Class: Atypical Antipsychotics
VA Class: CN709
Chemical Name: 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4] diazepine
CAS Number: 5786-21-0
Brands: Clozaril, FazaClo
[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.
The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.
BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.
RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .
FDA has deemed that clozapine has in effect an approved REMS. (See .) The REMS may apply to one or more preparations of clozapine and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). Also see Restricted Distribution Program under Dosage and Administration.
Substantial risk of potentially life-threatening agranulocytosis; reserve for use in the following indications: 1) for treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard antipsychotic therapy, either because of insufficient efficacy or an inability to achieve an effective dosage due to intolerable adverse effects.e f g 2) for reducing risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of reexperiencing suicidal behavior.e f g
Measure baseline WBC count and ANC before initiation of therapy and measure WBC count and ANC at regular intervals during treatment and for at least 4 weeks after discontinuance.e f g (See Agranulocytosis under Cautions.)
Available only through distribution systems that ensure periodic monitoring of WBC count and ANC prior to provision of patient’s next supply of drug.e f g (See Restricted Distribution under Dosage and Administration.)
Risk of seizures, particularly at higher dosages.1 Use with caution in patients with a history of seizures or other predisposing factors.1 Avoid activity where sudden loss of consciousness could cause serious risk to patient or others.1 (See Seizures under Cautions.)
- Increased Mortality in Geriatric Patients
Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis† receiving atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) compared with those receiving placebo (2.6%).c d e
- Other Cardiovascular and Respiratory Effects
Risk of orthostatic hypotension, with or without syncope, particularly during initial titration in association with rapid dosage escalation.1 Profound collapse may occur rarely, possibly accompanied by respiratory and/or cardiac arrest.1
In patients who have had even a brief interruption of therapy (i.e., ≥2 days since last dose), reinitiate therapy at dosage of 12.5 mg once or twice daily.1 (See Reinitiation of Therapy under Dosage and Administration.)
Caution advised when initiating clozapine in patients receiving benzodiazepines or other psychotropic agents since collapse, respiratory arrest, and cardiac arrest reported during initial treatment in such patients.1 See Specific Drugs under Interactions.
Uses for Clozapine
Management of treatment-resistant schizophrenia in severely ill patients who fail to respond adequately to other antipsychotic therapy and/or in whom such therapy produces intolerable adverse effects.1 2 3 10 14 21 33 34 61 63 64 87 121 156 306 (See Boxed Warning and see Agranulocytosis under Cautions.)
Suicide Risk Reduction in Schizophrenia and Schizoaffective Disorder
Reduction in risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state.1 306 327 328
In the principal supportive study for this use, most patients also received other treatments to reduce suicide risk, including concomitant psychotropic agents (i.e., antipsychotics, anxiolytics, antidepressants, mood stabilizers), hospitalization, and/or psychotherapy; contributions to efficacy unknown.1 327 329
Has been used in a limited number of patients with advanced, idiopathic parkinsonian syndrome for management of dopaminomimetic psychosis† associated with antiparkinsonian drug therapy, but adverse effects (e.g., sedation, confusion, increased parkinsonian manifestations) may limit benefit.16 69 88 132 193 194 237 251 254 292
Clozapine Dosage and Administration
Available only through distribution systems that ensure periodic blood tests prior to delivery of next supply of medication; dispensing is contingent on results of WBC count and ANC.e f g (See REMS and also see Agranulocytosis under Cautions.)
Upon initiating therapy, may dispense up to an additional 1-week supply to the patient to be held for emergencies (e.g., weather, holidays).e g Dispense ≤1 week supply ordinarily, but may dispense supply sufficient for therapy for a period of time equal to that of the monitoring period; patients monitored weekly may receive a 1-week (7-day) supply of medication, patients monitored biweekly may receive a 2-week supply, and patients eligible for monitoring every 4 weeks may receive a 28-day supply of medication, depending on WBC count and ANC results.e f g
Before initiating therapy in any patient, check Clozaril National Registry (phone number: 800-448-5938) to ensure patient does not have history of clozapine-induced agranulocytosis or severe leukopenia/granulocytopenia; do not administer to patients with such a history.1 3 6 (See Contraindications under Cautions.)
Just prior to administration of orally disintegrating tablet, peel blister backing completely off the blister and gently remove tablet; immediately place on the tongue to dissolve and swallow with or without liquid.387 When clozapine orally disintegrating tablets are divided, destroy the remaining half of the tablet.387
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Carefully adjust dosage according to individual requirements and response using lowest possible effective dosage.1 5 11 87 Avoid extended treatment in patients failing to show acceptable level of clinical response.1
Due to possibility that high dosages may increase risk of adverse reactions, particularly seizures,1 3 5 44 90 159 177 234 allow adequate time to respond to a given dosage before dosage escalation is considered.1 12 256
In a clinical study conducted by the National Institute of Mental Health (NIMH) in children (mean: 14 years of age), an initial dosage of 6.25–25 mg daily (depending on patient’s weight) was used; 322 323 dosages could be increased every 3–4 days by 1–2 times the initial dose on an individual basis up to a maximum of 525 mg daily.323
Initially, 12.5 mg (one-half of a 25-mg tablet) once or twice daily.1 213 281 292 296 302 306 318 If therapy is initiated with orally disintegrating tablets, destroy the remaining half tablet.387 If well tolerated, increase by 25–50 mg daily over a 2-week period until dosage of 300–450 mg daily is achieved.1 3 12 38 256 306
Continue daily administration in divided doses (e.g., 2–3 times daily) until effective and tolerable dosage reached,1 3 5 usually within 2–5 weeks, up to a maximum dosage of 900 mg daily.1 10 11 12 237 256 292
Optimum duration currently is not known, but maintenance therapy with antipsychotic agents is well established.1 In responsive patients, continue as long as clinically necessary and tolerated, but at lowest possible effective dosage; reassess need for continued therapy periodically.1
Suicide Risk Reduction
Initially, 12.5 mg once or twice daily.1 If therapy is initiated with orally disintegrating tablets, destroy the remaining half tablet.387 If well tolerated, increase by 25–50 mg daily over a 2-week period until a dosage of 300–450 mg daily is achieved.1
Make subsequent dosage increases no more than once or twice weekly, in increments ≤50–100 mg.1
Continue therapy for ≥2 years; 1 327 after 2 years, reassess patient’s risk of suicidal behavior.1 If clinician’s assessment indicates that risk for suicidal behavior is still present, continue therapy.1 Thereafter, reevaluate need to continue therapy at regular intervals.1
If the clinician determines the patient is no longer at risk for suicidal behavior, discontinue gradually and resume treatment of underlying disorder with an antipsychotic agent to which patient has previously responded.1
Discontinuance of Therapy
If abrupt discontinuance is required (e.g., due to leukopenia or agranulocytosis), observe carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound (e.g., headache, nausea, vomiting, diarrhea).1 Sudden withdrawal can lead to rapid decompensation and rebound psychosis.1 3 11 131 173 174
Reinitiation of Therapy
If restarted after brief interruption (i.e., ≥2 days) in therapy, reinitiate at dosage of 12.5 mg once or twice daily.1 3 256 318 If dosage well tolerated, it may be feasible to titrate back to therapeutic dosage more quickly than during initial treatment.1 318 However, reinitiate with extreme caution, even after brief interruptions of only 24 hours, in patients who have previously experienced respiratory or cardiac arrest during initial dosing but were subsequently titrated to therapeutic dosage.1 318
Maximum 900 mg daily.1
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1
Cautions for Clozapine
Uncontrolled seizure disorder.1
History of clozapine-induced agranulocytosis or severe granulocytopenia.1
Severe CNS depression or comatose states from any cause.1
Concomitant use of other agents with well-known potential to cause agranulocytosis or suppress bone marrow function.1
Known hypersensitivity to clozapine or any ingredient in the formulation.1
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
Agranulocytosis, defined as an ANC <500/mm3 and characterized by leukopenia (WBC count <2000/mm3) and relative lymphopenia, reported;139 estimated cumulative incidence of 1–2% after 1 year of therapy.1 5 6 20 139 Potentially fatal if not detected early and therapy interrupted.1
Unless patient is at risk for recurrent suicidal behavior, attempt ≥2 trials, each with a different agent for schizophrenia, at an adequate dosage and duration, before clozapine initiation since there is substantial risk of agranulocytosis.1 e f g (See Agranulocytosis in Boxed Warning.)
Incidence of agranulocytosis appears to rise steeply during first 2 months and peaks in third month, then falls substantially between the third and sixth months of therapy; after 6 months, incidence further declines but never reaches zero.e f g Reduction in monitoring frequency may result in increased incidence.1
No established risk factors for development of clozapine-induced agranulocytosis, except for evidence of substantial bone marrow suppression during initial therapy.1 However, a disproportionate number of US cases occurred in patients of Eastern European Jewish heritage; 1 2 12 139 230 237 most cases occurred within 4–16 weeks of drug exposure, but neither dose nor duration of therapy reliably predicts agranulocytosis.1 2
Agranulocytosis associated with other antipsychotic agents reportedly occurs more frequently in women, geriatric patients, and patients who are cachectic or have serious underlying medical conditions (e.g., immunocompromised, HIV infection);292 possible increased risk with clozapine use in such patients.1 292
Determine baseline WBC count and ANC before initiation of therapy.e f g Do not initiate therapy if baseline WBC count is <3500/mm3, baseline ANC is <2000/mm3, or patient has history of myeloproliferative disorder or previous clozapine-induced agranulocytosis or granulocytopenia.e f g
For first 6 months, monitor WBC counts and ANC every week; after 6 months of continuous therapy, if acceptable counts (i.e., WBC ≥3500/mm3 and ANC ≥2000/mm3) have been maintained, may monitor every other week.e f g After a further 6 months, if acceptable counts continue to be maintained, may reduce monitoring to every 4 weeks for the remainder of therapy.e f g After discontinuance, monitor weekly for at least 4 weeks from the day of discontinuance (regardless of reason for discontinuance) or until WBC ≥3500/mm3 and ANC ≥2000/mm3.e f g Dispensing of clozapine is contingent upon compliance with these required WBC and ANC tests.e f g (See Restricted Distribution under Dosage and Administration.)
Agranulocytosis develops upon rechallenge, often with a shorter latency.1 Patients who have experienced substantial bone marrow suppression during therapy are listed in a national master file.1 (See Restricted Distribution under Dosage and Administration.)
