Antipsychotic medications and sleep problems in patients with schizophrenia.

BACKGROUND: Sleep problems are common and related to a worse quality of life in patients with schizophrenia. Almost all patients with schizophrenia use antipsychotic medications, which usually increase sleep. Still, the differences in subjective sleep outcomes between different antipsychotic medications are not entirely clear. METHODS: This study assessed 5466 patients with schizophrenia and is part of the nationwide Finnish SUPER study. We examined how the five most common antipsychotic medications (clozapine, olanzapine, quetiapine, aripiprazole, and risperidone) associate with questionnaire-based sleep problems in logistic regression analyses, including head-to-head analyses between different antipsychotic medications. The sleep problems were difficulties initiating sleep, early morning awakenings, fatigue, poor sleep quality, short (≤6 h) and long sleep duration (≥10 h). RESULTS: The average number of antipsychotic medications was 1.59 per patient. Clozapine was associated with long sleep duration (49.0 % of clozapine users vs 30.2 % of other patients, OR = 2.05, 95 % CI 1.83-2.30, p < .001). Olanzapine and risperidone were in head-to-head analyses associated with less sleep problems than patients using aripiprazole, quetiapine, or no antipsychotic medication. Aripiprazole and quetiapine were associated with more insomnia symptoms and poorer sleep quality. Patients without antipsychotic medications (N = 159) had poorer sleep quality than patients with antipsychotic use, and short sleep duration was common (21.5 % of patients using antipsychotics vs 7.8 % of patients using antipsychotics, OR = 2.97, 95 % CI 1.98-4.44, p < .001). CONCLUSIONS: Prevalence of sleep problems is markedly related to the antipsychotic medication the patient uses. These findings underline the importance of considering and assessing sleep problems when treating schizophrenia patients with antipsychotics.

Long-term benzodiazepine use and risk of labor market marginalization in Finland: A cohort study with 5-year follow-up.

BACKGROUND: Benzodiazepines and related drugs (BZDRs) are widely used in the treatment of anxiety and sleep disorders, but cognitive adverse effects have been reported in long-term use, and these may increase the risk of labor market marginalization (LMM). The aim of this study was to investigate whether the risk of LMM is associated with new long-term BZDR use compared to short-term use. METHODS: This register-based nationwide cohort study from Finland included 37,703 incident BZDR users aged 18-60 years who initiated BZDR use in 2006. During the first year of use, BZDR users were categorized as long-term users (≥180 days) versus short-term users based on PRE2DUP method. The main outcome was LMM, defined as receipt of disability pension, long-term sickness absence (>90 days), or long-term unemployment (>180 days). The risk of outcomes was analyzed with Cox regression models, adjusted with sociodemographic background, somatic and psychiatric morbidity, other types of medication and previous sickness absence. RESULTS: During 5 years of follow-up, long-term use (34.4%, N = 12,962) was associated with 27% (adjusted Hazard Ratio, aHR 1.27, 95% CI 1.23-1.31) increased risk of LMM compared with short-term use. Long-term use was associated with 42% (aHR 1.42, 95% CI 1.34-1.50) increased risk of disability pension and 26% increased risk of both long-term unemployment and long-term sickness absence. CONCLUSIONS: These results indicate that long-term use of BZDRs is associated with increased risk of dropping out from labor market. This may be partly explained by cognitive adverse effects of prolonged BZDR use, which should be taken into account when prescribing BZDRs.

Investment by maternal grandmother buffers children against the impacts of adverse early life experiences.

Exogenous shocks during sensitive periods of development can have long-lasting effects on adult phenotypes including behavior, survival and reproduction. Cooperative breeding, such as grandparental care in humans and some other mammal species, is believed to have evolved partly in order to cope with challenging environments. Nevertheless, studies addressing whether grandparental investment can buffer the development of grandchildren from multiple adversities early in life are few and have provided mixed results, perhaps owing to difficulties drawing causal inferences from non-experimental data. Using population-based data of English and Welsh adolescents (sample size ranging from 817 to 1197), we examined whether grandparental investment reduces emotional and behavioral problems in children resulting from facing multiple adverse early life experiences (AELEs), by employing instrumental variable regression in a Bayesian structural equation modeling framework to better justify causal interpretations of the results. When children had faced multiple AELEs, the investment of maternal grandmothers reduced, but could not fully erase, their emotional and behavioral problems. No such result was observed in the case of the investment of other grandparent types. These findings indicate that in adverse environmental conditions the investment of maternal grandmothers can improve child wellbeing.

Development and Validation of a Machine Learning-Based Model of Mortality Risk in First-Episode Psychosis.

