Cognitive behavioural therapy for insomnia (CBT-I) in schizophrenia and schizoaffective disorder: protocol for a randomised controlled trial.

INTRODUCTION: Insomnia is a common symptom among patients with schizophrenia and schizoaffective disorder, negatively impacting symptom severity, functioning and well-being; however, it is rarely the direct focus of treatment. The main recommended treatment for insomnia is cognitive behavioural therapy (CBT-I). There is some evidence that CBT-I can also be used to treat insomnia in patients with schizophrenia, but only a few randomised controlled trials (RCTs) have been published. The aim of this ongoing RCT is to determine whether we can alleviate symptoms of insomnia and improve the quality of life in patients with schizophrenia and schizoaffective disorder through CBT-I delivered via the internet or in a group mode. METHODS AND ANALYSES: The aim of this study is to recruit 84-120 outpatients from the Psychosis Clinics of Helsinki University Hospital and the City of Helsinki Health Services. The main inclusion criteria are a diagnosis of schizophrenia or schizoaffective disorder and self-reported sleep problems. The study will be performed on a cyclic basis, with a target of 12-24 patients per cycle. Participants are randomly assigned into three groups: (1) a group receiving only treatment as usual (TAU), (2) internet-based individual therapy for insomnia (iCBT-I)+TAU or (3) group therapy for insomnia (GCBT-I) conducted via a virtual platform+TAU. The primary outcome measures are quantitative changes in the Insomnia Severity Index score and/or changes in health-related quality of life using the 15D quality of life measure. Secondary outcomes include self-reported variables for sleep, health, stress and the severity of psychotic and depressive symptoms; objective outcomes include actigraphy and bed sensor data to evaluate circadian rhythms and motor activity. Outcome measures are assessed at baseline and after the treatment period at weeks 12, 24 and 36. ETHICS AND DISSEMINATION: The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa, Finland, approved the study protocol. The results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04144231.

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 not 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.

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.

Association of antidepressant and benzodiazepine use, and anticholinergic burden with cognitive performance in schizophrenia.

Schizophrenia is characterized by cognitive impairment affecting everyday functioning. Earlier research has hypothesized that antidepressants may associate with better cognitive functioning, but results are mixed. This study explored the association between antidepressant use and cognitive performance in terms of reaction time and visual learning in a clinical sample. In addition, we examined benzodiazepine use and anticholinergic burden. Study participants were drawn from the SUPER-Finland cohort, collected among patients with psychotic illnesses in 2016-2018 throughout Finland (n = 10,410). The analysis included adults with a schizophrenia diagnosis (F20) and results from a cognitive assessment (n = 3365). Information about medications and psychosocial factors were gathered through questionnaire and interview. Cognitive performance was assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB) with two subtests measuring reaction time and visual learning. Almost 36 % of participants used at least one antidepressant. The use of antidepressants in general was not associated with performance in the reaction time and visual learning tasks. However, the use of SNRI antidepressants was associated with a faster reaction time. Benzodiazepine use and a higher anticholinergic burden were associated with poorer performance in both tests. The results strengthen earlier findings that there is no association between antidepressant use in general and cognitive performance in schizophrenia. However, the association of SNRI medications with a faster reaction time warrants further research. Moreover, the results suggest that more attention should be paid to the anticholinergic burden of the medications used by patients with schizophrenia, as well as avoiding continuous benzodiazepine use.

Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders.

PURPOSE: SUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland. PARTICIPANTS: 10 474 individuals aged 18 years or older were recruited throughout the country. The subjects have been genotyped with a genome-wide genotyping chip and exome sequenced. A subset of 897 individuals selected from known population sub-isolates were selected for whole-genome sequencing. Recruitment was done between November 2015 and December 2018. FINDINGS TO DATE: 5757 (55.2%) had a diagnosis of schizophrenia, 944 (9.1%) schizoaffective disorder, 1612 (15.5%) type I or type II bipolar disorder, 532 (5.1 %) psychotic depression, 1047 (10.0%) other psychosis and for 530 (5.1%) self-reported psychosis at recruitment could not be confirmed from register data. Mean duration of schizophrenia was 22.0 years at the time of the recruitment. By the end of the year 2018, 204 of the recruited individuals had died. The most common cause of death was cardiovascular disease (n=61) followed by neoplasms (n=40). Ten subjects had psychiatric morbidity as the primary cause of death. FUTURE PLANS: Compare the effects of common variants, rare variants and copy number variations (CNVs) on severity of psychotic illness. In addition, we aim to track longitudinal course of illness based on nation-wide register data to estimate how phenotypic and genetic differences alter it.