Frequency of WBC and ANC Monitoring
Initiation of therapy and first 6 months of therapy
Do not initiate in patients with a history of myeloproliferative disorder or clozapine-induced agranulocytosis or granulocytopenia
During second 6 months of therapy
All results for WBC ≥3500/mm3 and ANC ≥2000/mm3
After 12 months of therapy
All results for WBC ≥3500/mm3 and ANC ≥2000/mm3
Immature forms present
Discontinuance of therapy
Substantial decrease in WBC or ANC
Single decrease or cumulative decrease within 3 weeks of WBC ≥3000/mm3 or ANC ≥1500/mm3
Mild leukopenia/mild granulocytopenia
WBC ≥3000/mm3 but <3500/mm3 and/or ANC ≥1500/mm3 but <2000/mm3
Moderate leukopenia/moderate granulocytopenia
WBC ≥2000/mm3 but <3000/mm3 and/or ANC ≥1000/mm3 but <1500/mm3
Severe leukopenia/severe granulocytopenia
WBC <2000/mm3 and/or ANC <1000/mm3
Monitor until normal and for at least 4 weeks from day of discontinuance as follows: daily until WBC >3000/mm3 and ANC >1500/mm3, twice weekly until WBC >3500/mm3 and ANC >2000/mm3, then weekly after WBC >3500/mm3e f g
Consider bone marrow aspiration to determine granulopoietic status; if granulopoiesis is deficient, protective isolation with close observation may be indicated. If infection develops, perform cultures and institute appropriate anti-infective therapye f g
Monitor until normal and for at least 4 weeks from day of discontinuance as follows: daily until WBC >3000/mm3 and ANC >1500/mm3, twice weekly until WBC >3500/mm3 and ANC >2000/mm3, then weekly after WBC >3500/mm3e f g
Consider bone marrow aspiration to determine granulopoietic status; if granulopoiesis is deficient, protective isolation with close observation may be indicated. If infection develops, perform cultures and institute appropriate anti-infective therapy.e f g
If clozapine therapy is reinitiated after interruption, monitor WBC counts and ANC after reinitiating therapy based on duration of previous therapy, length of interruption of therapy, and previous WBC counts and ANC in the patient according to this schedule:e f g
Previous therapy duration <6 months, with no abnormal blood event (WBC ≥3500/mm3 and ANC ≥2000/mm3) and interruption in therapy ≥3 days but ≤1 month
Previous therapy duration <6 months, with no abnormal blood event and interruption in therapy >1 month
Previous therapy duration <6 months, with abnormal blood event (WBC <3500/mm3 or ANC <2000/mm3) but rechallengeable (i.e., WBC ≥2000/mm3 and ANC ≥1000/mm3 during previous therapy)
Previous therapy duration 6–12 months, with no abnormal blood event and interruption in therapy≥3 days but ≤1 month
Previous therapy duration 6–12 months, with no abnormal blood event and interruption in therapy >1 month
Previous therapy duration 6–12 months, with abnormal blood event (WBC <3500/mm3 or ANC <2000/mm3) but rechallengeable (i.e., WBC ≥2000/mm3 and ANC ≥1000/mm3 during previous therapy)
Previous therapy duration >12 months, with no abnormal blood event and interruption in therapy≥3 days but ≤1 month
Previous therapy duration >12 months, with no abnormal blood event and interruption in therapy >1 month
Previous therapy duration >12 months, with abnormal blood event (WBC <3500/mm3 or ANC <2000/mm3) but rechallengeable (i.e., WBC ≥2000/mm3 and ANC ≥1000/mm3 during previous therapy)
Contraindicated in patients with uncontrolled seizure disorders.1
Risk of seizure, particularly at high dosages (>600 mg daily) and/or in patients with elevated plasma clozapine concentrations;44 90 159 292 use with caution in patients with history of seizures or other predisposing factors (e.g., abnormal EEG without history of epilepsy, preexisting CNS pathology, history of electroconvulsive therapy [ECT], or perinatal or birth difficulties, family history of seizure or febrile convulsion).1 2 5 151 244 292
Increased risk of fatal myocarditis, particularly during, but not limited to, first month of therapy; consider possibility in patients with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, manifestations of heart failure, or ECG findings (e.g., ST-T wave abnormalities, arrhythmias).1 Not known whether eosinophilia is reliable predictor of myocarditis.1
Tachycardia may represent a presenting sign in patients with myocarditis; closely monitor patients with tachycardia during first month of therapy for other signs of myocarditis.1
Other Cardiovascular and Respiratory Effects
Use with caution in patients with cardiovascular and/or pulmonary disease due to risk of tachycardia, hypotension, collapse, and cardiac and/or respiratory arrest; carefully observe gradual dosage titration recommendations.1
Orthostatic hypotension, with or without syncope, possible; more likely to occur during initial titration in association with rapid dosage escalation or even with first dose, but may represent continuing risk in some patients.1
Tachycardia, sometimes sustained, possible; not simply reflex response to hypotension and is present in all positions monitored.
Possible ECG repolarization changes, including S-T segment depression and flattening or inversion of T waves, which normalize after discontinuance.1
Substantial cardiac events (i.e., CHF, pericarditis, pericardial effusions, ischemic changes, MI, arrhythmias, sudden death) reported.1 Sudden death reported rarely in psychiatric patients, with or without antipsychotic drug therapy; relationship to antipsychotic agent unknown.1
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, reported.1
Hyperglycemia and Diabetes Mellitus
Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents,331 332 333 including clozapine,1 318 a b Closely monitor patients with preexisting diabetes mellitus for worsening of glycemic control and perform fasting blood glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes).331 332 a b If manifestations of hyperglycemia occur, test for diabetes mellitus.331 332 a b Consider discontinuance in patients who develop severe hyperglycemia.1 a b
Cardiomyopathy reported, principally in patients <50 years of age and with duration of therapy >6 months.1 Caution advised if used in patients with cardiovascular disease; carefully observe gradual dosage titration recommendations.1
Consider possibility in patients with manifestations suggestive of cardiomyopathy, particularly exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, or peripheral edema.1 If cardiomyopathy confirmed, discontinue clozapine unless benefit clearly outweighs risk.1
Possible transient temperature elevations >38°C, with peak incidence within first 3 months of therapy; usually benign and self-limiting, but may necessitate discontinuance.1 Evaluate for possible underlying infectious process or development of agranulocytosis.1 Consider possibility of NMS in presence of high fever (see Neuroleptic Malignant Syndrome under Warnings).1
Due to initial sedative effects, closely follow recommendation for gradual dosage escalation.1
Risk of pulmonary embolism; consider possibility of pulmonary embolism in patients with DVT, acute dyspnea, chest pain, or other respiratory manifestations.1
Caution advised in patients with hepatic disease; hepatitis reported in patients with normal and preexisting hepatic function abnormalities.1
Perform hepatic function tests immediately in patients who develop nausea, vomiting, and/or anorexia during therapy; if clinically important increases in hepatic function tests or symptoms of jaundice occur, discontinue drug.1
Clozapine 25- or 100-mg orally disintegrating tablets contain aspartame, which is metabolized in the GI tract to provide about 1.74 or 6.96 mg of phenylalanine, respectively, per tablet.386 387 388 389 390 391
Use with caution in individuals whose condition may be aggravated by anticholinergic effects (e.g., patients with prostatic hyperplasia, ileus, urinary retention, angle-closure [obstructive, narrow-angle] glaucoma).1 3 146 237
Varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus, rarely fatal, reported.1 (See Contraindications under Cautions.) Treat constipation initially by maintaining adequate hydration and using bulk-forming laxatives; consult a gastroenterologist in more severe cases.1
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.1
Geriatric patients may be particularly susceptible to cardiovascular (e.g., orthostatic hypotension, tachycardia) and anticholinergic (e.g., urinary retention, constipation) adverse effects.1
Possible increased risk of death in geriatric patients with dementia-related psychosis.c d e Substantial (1.6-fold to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) for treatment of behavioral disorders†; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).c d e
Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.c d e g (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)
Use with caution in patients with hepatic disease.1 (See Hepatic Effects under Cautions.)
Use with caution in patients with renal disease.1
Common Adverse Effects
Drowsiness/sedation, dizziness/vertigo, headache, tremor, salivation, sweating, dry mouth, visual disturbances, tachycardia, hypotension, syncope, constipation, nausea, fever.1
Interactions for Clozapine
Metabolized by many CYP isoenzymes, particularly CYP1A2, CYP2D6, and CYP3A4.1 320 May inhibit CYP2D6; may make normal CYP2D6 metabolizers resemble ‘‘poor metabolizers’’ with regard to concomitant therapy with other drugs metabolized by CYP2D6.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors or inducers of CYP1A2, CYP2D6, or CYP3A4: potential pharmacokinetic interaction (altered clozapine metabolism).1 Risk of metabolic interaction caused by an effect of an individual isoform minimized, but use concomitantly with caution; dosage adjustment of clozapine and/or other drug may be necessary.1 320
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2D6: potential pharmacokinetic interaction (decreased metabolism of substrate); reduced dosage of either clozapine or substrate may be required.1
Drugs Affecting Seizure Threshold
Possible increased risk of seizure; avoid concomitant use if possible.1 16 90 176 177 253 255 292 If concomitant use is required, exercise caution (e.g., use low initial clozapine dosages and slowly titrate upward) and consider possible need for anticonvulsant therapy.292
Orthostatic hypotension, rarely with profound collapse and respiratory and/or cardiac arrest, reported with clozapine alone or during concomitant use with other psychotropic agents.1 318 Caution advised if used concomitantly.1 318
Additive CNS effects1
Avoid concomitant use1
Additive CNS effects1
Administer with caution; consult anesthesiologist regarding clozapine continuation in patients undergoing surgery involving general anesthesia1
Antiarrhythmic agents: quinidine or type IC (e.g., encainide, flecainide, propafenone)
Administer concomitantly with caution; dosage adjustment of either clozapine or antiarrhythmic agent may be necessary1
Additive anticholinergic effects1
Antidepressants, SSRIs (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)
Modest increases in plasma clozapine concentrations reported with concomitant use of certain SSRIs (i.e., fluoxetine, paroxetine, sertraline), but substantial increases in trough plasma clozapine concentrations reported with concomitant citaloprame f and fluvoxamine1 318
Severe hypotension, respiratory or cardiac arrest, and loss of consciousness reported after clozapine administration concurrently with or within 24 hours of benzodiazepine; reactions developed on first or second day of therapy1 166 188 237 281 296 318
Caution when clozapine is initiated in patients receiving benzodiazepines1
CNS depressants (e.g., opiate analgesics, sedative/hypnotics)
Additive or potentiated CNS effects1
Exercise caution to avoid excessive sedation1
Possible reversal of epinephrine’s vasopressor effects and subsequent further decrease in blood pressure1
Avoid epinephrine administration in treatment of clozapine-induced hypotension1
At least 1 death reported with concomitant use of oral haloperidol and IM clozapine (not commercially available in US)166
Causal relationship not established.166
Additive or potentiated hypotensive effects1
Nicotine (e.g., smoking)
Use concomitantly with caution1
If used concomitantly, monitor carefully for reemergence of psychotic manifestations; adjust clozapine dosage accordingly285
Possible decreased plasma clozapine concentrations, potentially resulting in decreased efficacy of previously effective clozapine dosage1
Rapidly12 16 38 67 102 235 and almost completely absorbed5 41 67 after oral administration; peak plasma concentrations attained within 1.5 or an average of 2.5 hours after single (25 or 100-mg) or multiple (100 mg twice daily) doses of clozapine as conventional tablets, respectively.1 2 3 46
Relative oral bioavailability of commercially available tablets (25- and 100-mg) is equivalent.1 3 5 Conventional and orally disintegrating tablets387 of clozapine have been shown to be bioequivalent.1 3 5 387
Plasma Protein Binding
In patients with poor metabolizer phenotypes of CYP2D6, increased plasma clozapine concentrations are possible at usual dosages.1
Orally disintegrating Tablets
Exact mechanism of antipsychotic action not fully elucidated;2 9 10 12 20 22 253 may involve serotonergic, adrenergic, and cholinergic neurotransmitter systems in addition to more selective, regionally specific effects on the mesolimbic dopaminergic system.5 15 19 67 170 212 237 256 288 290 292 293
Antagonism of histamine H1 receptors, cholinergic, and α1-adrenergic receptors may contribute to other therapeutic and adverse effects (e.g., somnolence, constipation, orthostatic hypotension).1 5 15 19 67 170 212 237 256 288 290 292 293
Advice to Patients
Importance of immediately informing clinician if lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration, flu-like symptoms, or other signs of infection occur.1
Risk of sedation and impairment of mental and/or physical abilities, especially during initial dosage titration; avoid activities requiring alertness until gain experience with the drug’s effects.1
Risk of seizure; avoid driving and other potentially hazardous activity during therapy.1
Risk of orthostatic hypotension, particularly during initial dosage titration.1
If therapy interrupted for ≥2 days, contact clinician for dosage instructions.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, as well as any concomitant illnesses (e.g., diabetes mellitus, seizure disorder, dementia, cardiovascular disease).1
Importance of informing clinician of existing or contemplated alcohol use.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Clozapine is available only through distribution systems that ensure periodic testing of leukocyte and absolute neutrophil counts as a condition of provision of the patient’s next supply of drug. The individual manufacturer should be contacted for additional information on current mechanisms for obtaining the drug.e f g
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Mylan, Teva, UDL
Clozaril (with povidone; scored)
Mylan, Teva, UDL
Clozaril (with povidone; scored)
Tablets, orally disintegrating
FazaClo (with aspartame; scored)
FazaClo (with aspartame; scored)
AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 14, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. Novartis Pharmaceuticals. Clozaril (clozapine) prescribing information. East Hanover, NJ; 2003 Jan.
