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.

Geographical variation in treated psychotic and other mental disorders in Finland by region and urbanicity.

PURPOSE: In Finland, prevalence of schizophrenia is higher in the eastern and northern regions and co-occurs with the distribution of schizophrenia polygenic risk scores. Both genetic and environmental factors have been hypothesized to contribute to this variation. We aimed to examine the prevalence of psychotic and other mental disorders by region and degree of urbanicity, and the impacts of socio-economic adjustments on these associations. METHODS: Nationwide population registers from 2011 to 2017 and healthcare registers from 1975 to 2017. We used 19 administrative and three aggregate regions based on the distribution of schizophrenia polygenic risk scores, and a seven-level urban-rural classification. Prevalence ratios (PRs) were calculated by Poisson regression models and adjusted for gender, age, and calendar year (basic adjustments), and Finnish origin, residential history, urbanicity, household income, economic activity, and physical comorbidity (additional adjustments) on an individual level. Average marginal effects were used to visualize interaction effects between region and urbanicity. RESULTS: A total of 5,898,180 individuals were observed. All mental disorders were slightly more prevalent (PR 1.03 [95% CI, 1.02-1.03]), and psychotic disorders (1.11 [1.10-1.12]) and schizophrenia (1.19 [1.17-1.21]) considerably more prevalent in eastern and northern than in western coastal regions. After the additional adjustments, however, the PRs were 0.95 (0.95-0.96), 1.00 (0.99-1.01), and 1.03 (1.02-1.04), respectively. Urban residence was associated with increased prevalence of psychotic disorders across all regions (adjusted PR 1.21 [1.20-1.22]). CONCLUSION: After adjusting for socioeconomic and sociodemographic factors, the within-country distribution of mental disorders no longer followed the traditional east-west gradient. Urban-rural differences, on the other hand, persisted after the adjustments.

A retrospective analysis of iv ketamine outcome on hospitalisations in an unselected psychiatric sample.

OBJECTIVE: This study aims to explore the outcome with iv ketamine treatment in a real-world clinical setting, primarily measured as posttreatment days hospitalised. METHODS: The psychiatric medical records of 46 patients having received iv ketamine on a psychiatric treatment indication between 2015 and 2018 were retrospectively examined. Analysis comparing the number and duration of hospital admissions before and after ketamine treatment as well as logistic regression analysis to investigate clinical predictors of effectiveness, were performed. To assess patients' severity of depressed symptoms records were screened for MADRS-S scores. RESULTS: No significant difference between pre- and posttreatment hospital days (p = 0.170), or number of hospitalisations (p = 0.740) were found. The response rate was 31% and remission rate 21%. None of the predictors showed statistical significance in the logistic model. CONCLUSION: Iv ketamine treatment showed effectiveness in reducing depressive symptoms even with complex patients in a real-world clinical setting. However, this did not translate to a reduction in hospitalisation. Highlighting the multifaceted challenges posed when implementing iv ketamine treatment in clinical practice.

Genetic risk scores associated with temperament clusters in Finnish depression patients.

OBJECTIVE: Cloninger's temperament dimensions have been studied widely in relation to genetics. In this study, we examined Cloninger's temperament dimensions grouped with cluster analyses and their association with single nucleotide polymorphisms (SNPs). This study included 212 genotyped Finnish patients from the Ostrobothnia Depression Study. METHODS: The temperament clusters were analysed at baseline and at six weeks from the beginning of the depression intervention study. We selected depression-related catecholamine and serotonin genes based on a literature search, and 59 SNPs from ten different genes were analysed. The associations of single SNPs with temperament clusters were studied. Using the selected genes, genetic risk score (GRS) analyses were conducted considering appropriate confounding factors. RESULTS: No single SNP had a significant association with the temperament clusters. Associations between GRSs and temperament clusters were observed in multivariate models that were significant after permutation analyses. Two SNPs from the DRD3 gene, two SNPs from the SLC6A2 gene, one SNP from the SLC6A4 gene, and one SNP from the HTR2A gene associated with the HHA/LRD/LP (high harm avoidance, low reward dependence, low persistence) cluster at baseline. Two SNPs from the HTR2A gene were associated with the HHA/LRD/LP cluster at six weeks. Two SNPs from the HTR2A gene and two SNPs from the COMT gene were associated with the HP (high persistence) cluster at six weeks. CONCLUSION: GRSs seem to associate with an individual's temperament profile, which can be observed in the clusters used. Further research needs to be conducted on these types of clusters and their clinical applicability.

