CLINICAL HANDBOOK OF SCHIZOPHRENIA

182 III. SOMATIC TREATMENTtion of drugs such as carbamazepine, which have bone marrow–suppressing effects, canpotentially increase the risk for agranulocytosis. It is necessary to monitor hematologicalstatus (white blood cell count [WBC] and absolute neutrophil count [ANC]) on a weeklybasis for the first 6 months of clozapine therapy (Table 18.1). Patients should be instructedto report onset of fever, sore throat, weakness, or other signs of infectionpromptly. If the total WBC falls below 3,000 or if the ANC falls below 1,500, medical orhematological consultation should be obtained. Agranulocytosis is a medical emergencyand is managed by reverse isolation and prophylactic broad-spectrum antibiotics. Treatmentwith granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophagecolony-stimulating factor (GM-CSF) have been reported to decrease morbidity and toshorten the duration of illness secondary to agranulocytosis. Other hematological side effectsassociated with clozapine therapy include benign leukocytosis (0.6%), leukopenia(3%), eosinophilia (10%), and elevated erythrocyte sedimentation rate.Neurological/Mental Status EffectsSedation, occurring in 10–58% of clozapine-treated individuals, is perhaps the most commonand immediately troubling neurological side effect. Fortunately, some sedation islikely to resolve gradually after early phases of titration. Additionally, effects of daytimesedation can be minimized by giving most of the clozapine dose at night.Clozapine reduces seizure threshold and the occurrence of seizures is dose related—0.7% per 100 mg dose. Valproate is preferred by many clinicians as the safest and besttoleratedanticonvulsant in clozapine-treated patients experiencing seizures.During the first few months of clozapine treatment some patients develop benign fevers(100–103°F). This is usually self-limiting, and can be managed with antipyretics.However, the more serious condition of neuroleptic malignant syndrome (NMS) also ismore common in the first 14 days of clozapine treatment. Concurrent treatment withlithium is a risk factor for NMS. Management of NMS includes discontinuation ofantipsychotic and supportive measures to reduce the body temperature, including use of ahypothermia blanket and hydration. Drugs such as amantadine, benzodiazepines, dantrolene,and bromocriptine can be effective. Electroconvulsive therapy (ECT) also has beenused in refractory cases.Finally, approximately 10% of clozapine-treated patients experience obsessive–compulsive symptoms such as repeated handwashing. Decreasing clozapine dose or additionof a serotonin selective reuptake inhibitor (SSRI) may help to alleviate these symptoms.Cardiovascular and Other Side EffectsCardiovascular side effects that may be associated with clozapine therapy include tachycardia,orthostatic hypotension, prolongation of QTc interval, deep vein thrombosis,myocarditis, and cardiomyopathy. Clozapine should be discontinued in patients who developmyocarditis or cardiomyopathy. Tachycardia is due to vagal inhibition and can betreated with beta-adrenergic antagonists such as atenolol; however, this may also potentiatethe hypotensive effects of clozapine. Low starting dose and gradual titration can reducethe hypotensive side effects. Additional treatment measures include fluid intake of atleast 2 liters/day, support stockings, increased sodium intake, and fludrocortisone treatment.Sialorrhea (hypersalivation) occurs in 31–54% of individuals on clozapine therapy.Sialorrhea may respond to clonidine patches (0.1 mg weekly). Anticholinergic agents maybe helpful for some patients but should be approached cautiously because of additive effectsand the possibility of anticholinergic delirium. Clozapine itself has strong anticho-