Differences in psychosocial functioning between psychotic disorders in the Finnish SUPER study.

BACKGROUND: Psychotic disorders differ in their impact on psychosocial functioning. However, few studies have directly compared psychosocial functioning and its determinants between schizophrenia, schizoaffective disorder (SAD), bipolar disorder (BD), and major depressive disorder with psychotic features (psychotic MDD). OBJECTIVE: We compared rates of independent living, employment, marriage, and having children between these diagnostic groups in a large national sample of participants with psychotic disorders in Finland. METHODS: A cross-sectional substudy of participants (N = 9148) aged 18 to 65 years in the Finnish SUPER study, recruited nationwide from health- and social care settings and with advertisements. Psychosis diagnoses, age of onset, and hospitalizations were collected from healthcare registers. Participants were interviewed for psychosocial functioning. Associations of age of onset, hospitalizations, gender, and education with psychosocial functioning were analyzed using logistic regression models. RESULTS: Of participants, 13.8% were employed or studying, 72.0% living independently and 32.5% had children. Overall, BD was associated with best, SAD and psychotic MDD with intermediate, and schizophrenia with worst level of psychosocial functioning. Greatest differences were found in independent living (OR 4.06 for BD vs. schizophrenia). In multivariate models, gender and number of hospitalizations predicted employment, marriage, and independent living in all diagnostic categories, and age of onset in some diagnostic categories. CONCLUSIONS: Level of functioning and psychosocial outcomes differed markedly between psychotic disorders, particularly in independent living. Outcomes were worst for schizophrenia and best for BD. Across all psychotic disorders, female gender and lifetime number of hospitalizations had strong independent associations with marriage, employment, and independent living.

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.

Cognitive functioning and cannabis use in first-episode psychosis.

AIM: Cannabis use is common in people with psychotic disorders. However, the effect of cannabis on cognition in psychosis remains unclear. Our study investigates relationships between the history of cannabis use and cognitive performance in patients with first-episode psychosis (FEP) during a one-year follow-up. METHODS: The present study included FEP (N = 91) and control (N = 61) groups. Cannabis use was evaluated with a self-report questionnaire, clinical assessment, and medical records during a lifetime and 12 months prior to the treatment onset (recent). Symptoms of psychosis and anxiety were evaluated on the brief psychiatric rating scale. Negative symptoms were assessed using the scale for the assessment of negative symptoms. Cognitive tests were used to evaluate neurocognition (summarized in the g factor) and social cognition. Crude regression analyses for the g factor included variables of cannabis use as independent variables. Full regression models were controlled for gender, education, and clinical symptoms. RESULTS: In the FEP group, men used cannabis more frequently than women. In the crude regression model for FEP patients, never having used cannabis was associated with a better neurocognitive profile at 12 months. In the full model, more severe anxiety symptoms were associated with better neurocognition at two months, and less severe negative symptoms were associated with better neurocognition at 12 months. Cannabis use was not associated with social cognition. No associations between cognitive performance and cannabis use emerged in the controls. CONCLUSION: Negative and affective symptom severity in FEP was associated with cognitive performance to a greater degree than a lifetime history of cannabis use.

Reaction Time and Visual Memory in Connection to Hazardous Drinking Polygenic Scores in Schizophrenia, Schizoaffective Disorder and Bipolar Disorder.