Polymorphisms in ERBB4 and TACR1 associated with dry mouth in clozapine-treated patients.

BACKGROUND: Sialorrhea is a common and uncomfortable adverse effect of clozapine, and its severity varies between patients. The aim of the study was to select broadly genes related to the regulation of salivation and study associations between sialorrhea and dry mouth and polymorphisms in the selected genes. METHODS: The study population consists of 237 clozapine-treated patients, of which 172 were genotyped. Associations between sialorrhea and dry mouth with age, sex, BMI, smoking, clozapine dose, clozapine and norclozapine serum levels, and other comedication were studied. Genetic associations were analyzed with linear and logistic regression models explaining sialorrhea and dry mouth with each SNP added separately to the model as coefficients. RESULTS: Clozapine dose, clozapine or norclozapine concentration and their ratio were not associated with sialorrhea or dryness of mouth. Valproate use (p = 0.013) and use of other antipsychotics (p = 0.015) combined with clozapine were associated with excessive salivation. No associations were found between studied polymorphisms and sialorrhea. In analyses explaining dry mouth with logistic regression with age and sex as coefficients, two proxy-SNPs were associated with dry mouth: epidermal growth factor receptor 4 (ERBB4) rs3942465 (adjusted p = 0.025) and tachykinin receptor 1 (TACR1) rs58933792 (adjusted p = 0.029). CONCLUSION: Use of valproate or antipsychotic polypharmacy may increase the risk of sialorrhea. Genetic variations in ERBB4 and TACR1 might contribute to experienced dryness of mouth among patients treated with clozapine.

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.

Predictors of short-term response and the role of heavy alcohol use in treatment of depression.

BACKGROUND: Depression and alcohol use disorders frequently co-occur. However, research on psychosocial interventions for treating this dual pathology is limited. The Ostrobothnian Depression Study (ODS) aimed to increase the systematic use of evidence-based methods, particularly among patients with comorbid depression and substance use in a naturalistic setting. This is a secondary analysis of the ODS study. The aim of the present study was to explore the predictors of a response to treatment during the first six months of the ODS intervention with a specific focus on the role of comorbid heavy alcohol use. METHODS: The study sample (n = 242) comprised psychiatric specialist care patients with depression (Beck Depression Inventory score ≥ 17) at baseline. Patients with a baseline Alcohol Use Disorders Identification Test (AUDIT) score > 10 (n = 99) were assigned to the AUD (Alcohol Use Disorder) group in this study. The ODS intervention comprised behavioral activation (BA) for all and additional motivational interviewing (MI) for those in AUD group. The predictors of response to treatment (minimum of 50% reduction in depressive symptoms) during the first six months were analyzed with logistic regression models. RESULTS: In the total sample at six months (n = 150), predictors of response to treatment were more severe depression (OR 1.10, CI 1.02-1.18), larger amounts of alcohol consumed (OR = 1.16, CI 1.03-1.31) and antipsychotic medication "not in use" (OR = 0.17, CI 0.07-0.44). In the non-AUD group (n = 100), more severe depression (OR 1.12, CI 1.01-1.25) and antipsychotics "not in use" (OR 0.20, CI 0.06-0.67) also predicted a positive response. Among AUD group patients (n = 50), larger amounts of alcohol consumed (OR 1.54, CI 1.04-2.27) and antipsychotic medication "not in use" (OR 0.12, CI 0.02-0.60) predicted a response to the treatment intervention. CONCLUSIONS: The severity of symptoms and comorbid disorders were found to predict better treatment response, suggesting that the intervention was more effective in patients with severe symptoms. Patients with depression should be treated effectively regardless of having concomitant AUD. The results of this study suggest that BA combined with MI should be one of the treatment options for this dual pathology. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02520271 (11/08/2015).

