Predictors of functional status at service entry and discharge among young people with first episode psychosis.

OBJECTIVE: Most patients with first episode psychosis (FEP) are neither studying nor employed (have a poor functional status) when first accessing care. Knowledge of the characteristics of patients with poor functioning and the features influencing functional status over time may pave the way to better treatment. METHOD: A medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics on 661 FEP patients who consecutively attended the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia, between 1998 and 2000. Functional status was ascertained using the modified vocational status index and was rated at baseline (poor or good) and according to its evolution over the treatment period (stable good, stable poor, deteriorating or improved functional status). RESULTS: 52.0% of patients had a poor functional status at service entry. They were more likely to be male with a non-affective psychosis. They also had lower levels of premorbid global functioning and education, and were more likely to have self-reported histories of learning disability, forensic issues, traumatic experiences and substance use. At service entry, they had more severe symptoms and poorer global functioning. 37% of these patients maintained a poor functional status at discharge, and 18% of those with a good functional status at service entry experienced a decline. CONCLUSIONS: Although psychosocial interventions might assist a young person with FEP with working towards functional goals, for some, the impact of factors such as ongoing substance use and forensic issues on functional status needs to be addressed.

Correlates of physical activity in people living with psychotic illness.

OBJECTIVE: In the light of the high prevalence of physical comorbidities in people with psychotic illness, there is a need to explore modifiable risk factors that may contribute to this disease burden. The benefits of physical activity to both physical and mental health have been well established. We aimed to examine the prevalence and correlates of physical activity in a national sample of adults living with psychotic illness. METHODS: Physical activity was assessed in 1801 people using the International Physical Activity Questionnaire. Participants were dichotomised into low and moderate-high physical activity groups and associations between physical activity and a range of sociodemographic, clinical and physical comorbidity variables were examined using logistic regression. RESULTS: More than half the participants were categorised in the moderate-high physical activity group with nearly half of the sample engaged in physical activity every day. There were significant associations between low physical activity and older age, unemployment, educational non-participation, antipsychotic medication use, social dysfunction, self-reported loneliness and obesity. However, there was no significant association between physical activity and sex, psychosis type, illness duration, physical comorbidity or negative symptoms. CONCLUSION: The findings from this study may inform future interventions designed to increase physical activity in people with psychotic illness.

Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study.

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13-19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.

A systematic review of antipsychotic drug effects on human gene expression related to risk factors for cardiovascular disease.

Psychosis is associated with an elevated risk for cardiovascular disease. We reviewed evidence for a causal association between experimentally controlled antipsychotic drug exposure and a change in the expression of genes relevant to cardiovascular disease in human cell lines. Reports from SCOPUS - V.4 (Elsevier) and MEDLINE (ISI) were assessed for global or candidate gene expression analysis, tissue and cell type, tissue source or cell line, antipsychotic drug and dosage, length of drug exposure and statistically significant fold change in gene expression after drug exposure; 29 eligible studies analysed gene expression in the brain, eye (as a model of neuronal cells), heart, kidney (as a model of any cell), liver, pancreas or skin. Antipsychotic drugs alter the expression of numerous genes related to cardiovascular health, including genes under the control of the sterol regulatory element binding protein transcription factors that control lipid and fatty acid biosynthesis.

Effects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis.

Prospective studies have suggested genetic variation in the neuregulin 1 (NRG1) and D-amino-acid oxidase activator (DAOA) genes may assist in differentiating high-risk individuals who will or will not transition to psychosis. In a prospective cohort (follow-up=2.4-14.9 years) of 225 individuals at ultra-high risk (UHR) for psychosis, we assessed haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning NRG1 and DAOA for their association with transition to psychosis, using Cox regression analysis. Two NRG1 htSNPs (rs12155594 and rs4281084) predicted transition to psychosis. Carriers of the rs12155594 T/T or T/C genotype had a 2.34 (95% confidence interval (CI)=1.37-4.00) times greater risk of transition compared with C/C carriers. For every rs4281084 A-allele the risk of transition increased by 1.55 (95% CI=1.05-2.27). For every additional rs4281084-A and/or rs12155594-T allele carried the risk increased ∼1.5-fold, with 71.4% of those carrying a combination of 3 of these alleles transitioning to psychosis. None of the assessed DAOA htSNPs were associated with transition. Our findings suggest NRG1 genetic variation may improve our ability to identify UHR individuals at risk for transition to psychosis.

Prospects for epigenetic research within cohort studies of psychological disorder: a pilot investigation of a peripheral cell marker of epigenetic risk for depression.