Importance: There is an absence of mortality risk assessment tools in first-episode psychosis (FEP) that could enable personalized interventions. Objective: To examine the feasibility of machine learning (ML) in discerning mortality risk in FEP and to assess whether such risk predictions can inform pharmacotherapy choices. Design, Setting, and Participants: In this prognostic study, Swedish nationwide cohort data (from July 1, 2006, to December 31, 2021) were harnessed for model development and validation. Finnish cohort data (from January 1, 1998, to December 31, 2017) were used for external validation. Data analyses were completed between December 2022 and December 2023. Main Outcomes and Measures: Fifty-one nationwide register variables, encompassing demographics and clinical and work-related histories, were subjected to ML to predict future mortality risk. The ML model's performance was evaluated by calculating the area under the receiver operating characteristic curve (AUROC). The comparative effectiveness of pharmacotherapies in patients was assessed and was stratified by the ML model to those with predicted high mortality risk (vs low risk), using the between-individual hazard ratio (HR). The 5 most important variables were then identified and a model was retrained using these variables in the discovery sample. Results: This study included 24 052 Swedish participants (20 000 in the discovery sample and 4052 in the validation sample) and 1490 Finnish participants (in the validation sample). Swedish participants had a mean (SD) age of 29.1 (8.1) years, 62.1% were men, and 418 died with 2 years. Finnish participants had a mean (SD) age of 29.7 (8.0) years, 61.7% were men, and 31 died within 2 years. The discovery sample achieved an AUROC of 0.71 (95% CI, 0.68-0.74) for 2-year mortality prediction. Using the 5 most important variables (ie, the top 10% [substance use comorbidities, first hospitalization duration due to FEP, male sex, prior somatic hospitalizations, and age]), the final model resulted in an AUROC of 0.70 (95% CI, 0.63-0.76) in the Swedish sample and 0.67 (95% CI, 0.56-0.78) in the Finnish sample. Individuals with predicted high mortality risk had an elevated 15-year risk in the Swedish sample (HR, 3.77 [95% CI, 2.92-4.88]) and an elevated 20-year risk in the Finnish sample (HR, 3.72 [95% CI, 2.67-5.18]). For those with predicted high mortality risk, long-acting injectable antipsychotics (HR, 0.45 [95% CI, 0.23-0.88]) and mood stabilizers (HR, 0.64 [95% CI, 0.46-0.90]) were associated with decreased mortality risk. Conversely, for those predicted to survive, only oral aripiprazole (HR, 0.38 [95% CI, 0.20-0.69]) and risperidone (HR, 0.38 [95% CI, 0.18-0.82]) were associated with decreased mortality risk. Conclusions and Relevance: In this prognostic study, an ML-based model was developed and validated to predict mortality risk in FEP. These findings may help to develop personalized interventions to mitigate mortality risk in FEP.

Antipsychotic Use and Psychiatric Hospitalization in First-Episode Non-affective Psychosis and Cannabis Use Disorder: A Swedish Nationwide Cohort Study.

BACKGROUND AND HYPOTHESIS: There is a paucity of research on treatment outcomes of patients with psychosis and cannabis use disorder (CUD). We aimed to compare the effectiveness of antipsychotics in reducing the risk of hospitalization in patients with first-episode psychosis (FEP) and co-occurring CUD. STUDY DESIGN: We utilized a nationwide Swedish cohort of patients with longitudinal register data from the year 2006 to 2021. Participants were patients with FEP and co-occurring CUD (n = 1820, 84.73% men, mean age 26.80 years, SD 8.25 years). The main outcome was hospitalization due to psychotic relapse. Hospitalization due to any psychiatric disorder or substance use disorder (SUD) were examined as secondary outcomes. Within-individual Cox regression models were used to study these associations. STUDY RESULTS: Use of any antipsychotic was associated with a 33% risk reduction of psychotic relapse (aHR = 0.67; 95% CI 0.60-0.75). Clozapine (0.43; 0.29-0.64), long-acting injectable (LAI) formulations of risperidone (0.40; 0.22-0.71), aripiprazole (0.42; 0.27-0.65), and paliperidone (0.46; 0.30-0.69) were associated with the lowest risk of relapse. The association between the LAI formulation of olanzapine and hospitalization due to psychosis was statistically non-significant (0.61; 0.35-1.05). Clozapine was associated with an 86% risk reduction of hospitalization due to SUD (0.14; 0.05-0.44). Of oral non-clozapine antipsychotics, aripiprazole was associated with the lowest risk of hospitalization due to psychotic relapse (0.61; 0.45-0.83). CONCLUSIONS: These findings support the use of clozapine, LAI formulations of second-generation antipsychotics other than olanzapine, or oral aripiprazole to prevent hospitalization in FEP and co-occurring CUD.