Socioeconomic status, psychotherapy duration, and return to work from disability due to common mental disorders.

OBJECTIVE: Low socioeconomic status (SES) is a risk factor for work disability due to common mental disorders (CMDs), one possible reason being inequal use of services. Psychotherapy is an evidence-based treatment for CMDs. This study examines socioeconomic and sociodemographic differences in psychotherapy attendance and an association of psychotherapy duration with return to work (RTW). METHODS: The study subjects (N = 12,263) were all Finnish citizens granted a disability pension (DP) due to CMDs in 2010-2012. Numbers of psychotherapy sessions (maximum 200) were collected from the nine-year interval around the DP grant. Socioeconomic and sociodemographic differences in psychotherapy duration (dependent variable) among DP recipients were studied using multinomial logistic regression models, likewise, the association between psychotherapy duration and RTW (dependent variable) among temporary DP recipients was examined. RESULTS: Higher SES, female gender, and younger age were positively associated with attending longer psychotherapies and surpassing the early treatment termination level (>10 sessions). Attending 11-60 psychotherapy sessions was positively associated with full RTW and partial RTW, whereas longer psychotherapies were not. Early termination was positively associated with partial RTW only. CONCLUSION: This study demonstrates varying tendencies among CMD patients from different backgrounds to attend long rehabilitative psychotherapies, which may create inequalities in RTW.

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.

The role of alcohol use and adiposity in serum levels of IL-1RA in depressed patients.

BACKGROUND: The role of Interleukin-1 Receptor antagonist (IL-1Ra), an innate antagonist to pro-inflammatory cytokine IL-1, has attracted increasing attention due to its potential pathogenic and therapeutic implications in depression. However, the role of alcohol and adiposity in modulating IL-1Ra cytokine pathway in depressed patients has remainned unknown. The aim of this study was to follow the changes in IL-1Ra serum levels in depressed patients with or without simultaneous alcohol use disorder (AUD) and different degrees of adiposity during 6 months of follow-up. MATERIALS AND METHODS: A total of 242 patients with depression were followed for 6 months. At baseline 99 patients had simultaneous AUD. Levels of serum IL-1Ra and common mediators of inflammation (IL-6, hs-CRP) were measured. Clinical assessments included Body Mass Index (BMI), Montgomery-Asberg Depression Rating Scale (MADRS) and Alcohol Use Disorders Identification Test (AUDIT) scores. RESULTS: Significant reductions in clinical symptoms and IL-1Ra were observed during 6-month follow-up. In hierarchical linear regression analysis, the effect of MADRS score, age, gender, and smoking had a combined effect of 2.4% in the model. The effect of AUDIT score increased the effect to 4.2% of variance (p = 0.08), whereas adding BMI increased the effect to 18.5% (p <  0.001). CONCLUSION: Adiposity may influence the IL-1Ra anti-inflammatory response in depressed patients, whereas the effect of alcohol consumption in these patients seems insignificant. These findings should be considered in studies on the role of IL-1Ra in depression. TRIAL REGISTRATION: Ostrobothnia Depression Study in ClinicalTrials.gov , Identifier NCT02520271 .

Socioeconomic factors and use of psychotherapy in common mental disorders predisposing to disability pension.

