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.

Do adverse perinatal events predict mortality in schizophrenia during midlife?

BACKGROUND: We examined mortality in schizophrenia spectrum disorder (SSD) and non-schizophrenic psychosis (NSSD) compared to individuals without psychosis, and whether perinatal factors predict mortality. METHODS: Within Northern Finland Birth Cohort 1966 (n=10 933; 203 with SSD, 178 with NSSD), mortality was followed until end of 2011 by national register. Wantedness of pregnancy, mother's antenatal depression, smoking and age, parity, paternal socio-economic status (SES) and family type at birth were examined as predictors of mortality. RESULTS: Mortality was higher in SSD (hazard ratio (HR) 3.60; 95% confidence interval (CI) 2.38-5.45) and NSSD (4.05; 2.65-6.17) compared to persons without psychoses after adjustment for gender. HR for natural death was 2.01 (0.82-4.91) in SSD and 4.63 (2.43-8.80) in NSSD after adjustment for gender. Corresponding figures for unnatural deaths were 4.71 (2.94-7.54) and 2.94 (1.56-5.55), respectively. Among non-psychotic persons, mother's depression, smoking and low SES predicted mortality after adjustment for gender and parental psychoses (and SES), whereas among psychosis those whose father was a farmer had lower risk of mortality compared to those with high SES. CONCLUSIONS: Individuals with SSD had a higher risk of unnatural death and individuals with NSSD of natural and unnatural deaths. Perinatal factors seem to be more important predictors of mortality in individuals without psychoses than with psychoses. According to population-based long follow-up data, it is important to pay attention to somatic morbidity behind natural causes of death in psychoses and to prevent suicides in order to prevent excess mortality.

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

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.

TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood.

BACKGROUND: CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2 gene-clusters influence smoking behavior. Our aim was to test developmental changes in their effects as well as the interplays between them and with nongenetic factors. METHODS: Participants included 4762 subjects from a general population-based, prospective Northern Finland 1966 Birth Cohort (NFBC 1966). Smoking behavior was collected at age 14 and 31 years. Information on maternal smoking, socioeconomic status, and novelty seeking were also collected. Structural equation modeling was used to construct an integrative etiologic model including genetic and nongenetic factors. RESULTS: Several single nucleotide polymorphisms in both gene-clusters were significantly associated with smoking. The most significant were in CHRNA3 (rs1051730, p = 1.1 × 10(-5)) and in TTC12 (rs10502172, p = 9.1 × 10(-6)). CHRNA3-rs1051730[A] was more common among heavy/regular smokers than nonsmokers with similar effect-sizes at age 14 years (odds ratio [95% CI]: 1.27 [1.06-1.52]) and 31 years (1.28 [1.13-1.44]). TTC12-rs10502172[G] was more common among smokers than nonsmokers with stronger association at 14 years (1.33 [1.11-1.60]) than 31 years (1.14 [1.02-1.28]). In adolescence, carriers of three-four risk alleles at either CHRNA3-rs1051730 or TTC12-rs10502172 had almost threefold odds of smoking regularly than subjects with no risk alleles. TTC12-rs10502172 effect on smoking in adulthood was mediated by its effect on smoking in adolescence and via novelty seeking. Effect of CHRNA3-rs1051730 on smoking in adulthood was direct. CONCLUSIONS: TTC12-ANKK1-DRD2s seemed to influence smoking behavior mainly in adolescence, and its effect is partially mediated by personality characteristics promoting drug-seeking behavior. In contrast, CHRNA5-CHRNA3-CHRNB4 is involved in the transition toward heavy smoking in mid-adulthood and in smoking persistence. Factors related to familial and social disadvantages were strong independent predictors of smoking.

Negative symptoms and their predictors in schizophrenia within the Northern Finland 1966 Birth Cohort.