2. Sandoz Pharmaceuticals. Formulary information on Clozaril (clozapine). East Hanover, NJ; 1989.
3. Sandoz Pharmaceuticals. Clozaril (clozapine) highlights for the pharmacist. East Hanover, NJ; 1989 Nov.
4. Neumayer JL. Neuroleptics and anxiolytic agents. In: Foye WO, ed. Principles of medicinal chemistry. 3rd ed. Philadelphia: Lea & Febiger; 1989:208-9.
5. Ereshefsky L, Watanabe MD, Tran-Johnson TK. Clozapine: an atypical antipsychotic agent. Clin Pharm. 1989; 8:691-709. [IDIS 259504] [PubMed 2572373]
6. Sandoz Pharmaceuticals. Treatment systems requirements: Clozaril (clozapine). East Hanover, NJ; 1991 Mar.
7. Lapierre YD, Ghadirian A, St. Laurent J et al. Clozapine in acute schizophrenia—efficacy and toxicity. Curr Ther Res. 1980; 27:391-400.
8. Steiner G, Franke A, Hadicke E. Tricyclic epines: novel (E)- and (Z)-11 H-dibenzo[b,e]azepines as potential central nervous system agents. Variation of the basic side chain. J Med Chem. 1986; 29:1877-88. [IDIS 222055] [PubMed 2876098]
9. Coward DM, Imperato A, Urwyler S et al. Biochemical and behavioural properties of clozapine. Psychopharmacology. 1989; 99(Suppl):S6-12. [PubMed 2573106]
10. Kane J, Honigfeld G, Singer J et al. Clozapine for the treatment-resistant schizophrenic: a double- blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988; 45:789-96. [IDIS 246014] [PubMed 3046553]
11. Bablenis E, Weber SS, Wagner RL. Clozapine: a novel antipsychotic agent. DICP. 1989; 23:109-15. [IDIS 251106] [PubMed 2658370]
12. Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin Psychiatry. 1989; 50:329-38. [IDIS 259062] [PubMed 2670914]
13. Ereshefsky L, Crismon ML, Saklad SR. Intraindividual pharmacokinetic assessment of clozapine. Pharmacotherapy. 1988; 8:137.
14. Marder SR, Van Putten T. Who should receive clozapine? Arch Gen Psychiatry. 1988; 45:856- 7.
15. Gedelsky GA, Nash JF, Berry SA et al. Basic biology of clozapine: electrophysiological and neuroendocrinological studies. Psychopharmacology. 1989; 99(Suppl):S13-7. [PubMed 2682728]
16. Wolters EC, Hurwitz TA, Peppard RF et al. Clozapine: an antipsychotic agent in Parkinson’s disease? Clin Neuropharmacol. 1989; 12:83-90.
17. Zapletalek M, Pazdirek S, Hubsch T et al. Clinical experience with clozapine in psychosis. Act Nerv Super. 1974; 16:203-4.
18. Criswell HE, Mueller RA, Breese GA. Clozapine antagonism of D-1 and D-2 dopamine receptor-mediated behaviors. Eur J Pharmacol. 1989; 159:141-7. [PubMed 2495973]
19. Burki HR, Sayers AC, Ruch W et al. Effects of clozapine and other dibenzo-epines on central dopaminergic and cholinergic systems. Arzneimittelforschung. 1977; 27:1561-5. [PubMed 20900]
20. Anon. Clozapine. Lancet. 1989; 2:1430-2. [PubMed 2574365]
21. Honigfeld G, Patin J, Singer J. Clozapine: antipsychotic activity in treatment-resistant schizophrenics. Adv Ther. 1984; 1:77-97.
22. Meltzer HY. Clozapine: the next stage in drug treatment of schizophrenia. Fair Oaks Hosp Psychiatry Lett. 1988; 6:10-4.
24. Lee T, Tang SW. Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain. Psychiatry Res. 1984; 12:277-85. [PubMed 6239298]
25. Seeger TF, Thal L, Gardner EL. Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: studies with chronic clozapine and haloperidol. Psychopharmacology. 1982; 76:182-7. [PubMed 6805029]
26. Wilk S, Stanley M. Clozapine concentrations in brain regions: relationship to dopamine metabolite increase. Eur J Pharmacol. 1978; 51:101-7. [PubMed 699976]
27. Mao CC, Marco E, Revuelta A et al. The turnover of q-aminobutyric acid in the nuclei of telencephalon: implications in the pharmacology of antipsychotics and of a minor tranquilizer. Biol Psychiatry. 1977; 12:359-71. [PubMed 17436]
28. Stimmel GL. Neuroleptics and the corpus striatum: clinical implications. Dis Nerv Syst. 1976; 37:219-24. [IDIS 59011] [PubMed 1253676]
29. Cohen BM, Benes FM, Baldessarini RJ. Atypical neuroleptics, dose-response relationships, and treatment-resistant psychosis. Arch Gen Psychiatry. 1989; 46:381-3. [IDIS 253921] [PubMed 2564764]
30. Kane JM, Cooper TB, Sachar EJ et al. Clozapine: plasma levels and prolactin response. Psychopharmacology. 1981; 73:184-7. [PubMed 6785813]
31. Sarafoff M, Davis L, Ruther E. Clozapine induced increase in human plasma norepinephrine. J Neural Transm. 1979; 46:175-80. [PubMed 512652]
32. Touyz SW, Beumont PJV, Saayman GS et al. A psychophysiological investigation of the short term effects of clozapine upon sleep parameters in normal young adults. Biol Psychiatry. 1977; 12:801-22. [PubMed 202346]
33. Matz R, Rick W, Oh D et al. Clozapine—a potential antipsychotic agent without extrapyramidal manifestations. Curr Ther Res. 1974; 16:687- 95. [IDIS 47748] [PubMed 4210458]
34. Claghorn J, Honigfeld G, Abuzzahab F et al. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol. 1987; 7:377-84. [IDIS 237321] [PubMed 3323261]
35. Spatz VR, Lorenzi E, Kugler J et al. Haufigkeit und Form von EEG-Anomalien bei Clozapintherapie. (German; with English abstract.) Arzneim-Forsch. 1978; 28: 1499-500.
36. Gardner EL, Seeger TF. Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation. Biol Psychiatry. 1983; 18:1357-62. [PubMed 6661466]
37. Raptopoulos P, Gaind R. Clozapine (Leponex) in schizophrenia: therapeutic efficacy and side-effects. Clin Trials J. 1976; 13:49-54.
38. Anon. Clozapine for schizophrenia. Med Lett Drugs Ther. 1990; 32:3-4. [PubMed 2403629]
39. Bondesson U, Lindstrom LH. Determination of clozapine and its N-demethylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection. Psychopharmacology. 1988; 95:472-5. [PubMed 3145517]
40. Haring C, Barnas C, Saria A et al. Dose-related plasma levels of clozapine. J Clin Psychopharmacol. 1989; 9:71-2. [IDIS 251948] [PubMed 2708561]
41. Cheng YF, Lundberg T, Bondesson U et al. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol. 1988; 34:445-9. [IDIS 244062] [PubMed 3203703]
42. Choc MG, Lehr RG, Hsuan F et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res. 1987; 4:402-5. [PubMed 3508549]
43. Gardiner TH, Lewis JM, Shore PA. Distribution of clozapine in the rat: localization in lung. J Pharmacol Exp Ther. 1987; 206:151-7.
44. Simpson GM, Cooper TA. Plasma clozapine levels and convulsions. Am J Psychiatry. 1978; 135:99-100. [PubMed 412427]
45. Haring C, Barnas C, Humpel C et al. Dose-related plasma levels of clozapine: differences in smokers and non-smokers. Psychopharmacology. 1988; 96:S186.
46. Ackenheil M. Clozapine—pharmacokinetic investigations and biochemical effects in man. Psychopharmacology. 1989; 99(Suppl):S32-7. [PubMed 2682731]
47. Sayers AC, Burki HR, Ruch W et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias: effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacology (Berl). 1975; 41:97-104.
48. Wilmot CA, Szczepanik AM. Effects of acute and chronic treatments with clozapine and haloperidol on serotonin (5-HT2) and dopamine (D2) receptors in the rat brain. Brain Res. 1989; 487:288-98. [PubMed 2525063]
49. Fink M, Irwin P, Weinhold P. EEG profile studies of clozapine in volunteers and psychiatric patients. Pharmakopsychiatr Neuro-Psychopharmakol. 1979; 12:184-90.
50. Gianutsos G, Moore KE. Dopaminergic supersensitivity in striatum and olfactory tubercle following chronic administration of haloperidol or clozapine. Life Sci. 1977; 20:1585-92. [PubMed 875633]
51. Richelson E. Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J Clin Psychiatry. 1984; 45:331-6. [PubMed 6146602]
52. Simpson GM, Varga E. Clozapine—a new antipsychotic agent. Curr Ther Res. 1974; 16:679-86. [IDIS 47747] [PubMed 4210457]
53. Van Praag HM, Korf J, Dols LCW. Clozapine versus perphenazine: the value of the biochemical mode of action of neuroleptics in predicting their therapeutic activity. Br J Psychiatry. 1976; 129:547-55. [PubMed 1000139]
54. Shopsin B, Klein H, Aaronsom M et al. Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients. Arch Gen Psychiatry. 1979; 36:657-64. [PubMed 375865]
55. Gerlach J, Koppelhus P, Helweg E et al. Clozapine and haloperidol in a single-blind cross-over trial: therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr Scand. 1984; 50:410-24.
56. Fischer-Cornelssen KA, Ferner UJ. An example of European multicenter trials: multispectral analysis of clozapine. Psychopharmacol Bull. 1976; 12:34-9. [PubMed 769027]
57. Povlsen UJ, Noring U, Fog R et al. Tolerability and therapeutic effect of clozapine. Acta Psychiatr Scand. 1985; 71:176-85. [PubMed 3883696]
58. Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand. 1988; 77:524-9. [PubMed 3407421]
59. Chouinard G, Annable L. Clozapine in the treatment of newly admitted schizophrenic patients: a pilot study. J Clin Pharmacol. 1976; 3:298-97.
60. Battegay R, Cotar B, Fleischhauer J et al. Results and side-effects of treatment with clozapine (Leponex). Compr Psychiatry. 1977; 18:423-8. [PubMed 891163]
61. Singer K, Law SK. A double-blind comparison of clozapine (Leponex) and chlorpromazine in schizophrenia of acute symptomatology. J Int Med Res. 1974; 2:433-5.
62. Guirguis E, Voiseskos G, Gray J et al. Clozapine (Leponex) vs chlorpromazine (Largactil) in acute schizophrenia (a double-blind controlled study). Curr Ther Res. 1977; 21:707-19.
63. Chiu E, Burrows G, Stevenson J. Double-blind comparison of clozapine with chlorpromazine in acute schizophrenic illness. Aust NZ J Psychiatry. 1976; 10:343-7.
