Heidi Taipale

Purpose: To present updated estimates from a nationwide Swedish study comparing dispensed medications with forensic toxicological findings (2006–2013), following re‐evaluation of the toxicology dataset to address periods with non‐uniform analytical detection and inconsistent testing. Methods: Observations from time periods with non‐uniform detection or inconsistent testing were excluded. Analyses were repeated using the PRE2DUP method to model drug exposure. Agreement between PRE2DUP‐modelled exposure and post‐mortem toxicology was assessed using sensitivity, specificity, predicted adherence, and Cohen's κ . Results: After exclusion of inconsistent testing periods, the number of individuals for affected substances was reduced (10 060 vs. 18 627). Proportional changes in sensitivity and specificity were negligible. In contrast, predicted adherence and Cohen's κ improved across several substances. Moderate to substantial proportional increases were observed for selected medications but translated into only small group‐level effects (approximately 2%–7%). The largest improvements were observed for cardiovascular drugs, beta‐blockers, for which Cohen's κ and predicted adherence increased substantially (approximately 40%–55%) at the class level; notably, only for these substances did Cohen's κ shift interpretation (from fair to moderate agreement). Overall, proportional improvements across all substances were moderate (approximately 10%–15%). Despite these changes, overall agreement patterns remained comparable to the original results. Conclusions: After exclusion of periods with non‐uniform or incomplete toxicological testing, agreement between PRE2DUP‐modelled exposure and forensic toxicology improved overall. Moderate increases observed for a few individual medications translated into only small effects at the group level, except for cardiovascular drugs, for which improvements were substantial. These updates do not materially alter the original interpretation but strengthen the validity of register‐based drug exposure modelling.

Importance: Clozapine is the only evidence-based treatment for treatment-resistant schizophrenia (TRS), yet substantial international variation in its use has been reported. Objective: To provide a comprehensive and updated assessment of international clozapine utilisation by estimating prevalence across countries using a standardised methodology and examining factors associated with variation in use. Design, Setting, and Participants: Repeated cross-sectional study using population-based data from 2015 to 2024. Individual-level data were obtained from 36 countries and 1 special administrative region, supplemented by national clozapine consumption data from 5 additional countries. Analyses were conducted separately for adults (20-64 years; primary analysis), adolescents (10-19 years), and older adults (≥65 years). Main Outcomes and Measures: Annual outpatient clozapine utilisation prevalence per 100,000 population by age group, sex, country and calendar year. Associations between clozapine utilisation prevalence and country-level health system, demographic, and socioeconomic indicators were also examined. Results: We analysed data from more than 1.1 billion people across all inhabited continents. In 2024, crude adult clozapine use prevalence was highest in Croatia (415.3 per 100,000 population) and Finland (302.0 per 100,000), and lowest in Oman (0.5 per 100,000) and Ethiopia (0.3 per 100,000), representing a 1,384-fold difference. Across most countries, utilisation peaked among individuals aged 50 to 59 years. The male-to-female prevalence ratio ranged from 0.4 in the United Arab Emirates to 2.8 in Colombia. Among adolescents, prevalence was highest in Colombia (42.7 per 100,000) and Croatia (24.4 per 100,000), while among older adults it was highest in Croatia (406.9 per 100,000) and Iceland (339.7 per 100,000). Across all countries, adult clozapine utilisation increased by 17% (95% CI, 16%-18%), from 44.7 per 100,000 population (95% CI, 44.5-44.9) to 52.2 per 100,000 population (95% CI, 51.1-52.4). Country-specific trends ranged from a 71% decrease to a 342% increase. None of the examined indicators explained variation in clozapine utilisation across countries. Conclusion and relevance: Clozapine use increased modestly over the past decade but remained highly variable between countries. This variation was not explained by national socioeconomic, healthcare-system, or monitoring-related factors, suggesting an important role for clinical and service-level barriers. The concentration of clozapine use in later adulthood is consistent with delayed initiation and highlights opportunities to improve timely access to evidence-based treatment for TRS. Funding: Hsien-Yuan Lane: National Science and Technology Council, Taiwan (NSTC 114-2629-B-039-001-); The China Medical University Hospital Research Project (DMR-113-009 and DMR-114-046). Philippe Mortier: Miguel Servet grant CP21/00078 co–financed by the Instituto de Salud Carlos III (ISCIII) and co–funded by the European Union; grant PI22/00107 funded by ISCIII and co–funded by the European Union; and grant 202220–30–31 from the Fundació la Marató de TV3. Heidi Taipale: Sigrid Jusélius Foundation grant.

