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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., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Forests and their provision of ecosystem services are endangered by climate change. Tree-species diversification has been identified as a key adaptation strategy to balance economic risks and returns in forest stands. Yet, whether this synergy between ecology and economics persists under large-scale extreme weather events remains unanswered. Our model accounts for both, small-scale disturbances in individual stands and extreme weather events that cause spatio-temporally correlated disturbances in a large number of neighboring stands. It economically optimizes stand-type allocations in a large forest enterprise with multiple planning units. Novel components are: spatially explicit site heterogeneity and a comparison of economic diversification strategies under local and regionally coordinated planning by simplified measures for [Formula: see text], [Formula: see text], and [Formula: see text]-diversity of stand types. [Formula: see text]-diversity refers to the number and evenness of stand types in local planning units, [Formula: see text]-diversity to the dissimilarity of the species composition across planning units, and [Formula: see text]-diversity to the number and evenness of stand types in the entire enterprise. Local planning led to stand-type diversification within planning units ([Formula: see text]-diversity), while regionally coordinated planning led to diversification across planning units ([Formula: see text]-diversity). We observed a trend towards homogenization of stand-type composition likely selected under economic objectives with increasing extreme weather events. No diversification strategy fully buffered the adverse economic consequences. This led to fatalistic decisions, i.e., selecting stand types with low investment risks but also low resistance to disturbances. The resulting forest structures indicate potential adverse consequences for other ecosystem services. We conclude that high tree-species diversity may not necessarily buffer economic consequences of extreme weather events. Forest policies reducing forest owners' investment risks are needed to establish stable forests that provide multiple ecosystem services., (© 2024. The Author(s).)

Background: Non-adherence to medications is common in bipolar disorder but its prevalence estimations have varied significantly. In addition, non-adherence is known to increase the risk of poor clinical outcomes. Therefore, we studied how common primary non-adherence for mood stabilizers and antipsychotics is in Finland and which factors are associated with it., Methods: Nationwide sample of persons diagnosed with bipolar disorder during 1987-2018 were identified from registers. Dispensings of their electronic prescriptions during 2015-2018 were followed up to define rates of primary non-adherence. Primary non-adherence was defined as having at least one non-dispensed mood stabilizer or antipsychotic prescription during 2015-2018. In a broader definition, non-adherence was defined as having ≥20 % of mood stabilizer and/or antipsychotic prescriptions non-dispensed. Adjusted logistic regression was used to assess risk factors for non-adherence., Results: The study cohort included 33,131 persons and 59.1 % had at least one non-dispensed mood stabilizer or antipsychotic prescription. 31.0 % of the cohort was non-adherent to ≥20 % of their mood stabilizer and/or antipsychotic prescriptions. Lithium and clozapine had the lowest proportions of non-dispensed prescriptions. Especially young age, recent bipolar disorder diagnosis, multiple hospitalizations due to bipolar disorder, and use of benzodiazepines or antidepressants were associated with an increased risk of non-adherence., Limitations: This study was based on register data, and patient-reported reasons for medication non-adherence could not be included., Conclusions: The majority of patients with bipolar disorder do not use their medications as prescribed. Patient-specific risk for non-adherence should be assessed and those at high risk for non-adherence should be followed closely., Competing Interests: Declaration of competing interest J.L. has received funding from the Finnish Medical Foundation and the Finnish Foundation for Psychiatric Research. J.T., H.T., and A.T. have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. H.T. reports personal fees from Gedeon Richter, Janssen-Cilag, Lundbeck and Otsuka. J.T. has been a consultant to HLS Therapeutics, Orion, and WebMed Global, and has received honoraria from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Mediuutiset, Otsuka, Sidera, and Sunovion. M.L. is a board member of Genomi Solutions Ltd. and Nursie Health Ltd., has received honoraria from Sunovion, Orion Pharma, Otsuka, Lundbeck, Recordati and Janssen-Cilag and research funding from the Finnish Medical Foundation and the Finnish Cultural Foundation. This study was funded by the Academy of Finland., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Background: Improved treatments for bipolar disorder (BD) are needed. Drug repurposing aims to find novel targets for drugs that have been used for other indications. This study investigated the risk of psychiatric hospitalization associated with use of calcium-channel blockers (CCBs; dihydropyridines, diltiazem, verapamil) and adenosine modulators (allopurinol, dipyridamole) in BD in within-individual design., Methods: Individuals diagnosed with BD (ICD-10: F30-F31) were identified from the inpatient, specialized outpatient, sickness absence, and disability pension registers during 1996-2018 in Finland (N = 60,045). The main outcome was hospitalization due to affective symptoms (ICD-10: F30-F39). Within-individual models in stratified Cox regression were used