Attention-Deficit/Hyperactivity Disorder Medications and Work Disability and Mental Health Outcomes.

Importance: Individuals with attention-deficit/hyperactivity disorder (ADHD) often have comorbid psychiatric conditions. Relatively little is known about how specific ADHD medications are associated with overall treatment outcomes among these patients. Objective: To investigate the association of the use of specific ADHD medications with hospitalization outcomes and work disability among adolescents and adults with ADHD. Design, Setting, and Participants: This nationwide register-based cohort study identified individuals (aged 16-65 years) with ADHD from Swedish nationwide registers of inpatient health care, specialized outpatient health care, sickness absence, and disability pension during the years 2006 to 2021. Data analysis was performed from November 2022 to August 2023. Exposure: Use of specific ADHD medications. Main Outcomes and Measures: The main outcome measure was psychiatric hospitalization, and secondary outcomes were suicide attempt and/or death by suicide, nonpsychiatric hospitalization, and work disability (ie, sickness absence or disability pension). The risk of outcomes between use vs nonuse periods of ADHD medications was compared in a within-individual design, where a person acts as their own control, and was analyzed with stratified Cox models. Results: A total of 221 714 persons with ADHD were included in the study cohort (mean [SD] age, 25.0 [11.2] years; 120 968 male individuals [54.6%]). Methylphenidate was the most commonly used ADHD medication (151 837 individuals [68.5%]), followed by lisdexamphetamine (78 106 individuals [35.2%]) during the follow-up (mean [SD], 7.0 [4.7] years). The following medications were associated with a decreased risk of psychiatric hospitalization: amphetamine (adjusted hazard ratio [aHR], 0.74; 95% CI, 0.61-0.90), lisdexamphetamine (aHR, 0.80; 95% CI, 0.78-0.82), ADHD drug polytherapy (aHR, 0.85; 95% CI, 0.82-0.88), dexamphetamine (aHR, 0.88; 95% CI, 0.83-0.94), and methylphenidate (aHR, 0.93; 95% CI, 0.92-0.95). No associations were found for modafinil, atomoxetine, clonidine, and guanfacine. Decreased risk of suicidal behavior was associated with the use of dexamphetamine (aHR, 0.69; 95% CI, 0.53-0.89), lisdexamphetamine (aHR, 0.76; 95% CI, 0.68-0.84), and methylphenidate (aHR, 0.92; 95% CI, 0.86-0.98). None of the medications was associated with increased risk of nonpsychiatric hospitalization; instead, use of amphetamine, lisdexamphetamine, polytherapy, dexamphetamine, methylphenidate, and atomoxetine were associated with decreased risk of nonpsychiatric hospitalization. The results regarding work disability were significant only for the use of atomoxetine (aHR, 0.89; 95% CI, 0.82-0.97), especially among adolescents and young adults aged 16 to 29 years, (aHR, 0.82; 95% CI, 0.73-0.92). Conclusions and Relevance: In this nationwide cohort study of adolescents and adults with ADHD, the use of ADHD medication was associated with fewer hospitalizations for both psychiatric and nonpsychiatric morbidity and lower suicidal behavior.

Efficacy and effectiveness of antipsychotics in schizophrenia: network meta-analyses combining evidence from randomised controlled trials and real-world data.

BACKGROUND: There is debate about the generalisability of results from randomised clinical trials (RCTs) to real-world settings. Studying outcomes of treatments for schizophrenia can shed light on this issue and inform treatment guidelines. We therefore compared the efficacy and effectiveness of antipsychotics for relapse prevention in schizophrenia and estimated overall treatment effects using all available RCT and real-world evidence. METHODS: We conducted network meta-analyses using individual participant data from Swedish and Finnish national registries and aggregate data from RCTs. The target population was adults (age >18 and <65 years) with schizophrenia and schizoaffective disorder with stabilised symptoms. We analysed each registry separately to obtain hazard ratios (HRs) and 95% CIs for relapse within 6 months post-antipsychotic initiation as our main outcome. Interventions studied were antipsychotics, no antipsychotic use, and placebo. We compared HRs versus a reference drug (oral haloperidol) between registries, and between registry individuals who would be eligible and ineligible for RCTs, using the ratio of HRs. We synthesised evidence using network meta-analysis and compared results from our network meta-analysis of real-world data with our network meta-analysis of RCT data, including oral versus long-acting injectable (LAI) formulations. Finally, we conducted a joint real-world and RCT network meta-analysis. FINDINGS: We included 90 469 individuals from the Swedish and Finnish registries (mean age 45·9 [SD 14·6] years; 43 025 [47·5%] women and 47 467 [52·5%] men, ethnicity data unavailable) and 10 091 individuals from 30 RCTs (mean age 39·6 years [SD 11·7]; 3724 [36·9%] women and 6367 [63·1%] men, 6022 White [59·7%]). We found good agreement in effectiveness of antipsychotics between Swedish and Finnish registries (HR ratio 0·97, 95% CI 0·88-1·08). Drug effectiveness versus no antipsychotic was larger in RCT-eligible than RCT-ineligible individuals (HR ratio 1·40 [1·24-1·59]). Efficacy versus placebo in RCTs was larger than effectiveness versus no antipsychotic in real-world (HR ratio 2·58 [2·02-3·30]). We found no evidence of differences between effectiveness and efficacy for between-drug comparisons (HR ratio vs oral haloperidol 1·17 [0·83-1·65], where HR ratio >1 means superior effectiveness in real-world to RCTs), except for LAI versus oral comparisons (HR ratio 0·73 [0·53-0·99], indicating superior effectiveness in real-world data relative to RCTs). The real-world network meta-analysis showed clozapine was most effective, followed by olanzapine LAI. The RCT network meta-analysis exhibited heterogeneity and inconsistency. The joint real-world and RCT network meta-analysis identified olanzapine as the most efficacious antipsychotic amongst those present in both RCTs and the real world registries. INTERPRETATION: LAI antipsychotics perform slightly better in the real world than according to RCTs. Otherwise, RCT evidence was in line with real-world evidence for most between-drug comparisons, but RCTs might overestimate effectiveness of antipsychotics observed in routine care settings. Our results further the understanding of the generalisability of RCT findings to clinical practice and can inform preferential prescribing guidelines. FUNDING: None.

Labour market integration among young adults diagnosed with attention-deficit/hyperactivity disorder (ADHD) at working age.

METHODS: Multiple Swedish nationwide registers were used to identify 8045 individuals, aged 20-29, with an incident diagnosis of ADHD 2006-2011. Labour market integration was conceptualized according to the core-peripheral model as a continuum from a strong (core) to a weak (peripheral) connection to the labour market. Sequence analyses categorized clusters of labour market integration, from 1 year before to 5 years after their ADHD diagnosis for individuals diagnosed with ADHD and a matched control group without ADHD. Multinomial logistic regression computed odds ratios (ORs) with 95% confidence intervals (CIs) between sociodemographic factors and comorbid disorders and the identified clusters. RESULTS: About one-fourth of the young adults diagnosed with ADHD belonged to clusters characterized by a transition to a mainly peripheral labour market position, which was approximately four-times higher compared to controls without ADHD. Foremost, those living in small cities/villages (OR 1.9; CI 1.5-2.2), those having comorbid autism-spectrum disorder (OR 13.7; CI 6.8-27.5) or schizophrenia/psychoses (OR 7.8; CI 3.8-15.9) were associated with a transition towards a peripheral labour market position throughout the study period. Those with a high educational level (OR 0.1; CI 0.1-0.1), and men (OR 0.7; CI 0.6-0.8) were less likely to have a peripheral labour market position. CONCLUSIONS: Young adults diagnosed with ADHD are four-times more likely to be in the peripheral labour market position compared to those without ADHD. To increase labour market participation, special attention is warranted to those with low educational level, those living outside big cities and those with comorbid mental disorders.

Step-Gap in Upward Support: The Role of Biological Relatedness and Childhood Co-residence Duration.

OBJECTIVES: Although prior research has detected a step-gap in intergenerational relationships in various aspects, there is a lack of studies examining adult children's support toward their biological parents and stepparents. We investigated (i) whether adult children provide more support to their biological parents than stepparents and (ii) whether the childhood co-residence duration is associated with the support given to stepparents. METHODS: The data were drawn from the German Family Panel (pairfam). Upward support was indicated by using 3 different measures, namely, financial, practical, and emotional support provided by adult children to their biological parents and stepparents. A path analysis was conducted to detect the potential differences regarding upward support. RESULTS: More support was channeled toward the biological parents than the stepparents. Moreover, the length of co-residence during childhood and adolescence was positively associated with the frequency of support provided toward the stepparents. Consequently, an increased childhood co-residence duration decreased the step-gap in upward support, although it did not fully eliminate it. DISCUSSION: The findings showed that stepparents are in a more disadvantaged position than the biological parents regarding receiving support from their adult children. In the context of a high old-age dependency ratio, it is important to recognize that stepparents may not have the opportunity to receive adequate support from their families as compared to individuals with biological children.

Effect of severity of depression on augmentation of antidepressant medication in young adults with depression.

