This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.
An increasing number of synthetic cannabinoids have become available on the black market in recent years, and health professionals have seen a corresponding increase in use of these compounds among patients with psychiatric disorders. Unfortunately, there is almost no research available in the literature on this topic, and what little exists is based on case reports of individuals without psychiatric disorders. Synthetic cannabinoids are functionally similar to, but structurally different from, delta-9-tetrahydrocannabinol, the active principle in cannabis, and are problematic for many reasons. The psychotropic action of synthetic cannabinoids in patients with schizophrenia is unpredictable, with very diverse clinical presentations. These drugs can be much more potent than delta-9-tetrahydrocannabinol, they are readily available and difficult to detect. The gold standard for identification of synthetic cannabinoids is gas chromatography with mass spectrometry, but even this is difficult because new formulations of these designer drugs are constantly emerging. In this manuscript, we provide an overview and discussion of synthetic cannabinoids and present four cases of patients with synthetic cannabinoid intoxication who were hospitalized in our intensive psychiatric unit at the time of intoxication. All patients had a history of schizophrenia and had been hospitalized several times previously. While hospitalized, they smoked an unknown substance brought in by a visitor, which was then confirmed using gas chromatography with mass spectrometry to be the synthetic cannabinoid AM-2201. Our patients experienced predominantly psychiatric adverse clinical effects. We observed the appearance of new psychotic phenomena, without exacerbation of their previously known psychotic symptoms, as well as the occurrence or marked worsening of mood and anxiety symptoms. Despite several similar reactions, and even though they ingested the same exact substance, the clinical picture differed markedly between individual patients. We assume that the acute effects of synthetic cannabinoids in patients with schizophrenia would be different from those in persons without psychotic disorders. The reasons for this difference could be the actual symptomatology of the presenting disorder, the impact of psychopharmacotherapy, individual patient differences and probably many, as yet unknown, factors. The long-term consequences of synthetic cannabinoid use on preexisting psychotic disorders are unclear.
ObjectiveMost guidelines for the management of aggressive behavior in acute psychiatric patients describe the use of de-escalation as the first-choice method, but the evidence for its effectiveness is inconsistent. The aim of the study was to assess the effect of verbal and non-verbal de-escalation on the incidence and severity of aggression and the use of physical restraints in acute psychiatric wards.MethodsA multi-center cluster randomized study was conducted in the acute wards of all psychiatric hospitals in Slovenia. The research was carried out in two phases, a baseline period of five consecutive months and an intervention period of the same five consecutive months in the following year. The intervention was implemented after the baseline period and included training in verbal and non-verbal de-escalation techniques for the staff teams on experimental wards.ResultsIn the baseline study period, there were no significant differences in the incidence of aggressive behavior and physical restraints between the experimental and control groups. The incidence rates of aggressive events, severe aggressive events, and physical restraints per 100 treatment days decreased significantly after the intervention. Compared to the control group, the incidence rate of aggressive events was 73% lower in the experimental group (IRR = 0.268, 95% CI [0.221; 0.342]), while the rate of severe events was 86% lower (IRR = 0.142, 95% CI [0.107; 0.189]). During the intervention period, the incidence rate of physical restraints due to aggression in the experimental group decreased to 30% of the rate in the control group (IRR = 0.304, 95% CI [0.238; 0.386]). No reduction in the incidence of restraint used for reasons unrelated to aggression was observed. After the intervention, a statistically significant decrease in the severity of aggressive incidents (p < 0.001) was observed, while the average duration of restraint episodes did not decrease.ConclusionDe-escalation training is effective in reducing the incidence and severity of aggression and the use of physical restraints in acute psychiatric units.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT05166278].
In the above-mentioned article, the spelling of 5 authors last names has been wrong and these names have been corrected.This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
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