Negative symptoms are a major scientific and therapeutic challenge in schizophrenia. We report the occurrence and predicting factors of negative symptoms at two time points in a population-based birth cohort. The negative symptoms of subjects with Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R) schizophrenia (n=46) were scrutinized at the first hospitalization due to psychosis from hospital records (first-episode psychosis) and with an interview approximately 10 years later (follow-up phase). Developmental and sociodemographic predictors of negative symptoms in first-episode psychosis, follow-up phase and at both measurements were analysed. Forty-one percent of the subjects had negative symptoms at the first episode, 39% in the follow-up phase, and in 24% the symptoms persisted at both measurements. Smoking at the age of 14, definite psychosocial stressor and not being married predicted more negative symptoms whereas good school performance and using less alcohol at age 14 predicted fewer persistent negative symptoms. These findings are new. However, we were not able to identify any major premorbid phenotype or endophenotype predicting negative symptoms which support the view that negative symptoms might mainly be a specific part of the illness.

Schizophrenia and sudden cardiac death: a review.

Schizophrenia is a devastating mental disorder, which is often associated with severe loss of functioning and shortened life expectancy. Suicides and accidents are well-known causes of the excess mortality, but patients with schizophrenia have also been reported to be three times as likely to experience sudden unexpected death as individuals from the general population. This review is aimed to offer an update of the prevalence and mechanisms for sudden cardiac death in schizophrenia. The PubMed database was searched from 1966 up to May 2007 with key words schizophrenia AND " sudden cardiac death" OR "autonomic dysfunction" OR "torsades de pointes". Part of the high death rates may be explained by long-lasting negative health habits, disease- and treatment-related metabolic disorders, and consequent increased frequencies of cardiovascular diseases. The antipsychotic medications may also increase the risk as some antipsychotics may cause prolongation of QT-time, serious ventricular arrhythmias and predispose to sudden death. Autonomic dysfunction seen as low heart rate variability and decreased baroreflex sensitivity may also contribute via malignant arrhythmias. Due to the complex interaction of various risk factors for sudden death, the patients need a comprehensive follow-up of their physical health. In addition, more studies on the role and prevalence of autonomic dysfunction in psychotic patients are needed.

Poor premorbid school performance is associated with later cigarette smoking among schizophrenia patients.

Schizophrenia patients who smoke have been postulated to have genetically mediated dysfunctional nicotinic neurotransmission. We hypothesized that this nicotinic dysfunction would manifest as poorer school performance in adolescence, before the onset of illness, in smoking compared with non-smoking schizophrenia patients. Over a 31-year follow-up period, 100 (65 men) cohort members of the Northern Finland 1966 Birth Cohort were hospitalized and diagnosed with DSM-III-R schizophrenia. The information on school performance was obtained at the end of compulsory schooling at age 16 years. The information on smoking habits was gathered from a questionnaire mailed to cohort members at the age of 31 years. Compared with non-smoking schizophrenia patients, schizophrenia patients who smoked in adulthood had lower overall mean grades, lower mean grades in combined mathematical subjects, and lower grades in music. Poor school performance might represent premorbid nicotinergic dysfunction associated with cognitive deficits in future smokers among schizophrenia patients compared with those who remained non-smokers.

Is initiation of smoking associated with the prodromal phase of schizophrenia?

OBJECTIVE: Although the association between smoking and schizophrenia is well known, little attention has been paid to the time between initiation of smoking and onset of schizophrenia. Our goal was to study this putative temporal relation among patients with schizophrenia. METHODS: We used data from the Northern Finland 1966 Birth Cohort (n = 11,017) linked with the National Finnish Hospital Discharge Register to study age at initiation of smoking and age at onset of schizophrenia, and we examined associations between family and environmental factors and the retrospectively determined regular smoking among patients with schizophrenia. RESULTS: Our main finding was that the initiation of regular smoking was closely related to the onset of schizophrenia. The mean difference in time between the initiation of regular smoking and the onset of schizophrenia among patients (n = 30) was 2.3 (standard deviation [SD] 6.6) years, which was statistically significantly lower than that for subjects with other psychoses (n = 18) (8.6 [SD 6.3] yr) (p < 0.001). Among patients with schizophrenia, the increased likelihood of smoking was associated only with paternal smoking in the family environment, but not with any other background factors (odds ratio 3.5, 95; confidence interval 1.9-11.3). CONCLUSION: Smoking may be a sign of the prodromal phase of schizophrenia.