The purpose of this study was to explore the association of cognition with hazardous drinking Polygenic Scores (PGS) in 2649 schizophrenia, 558 schizoaffective disorder, and 1125 bipolar disorder patients in Finland. Hazardous drinking PGS was computed using the LDPred program. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: the 5-choice serial reaction time task, or Reaction Time (RT) test, and the Paired Associative Learning (PAL) test. The association between hazardous drinking PGS and cognition was measured using four cognition variables. Log-linear regression was used in Reaction Time (RT) assessment, and logistic regression was used in PAL assessment. All analyses were conducted separately for males and females. After adjustment of age, age of onset, education, household pattern, and depressive symptoms, hazardous drinking PGS was not associated with reaction time or visual memory in male or female patients with schizophrenia, schizoaffective, and bipolar disorder.

Reaction Time and Visual Memory in Connection to Alcohol Use in Persons with Bipolar Disorder.

The purpose of this study was to explore the association of cognition with hazardous drinking and alcohol-related disorder in persons with bipolar disorder (BD). The study population included 1268 persons from Finland with bipolar disorder. Alcohol use was assessed through hazardous drinking and alcohol-related disorder including alcohol use disorder (AUD). Hazardous drinking was screened with the Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) screening tool. Alcohol-related disorder diagnoses were obtained from the national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on A tablet computer: the 5-choice serial reaction time task, or reaction time (RT) test and the Paired Associative Learning (PAL) test. Depressive symptoms were assessed with the Mental Health Inventory with five items (MHI-5). However, no assessment of current manic symptoms was available. Association between RT-test and alcohol use was analyzed with log-linear regression, and eß with 95% confidence intervals (CI) are reported. PAL first trial memory score was analyzed with linear regression, and ß with 95% CI are reported. PAL total errors adjusted was analyzed with logistic regression and odds ratios (OR) with 95% CI are reported. After adjustment of age, education, housing status and depression, hazardous drinking was associated with lower median and less variable RT in females while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores in females. Our findings of positive associations between alcohol use and cognition in persons with bipolar disorder are difficult to explain because of the methodological flaw of not being able to separately assess only participants in euthymic phase.

Reaction Time and Visual Memory in Connection with Alcohol Use in Schizophrenia and Schizoaffective Disorder.

The purpose of this study was to explore the association between cognition and hazardous drinking and alcohol use disorder in schizophrenia and schizoaffective disorder. Cognition is more or less compromised in schizophrenia, and schizoaffective disorder and alcohol use might aggravate this phenomenon. The study population included 3362 individuals from Finland with diagnoses of schizophrenia or schizoaffective disorder. Hazardous drinking was screened with the AUDIT-C (Alcohol Use Disorders Identification Test for Consumption) screening tool. Alcohol use disorder (AUD) diagnoses were obtained from national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: The Five-Choice Serial Reaction Time Task (5-CSRTT) or the reaction time (RT) test and the Paired Associative Learning (PAL) test. The association between alcohol use and the RT and PAL tests was analyzed with log-linear regression and logistic regression, respectively. After adjustment for age, education, housing status, and the age at which the respondents had their first psychotic episodes, hazardous drinking was associated with a lower median RT in females and less variable RT in males, while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores (TEASs) in females. Our findings of positive associations between alcohol and cognition in schizophrenia and schizoaffective disorder are unique.

Anxiety symptoms in first-episode psychosis.

