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.
In a comparison of suicides and natural deaths, the concentrations both of flunitrazepam and nitrazepam (sleeping medications) were significantly higher among the suicides. In four cases benzodiazepines were the sole cause of death.In Australia, a study of 16 deaths associated with toxic concentrations of benzodiazepines during the period of 5 years leading up to July 1994 found preexisting natural disease as a feature of 11 cases; 14 cases were suicides. Cases where other drugs, including ethanol, had contributed to the death were excluded. In the remaining five cases, death was caused solely by benzodiazepines. Nitrazepam and temazepam were the most prevalent drugs detected, followed by oxazepam and flunitrazepam. A review of self poisonings of 12 months 1976 - 1977 in Auckland, New Zealand, found benzodiazepines implicated in 40% of the cases. A 1993 British study found flurazepam and temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s. Flurazepam, now rarely prescribed in the United Kingdom and Australia, had the highest fatal toxicity index of any benzodiazepine (15.0) followed by Temazepam (11.9), versus 5.9 for benzodiazepines overall, taken with or without alcohol.Etizolam overdose deaths are rising - for instance, the National Records of Scotland report on drug-related deaths, implicated 548 deaths from street Etizolam in 2018, almost double the number from 2017 (299) and only six years from the first recorded death (in 2012). The 548 deaths were 45% of all drug-related deaths in Scotland in 2018. References


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