Debra L. Foley

Long-term Follow-up of a Group at Ultra High Risk (“Prodromal”) for Psychosis: The PACE 400 Study

IMPORTANCE The ultra high-risk (UHR) criteria were introduced to prospectively identify patients at high risk of psychotic disorder. Although the short-term outcome of UHR patients has been well researched, the long-term outcome is not known. OBJECTIVE To assess the rate and baseline predictors of transition to psychotic disorder in UHR patients up to 15 years after study entry. DESIGN Follow-up study of a cohort of UHR patients recruited to participate in research studies between 1993 and 2006. SETTING The Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service for UHR patients in Melbourne, Australia. PARTICIPANTS Four hundred sixteen UHR patients previously seen at the PACE clinic. MAIN OUTCOMES AND MEASURES Transition to psychotic disorder, as measured using the Comprehensive Assessment of At-Risk Mental States, Brief Psychiatric Rating Scale/Comprehensive Assessment of Symptoms and History, or state public mental health records. RESULTS During the time to follow-up (2.4-14.9 years after presentation), 114 of the 416 participants were known to have developed a psychotic disorder. The highest risk for transition was within the first 2 years of entry into the service, but individuals continued to be at risk up to 10 years after initial referral. The overall rate of transition was estimated to be 34.9% over a 10-year period (95% CI, 28.7%-40.6%). Factors associated with transition included year of entry into the clinic, duration of symptoms before clinic entry, baseline functioning, negative symptoms, and disorders of thought content. CONCLUSIONS AND RELEVANCE The UHR patients are at long-term risk for psychotic disorder, with the highest risk in the first 2 years. Services should aim to follow up patients for at least this period, with the possibility to return for care after this time. Individuals with a long duration of symptoms and poor functioning at the time of referral may need closer monitoring. Interventions to improve functioning and detect help-seeking UHR patients earlier also may be indicated.

Prospects for Epigenetic Epidemiology

Epigenetic modification can mediate environmental influences on gene expression and can modulate the disease risk associated with genetic variation. Epigenetic analysis therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. The spatial and temporal variance in epigenetic profile is of particular relevance for developmental epidemiology and the study of aging, including the variable age at onset for many common diseases. This review serves as a general introduction to the topic by describing epigenetic mechanisms, with a focus on DNA methylation; genetic and environmental factors that influence DNA methylation; epigenetic influences on development, aging, and disease; and current methodology for measuring epigenetic profile. Methodological considerations for epidemiologic studies that seek to include epigenetic analysis are also discussed.

Systematic review of early cardiometabolic outcomes of the first treated episode of psychosis.

CONTEXT The increased mortality associated with schizophrenia is largely due to cardiovascular disease. Treatment with antipsychotics is associated with weight gain and changes in other cardiovascular risk factors. Early identification of modifiable cardiovascular risk factors is a clinical imperative but prospective longitudinal studies of the early cardiometabolic adverse effects of antipsychotic drug treatment other than weight gain have not been previously reviewed. OBJECTIVES To assess the methods and reporting of cardiometabolic outcome studies of the first treated episode of psychosis, review key findings, and suggest directions for future research. DATA SOURCES PsycINFO, MEDLINE, and Scopus from January 1990 to June 2010. STUDY SELECTION Subjects were experiencing their first treated episode of psychosis. Subjects were antipsychotic naive or had been exposed to antipsychotics for a short known period at the beginning of the study. Cardiometabolic indices were assessed. Studies used a longitudinal design. DATA EXTRACTION Sixty-four articles were identified describing 53 independent studies; 25 studies met inclusion criteria and were retained for detailed review. DATA SYNTHESIS Consolidated Standards of Reporting Trials and Strengthening the Reporting of Observational Studies in Epidemiology checklists were used to assess the methods and reporting of studies. A qualitative review of findings was conducted. CONCLUSIONS Two key hypotheses were identified based on this review: (1) in general, there is no difference in cardiovascular risk assessed by weight or metabolic indices between individuals with an untreated first episode of psychosis and healthy controls and (2) cardiovascular risk increases after first exposure to any antipsychotic drug. A rank order of drugs can be derived but there is no evidence of significant class differences. Recommended directions for future research include assessing the effect on cardiometabolic outcomes of medication adherence and dosage effects, determining the therapeutic window for antipsychotic use in adults and youth, and testing for moderation of outcomes by demographic factors, including sex and age, and clinical and genetic factors.

