Epigenetic predictors of psychotic symptoms in adolescence

 This thesis focused on the role of epigenetic processes in the development of psychotic symptoms during adolescence. The findings suggest that exposure to influenza and/or diabetes/glycosuria during gestation may predispose an individual to the later development of psychotic symptoms via altered expression of specific genes involved in early brain development.

Childhood neurodevelopmental factors and risk of psychotic experiences in early adolescence: genotypic variation and developmental endophenotypes

This thesis was about understanding the childhood developmental factors that may lead to psychotic experiences in early adolescence. It also contributed to efforts towards preventative strategies for children with a high risk of psychotic symptoms, and arguably schizophrenia. Based on the findings, the author concluded, that further research on this topic should focus on the development of early detection methods and interventions for high risk children.

Psychotic-like experiences in a community sample of adolescents: implications for the continuum model of psychosis and prediction of schizophrenia

Studies conducted in community samples suggest that psychotic-like experiences are common in the general population, leading to suggestions that they are either variations of normal personality or are different expressions of underlying vulnerability to psychotic disorder. Different types of psychotic symptoms may exist, some being normal variants and some having implications for mental health and functioning. The aim of the present study was to determine if different subtypes of psychotic-like experiences could be identified in a community sample of adolescents and to investigate if particular subtypes were more likely to be associated with psychosocial difficulties, that is, distress, depression and poor functioning, than other subtypes. Eight hundred and seventy-five Year 10 students from 34 schools participated in a cross-sectional survey that measured psychotic-like experiences using the Community Assessment of Psychic Experiences; depression using the Centre for Epidemiologic Studies Depression Scale; and psychosocial functioning using the Revised Multidimensional Assessment of Functioning Scale. Factor analysis was conducted to identify any subtypes of psychotic experiences. Four subtypes of psychotic-like experiences were identified: Bizarre Experiences, Perceptual Abnormalities, Persecutory Ideas, and Magical Thinking. Intermittent, infrequent psychotic experiences were common, but frequent experiences were not. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas were strongly associated with distress, depression and poor functioning. Magical Thinking was only weakly associated with these variables. Overall these findings may suggest that infrequent psychotic-like experiences are unlikely to be a specific risk factor for onset of a psychotic disorder in community samples. Given that the different subtypes had varying associations with current difficulties it is suggested that not all subtypes confer the same risk for onset of psychotic disorder and poor outcome. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas may represent expressions of underlying vulnerability to psychotic disorder, but Magical Thinking may be a normal personality variant.

The relationship between personality traits and psychotic like experiences in a large non-clinical adolescent sample

Objective: The relationship between personality and psychosis is well established. It has been suggested that this relationship may be partly accounted for by higher levels of depression in individuals with certain personality traits. We explored whether the link between personality and psychotic symptoms is already apparent in adolescence, and if this association would still hold when depression was controlled for. Method: 654 secondary school students were surveyed via self-report questionnaires measuring the Five-Factor model of personality (NEO-FFI), depression (CES-D) and psychotic-like experiences (CAPE). Results: Positive associations were found between Neuroticism and all CAPE-subscales except Magical Thinking, which was in turn associated with all other personality traits when at high levels. Agreeableness was negatively associated with all CAPE-subscales, while Openness to Experience was only positively associated with Persecutory Ideas and Magical Thinking. After controlling for depression, many of the significant associations remained. Conclusion: Our findings suggest that the chance of having psychotic like experiences is more likely for adolescents with certain personality traits. These associations are not fully explained by depression, especially when psychotic experiences are at higher levels. Future research is needed to investigate if these personality traits might put a person at risk for the development of full-blown psychosis.

Is early intervention in psychosis cost-effective over the long term?

Objective: This study assesses the long-term cost-effectiveness of a comprehensive model of mental health care for first-episode psychosis. The study is an extension of a previous economic evaluation of the Early Psychosis Prevention and Intervention Centre (EPPIC) that assessed the first-year costs and outcomes of treatment.

