Background and objectives: Glaucoma is one of the leading causes of irreversible blindness worldwide and is increasingly recognized as a potential adverse effect of various pharmacological agents. It has been suggested that psychotropic medications influence glaucoma risk, but findings across studies have remained inconsistent. We aimed to clarify the association between psychotropic drug use and glaucoma through a Bayesian meta-analysis.
Methods: We conducted a systematic literature search up to December 2024. Studies that examined the relationship between psychotropic medications and glaucoma or intraocular pressure (IOP), and reported odds ratios (ORs), relative risks (RRs), or mean differences, were eligible. Bayesian random-effects models were applied using informative priors based on existing evidence for specific compounds. Estimates were reported as pooled ORs and Hedges' g with corresponding 95% credible intervals (CrIs).
Results: A total of 22 observational studies, including 293,228 users of psychotropic medications, met the inclusion criteria. Selective serotonin reuptake inhibitors (SSRIs) were associated with a modestly reduced risk of open-angle glaucoma (OR = 0.832, 95% CrI: 0.753-0.921) and a small but consistent reduction in IOP (Hedges' g = -0.332, 95% CrI: -0.487 to -0.179). Although tricyclic antidepressants were expected to have a direct causative effect, results did not show a significant association with glaucoma risk (OR = 1.466, 95% CrI: 0.700-3.338). Benzodiazepines were associated with a significantly increased risk of glaucoma (OR = 1.550, 95% CrI: 1.436-1.674), with consistent effects across both short- and long-acting compounds. Topiramate demonstrated a strong association with acute angle-closure glaucoma (OR = 3.930, 95% CrI: 1.784-11.465), in accordance with its known mechanism of inducing anterior displacement of the lens-iris diaphragm. Studies on methylphenidate, limited to pediatric populations, suggested a modest but non-significant reduction in IOP compared with untreated individuals. Evidence on antipsychotics was inconsistent, precluding any quantitative synthesis.
Conclusions: While some drug classes (e.g., benzodiazepines, topiramate) show a strong association with glaucoma, results for other compounds must be taken judiciously. The high level of heterogeneity, and the presence of special populations suggest caution when moving to real-life scenarios. Nonetheless, our results highlight the importance of ophthalmologic monitoring in patients prescribed with psychiatric drugs (e.g., benzodiazepines or topiramate), at risk for angle closure.
Background: Prolactin elevation associated with antipsychotic use significantly affects medication adherence and long-term treatment outcomes in patients with schizophrenia. The currently available data are insufficient to guide the monitoring and management of elevated prolactin levels in patients on antipsychotic medications. This study aimed to explore the patterns of prolactin level elevation associated with nine second-generation antipsychotics (SGAs) in a real-world setting and compare the associated risks.
Methods: This retrospective cohort study utilized data from the inpatient electronic medical records of a large mental health center in China from 2007 to 2019. The study included patients diagnosed with schizophrenia (ICD-10 criteria) who received SGA therapy and whose serum prolactin levels were measured. Exposures were the use of nine specific SGAs (amisulpride, risperidone, paliperidone, ziprasidone, olanzapine, perospirone, quetiapine, clozapine, or aripiprazole), including polytherapy and monotherapy. The primary outcome was incident prolactin elevation in patients during hospitalization. An adjusted stratified Cox proportional hazards regression analysis was used to compare the hazard ratios (HRs) of prolactin level elevation across the nine SGAs. In addition, a dose-response analysis of these SGAs was conducted using the defined daily dose (DDD) method. Dose categories were as follows: < 0.6 DDDs/day (low dose), 0.6 to < 1.1 DDDs/day (medium dose), and ≥ 1.1 DDDs/day (high dose).
Results: This study included 6489 patients with schizophrenia (mean [SD] age, 35.1 [14.2] years; 3396 males [52.3%]). Compared with the nonexposure, amisulpride (HR 2.76, 95% confidence interval [CI] 2.12-3.59), risperidone (HR 2.70, 95% CI 2.30-3.16), paliperidone (HR 1.84, 95% CI 1.37-2.46), and ziprasidone (HR 1.36, 95% CI 1.06-1.76) were associated with the highest risk of prolactin elevation. In contrast, quetiapine (HR 0.73, 95% CI 0.61-0.87), clozapine (HR 0.59, 95% CI 0.46-0.76), and aripiprazole (HR 0.30, 95% CI 0.23-0.37) were associated with the lowest risk. Amisulpride posed the highest risk among male patients, whereas risperidone posed the highest risk among female patients. Different types of dose-response associations were detected in seven SGAs.
Conclusion: This cohort study, conducted in an inpatient setting, identified different risks of prolactin elevation associated with SGAs, along with their dose-response curves. Sex and age must be considered when prolactin elevation is analyzed in patients with schizophrenia who are treated with SGAs.
Trial registration: ClinicalTrials.gov identifier: NCT04002258.
Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative disorders with few effective drug treatments available. An underrated element of these diseases is that glucose uptake and energy utilization is much reduced in neurons. In the brains of patients, signaling of insulin, insulin-like growth factor 1, and other growth factors is downregulated early on. This leads to reduced glucose utilization and impaired mitochondrial function. In an attempt to compensate for the loss, other pathways are upregulated, e.g., the increased use of ketones produced from fatty acids by astrocytes that are shuttled to neurons. In addition, amino acids are increasingly used to generate energy. Despite this, neurons generate less and less energy over time, leading to impaired synaptic activity, reduced cell repair, mitogenesis, autophagy, the accumulation of misfolded proteins, and finally, to cell death. At the same time, the chronic inflammation response in the brain that is part of these diseases continues to damage neurons. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones and growth factors that have shown neuroprotective effects in animal studies and in clinical trials. GLP-1 and GIP receptor agonists were able to reduce inflammation while normalizing growth factor signaling and energy utilization in the brain. Insulin signaling was improved and energy utilization, glucose uptake, mitogenesis, and mitochondrial functionality was brought back to physiological levels. In addition, the chronic inflammation response and the levels of proinflammatory cytokines in the brain were much reduced. Clinical trials testing GLP-1 receptor agonists in patients with AD or PD have been conducted and have shown first successes, serving as proof of concept that activating GLP-1 receptor is a sensible strategy to treat AD/PD. A phase II study testing liraglutide in patients with AD showed first improvements, and two phase II trials testing exendin-4 (exenatide, Bydureon®) or lixisenatide showed improvements in patients with PD. A recent phase III trial testing exendin-4 did not show an improvement, which may be linked to the lack of insulin desensitization in the study participants. Semaglutide (Rybelsus®; Wegovy®; Ozempic®) is currently in two phase III trials for AD. Current drugs that are on the market have a long half-life in the blood and do not readily cross the blood-brain barrier (BBB). Newer dual GLP-1/GIP receptor agonists have been developed that can more easily cross the BBB and that show improved protection in animal models of AD and PD. Therefore, GLP-1 and GIP receptor agonists that can cross the BBB show promise as treatments for chronic neurodegenerative disorders.
Background and objectives: The rising prescription rates and opioid-related harms in France highlight the need for local data. Evaluating this association may help identify vulnerable subgroups and guide safer prescribing practices. This study aimed to assess the association between opioid analgesic dispensation and the risk of suicide attempt in the French population. Secondary objectives included evaluation of a dose-response relationship and examination of the potential additive effects of co-prescriptions with benzodiazepines or gabapentinoids.
Methods: We conducted a nationwide, population-based case-crossover study using data from the French National Health Insurance Database (Système National des Données de Santé, SNDS), covering 98.8% of the French population. Adults aged 18 years or older who were hospitalized for a first suicide attempt between 1 January 2013 and 31 December 2020, and who had received at least one opioid analgesic dispensation in the preceding year (excluding buprenorphine and methadone) were included. Opioid analgesic exposure during the 84 days before the attempt was compared with three earlier 84-day control periods.
Results: Among 158,400 patients (mean age 47.0 years; 64.0% women), opioid analgesic dispensation was associated with a higher risk of suicide attempt (odds ratio [OR] = 1.26; 95% confidence interval 1.25-1.28). The risk was greater for strong opioid analgesics (OR = 1.73) and higher morphine-equivalent doses. Co-prescription with benzodiazepines or gabapentinoids further increased risk.
Conclusions: Opioid analgesic use, especially at higher doses or in combination with benzodiazepines or gabapentinoids, was associated with an increased risk of suicide attempt. Clinical vigilance is warranted when prescribing these medications.
Trial registration: NCT04211077, registered 3 January 2020 (retrospectively registered).
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a cornerstone therapy for type 2 diabetes mellitus (T2DM) and heart failure, are emerging as a promising therapeutic class for the management of ischemic stroke (IS). Given that T2DM is a significant risk factor for IS, understanding the potential neuroprotective role of SGLT2i is of paramount clinical importance. This review provides a systematic and logically structured synthesis of the current evidence, beginning with foundational preclinical studies in animal models that consistently demonstrate a reduction in infarct volume and improved neurological outcomes. We then transition to the extensive clinical evidence, primarily from large-scale real-world observational studies, that has confirmed a significant reduction in stroke risk, particularly in high-risk T2DM populations. The strengths and limitations of this evidence base are critically appraised, highlighting the robustness of the findings while acknowledging the predominantly observational nature of the data and the lack of stroke-specific primary endpoints in major trials. The neuroprotective benefits of SGLT2i appear to be multifactorial; this review delves into the potential mechanisms, emphasizing a foundational, glucose-dependent pathway of ameliorating hyperglycemia-induced neurotoxicity, which is complemented by a suite of pleiotropic, glucose-independent effects, including the induction of mild ketosis, attenuation of neuroinflammation, and preservation of the neurovascular unit. Finally, we address the key clinical challenges to their application, such as the management of euglycemic ketoacidosis, and outline crucial directions for future research, underscoring the need for dedicated randomized trials.
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