An international research agenda for clozapine-resistant schizophrenia

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life.</p

Prevalence, time trends, and correlates of major depressive episode and other psychiatric conditions among young people amid major social unrest and COVID-19 in Hong Kong: a representative epidemiological study from 2019 to 2022Research in context

Summary: Background: Hong Kong is among the many populations that has experienced the combined impacts of social unrest and the COVID-19 pandemic. Despite concerns about further deteriorations in youth mental health globally, few epidemiological studies have been conducted to examine the prevalence and correlates of major depressive episode (MDE) and other major psychiatric disorders across periods of population-level changes using diagnostic interviews. Methods: We conducted a territory-wide household-based epidemiological study from 2019 to 2022 targeting young people aged 15–24 years. MDE, generalised anxiety disorder (GAD), panic disorder (PD), and bipolar disorder (BD) were assessed using the Composite International Diagnostic Interview–Screening Scales in 3340 young people. Psychotic disorders were assessed by experienced psychiatrists according to the DSM. Help-seeking patterns were also explored. Findings: 16.6% had any mental disorder (13.7% 12-month MDE, 2.3% BD, 2.1% GAD, 1.0% PD, 0.6% psychotic disorder). The prevalence of MDE increased from 13.2% during period 1 (May 2019–June 2020) to 18.1% during period 2 (July–December 2020), followed by 14.0% during period 3 (January–June 2021) and 13.2% during period 4 (July 2021–June 2022). Different stressors uniquely contributed to MDE across periods: social unrest-related stressors during period 1, COVID-19 stressors during period 2, and personal stressors during periods 3–4. Lower resilience, loneliness, frequent nightmares, and childhood adversity were consistently associated with MDE. Compared to other conditions, those with MDE showed the lowest service utilisation rate (16.7%). Perceiving services to “cost too much” and “talked to friends or relatives instead” were among the major reasons for not seeking help. MDE was also significantly associated with poorer functioning and health-related quality of life. Interpretation: MDE can be sensitive to population-level changes, although its persistently elevated prevalence across the study period is of concern. Efforts to mitigate their impacts on youth mental health alongside personal risk factors are needed. Further work is required to increase the availability and acceptability of youth-targeted mental health services. Funding: Food and Health Bureau (HKSAR Government)

Striatal dopamine synthesis capacity and its association with negative symptoms upon resolution of positive symptoms in first-episode schizophrenia and delusional disorder

Rationale: How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms. Objective: A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3 months in first-episode SZ and DD patients. Methods: Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3 months. All patients received an 18F-DOPA PET/MR scan at baseline. Results: Baseline striatal DSC (Kocc;30–60) was inversely associated with negative symptoms at 3 months in first-episode SZ patients (rs = − 0.80, p = 0.010). This association remained in SZ patients even when controlling for baseline negative, positive, and depressive symptoms, as well as cumulative antipsychotic dosage (β = − 0.69, p = 0.012). Such associations were not observed in first-episode DD patients. Meanwhile, the severity of negative symptoms at 3 months was associated with more positive symptoms in DD patients (rs = 0.74, p = 0.010) and not in SZ patients. Conclusions: These findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications