Multi-omics data integration methods and their applications in psychiatric disorders.

To study mental illness and health, in the past researchers have often broken down their complexity into individual subsystems (e.g., genomics, transcriptomics, proteomics, clinical data) and explored the components independently. Technological advancements and decreasing costs of high throughput sequencing has led to an unprecedented increase in data generation. Furthermore, over the years it has become increasingly clear that these subsystems do not act in isolation but instead interact with each other to drive mental illness and health. Consequently, individual subsystems are now analysed jointly to promote a holistic understanding of the underlying biological complexity of health and disease. Complementing the increasing data availability, current research is geared towards developing novel methods that can efficiently combine the information rich multi-omics data to discover biologically meaningful biomarkers for diagnosis, treatment, and prognosis. However, clinical translation of the research is still challenging. In this review, we summarise conventional and state-of-the-art statistical and machine learning approaches for discovery of biomarker, diagnosis, as well as outcome and treatment response prediction through integrating multi-omics and clinical data. In addition, we describe the role of biological model systems and in silico multi-omics model designs in clinical translation of psychiatric research from bench to bedside. Finally, we discuss the current challenges and explore the application of multi-omics integration in future psychiatric research. The review provides a structured overview and latest updates in the field of multi-omics in psychiatry.

Vitamin D and clinical symptoms in First Episode Psychosis (FEP): A prospective cohort study.

BACKGROUND: There is a paucity of longitudinal research investigating vitamin D in people with early psychosis. METHOD: Vitamin D levels were measured in 168 patients (64% (n = 108) male, mean age 29.3 (9.8) years) with first episode psychosis (FEP), along with measures of clinical state at baseline and at 12 months follow up. We assessed the a) cross sectional, and; b) longitudinal relationships between continuous and categorical 25-hydroxyvitamin D (25(OH)D) levels and clinical symptoms at first contact for psychosis and at 12 months. RESULTS: In FEP, 80% (n = 134) at baseline, and 76% at 12 months follow up, had suboptimal vitamin D levels (<20 ng/ml). Suboptimal levels of 25 (OH) D at baseline were not cross-sectionally associated with clinical symptoms. Higher vitamin D levels at baseline (n = 77) were significantly associated with better visual reproduction-immediate recall (ß = 0.249, 95%CI = -0.012-0.871, p = 0.044). Higher baseline vitamin D levels were prospectively associated with lower total PANSS (ß = -0.24, 95%CI = -0.47-0.01, p = 0.04) and PANSS negative symptom scores (ß = -0.12, 95%CI = -0.23-0.01, p = 0.04) at 12 months. CONCLUSION: We identified a prospective association between higher baseline serum Vitamin D levels and lower total psychotic symptoms and negative symptoms of psychosis at 12 months after first contact for psychosis. The results of this study require replication in larger prospective studies, and highlight the need for large randomised trials to assess the effect of vitamin D supplementation on symptoms of psychosis in FEP.

Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness.

RATIONALE: Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before. OBJECTIVES: This study aims to systematically review the effects of stress on microglia, as indexed by the histological microglial marker ionised calcium binding adaptor molecule 1 (Iba-1), and consider the implications of these for the role of stress in the development of mental disorders. METHODS: A systematic review was undertaken using pre-defined search criteria on PubMed and EMBASE. Inclusion and data extraction was agreed by two independent researchers after review of abstracts and full text. RESULTS: Eighteen studies met the inclusion criteria. These used seven different psychosocial stressors, including chronic restraint, social isolation and repeated social defeat in gerbils, mice and/or rats. The hippocampus (11/18 studies) and prefrontal cortex (13/18 studies) were the most frequently studied areas. Within the hippocampus, increased Iba-1 levels of between 20 and 200 % were reported by all 11 studies; however, one study found this to be a duration-dependent effect. Of those examining the prefrontal cortex, ∼75 % found psychosocial stress resulted in elevated Iba-1 activity. Elevations were also consistently seen in the nucleus accumbens, and under some stress conditions in the amygdala and paraventricular nucleus. CONCLUSIONS: There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions. These effects were seen with early-life/prenatal stress, as well as stressors in adulthood. We consider these findings in terms of the two-hit hypothesis, which proposes that early-life stress primes microglia, leading to a potentiated response to subsequent stress. The implications for understanding the pathoaetiology of mental disorders and the development of new treatments are also considered.

Functional outcome in people at high risk for psychosis predicted by thalamic glutamate levels and prefronto-striatal activation.

Little is known about the neurobiological factors that determine functional outcome in people at high risk for psychosis. We use multimodal neuroimaging to investigate whether cortical responses during a cognitive task and thalamic glutamate levels were associated with subsequent functional outcome. Sixty subjects participated: 27 healthy controls (CTRL) and 33 at ultrahigh risk (UHR) for psychosis. At baseline, cortical responses during a verbal fluency task were measured using functional Magnetic Resonance Imaging (fMRI) and proton Magnetic Resonance Spectroscopy (1H-MRS) was used to measure thalamic glutamate levels. The UHR subjects were then followed clinically for a mean duration of 18 months, and subdivided into "good" and "poor" functional outcome subgroups according to their Global Assessment of Function score at follow-up. UHR subjects with a poor functional outcome showed greater cortical and subcortical activation than UHR subjects with a good functional outcome. They also had lower levels of thalamic glutamate and showed a negative relationship between thalamic glutamate levels and prefrontal-striatal activation that was not present in the good functional outcome or control groups. In people at high risk for psychosis, their subsequent level of functioning may depend on the extent to which neurophysiological and neurochemical function is perturbed when they first present to clinical services.

Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies.

BACKGROUND: The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. AIMS: To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia. METHOD: Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions. RESULTS: The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d = -0.32 (95% CI -0.68 to 0.03) for the thalamus, d = -0.23 (95% CI -0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI -0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus. CONCLUSIONS: There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis.

Is antipsychotic treatment linked to low bone mineral density and osteoporosis? A review of the evidence and the clinical implications.

OBJECTIVE: Osteoporosis is increasingly common worldwide and there is a growing concern that the long-term use of antipsychotic medications increases the risk of this disorder. In this review, we consider whether antipsychotics may contribute to the development of osteoporosis through reductions in bone mineral density, discuss the possible mechanisms involved and consider the clinical implications of such a relationship. METHODS: We searched the literature for studies in this area published between 1966 and 2010 using the Medline and PubMed databases, supplemented by hand searches of retrieved reports. RESULTS: The available data indicate that statistically significant reductions in bone mineral density are frequently seen in patients prescribed with antipsychotic medications and suggest that there is a higher incidence of clinically significant reductions compared with the normal population. CONCLUSIONS: Clinicians should be aware for the potential negative effects of antipsychotic medications on bone mineral density, particularly in patients with additional risk factors for osteoporosis. Recommendations regarding routine monitoring of bone mineral density for patients prescribed antipsychotic medications cannot be made on the basis of existing evidence, and more research is required.