Clozapine Management for Internists

Case Vignette 1

Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.

Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]

Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]

Case Vignette 2

Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 10³/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.

Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]

Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]

Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]

Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.

Case Vignette 3

Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.

Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.

Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]

Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.

Case Vignette 4

Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm³ and absolute neutrophil count (ANC) of 4700/mm³. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm³ and ANC to 2200/mm³. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm³ and ANC at 790/mm³. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm³ and ANC >1500/mm³. An alternate psychotropic medication was initiated several weeks thereafter.

Neutropenia (white blood cell count <3000/mm³) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm³.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]

In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]

The most feared complication of clozapine remains agranulocytosis, defined as ANC<500/mm³,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]

The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]

Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm³.[21, 41]

Case Vignette 1

Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.

Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]

Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]

Case Vignette 2

Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 10³/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.

Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]

Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]

Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]

Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.

Case Vignette 3

Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.

Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.

Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]

Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.

Case Vignette 4

Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm³ and absolute neutrophil count (ANC) of 4700/mm³. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm³ and ANC to 2200/mm³. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm³ and ANC at 790/mm³. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm³ and ANC >1500/mm³. An alternate psychotropic medication was initiated several weeks thereafter.

Neutropenia (white blood cell count <3000/mm³) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm³.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]

In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]

The most feared complication of clozapine remains agranulocytosis, defined as ANC<500/mm³,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]

The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]

Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm³.[21, 41]

Case Vignette 1

Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.

Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]

Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]

Case Vignette 2

Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 10³/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.

Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]

Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]

Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]

Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.

Case Vignette 3

Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.

Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.

Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]

Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.

Case Vignette 4

Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm³ and absolute neutrophil count (ANC) of 4700/mm³. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm³ and ANC to 2200/mm³. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm³ and ANC at 790/mm³. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm³ and ANC >1500/mm³. An alternate psychotropic medication was initiated several weeks thereafter.

Neutropenia (white blood cell count <3000/mm³) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm³.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]

In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]

The most feared complication of clozapine remains agranulocytosis, defined as ANC<500/mm³,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]

The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]

Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm³.[21, 41]