Genetic contribution to microglial activation in schizophrenia.

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1ß) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.

Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. The etiology behind the disorder remains elusive although it is hypothesized to be associated with the aberrant response to neurotransmitters, such as dopamine and glutamate. Therefore, investigating the link between dysregulated metabolites and distorted neurodevelopment holds promise to offer valuable insights into the underlying mechanism of this complex disorder. In this study, we aimed to explore a presumed correlation between the transcriptome and the metabolome in a SCZ model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at various developmental stages, reflecting neuroepithelial-like cells, radial glia, young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted metabolomics and the two modalities were used to construct integrative networks in silico. This multi-omics analysis revealed significant perturbations in the polyamine and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine pathway as an alternative route for GABA production. These findings indicate an imbalance of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits to be causative for SCZ and establishes a novel in silico approach that enables for integrative correlation of metabolic and transcriptomic data of psychiatric disease models.

Dosing levels of antipsychotics and mood stabilizers in bipolar disorder: A Nationwide cohort study on relapse risk and treatment safety.

BACKGROUND: Finding effective treatment regimens for bipolar disorder is challenging, as many patients suffer from significant symptoms despite treatment. This study investigated the risk of relapse (psychiatric hospitalization) and treatment safety (non-psychiatric hospitalization) associated with different doses of antipsychotics and mood stabilizers in persons with bipolar disorder. METHODS: Individuals aged 15-65 with bipolar disorder were identified from Finnish national health registers in 1996-2018. Studied antipsychotics included olanzapine, risperidone, quetiapine, aripiprazole; mood stabilizers lithium, valproic acid, lamotrigine, and carbamazepine. Medication use was divided into three time-varying dose categories: low, standard, and high. The studied outcomes were risk of psychiatric hospitalization (relapse) and the risk of non-psychiatric hospitalization (treatment safety). Stratified Cox regression in within-individual design was used. RESULTS: The cohort included 60,045 individuals (mean age 41.7 years, SD 15.8; 56.4% female). Mean follow-up was 8.3 years (SD 5.8). Of antipsychotics, olanzapine and aripiprazole were associated with a decreased risk of relapse in low and standard doses, and risperidone in low dose. The lowest adjusted hazard ratio (aHR) was observed for standard dose aripiprazole (aHR 0.68, 95% CI 0.57-0.82). Quetiapine was not associated with a decreased risk of relapse at any dose. Mood stabilizers were associated with a decreased risk of relapse in low and standard doses; lowest aHR was observed for standard dose lithium (aHR 0.61, 95% CI 0.56-0.65). Apart from lithium, high doses of antipsychotics and mood stabilizers were associated with an increased risk of non-psychiatric hospitalization. Lithium was associated with a decreased risk of non-psychiatric hospitalization in low (aHR 0.88, 95% CI 0.84-0.93) and standard doses (aHR 0.81, 95% CI 0.74-0.88). CONCLUSIONS: Standard doses of lithium and aripiprazole were associated with the lowest risk of relapse, and standard dose of lithium with the lowest risk of non-psychiatric hospitalization. Quetiapine was not associated with decreased risk of relapse at any dose.

Cardiovascular mortality in bipolar disorder: Population-based cohort study.

BACKGROUND: Limited evidence base on cause-specific excess cardiovascular disease (CVD) mortality in bipolar disorder (BD) is a barrier to developing preventive interventions aimed at reducing the persistent mortality gap in BD. OBJECTIVE: To investigate cause-specific CVD mortality in BD. METHODS: We identified all individuals aged 15+ years during 2004-2018 with a diagnosis of BD using Finnish nationwide routine data. Standardised mortality ratios (SMR) with 95% confidence intervals (CI) were calculated using the mortality rates in the general population as weights. RESULTS: 53,273 individuals with BD (57% women; median age at BD diagnosis, 40 years), were followed up for 428,426 person-years (median, 8.2 years). There were 5988 deaths due to any cause, of which 26% were due to CVD. The leading cause of absolute excess CVD mortality was coronary artery disease (CAD). The leading causes of relative excess mortality were cardiomegaly (SMR, 4.51; 95% CI, 3.58-5.43), venous thromboembolism (3.03; 2.26-3.81), cardiomyopathy (2.46; 1.95-2.97), and hypertensive heart disease (2.12; 1.71-2.54). The leading causes of absolute CVD mortality showed markedly lower relative excess, including CAD (1.47; 1.34-1.61), ischaemic stroke (1.31; 1.06-1.54), and acute myocardial infarction (1.12; 0.98-1.25). Due to the higher relative excess mortality, structural and functional heart disorders contributed as much as atherosclerotic and ischaemic disorders to the absolute excess mortality. CONCLUSIONS: Cardiomyopathy and hypertensive heart disease as the leading causes of relative excess mortality emphasise the contribution of structural and functional heart disorders to the overall excess mortality alongside coronary artery disease. Interventions targeted at these modifiable causes of death should be priorities in the prevention of premature excess CVD mortality in BD.

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.

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.

Mortality in psychotic depression: 18-year follow-up study.

BACKGROUND: Evidence on the role of co-occurring psychiatric disorders in mortality associated with psychotic depression is limited. AIMS: To estimate the risk of cause-specific mortality in psychotic depression compared with severe non-psychotic depression while controlling for comorbid psychiatric disorders. METHOD: This cohort study used routine data from nationwide health registers in Finland. Eligible participants had their first diagnosis for psychotic depression or for severe non-psychotic depression between the years 2000 and 2018, had no pre-existing diagnoses for schizophrenia spectrum disorders or bipolar disorder, and were aged 18-65 years at the index diagnosis. Causes of death were defined by ICD-10 codes. The follow-up time was up to 18 years. RESULTS: We included 19 064 individuals with incident psychotic depression and 90 877 individuals with incident non-psychotic depression. Half (1199/2188) of the deaths in those with psychotic depression occurred within 5 years from the index diagnosis and the highest relative risk was during the first year after the diagnosis. Compared with individuals with non-psychotic depression, those with psychotic depression had a higher risk of all-cause mortality (adjusted hazard ratio, aHR = 1.59, 95% CI 1.48-1.70), suicides (aHR = 2.36, 95% CI 2.11-2.64) and fatal accidents (aHR 1.63, 95% CI 1.26-2.10) during the subsequent 5-year period after the index diagnosis. CONCLUSIONS: Psychotic symptoms markedly added to the mortality risk associated with severe depression after controlling for psychiatric comorbidity. Prompt treatment and enhanced monitoring for psychotic symptoms is warranted in all patients with severe depression to prevent deaths because of suicides and other external causes.

Functional Characterization of Six SLCO1B1 (OATP1B1) Variants Observed in Finnish Individuals with a Psychotic Disorder.

Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2',7'-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.

Association of pharmacological treatments and real-world outcomes in borderline personality disorder.

OBJECTIVE: Most patients with borderline personality disorder (BPD) receive psychopharmacological treatment, but clinical guidelines on BPD lack consensus on the role of pharmacotherapy. We investigated the comparative effectiveness of pharmacological treatments for BPD. METHODS: We identified patients with BPD with treatment contact during 2006-2018 using Swedish nationwide register databases. By leveraging within-individual design, in which each individual was used as their own control to eliminate selection bias, we assessed the comparative effectiveness of pharmacotherapies. For each medication, we calculated the hazard ratios (HRs) for the following outcomes: (1) psychiatric hospitalization and (2) hospitalization owing to any cause or death. RESULTS: We identified 17,532 patients with BPD (2649 men; mean [SD] age = 29.8 [9.9]). Treatment with benzodiazepines (HR = 1.38, 95% CI = 1.32-1.43), antipsychotics (HR = 1.19, 95% CI = 1.14-124), and antidepressants (HR = 1.18, 95% CI = 1.13-1.23) associated with increased risk of psychiatric rehospitalization. Similarly, treatment with benzodiazepines (HR = 1.37, 95% CI = 1.33-1.42), antipsychotics (HR = 1.21, 95% CI = 1.17-1.26), and antidepressants (HR = 1.17, 95% CI = 1.14-1.21) was associated with a higher risk of all-cause hospitalization or death. Treatment with mood stabilizers did not have statistically significant associations with the outcomes. Treatment with ADHD medication was associated with decreased risk of psychiatric hospitalization (HR = 0.88, 95% CI = 0.83-0.94) and decreased risk of all-cause hospitalization or death (HR = 0.86, 95% CI = 0.82-0.91). Of the specific pharmacotherapies, clozapine (HR = 0.54, 95% CI = 0.32-0.91), lisdexamphetamine (HR = 0.79, 95% CI = 0.69-0.91), bupropion (HR = 0.84, 95% CI = 0.74-0.96), and methylphenidate (HR = 0.90, 95% CI = 0.84-0.96) associated with decreased risk of psychiatric rehospitalization. CONCLUSIONS: ADHD medications were associated with a reduced risk of psychiatric rehospitalization or hospitalization owing to any cause or death among individuals with BPD. No such associations were found for benzodiazepines, antidepressants, antipsychotics, or mood stabilizers.