Cohort studies have considerable prima facie value for investigating epigenetic processes in psychological disorder; however, the future prospects for such studies will depend on valid peripheral markers. The purpose of this pilot study was to investigate association between buccal cell methylation and risk for depression. Epigenotyping was limited to promoter methylation of the serotonin transporter gene (5HTT). A transcription limiting VNTR in the 5HTT promoter (5HTTLPR) was also genotyped. A nested sample of 25 depressed and 125 non-depressed adolescents was drawn from an established longitudinal study of adolescent health. There was no association between depressive symptoms and either buccal cell 5HTT methylation or 5HTTLPR. However, depressive symptoms were more common among those with elevated buccal cell 5HTT methylation who carried 5HTTLPR short-allele (OR 4.9, CI 1.9-13, p=0.001). Both complete and partial (as little as 10%) methylation of a 5HTT reporter gene in an expressing cell line reduced 5HTT activity. Replication is needed.

Gender differences in premorbid, entry, treatment, and outcome characteristics in a treated epidemiological sample of 661 patients with first episode psychosis.

OBJECTIVES: Gender differences in psychotic disorder have been observed in terms of illness onset and course; however, past research has been limited by inconsistencies between studies and the lack of epidemiological representative of samples assessed. Thus, the aim of this study was to elucidate gender differences in a treated epidemiological sample of patients with first episode psychosis (FEP). METHODS: A medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics of 661 FEP consecutive patients treated at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. RESULTS: Prior to onset of psychosis, females were more likely to have a history of suicide attempts (p=.011) and depression (p=.001). At service entry, females were more likely to have depressive symptoms (p=.007). Conversely, males had marked substance use problems that were evident prior to admission (p<.001) and persisted through treatment (p<.001). At service entry, males also experienced more severe psychopathology (p<.001) and lower levels of functioning (GAF, p=.008; unemployment/not studying p=.004; living with family, p=.003). Treatment non-compliance (p<.001) and frequent hospitalisations (p=.047) were also common for males with FEP. At service discharge males had significantly lower levels of functioning (GAF, p=.008; unemployment/not studying p=.040; living with family, p=.001) compared to females with FEP. CONCLUSIONS: Gender differences are evident in illness course of patients with FEP, particularly with respect to past history of psychopathology and functioning at presentation and at service discharge. Strategies to deal with these gender differences need to be considered in early intervention programs.

Monoamine oxidase A and childhood adversity as risk factors for conduct disorder in females.

BACKGROUND: Recent studies among males have reported a genotype-environment interaction (GxE) in which low-activity alleles at the monoamine oxidase A (MAOA) locus conferred greater sensitivity to the effects of childhood adversity on risk for conduct disorder (CD). So far, few studies of females have controlled for gene-environment correlation or used females heterozygous for this X-linked gene. METHOD: Logistic regression analysis of a sample of 721 females ages 8-17 years from the longitudinal Virginia Twin Study of Adolescent Behavioral Development (VTSABD) assessed the additive effects of MAOA genotypes on risk for CD, together with the main effect of childhood adversity and parental antisocial personality disorder (ASP), as well as the interaction of MAOA with childhood adversity on risk for CD. RESULTS: A significant main effect of genotype on risk for CD was detected, where low-activity MAOA imparted the greatest risk to CD in girls while controlling for the significant effects of maternal ASP and childhood adversity. Significant GxE with weak effect was detected when environmental exposure was untransformed, indicating a higher sensitivity to childhood adversity in the presence of the high-activity MAOA allele. The interaction was no longer statistically significant after applying a ridit transformation to reflect the sample sizes exposed at each level of childhood adversity. CONCLUSIONS: The main effect of MAOA on risk for CD in females, its absence in males and directional difference of interaction is suggestive of genotype-sex interaction. As the effect of GxE on risk for CD was weak, its inclusion is not justified.

Genetic and environmental risk factors for depression assessed by subject-rated symptom check list versus structured clinical interview.

BACKGROUND: It is not known if a subject's characteristic level of self-rated depression symptoms index their genetic or environmental liability to major depressive disorder when measurement error and other occasion-specific influences are taken into account. METHOD: Monozygotic (N = 408) and dizygotic (N = 295) adult female twin pairs from a population-based registry were surveyed twice with an average follow-up interval of 61 months. At each occasion subjects completed a structured clinical interview (SCID) to assess lifetime history of major depression and the subject-rated Symptom Check List (SCL) to assess current level of depressive symptomatology. A bivariate measurement model was used to estimate the genetic and environmental correlations between liability to reliably diagnosed lifetime history of major depression and the characteristic or temporally stable SCL depression score. RESULTS: The genetic and non-familial environmental correlation between liability to reliably diagnosed major depression and the characteristic level of SCL depression symptoms (and the proportion of variance shared between measures) is +0.70 and +0.24 respectively. CONCLUSIONS: When allowance is made for diagnostic unreliability and temporal fluctuations in the level of subject-rated symptoms, 70% of the variance in genetic risk factors and 24% of the variance in environmental risk factors is shared by a diagnosis of lifetime major depression and total SCL depression symptom score. SCL depression scores may therefore be a useful screening measure for many of the genetic risk factors which influence liability to major depression.