Teenage smoking and substance use as predictors of severe alcohol problems in late adolescence and in young adulthood.

PURPOSE: To study the association between adolescent alcohol use, smoking, other substance use, and later substance-use-related problems in a large general population sample in Northern Finland. METHODS: Data from the Northern Finland 1966 Birth Cohort (n = 11,017) were linked with National Crime Registers and the Finnish Hospital Discharge Register. Information on adolescent alcohol use, smoking, and other substance use was gathered via a questionnaire in 1980 and 1981, when subjects' age was 14 years. Logistic regression analyses were performed to examine the association between alcohol use frequency, tendency for heavy drunkenness, smoking and other substance use in adolescence, and drunk driving offenses between ages 15 and 32 years and hospital-treated substance use disorders between ages 16 and 31 years, adjusting for parental social class, family type, and school performance. RESULTS: The most powerful predictor for drunk driving was regular smoking at the age of 14 years (AOR 6.8, 95% CI 4.6-10.1 for males and 6.3, 95% CI 1.9-20.6 for females). Hospital-treated substance use disorders were associated with male regular smoking (AOR 9.4, 95% CI 4.6-19.2) and female regular alcohol use (AOR 7.5, 95% CI 2.6-21.5), and having often been heavily drunk (AOR 12.7, 95% CI 4.0-40.4) at the age of 14 years. CONCLUSIONS: Teenage regular and heavy alcohol use and smoking are important predictors for substance-use-related problems later in adolescence and in young adulthood. Adolescents with early onset regular smoking and with drunkenness-oriented alcohol use are especially at risk for developing hazardous substance use later in life.

Hyperlipidemia in persons using antipsychotic medication: a general population-based birth cohort study.

BACKGROUND: Shortly after phenothiazines were introduced, they were found to elevate serum triglyceride and total cholesterol levels. During the past decade, an increasing body of literature has also documented this effect in atypical antipsychotics. Previous studies of antipsychotic-associated hyperlipidemias are based on clinical samples, mostly from case series. We studied the prevalence of hyperlipidemia in subjects who did and did not take antipsychotic medication in a prospective, general population-based birth cohort. METHOD: The study sample consisted of 5654 members of the unselected Northern Finland 1966 Birth Cohort who participated in the 1997-1998 clinical examination at 31 years of age. Blood samples were taken after an overnight fast, and serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels were determined. Health habits and other possible correlates for hyperlipidemia were assessed using a questionnaire. The sample was analyzed in 4 categories according to use of antipsychotic medication: (1) atypical, (2) typical, (3) atypical and typical (for the 3 antipsychotic categories, total N = 45), and (4) no antipsychotic medication (N = 5609). Nonparametric tests and multiple logistic regression analysis were used to measure the effect of antipsychotics on serum lipids. RESULTS: High lipid levels were found in persons treated with both atypical and typical medication (mean total cholesterol = 233 mg/dL, mean triglycerides = 163 mg/dL). Mean total cholesterol and triglycerides were also high in subjects who used only typical medication (215 mg/dL and 148 mg/dL, respectively). The prevalence of hypercholesterolemia, high LDL cholesterol, and hypertriglyceridemia was high in persons using antipsychotic medication (31.1%, 20.0%, and 22.2%, respectively) compared with persons not using such medication (12.2%, 10.2%, and 7.0%, respectively). After we adjusted for risk factors for hyperlipidemia (sex, diet, waist circumference, physical exercise, smoking, and alcohol consumption), the results of logistic regression analysis showed that in persons treated with antipsychotic medication the risk of hypercholesterolemia was 2.8 (95% CI = 1.4 to 5.6); of hypertriglyceridemia, 2.3 (95% CI = 1.0 to 5.4); and of high LDL cholesterol, 1.6 (95% CI = 0.7 to 3.5). CONCLUSION: Lipid levels in subjects who used both atypical and typical medication and those who used only typical medication were high even in young age. As these persons are at special risk of hyperlipidemia, their lipid levels should be regularly monitored, and a cholesterol-lowering diet, as well as medication, should be considered. The results indicate an elevated risk of hyperlipidemia in persons using antipsychotic medication independent of the other risk factors assessed.

