Biological endophenotypes of prodromal psychosis and depression

The identification of biomarkers to predict risk and clinical outcomes beyond clinical observation in psychiatry is a key priority in contemporary mental health research. Individuals at elevated risk for mental disorders have been the focus of such efforts as they represent a potentially viable target group for early intervention and indicated prevention. Early intervention and indicated prevention efforts for individuals at ultrahigh risk (UHR) for psychosis might benefit from such biomarkers to enable better risk prediction and to discern who will benefit from treatment. Alterations in neuroendocrine, immune and oxidative stress markers as well as abnormalities in lipid biology are robust findings in biological psychiatry. On the other hand, mounting evidence suggests that First Nations people including the Aboriginal and/or Torres Strait Islander people of Australia have a higher risk for common and severe mental illness, most likely attributable to social and environmental health determinants. However the role of stress-related biomarkers in this context remains poorly understood. Consequently, the aims of this thesis were to examine (1) a multisystem biomarker index known as allostatic load in two high-risk populations and to (2) examine the role of lipid biology in these groups. The first part of this thesis explores the role of allostatic load (AL) and omega-3 (ω-3) polyunsaturated fatty acids (PUFA) in two clinical studies of patients with schizophrenia, first-episode psychosis and individuals at UHR for psychosis. The second part explores the role of AL and dietary ω-3 PUFA in a community-based study of Aboriginal and/or Torres Strait Islander people, who are at increased risk for mental ill-health according to recent national reports. The above aims are achieved through meta-analysis of existing studies of cortisol in psychotic disorders, secondary analysis of two clinical studies, and in a cross-sectional multi-site community-based study of Aboriginal and/or Torres Straight Islander adolescents and young adults attending a health check. First, flattened cortisol-awakening response is reported in patients with schizophrenia and first-episode psychosis relative to controls, but not in UHR individuals, suggesting neuroendocrine dysregulation during some stages of the psychosis spectrum. Secondly, informed by these findings, a study of AL demonstrated elevated AL in patients with schizophrenia and first-episode psychosis that was positively correlated with positive psychotic symptoms and negatively correlated with functioning at trend level. No prospective association of AL and treatment response and symptomatic ix remission was identified. Next, secondary analysis of a multi-centre randomised controlled trial investigated AL in youth at UHR for psychosis. This study revealed prospective associations of high AL with impairments in social and occupational functioning. Next, the prospective association of PUFA status and clinical outcomes in a 12-month follow-up is reported, which demonstrated a selective relationship of low ω-3 PUFA levels with mood disorders and no association with psychotic or anxiety disorders. The second part of the thesis reports depression rates in three remote communities, explores the relationship of depression with hair cortisol and AL, and reports an association of low plasma levels of o ω-3 PUFA with depressive symptoms. Collectively, the data presented in this thesis demonstrate complex associations of a multisystem biomarker index and ω-3 PUFA with mental ill-health. Ultimately, multisystem indices like AL may be used in future research to establish their utility as a clinical prognostic risk index. By studying membrane lipids in an ethnic minority group, this thesis was able to show an association of high dietary intake of ω-3 PUFA and low levels of depression, which may serve as a protective factor

Allostatic load is associated with positive symptoms in schizophrenia and first-episode psychosis and decreases with antipsychotic therapy