BACKGROUND: Research in high-income countries has identified low socioeconomic status as a risk factor for disability pension (DP) due to common mental disorders (CMDs). Psychotherapy is an evidence-based treatment for the majority of CMDs along with medication and it is often targeted to prevent work disability. This study examines socioeconomic differences in the use of rehabilitative psychotherapy in Finland, where citizens have universal health coverage, but psychotherapy is partly dependent on personal finance. METHODS: The study subjects (N = 22,501) were all the Finnish citizens granted a DP due to CMD between 2010 and 2015 and a comparison group (N = 57,732) matched based on age, gender, and hospital district. Socioeconomic differences in psychotherapy use were studied using logistic regression models. Socioeconomic status was defined by education, income, and occupation. Age, gender, and family status were also examined. RESULTS: A lower level of education, lower occupational status (blue-collar worker), male gender, and older age, were associated with less frequent psychotherapy use, in both groups. Education was the strongest component of socioeconomic status associated with psychotherapy use, but the role of income was not straightforward. Unemployment when approaching DP, but not otherwise, was a risk factor for not receiving rehabilitative psychotherapy. Socioeconomic disparities were not any smaller among CMD patients approaching DP than in the comparison group. CONCLUSION: This study demonstrates the disparity in the provision of psychotherapy for CMD patients, even on the verge of DP with an acute need for services. This disparity is partly related to a complex interplay of socioeconomic factors and the service system characteristics. Factors predisposing to unequal access to mental health services are presumably diverse and should be studied further.

Clozapine-Related Diarrhea and Colitis: Report of 4 Cases.

BACKGROUND: During clozapine treatment, diarrhea is a rare but clinically relevant adverse effect. Cases of microscopic colitis and eosinophilic colitis have been previously reported. PROCEDURES: We present 4 patients who developed severe diarrhea in early weeks of clozapine therapy. FINDINGS: Two patients had significant peripheral eosinophilia 1 week after diarrhea symptoms. One of these patients also had Charcot-Leyden crystals in stool afterward, confirming the presence of eosinophils in the gut lumen. One of our patients had a confirmed microscopic colitis and later also neutropenia, which required treatment. CONCLUSIONS: Charcot-Leyden crystals in stool may be associated with concurrent diarrhea and eosinophilia during clozapine treatment, which is a previously unreported finding. Occurrence of blood dyscrasias with diarrhea symptoms during clozapine treatment needs further investigation to understand the possible shared mechanisms.

The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression.

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

Assessment of alcohol consumption in depression follow-up using self-reports and blood measures including inflammatory biomarkers.

AIMS: Alcohol consumption has been suggested a major role in the pathogenesis and prognosis of depression. However, reliable identification of hazardous drinking continues to be problematic. We compared the accuracy of different biomarkers and self-reports of alcohol consumption in the follow-up study of depression. METHODS: Data from 202 patients with major depressive disorder were obtained through self-reports, AUDIT and AUDIT-C questionnaires and biomarker analyses. The clinical assessments and measurements of biomarkers (GT, CDT, GT-CDT-combination, MCV, ALT, AST, hs-CRP, IL-6) were performed at baseline and after six months of treatment. Based on self-reported alcohol intake at baseline the patients were classified to three subgroups. RESULTS: About 27.2% of patients were categorized to high-risk drinkers, 26.3% low-risk drinkers and 46.5% abstainers. High-risk drinkers showed significantly higher mean values of GT, CDT, GT-CDT-combination and IL-6 than abstainers, diagnostic accuracy being highest with the combined marker of GT-CDT. The accuracy of AUDIT and AUDIT-C to detect high-risk drinking was also significant. During follow-up, the differences observed in the biomarkers at baseline disappeared together with recovery from depression. CONCLUSIONS: Our data suggest the combined use of GT-CDT and AUDIT questionnaires to improve the identification of drinking of patients with depression. This approach could be useful for improving treatment adherence and outcome in depressed patients.

What is important for the sustained implementation of evidence-based brief psychotherapy interventions in psychiatric care? A quantitative evaluation of a real-world programme.

