Saana Eskelinen

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

BACKGROUND: Despite the abundant literature on physical comorbidity, the full range of the concurrent somatic healthcare needs among individuals with schizophrenia has rarely been studied. AIMS: This observational study aimed to assess the distressing somatic symptoms and needs for physical health interventions in outpatients with schizophrenia, and factors predicting those needs. METHODS: A structured, comprehensive health examination was carried out, including a visit to a nurse and a general practitioner on 275 outpatients with schizophrenia. The required interventions were classified by type of disease. Logistic regression was used to assess the influence of sociodemographic factors, lifestyle, functional limitations, factors related to psychiatric disorder, and healthcare use on the need for interventions. RESULTS: In total, 44.9% of the patients (mean age 44.9 years) reported somatic symptoms affecting daily life; 87.6% needed specific interventions for a disease or condition, most commonly for cardiovascular, dermatological, dental, ophthalmological, and gastrointestinal conditions, and for altered glucose homeostasis. Smoking and obesity predicted significantly a need of any intervention, but the predictors varied in each disease category. Strikingly, use of general practitioner services during the previous year did not reduce the need for interventions. CONCLUSIONS: Health examinations for outpatients with schizophrenia revealed numerous physical healthcare needs. The health examinations for patients with schizophrenia should contain a medical history taking and a physical examination, in addition to basic measurements and laboratory tests. Prevention and treatment of obesity and smoking should be given priority in order to diminish somatic comorbidities in schizophrenia.

BACKGROUND: Schizophrenia patients are in danger of developing metabolic syndrome (MetS) and its outcomes type 2 diabetes and cardiovascular disease. Antipsychotic treatment and adverse lifestyle increase the burden of metabolic problems in schizophrenia, but little is known about the role of patients' current psychiatric problems and living arrangements in MetS. AIMS: This study aims to evaluate correlations between MetS, severity of psychiatric symptoms, living arrangements, health behaviour and antipsychotic medication in outpatients with schizophrenia spectrum disorders. METHODS: A general practitioner and psychiatric nurses performed a comprehensive health examination for all consenting patients with schizophrenia spectrum disorders treated in a psychosis outpatient clinic. Examination comprised of an interview, a questionnaire, measurements, laboratory tests and a general clinical examination. Diagnosis of MetS was made according to International Diabetes Federation (IDF) definition. Correlations were calculated and logistic regression analysis performed with SAS. RESULTS: 276 patients (men n = 152, mean age ± standard deviation = 44.9 ± 12.6 years) participated in the study; 58.7% (n = 162) of them had MetS according to the IDF definition. Clozapine use doubled the risk of MetS (OR = 2.04, 95% CI 1.09-3.82, P = 0.03), whereas self-reported regular physical activity decreased the risk significantly (OR = 0.32, 95% CI 0.18-0.57, P < 0.001). We found no correlations between MetS and living arrangements or current severity of psychiatric symptoms. CONCLUSIONS: MetS was alarmingly common in our sample. Even moderate physical activity was associated with decreased risk of MetS. Promotion of a physically active lifestyle should be one of the targets in treatment of schizophrenia, especially in patients using clozapine.

BACKGROUND: Poor adherence and negative attitudes to treatment are common clinical problems when treating psychotic disorders. This study investigated how schizophrenia core symptoms and daily functioning affect treatment adherence and attitudes toward antipsychotic medication and to compare patients using clozapine or other antipsychotics. METHOD: A cross-sectional study with data from 275 patients diagnosed with schizophrenia spectrum disorder. Patients adherence, attitudes, insight and side-effects were evaluated using the Attitudes toward Neuroleptic Treatment scale. Overall symptomology was measured using the Brief Psychiatric Rating Scale (BPRS), the Health of the Nation Outcome Scale (HoNOS). The functioning was assessed using activities of daily living scale, instrumental activities of daily living scale and social functioning of daily living scale. RESULTS: Self-reported treatment adherence was high. Of the patients, 83% reported using at least 75% of the prescribed medication. Having more symptoms was related with more negative attitude towards treatment. There was a modest association with functioning and treatment adherence and attitude toward antipsychotic treatment. Attitudes affected on adherence in non-clozapine but not in clozapine groups. CONCLUSION: Early detection of non-adherence is difficult. Systematic evaluation of attitudes toward the treatment could be one way to assess this problem, along with optimized medication, prompt evaluation of side effects and flexible use of psychosocial treatments.