Pharmacotherapy may reduce overall suicide risk in bipolar disorder, but prescribed medicines can also be causative agents in suicidal and accidental poisonings. This nationwide, nested case–control study utilized data from several national registers in Finland in 1996–2018. In a cohort of 60 045 individuals aged 15–65 with bipolar disorder, cases with fatal poisoning due to medicines or illicit substances were matched by age and sex to four controls each. The association between fatal poisoning and medicine use in the prior 2 weeks was examined using conditional logistic regression. The 777 (1.3%) cases who died of poisoning due to medicines or illicit substances during the study period were matched to 3108 controls. Of cases, 56.5% ( n = 439) died of a suicidal poisoning and 38.4% ( n = 298) of an accidental poisoning. After adjusting for sociodemographic characters, comorbidities and other medicine use, tricyclic antidepressants (aOR 3.07, 95% CI 2.09–4.50), gabapentinoids (3.05, 2.08–4.47), opioids (2.65, 1.88–3.75), benzodiazepines (2.13, 1.71–2.64), Z‐drugs (2.19, 1.66–2.88) and antipsychotics (1.94, 1.56–2.40) were associated with fatal poisonings. While the associations may reflect clinical severity of the disorder among users of these medicines, increased caution is warranted when prescribing them to individuals at elevated risk of poisoning.

Aims: This study aimed to investigate the incidence of low‐dose quetiapine initiation and associated factors in adults newly diagnosed with depression in primary care. Methods: We obtained medication dispensing records, primary and secondary care diagnoses and employment status for antipsychotic‐naïve individuals aged 16–65 newly diagnosed with depression in primary healthcare from several national Finnish registers in 2016–2022. We then calculated the incidence of low‐dose (≤50 mg) quetiapine initiation from 2 years before to 2 years after the depression diagnosis. Modified Poisson regression models derived adjusted risk ratios (aRRs) and 95% confidence intervals (CIs), assessing the association between covariates and low‐dose quetiapine initiation. Results: Of the 189 115 individuals with depression, 13.4% (25 373) initiated low‐dose. The incidence of low‐dose quetiapine peaked in the first 30 days following the depression diagnosis, constituting 14.8% of all initiations. Initiation had the strongest association with younger age (16–24 vs . 55–65 years: aRR 1.87, 95%CI 1.80–1.96) and psychiatric comorbidities, especially alcohol use disorder (1.44, 1.39–1.50) and other substance use disorders (1.27, 1.19–1.36). Ischaemic heart diseases had a positive association (1.13, 1.04–1.22), while hyperlipidaemia had a negative association (0.91, 0.86–0.97); other cardiometabolic conditions had no significant associations. Among other medications assessed, SSRI and hypnotic antidepressant use had the strongest associations with low‐dose quetiapine initiation (1.81, 1.77–1.86 and 1.81, 1.77–1.85, respectively). Conclusions: Low‐dose quetiapine initiation is common among adults newly diagnosed with depression in primary care. The benefits of this practice should be weighed against cardiometabolic and other adverse effects.