Real-world effectiveness of mood stabilizer use in schizophrenia.

OBJECTIVE: Mood stabilizers (MS) are often used as adjunctive medication in patients with schizophrenia. The aim of this study was to investigate the real-world effectiveness of MS use in persons with schizophrenia. METHODS: The study cohort included all persons treated in inpatient care due to schizophrenia during 1972-2014 in Finland (N = 61,889). Drug purchase data were obtained from the national Prescription register and modeled with the PRE2DUP method. The follow-up period covered the years 1996-2017. Mood stabilizers included carbamazepine, valproic acid, lamotrigine, and lithium. The main outcome was psychosis hospitalization. We utilized within-individual design to compare the risk of outcome between time-periods of MS use and non-use within the same person. Stratified Cox regression analyses were conducted with adjusted hazard ratios (aHR) and 95% confidence intervals (CIs). RESULTS: Mean age at cohort entry was 46.2 years (SD 16.0) and 50.3% were male. During the follow-up (maximum of 22 years, median 14.8 years, interquartile range 7.5-22.0), 28.1% (N = 17,370) of the study cohort used MS, valproic acid being the most often used one (60.4%, N = 10,483). Risk of psychosis hospitalization was lower during MS use than non-use (aHR 0.88, 95% CI 0.86-0.90). Use of lithium (0.84, 0.81-0.87), valproic acid (0.87, 0.85-0.90), and lamotrigine (0.90, 0.85-0.95) were associated with lower risk of psychosis hospitalization compared with their non-use, whereas carbamazepine use was not. CONCLUSIONS: Mood stabilizers were relatively often used as adjunctive treatments in schizophrenia and their use was associated with a 12% decreased risk of psychosis rehospitalization, a marker of relapse in schizophrenia.

Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia.

Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)-derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron-astrocyte co-cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ.

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder.

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Associations between antipsychotic use, substance use and relapse risk in patients with schizophrenia: real-world evidence from two national cohorts.

BACKGROUND: Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid substance use disorder (SUD) is very sparse, and non-existent on the prevention of the development of SUDs in patients with schizophrenia. AIMS: To compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risk of developing an initial SUD, and psychiatric hospital admission and SUD-related hospital admission among patients with an SUD. METHOD: Two independent national cohorts including all persons diagnosed with schizophrenia (N = 45 476) were followed up for 22 (Finland: 1996-2017) and 11 (Sweden: 2006-2016) years. Risk of developing an SUD was calculated with between-individual models, and risks of psychiatric and SUD-related hospital admission were calculated with within-individual models, using Cox regression and adjusted hazard ratios (aHRs) for using versus not using certain antipsychotics. RESULTS: For patients with schizophrenia without an SUD, clozapine use (Finland: aHR 0.20, 95% CI 0.16-0.24, P < 0.001; Sweden: aHR 0.35, 95% CI 0.24-0.50, P < 0.001) was associated with lowest risk of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (aHR 0.54, 95% CI 0.44-0.66) in Sweden, and third lowest risk (aHR 0.47, 95% CI 0.42-0.53) in Finland. Risk of relapse (psychiatric hospital admission and SUD-related hospital admission) were lowest for clozapine, antipsychotic polytherapy and long-acting injectables in both countries. Results were consistent across both countries. CONCLUSIONS: Clozapine and antipsychotic polytherapy are most strongly associated with reduced risk of developing SUDs among patients with schizophrenia, and with lower relapse rates among patients with both diagnoses.