PURPOSE: Behavioural activation and motivational interviewing, both evidence-based treatments (EBTs), were implemented in secondary psychiatric care. This longitudinal evaluation of a real-world programme focused on the penetration of EBT adoption and its associations with therapist-related and perceived intervention-related variables. The implementation plan was also compared to sub-processes of Normalization Process Theory. MATERIAL AND METHODS: Six participating units employed 72 therapists regularly and they comprise the target group. Due to staff turnover, a total of 84 therapists were trained stepwise. Three survey points (q1, q2, q3) were set for a four-year cycle beginning a year after the initial training and completed 4-5 months after closing patient recruitment. The implementation plan included two workshop days, one for each EBT, and subsequent case consultation groups and other more general strategies. RESULTS: Fifty-seven (68%) of programme-trained therapists responded to one or more of three questionnaires. The self-reported penetration covers about a third of the target group a few months after the completion of the programme. Therapists' favourable perceptions of the EBTs regarding relative advantage, compatibility and complexity were associated with their sustained adoption. Therapists' background factors (e.g. work experience) and positive adoption intention at q1 did not predict the actual adoption of the EBTs at q3. No specific sustainment strategies were included in the implementation plan. CONCLUSION: Brief but multi-faceted training with subsequent case consultations promoted the adoption of EBTs in a real-world setting. Adding specific sustainment strategies to the implementation plan is proposed to ensure the long-term survival of the implementation outcomes.

Implementing physical exercise and music interventions for patients suffering from dementia on an acute psychogeriatric inpatient ward.

Background: Increasing attention is focusing on psychosocial interventions for treating patients with dementia. Aims: This observational intervention study investigated the impact of physical exercise and music interventions among patients with dementia on an acute psychogeriatric ward. Materials and methods: The data were collected during February 2009-December 2010 (n = 89; treatment as usual) and during April 2011-March 2013 (n = 86; treatment as usual with physical exercise, e.g. balance, flexibility, strength training, and music interventions, e.g. singing, listening to music and playing instruments). The primary outcome measure was the Neuropsychiatric Inventory and the secondary outcome measures were the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the Barthel Index, and the Mini-Mental State Examination. Results: In both groups, neuropsychiatric symptoms (NPS) decreased (p < .001) but daily functioning deteriorated (p < .001). No significant between-group differences for either outcome variable were found. Based on linear mixed models, fewer exercise sessions associated with more severe symptoms (p = .030), and the time variable (admission/discharge) with a decline in the level of NPS (p < .001). Moreover, female gender (p = .026) and more exercise sessions (p = .039) associated with an increased level of functioning (p = .031) and the time variable (admission/discharge) with a drop in the level of functioning during hospitalization (p < .001). Conclusion: Although no differences were found between the study groups, analysis within the intervention group suggest that physical exercise may have some positive effects for both NPS and the level of functioning in some patients with dementia while no positive effects regarding music interventions were found.

Genetic Polymorphisms Associated With Constipation and Anticholinergic Symptoms in Patients Receiving Clozapine.

BACKGROUND: Clozapine impairs gastrointestinal motility owing to its anticholinergic and antiserotonergic properties. This commonly leads to constipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic receptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms during clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT). PROCEDURES: Blood samples from 176 clozapine-treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholinergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single-nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS). RESULTS: No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was associated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining variables (permuted P = 0.014). Generalized linear univariate model analysis performed on the opiate-induced constipation-associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002). CONCLUSIONS: Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility.

The association of alcohol use and quality of life in depressed and non-depressed individuals: a cross-sectional general population study.

PURPOSE: To compare the associations of alcohol-related variables with Quality of Life (QoL) in depressed and non-depressed individuals of the general population. METHODS: This cross-sectional study utilized data from the FINRISK 2007 general population survey. A subsample (n = 4020) was invited to participate in an interview concerning alcohol use. Of them, 2215 (1028 men, 1187 women; response rate 55.1%) were included in the analyses. Bivariate associations between mean weekly alcohol consumption, frequency of binge drinking, Alcohol Use Disorders Identification Test (AUDIT)-score and QoL were analysed according to categorization into depressed and non-depressed using the Beck Depression Inventory, Short Form. Linear regression models were calculated in order to determine the associations of the alcohol variables and QoL after adjusting for socio-demographic variables as well as somatic and mental illness. RESULTS: Depressed individuals had lower mean QoL and higher AUDIT-scores than non-depressed respondents. Bivariate correlations showed that mean weekly alcohol consumption, frequency of binge drinking and AUDIT-scores were statistically significantly associated with impaired QoL in depressed individuals. Abstinence was not associated with QoL. After adjustment for covariates, frequency of binge drinking and AUDIT-score were statistically significantly associated with QoL in depressed individuals and AUDIT-score in the non-depressed group. When analysing all respondents regardless of depression, both AUDIT-score and binge drinking were associated with QoL. CONCLUSIONS: Of the alcohol-related variables, binge drinking and alcohol problems indicated by AUDIT-score contributed to impaired QoL in depressed individuals and both should be assessed as part of the clinical management of depression.