AIM: Anxiety disorders and symptoms are common in people with psychotic disorders, having a negative impact on clinical status, function level and overall prognosis. However, research on the significance of anxiety in predicting remission and long-term functioning in first-episode psychosis (FEP) is still scarce. This study investigated the effects of anxiety and obsessive-compulsive symptoms (OCS) on clinical and functional improvement in individuals with FEP. METHODS: FEP patients (N = 97) aged 18-40 years were recruited from the University Hospital District of Helsinki and the City of Helsinki. Psychotic and anxiety symptoms were measured using the Brief Psychiatric Rating Scale. Obsessive-compulsive symptoms were assessed using the Obsessive-Compulsive Inventory (OCI-R), and functioning was evaluated using the Social and Occupational Functioning Assessment Scale (SOFAS). Follow-up measurements were performed at 2 and 12 months. We specifically studied whether anxiety and obsessive-compulsive symptoms at the 2-month follow-up assessment, at a time when the initial treatment response had been achieved, would predict outcomes at 12 months. RESULTS: Symptoms of anxiety and OCS correlated moderately with each other and psychotic symptoms, but at the 12-month follow-up, OCS no longer correlated significantly with psychotic and anxiety symptoms. When the level of psychotic symptoms was adjusted for, more severe OCS at the 2-month follow-up was associated with a lower rate of remission at 12 months, whereas a higher level of anxiety symptoms at 2 months was associated with better functioning at 12 months. CONCLUSIONS: OCS may be predictive of poorer clinical outcomes, whereas anxiety symptoms may predict better functional outcomes.

An interaction between NDE1 and high birth weight increases schizophrenia susceptibility.

Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes of the DISC1 pathway and birth weight, in relation to schizophrenia susceptibility in a Finnish schizophrenia family cohort. The study sample consisted of 457 subjects with both genotype and birth weight information. Gender and place of birth were adjusted for in the models. We found a significant interaction between birth weight and two NDE1 markers in relation to increased schizophrenia risk: a four SNP haplotype spanning NDE1 (b=1.26, SE=0.5, p=0.012) and one of its constituent SNPs rs4781678 (b=1.33, SE=0.51, p=0.010). Specifically, high birth weight (>4000g) was associated with increased schizophrenia risk among subjects homozygous for the previously identified risk alleles. The study was based on a family study sample with high genetic loading for schizophrenia and thus our findings cannot directly be generalized as representing the general population. Our results suggest that the functions mediated by NDE1 during the early stages of neurodevelopment are susceptible to the additional disruptive effects of pre- and perinatal environmental factors associated with high birth weight, augmenting schizophrenia susceptibility.

An association between both low and high birth weight and increased disorganized and negative symptom severity in schizophrenia and other psychoses.

Longitudinal cohort studies have implicated an association between both low and high birth weight and increased schizophrenia risk. In this study, we investigated the effect of birth weight on the symptom severity of psychotic disorders including schizophrenia in a Finnish schizophrenia family study sample. We used a multivariate GEE (General Estimating Equation) regression model to investigate the association of birth weight and symptom severity in 282 subjects with a primary psychotic disorder, 178 of whom had a diagnosis of schizophrenia. The Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS) were used as a measure of symptom severity. Sex, place of birth and year of birth were adjusted for in the model. Both low and high birth weight were associated with more severe symptoms with respect to bizarre behaviour, affective flattening and attentional impairment. In addition, low birth weight was associated with more severe symptoms with respect to positive formal thought. Our findings suggest that both low and high birth weight can influence the symptom severity of psychotic disorders. Our results implicate an association between both low and high birth weight and disorganized and negative symptoms.

An association between high birth weight and schizophrenia in a Finnish schizophrenia family study sample.

Longitudinal cohort studies have implicated an association between both low and high birth weight and schizophrenia. It has been suggested that schizophrenia associated genes could augment an individual's susceptibility to adverse prenatal and perinatal environmental events. We investigated the association between birth weight and schizophrenia in a large Finnish schizophrenia family study sample. We utilized the birth weight data of 1051 offspring from 315 Finnish families with at least one offspring with a diagnosis of schizophrenia. We used a multivariate COX frailty model to analyze the effect of birth weight on the risk of developing schizophrenia within the families. Using information from the Medication Reimbursement Register and patient interviews, we further investigated the association of maternal type 2 diabetes and schizophrenia risk among offspring. High birth weight (>4000g) was associated with a 1.68-fold increase in schizophrenia susceptibility. Maternal diabetes at the time of data collection, a proxy for gestational diabetes, was associated with a 1.66-fold increase in the risk of developing schizophrenia among offspring. Our results corroborate recent findings showing an association between high birth weight and schizophrenia. Our results also point to a potential birth-weight independent association between maternal type 2 diabetes and schizophrenia among offspring.