Inflammation, hippocampal volume, and cognition in schizophrenia: results from the Northern Finland Birth Cohort 1966.

Increased blood interleukin-6 (IL-6) levels are a replicated abnormality in schizophrenia, and may be associated with smaller hippocampal volumes and greater cognitive impairment. These findings have not been investigated in a population-based birth cohort. The general population Northern Finland Birth Cohort 1966 was followed until age 43. Subjects with schizophrenia were identified through the national Finnish Care Register. Blood IL-6 levels were measured in n = 82 subjects with schizophrenia and n = 5373 controls at age 31. Additionally, 31 patients with schizophrenia and 63 healthy controls underwent brain structural MRI at age 34, and cognitive testing at ages 34 and 43. Patients with schizophrenia had significantly higher median (interquartile range) blood IL-6 levels than controls (5.31, 0.85-17.20, versus 2.42, 0.54-9.36, p = 0.02) after controlling for potential confounding factors. In both schizophrenia and controls, higher blood IL-6 levels were predictors of smaller hippocampal volumes, but not cognitive performance at age 34. We found evidence for increased IL-6 levels in patients with midlife schizophrenia from a population-based birth cohort, and replicated associations between IL-6 levels and hippocampal volumes. Our results complement and extend the previous findings, providing additional evidence that IL-6 may play a role in the pathophysiology of schizophrenia and associated brain alterations.

Long-term antipsychotic use and brain changes in schizophrenia - a systematic review and meta-analysis.

OBJECTIVE: The association between long-term antipsychotic treatment and changes in brain structure in schizophrenia is unclear. Our aim was to conduct a systematic review and a meta-analysis on long-term antipsychotic effects on brain structures in schizophrenia focusing on studies with at least 2 years of follow-up between MRI scans. DESIGN: Studies were systematically collected using 4 databases, and we also contacted authors for unpublished data. We calculated correlations between antipsychotic dose and/or type and brain volumetric changes and used random effect meta-analysis to study correlations by brain area. RESULTS: Thirty-one publications from 16 samples fulfilled our inclusion criteria. In meta-analysis, higher antipsychotic exposure associated statistically significantly with parietal lobe decrease (studies, n = 4; r = -.14, p = .013) and with basal ganglia increase (n = 4; r = .10, p = .044). Most of the reported correlations in the original studies were statistically nonsignificant. There were no clear differences between typical and atypical exposure and brain volume change. The studies were often small and highly heterogeneous in their methods and seldom focused on antipsychotic medication and brain changes as the main subject. CONCLUSIONS: Antipsychotic medication may associate with brain structure changes. More long-term follow-up studies taking into account illness severity measures are needed to make definitive conclusions.

Psychiatric hospital admission and long-term care in patients with very-late-onset schizophrenia-like psychosis.

OBJECTIVE: In this register-based study the rates and durations of psychiatric hospitalizations were compared between patients with very-late-onset schizophrenia-like psychosis (VLOSLP, n = 918) and elderly patients with illness onset before 60 years (n = 6142). The proportion of patients ending up in long-term care (LTC) or long-lasting psychiatric hospital care (LLP) was also studied. METHODS: A sample of patients with schizophrenia aged 65 or over was collected from the Finnish Hospital Discharge Register. Psychiatric hospitalizations were calculated per year, and logistic regression was used to compare onset groups and factors associated with ending up in LTC/LLP. RESULTS: Between 1999 and 2003, 27% of patients with VLOSLP and 23% of patients with earlier onset had at least one psychiatric hospitalization (p = 0.020). When the rates of patients' stays in psychiatric hospital per year were compared, the only difference was that in the first year 14% (141/918) and 11% (679/6142) had at least one day in psychiatric hospital (p < 0.001) respectively. In logistic regression onset group of schizophrenia was not associated with LTC/LLP, except weakly the VLOSLP group in women (p = 0.042, OR 1.23). Patients having any cardiovascular disease (p < 0.001, OR 0.63) or a respiratory disease (p = 0.008, OR 0.73) were less likely to end up in LTC/LLP. CONCLUSION: The patients with VLOSLP needed more psychiatric hospital care than those with earlier illness onset. Ending up in LTC/LLP was equally common in both onset groups, but some physical diseases, such as cardiovascular and respiratory, diminished the likelihood of this.