Behavioral activation versus treatment as usual in naturalistic sample of psychiatric patients with depressive symptoms: a benchmark controlled trial.

BACKGROUND: More systematic use of evidence-based brief therapies is needed in the treatment of depression within psychiatric care. The aim of this study was to explore the impact of behavioral activation therapy (BA) for patients with depressive symptoms in a routine clinical setting of secondary psychiatric care. METHODS: The BA-treated intervention group (n = 242) comprised patients with depressive symptoms (Beck Depression Inventory (BDI) score ≥ 17 at baseline). The control group (n = 205) patients received treatment as usual in the same catchment area. The groups were matched at baseline using BDI and Alcohol Use Disorders Identification Test scores and inpatient/outpatient status. The groups were compared at 6-, 12- and 24-month follow-up points on functional outcome (Global Assessment of Functioning scale), service use, dropout and deaths. The Montgomery-Åsberg Depression Rating Scale was used to assess depressive symptoms in the intervention group. RESULTS: The estimated difference in GAF score between intervention and control group patients was significant at 12- and 24-months follow-up points in favor of intervention group (GAF score difference 4.85 points, p = 0.006 and 5.71 points, p = 0.005, respectively; estimate for patient group 2.26, p = 0.036). The rates of dropout, mortality and service use were similar between the groups. Among the intervention group patients, the estimated improvement in MADRS score compared to baseline was statistically significant throughout the follow-up (p < 0.001 at all follow-up points). CONCLUSIONS: The systematic use of BA among secondary psychiatric care depressive patients provides encouraging results despite the patients had various comorbid non-psychotic disorders. TRIAL REGISTRATION: ClinicalTrials.gov , Identifier NCT02520271, Release Date: 06/27/2015, retrospectively registered.

Pessimism, diet, and the ability to improve dietary habits: a three-year follow-up study among middle-aged and older Finnish men and women.

BACKGROUND: Dietary habits have a great influence on physiological health. Even though this fact is generally recognized, people do not eat as healthily as they know they should. The factors that support a healthy diet, on the other hand, are not well known. It is supposed that there is a link between personal traits and dietary habits. Personal traits may also partially explain why some people manage to make healthy dietary changes while some fail to do so or are not able to try to make changes even when they desire to do so. There is some information suggesting that dispositional optimism plays a role in succeeding in improving dietary habits. The aim of this study was to determine the role of optimism and pessimism in the process of dietary changes. METHODS: Dispositional optimism and pessimism were determined using the revised Life Orientation Test in 2815 individuals (aged 52-76 years) participating in the GOAL study in the region of Lahti, Finland. The dietary habits of the study subjects were analysed. After 3 years, the subjects' dietary habits and their possible improvements were registered. The associations between dispositional optimism and pessimism, dietary habits at baseline, and possible changes in dietary habits during the follow-up were studied with logistic regression. We also studied if the dietary habits or certain lifestyle factors (e.g. physical exercising and smoking) at baseline predicted success in improving the diet. RESULTS: Pessimism seemed to correlate clearly negatively with the healthiness of the dietary habits at baseline - i.e. the higher the level of pessimism, the unhealthier the diet. Optimism also showed a correlation with dietary habits at baseline, although to a lesser extent. Those who managed to improve their dietary habits during follow-up or regarded their dietary habits as healthy enough even without a change were less pessimistic at baseline than those who failed in their attempts to improve their diet or did not even try, even when they recognized the need for a change. CONCLUSIONS: Pessimistic people are more likely to eat an unhealthy diet than others. Pessimism reduces independently the possibilities to improve dietary patterns.