Background: Current pathophysiological models of schizophrenia suggest that stress contributes to the etiology and trajectory of the disorder. We investigated whether cumulative exposure to stress, quantified by allostatic load (AL), an integrative index of immune, metabolic, and neuroendocrine dysregulation, is elevated in patients with schizophrenia (SCZ) and first-episode psychosis (FEP) and related to psychotic symptoms and social and occupational functioning and assessed the temporal dynamics of AL in response to treatment with second-generation antipsychotics. Methods: We assessed AL in a naturalistic study of unmedicated patients with SCZ (n = 28), FEP (n = 28), and healthy controls matched for age and gender (n = 53) at baseline and 6 and 12 weeks after commencement of antipsychotic therapy. Biomarkers for the AL index were selected based on (1) representation of several physiological systems including the cardiovascular, neuroendocrine, immune, and metabolic systems; (2) use in previous AL research; and (3) associations with disease risk. We adopted a scaled AL algorithm whereby each marker proportionally contributes to the overall AL index. Unadjusted and adjusted differences between patients with SCZ, FEP, and controls in AL were tested with ANCOVA, and partial correlations were used to test associations of AL with psychometric variables. Results: AL was higher in patients with SCZ compared to controls (4.91 ± 1.89 vs. 2.87 ± 1.62, P < .001), patients with FEP compared to controls (3.80 ± 1.66 vs. 2.87 ± 1.62, P = .020) but not different between patients with SCZ and patients with FEP (P = .302). Adjusting for age and smoking, we found that positive symptoms were positively correlated with AL across all patients with a psychotic disorder (adjusted R = .520, P < .001) and Global Assessment of Functioning (GAF) scores were negatively correlated with AL at trend level (adjusted R = −.251, P = .070). No significant associations were found for negative symptoms (P = .582). AL decreased after treatment with olanzapine, risperidone, or quetiapine was commenced in patients with SCZ and FEP between the baseline assessment and the 6- and 12-week follow-up. Conclusion: Our data provide evidence for cumulative physiological dysregulation in patients with SCZ and FEP that is linked to the experience of current positive psychotic symptoms. AL could be a useful model that takes stress, long-term adaptation, and its failures into account to further understand the pathophysiology of schizophrenia

Cortisol awakening response and acute stress reactivity in First Nations people

First Nations people globally have a higher incidence of mental disorders and non-communicable diseases. These health inequalities are partially attributed to a complex network of social and environmental factors which likely converge on chronic psychosocial stress. We hypothesized that alterations in stress processing and the regulation of the hypothalamic-pituitary-adrenal axis might underlie health disparities in First Nations people. We assessed the cortisol awakening response and the dynamic response to a laboratory induced psychosocial stress of young Indigenous tertiary students (n = 11, mean age 23.82 years) and non-Indigenous students (n = 11) matched for age and gender. Indigenous participants had a blunted cortisol awakening response (27.40 (SD 35.00) vs. 95.24 (SD 55.23), p = 0.002), which was differentially associated with chronic experience of stress in Indigenous (r = −0.641, p = 0.046) and non-Indigenous (r = 0.652, p = 0.03) participants. The cortisol response to the laboratory induced psychosocial stress did not differ between groups. Self-reported racial discrimination was strongly associated with flattened cortisol response to stress (r = −0676, p = 0.022) and with heart rate variability (r = 0.654, p = 0.040). Our findings provide insight into potential biological factors underlying health discrepancies in ethnic minority groups

Acceptability and feasibility of a multidomain harmonized data collection protocol in youth mental health

Objective To develop targeted treatment for young people experiencing mental illness, a better understanding of the biological, psychological, and social changes is required, particularly during the early stages of illness. To do this, large datasets need to be collected using standardized methods. A harmonized data collection protocol was tested in a youth mental health research setting to determine its acceptability and feasibility. Method Eighteen participants completed the harmonization protocol, including a clinical interview, self-report measures, neurocognitive measures, and mock assessments of magnetic resonance imaging (MRI) and blood. The feasibility of the protocol was assessed by recording recruitment rates, study withdrawals, missing data, and protocol deviations. Subjective responses from participant surveys and focus groups were used to examine the acceptability of the protocol. Results Twenty-eight young people were approached, 18 consented, and four did not complete the study. Most participants reported positive subjective impressions of the protocol as a whole and showed interest in participating in the study again, if given the opportunity. Participants generally perceived the MRI and neurocognitive tasks as interesting and suggested that the assessment of clinical presentation could be shortened. Conclusion Overall, the harmonized data collection protocol appeared to be feasible and generally well-accepted by participants. With a majority of participants finding the assessment of clinical presentation too long and repetitive, the authors have made suggestions to shorten the self-reports. The broader implementation of this protocol could allow researchers to create large datasets and better understand how psychopathological and neurobiological changes occur in young people with mental ill-health

Hair cortisol, allostatic load, and depressive symptoms in Australian Aboriginal and Torres Strait Islander people