Patients with very-late-onset schizoprhenia-like psychosis have higher mortality rates than elderly patients with earlier onset schizophrenia.

OBJECTIVE: In this register-based study of schizophrenia patients aged 65 years or above, mortality and causes of death diagnosed at age of 60+ (very-late-onset schizophrenia-like psychosis, VLOSLP) were studied in comparison with sex- and age-matched general Finnish population. Standardized Mortality Ratios (SMRs) of VLOSLP patients were also compared with those of earlier onset (below 60 years) schizophrenia patients, and hazard of death was calculated between these patient groups. METHODS: The data was obtained from Finnish nationwide registers and consisted of 918 VLOSLP patients and 6142 earlier onset patients who were at least 65 years on 1 January 1999. The register-based follow-up for mortality covered 10 years between 1999 and 2008. RESULTS: Overall SMR was 5.02 (4.61-5.46) in the group of VLOSLP patients and 2.93 (2.83-3.03) in the group of earlier onset patients. In men, SMRs were 8.31 (7.14-9.62; n = 179) and 2.91 (2.75-3.07, n = 1316) and in women 4.21 (3.78-4.66; n = 364) and 2.94 (2.82-3.07, n = 2055). In the VLOSLP group, SMRs were higher in most causes-of-death categories such as accidents, respiratory diseases, dementias, neoplasms and circulatory diseases. However, in direct comparison adjusted for several variables, the difference between these groups was minimal (Hazard Ratio, HR, 1.16 95%CI 1.05-1.27, p = 0.003). CONCLUSION: Patients with VLOSLP, especially men, are at even higher risk of death than schizophrenia patients with earlier onset. Physical comorbidities and accidents in the VLOSLP group mostly explained this result. Targeted clinical interventions with effective collaboration between psychiatry and primary and specialist-level somatic care are crucial to reduce their excess mortality

Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis.

BACKGROUND: Duration of untreated psychosis (DUP) is one of the few potentially modifiable predictors of outcomes of schizophrenia. Long DUP as a predictor of poor short-term outcome has been addressed in previous meta-analyses, but the long-term effects of DUP remain unclear. AIMS: To analyse the associations between DUP and long-term outcomes of schizophrenia. METHOD: A systematic literature search was performed using seven electronic databases and manual searches. Random effects weighted meta-analysis with correlation coefficients was used to pool the results. RESULTS: We identified 3493 unique publications, from which 33 samples met our predefined selection criteria. Long DUP correlated statistically significantly with poor general symptomatic outcome, more severe positive and negative symptoms, lesser likelihood of remission and poor social functioning and global outcome (correlations 0.13-0.18). Long DUP was not associated with employment, quality of life or hospital treatment. CONCLUSIONS: The small but mostly consistent correlation between long DUP and poor outcome indicates that early intervention in psychosis may have at least subtle positive effects on the long-term course of illness.

Use of antidepressant medication and suicidal ideation-the Northern Finland Birth Cohort 1966.

OBJECTIVE: The aim was to study the association between use of antidepressant medication and suicidal ideation in different diagnostic groups in a large population-based cohort. METHODS: Information on prescribed drugs within the Northern Finland Birth Cohort 1966 was collected at the age of 31 years with postal questionnaire (N= 8218). The presence of suicidal ideation was assessed via the Hopkins Symptom Checklist-25 questionnaire. We studied associations between suicidal ideation and antidepressant medication in various diagnostic and symptom groups, and it adjusted for symptoms of depression and anxiety. RESULTS: Suicidal ideation was associated with the use of antidepressant medication in all diagnostic groups, but the association disappeared with adjustment for other symptoms of depression and anxiety. Subjects who reported insomnia and used antidepressants had suicidal ideation more commonly than did subjects who were not using antidepressants even when other symptoms were adjusted for (p = 0.02). There were no statistically significant differences between antidepressant groups or doses. CONCLUSION: In a large unselected cohort, antidepressant medication was not associated with increased suicidal ideation when other symptoms of depression and anxiety were taken into account. The assessment of insomnia might be useful for identifying individuals liable to have increased suicidal ideation while on antidepressant medication.

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

The contribution of first-episode illness characteristics and cumulative antipsychotic usage to progressive structural brain changes over a long-term follow-up in schizophrenia.