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.

Cardiometabolic risk factors in people with psychotic disorders: The second Australian national survey of psychosis

Objective: To determine the prevalence of cardiometabolic risk factors in Australian adults with a psychotic disorder. Method: Data were collected during the interview phase of the second Australian survey of psychosis, a population-based survey of Australians aged 18 to 64 years with a psychotic disorder. Body mass index, waist circumference and blood pressure were measured. Participants were asked about diagnoses of relevant medical conditions, medications, smoking and physical activity. Fasting blood samples were analysed for glucose, high-density lipoprotein cholesterol, total cholesterol and triglycerides. The prevalence of metabolic syndrome was determined using the harmonized criteria developed by the International Diabetes Federation and other bodies. Results: A total of 1087 men (60%) and 738 women (40%) participated. Their mean age was 38.36 (SD 11.16) years; 773 (42%) were aged 18–34 years and 1052 (58%) 35–64 years. Three-quarters were overweight or obese and 82% had abdominal obesity. Almost half were hypertensive. Two-thirds were current smokers and 81% had a lifetime history of smoking. Levels of physical activity were very low. About 30% reported a diagnosis of hypertension or high cholesterol, 20% knew they had diabetes or high blood sugar and 18% had cardiovascular disease. Half of those with self-reported hypertension were taking antihypertensive drugs, and about 40% with hypercholesterolemia or hyperglycaemia were receiving medication for these conditions. Seventy per cent (N = 1286) of participants provided fasting blood samples. Abnormal levels of high-density lipoprotein cholesterol and triglycerides were each found in almost half of participants and almost one-third had elevated fasting glucose. More than half of participants (54.8%) met criteria for metabolic syndrome. Conclusions: Australians living with psychosis have high rates of cardiometabolic risk factors. There are a number of obvious targets for prevention and treatment, including obesity (especially in women), smoking (more prevalent in men), hypertension, hyperlipidaemia and sedentary lifestyle.

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.

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.

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 influences on the relative timing of pubertal change.

A multicategory item-response theory model was developed to characterize developmental changes in three items relating to the assessment of puberty in adolescent twin girls and boys. The model allowed for the fixed effects of age on probability of endorsing the responses and for the random effects of individual differences on the timing of pubertal changes relative to chronological age. In girls, the model was applied three-wave data on twin pairs (N = 414 female monozygotic [MZ] and 197 female dizygotic [DZ] pairs) and female twins from boy-girl pairs (N = 300 twins) from the Virginia Twin Study of Adolescent Behavioral Development. In boys, the data comprised 318 MZ and 185 DZ pairs and 297 male twins from boy-girl pairs. A total of 3172 and 2790 individual twin assessments were available in girls and boys, respectively, spanning ages 8-17 years. The availability of twin data allows the contributions of genes, the shared environment and individual unique environmental experiences to be resolved in the relative timing of pubertal changes. Parameters of the mixed model including fixed effects of age and random effects of genes and environment were estimated by Markov Chain Monte Carlo simulations using the BUGS algorithm for Gibbs sampling. The estimated standard deviation of random differences in the timing of puberty relative to age was 0.96 years in girls and 1.01 years in boys. The estimated intraclass correlations for the relative timing of pubertal changes were 0.99 +/-0.01 in MZ girls, 0.52 +/-0.02 in DZ girls, 0.88 +/-0.04 in MZ boys and 0.44+/-0.02 in DZ boys, indicating a very large contribution of genetic factors to the relative timing of pubertal change in both sexes. Additive genetic factors account for an estimated 96.3+/-3.3% of the total variance in random effects in girls and 88.0+/-3.6% in boys. Shared environmental influences account for 3.6+/-3.4% in girls and 0% in boys. In girls, nonshared environmental effects explain 0.1+/-0.1% of the total residual variance. The comparable figure in boys is 12.0+/-3.6%.

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 childrens 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.