<unk>  may cause serious and potentially fatal adverse effects.<unk>  carries five black box warnings, including (1) severe neutropenia (low levels of neutrophils), (2) orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting, (3) seizures, (4) myocarditis (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis. Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension. Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to<unk> 's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to<unk> . Sexual problems, like retrograde ejaculation, have been reported while taking<unk> . Despite the risk for numerous side effects, many side effects can be managed while continuing to take<unk> . Neutropenia and agranulocytosis<unk>  Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and<unk>  Induced Agranulocytosis (CIA) in 0.4%. These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk<unk>  is only used with mandatory absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS). The exact schedules and blood count thresholds vary internationally and the thresholds at which<unk>  can be used in the U.S. has been lower than those currently used in the U.K. and Australiasia for some time. The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7700 patients treated. Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks. After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still. When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then<unk>  is stopped immediately and can then no longer be used within the medicinal licence. Stopping<unk>  almost always results in resolution of the neutrophil reduction. However severe agranulocytosis can result in spontaneous infection and death. is a severe decrease in the amount of a specific kind of white blood cell called granulocytes.<unk>  carries a black box warning for drug-induced agranulocytosis. Rapid point-of-care tests may simplify the monitoring for agranulocytosis.<unk>  rechallenge A<unk>  "rechallenge" is when someone that experienced agranulocytosis while taking<unk>  starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce<unk>  but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had<unk>  stopped according to the US criteria only 7 would have had<unk>  stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use<unk>  without difficulty and only 1 had a fall in neutrophils below the US cut off. Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited. Cardiac toxicity<unk>  can rarely cause myocarditis and cardiomyopathy. A large meta-analysis of<unk>  exposure to over 250,000 people revealed that these occurred in approximately 7 in 1000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after<unk>  initiation and observing the patient for signs and symptoms of illness. Signs of heart failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of<unk> -induced myocarditis is increased with increasing rate of<unk>  dose titration, increasing age and concomitant sodium valproate. A large electronic health register study has revealed that nearly 90% of cases of suspected<unk>  related myocarditis are false positives. Rechallenge after<unk>  induced myocarditis has been performed and a protocol for this specialist approach has been published. A systematic review of rechallenge after myocarditis has show success in over 60% of reported cases. Gastrointestinal hypomotility Another underrecognized and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Colonic hypomotility has been shown to occur in up to 80% of people prescribed<unk>  when gastrointestinal function is measured objectively using radiopaque markers.<unk> -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<unk>  and other antipsychotic medication. Monitoring bowel function and the preemptive use of laxatives for all<unk> -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<unk>  (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<unk>  is a muscarinic antagonist at the M1, M2, M3, and M5 receptors,<unk>  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.<unk> -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<unk>  rarely has been known to cause neuroleptic malignant syndrome. Urinary incontinence<unk>  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<unk> . When discontinuing<unk> , 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<unk> . 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<unk>  may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. Pneumonia International adverse drug effect databases indicate that<unk>  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<unk> 's effects on the resolution of inflammation. Overdose Symptoms of overdose can include; sedation, confusion, tachycardia, seizures and ataxia.Fatalities have been reported due to<unk>  overdose, though overdoses > 4000 mg have been survived.
Clozapine
Desmethylclozapine
Chlorpromazine
Ziprasidone
Aripiprazole
Lorpiprazole
Risperidone
Chlortalidone