BACKGROUND: Antipsychotics (AP) have been used to augment antidepressant (AD) medication in treatment-resistant depression. In this study we examined factors (including severity of depression and initial antidepressant) affecting AP augmentation, as well as which APs were initiated as augmentation in young adults. METHODS: Data were extracted from Finnish nationwide registers. Of persons aged 18-29 years diagnosed with a depression during 2004-2017 we focused on incident AD users (who initiated AD 6 months before and after the diagnosis) whose severity level of depression was recorded (N = 21,966). AP augmentation was studied during 1 year after diagnosis of depression. Persons diagnosed with severe depression with psychotic features (n = 1486) were excluded from main analyses and analyzed separately. RESULTS: Overall, 8.4% of new antidepressant users initiated AP augmentation. Risk of augmentation increased with severity of depression as 3.9%, 5.8%, and 14.0% of persons with mild, moderate, and severe depression, respectively, initiated augmentation. Male sex, comorbid anxiety and personality disorders, substance abuse and selfharm/suicide attempt were positively associated with augmentation. Compared to citalopram, use of tricyclic antidepressant, paroxetine and venlafaxine were associated with increased risk of augmentation, while use of bupropion was associated with a decreased risk. Quetiapine and risperidone were the most common APs used in augmentation. Among persons with severe depression with psychotic features, use of sertraline was associated with AP augmentation, whereas use of fluoxetine decreased risk of augmentation. CONCLUSIONS: Use of APs as augmentation of AD therapy was common in severe depression. Comorbidities had only a small effect to augmentation, but selection of initial AD was more closely associated to risk of augmentation. Interestingly, use of bupropion decreased risk of augmentation, which warrants further studies, as well as the decrease in risk of augmentation when fluoxetine in case of psychotic depression was used.

Maternal psychiatric and somatic illness, and the risk of unintentional injuries in children: variation by type of maternal illness, type of injury and child age.

BACKGROUND: Maternal mental illness appears to increase the risk of unintentional childhood injuries, which are a common cause of morbidity and mortality in early childhood. However, little is known about the variations in this association by type of injury and child's age, and studies on the effects of maternal somatic illness on children's injury risk are scarce. METHODS: We used Finnish total population register data from 2000 to 2017 to link 1 369 325 children to their biological mothers and followed them for maternal illness and childhood injuries until the children's sixth birthday. Cox regression models were used to examine the associations between maternal illness and children's injuries by type of illness (neurological, psychiatric and cancer), type of injury (transport injuries, falls, burns, drowning or suffocations, poisonings, exposure to inanimate and animate mechanical forces) and child's age (<1 year-olds, 1-2 year-olds, 3-5 year-olds). RESULTS: After adjustment for family structure, maternal age at birth, maternal education, income, child's gender, native language and region of residence, children of unwell mothers showed a higher risk of injuries (HR: 1.21, 95% CI: 1.19 to 1.23). This association was clear for maternal neurological (HR: 1.31, 95% CI: 1.26 to 1.36) and psychiatric illnesses (HR: 1.20, 95% CI: 1.18 to 1.23) but inconsistent for cancer. Maternal illness predicted an increased risk of injury across all age groups. CONCLUSIONS: Maternal mental and somatic illness may both increase children's injury risk. Adequate social and parenting support for families with maternal illness may reduce childhood injury.

Sustainable labour market participation among working young adults with diagnosed attention deficit/hyperactivity disorder (ADHD).

Background: The aims were to study the sustainability of labour-market participation five years after an incident diagnosis of attention-deficit/hyperactivity disorder (ADHD) among young adults with gainful employment, and to examine the impact of sociodemographic-, work- and health-related factors on these findings. Methods: Swedish registers identified 2517 individuals, 19-29 years old, with an incident diagnosis of ADHD and gainful employment during 2006-2011. Labour-market participation was measured by the core-peripheral model, a model that measures the connection to the labour market from a weak connection (peripheral) to a strong connection (core). Sequence analysis analysed clusters of labour-market participation, from one year before and up to five years after diagnosis. Odds ratios (OR) with 95% confidence intervals (CI) between sociodemographic factors, comorbid disorders, and the identified clusters were analysed by multinomial logistic regression. Results: Five clusters of labour-market participation were identified: 60% of individuals belonged to a cluster that maintained labour-market participation throughout the study period (core, close to core); 20% belonged to a cluster with a transition to a weak connection to the labour market (close to peripheral, peripheral); and 20% belonged to a cluster with "middle" labour-market participation, characterised by having long periods of sick leave and unemployment. Individuals with elementary school as highest attained education (OR:4.03;CI:2.35-6.93), comorbid mental disorders (OR:2.77;CI:2.10-3.66), or living in villages/small cities (OR:1.77;CI:1.25-2.51) were most likely to belong to a cluster transitioning towards a "peripheral" labour-market participation. Men were less likely to have peripheral labour-market participation than women (OR:0.55;CI:0.40-0.75). Conclusions: Over half of working individuals with ADHD maintain a strong attachment to the labour market several years after their first diagnosis of ADHD. Therefore, it is important to target those who have problems maintaining a position in the labour market, including women, those with low educational levels, and those living outside large cities.