Exposure to antipsychotics as well as certain first-episode illness characteristics have been associated with greater gray matter (GM) deficits in the early phase of schizophrenia. Whether the first-episode illness characteristics affect the long-term progression of the structural brain changes remain unexplored. We therefore assessed the role of first-episode illness characteristics and life-time antipsychotic use in relation to long-term structural brain GM changes in schizophrenia. Individuals with schizophrenia (SZ, n = 29) and non-psychotic controls (n = 61) from the Northern Finland Birth Cohort 1966 underwent structural MRI at the ages of 34 (baseline) and 43 (follow-up) years. At follow-up, the average duration of illness was 19.8 years. Voxel-based morphometry was used to assess the effects of predictors on longitudinal GM changes in schizophrenia-relevant brain areas. Younger age of onset (AoO), higher cumulative antipsychotic dose and severity of symptoms were associated with greater GM deficits in the SZ group at follow-up. None of the first-episode illness characteristics were associated with longitudinal GM changes during 9-year follow-up period. We conclude that a younger AoO and high life-time antipsychotic use may contribute to progression of structural brain changes in schizophrenia. Apart from AoO, other first-episode illness characteristics may not contribute to longitudinal GM changes in midlife.

Phenotype mining in CNV carriers from a population cohort.

Phenotype mining is a novel approach for elucidating the genetic basis of complex phenotypic variation. It involves a search of rich phenotype databases for measures correlated with genetic variation, as identified in genome-wide genotyping or sequencing studies. An initial implementation of phenotype mining in a prospective unselected population cohort, the Northern Finland 1966 Birth Cohort (NFBC1966), identifies neurodevelopment-related traits-intellectual deficits, poor school performance and hearing abnormalities-which are more frequent among individuals with large (>500 kb) deletions than among other cohort members. Observation of extensive shared single nucleotide polymorphism haplotypes around deletions suggests an opportunity to expand phenotype mining from cohort samples to the populations from which they derive.

Change in antipsychotic usage pattern and risk of relapse in older patients with schizophrenia.

OBJECTIVE: The aim of this study was to explore the use of first (FGAs) and second generation antipsychotics (SGAs) in older outpatients with schizophrenia and schizoaffective disorder. Factors associated with schizophrenic relapses were also studied. METHODS: The study sample consisting of 8792 patients aged 64 years or more was collected from Finnish nationwide registers. The register data on the use of FGAs and SGAs were followed up between 1998 and 2003. Factors associated with psychiatric hospitalization in 1999 indicating relapse were studied using logistic regression analysis. RESULTS: The use of SGAs increased from 2.8% to 12.4%, and the use of FGAs decreased from 57.5% to 39.4%. The use of a combination of SGAs and FGAs increased from 4.0% to 8.5%. The proportion of those who did not buy any antipsychotics varied between 35.8% and 39.7%. The number of patients hospitalized on psychiatric wards within a year (1999; relapsed) was 8.8%. Factors independently associated with relapse were use of combined FGAs and SGAs [odds ratio (OR) 1.70, p = 0.001] and use of antidepressants (OR 1.27, p = 0.019). Diagnosis of cardiovascular disease was negatively associated with risk of schizophrenic relapse (OR 0.84, p = 0.040). CONCLUSION: The use of SGAs increased while the use of FGAs decreased in older outpatients with schizophrenia. Almost 40% of the study sample did not use any antipsychotic medication. The 1-year relapse rate was 8.8%. Several factors, such as combined use of FGAs and SGAs, or antidepressants, were associated with schizophrenic relapse, whereas cardiovascular disease showed a negative association with the relapse.

Psychotropic medications and the risk of sudden cardiac death during an acute coronary event.