Twenty-year medication use trends in first-episode bipolar disorder.

OBJECTIVES: To study the medication use patterns in patients newly diagnosed with bipolar disorder (BD) in Finland during the past 20 years. METHODS: All persons diagnosed with BD between 1996 and 2018, aged 16-65 years, with no previous BD diagnosis were identified from nationwide Finnish registers (N = 26,395). The point prevalences of medication use were observed up until 5 years after the first diagnosis. Five sub-cohorts according to calendar year of first diagnosis were also formed and the prevalence of medication use was compared between sub-cohorts 3 months after diagnosis. Medication data were modeled with the PRE2DUP-method using dispensing data. RESULTS: The prevalence of overall medication use declined during the 5-year follow-up period in the total cohort. The highest prevalence of use was seen 3 months after diagnosis for the three main medication classes-antidepressants (40.8%), antipsychotics (30.8%) and mood stabilizers (29.2%). The prevalence of lithium use varied between 5.9% and 6.5% during the 5 years in the total cohort, and the lowest prevalence of use at 3 months was seen in sub-cohort diagnosed in 2016-2018 (4.1%) versus 12.1% in 1996-2000 sub-cohort. The prevalence of benzodiazepine use was between 12.4% and 13.5% and the prevalence of Z-drugs was between 7.3% and 7.9% during the 5 years. The prevalence of long-acting injectable antipsychotic (LAI) use was the highest in patients diagnosed in 2016-2018, although still only 0.8%. CONCLUSIONS: (i) The use of antidepressants is too prevalent, (ii) the use of lithium is declining and needs to be increased, and (iii) LAIs are markedly underutilized as compared to their oral counterparts.

Healthcare utilization, costs, and productivity losses in treatment-resistant depression in Finland - a matched cohort study.

BACKGROUND: Due to its relatively high prevalence and recurrent nature, depression causes a major burden on healthcare systems, societies and individuals. Our objective was to investigate healthcare resource utilization and costs associated with treatment-resistant depression (TRD) compared with non-treatment-resistant depression in Finland. METHODS: Of all patients aged 16-65 years and diagnosed with depression in Finland during 2004-2016, persons with TRD (N = 15,405) were identified from nationwide registers and matched 1:1 with comparison persons with depression who initiated antidepressant use but did not have TRD at the time of matching. TRD was defined as initiation of a third treatment trial after having failed two pharmacological treatment trials. Follow-up period covered 5 years after TRD or corresponding matching date (until end of 2018). Health care resource utilization was studied with negative binomial regression and costs of TRD (per patient per year) with generalized estimating equations, by adjusting for baseline costs, comorbidity and baseline severity of depression. RESULTS: Persons with TRD (mean age 38.7, SD 13.1, 60.0% women) had more health care utilization and work disability (sick leaves and disability pensions), adjusted incidence rate ratio for work disability days was 1.72 (95% CI 1.64-1.80). This resulted in 1.9-fold higher total costs for persons with TRD (15,907 versus 8335 EUR), adjusted mean difference 7572 (95% CI 7215-7929) EUR per patient per year, higher productivity losses (due to sick leaves and disability pensions, mean difference 5296, 95% CI 5042-5550), and direct healthcare costs (2003, 95% CI 1853-2151) compared with non-TRD patients. Mean difference was the highest during the first year after TRD (total costs difference 11,760, 95% CI 11,314-12,206) and the difference decreased gradually after that. CONCLUSION: Treatment-resistant depression is associated with about two-fold cost burden compared with non-treatment-resistant depression.

Neurobiological roots of psychopathy.

