Cuiling Wei

Direct clinical comparisons between lithium and valproate for suicide prevention remain limited and inconclusive. We aimed to evaluate their effectiveness of suicide prevention using a retrospective cohort study and meta-analysis. We conducted a retrospective cohort study using electronic health records from the Hong Kong Hospital Authority, including patients with bipolar disorder who initiated lithium or valproate monotherapy between 2003 and 2023. Inverse probability of treatment weighting was applied to balance baseline characteristics, and weighted Cox proportional hazards regression estimated hazard ratios (HRs) for suicide risk. We also searched electronic databases for randomized controlled trials (RCTs) and observational studies comparing lithium, valproate, and nontreatment controls. Pairwise meta-analyses and network meta-analyses were performed to synthesize direct and indirect evidence. The cohort study included 1,379 lithium users and 5,556 valproate users, with no significant difference in suicide risk between groups (weighted HR = 0.76, 95% confidence interval [CI]: 0.54–1.08). The meta-analysis identified 3 RCTs and 12 observational studies. Meta-analysis of RCTs was precluded due to methodological incompatibilities. Pairwise meta-analysis of eight observational studies showed no significant difference between lithium and valproate (pooled HR = 0.87, 95% CI: 0.69–1.09). Network meta-analysis showed that both lithium (network HR = 0.46, 95% CI: 0.33-0.64) and valproate (network HR = 0.63, 95% CI: 0.45-0.88) were associated with lower suicide risk than no treatment, with no significant difference between the two agents (network HR = 0.73, 95% CI: 0.52-1.02). Lithium and valproate showed comparable effectiveness in reducing suicide risk, while both were associated with lower risk than no treatment. The choice between these two mood stabilizers should be guided by individual patient characteristics and safety considerations.

Background: Prostate cancer is one of the most diagnosed cancers among men worldwide. Prolactin is a pituitary hormone that can influence androgen regulation, and antipsychotics that increase prolactin may suppress testosterone levels. Because lower free testosterone has been associated with lower prostate cancer risk, prolactin-increasing antipsychotics may have a potential protective effect. However, this association has not been well characterized in real-world comparative studies. Methods: Using territory-wide electronic health records from Hong Kong covering the period from 1 January 2004 to 31 December 2023, we conducted a retrospective cohort study and nested case-control analysis among adults prescribed antipsychotics. We excluded individuals with a history of cancer, organ transplantation, or sexually transmitted infections. Baseline characteristics included demographics, comorbidities, and co-medications. The outcome was incident prostate cancer. Cohort incidence rate ratios (IRRs) were estimated using Poisson regression incorporating inverse probability of treatment weighting (IPTW) and multivariable adjustment. Based on biological hypotheses of cellular adaptation, the prespecified primary exposure window was 1–5 years. Conditional logistic regression estimated odds ratios (ORs) for longer-term prolactin-increasing antipsychotic use versus short-term use or non-use in the nested case-control analysis. Results: The primary cohort analysis included 81,177 individuals. During the prespecified 1–5-year exposure window, prolactin-increasing antipsychotic users had lower observed prostate cancer incidence than prolactin-sparing antipsychotic users (adjusted IRR 0.410, 95% CI 0.237–0.710). The nested case-control analysis identified 291 cases and showed a similar association for 1–5 years of use (adjusted OR 0.569, 95% CI 0.356–0.909). The association was directionally consistent across age groups and appeared stronger among individuals older than 75 years, but estimates varied in magnitude by age. Conclusion: Prolactin-increasing antipsychotics were associated with lower observed prostate cancer risk during 1–5 years of exposure. These findings are consistent with hypothesized mechanisms of androgen deprivation and subsequent cellular adaptation, although residual confounding cannot be excluded.

Objective: Topiramate has been linked to increased glaucoma risk, potentially through mechanisms involving ocular fluid shifts. However, comparative risks vs other antiseizure medications (ASMs) and variation by sex or indication remain uncertain. This study evaluates glaucoma incidence in topiramate initiators compared to valproate or lamotrigine users among patients with epilepsy or migraine. Methods: We conducted a retrospective active‐comparator, new‐user cohort study using electronic health records from the IQVIA Medical Research Data among patients with epilepsy or migraine initiating topiramate, valproate, or lamotrigine. Patients with prior ASM use, limited washout period and follow‐up, or pre‐existing glaucoma were excluded. The outcome was incident glaucoma within 1 year, censored at glaucoma occurrence, death, discontinuation, switch, or September 30, 2023. Covariates included age, sex, race, lifestyle factors, comorbidities, and medication history. Propensity score–based inverse probability weighting balanced characteristics, and crude and weighted Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup analyses were conducted by sex, age, and indication. Results: The cohort included 688 topiramate, 4490 valproate, and 4179 lamotrigine initiators. After weighting, the 1‐year absolute risk increase was approximately 2.4% when comparing topiramate to valproate, and about 2.0% compared to lamotrigine. Topiramate was associated with higher glaucoma risk vs valproate (adjusted HR 2.66, 95% CI 1.12–6.32) and lamotrigine (adjusted HR 3.57, 95% CI 1.76–7.26). Risks were elevated in female (vs valproate: HR 5.31, 95% CI 1.48–19.08; vs lamotrigine: HR 5.73, 95% CI 2.38–13.79) or epilepsy patients (vs valproate: HR 2.23, 95% CI 1.04–4.76; vs lamotrigine: HR 5.08, 95% CI 2.32–11.14), but not in male or migraine patients. Significance: Topiramate use substantially increases glaucoma risk compared with valproate and lamotrigine, particularly among female or epilepsy patients. No significant association in male or migraine patients was observed. These findings may inform targeted ophthalmologic monitoring in high‐risk groups and use of alternative ASMs.

Background: Clozapine is widely regarded as a highly efficacious psychotropic drug that is largely underused worldwide. Recent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is not well-established due to the absence of analytic cohort studies. The clinical significance of such a potential risk remains unclear. Methods and findings: We extracted data from a territory-wide public healthcare database from January 2001 to August 2022 in Hong Kong to conduct a retrospective cohort study of anonymized patients aged 18⁺ years with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90⁺ days, with at least 2 prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment (IPTW) based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated. In total, 9,965 patients with a median follow-up period of 6.99 years (25th to 75th percentile: 4.45 to 10.32 years) were included, among which 834 were clozapine users. After IPTW, the demographic and clinical characteristics of clozapine users were comparable to those of olanzapine users. Clozapine users had a significant weighted IRR of 2.22 (95% confidence interval (CI) [1.52, 3.34]; p < 0.001) for HM compared to olanzapine users. The absolute rate difference was estimated at 57.40 (95% CI [33.24, 81.55]) per 100,000 person-years. Findings were consistent across subgroups by age and sex. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers. The main limitation of this observational study is the potential residual confounding effects that could have arisen from the lack of randomization in clozapine or olanzapine use. Conclusions: Absolute rate difference in HM incidence associated with clozapine is small despite a 2-fold elevated rate. Given the rarity of HM and existing blood monitoring requirements, more restrictive indication for clozapine or special warnings may not be necessary.