64. Gelenberg AJ, Doller JC. Clozapine versus chlorpromazine for the treatment of schizophrenia: preliminary results from a double-blind study. J Clin Psychiatry. 1979; 40:238-40. [PubMed 374401]
65. Ekblom B, Haggstrom JE. Clozapine (Leponex) compared with chlorpromazine: a double-blind evaluation of pharmacological and clinical properties. Curr Ther Res. 1974; 16:945-57. [PubMed 4154183]
66. Leon CA. Therapeutic effects of clozapine. A 4-year follow-up of a controlled clinical trial. Acta Psychiatr Scand. 1979; 59:471-80. [PubMed 380268]
67. Sayers AC, Amsler HA. Clozapine. In: Goldberg ME, ed. Pharmacological and biochemical properties of drug substances. American Pharmacological Association Academy of Pharmaceutical Science. 1977:1-31.
68. Pakkenberg H, Pakkenberg B. Clozapine in the treatment of tremor. Acta Neurol Scand. 1986; 73:295-7. [PubMed 3521185]
69. Scholz E, Dichgans J. Treatment of drug-induced exogenous psychosis in parkinsonism with clozapine and fluperlapine. Eur Arch Psychiatry Neurol Sci. 1985; 235:60-4. [PubMed 2864254]
70. Honigfeld G. Sandoz and the monitoring of patients receiving clozapine. JAMA. 1991; 265:1529. [PubMed 1999902]
71. Cold JA, Wells BG, Froemming JH. Seizure activity associated with antipsychotic therapy. DICP. 1990; 24:1012. [IDIS 271702] [PubMed 2244402]
72. Walker JM, Matsumoto RR, Bowen WD et al. Evidence of a role for haloperidol-sensitive w-″opiate’ receptors in the motor effects of antipsychotic drugs. Neurology. 1988; 38:961-5. [PubMed 2897093]
73. Caine ED, Polinsky RJ, Kartzinel R et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979; 136:317-20. [IDIS 112667] [PubMed 154301]
74. Rodova A, Svestka J, Nahunek K et al. A blind comparison of clozapine and perphenazine in schizophrenics. Act Nerv Super. 1973; 15:94-5.
75. Faltus F, Hynek V, Dolezalova V et al. Experience in the treatment of schizophrenia with clozapine. Act Nerv Super. 1973; 15:95.
76. Shopsin B, Feiner NF. The current status of clozapine. Psychopharmacol Bull. 1983; 19:563-4. [PubMed 6635130]
77. Singer JM. Clozapine and tardive dyskinesia. Arch Gen Psychiatry. 1983; 40:347. [PubMed 6338857]
78. Carroll BJ, Curtis GC, Kokmen E. Paradoxical response to dopamine agonists in tardive dyskinesia. Am J Psychiatry. 1977; 134:785-9. [IDIS 90312] [PubMed 17308]
79. Jeste DV, Wyatt RJ. Clozapine and tardive dyskinesia. Arch Gen Psychiatry. 1983; 40:347-8. [PubMed 6338857]
80. Jeste DV, Wyatt RJ. Therapeutic strategies against tardive dyskinesia. Two decades of experience. Arch Gen Psychiatry. 1983; 39:803-16.
81. Gerlach G, Simmelsgaard H. Tardive dyskinesia during and following treatment with haloperidol, haloperidol + biperiden, thioridazine, and clozapine. Psychopharmacology. 1978; 59:105-12. [PubMed 103110]
82. Gerbino L, Shopsin B, Collora M. Clozapine in the treatment of tardive dyskinesia: an interim report. In: Fann WE, Smith RC, Davis JM et al, eds. Tardive dyskinesia research & treatment. New York: SP Medical & Scientific Books. 1980:475-89.
83. Meltzer HY. Duration of clozapine trial in neuroleptic-resistant schizophrenia. Arch Gen Psychiatry. 1989; 46:672. [IDIS 256918] [PubMed 2567591]
84. Kane JM. The current status of neuroleptic therapy. J Clin Psychiatry. 1989; 50:322-8. [IDIS 259061] [PubMed 2570063]
85. Wood MJ, Rubinstein M. An atypical responder to clozapine. Am J Psychiatry. 1990; 147:369. [IDIS 264161] [PubMed 2309959]
86. Simpson GM, Pi EH, Srmek JJ Jr. Management of tardive dyskinesia: current update. Drugs. 1982; 23:381-93. [IDIS 151454] [PubMed 7047137]
87. Panteleeva GP, Kovskaya MYT, Belyaev BS et al. Clozapine in the treatment of schizophrenic patients: an international multicenter trial. Clin Ther. 1987; 10:57-68. [PubMed 3329966]
88. Wolters EC, Hurwitz TA, Mak E et al. Clozapine in the treatment of parkinsonian patients with dopaminomimetic psychosis. Neurology. 1990; 40:832-4. [IDIS 265678] [PubMed 1970427]
89. Small JG, Milstein V, Marhenke JD et al. Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis. J Clin Psychiatry. 1987; 48:263-7. [IDIS 232363] [PubMed 2885310]
90. Ayd FJ Jr. Clozapine update: benefits and risks. Int Drug Ther Newsl. 1989; 24:37-9.
91. Pfaus JG, Phillips AG. Differential effects of dopamine receptor antagonists on the sexual behavior of male rats. Psychopharmacology. 1989; 98:363-8. [PubMed 2568656]
92. Blackburn JR, Phillips AG. Blockade of acquisition of one-way conditioned avoidance responding by haloperidol and metoclopramide but not by thioridazine or clozapine: implications for screening new antipsychotic drugs. Psychopharmacology. 1989; 98:453-9. [PubMed 2570431]
93. Hu XT, Wang RY. Haloperidol and clozapine: differential effects on the sensitivity of caudate-putamen neurons to dopamine agonists and cholecystokinin following one month continuous treatment. Brain Res. 1989; 486:325-33. [PubMed 2786442]
94. Nash JF, Meltzer HY, Gudelsky GA. Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. Eur J Pharmacol. 1988; 151:463-9. [PubMed 2905661]
95. Ashby CR, Wang RY. Effects of antipsychotic drugs on 5-HT2 receptors in the medial prefrontal cortex: microiontophoretic studies. Brain Res. 1990; 506:346-8. [PubMed 1967969]
96. Black JL, Richelson E. Antipsychotic drugs: prediction of side-effect profiles based on neuroreceptor data derived from human brain tissue. Mayo Clin Proc. 1987; 62:369-72. [IDIS 228750] [PubMed 2883343]
97. Farde L, Wiesel FA, Halldin C et al. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988; 45:71-6. [IDIS 236798] [PubMed 2892477]
98. Ashby CR, Hitzemann R, Rubinstein JE et al. One year treatment with haloperidol or clozapine fails to alter neostriatal D1- and D2-dopamine receptor sensitivity in the rat. Brain Res. 1989; 493:194-7. [PubMed 2570618]
99. Compton DR, Johnson KM. Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens. J Pharmacol Exp Ther. 1989; 248:521-30. [PubMed 2918468]
100. Andersen PH, Braestrup C. Evidence for different states of dopamine D1 receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of D1 receptor. J Neurochem. 1986; 47:1822-31. [PubMed 2945903]
101. Matsubara S, Meltzer HY. Effect of typical and atypical antipsychotic drugs on 5-HT2 receptor density in rat cerebral cortex. Life Sci. 1989; 45:1397-406. [PubMed 2571912]
102. Balant-Gorgia AE, Balant L. Antipsychotic drugs: clinical pharmacokinetics of potential candidates for plasma monitoring. Clin Pharmacokinet. 1987; 13:65-90. [IDIS 233461] [PubMed 2887326]
103. Leppig M, Bosch B, Naber D et al. Clozapine in the treatment of 121 out-patients. Psychopharmacology. 1989; 99(Suppl):S77-9.
104. Casey DE. Clozapine: neuroleptic-induced EPS and tardive dyskinesia. Psychopharmacology. 1989; 99(Suppl):S47-53. [PubMed 2682732]
105. Steiger A, Benkert O. Examination and treatment of sleep-related painful erections—a case report. Arch Sexual Behav. 1989; 18:263-7.
106. Norris DL, Israelstam K. Clozapine (Leponex) overdosage. S Afr Med J. 1975; 49:385. [IDIS 53157] [PubMed 1145356]
107. Schuster P, Gabriel E, Kufferle B et al. Reversal by physostigmine of clozapine-induced delirium. Clin Tox. 1977; 10:437-41.
108. Haring C, Meise U, Humpel C et al. Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology. 1989; 99(Suppl):S38-40. [PubMed 2813665]
109. Blum A, Girke W. Marked increase in REM sleep produced by a new antipsychotic compound. Clin Electroencephalography. 1973; 4:80-4.
110. Gerlach J, Jorgenson EO, Peacock L. Long-term experience with clozapine in Denmark: research and clinical practice. Psychopharmacology. 1989; 99(Suppl): S92-6. [PubMed 2682734]
111. Lieberman J, Johns C, Cooper T et al. Clozapine pharmacology and tardive dyskinesia. Psychopharmacology. 1989; 99(Suppl):S54-9. [PubMed 2479047]
112. Heh CW, Herrera J, DeMet E et al. Neuroleptic-induced hypothermia associated with amelioration of psychosis in schizophrenia. Neuropsychopharmacology. 1988; 1:149-56. [PubMed 3251495]
113. Marco LA, Joshi RS, Brigham TE et al. Effects of clozapine on ketamine-induced linguopharyngeal events in rats. Eur J Pharmacol. 1989; 164:171-3. [PubMed 2753078]
114. Levinson B. Clozapine (Leponex) overdosage. S Afr Med J. 1975; 49:21. [IDIS 49922] [PubMed 1111134]
115. Mattes J. Clozapine for refractory schizophrenia: an open study of 14 patients treated up to 2 years. J Clin Psychiatry. 1989; 50:389-91. [IDIS 260228] [PubMed 2571612]
116. Hemphill RE, Pascoe FD, Zabow T. An investigation of clozapine in the treatment of acute and chronic schizophrenia and gross behavior disorders. S Afr Med J. 1975; 49:2121-5. [IDIS 63817] [PubMed 1209429]
117. Meltzer HY, Koenig JI, Nash JF et al. Melperone and clozapine: neuroendocrine effects of atypical neuroleptic drugs. Acta Psychiatr Scand. 1989; 352(Suppl): 24-9.
118. Borison RL, Diamond BI, Sinha D et al. Clozapine withdrawal rebound psychosis. Psychopharmacol Bull. 1988; 24:260-3. [PubMed 3212159]
119. Menon MK, Gordon LI, Fitten J. Interaction between clozapine and a lipophilic α1-adrenergic agonist. Life Sciences. 1988; 43:1791-804. [PubMed 2904633]
120. Conley RR, Schultz C, Baker RW et al. Clozapine efficacy in schizophrenic nonresponders. Psychopharmacol Bull. 1988; 24:269-74. [PubMed 3212161]
121. Kane JM, Honigfeld G, Singer J et al. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988; 24:62-7. [PubMed 3290950]
122. Naber D, Grohmann R, Muller-Spahn F et al. Efficacy and adversive effects of clozapine in the treatment of schizophrenia and tardive dyskinesia. Psychopharmacology. 1988; 96(Suppl):S187.
123. Paunovic VR, Jasovic-Gasic MM, Bogdanovic MR et al. Clozapine in the treatment of negative symptoms in schizophrenia. Psychopharmacology. 1988; 96(Suppl):S344.
124. Kiejna A. Clinical evaluation of clozapine treatment in mental disorders. Psychopharmacology. 1988; 96(Suppl):S345.
125. Pfeiffer RF, Kang J, Graber B et al. Clozapine for psychosis in Parkinson’s disease. Neurology. 1989; 39(Suppl 1):231.
