate parameters. Under amitriptyline treatment, HRV parameters were found to correlate significantly with the plasma levels of amitriptyline/nortriptyline in a group of 104 depressed patients. Thus, determination of decreased HRV parameters is suggested to be a useful tool for the detection of overdosage with amitriptyline. It has not yet been elucidated whether or not the observed HRV decrease, which is probably at least in part due to the anticholinergic side effects of clozapine and amitriptyline, has any impact on patient health.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amitriptyline; Arrhythmias, Cardiac; Autonomic Nervous System; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Overdose; Drug Therapy, Combination; Electrocardiography; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Psychotropic Drugs; Schizophrenia

In case I, a 31-year-old man who had undergone unusual high-performance training, painful swellings occurred in the left arm and creatine kinase activity was raised (28,644 U/l), as well as that of the transaminases. A rapid urine test for blood was positive, but the sediment was free of red blood cells. There were no other pathological findings. Fluid intake was increased to 31 daily and on the third day he was symptom-free and creatine kinase activity had fallen to 6475 U/l, reaching normal values on the 15th day. Case 2 concerned a 28-year-old woman with paranoid schizophrenia who had taken several tablets of clozapine and then remained in bed for 3 days. She complained of pain in the region of the gluteus maximus muscles, exacerbated on pressure but otherwise unremarkable. Creatine kinase was raised to 21,492 U/l, creatine to 186 mumol/l, and the transaminases were likewise increased. The urine strip-test for blood was twice positive. She was treated with frusemide (80 mg daily) and infusions of electrolyte solution (21 daily). She became pain-free on the second day and the various enzyme activities rapidly fell to normal.

Topics: Adult; Clozapine; Combined Modality Therapy; Creatine Kinase; Drug Overdose; Exercise; Female; Fluid Therapy; Furosemide; Hematuria; Humans; Male; Physical Education and Training; Rhabdomyolysis; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Overdose; Electrocardiography; Fatal Outcome; Humans; Male; Myocarditis; Schizophrenia

Topics: Adult; Child, Preschool; Clozapine; Drug Overdose; Female; Humans; Male

Topics: Adult; Arsenic Poisoning; Cause of Death; Child, Preschool; Clozapine; Diagnosis, Differential; Drug Overdose; Expert Testimony; Fat Emulsions, Intravenous; Female; Homicide; Humans; Infant; Insanity Defense; Male; Middle Aged; Poisoning; Poisons; Postmortem Changes; Strychnine