Pregnancy and perinatal complications associated with risks for common psychiatric disorders in a population-based sample of female twins.

The association between pregnancy and perinatal complications (PPCs) and risks for adult psychiatric disorders other than psychoses has received relatively limited attention. In this study, we aim to characterize the associations between PPCs and risks for anxiety, affective, substance use, and eating disorders in a population-based sample of twins. Personal interviews were conducted with 1,806 female twin subjects to assess their lifetime history of alcoholism, anorexia nervosa, bulimia nervosa, generalized anxiety disorder, major depression, panic disorder, simple phobias, and social phobias. PPCs were retrospectively assessed at personal interview with the subject's parents. The associations between PPCs and risks for psychiatric disorders are characterized using logistic regression. In this sample of twins, gestational age is associated with a significantly increased risk for anorexia nervosa and pregnancy complications are associated with a significantly increased risk for both anorexia nervosa and bulimia nervosa. Pregnancy and perinatal complications may be associated with an increased risk for eating disorders in women.

Parental concordance and comorbidity for psychiatric disorder and associate risks for current psychiatric symptoms and disorders in a community sample of juvenile twins.

In this report we characterize associations between parental psychiatric disorders and children's psychiatric symptoms and disorders using a population-based sample of 850 twin families. Juvenile twins are aged 8-17 years and are personally interviewed about their current history of DSM-III-R conduct, depression, oppositional-defiant, overanxious, and separation anxiety disorders using the CAPA-C. Mothers and fathers of twins are personally interviewed about their lifetime history of DSM-III-R alcoholism, antisocial personality disorder, generalized anxiety disorder, major depression, panic disorder/agoraphobia, social phobia, and simple phobia using a modified version of the SCID and the DIS. Generalized least squares and logistic regression are used to identify the juvenile symptoms and disorders that are significantly associated with parental psychiatric histories. The specificity of these associations is subsequently explored in a subset of families with maternal plus parental psychiatric histories with a prevalence > 1%. Parental depression that is not comorbid or associated with a different spousal disorder is associated with a significantly elevated level of depression and overanxious disorder symptoms and a significantly increased risk for overanxious disorder. Risks are higher for both symptomatic domains in association with maternal than paternal depression, and highest in association with maternal plus paternal depression. Risks for otherjuvenile symptoms and disorders index the comorbid and spousal histories with which parental depression is commonly associated. Paternal alcoholism that is not comorbid or associated with a maternal disorder is not significantly associated with current psychiatric symptoms or disorders in offspring. Risks for oppositional-defiant or conduct symptoms/disorders in the offspring of alcoholic parents index parental comorbidity and/or other spousal histories.

Does intra-uterine growth discordance predict differential risk for adult psychiatric disorder in a population-based sample of monozygotic twins?

The study of discordant monozygotic twins may identify important developmental risk factors for adult psychiatric disorder. Differential experience in utero is one candidate environmental risk factor that may distinguish monozygotic twins. In this report, we examine whether intra-pair differences in birth weight predicts discordance for adult psychiatric disorders in 527 female monozygotic twin pairs from a population-based twin registry. Twins were personally interviewed about their lifetime history of DSM-III-R alcoholism, anorexia nervosa, bulimia nervosa, generalized anxiety disorder, major depression, panic disorder, social phobia and simple phobia. Birth weight was estimated from birth certificates, or from retrospective maternal, paternal and self-reports. Conditional logistic regression is used to characterize the association between intra-pair differences in birth weight and discordance for psychiatric disorder in monozygotic twins. The twin with the heavier birth weight in discordant pairs is (insignificantly) more likely to have a history of alcoholism or bulimia. The twin with the lighter birth weight in discordant pairs is (insignificantly) more likely to have a history of major depression, simple phobia, panic disorder, anorexia nervosa, social phobia or generalized anxiety disorder. For all psychiatric disorders examined, the lighter (or heavier) co-twin at birth is not systematically the affected twin within discordant pairs.

Assortative mating for major psychiatric diagnoses in two population-based samples.