Criminality in the offspring of antenatally depressed mothers: a 33-year follow-up of the Northern Finland 1966 Birth Cohort.

BACKGROUND: No epidemiological studies have been reported on the association between mothers' antenatal depression and criminality in their offspring. METHODS: The material consists of a general population cohort of 12059 children born in 1966 in Northern Finland and followed to the end of 1998. Mothers were asked at midgestation by a nurse at the antenatal clinic if they felt themselves to be depressed. The Finnish Ministry of Justice provided information for all descendants on criminal offences. The associations between maternal depression and subgroups of violent and non-violent, violent recidive and non-recidive criminality in male and female offspring were analysed. RESULTS: Of the mothers 14% had depressed mood during pregnancy. A total of 607 (10.9%) male and 72 (1.3%) female criminal offenders were included in the cohort. When adjusted for mother's marital status, smoking, wantedness of the pregnancy, place of residence, socioeconomic status and perinatal complications, the odds ratio (OR) for males was 1.4 (95% CI 1.0-1.9) in the association between maternal depression and non-violent offenders, 1.6 (1.1-2.4) between maternal depression and violent offenders and 1.7 (1.0-3.0) between maternal depression and violent recidivists. The adjusted OR for females involved in non-violent crimes was 1.7 (0.9-3.3) and 0.6 (0.1-6.0) for violent crimes. LIMITATIONS: Maternal depression was not checked using a standardized assessment. CONCLUSIONS: For male offspring of antenatally depressed mothers there was a significant but slight increase in criminality. The emotional state of a pregnant mother may have some, but limited, influence on later criminality in the offspring.

Predictors of female criminality: findings from the Northern Finland 1966 birth cohort.

OBJECTIVE: Females still commit fewer criminal offenses than males, but the percentage of female offending has been increasing during the past few decades. Thus there is a need for original studies into the perinatal contribution to the etiology of female offending. METHOD: A large, prospectively collected birth cohort database of female members (N = 5,056) was available. Information on perinatal biological and psychosocial risks as well as data from the National Crime Registers up to 32 years of age were collected and analyzed by logistic regression and a chi2 automatic interaction detection (CHAID) analysis. RESULTS: The absence of the father during childhood was the strongest risk factor in predicting female criminality (odds ratio 2.5; 95% confidence interval 1.4-4.3). Furthermore, in the families in which the father was present, maternal smoking during pregnancy together with being born unwanted correlated with an increased prevalence of criminal offending significantly up to 7.2%. CONCLUSIONS: CHAID analysis proved to be a useful statistical method in predicting female adult criminality after preceding perinatal risks. It revealed that the risk factors were mainly familial, the paternal factor being the most important one in determining the probability of daughters committing criminal offenses.

Weight gain and glucose and lipid metabolism disturbances during antipsychotic medication: a review.

Antipsychotic medication is the mainstay of treatment for functional psychotic illnesses. However, for some patients weight gain and the disturbances in blood-lipid levels and glucose balance associated with their use are significant disadvantages, and pose health risks that may affect prognosis. A substantial body of evidence suggests that weight gain is at least partly related to the blocking effects of antipsychotic medication on serotonin- and histamine-mediated neurotransmission. The disadvantages associated with weight gain can be reduced by an appropriate choice of antipsychotic and avoidance of polypharmacy, by regular monitoring of the patient's weight, and, if necessary, by the patient's participation in a dieting programme.