Chronic stress and adversity are associated with poor mental health and are thought to contribute to the existing mental health gap between Aboriginal and Torres Strait Islander people and other Australians. Hair cortisol and allostatic load (AL) are indices of sustained stress and may be mediators of the effects of stress on health. The aim of this study was to examine the relationship between hair cortisol, AL, and depressive symptoms. This cross-sectional study comprised 329 Aboriginal and Torres Strait Islander adolescents and adults recruited at two health screening programs operating in three communities in north Queensland. We measured hair cortisol and calculated an AL index from 10 biomarkers. We assessed depressive symptoms with a version of the Patient Health Questionnaire-9 adapted for Aboriginal and Torres Strait Islander people (aPHQ-9). We found differences in cortisol and AL between the screening programs and communities, which were not explained by depressive symptoms. Overall aPHQ-9 scores were unrelated to hair cortisol (p = .25 and p = .94) and AL (p = .30 and p = .88) when age, gender and smoking were taken into account. However, anhedonia (p = .007) and insomnia (p = .006) sub-scores were each significantly associated with AL in one study site. Our present data did not demonstrate overall associations of stress biomarkers and multisystem dysregulation with depressive symptoms, which suggests that the relationship between cumulative stress and depression may be better explained by other factors in this population. The specific association between anhedonia and insomnia with AL indicates that chronic multisystem dysregulation plays a role in these features of depression in this population

Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial.

BACKGROUND Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs

Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis.

Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins

Relationship Between Polyunsaturated Fatty Acids and Psychopathology in the NEURAPRO Clinical Trial

Background: Deficiencies in membrane polyunsaturated fatty acids (PUFA) such as omega-3 (n-3) fatty acids are thought to contribute to the pathophysiological processes underlying psychotic disorders. Emerging evidence suggests that the levels of PUFA are related to clinical symptoms but significant heterogeneity exists between studies. Here, we investigated associations of membrane PUFA with clinical symptoms and functioning in a large sample of individuals at ultra-high risk (UHR) for psychosis. Methods: A total of 285 participants of the NEURAPRO clinical trial were investigated for erythrocyte PUFA levels, including the n-3 index, n-6/n-3 PUFA ratio, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Severity of general psychopathology [Brief Psychiatric Rating Scale (BPRS)], psychotic symptoms (BPRS psychosis subscale), negative symptoms [Scale for the Assessment of Negative Symptoms (SANS)], manic symptoms [Young Mania Rating Scale (YMRS)], depressive symptoms [Montgomery Asberg Depression Rating Scale (MADRS)], and functioning [Social and Occupational Functioning Scale (SOFAS), Global Functioning Social (GF-S) and Role (GF-R) scales] were assessed concurrently. Partial correlation taking into account the effects of gender, age, and smoking was used to examine the relationship between PUFAs and symptoms severity. Results: The n-3 index negatively correlated with the severity of general psychopathology, psychotic symptoms, depressive symptoms, and manic symptoms. The n-6/n-3 PUFA ratio positively correlated with severity of psychotic and depressive symptoms. The n-3 PUFA DHA negatively correlated with the severity of general psychopathology, positive, manic, and depressive symptoms. EPA negatively correlated with manic symptoms. Nervonic acid, an n-9 monounsaturated fatty acid, positively correlated with general psychopathology, positive and negative symptoms, depressive symptoms, and manic symptoms. The long-chain saturated fatty acid tetracosanoic acid positively correlated with general psychopathology, positive, manic, and depressive symptoms. Conclusions: Partially consistent with a previous study, psychotic symptoms, depressive symptoms, and symptoms of mania were associated with several classes of FAs in the present study. These findings support the relevance of membrane fatty acids for the onset of psychotic symptoms and indicate that FAs should be further evaluated as biomarkers in the UHR for psychosis group. Clinical Trial Registration: ANZCTR, identifier: 12608000475347

"More than skin deep": stress neurobiology and mental health consequences of racial discrimination

Ethnic minority groups across the world face a complex set of adverse social and psychological challenges linked to their minority status, often involving racial discrimination. Racial discrimination is increasingly recognized as an important contributing factor to health disparities among non-dominant ethnic minorities. A growing body of literature has recognized these health disparities and has investigated the relationship between racial discrimination and poor health outcomes. Chronically elevated cortisol levels and a dysregulated hypothalamic–pituitary–adrenal (HPA) axis appear to mediate effects of racial discrimination on allostatic load and disease. Racial discrimination seems to converge on the anterior cingulate cortex (ACC) and may impair the function of the prefrontal cortex (PFC), hence showing substantial similarities to chronic social stress. This review provides a summary of recent literature on hormonal and neural effects of racial discrimination and a synthesis of potential neurobiological pathways by which discrimination affects mental health