126. Ostergaard K, Dupont E. Clozapine treatment of drug-induced psychotic symptoms in late stages of Parkinson’s disease. Acta Neurol Scand. 1988; 78:349-50. [PubMed 3223229]
127. Helmchen H. Clinical experience with clozapine in Germany. Psychopharmacology. 1989; 99(Suppl): S80-3. [PubMed 2573107]
128. Naber D, Leppig M, Grohmann R et al. Efficacy and adverse effects of clozapine in the treatment of schizophrenia and tardive dyskinesia—a retrospective study of 387 patients. Psychopharmacology. 1989; 99(Suppl):S73-6.
129. Honigfeld G, Patin J. Predictors of response to clozapine therapy. Psychopharmacology. 1989; 99(Suppl):S64-7. [PubMed 2813666]
130. Gaertner HJ, Fischer E, Hoss J. Side effects of clozapine. Psychopharmacology. 1989; 99(Suppl):S97-100. [PubMed 2813671]
131. Ekblom B, Eriksson K, Lindstrom LH. Supersensitivity psychosis in schizophrenia patients after sudden clozapine withdrawal. Psychopharmacology. 1984; 83:293-4. [PubMed 6433395]
132. Friedman JH, Lannon MC. Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology. 1989; 39:1219-21. [IDIS 258570] [PubMed 2771073]
133. Friedman JH, Lannon MC. Clozapine treatment of psychosis in Parkinson’s disease. Neurology. 1989; 39(Suppl 1):389.
134. Friedman JH, Max J, Swift R. Idiopathic Parkinson’s disease in a chronic schizophrenic patient: long-term treatment with clozapine and L-DOPA. Clin Neurology. 1987; 10:470-5.
135. Classen W, Laux G. Sensorimotor and cognitive performance of schizophrenic inpatients treated with haloperidol, flupenthixol, or clozapine. Pharmacopsychiatry. 1988; 21: 295-7.
136. Krupp P, Barnes P. Leponex—associated granulocytopenia: a review of the situation. Psychopharmacology. 1989; 99:S118-21. [PubMed 2682727]
137. Hippius H. The history of clozapine. Psychopharmacology. 1989; 99(Suppl):S3-5.
138. Claas FHJ. Drug-induced agranulocytosis; review of possible mechanisms, and prospects for clozapine studies. Psychopharmacology. 1989; 99(Suppl):S113-7.
139. Lieberman JA, Johns CA, Kane JM et al. Clozapine-induced agranulocytosis: non-cross-reactivity with other psychotropic drugs. J Clin Psychiatry. 1988; 49:271-7. [IDIS 244405] [PubMed 3391979]
140. MacAllister CG, Rapaport MH, Pickar D et al. Effects of short-term administration of antipsychotic drugs on lymphocyte subsets in schizophrenic patients. Arch Gen Psychiatry. 1989; 46:956-7. [IDIS 263657] [PubMed 2572208]
141. Heimpel H. Drug-induced agranulocytosis. Med Toxicol Adverse Drug Exp. 1988; 3:449-62. [IDIS 250047] [PubMed 3063921]
142. Amsler HA, Teerenhovi L, Barth E et al. Agranulocytosis in patients treated with clozapine: a study of the Finnish epidemic. Acta Psychiatr Scand. 1977; 56:241-8. [PubMed 920225]
143. Ackenheil M, Beckmann H, Greil W et al. Antipsychotic efficacy of clozapine in correlation to changes in catecholamine metabolism in man. In: Forrest IS, Carr CJ, Usdin E, eds. The phenothiazines and strucurally related drugs. New York: Raven Press; 1974:647-57.
144. Baum MJ, Starr MS. Inhibition of sexual behavior by dopamine antagonist or serotonin agonist drugs in castrated male rats given estradiol or dihydrotestosterone. Pharmacol Biochem Behav. 1980; 13:57-67. [PubMed 7403222]
145. Gerlach J, Thorsen K, Fog R. Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients. Psychopharmacology (Berl). 1975; 40:341-50.
146. Reynolds FEF, ed. Martindale: the extra pharmacopoeia. 29th ed. London: The Pharmaceutical Press; 1987:727.
147. Muller T, Becker T, Fritze J. Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet. 1988; 31:1500.
148. Pope HG Jr, Cole JO, Choras PT et al. Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis. 1986; 174:493-5. [PubMed 3090198]
149. Chaimowitz GA, Gomes U, Maze SS. Neuroleptic malignant syndrome. CMAJ. 1988; 138: 51-3. [IDIS 237168] [PubMed 3275480]
150. Cohen S, Chiles J, MacNaughton A. Weight gain associated with clozapine. Am J Psychiatry. 1990; 147:503-4. [IDIS 264701] [PubMed 2316740]
151. Sriwatanakul K. Minimizing the risk of antipsychotic-associated seizures. Drug Therapy. 1982; 12:207-11.
152. Girke W, Blum A, Wiemann H. Rapid eye movement (REM) sleep under an antipsychotically active dibenzodiazepine derivative. Electroencephalogr Clin Neurophysiol. 1972; 32:708-9.
153. Jenkins M, Metzer WS. Avoidance of metoclopramide for the treatment of clozapine-induced nausea. J Clin Psychiatry. 1990; 51:210. [IDIS 267289] [PubMed 2335497]
154. Banki CM. Alterations of cerebrospinal fluid 5-hydroxyindoleacetic acid, and total blood serotonin content during clozapine treatment. Psychopharmacology. 1978; 56:195-8. [PubMed 417371]
155. Pentel PR, Benowitz NL. Tricyclic antidepressant poisoning: management of arrhythmias. Med Toxicol. 1986; 1:101-21. [IDIS 221648] [PubMed 3784839]
156. Gerlach J, Koppelhus P, Helweg E et al. Clozapine and haloperidol in a single-blind cross-over trial: therapeutic and biochemical treatment of schizophrenia. Acta Psychiatr Scand. 1974; 50:410-24. [PubMed 4153596]
157. Anderman B, Griffith RW. Clozapine-induced agranulocytosis: a situation report up to August 1976. Eur J Clin Pharmacol. 1977; 11:199-210. [PubMed 852497]
158. Gianutsos G, Moore K. Possible significance of clozapine-induced increase in brain dopamine. Res Commun Chem Path Pharmacol. 1977; 17:29-39.
159. Simpson GM, Lee JH, Shrivastava RK. Clozapine in tardive dyskinesia. Psychopharmacology. 1978; 56:75-80. [PubMed 415329]
160. de la Chapelle A, Kari C, Nurminen M et al. Clozapine-induced agranulocytosis: a genetic and epidemiological study. Hum Genet. 1977; 37:183-94. [PubMed 885538]
161. Snyder SH, Greenberg D, Yamumura HI. Antischizophrenic drugs: affinity for muscarinic cholinergic receptor sites in the brain predicts extrapyramidal effects. J Psychiatr Res. 1974; 11:91-5. [PubMed 4156796]
162. Nair NPV, Zicherman V, Schwartz G. Dopamine and schizophrenia: a reappraisal in light of clinical studies with clozapine. Can Psychiatr Assoc J. 1977; 22:285-93. [PubMed 21741]
163. Kirkegaard A, Jensen A. An investigation of some side effects in 47 psychotic patients during treatment with clozapine and discontinuing of the treatment. Arzneimittelforschung. 1979; 29:851-8. [PubMed 40576]
164. Snyder SH, Banerjee SP, Yamamura HI et al. Drugs, neurotransmitters, and schizophrenia. Science. 1974; 184:1243-53. [PubMed 17784215]
165. Burki HR, Eichenberger E, Sayers AC et al. Clozapine and the dopamine hypothesis of schizophrenia, a critical appraisal. Pharmakopsychiatr Neuro-Psychopharmakol. 1975; 8:115-21.
166. Grohmann R, Ruther E, Sassim N et al. Adverse effects of clozapine. Psychopharmacology. 1989: 99(Suppl):S101-4.
167. Kalow W. Genetic variaitons in the human cytochrome P-450 system. Eur J Clin Pharmacol. 1987; 31:633-41. [IDIS 228825] [PubMed 3549324]
168. Kalow W. Ethnic differences in drug metabolism. Clin Pharmacokinet. 1982; 7:373-400. [IDIS 158518] [PubMed 6754206]
169. Roubicek J, Major I. EEG profile and behavioral changes after a single dose of clozapine in normals and schizophrenics. Biol Psychiatr. 1977; 12:613-4.
170. Chiodo LA, Bunney BS. Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons. J Neoroscience. 1985; 5:2539-44.
171. Ackenheil VM, Brau H, Burkhart A et al. Antipsychotische Wirksamkeit im Verhaltnis zum Plasmaspiegel von Clozapin. (German; with English abstract.) Arzneim-Forsch. 1976; 26:1156-8.
172. Claghorn JL, Abuzzahab FS, Wang R et al. The current status of clozapine. Psychopharmacol Bull. 1983; 19:138-40.
173. Perenyi A, Kuncz E, Bagdy G. Early relapse after sudden withdrawal or dose reduction of clozapine. Psychopharmacology. 1985; 86:244. [PubMed 3927364]
174. Eklund K. Supersensitivity and clozapine withdrawal. Psychopharmacology. 1987; 91:135. [PubMed 3103155]
175. Richelson E, Nelson A. Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro. Eur J Pharmacol. 1984; 103:197-204. [PubMed 6149136]
176. Schmauss M, Wolff R, Erfurth A et al. Tolerability of long term clozapine treatment. Psychopharmacology. 1989; 99(Suppl):S105-8. [PubMed 2813663]
177. Haller E, Binder RL. Clozapine and seizures. Am J Psychiatry. 1990; 147:1069-71. [IDIS 269586] [PubMed 2375443]
178. Burki HR, Ruch W, Asper H et al. Pharmakologische und neurochemische Wirkungen von Clozapin: neue Gesichtspunkte in der medikamentosen Behandlung der Schizophrenie. (German; with English abstract.) Schweiz Med Wochenschr. 1973; 103:1716-24.
179. Meltzer HY, Goode DJ, Schyve PM et al. Effect of clozapine on human serum prolactin levels. Am J Psychiatry. 1979; 136:1550-5. [IDIS 107610] [PubMed 507205]
180. Chiodo SA, Bunney BS. Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neuroscience. 1983; 3:1607-19.
181. Barrett N, Ormiston S, Molyneux V. Clozapine: a new drug for schizophrenia. J Psychosocial Nurs. 1990; 28:24-8.
182. Pi EH, Simpson GM. Atypical neuroleptics: clozapine and the benzamides in the prevention and treatment of tardive dyskinesia. Mod Probl Pharmacopsychiat. 1983; 21:80-6.
183. Crome P. Poisoning due to tricyclic antidepressant overdosage: clinical presentation and treatment. Med Toxicol. 1986; 1:261-5. [IDIS 222612] [PubMed 3537621]
184. Small JG, Milstein V, Small IF et al. Computerized EEG profiles of haloperidol, chlorpromazine and placebo in treatment resistant schizophrenia. Clin Encephalogr. 1987; 18:124-35.
185. Meltzer HY, Nash JF, Koenig JI. Clozapine: neuroendocrine studies of an atypical neuroleptic. Clin Neuropharmacol. 1986; 9(Suppl 4):316-8. [PubMed 2882843]
186. Thorup M, Fog R. Clozapine treatment of schizophrenic patients: plasma concentration and coagulation factors. Acta Psychiatr Scand. 1977; 55:123-6. [PubMed 842385]
187. Kuha S, Miettinen E. Long-term effect of clozapine in schizophrenia: a retrospective study of 108 schizophrenic patients treated with clozapine for up to 7 years. Nord Psykiat T. 1986; 40:225- 30.
