Body weight gain in clozapine-treated patients: Is norclozapine the culprit?

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.

Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring: Can the regulations be relaxed?

After the introduction of clozapine eight Finnish patients died after developing agranulocytosis. Clozapine was withdrawn from the market and only reintroduced with strict mandatory white blood cell monitoring as long as treatment lasts and thresholds at which clozapine must be discontinued definitively. The fear of agranulocytosis and the need for intensive blood monitoring is the single most important barrier for prescribers and patients alike and leads to underprescription of the only effective and approved medication for treatment-resistant schizophrenia. We summarize evidence that the risk of agranulocytosis is smaller than perceived at the time of reintroduction, is concentrated in the first 18 weeks of treatment, is not greater than with other antipsychotics thereafter and that frequent blood monitoring has not demonstrably decreased the rate of agranulocytosis. Therefore we propose 1) mandatory monitoring of the absolute neutrophil count (ANC) exclusively during the first 18 weeks of clozapine treatment, 2) that thereafter the prescriber and the well-informed patient decide together about further monitoring frequency, 3) that clozapine treatment must be stopped if the ANC falls below 1.0 × 109/L. Continuation of clozapine or a rechallenge are possible if prescriber and patient determine that the benefits outweigh the risks. 4) National registries which control the haematologic monitoring are unnecessary and do not help to reduce clozapine-induced agranulocytosis. They should at least be restricted to the first 18 weeks of clozapine use.

Evaluation of a Collaborative Care Program for Patients With Treatment-Resistant Schizophrenia: Protocol for a Multiple Case Study.

BACKGROUND: Approximately one-third of all patients with schizophrenia are treatment resistant. Worldwide, undertreatment with clozapine and other effective treatment options exist for people with treatment-resistant schizophrenia (TRS). In this respect, it appears that regular health care models do not optimally fit this patient group. The Collaborative Care (CC) model has proven to be effective for patients with severe mental illness, both in primary care and in specialized mental health care facilities. The key principles of the CC model are that both patients and informal caregivers are part of the treatment team, that a structured treatment plan is put in place with planned evaluations by the team, and that the treatment approach is multidisciplinary in nature and uses evidence-based interventions. We developed a tailored CC program for patients with TRS. OBJECTIVE: In this paper, we provide an overview of the research design for a potential study that seeks to gain insight into both the process of implementation and the preliminary effects of the CC program for patients with TRS. Moreover, we aim to gain insight into the experiences of professionals, patients, and informal caregivers with the program. METHODS: This study will be underpinned by a multiple case study design (N=20) that uses a mixed methods approach. These case studies will focus on an Early Psychosis Intervention Team and 2 Flexible Assertive Community treatment teams in the Netherlands. Data will be collected from patient records as well as through questionnaires, individual interviews, and focus groups. Patient recruitment commenced from October 2020. RESULTS: Recruitment of participants commenced from October 2020, with the aim of enrolling 20 patients over 2 years. Data collection will be completed by the end of 2023, and the results will be published once all data are available for reporting. CONCLUSIONS: The research design, framed within the process of developing and testing innovative interventions, is discussed in line with the aims of the study. The limitations in clinical practice and specific consequences of this study are explained. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35336.