Background: Pharmacotherapies have shown limited efficacy in cannabis use disorder (CUD). This exploratory study examined the real-world effectiveness of commonly used psychiatric medications in reducing the risk of substance use and psychiatric hospitalisations among individuals with CUD. Methods: We conducted a nationwide prospective cohort study using Swedish health and administrative registers. The cohort included 51,947 individuals aged 16–64 years with a first CUD diagnosis (ICD-10 F12) between 2006 and 2021. Medication use was modelled as time-dependent with the PRE2DUP method. Within-individual Cox regression was used to compare hospitalisation risk during medication use versus non-use. The primary outcome was hospitalisation for substance use disorder (SUD). Results: ADHD (aHR: 0.85; 95% CI: 0.81–0.88) and SUD medications (aHR: 0.97; 0.93–0.99) were associated with reduced SUD hospitalisation risk. In contrast, antipsychotics (aHR: 1.12; 1.09–1.15), antidepressants (aHR: 1.09; 1.06–1.11), and benzodiazepines (aHR: 1.14; 1.11–1.17) were associated with increased risk, while mood stabilisers showed no significant effect. Specific agents, including clozapine (aHR: 0.47; 0.31–0.73), naltrexone (aHR: 0.79; 0.71–0.88), buprenorphine (aHR: 0.92; 0.88–0.96), lisdexamfetamine (aHR: 0.74; 0.69–0.79), methylphenidate (aHR: 0.90; 0.86–0.94), and ADHD polytherapy (aHR: 0.85; 0.75–0.96), were associated with reduced risk. Conclusions: Most psychiatric medications were not associated with a reduced risk of SUD in individuals diagnosed with CUD. However, pharmacotherapies for ADHD, opioid or alcohol use disorder, and treatment-resistant schizophrenia were linked to better outcomes, likely reflecting the underlying clinical trajectories of other comorbid psychiatric disorders rather than direct therapeutic effects on CUD.

Background: Comorbid attention-deficit/hyperactivity disorder (ADHD) increases the burden in bipolar disorder (BD). Concerns about the risk/benefit balance of ADHD treatment have been raised. Objective: This study aimed to investigate the association between hospital admissions and add-on ADHD medications to antipsychotics and/or mood-stabilisers (APs/MSs) compared with AP/MS alone in BD. Methods: Individuals with BD prescribed ADHD medications in Sweden during 2006–2021 were identified from national registers of inpatient care, specialised outpatient care, sickness absence and disability pension. ADHD treatment was defined as stimulants (mostly methylphenidate and lisdexamfetamine, rarely amphetamine, dexamphetamine) and non-stimulants (atomoxetine, modafinil). Add-on ADHD treatment to concomitant AP/MS was compared with treatment periods with AP/MS without ADHD treatment, using within-individual models where individuals acted as their own control. Adjusted HRs (aHRs) and CIs (95% CIs) were calculated for the primary outcome of psychiatric hospitalisation, and for the secondary outcomes: substance-use-related, somatic or mania-related hospitalisations, and all-cause hospitalisation/mortality. Results: Altogether, 17 971 individuals (mean age=32.0±11.6 years, males=37.6%, ADHD=88.9%, follow-up=8.9±4.4 years) with BD who used any ADHD treatment were included. compared with the use of AP/MS alone, add-on stimulant use was related to a lower risk of psychiatric hospitalisations (aHR=0.89, 95% CI 0.85 to 0.93), substance-related hospitalisations (aHR=0.75, 95% CI 0.70 to 0.81) and all-cause hospitalisations/mortality (aHR=0.90, 95% CI 0.87 to 0.93), but was not associated with increased risk for somatic (aHR=1.00, 95% CI 0.90 to 1.12) or mania-related hospitalisations (aHR=0.93, 95% CI 0.72 to 1.20). Of commonly used specific ADHD medications, add-on lisdexamfetamine (aHR=0.81, 95% CI 0.75 to 0.87) and methylphenidate (aHR=0.92, 95% CI 0.88 to 0.97) were associated with decreased risk of psychiatric hospitalisations while add-on atomoxetine was not. Findings on substance-use-related hospitalisations were significant only for stimulants, specifically lisdexamfetamine (aHR=0.70, 95% CI 0.61 to 0.79) and methylphenidate (aHR=0.80, 95% CI 0.74 to 0.86). Conclusions: Among individuals with BD who received ADHD medications, add-on lisdexamfetamine and methylphenidate were associated with lower risks of psychiatric and substance-use-related hospital admissions, compared with AP/MS use alone. No significant association was found between ADHD medication use and mania-related hospitalisations or somatic admissions when these medications were used together with AP/MS. Larger samples are needed to reach adequate statistical power and conclusive findings on atomoxetine, dexamfetamine and modafinil. Clinical implications: The findings of this study suggested that the treatment of comorbid ADHD could be considered after adequate mood-stabilisation in patients with BD.