188. Sassim N, Grohmann R. Adverse drug reactions with clozapine and simultaneous application of benzodiazepines. Pharmacopsychiatry. 1988; 21:306-7. [PubMed 2907633]
189. Hemphill RE, Pascoe FD, Zabow T. Clozapine (Leponex) in psychiatric treatment. S Afr Med J. 1974; 48:2168. [IDIS 47805] [PubMed 4428299]
190. Herrera JM, Costa J, Sramek J et al. Clozapine in refractory schizophrenics: preliminary findings. Schizophrenia Res. 1988; 1:305-6.
191. Zapletalek M, Preiningerova O, Pazdirek S et al. Dlouhodoba lecba psychoz schizofrenniho okruhu clozapinem a vyznam vedlejsich priznaku. (Czech; with English abstract.) Cesk Psychiatr. 1977; 73:73-80.
192. Ichikawa J, Meltzer HY. The effect of chronic clozapine and haloperidol on basal dopamine release and metabolism in rat striatum and nucleus accumbens studied by in vivo microdialysis. Eur J Pharmacol. 1990; 176:371-4. [PubMed 2184042]
193. Bernardi F, Del Zompo M. Clozapine in idiopathic Parkinson’s disease. Neurology. 1990; 40:1151. [IDIS 269206] [PubMed 2393440]
194. Friedman JH, Lannon MC. Clozapine in idiopathic Parkinson’s disease. Neurology. 1990; 40:1151-2. [IDIS 269206] [PubMed 2393440]
195. Blum A. Triad of hyperthermia, increased REM sleep, and cataplexy during clozapine treatment? J Clin Psychiatry. 1990; 51:259-60. Letter.
196. Dick P, Remy M, Rey-Bellet JJ. Essai de comparaison de deux antipsychotiques: la chlorpromazine et la clozapine. (French; with English abstract.) Ther Umsch. 1972; 32:497-500.
197. Pere JJ, Chaumet-Riffaud D. Clozapine et schizophrenie resistante. (French; with english abstract.) Encephale. 1990; 16:143-5.
198. Rao TS, Cler JA, Oei EJ et al. Increased release of dopamine in vivo by BMY-14802: contrasting pattern to clozapine. Neuropharmacology. 1990; 29:503-6. [PubMed 1972552]
199. Sternberg DE. Neuroleptic malignant syndrome: the pendulum swings. Am J Psychiatr. 1986; 143:1273-5. [PubMed 2876648]
200. Pope HG Jr, Keck PE Jr, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatr. 1986; 143:1227-33. [IDIS 222098] [PubMed 2876647]
201. Anon. Neuroleptic malignant syndrome. Lancet. 1984: 545-6. Editorial.
202. Guze BH, Baxter LR Jr. Neuroleptic malignant syndrome. N Engl J Med. 1985; 313: 163-4. [IDIS 201909] [PubMed 3892294]
203. Sangal R, Dimitrijevic R. Neuroleptic malignant syndrome: successful treatment with pancuronium. JAMA. 1985; 254:2795-6. [IDIS 206401] [PubMed 4057490]
204. Szabadi E. Neuroleptic malignant syndrome. BMJ. 1984; 288:1399-400. [PubMed 6144347]
205. Pearlman CA. Neuroleptic malignant syndrome: a review of the literature. J Clin Psychopharmacol. 1986; 6:257-73. [IDIS 221955] [PubMed 2877012]
206. Harpe C, Stoudemire A. Aetiology and treatment of neuroleptic malignant syndrome. Med Toxicol Adverse Drug Exp. 1987; 2:166-76.
207. Henderson VW, Wooten GF. Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology. 1981; 31:132-7.
208. McCarron MM, Boettger ML, Peck JJ. A case of neuroleptic malignant syndrome successfully treated with amantadine. J Clin Psychiatry. 1082; 43:381-2.
209. Ayd FJ Jr. Neuroleptic malignant syndrome: new therapies. Int Drug Therapy Newsl. 1983; 18:10-2.
210. Smego RA Jr, Durack DT. The neuroleptic malignant syndrome. Arch Intern Med. 1982; 142:1183-5. [IDIS 151955] [PubMed 6124221]
211. Addonizio G, Susman VL, Roth SD. Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients. Am J Psychiatry. 1986; 143:1587- 90. [IDIS 224200] [PubMed 3789214]
212. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gilman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Macmillan Publishing Company; 1990:387-404.
213. Anon. Clozaril concomitant use with benzodiazepines. 1991; 53(Aug 5):T&G-6.
214. Stock B, Spiteller G, Heipertz R. Austausch aromatisch gebundenen Halogens gegen OH- und SCH3- bei der Metabolisierung des Clozapins im menschlichen Körper. Arzneimittelforschung. 1977; 27:982-90. [PubMed 577884]
215. Lipsitz L. Orthostatic hypotension in the elderly. N Engl J Med. 1989; 321:952-7. [IDIS 259578] [PubMed 2674714]
216. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med. 1989; 321:303-9. [IDIS 257650] [PubMed 2664519]
217. Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs; proposed addition of “geriatric use” subsection in the labeling; proposed rule. Fed Regist. 1990; 55:46134-7.
218. Crismon ML, Ereshefsky L, Sakland SR. A comparison of clozapine absorption in the postprandial versus fasting states. Pharm Res. 1988; 10:S171.
219. Choc MG, Hsuan F, Honigfeld G. Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients. Pharm Res. 1990; 7:347-51. [PubMed 2194198]
220. Hartvig P, Eckernas SA, Lindstrom L et al. Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET). Psychopharmacology (Berl). 1986; 89:248-52. [PubMed 3088645]
221. Salzman C. Mandatory monitoring of side effects the “bundling” of clozapine. N Engl J Med. 1990; 323:827-9. [IDIS 270546] [PubMed 2392135]
222. Zellmer WA. An unsavory concoction. Am J Hosp Pharm. 1990; 47:783. [PubMed 2321652]
223. Stimmel GL. Schizophrenia. In: Herfindal ET, Gourley DR, Hart LL, eds. Clinical Pharmacy and Therapeutics. 4th ed. Baltimore, MD; Williams & Wilkins: 1988:639-51.
224. Ereshefsky L, Richards A. Psychoses. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. Vancouver, BC: Applied Therapeutics, Inc; 1988:1189-230.
225. Meltzer HY, Bastani B, Kwon KY et al. A prospective study of clozapine in treatment-resistant schizophrenic patients. I. Preliminary report. Psychopharmacology. 1989; 99(Suppl):S68-72. [PubMed 2813667]
226. Meltzer HY. Clozapine and electroconvulsive therapy. Arch Gen Psychiatry. 1990; 47:291. [PubMed 2306170]
227. Meltzer HY, Burnett S, Bastani B et al. Effects of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Community Psychiatry. 1990; 41:892-7. [PubMed 2401480]
228. Gosselin RE, Smith RP, Hodge HC et al. Clinical toxicology of commercial products. 5th ed. Baltimore: The Williams and Wilkins Co; 1984:III-205-13.
229. Goldfrank LR, Lewin NA, Flomenbaum NE et al. Psychotropics. Antidepressants: tricyclics, tetracyclics, monoamine oxidase inhibitors, and others. In: Goldfrank LR, Flomenbaum NE, Lewin NA et al, eds. Goldfrank’s toxicologic emergencies. 3rd ed. Norwalk, CT: Appleton-Century-Crofts; 1986:351-9.
230. Lieberman JA, Yunis J, Egea E et al. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry. 1990; 47:945-8. [IDIS 273624] [PubMed 2222133]
231. Borison RL, Shah C, Shelhorse M et al. Clinical pharmacology of clozapine. Pharmacologist. 1984; 26:179.
232. Ackenheil M, Blatt B, Lampart C. Biochemical changes in man and animals following clozapine treatment. J Pharmacol. 1974; 5(Suppl 2):1.
233. Murray AM, Waddington JL. Behavioral indices of the interaction of clozapine with D1 and D2 dopamine receptors. Br J Pharmacol. 1989; 98(Suppl):814P. [PubMed 2611521]
234. Anon. Clozapine-induced seizures. Int Drug Ther Newsl. 1990; 25:37-8.
235. Lovdahl MJ, Perry PJ, Miller DD. The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography. Ther Drug Monitor. 1991; 13:69-72.
236. Perry PJ, Miller DD, Arndt SV et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry. 1991; 148:231-5. [IDIS 277490] [PubMed 1670979]
237. Baldessarini RJ, Frankenburg FR. Clozapine: a novel antipsychotic agent. N Engl J Med. 1991; 324: 746-54. [IDIS 278680] [PubMed 1671793]
238. Haring C, Fleischhacker WW, Schett P et al. Influence of patient-related variables on clozapine plasma levels. Am J Psychiatry. 1990; 147:1471-5. [IDIS 273444] [PubMed 2221158]
239. Wirshing WC, Phelan CK, Van Putten T et al. Effects of clozapine on treatment-resistant akathisia and comcomitant tardive dyskinesia. Am J Psychopharmacol. 1990; 10:371-3.
240. Van Putten T, Wirshing WC, Marder S. Tardive Meige syndrome responsive to clozapine. Am J Psychopharmacol. 1990; 10:381-2.
241. Leadbetter RA, Vieweg V. Clozapine-induced weight gain. Am J Psychiatry. 1990; 147:1693-4.
242. Carson WH, Forbes RA. Clozapine-induced weight gain. Am J Psychiatry. 1990; 147:1694. [IDIS 275582] [PubMed 2244654]
243. Cohen S, Chiles J, MacNaughton A. Clozapine-induced weight gain. Am J Psychiatry. 1990; 147:1694. [IDIS 275582] [PubMed 2244654]
244. Cold JA, Wells BG, Froemming JH. Seizure activity associated with antipsychotic therapy. DICP. 1990; 24:601-6. [IDIS 266815] [PubMed 1972826]
245. Meltzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl). 1989; 99(Suppl):S18-27.
246. Carvey PM, Nath ST, Kao LC et al. Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm. Eur J Pharmacol. 1990; 184:43-53. [PubMed 2209714]
247. Watling KJ, Beer MS, Stanton JA et al. Interaction of the atypical neuroleptic clozapine with 5-HT3 receptors in the cerebral cortex and superior cervical ganglion of the rat. Eur J Pharmacol. 1990; 182:465-72. [PubMed 1977590]
248. Invernizzi R, Morali F, Pozzi L et al. Effects of acute and chronic clozapine on dopamine release and metabolism in the striatum and nucleus accumbens of conscious rats. Br J Pharmacol. 1990; 100:774-8. [PubMed 2207499]
249. O’Dell SJ, La Hoste GJ, Widmark CB et al. Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain. Synapse. 1990; 6:146-53. [PubMed 2237777]
250. Uehlinger C, Baumann P. Clozapine as an alternative treatment for neuroleptic-induced gynecomastia. Am J Psychiatry. 1990; 148:392-3.