Method: The current study used a matched, historical control group design with a follow-up of approximately 8 years. Complete follow-up data were available for 65 of the original 102 participants. Direct public mental health service costs incurred subsequent to the first year of treatment and symptomatic and functional outcomes of 32 participants initially treated for up to 2 years at EPPIC were compared with a matched cohort of 33 participants initially treated by generic mental health services. Treatment-related resource use was measured and valued using Australian published prices.

Results: Almost 8 years after initial treatment, EPPIC subjects displayed lower levels of positive psychotic symptoms (P = .007), were more likely to be in remission (P = .008), and had a more favorable course of illness (P = .011) than the controls. Fifty-six percent of the EPPIC cohort were in paid employment over the last 2 years compared with 33% of controls (P = .083). Each EPPIC patient costs on average A$3445 per annum to treat compared with controls, who each costs A$9503 per annum.

Conclusions: Specialized early psychosis programs can deliver a higher recovery rate at one-third the cost of standard public mental health services. Residual methodological limitations and limited sample size indicate that further research is required to verify this finding.

Underlying neurobiology and clinical correlates of mania status after subthalamic nucleus deep brain stimulation in Parkinson's Disease : a review of the literature

Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson's disease (PD). The authors review the current literature to identify the clinical correlates associated with subthalamic nucleus (STN) DBS-induced hypomania/mania in PD patients. Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male sex, and/or early-onset PD. STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanisms of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight toward development of future DBS mood-stabilization therapies.

Dynamic association between interpersonal functioning and positive symptom dimensions of psychosis over time: a longitudinal study of healthy adolescents

Cross-sectional studies have indicated that alterations in social functioning, particularly interpersonal functioning, are associated with the occurrence of psychotic symptoms and experiences at different levels of the extended psychosis phenotype (ranging from population psychometric expression of liability to overt psychotic disorder). However, more research is needed on the development of this association over time

Social cognition, neurocognition and symptomatology in first episode psychosis

 The main finding was that first-episode psychosis (FEP) displayed impaired social cognition compared to healthy control subjects. Certain psychotic symptoms were associated with poorer social cognition in the FEP group. Symptomatology, and not cognitive variables, predicted social functioning in FEP patients

Predictors of treatment response in young people at ultra-high risk for psychosis who received long-chain omega-3 fatty acids.

Previous efforts in the prospective evaluation of individuals who experience attenuated psychotic symptoms have attempted to isolate mechanisms underlying the onset of full-threshold psychotic illness. In contrast, there has been little research investigating specific predictors of positive outcomes. In this study, we sought to determine biological and clinical factors associated with treatment response, here indexed by functional improvement in a pre-post examination of a 12-week randomized controlled intervention in individuals at ultra-high risk (UHR) for psychosis. Participants received either long-chain omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) or placebo. To allow the determination of factors specifically relevant to each intervention, and to be able to contrast them, both treatment groups were investigated in parallel. Univariate linear regression analysis indicated that higher levels of erythrocyte membrane α-linolenic acid (ALA; the parent fatty acid of the ω-3 family) and more severe negative symptoms at baseline predicted subsequent functional improvement in the treatment group, whereas less severe positive symptoms and lower functioning at baseline were predictive in the placebo group. A multivariate machine learning analysis, known as Gaussian Process Classification (GPC), confirmed that baseline fatty acids predicted response to treatment in the ω-3 PUFA group with high levels of sensitivity, specificity and accuracy. In addition, GPC revealed that baseline fatty acids were predictive in the placebo group. In conclusion, our investigation indicates that UHR patients with higher levels of ALA may specifically benefit from ω-3 PUFA supplementation. In addition, multivariate machine learning analysis suggests that fatty acids could potentially be used to inform prognostic evaluations and treatment decisions at the level of the individual. Notably, multiple statistical analyses were conducted in a relatively small sample, limiting the conclusions that can be drawn from what we believe to be a first-of-its-kind study. Additional studies with larger samples are therefore needed to evaluate the generalizability of these findings.