BACKGROUND: Previous studies on assortment for psychiatric disorders have reported discrepant findings. We aimed to test whether there is a significant association for psychiatric diagnoses, including alcoholism, generalized anxiety disorder, major depressive disorder, panic disorder and phobias between husbands and wives in two population-based samples. We further evaluated whether marital resemblance occurs primarily within or across psychiatric disorders and if assortment for psychopathology is primary or secondary to assortment for correlated variables. METHODS: A model for mate selection addressed whether the correlation between mates for psychiatric disorders arises from direct assortment (primary homogamy) or through correlation with other variables for which assortment occurs (secondary homogamy) or through cross-variable assortment. The model accounted for within-person co-morbidity as well as across-spouse data. RESULTS: Findings suggested that a moderate degree of assortment exists both within and across psychiatric diagnoses. Only a small amount of the observed marital resemblance for mental illness could be explained by assortment for correlated variables such as age, religious attendance and education. Similar results were obtained for the two samples separately and confirmed in their joint analysis, revealing that the co-morbidity and assortment findings, except for the marital correlation for age, religious attendance and education, replicate across samples. CONCLUSIONS: Significant but moderate primary assortment exists for psychiatric disorders. The bias in twin studies that have ignored the small amount of assortment is negligible.

Reliability of a lifetime history of major depression: implications for heritability and co-morbidity.

BACKGROUND: In unselected samples, the diagnosis of major depression (MD) is not highly reliable. It is not known if occasion-specific influences on reliability index familial risk factors for MD, or how reliability is associated with risk for co-morbid anxiety disorders. METHODS: An unselected sample of 847 female twin pairs was interviewed twice, 5 years apart, about their lifetime history (LTH) of MD, generalized anxiety disorder (GAD) and panic disorder (PD). Familial influences on reliability were examined using structural equation models. Logistic regression was used to identify clinical features that predict reliable diagnosis. Co-morbidity was characterized using the continuation ratio test. RESULTS: The reliability of a LTH of MD over 5 years was fair (kappa = 0.43). There was no evidence for occasion-specific familial influences on reliability, and heritability of reliably diagnosed MD was estimated at 66%. Subjects with unreliably diagnosed MD reported fewer symptoms and, if diagnosed with MD only at the first interview, less impairment and help seeking, or, if diagnosed with MD only at the second interview, fewer episodes and a longer illness. A history of co-morbid GAD or PD is more prevalent among subjects with reliably diagnosed MD. CONCLUSIONS: A diagnosis of MD based on a single psychiatric interview incorporates a substantial amount of measurement error but there is no evidence that transient influences on recall and diagnosis index familial risk for MD. Quantitative indices of risk for MD based on multiple interviews should reflect both the characteristics of MD and the temporal order of positive diagnoses.

A longitudinal study of stressful life events assessed at interview with an epidemiological sample of adult twins: the basis of individual variation in event exposure.

This study investigates the basis of individual variation in exposure to stressful life events (SLEs). A population based sample of 547 MZ and 390 DZ female-female twin pairs, aged between 17 and 55 years, were surveyed by two structured interviews, separated by at least 1 year, that enquired about SLEs experienced during the preceding 12 months. Data were analysed with a model that resolves occasion specific ("random') versus enduring ("stable') influences on SLEs. The latter is partitioned into that due to genetic, familial environmental and unique environmental factors. We demonstrate that both random factors and stable individual differences underlie variation in self-reported exposure to SLEs. For most network events this stable variance makes a relatively small contribution to the total variance in SLEs exposure and is almost entirely due to genetic or familial environmental effects. Stable individual differences are more important determinants of personal SLEs, and these reflect both familial factors as well as previous experiences unshared by relatives.

Familial risk of psychosis as a function of putative organic etiology in psychotic probands: evaluation of a population-based sample.

It is unresolved what, if any, characteristics should be used as a basis for assigning psychotic probands to different liability classes in high density family studies seeking to detect possible genetic linkage. Justification for any such assignments should ideally ensue from empirical evaluation of unselected samples. It has been suggested that the genetic liability of probands with an "organic" psychosis is lower than that found in "primary" cases. Should such cases be assigned differential liabilities in linkage analyses as one way of modeling etiologic heterogeneity? Utilizing data from a population-based family study conducted in County Roscommon in Western Ireland, we examined risk in the relatives of psychotic probands as a function of clinician ratings reflecting the probability that the proband's illness was organic. Contrary to expectation, risk was not significantly lower in relatives of probands whose illness was rated as organic by experienced clinicians. Attempts to identify possible phenocopies of psychosis with a lower familial liability in this treated epidemiologic sample were unsuccessful.