251. Friedman JH. Clozapine and the mandatory monitoring system. N Engl J Med. 1991; 324:491. [IDIS 279829] [PubMed 1703281]
252. Chiles JA, Cohn S, McNaughton A. Dropping objects: possible mild cataplexy associated with clozapine. J Nerv Ment Dis. 1990; 178:663-4. [PubMed 2230752]
253. Hamilton D. Clozapine: a new antipsychotic drug. Arch Psychiatr Nurs. 1990; 4:278-81. [PubMed 2241248]
254. Sajatovic M, Verbanac P, Ramirez LF et al. Clozapine treatment of psychiatric symptoms resistant to neuroleptic treatment in patients with Huntington’s chorea. Neurology. 1991; 41:156. [IDIS 276720] [PubMed 1670739]
255. Ryan PM. Epidemiology, etiology, diagnosis, and treatment of schizophrenia. Am J Hosp Pharm. 1991; 48:1271-80. [PubMed 1677528]
256. Fitton A, Heel RC. Clozapine: a review of its pharmacological properties, and therapeutic use in schizophrenia. Drugs. 1990; 40:722-47. [PubMed 2292234]
257. Bartholini G. Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic system. J Pharm Pharmacol. 1976; 28:429-33. [PubMed 6752]
258. Westerink BH, Korf J. Regional rat brain levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid: concurrent fluorometric measurement and influence of drugs. Eur J Pharmacol. 1976; 38:281-91. [PubMed 954842]
259. Zivkovic B, Guidotti A, Revuelta A et al. Effect of thioridazine, clozapine and other antipsychotics on the kinetic state of tyrosine hydroxylase and on the turnover rate of dopamine in striatum and nucleus accumbens. J Pharmacol Exp Ther. 1975; 194:37-46. [PubMed 239221]
260. Wilk S, Glick SD. Dopamine metabolism in the nucleus accumbens: the effect of clozapine. Eur J Pharmacol. 1976; 37:203-6. [PubMed 1278242]
261. Westerink BH, Korf J. Influence of drugs on striatal and limbic homovanillic acid concentration in the rat brain. Eur J Pharmacol. 1975; 33:31-40. [PubMed 126169]
262. Sanger DJ. The effects of clozapine on shuttle-box avoidance responding in rats: comparisons with haloperidol and chlordiazepoxide. Pharmacol Biochem Behav. 1985; 23:231-6. [PubMed 4059310]
263. Farde L, Wiesel FA, Nordstrom AL et al. D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology. 1989; 99(Suppl):S28-31. [PubMed 2573104]
264. Rebec GV, Alloway KD, Bashore T. Differential actions of classical and atypical antipsychotic drugs on spontaneous neuronal activity in the amygdaloid complex. Pharmacol Biochem Behav. 1981; 14:49-56. [PubMed 6110210]
265. Rebec GV, Anderson GD. Regional neuropharmacology of the antipsychotic drugs: implications for the dopamine hypothesis of schizophrenia. Behav Assessment. 1986; 8:11-29.
266. Anderson GD, Rebec GV. Clozapine and haloperidol in the amygdaloid complex: differential effects on dopamine transmission with long-term treatment. Biol Psychiatry. 1988; 23:497-506. [PubMed 2830920]
267. Halperin R, Guerin JJ, Davis KL. Regional differences in the induction of behavioral supersensitivity by prolonged treatment with atypical neuroleptics. Psychopharmacology. 1989; 98:386-91. [PubMed 2568659]
268. Fischer PA, Baas H, Hefner R. Treatment of parkinsonian tremor with clozapine. J Neural Transm Park Dis Dement Sect. 1990; 2:233-8. [PubMed 2257063]
269. Schott K, Ried S, Stevens I et al. Neuroleptically induced dystonia in Huntington’s disease: a case report. Eur Neurol. 1989; 29:39-40. [PubMed 2523309]
270. Susic V, Kovacevic R, Momirov D et al. Effects of clozapine (Leponex) on sleep patterns in the cat. Arch Int Physiol Biochim. 1977; 85:455- 9. [PubMed 72523]
271. Ruch W, Asper H, Burki HR. Effect of clozapine on the metabolism of serotonin in rat brain. Psychopharmacologia. 1976; 46:103-9. [PubMed 1257359]
272. Touyz SW, Saayman GS, Zabow T. A psychophysiological investigation of the long-term effects of clozapine upon sleep patterns of normal young adults. Psychopharmacology. 1978: 56:69-73.
273. Friedman JH, Lannon MC. Clozapine-responsive tremor in Parkinson’s disease. Mov Dis. 1990; 5:225-9.
274. Müller P, Heipertz R. Zur Behandlung manischer Psychosen mit Clozapin. (German; with English abstract.) Fortschr Neurol Psychiatr Ihrer Grenzgeb. 1977; 45:420-4.
275. Doepp S, Buddeberg C. Extrapyramidale Symptome unter Clozapin. Nervenarzt. 1975; 46:589-90. [PubMed 811999]
276. Schyve PM, Smithline F, Meltzer HY. Neuroleptic-induced prolactin level elevation and breast cancer: an emerging clinical issue. Arch Gen Psychiatry. 1978; 35:1291-1301. [PubMed 30426]
277. Ingram DM, Nottage EM, Roberts AN. Prolactin and breast cancer risk. Med J Aust. 1990; 153:469-73. [PubMed 2215338]
278. Meyer F, Brown JB, Morrison AS et al. Endogenous sex hormones, prolactin, and breast cancer in premenopausal women. J Natl Cancer Inst. 1986; 77:613-6. [PubMed 3462404]
279. Wang DY, Sturzaker HE, Kwa HG et al. Nyctohemeral changes in plasma prolactin levels and their relationship to breast cancer risk. Int J Cancer. 1984; 33:629-32. [PubMed 6724738]
280. Braden NJ, Jackson JE, Walson PD. Tricyclic antidepressant overdose. Ped Clin North Am. 1986; 33:287-98.
281. Public Citizen Health Research Group. Citizen’s petition to Food and Drug Administration for Dear Doctor Letter and box warning on clozapine regarding risk of respiratory arrest. Washington, DC; 1991 May 29.
282. Robins. Quinidex Extentabs prescribing information. In: Barnhart ER, publisher. Physicians’ desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc; 1991:1805-6.
283. Parke-Davis. Procan SR prescribing information. In: Barnhart ER, publisher. Physicians’ desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc; 1991:1690-2.
284. DasGupta K, Young A. Clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry. 1991; 52:105-7. [IDIS 279874] [PubMed 2005072]
285. Miller DD. Effect of phenytoin on plasma clozapine concentrations in two patients. J Clin Psychiatry. 1991; 52:23-5. [IDIS 277386] [PubMed 1988414]
286. Goumeniouk AD, Ancill RJ, MacEwan GW et al. A case of drug-drug interaction involving clozapine. Can J Psychiatry. 1991; 36:234-5. [PubMed 1829392]
287. Iamperato A, Di Chiara G. Dopamine release and metabolism in awake rats after systemic neuroleptics as studied by trans-striatal dialysis. J Neurosci. 1985; 5:297-306. [PubMed 2857776]
288. Van Tol HH, Bunzow JR, Guan HC et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991; 350:610-4. [PubMed 1840645]
289. Sunahara RK, Guan HC, O’Dowd BF et al. Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature. 1991; 350:614-9. [PubMed 1826762]
290. Sokoloff P, Giros B, Martres MP et al. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990; 347:146-51. [PubMed 1975644]
291. Anon. Now we understand antipsychotics? Lancet. 1990; 336:1222-3. Editorial.
292. Reviewers’ comments (personal observations); 1991 Sep.
293. Chen JP, Paredes W, Gardner EL. Chronic treatment with clozapine selectively decreases basal dopamine release in nucleus accumbens but not in caudate-putamen as measured by in vivo brain microdialysis: further evidence for depolarization block. Neurosci Lett. 1991; 122:127-31. [PubMed 2057129]
294. Blaha CD, Lane RF. Chronic treatment with classical and atypical antipsychotic drugs differentially decreases dopamine release in striatum and nucleus accumbens in vivo. Neurosci Lett. 1987; 78:199-204. [PubMed 2888060]
295. Cohen BM, Keck PE, Satlin A et al. Prevalence and severity of akathisia in patients on clozapine. Biol Psychiatry. 1991; 29:1215-9. [PubMed 1888803]
296. Friedman LJ, Tabb SE, Worthington JJ et al. Clozapine—a novel antipsychotic agent. N Engl J Med. 1991; 325:518. [IDIS 284066] [PubMed 1852187]
297. Finkel MJ, Schwimmer JL. Clozapine—a novel antipsychotic agent. N Engl J Med. 1991; 325: 518-9.
298. Lieberman JA, Saltz BL, Johns CA et al. The effects of clozapine on tardive dyskinesia. Br J Psychiatry. 1991; 158:503-10. [PubMed 1675900]
299. Anderson ES, Powers PS. Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry. 1991; 52:102-4. [IDIS 279873] [PubMed 2005071]
300. Miller DD, Sharafuddin MJ, Kathol RG. A case of clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry. 1991; 52:99-101. [IDIS 279872] [PubMed 1672311]
301. Black JL, Richelson E, Richardson JW. Antipsychotic agents: a clinical update. Mayo Clin Proc. 1985; 60:777-89. [IDIS 207076] [PubMed 2865413]
302. Frankenburg F, Baldessarini RJ. Clozapine—a novel antipsychotic agent. N Engl J Med. 1991; 325:518. [IDIS 284066] [PubMed 1852187]
303. Gerson SL, Lieberman JA, Friedenberg WR et al. Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet. 1991; 338:262. [IDIS 283646] [PubMed 1676820]
304. Nair NP, Lal S, Cervantes P et al. Effect of clozapine on apomorphine-induced growth hormone secretion and serum prolactin concentrations in schizophrenia. Neuropsychobiology. 1979; 5:136-42. [PubMed 431802]
305. Sandoz Pharmaceuticals, East Hanover, NJ: Personal Communication.
306. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2004; 161(Suppl):1-56.
307. van de Loosdrecht AA, Faber HJ, Hordijk P et al. Clozapine-induced agranulocytosis: a case report. Immunopathophysiological considerations. Neth J Med. 1998; 52:26-9. [PubMed 9573739]
308. Sperner-Unterweger B, Czeipek I, Gaggl S et al. Treatment of severe clozapine-induced neutropenia with granulocyte colony-stimulating factor (G-CSF): remission despite continuous treatment with clozapine. Br J Psychiatry. 1998; 172:82-4. [IDIS 403045] [PubMed 9534838]
309. Rudolf J, Grond M, Neveling M et al. Clozapine-induced agranulocytosis and thrombopenia in a patient with dopaminergic psychosis. J Neural Transm. 1997; 104:1305-11. [PubMed 9503276]
310. Wickramanayake PD, Scheid C, Josting A et al. Use of granulocyte colony-stimulating factor (filgrastim) in the treatment of non-cytotoxic drug-induced agranulocytosis. Eur J Med Res. 1995; 18:153-6.
311. Chin-Yee I, Bezchlibnyk-Butler K, Wong L. Use of cytokines in clozapine-induced agranulocytosis. Can J Psychiatry. 1996; 41:280-4. [PubMed 8793147]
312. Chengappa KN, Gopalani A, Haught MK et al. The treatment of clozapine-associated agranulocytosis with granulocyte colony-stimulating factor (G-CSF). Psychopharmacol Bull. 1996; 32:111-21. [PubMed 8927660]
313. van Melick EJ, Touw DJ, Haak HL. [Agranulocytosis caused by clozapine: the importance of leukocyte monitoring and efficacy of hematopoietic growth factors.] (Dutch; with English abstract.) Ned Tijdschr Geneeskd. 1995; 139:2437-40.