Background: Randomised trials suggest long-acting injectable antipsychotics (LAIs) may outperform oral antipsychotics (OAPs) regarding adherence and relapse prevention in bipolar disorder (BD). We aimed to compare the effectiveness and tolerability of LAIs versus OAPs in observational studies. Methods: Searching MEDLINE/Embase/PsycINFO until March-25-2025, we conducted a systematic review and random-effects meta-analysis (pre-registered protocol: https://osf.io/gkwrp ) of observational studies comparing LAIs versus OAPs in people with BD (primary outcome = study-defined relapse/psychiatric hospitalisation). Results: Seventeen studies (4 = cohort, 13 = mirror-image studies; 6186/3676 participants with BD, respectively, high-quality per Newcastle–Ottawa Scale Score ≥7 = 47.1%) were included. The relative risk (RR) for study-defined relapse/psychiatric hospitalisation was significantly lower with LAIs versus OAPs in cohort ( k = 4, RR = 0.63, 95% confidence interval (CI) = 0.44;0.90, P = 0.026) and mirror-image studies ( k = 5, RR = 0.46, 95% CI = 0.28;0.77, P = 0.013). LAIs were not significantly superior to OAPs in high-quality cohort studies ( k = 3, P = 0.78) but in those adjusted for >5 factors ( k = 2, RR = 0.56, 95% CI = 0.37;0.84, P = 0.006) nor in high-quality mirror-image studies ( k = 2, P = 0.38), but in each second-generation antipsychotic-LAIs study (aripiprazole-LAI: k = 2, risperidone-LAI: k = 1) ( k = 3, RR = 0.40, 95% CI = 0.20;0.80, P = 0.03). In cohort studies, LAIs and OAPs did not differ regarding psychiatric hospitalisations ( k = 3, P = 0.078) but data on discontinuation and mortality risk were lacking/not meta-analysable. In mirror-image studies, LAIs were associated with significantly lower psychiatric ( k = 4, RR = 0.50, 95% CI = 0.25;0.99, P = 0.048) and depression-related ( k = 2, RR = 0.46, 95% CI = 0.24;0.86, P = 0.014), but not mania-related hospitalisation risk ( k = 2, P = 0.075). LAIs were associated with fewer psychiatric hospitalisations ( k = 7, SMD = −1.73, 95% CI = −2.88;−0.57, P = 0.011), hospitalisation days ( k = 9, SMD = −1.35, 95% CI = −2.19;−0.52, P = 0.006), mania-related hospitalisations ( k = 3, SMD = −0.87, 95% CI = −1.19;−0.56, P < 0.001) and manic episodes ( k = 3, SMD = −1.13, 95% CI = −2.00;−0.26, P = 0.03), but not any mood ( k = 4, P = 0.13) or depressive episodes ( k = 3, P = 0.14). Tolerability outcomes were missing, and GRADE certainty-of-evidence was “ low” to “very low”. Discussion: LAIs were superior versus OAPs in preventing relapse/hospitalisation in cohort and mirror-image studies, in the latter particularly for mania-related outcomes. More robust mirror-image and controlled cohort studies are needed to better assess the effectiveness and tolerability of LAI antipsychotics in BD. Plain Language Summary Title: Effectiveness of Long-Acting Injectable Antipsychotics versus Oral Antipsychotics in People with Bipolar Disorder: A Systematic Review and Meta-Analysis of Observational Studies