has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers. clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis. a cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication. monitoring bowel function and the preemptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae. hypersalivation hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%). the saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day. while clozapine is a muscarinic antagonist at the m1, m2, m3, and m5 receptors, clozapine is a full agonist at the m4 subset. because m4 is highly expressed in the salivary gland, its m4 agonist activity is thought to be responsible for hypersalivation. clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication. besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine, diphenhydramine and topical anticholinergic medications like ipratropium bromide. mild hypersalivation may be managed by sleeping with a towel over the pillow at night. central nervous system cns side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal eeg, worsening of psychosis, paresthesia, status epilepticus, and obsessive compulsive symptoms. similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome. urinary incontinence clozapine is linked to urinary incontinence, though its appearance may be under-recognized. withdrawal effects abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation. abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis. doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. when discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects. weight gain and diabetes in addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine. impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. the data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. for people who gain weight because of clozapine, taking metformin may reportedly improve three of the five components of the metabolic syndrome: waist circumference, fasting glucose, and fasting triglycerides. pneumonia international adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events. the mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation, immune effects of clozapine's effects on the resolution of inflammation. overdose symptoms of overdose can be variable, but often include; sedation, confusion, tachycardia, seizures and ataxia. fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000 mg have been survived. drug interactions fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine. when carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine. patients should be monitored for "decreased therapeutic effects of clozapine if carbamazepine" is started or increased. if carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. the study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis. ciprofloxacin is an inhibitor of cyp1a2 and clozapine is a major cyp1a2 substrate. randomized study reported elevation in clozapine concentration in subjects concurrently taking ciprofloxacin. thus, the prescribing information for clozapine recommends "reducing the dose of clozapine by one-third of original dose" when ciprofloxacin and other cyp1a2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose. pharmacology pharmacodynamics