Real-world use of pharmacological treatments for incident bipolar disorder: A Finnish nationwide cohort study.

BACKGROUND: Pharmacotherapy remains crucial for treating bipolar disorder (BD), but knowledge on the treatments actually used by newly diagnosed patients in real-world settings is sparse. METHODS: Individuals newly diagnosed with BD during 1996-2018, aged 15-65 years, were identified from national Finnish registers. The patients' use of different drug classes (mood stabilizers, antipsychotics and antidepressants) or combinations of these drug classes were followed from initial pharmacotherapy (first line) after BD diagnosis until the fifth line of treatment or until the two-year follow-up time ended. Clinical and sociodemographic factors associated with antidepressants-only as the first treatment line were assessed with logistic regression. RESULTS: 82.6 % of all patients used BD medication during the follow-up. 33.9 % had antidepressants-only as the first, 22.9 % as the second and 19.7 % as the third treatment line. Use of combinations of mood stabilizers, antipsychotics and antidepressants increased by successive treatment lines. Factors associated with antidepressants-only as the first treatment line included older age (>45 years aOR 2.20, 95% CI: 2.01-2.40, 25-45 years: 1.55, 1.42-1.68, compared with those aged <25), diabetes (1.35, 1.17-1.55) and female sex (1.29, 1.21-1.37). BD diagnosis registered in 2016-2018 (0.48, 0.42-0.55) and substance abuse (0.77, 0.71-0.83) were associated with decreased odds. LIMITATIONS: Due to the register-based nature of this study, not all potentially important clinical factors influencing medication use could be controlled for. CONCLUSIONS: A large proportion of patients with bipolar disorder are not treated according to treatment guidelines, as use of antidepressants alone is common. Reasons for not following evidence-based recommendations need to be further researched.

Real-world effectiveness of pharmacological treatments for bipolar disorder: register-based national cohort study.

BACKGROUND: Pharmacological treatment patterns for bipolar disorder have changed during recent years, but for better or worse? AIMS: To investigate the comparative real-world effectiveness of antipsychotics and mood stabilisers in bipolar disorder. METHOD: Register-based cohort study including all Finnish residents aged 16-65 with a diagnosis of bipolar disorder from in-patient care, specialised out-patient care, sickness absence and disability pensions registers between 1996 and 2018, with a mean follow-up of 9.3 years (s.d. = 6.4). Antipsychotic and mood stabiliser use was modelled using the PRE2DUP method and risk for hospital admission for psychiatric and non-psychiatric reasons when using versus not using medications was estimated using within-individual Cox models. RESULTS: Among 60 045 individuals (56.4% female; mean age 41.7 years, s.d. = 15.8), the five medications associated with lowest risk of psychiatric admissions were olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37-0.80), haloperidol LAI (aHR = 0.62, 0.47-0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52-0.85), lithium (aHR = 0.74, 95% CI 0.71-0.76) and clozapine (aHR = 0.75, 95% CI 0.64-0.87). Only ziprasidone (aHR = 1.26, 95% CI 1.07-1.49) was associated with a statistically higher risk. For non-psychiatric (somatic) admissions, only lithium (aHR = 0.77, 95% CI 0.74-0.81) and carbamazepine (aHR = 0.91, 95% CI 0.85-0.97) were associated with significantly reduced risk, whereas pregabalin, gabapentin and several oral antipsychotics, including quetiapine, were associated with an increased risk. Results for a subcohort of first-episode patients (26 395 individuals, 54.9% female; mean age 38.2 years, s.d. = 13.0) were in line with those of the total cohort. CONCLUSIONS: Lithium and certain LAI antipsychotics were associated with lowest risks of psychiatric admission. Lithium was the only treatment associated with decreased risk of both psychiatric and somatic admissions.

Cause-specific excess mortality after first diagnosis of bipolar disorder: population-based cohort study.

