Rare coding variants in ten genes confer substantial risk for schizophrenia.

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.

Physical health examination in outpatients with schizophrenia: the cost effectiveness of laboratory screening tests.

BACKGROUND: Guidelines on laboratory screening in schizophrenia recommend annual monitoring of fasting lipids and glucose. The utility and the cost effectiveness of more extensive laboratory screening have not been studied. METHODS: The Living Conditions and the Physical Health of Outpatients with Schizophrenia Study provided a comprehensive health examination, including a laboratory test panel for 275 participants. We calculated the prevalence of the results outside the reference range for each laboratory test, and estimated the cost effectiveness to find an aberrant test result using the number needed to screen to find one abnormal result (NNSAR) and the direct cost spent to find one abnormal result (DCSAR, NNSAR x direct cost per test) formulas. In addition, we studied whether patients who were obese or used clozapine had more often abnormal results. RESULTS: A half of the sample had 25-hydroxyvitamin D below, and almost one-fourth cholesterol, triglycerides or glucose above the reference range. One-fifth had sodium below and gamma glutamyltransferase above the reference range. NNSAR was highest for potassium (137) and lowest for 25-hydroxyvitamin D (2). DCSAR was below 5€ for glucose, all lipids and sodium, and below 10€ for creatinine and gamma glutamyltransferase. Potassium (130€), pH-adjusted ionized calcium (33 €) and thyroid stimulating hormone (33€) had highest DCSARs. Several abnormal results were more common in obese and clozapine using patients. CONCLUSIONS: An annual laboratory screening panel for an outpatient with schizophrenia should include fasting glucose, lipids, sodium, creatinine, a liver function test and complete blood count, and preferably 25-hydroxyvitamin D.

Dyspepsia and constipation in patients with schizophrenia spectrum disorders.

Constipation and dyspepsia are disturbing gastrointestinal symptoms that are often ignored in research on physical comorbidities of schizophrenia. The aim was to assess dyspepsia and constipation in a sample of outpatients with schizophrenia spectrum psychoses. A general practitioner performed a thorough physical health check for 275 outpatients and diagnosed constipation and dyspepsia. This study assessed the possible contribution of several sociodemographic, lifestyle, and clinical variables to constipation and dyspepsia using logistic regression analysis. This study also assessed whether these symptoms were associated with abnormal laboratory findings. The prevalence of constipation was 31.3%, and of dyspepsia 23.6%. Paracetamol (OR =3.07, 95% CI =1.34-7.02) and clozapine use (OR =5.48, 95% CI =2.75-10.90), older age (OR =1.04, 95% CI =1.01-1.06), and living in sheltered housing (OR =2.49, 95% CI =1.16-5.33) were risk factors for constipation. For dyspepsia the risk factors were female sex (OR =2.10, 95% CI =1.15-3.83), non-steroidal anti-inflammatory drugs (OR =2.47, 95% CI =1.13-5.39), and diabetes medication (OR =2.42, 95% CI =1.12-5.25). Patients with dyspepsia had lower haemoglobin and haematocrit and higher glucose values than those without dyspepsia. Patients with constipation had lower thrombocyte values than patients without constipation. However, these findings were explained by factors pre-disposing to constipation and dyspepsia. Clozapine use markedly increases the risk of constipation and may lead to life-threatening complications. In addition, analgesics and diabetes medication were related to gastrointestinal symptoms. These medications and their association to gastrointestinal symptoms should be kept in mind when treating patients with schizophrenia.

Multiple physical healthcare needs among outpatients with schizophrenia: findings from a health examination study.

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.

Diabetes and Schizophrenia.

People with schizophrenia have 2- to 5-fold higher risk of type 2 diabetes than the general population. The traditional risk factors for type 2 diabetes, especially obesity, poor diet, and sedentary lifestyle, are common in people with schizophrenia already early in the course of illness. People with schizophrenia also often have low socioeconomic status and income, which affects their possibilities to make healthy lifestyle choices. Antipsychotic medications increase the risk of type 2 diabetes both directly by affecting insulin sensitivity and indirectly by causing weight gain. Lifestyle modification interventions for prevention of diabetes should be an integral part of treatment of patients with schizophrenia. In the treatment of type 2 diabetes in patients with schizophrenia, communication and collaboration between medical care and psychiatric treatment providers are essential.

Clozapine use and sedentary lifestyle as determinants of metabolic syndrome in outpatients with 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.