AIMS: Psychotropic medication increases cardiac mortality, but the reasons for this association are not clear. We studied the role of psychotropic drugs as a triggering factor of sudden cardiac death (SCD) during an acute coronary event. METHODS AND RESULTS: The use of medication was compared between victims of SCD and survivors of an acute coronary event in a case-control study including a consecutive series of victims of SCD (n= 1814, mean age 65 ± 11 years) verified to be due to an acute coronary event at medico-legal autopsy and consecutive series of patients surviving an acute myocardial infarction (AMI; n= 1171, mean age 66 ± 12 years). The medication history was obtained from autopsy/hospital records and interviews with relatives of SCD victims and AMI patients. The use of antipsychotics [9.7 vs. 2.4%, odds ratio (OR) 4.4, 95% confidence interval (CI) 2.9-6.6; P< 0.001] and antidepressants (8.6 vs. 5.5%, OR: 1.6, 95% CI: 1.2-2.2; P= 0.003) was more common in the SCD than AMI group, but the use of benzodiazepines did not differ between the groups (11.7 vs. 13.2%; P= 0.270). The use of antipsychotics remained as a significant risk factor for SCD after adjustment for confounding variables (OR: 3.4, 95% CI: 1.8-6.5; P< 0.001). Combined use of phenothiazines and any antidepressant was associated with a very high risk of SCD (OR: 18.3, 95% CI: 2.5-135.3; P< 0.001). CONCLUSION: The use of psychotropic drugs, especially combined use of antipsychotic and antidepressant drugs, is strongly associated with an increased risk of SCD at the time of an acute coronary event.

m-RESIST, a Mobile Therapeutic Intervention for Treatment-Resistant Schizophrenia: Feasibility, Acceptability, and Usability Study.

BACKGROUND: In the European Union, around 5 million people are affected by psychotic disorders, and approximately 30%-50% of people with schizophrenia have treatment-resistant schizophrenia (TRS). Mobile health (mHealth) interventions may be effective in preventing relapses, increasing treatment adherence, and managing some of the symptoms of schizophrenia. People with schizophrenia seem willing and able to use smartphones to monitor their symptoms and engage in therapeutic interventions. mHealth studies have been performed with other clinical populations but not in populations with TRS. OBJECTIVE: The purpose of this study was to present the 3-month prospective results of the m-RESIST intervention. This study aims to assess the feasibility, acceptability, and usability of the m-RESIST intervention and the satisfaction among patients with TRS after using this intervention. METHODS: A prospective multicenter feasibility study without a control group was undertaken with patients with TRS. This study was performed at 3 sites: Sant Pau Hospital (Barcelona, Spain), Semmelweis University (Budapest, Hungary), and Sheba Medical Center and Gertner Institute of Epidemiology and Health Policy Research (Ramat-Gan, Israel). The m-RESIST intervention consisted of a smartwatch, a mobile app, a web-based platform, and a tailored therapeutic program. The m-RESIST intervention was delivered to patients with TRS and assisted by mental health care providers (psychiatrists and psychologists). Feasibility, usability, acceptability, and user satisfaction were measured. RESULTS: This study was performed with 39 patients with TRS. The dropout rate was 18% (7/39), the main reasons being as follows: loss to follow-up, clinical worsening, physical discomfort of the smartwatch, and social stigma. Patients' acceptance of m-RESIST ranged from moderate to high. The m-RESIST intervention could provide better control of the illness and appropriate care, together with offering user-friendly and easy-to-use technology. In terms of user experience, patients indicated that m-RESIST enabled easier and quicker communication with clinicians and made them feel more protected and safer. Patients' satisfaction was generally good: 78% (25/32) considered the quality of service as good or excellent, 84% (27/32) reported that they would use it again, and 94% (30/32) reported that they were mostly satisfied. CONCLUSIONS: The m-RESIST project has provided the basis for a new modular program based on novel technology: the m-RESIST intervention. This program was well-accepted by patients in terms of acceptability, usability, and satisfaction. Our results offer an encouraging starting point regarding mHealth technologies for patients with TRS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03064776; https://clinicaltrials.gov/ct2/show/record/NCT03064776. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2017-021346.

Neuregulin-1 genotype is associated with structural differences in the normal human brain.

The human neuregulin-1 (NRG-1) gene is highly expressed in the brain, is implicated in numerous functions associated with neuronal development, and is a leading candidate gene for schizophrenia. The T allele of SNP8NRG243177, part of a risk haplotype for schizophrenia, has been previously associated with decreases in white matter in the right anterior internal capsule and the left anterior thalamic radiation. To our knowledge no studies have described the effects of SNP8NRG243177 on grey matter volume at a voxelwise level. We assessed associations between this SNP and brain structure in 79 general population volunteers from the Northern Finland 1966 Birth Cohort (NFBC 1966). We show, for the first time, that genetic variation in SNP8NRG243177 is associated with variation in frontal brain structure in both grey and white matter. T allele carriers showed decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus, as well as decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and external capsule regions traversed by major white matter tracts of the anterior thalamic radiation, and the inferior fronto-occipital fasciculus. These results suggest that this genetic variant may mediate risk for schizophrenia, in part, through its effect on brain structure in these regions.