BACKGROUND: Bipolar disorder (BD) is associated with increased mortality, but evidence on cause-specific mortality is limited. OBJECTIVE: To investigate cause-specific premature excess mortality in BD. METHODS: Finnish nationwide cohort study of individuals with and without a diagnosis of BD who were aged 15-64 years during 2004-2018. Standardised mortality ratios (SMRs) with 95% CIs were calculated for BD using the mortality rates in the Finnish general population without BD as weights. Causes of death were defined by the International Classification of Diseases, 10th revision codes. FINDINGS: Of the included 47 018 individuals with BD, 3300 (7%) died during follow-up. Individuals with BD had sixfold higher mortality due to external causes (SMR: 6.01, 95% CI: 5.68, 6.34) and twofold higher mortality due to somatic causes (SMR: 2.06, 95% CI: 1.97, 2.15). Of the deaths due to external causes, 83% (1061/1273) were excess deaths, whereas 51% (1043/2027) of the deaths due to somatic causes were excess. About twice the number of potential years of life were lost in excess due to external causes than due to somatic causes. Alcohol-related causes contributed more to excess mortality than deaths due to cardiovascular disease. CONCLUSION: External causes of death contributed more to the mortality gap than somatic causes after controlling for age-specific background general population mortality. CLINICAL IMPLICATION: A balanced consideration between therapeutic response, different treatment options and risk of cause-specific mortality is needed to prevent premature mortality in BD and to reduce the mortality gap.

Comparative Effectiveness of Pharmacotherapies for the Risk of Attempted or Completed Suicide Among Persons With Borderline Personality Disorder.

Importance: Suicidal behavior is a significant clinical concern in individuals with borderline personality disorder (BPD), but the effectiveness of pharmacotherapy on reducing suicide risk has remained unknown. Objective: To study the comparative effectiveness of different pharmacotherapies in preventing attempted or completed suicides in patients with BPD in Sweden. Design, Setting and Participants: In this comparative effectiveness research study, nationwide Swedish register databases of inpatient care, specialized outpatient care, sickness absences, and disability pensions were used to identify patients aged 16 to 65 years with registered treatment contact due to BPD during 2006 to 2021. Data were analyzed from September to December 2022. A within-individual design was used, in which each patient was used as their own control to eliminate selection bias. To control protopathic bias, sensitivity analyses were conducted, in which the first 1 or 2 months of medication exposure were omitted from the analyses. Main outcomes and Measures: Hazard ratio (HR) for attempted or completed suicide. Results: A total of 22 601 patients with BPD (3540 [15.7%] men; mean [SD] age, 29.2 [9.9] years) were included. During the 16-year follow-up (mean [SD] follow-up, 6.9 [5.1] years), 8513 hospitalizations due to attempted suicide and 316 completed suicides were observed. Attention-deficit/hyperactive disorder (ADHD) medication treatment, compared with its nonuse, was associated with a decrease in the risk of attempted or completed suicide (HR, 0.83; 95% CI, 0.73-0.95; false discovery rate [FDR]-corrected P = .001). Treatment with mood stabilizers did not have a statistically significant association with the main outcome (HR, 0.97; 95% CI, 0.87-1.08; FDR-corrected P = .99). Antidepressant (HR, 1.38; 95% CI, 1.25-1.53; FDR-corrected P < .001) and antipsychotic (HR, 1.18; 95% CI, 1.07-1.30; FDR-corrected P < .001) treatments were associated with an elevated risk of attempted or completed suicide. Of the investigated pharmacotherapies, treatment with benzodiazepines was associated with the highest risk of attempted or completed suicide (HR, 1.61; 95% CI, 1.45-1.78; FDR-corrected P < .001). These results remained similar when controlling for potential protopathic bias. Conclusions and Relevance: In this comparative effectiveness research study of a Swedish nationwide cohort, ADHD medication was the only pharmacological treatment associated with reduced risk of suicidal behavior among patients with BPD. Conversely, the findings suggest that benzodiazepines should be used with care among patients with BPD due to their association with increased risk of suicide.

Parental Investment by Birth Fathers and Stepfathers : Roles of Mating Effort and Childhood Co-residence Duration.

This study investigates the determinants of paternal investment by birth fathers and stepfathers. Inclusive fitness theory predicts higher parental investment in birth children than stepchildren, and this has consistently been found in previous studies. Here we investigate whether paternal investment varies with childhood co-residence duration and differs between stepfathers and divorced birth fathers by comparing the investment of (1) stepfathers, (2) birth fathers who are separated from the child's mother, and (3) birth fathers who still are in a relationship with her. Path analysis was conducted using cross-sectional data from adolescents and younger adults (aged 17-19, 27-29, and 37-39 years) from the German Family Panel (pairfam), collected in 2010-2011 (n = 8326). As proxies of paternal investment, we used financial and practical help, emotional support, intimacy, and emotional closeness, as reported by the children. We found that birth fathers who were still in a relationship with the mother invested the most, and stepfathers invested the least. Furthermore, the investment of both separated fathers and stepfathers increased with the duration of co-residence with the child. However, in the case of financial help and intimacy, the effect of childhood co-residence duration was stronger in stepfathers than in separated fathers. Our findings support inclusive fitness theory and mating effort theory in explaining social behavior and family dynamics in this population. Furthermore, social environment, such as childhood co-residence was associated with paternal investment.

