including multiple investigations for other causes of psychosis and comorbidities including; mri brain imaging, thyroid function tests, b12, folate and serum calcium levels, infection screening for blood borne viruses including hepatitis b and c, hiv and syphilis as well as screening for autoimmune psychosis by anti-nmda, anti-vgkc and anti-nuclear antibody screening. investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, crp and bnp and for neuroleptic malignant syndrome ck. the dose of clozapine is initially low and gradually increased over a number of weeks. initial doses may range from 6.5 to 12.5 mg/d increasing stepwise typically to doses in the range of 250–350 mg per day at which point an assessment of response will be performed. in the uk the average clozapine dose is 450 mg/d. but response is highly variable and some patients respond at much lower doses and vice versa. monitoring during the initial dose titration phase the following are typically monitored; usually daily at first; pulse, blood pressure and since orthostatic hypotension can be problematic this should be monitored both sitting and standing. if there is a significant drop then the rate of the dose increase may be slowed, temperature. weekly tests include; mandatory full blood counts are performed weekly for the first 18 weeks. in some services there will also be monitoring of markers that might indicate myocarditis; troponin, crp and bnp although the exact tests and frequency vary between services. weight is usually measured weekly. thereon other investigations and monitoring will always include full blood counts (fortnightly for 1 year then monthly). weight, waist circumference, lipids and glucose or hba1c may also be monitored. clozapine response and treatment optimisation as with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week. that said responses, especially those which are partial, can be delayed. quite what an adequate trial of clozapine is, is uncertain but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/l. there is considerable inter-individual variation. a significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900 mg/day. options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. avoiding unnecessary polypharmacy is a general principle in drug treatment. optimising blood sampling the neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. there is a significant margin of safety. some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. a knowledge of neutrophil biology allows blood sampling optimisation. neutrophils show a diurnal variation in response to the natural cycle of g-csf production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. however this is a disruption to usual hospital practice. other practical steps are to ensure that blood results become available in hours and when senior staff are available. underuse of clozapine clozapine is widely recognised as being underused with wide variation in prescribing, especially in patients with african heritage. psychiatrists prescribing practices have been found to be the most significant variable regarding variance in its use. surveys of psychiatrists attitudes to clozapine have found that many had little experience in its use, over estimated the incidence and were fearful of side effects, and did not appreciate that many patients prefer to take clozapine than other antipsychotics, are reluctant to prescribe clozapine, had little experience in its use and believed that patients treated with clozapine were less satisfied than those treated with other antipsychotics. in contrast to many psychiatrists expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive. whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation. clozapine is no longer actively marketed and this may also be one of the explanations for its underuse. despite the strong evidence and universal endorsement by national and international treatment guidelines and the experiences of patients themselves, most people eligible for clozapine are not treated with it. a large study in england found that approximately 30% of those eligible for clozapine were being treated with it. those patients that do start clozapine usually face prolonged delay, multiple episodes of psychosis and treatments such as high dose antipsychotics or polypharmacy. instead of two previous antipsychotics many will have been exposed to ten or more drugs which were not effective. in a study of 120 patients conducted in four hospitals in south-east london, found a mean of 9.2 episodes of antipsychotic prescription before clozapine was initiated and the mean delay in using clozapine was 5 years. treatments that have no evidence base or are regarded as actively harmful are used instead multiple and or high-dose treatment. racial disparity in the use of clozapine a general finding in healthcare provision is that minority groups receive inferior treatment; this is a particular finding in the us. in the us a general finding is that compared to their white peers african american people are less likely to be prescribed the second generation antipsychotics, which are more expensive than alternatives and this was even apparent and especially so for clozapine when comparison was made in the veterans affairs medical system and when differences regarding socioeconomic factors were taken into account. as well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia. benign ethnic neutropenia benign reductions in neutrophils are observed in individuals of all ethnic backgrounds ethnic neutropenia (ben), neutropenia without immune dysfunction or increased liability to infection is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. ben is associated with several ethnic groups, but in particular those with black african and west african ancestry. a difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations. for significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take ben into account. since 2002, clozapine monitoring services in the uk have used reference ranges 0.5 × 109/l lower for patients with haematologically confirmed ben and similar adjustments are available in the current us criteria, although with lower permissible minima. but even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. the duffy–null polymorphism, which protects against some types of malaria, is predictive of ben. adverse effects clozapine may cause serious and potentially fatal adverse effects. clozapine 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 clozapine's anticholinergic effects. extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. sexual problems, like retrograde ejaculation, have been reported while taking clozapine. rare adverse effects include periorbital edema. despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine. neutropenia and agranulocytosis main article: agranulocytosis clozapine induced neutropenia (cin) occurs in approximately 3.8% of cases and clozapine induced agranulocytosis (cia) in 0.4%. these are potentially serious side effects and agranulocytosis can result in death. to mitigate this risk clozapine 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 clozapine can be used in the u.s. has been lower than those currently used in the u.k. and australasia 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 clozapine is stopped immediately and can then no longer be used within the medicinal licence. stopping clozapine 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. clozapine carries a black box warning for drug-induced agranulocytosis. rapid point-of-care tests may simplify the monitoring for agranulocytosis. clozapine rechallenge a clozapine "rechallenge" is when someone that experienced agranulocytosis while taking clozapine 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 clozapine 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 clozapine stopped according to the us criteria only 7 would have had clozapine stopped if the us cut offs had been used. of these 62 were rechallenged, 59 continued to use clozapine 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 clozapine can rarely cause myocarditis and cardiomyopathy. a large meta-analysis of clozapine 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 clozapine 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 clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate. a large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives. rechallenge after clozapine 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