Psychopathy is an extreme form of antisocial behavior, with about 1% prevalence in the general population, and 10-30% among incarcerated criminal offenders. Although the heritability of severe antisocial behavior is up to 50%, the genetic background is unclear. The underlying molecular mechanisms have remained unknown but several previous studies suggest that abnormal glucose metabolism and opioidergic neurotransmission contribute to violent offending and psychopathy. Here we show using iPSC-derived cortical neurons and astrocytes from six incarcerated extremely antisocial and violent offenders, three nonpsychopathic individuals with substance abuse, and six healthy controls that there are robust alterations in the expression of several genes and immune response-related molecular pathways which were specific for psychopathy. In neurons, psychopathy was associated with marked upregulation of RPL10P9 and ZNF132, and downregulation of CDH5 and OPRD1. In astrocytes, RPL10P9 and MT-RNR2 were upregulated. Expression of aforementioned genes explained 30-92% of the variance of psychopathic symptoms. The gene expression findings were confirmed with qPCR. These genes may be relevant to the lack of empathy and emotional callousness seen in psychopathy, since several studies have linked these genes to autism and social interaction.

Correction: Neurobiological roots of psychopathy.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Morbidity and mortality in schizophrenia with comorbid substance use disorders.

OBJECTIVE: Schizophrenia is highly comorbid with substance use disorders (SUD) but large epidemiological cohorts exploring the prevalence and prognostic significance of SUD are lacking. Here, we investigated the prevalence of SUD in patients with schizophrenia in Finland and Sweden, and the effect of these co-occurring disorders on risks of psychiatric hospitalization and mortality. METHODS: 45,476 individuals with schizophrenia from two independent national cohort studies, aged <46 years at cohort entry, were followed during 22 (1996-2017, Finland) and 11 years (2006-2016, Sweden). We first assessed SUD prevalence (excluding smoking). Then, we performed Cox regression on risk of psychiatric hospitalization and all-cause and cause-specific mortality in SUD compared with those without SUD. RESULTS: The prevalence of SUD ranged from 26% (Finland) to 31% (Sweden). Multiple drug use (n = 4164, 48%, Finland; n = 3268, 67%, Sweden) and alcohol use disorders (n = 3846, 45%, Finland; n = 1002, 21%, Sweden) were the most prevalent SUD, followed by cannabis. Any SUD comorbidity, and particularly multiple drug use and alcohol use, were associated with 50% to 100% increase in hospitalization (aHR any SUD: 1.53, 95% CI = 1.46-1.61, Finland; 1.83, 1.72-1.96, Sweden) and mortality (aHR all-cause mortality: 1.65, 95% CI = 1.50-1.81, Finland; 2.17, 1.74-2.70, Sweden) compared to individuals without SUD. Elevated mortality risks were observed especially for suicides and other external causes. All results were similar across countries. CONCLUSION: Co-occurring SUD, and particularly alcohol and multiple drug use, are associated with high rates of hospitalization and mortality in schizophrenia. Preventive interventions should prioritize detection and tailored treatments for these comorbidities, which often remain underdiagnosed and untreated.

Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.

VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but, unexpectedly, we found that high doses of VEGF-B promote ventricular arrhythmias (VAs). VEGF-B knockout, alpha myosin heavy-chain promoter (αMHC)-VEGF-B transgenic mice, and pigs transduced intramyocardially with adenoviral (Ad)VEGF- B186 were studied. Immunostaining showed a 2-fold increase in the number of nerves per field (76 vs. 39 in controls, p < 0.001) and an abnormal nerve distribution in the hypertrophic hearts of 11- to 20-month-old αMHC-VEGF-B mice. AdVEGF-B186 gene transfer (GT) led to local sprouting of nerve endings in pig myocardium (141 vs. 78 nerves per field in controls, p < 0.05). During dobutamine stress, 60% of the αMHC-VEGF-B hypertrophic mice had arrhythmias as compared to 7% in controls, and 20% of the AdVEGF-B186-transduced pigs and 100% of the combination of AdVEGF-B186- and AdsVEGFR-1-transduced pigs displayed VAs and even ventricular fibrillation. AdVEGF-B186 GT significantly increased the risk of sudden cardiac death in pigs when compared to any other GT with different VEGFs (hazard ratio, 500.5; 95% confidence interval [CI] 46.4-5,396.7; p < 0.0001). In gene expression analysis, VEGF-B induced the upregulation of Nr4a2, ATF6, and MANF in cardiomyocytes, molecules previously linked to nerve growth and differentiation. Thus, high AdVEGF-B186 overexpression induced nerve growth in the adult heart via a VEGFR-1 signaling-independent mechanism, leading to an increased risk of VA and sudden cardiac death.