and adjusted hazard ratios (aHR) with 95 % confidence intervals (CIs) reported., Results: Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR 0.83, 95 % CI 0.78-0.88) when all CCBs were analyzed together. Of specific CCBs, use of diltiazem (0.71, 0.55-0.91) and dihydropyridines (0.83, 0.78-0.89) were associated with a decreased risk but verapamil was not (0.93, 0.73-1.19). Use of adenosine modulators in general was associated with a decreased risk of hospitalizations due to affective symptoms (0.87, 0.79-0.96). Both allopurinol (0.85, 0.74-0.97) and dipyridamole (0.89, 0.78-1.00) were associated with a marginally decreased risk. Thiazide diuretic use as a negative control was not associated with the risk of hospitalization due to affective symptoms (0.97, 0.83-1.13)., Limitations: Due to the observational nature of this study, causation cannot be confirmed., Conclusions: Dihydropyridines and diltiazem were associated with a decreased risk of psychiatric hospitalization in bipolar disorder. Results for allopurinol and dipyridamole were inconclusive., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the long-term real-world effectiveness of antipsychotics and other psychopharmacotherapies in the treatment of schizoaffective disorder (SCHAFF)., Method: Two nationwide cohorts of SCHAFF patients were identified from Finnish and Swedish registers. Within-individual design was used with stratified Cox regression. The main exposure was use of antipsychotics. Adjunctive pharmacotherapies included mood stabilizers, antidepressants, and benzodiazepines and benzodiazepine-related drugs. The main outcome was hospitalization due to psychosis., Results: The Finnish cohort included 7655 and the Swedish cohort 7525 patients. Median follow-up time was 11.2 years (IQR 5.6-11.5) in the Finnish and 7.6 years (IQR 3.8-10.3) in the Swedish cohort. Clozapine and long-acting injectable (LAI) antipsychotics were consistently associated with a decreased risk of psychosis hospitalization and treatment failure (psychiatric hospitalization, any change in medication, death) in both cohorts. Quetiapine was not associated with a decreased risk of psychosis hospitalization. Mood stabilizers used in combination with antipsychotics were associated with a decreased risk of psychosis hospitalization (Finnish cohort HR 0.76, 95% CI 0.71-0.81; Swedish cohort HR 0.84, 0.78-0.90) when compared with antipsychotic monotherapy. Combination of antidepressants and antipsychotics was associated with a decreased risk of psychosis hospitalization in the Swedish cohort (HR 0.90, 0.83-0.97) but not in the Finnish cohort (1.00, 0.94-1.07), and benzodiazepine use was associated with an increased risk (Finnish cohort HR 1.07, 1.01-1.14; Swedish cohort 1.21, 1.13-1.30)., Conclusions: Clozapine, LAIs, and combination therapy with mood stabilizers were associated with the best outcome and use of quetiapine and benzodiazepines with the worst outcome in the treatment of SCHAFF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Relapses remain common among individuals with schizophrenia indicating a need for improved treatments. Creating a completely new drug molecule is expensive and time consuming, and therefore drug repurposing should be considered. Aim of this study was to investigate the risk of psychiatric rehospitalization associated with use of adenosine modulators (AMs) and calcium channel blockers (CCBs) in schizophrenia. Individuals diagnosed with schizophrenia (N = 61,889) in inpatient care between 1972-2014 in Finland were included. The follow-up lasted from 1996 to 2017. Main exposures were use of AMs (allopurinol and dipyridamole) and CCBs (dihydropyridines, diltiazem, and verapamil). Thiazide diuretics were used as a negative control. Within-individual models in stratified Cox regression were used and adjusted hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Use of AMs was associated with a reduced risk of psychiatric rehospitalization on drug class level (HR 0.74, 95% CI 0.65-0.84, P < 0.0001), as well as on the level of individual drugs (allopurinol HR 0.82, 95% CI 0.70-0.97, P = 0.02; dipyridamole HR 0.65, 95% CI 0.55-0.77, P < 0.0001). Use of CCBs was associated with a reduced risk of psychiatric rehospitalization on drug class level (HR 0.81, 95% CI 0.77-0.86, P < 0.0001). From the different CCBs, only exposure to dihydropyridines was associated with a reduced risk (HR 0.79, 95% CI 0.74-0.84, P < 0.0001). No effect was observed for the negative control, thiazide diuretics (HR 0.96, 0.90-1.02, P = 0.20). The effects of dipyridamole and dihydropyridines were more pronounced among younger persons and combination of AMs, and CCBs was associated with a lower risk than either drug class as monotherapy. These results indicate a need for randomized controlled trials of these drugs.

The purpose of this research was to evaluate the level of nicotine dependence (ND) and to examine its association to psychiatric disorders in a representative clinical sample of adolescent psychiatric inpatients. The modified Fagerstrom Tolerance Questionnaire (mFTQ) was used to assess the level of ND. Psychiatric DSM-IV diagnoses were obtained by using the Schedule for affective disorder and schizophrenia for school-age children (K-SADS-PL). Of the total of 342 inpatients in the study sample, 259 (75.7%) reported to be current smokers. A sum score 6 or higher in the mFTQ, indicating a high level of ND, was found in 37.9% of all smokers. An increased likelihood for high level of ND was associated with substance related disorders (OR 5.1, 95% CI 2.8-9.3), conduct disorder and oppositional defiant disorders (OR 2.4, 95% CI 1.4-4.4). The usefulness of mFTQ in measuring ND among adolescent inpatients is apparent. Therefore, it can be recommended to be used as a routine screening instrument for ND among adolescents hospitalized due to psychiatric disorders.