Mortality and causes of death in older patients with schizophrenia.

OBJECTIVE: The aim of this study was to evaluate mortality and causes of death in older patients with schizophrenia in comparison with the general population. The mortality of patients experiencing relapse was also compared with those in remission. METHODS: The study sample consists of patients (n = 9461) over 65 years by the first of January 1999, with schizophrenia or schizoaffective disorder (ICD-8, ICD-9: 295, ICD-10: F20, F25) as the main register diagnosis during the period 1969-1998. The sample was collected from nationwide registers in Finland and followed up between 1999 and 2008. RESULTS: Overall Standard Mortality Ratio (SMR) of the older schizophrenia patients was 2.69 [95% confidence interval, 2.62-2.76]. For natural causes of death, overall SMR was 2.58 (2.51-2.65; n = 5301), and for unnatural causes of death, it was 11.04 (9.75-12.47; n = 262). The most common causes of death matched those in the general population. Of patients who died during follow-up, 31% (1709/5596) had at least one psychiatric hospitalization within 5 years before follow-up. The SMR for this group was higher (3.92; 3.73-4.11) than in those patients (2.37; 2.29-2.44) with no such treatment during that time. CONCLUSION: All-cause mortality of older patients with schizophrenia was almost threefold that of general population. They died for similar reasons to the general population; however, deaths for unnatural causes were especially common (accidents and suicides). Those patients still experiencing relapses in older age have an increased risk of death compared with those with schizophrenia in remission.

Use of antipsychotic medication and suicidality--the Northern Finland Birth Cohort 1966.

In addition to psychoses, antipsychotic drugs are nowadays also prescribed for other psychiatric disturbances, such as mood disorders. We wanted to find out whether there is any association between the use of antipsychotic drugs and suicidality in cases of psychotic and non-psychotic disorders. Our sample was the population-based Northern Finland 1966 Birth Cohort. Information on the use of prescribed drugs was collected in 1997 from the nationwide medication register and with a postal questionnaire (N = 8218). The presence of suicidal ideation was assessed cross-sectionally using the Symptom Check List-25 questionnaire. We studied associations between suicidal ideation, adjusted for symptoms of depression and anxiety, and antipsychotic medication in different diagnostic groups (schizophrenia, other psychosis and no psychosis). Individuals receiving antipsychotic medication (n = 70, 0.9%) had in general more suicidal ideation regardless of diagnostic group, although the associations diminished when taking other symptoms into account. There were no statistically significant differences between those taking typical and atypical antipsychotics. In the non-psychotic group, higher antipsychotic doses were associated with more suicidal ideation even when adjusted for symptoms of depression and anxiety (p < 0.05). In the cases of schizophrenia or other forms of psychosis, no such associations were observed. Our results suggest that one should take suicidal ideation into account when prescribing antipsychotic medication, especially for off-label use.

Ante- and perinatal circumstances and risk of attempted suicides and suicides in offspring: the Northern Finland birth cohort 1966 study.

PURPOSE: To investigate those ante- and perinatal circumstances preceding suicide attempts and suicides, which have so far not been studied intensively. METHODS: Examination of the Northern Finland Birth Cohort 1966 (n = 10,742), originally based on antenatal questionnaire data and now followed up from mid-pregnancy to age 39, to ascertain psychiatric disorders in the parents and offspring and suicides or attempted suicides in the offspring using nationwide registers. RESULTS: A total of 121 suicide attempts (57 males) and 69 suicides (56 males) had occurred. Previously unstudied antenatal factors (maternal depressed mood and smoking, unwanted pregnancy) were not related to these after adjustment. Psychiatric disorders in the parents and offspring were the risk factors in both genders. When adjusted for these, the statistically significant risk factors among males were a single-parent family for suicide attempts (OR 3.71, 95% CI 1.62-8.50) and grand multiparity for suicides (OR 2.67, 95% CI 1.15-6.18). When a psychiatric disorder in females was included among possible risk factors for suicide attempts, it alone remained significant (OR 15.55, 8.78-27.53). CONCLUSIONS: A single-parent family was a risk factor for attempted suicides and grand multiparity for suicides in male offspring even after adjusting for other ante- and perinatal circumstances and mental disorders in the parents and offspring. Mothers' antenatal depressed mood and smoking and unwanted pregnancy did not increase the risk of suicide, which is a novel finding.