Young adult sequelae of adolescent cannabis use: an integrative analysis

 Background: Debate continues about the consequences of adolescent cannabis use. Existing data are limited in statistical power to examine rarer outcomes and less common, heavier patterns of cannabis use than those already investigated; furthermore, evidence has a piecemeal approach to reporting of young adult sequelae. We aimed to provide a broad picture of the psychosocial sequelae of adolescent cannabis use. Methods: We integrated participant-level data from three large, long-running longitudinal studies from Australia and New Zealand: the Australian Temperament Project, the Christchurch Health and Development Study, and the Victorian Adolescent Health Cohort Study. We investigated the association between the maximum frequency of cannabis use before age 17 years (never, less than monthly, monthly or more, weekly or more, or daily) and seven developmental outcomes assessed up to age 30 years (high-school completion, attainment of university degree, cannabis dependence, use of other illicit drugs, suicide attempt, depression, and welfare dependence). The number of participants varied by outcome (N=2537 to N=3765). Findings: We recorded clear and consistent associations and dose-response relations between the frequency of adolescent cannabis use and all adverse young adult outcomes. After covariate adjustment, compared with individuals who had never used cannabis, those who were daily users before age 17 years had clear reductions in the odds of high-school completion (adjusted odds ratio 0·37, 95% CI 0·20-0·66) and degree attainment (0·38, 0·22-0·66), and substantially increased odds of later cannabis dependence (17·95, 9·44-34·12), use of other illicit drugs (7·80, 4·46-13·63), and suicide attempt (6·83, 2·04-22·90). Interpretation: Adverse sequelae of adolescent cannabis use are wide ranging and extend into young adulthood. Prevention or delay of cannabis use in adolescence is likely to have broad health and social benefits. Efforts to reform cannabis legislation should be carefully assessed to ensure they reduce adolescent cannabis use and prevent potentially adverse developmental effects. Funding: Australian Government National Health and Medical Research Council. © 2014 Elsevier Ltd.

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics : meta-analysis and implications

The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural-immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g=0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P<0.001, 24 between-group comparisons, n=82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g=0.01, 95% CI -0.20 to 0.22, P=0.803, 8 within-group comparisons, n=713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.

Theory of mind in major depressive disorder: a meta-analysis

OBJECTIVE: Social cognitive deficits can contribute to risk for depression and to psychosocial impairment during depression. However, available evidence suggests that emotion recognition is only marginally impaired in major depressive disorder (MDD). Recent studies have investigated theory of mind (ToM) abilities, a cognitively more demanding aspect of social cognition. METHODS: We conducted a meta-analysis of studies comparing ToM abilities in MDD and healthy controls. 18 studies comparing 613 patients with MDD and 529 healthy controls were included. RESULTS: MDD patients significantly underperformed healthy controls in ToM (d=0.51-0.58). ToM impairment in MDD was evident in response to different types of ToM tasks (verbal/visual and cognitive/affective and reasoning/decoding). ToM impairment was significantly related to severity of depressive symptoms. CONCLUSION: Theory of mind abilities are impaired during depression and can potentially contribute to psychosocial difficulties during depression. There is a need to investigate ToM abilities in different subtypes and stages of depression, especially in remitted patients.