314. Gerson SL. G-CSF and the management of clozapine-induced agranulocytosis. J Clin Psychiatry. 1994; 55(Suppl B):139-42. [IDIS 338558] [PubMed 7525542]
315. Gullion G, Yeh HS. Treatment of clozapine-induced agranulocytosis with recombinant granulocyte colony-stimulating factor. J Clin Psychiatry. 1994; 55:401-5. [IDIS 338333] [PubMed 7523362]
316. Nielsen H. Recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) treatment of clozapine-induced agranulocytosis. J Intern Med. 1993; 234:529-31. [IDIS 321935] [PubMed 7693847]
317. Barnas C, Zwierzina H, Hummer M et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry. 1992; 53:245-7. [IDIS 299873] [PubMed 1639744]
318. Zenith Goldline Pharmaceuticals. Clozapine tablets prescribing information. Miami, FL; 1999 Feb.
319. Sandoz Pharmaceuticals. Clozaril (clozapine) prescribing information. East Hanover, NJ; 1991 Apr 15.
320. Taylor D. Pharmacokinetic interactions involving clozapine. B J Psychiatry. 1997; 171:109-12.
321. Carbamazepine interactions: clozapine (Clozaril). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 2000:197.
322. McClellan J, Werry J, the Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry. 2001; 40(Suppl 7): 4-23S.
323. Kumra S, Frazier JA, Jacobsen LK et al. Childhood-onset schizophrenia. Arch Gen Psychiatry. 1996; 53:1090-7. [IDIS 378551] [PubMed 8956674]
324. Bess AL, Cunningham SR. Dear health care provider letter regarding important labeling changes Clozaril. East Hanover, NJ: Novartis; 2002 Feb
325. Gerson SL, Arce C. N-desmethylclozapine: a clozapine metabolite that suppresses haemopoiesis. Br J Haematol. 1994; 86:555-61. [PubMed 8043437]
326. Piscitelli SC, Frazier JA, McKenna K. Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. J Clin Psychiatry. 1994; 55(Suppl B):94-7. [IDIS 338546] [PubMed 7961584]
327. Meltzer HY, Alphs L, Green AI et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003; 60:82-91. [IDIS 491656] [PubMed 12511175]
328. Anon. Clozaril shows effect on suicidality, not definitive superiority to Zyprexa. F-D-C Rep. 2002; 64:27-8.
329. Food and Drug Administration. Review and evaluation of clinical data for clozapine for suicidality. NDA No. 19-758/S-047. Rockville, MD: 2002 Aug 1.
330. Garcia G, Crismon ML, Dorson PG. Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol. 1994; 14:426-8 [IDIS 340027] [PubMed 7884026]
331. Eli Lilly and Company. Zyprexa (olanzapine) tablets and Zyprexa Zydis (olanzapine) orally disintegrating tablets prescribing information. Indianapolis, IN; 2003 Sep 16.
332. Eli Lilly and Company. Lilly announces FDA notification of class labeling for atypical antipsychotics regarding hyperglycemia and diabetes. Indianapolis, IN; 2003 Sep 17. Press release.
333. Cunningham F, Lambert B, Miller DR et al. Antipsychotic induced diabetes in veteran schizophrenic patients. In: Abstracts of the 1st International Conference on Therapeutic Risk Management and 19th International Conference on Pharmacoepidemiology, Philadelphia, PA; 2003 Aug 21-24. Pharmacoepidemiol Drug Saf. 2003; 12(suppl 1): S154-5.
334. Otsuka America Pharmaceutical, Inc. Abilify (aripiprazole) tablets prescribing information. Rockville, MD; 2004 Sep.
335. AstraZeneca Pharmaceuticals. Seroquel (quetiapine fumarate) tablets prescribing information. Wilmington, DE; 2004 Jul.
336. Janssen Pharmaceutica. Risperdal (risperidone) tablets and oral solution prescribing information. Titusville, NJ; 2003 Oct.
337. Pfizer Inc. Geodon (ziprasidone) prescribing information. New York, NY; 2004 Aug.
338. Lewis-Hall F. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Princeton, NJ: Bristol-Myers Squibb Company; 2004 Mar 25. From FDA website.
339. Bess AL, Cunningham SR. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004 Apr 1. From the FDA website.
340. Eisenberg P. Dear health care professional letter regarding safety data on Zyprexa (olanzapine) – hyperglycemia and diabetes. Indianapolis, IN: Eli Lilly and Company; 2004 Mar 1. From the FDA website.
341. Macfadden W. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Wilmington, DE: AstraZeneca Pharmaceuticals; 2004 Apr 22. From the FDA website.
342. Mahmoud RA. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Titusville, NJ: Janssen Pharmaceutica, Inc; 2004. From the FDA website.
343. Clary CM. Dear health care practitioner letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. New York NY: Pfizer Global Pharmaceuticals; 2004 Aug. From the FDA website.
344. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity.. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004; 27:596-601. [PubMed 14747245]
345. Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics. Drugs. 2004; 64:701-23. [PubMed 15025545]
346. Citrome LL, Jaffe AB. Relationship of atypical antipsychotics with development of diabetes mellitus. Ann Pharmacother. 2003; 37:1849-57. [IDIS 510453] [PubMed 14632602]
347. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161(Suppl):1-56.
348. Sumiyoshi T, Roy A, Anil AE et al. A comparison of incidence of diabetes mellitus between atypical antipsychotic drugs. J Clin Psychopharmacol. 2004; 24:345-8. [IDIS 515736] [PubMed 15118492]
349. Expert Group. ’Schizophrenia and Diabetes 2003’ expert consensus meeting, Dublin, 3–4 October 2003: consensus summary. Br J Psychiatry. 2004; 47(Suppl):S112-4.
350. Marder SR, Essock SM, Miller AL et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry. 2004; 161:1334-49. [IDIS 520856] [PubMed 15285957]
351. Holt RI. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2086-7. [IDIS 524618] [PubMed 15277449]
352. Citrome L, Volavka J. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2087-8. [IDIS 524619] [PubMed 15277450]
353. Isaac MT, Isaac MB. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2088. [IDIS 524620] [PubMed 15277451]
354. Boehm G, Racoosin JA, Laughren TP et al. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2088-9. [IDIS 524621] [PubMed 15277452]
355. Barrett EJ. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to Holt, Citrome and Volevka, Isaac and Isaac, and Boehm et al. Diabetes Care. 2004; 27:2089-90.
356. Fuller MA, Shermock KM, Secic M et al. Comparative study of the development of diabetes mellitus in patients taking risperidone and olanzapine. Pharmacotherapy. 2002; 23:1037-43.
357. Koller EA, Cross JT, Doraiswamy PM et al. Risperidone-associated diabetes mellitus: a pharmacovigilance study. Pharmacotherapy. 2003; 23:735-44. [IDIS 498493] [PubMed 12820816]
358. Koller EA, Weber J, Doraiswamy PM et al. A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus. J Clin Psychiatry. 2004; 65:857-63. [IDIS 518849] [PubMed 15291665]
359. Ananth J, Johnson KM, Levander EM et al. Diabetic ketoacidosis, neuroleptic malignant syndrome, and myocardial infarction in a patient taking risperidone and lithium carbonate. J Clin Psychiatry. 2004; 65:724. [IDIS 516345] [PubMed 15163265]
360. Torrey EF, Swalwell CI. Fatal olanzapine-induced ketoacidosis. Am J Psychiatry. 2003; 160:2241. [IDIS 516756] [PubMed 14638601]
361. Wehring HJ, Kelly DL, Love RC et al. Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry. 2003; 160:2241-2. [IDIS 516757] [PubMed 14638600]
362. Koro CE, Fedder DO, L’Italien GJ et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ. 2002; 325:243. [IDIS 485916] [PubMed 12153919]
363. Citrome LL. Efficacy should drive atypical antipsychotic treatment. BMJ. 2003; 326:283. [IDIS 492968] [PubMed 12561827]
364. Anon. Which atypical antipsychotic for schizophrenia?. Drug Ther Bull. 2004; 42:57-60. [PubMed 15310154]
365. Anon. Atypical antipsychotics and hyperglycaemia. Aust Adv Drug React Bull. 2004; 23:11-2.
366. Sussman N. The implications of weight changes with antipsychotic treatment. J Clin Psychopharmacol. 2003; 23 (Suppl 1):S21-6.
367. Gianfrancesco F, Grogg A, Mahmoud R et al. Differential effects of antipsychotic agents on the risk of development of type 2 diabetes mellitus in patients with mood disorders. Clin Ther. 2003; 25:1150-71. [IDIS 497269] [PubMed 12809963]
368. Bushe C, Leonard B. Association between atypical antipsychotic agents and type 2 diabetes: review of prospective clinical data. Br J Psychiatry Suppl. 2004; 47:S87-93. [PubMed 15056600]
369. Cavazzoni P, Mukhopadhyay N, Carlson C et al. Retrospective analysis of risk factors in patients with treatment-emergent diabetes during clinical trials of antipsychotic medications. Br J Psychiatry Suppl. 2004; 47:s94-101. [PubMed 15056601]
370. Gianfrancesco FD, Grogg AL, Mahmoud RA et al. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry. 2002; 63:920-30. [IDIS 488480] [PubMed 12416602]
371. Etminan M, Streiner DL, Rochon PA. Exploring the association between atypical neuroleptic agents and diabetes mellitus in older adults. Pharmacotherapy. 2003; 23:1411-15. [IDIS 510498] [PubMed 14620387]
372. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry. 2004; 161:1709-11. [IDIS 522186] [PubMed 15337666]
373. Sernyak MJ, Leslie DL, Alarcon RD et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry. 2002; 159:561-6. [IDIS 494206] [PubMed 11925293]
374. Geller WK, MacFadden W. Diabetes and atypical neuroleptics. Am J Psychiatry. 2003; 160:388. [IDIS 513919] [PubMed 12562601]
375. Gianfrancesco FD. Diabetes and atypical neuroleptics. Am J Psychiatry. 2003; 160:388-9; author reply 389. [IDIS 513920] [PubMed 12562599]
376. Lamberti JS, Crilly JF, Maharaj K. Prevalence of diabetes mellitus among outpatients with severe mental disorders receiving atypical antipsychotic drugs. J Clin Psychiatry. 2004; 65:702-6. [IDIS 516341] [PubMed 15163259]
377. Lee DW, Fowler RB. Olanzapine/risperidone and diabetes risk. J Clin Psychiatry. 2003; 64:847-8; author reply 848. [IDIS 500324] [PubMed 12934988]
378. Bristol-Myers Squibb, Princeton, NJ: Personal communication.
379. AstraZeneca, Wayne, PA: Personal communication.
380. Eli Lilly and Company, Indianapolis, IN: Personal communication.
381. Novartis Pharmaceuticals Corporation, East Hanover, NJ: Personal communication.
382. Janssen Pharmaceuticals, Titusville, NJ: Personal communication.
383. Citrome LL. The increase in risk of diabetes mellitus from exposure to second generation antipsychotic agents. Drugs Today (Barc). 2004; 40:445-64. [PubMed 15319799]
384. Citrome L, Jaffe A, Levine J et al. Relationship between antipsychotic medication treatment and new cases of diabetes among psychiatric inpatients. Psychiatr Serv. 2004; 55:1006-13. [PubMed 15345760]
385. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website.
386. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. 1982; 24:1 2. [PubMed 7054648]
387. Alamo Pharmaceuticals. Fazaclo (clozapine) prescribing information. Beverly Hills, CA; 2004 May.
388. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA. 1985; 254:400 2. [IDIS 202002] [PubMed 2861297]
389. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm. 1984; 9:26,28 30.
390. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist. 1983; 48:54993 5.
391. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376 82.
392. Food and Drug Administration. Alert for healthcare professionals: clozapine (marketed as clozaril). Rockville, MD; undated. From the FDA website.
a. Ivax Pharmaceuticals. Clozapine tablets prescribing information. Miami, FL; 2004 Jan.
b. Bess AL, Cunningham SR. Dear health care provider letter regarding hyperglycemia and diabetes mellitus in patients receiving atypical antipsychotics (e.g., Clozaril). East Hanover, NJ: Novartis; 2004 Apr.
c. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website.
d. Eli Lilly and Company. Zyprexa (olanzapine) tablets, Zyprexa Zydis (olanzapine) orally disintegrating tablets, and Zyprexa intramuscular (olanzapine) for injection prescribing information. Indianapolis, IN; 2005 Apr 14.
e. Novartis Pharmaceuticals. Clozaril (clozapine) prescribing information. East Hanover, NJ; 2005 May.
f. Bess AL, Cunningham SR. Dear health care provider letter regarding revised prescribing information for Clozaril tablets. East Hanover, NJ: Novartis; 2005 Dec.
g. Alamo Pharmaceuticals. Fazaclo (clozapine) prescribing information. Beverly Hills, CA; 2005 May.