Differential grandparental investment when maternal grandmothers are living versus deceased.

Grandparents can increase their inclusive fitness by investing time and resources in their grandchildren. However, not all grandparents make such investments equally, and between-grandparent differences in this regard can be predicted based on paternity uncertainty, lineage and grandparents' sex. Using population-based data for English and Welsh adolescents (n = 1430), we examined whether the death of the most important grandparent (in terms of investment), the maternal grandmother (MGM), changes relative support for existing hypotheses predicting differential grandparental-investment patterns. To contrast the predictions of the grandparental investment hypotheses, we used generalized order-restricted information criterion approximation. We consequently found that, when MGMs are alive, the most-supported hypothesis is 'discriminative grandparental solicitude', which ranks grandparental investment as MGMs > maternal grandfathers (MGFs) > paternal grandmothers (PGMs) > paternal grandfathers (PGFs). However, when MGMs are deceased, the paternity uncertainty hypothesis (MGFs = PGMs > PGFs) receives the most support; this is due to increased investment by PGMs. Thus, when the heaviest investors (i.e. MGMs) are deceased, PGM investments are closer to-but do not exceed-MGF investments.

The role of sociodemographic and clinical factors in the initiation and discontinuation of attention deficit hyperactivity disorder medication among young adults in Sweden.

Introduction: Long-term medication use is a recommended treatment for attention-deficit/hyperactivity disorder (ADHD), however, discontinuation is common. Non-medical factors which might influence initiation and discontinuation are understudied. Therefore, we investigated how different sociodemographic factors and comorbidities were associated with the initiation and discontinuation of ADHD medication use among young adults. Methods and results: We conducted a population-based prospective cohort study using individually linked administrative register data, in which we included all individuals residing in Sweden, between the age of 19 and 29 who were first diagnosed with ADHD between January 2006 and December 2016 (n = 59224). ADHD medication initiation was defined as the first prescription of ADHD medication in the period from 3 months before to 6 months after the cohort entry date. Those who initiated ADHD medication were followed up for medication use until discontinuation, death/emigration, or until 2019. Logistic and Cox regression models were used to investigate the associations between sociodemographics, health-related predictors and initiation, as well as discontinuation. Overall, 48.7% of the 41399 individuals initiated ADHD medication, most often methylphenidate (87%). Among the initiators, 15462 (77%) discontinued medication use during the follow-up (median time: 150 days). After mutually adjusting all other predictors, initiation was positively associated with older age, male sex, higher level of education, and negatively associated with living at home with parents, immigrant status, being unemployed during the year before inclusion, being on disability pension, having autism, substance use, schizophrenia-spectrum disorders, other mental disability/developmental disorders, cardiovascular diseases or previous accidents. Discontinuation was positively associated with being born abroad, living in big cities, being unemployed during the year before inclusion, having cancer, and negatively associated with a higher educational level, having depression, anxiety or stress-related disorder, autism spectrum disorder or diabetes. Conclusion: Besides medical factors, sociodemographics, such as educational attainment and immigrant status might also play a role in the initiation and discontinuation of ADHD medication use among young adults newly diagnosed with ADHD.

Grandparental co-residence and grandchild survival: the role of resource competition in a pre-industrial population.

Although grandparents are and have been important alloparents to their grandchildren, they are not necessarily only beneficial but can also compete with grandchildren over limited resources. Competition over parental care or other resources may exist especially if grandparents live in the same household with grandchildren and it can be dependent on grandchild age. By utilizing demographic data collected from historic population registers in Finland between 1761 and 1895 (study sample n = 4041) we investigate whether grandparents living in the same household with grandchildren are detrimental or beneficial for grandchild survival. Having a living but not co-residing grandmother or grandfather were both associated with better survival whereas having a co-resident grandfather was associated with lower chance to survive for infants (age < 1 year). Separating the effect between maternal and paternal grandparents and grandmothers and grandfathers revealed no differences in the effects between lineages. Negative effect of having a co-residing grandfather was not significant when grandfathers were separated for lineage specific models. These results implicate that accounting for the co-residence status and child's age, grandparents were mostly beneficial when not co-residing with very young children and that having a co-residing grandfather at that age could be associated with lower chances to survive. Predictions made by grandmother hypothesis and resource competition both received support. The results presented here also offered comparison points to preindustrial and contemporary three-generational families.