Antioxidant treatments for schizophrenia

Background: There is accumulating evidence that progressive changes in brain structure and function take place as schizophrenia unfolds. Among many possible candidates, oxidative stress may be one of the mediators of neuroprogression, grey matter loss and subsequent cognitive and functional impairment. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative stress or its consequences. They may act from directly scavenging free radicals to increasing anti-oxidative defences. There is evidence that current treatments impact oxidative pathways and may to some extent reverse pro-oxidative states in schizophrenia. The existing literature, however, indicates that these treatments do not fully restore the deficits in antioxidant levels or restore levels of oxidants in schizophrenia. As such, there has been interest in developing interventions aimed at restoring this oxidative balance beyond the benefits of antipsychotics in this direction. If antioxidants are to have a place in the treatment of this serious condition, the relevant and up-to-date information should be available to clinicians and investigators. Objectives: To evaluate the effect of antioxidants as add-on treatments to standard antipsychotic medication for improving acute psychotic episodes and core symptoms, and preventing relapse in people with schizophrenia. Search methods: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran this search in November 2010, and again on 8 January 2015. We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. Selection criteria: We included reports if they were randomised controlled trials (RCTs) involving people with schizophrenia who had been allocated to either a substance with antioxidant potential or to a placebo as an adjunct to standard antipsychotic treatment. Data collection and analysis: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. Main results: The review includes 22 RCTs of varying quality and sample size studying Ginkgo biloba, N-acetyl cysteine (NAC), allopurinol, dehydroepiandrosterone (DHEA), vitamin C, vitamin E or selegiline. Median follow-up was eight weeks. Only three studies including a minority of the participants reported our a priori selected primary outcome of clinically important response. Short-term data for this outcome (measured as at least 20% improvement in scores on Positive and Negative Syndrome Scale (PANSS)) were similar (3 RCTs, n = 229, RR 0.77, 95% CI 0.53 to 1.12, low quality evidence). Studies usually reported only endpoint psychopathology rating scale scores. Psychotic symptoms were lower in those using an adjunctive antioxidant according to the PANSS ( 7 RCTS, n = 584, MD -6.00, 95% CI -10.35 to -1.65, very low quality evidence) and the Brief Psychiatric Rating Scale (BPRS) (8 RCTS, n = 843, MD -3.20, 95% CI -5.63 to -0.78, low quality evidence). There was no overall short-term difference in leaving the study early (16 RCTs, n = 1584, RR 0.73, 95% CI 0.48 to 1.11, moderate quality evidence), or in general functioning (2 RCTs, n = 52, MD -1.11, 95% CI -8.07 to 5.86, low quality evidence). Adverse events were generally poorly reported. Three studies reported useable data for 'any serious adverse effect', results were equivocal (3 RCTs, n = 234, RR 0.65, 95% CI 0.19 to 2.27, low quality evidence). No evidence was available for relapse, quality of life or service use. Authors' conclusions: Although 22 trials could be included in this review, the evidence provided is limited and mostly not relevant to clinicians or consumers. Overall, although there was low risk of attrition and selective data reporting bias within the trials, the trials themselves were not adequately powered and need more substantial follow-up periods. There is a need for larger trials with longer periods of follow-up to be conducted. Outcomes should be meaningful for those with schizophrenia, and include measures of improvement and relapse (not just rating scale scores), functioning and quality of life and acceptability and, importantly, safety data.

Melatonin : an overlooked factor in schizophrenia and in the inhibition of anti-psychotic side effects

This paper reviews melatonin as an overlooked factor in the developmental etiology and maintenance of schizophrenia; the neuroimmune and oxidative pathophysiology of schizophrenia; specific symptoms in schizophrenia, including sleep disturbance; circadian rhythms; and side effects of antipsychotics, including tardive dyskinesia and metabolic syndrome. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this review using keywords: schizophrenia, psychosis, tardive dyskinesia, antipsychotics, metabolic syndrome, drug side effects and melatonin. Articles were selected on the basis of relevance to the etiology, course and treatment of schizophrenia. Melatonin levels and melatonin circadian rhythm are significantly decreased in schizophrenic patients. The adjunctive use of melatonin in schizophrenia may augment the efficacy of antipsychotics through its anti-inflammatory and antioxidative effects. Further, melatonin would be expected to improve sleep disorders in schizophrenia and side effects of anti-psychotics, such as tardive dyskinesia, metaboilic syndrome and hypertension. It is proposed that melatonin also impacts on the tryptophan catabolic pathway via its effect on stress response and cortisol secretion, thereby impacting on cortex associated cognition, amygdala associated affect and striatal motivational processing. The secretion of melatonin is decreased in schizophrenia, contributing to its etiology, pathophysiology and management. Melatonin is likely to have impacts on the metabolic side effects of anti-psychotics that contribute to subsequent decreases in life-expectancy.