Use of inverse probability weighting to adjust for non-participation in estimating brain volumes in schizophrenia patients.

Low participation is a potential source of bias in population-based studies. This article presents use of inverse probability weighting (IPW) in adjusting for non-participation in estimation of brain volumes among subjects with schizophrenia. Altogether 101 schizophrenia subjects and 187 non-psychotic comparison subjects belonging to the Northern Finland 1966 Birth Cohort were invited to participate in a field study during 1999-2001. Volumes of grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) were compared between the 54 participating schizophrenia subjects and 100 comparison subjects. IPW by illness-related auxiliary variables did not affect the estimated GM and WM mean volumes, but increased the estimated CSF mean volume in schizophrenia subjects. When adjusted for intracranial volume and family history of psychosis, IPW led to smaller estimated GM and WM mean volumes. Especially IPW by a disability pension and a higher amount of hospitalisation due to psychosis had effect on estimated mean brain volumes. The IPW method can be used to improve estimates affected by non-participation by reflecting the true differences in the target population.

Glucocorticoid receptor (NR3C1) gene polymorphisms and onset of alcohol abuse in adolescents.

Onset of alcohol use at an early age increases the risk for later alcohol dependence. We investigated the role of the glucocorticoid receptor (GR) gene (NR3C1) in onset of alcohol use and abuse in 14-year-old adolescents (n=4534). Several NR3C1 polymorphisms were associated with onset of alcohol drinking or drunkenness at this age. Strongest associations were observed in females, with one marker (rs244465) remaining significant after correction for multiple testing (P(adj) =0.0067; odds ratio=1.7, for drunkenness). Our data provide the first evidence that GR modulates initiation of alcohol abuse and reveal a polymorphism that might contribute to susceptibility to addiction.

Identifying schizophrenia and other psychoses with psychological scales in the general population.

We study the predictive power and associations of several psychopathology and temperament scales with respect to schizophrenia and other psychotic disorders. Measures of psychopathology (Physical and Social Anhedonia Scales, Perceptual Aberration Scale, Hypomanic Personality Scale, Bipolar II Scale, and Schizoidia Scale) and the Temperament and Character Inventory were included in the 31-year follow-up of the prospective Northern Finland 1966 birth cohort (N = 4926). The Perceptual Aberration Scale was the best scale for concurrent validity in psychoses, and also the best psychopathology scale in terms of discriminant validity. Participants scoring high in hypomanic personality were at the highest risk for developing psychosis during the 11-year follow-up. Harm avoidance was a dominant temperament dimension in individuals with psychosis compared with participants without psychiatric diagnoses. These scales are useful as vulnerability markers in studying psychoses.

Predictors of response to pharmacological treatments in treatment-resistant schizophrenia - A systematic review and meta-analysis.

BACKGROUND: As the burden of treatment-resistant schizophrenia (TRS) on patients and society is high it is important to identify predictors of response to medications in TRS. The aim was to analyse whether baseline patient and study characteristics predict treatment response in TRS in drug trials. METHODS: A comprehensive search strategy completed in PubMed, Cochrane and Web of Science helped identify relevant studies. The studies had to meet the following criteria: English language clinical trial of pharmacological treatment of TRS, clear definition of TRS and response, percentage of response reported, at least one baseline characteristic presented, and total sample size of at least 15. Meta-regression techniques served to explore whether baseline characteristics predict response to medication in TRS. RESULTS: 77 articles were included in the systematic review. The overall sample included 7546 patients, of which 41% achieved response. Higher positive symptom score at baseline predicted higher response percentage. None of the other baseline patient or study characteristics achieved statistical significance at predicting response. When analysed in groups divided by antipsychotic drugs, studies of clozapine and other atypical antipsychotics produced the highest response rate. CONCLUSIONS: This meta-analytic review identified surprisingly few baseline characteristics that predicted treatment response. However, higher positive symptoms and the use of atypical antipsychotics - particularly clozapine -was associated with the greatest likelihood of response. The difficulty involved in the prediction of medication response in TRS necessitates careful monitoring and personalised medication management. There is a need for more investigations of the predictors of treatment response in TRS.