Retrospectively assessed childhood trauma experiences are associated with illness severity in mental disorders adjusted for symptom state.

Converging evidence suggests that childhood trauma is a causal factor in schizophrenia (SZ) and in bipolar disorders (BD). Here, we investigated whether retrospective reports are associated with severity of illness, independent of current symptom state in a large sample of participants with SZ or BD. We included 1260 individuals (SZ [n = 461], BD [n = 352]), and healthy controls; HC [n = 447]) recruited from the same catchment area. A history of childhood trauma was obtained with the Childhood Trauma Questionnaire (CTQ). Diagnosis and episodes were obtained with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Clinical symptoms (state) were assessed with the Positive and Negative Syndrome scale (PANSS), the Calgary Depression Scale (CDSS). Trait related illness characteristics were assessed with age at illness onset, number of episodes, and lifetime suicide attempts. Patients who reported multiple types of childhood trauma experiences had significantly more severe illness course including an earlier illness onset, more mood episodes, and increased risk of at least one suicide attempt, also after adjusting for current symptom state. Retrospective assessed childhood trauma experiences are associated with illness severity in mental disorders adjusted for symptom state. Our results strengthen the role of childhood trauma in development of psychopathology.

The shared genetic basis of mood instability and psychiatric disorders: A cross-trait genome-wide association analysis.

Recent genome-wide association studies of mood instability (MOOD) have found significant positive genetic correlation with major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. GWAS summary statistics for schizophrenia (SCZ, n = 105,318), bipolar disorder (BIP, n = 413,466), DEP (n = 450,619), attention-deficit hyperactivity disorder (ADHD, n = 53,293), and MOOD (n = 363,705) were analyzed using the bivariate causal mixture model and conjunctional false discovery rate methods. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg = 0.10-0.62). Of 10.4 K genomic variants influencing MOOD, 4 K-9.4 K influenced psychiatric disorders. Furthermore, MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25. Fifty-three jointly associated loci were overlapping across two or more disorders, seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, "synapse organization." The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions may relate to differences in the core clinical features of each disorder.

Telomeres are shorter and associated with number of suicide attempts in affective disorders.

BACKGROUND: Shorter telomere length is a putative biomarker of accelerated aging and has been associated with affective disorders and mortality. Psychological factors and behaviors associated with telomere shortening are yet to be clarified. Here, we investigate the association between history of suicide attempts and telomere length in patients with affective disorders. METHODS: Leucocyte telomere length was determined by quantitative real-time Polymerase Chain Reaction (qPCR) in patients with affective disorders (n = 248) including bipolar disorders type I (n = 159), type II (n = 67), major depressive disorder (n = 22), and healthy controls (n = 401). Diagnosis, duration of illness, and age at onset were assessed using the Structural Clinical Interview for DSM-IV (SCID-I). Number of lifetime suicide attempts were based on self-reports. Effect size was calculated using Cohen's d. RESULTS: Telomere length was reduced in patients with affective disorders relative to healthy controls (d = 0.18, F = 5.26, p = 0.02). Among patients, a higher number of suicide attempts was associated with shorter telomere length (ß = -0.24, t = -3.83, CI = -0.44 to -0.14, p < 0.001), also when controlling for duration of illness and age at onset (ß = -.23, CI = -.42 to -.12, p = 0.001). Multiple suicide attempts were associated with telomere length reduction comparable to eight years lifespan, adjusted for demographic and clinical characteristics. CONCLUSIONS: While longitudinal data are needed to clarify the temporal course, previous suicide attempts and related distress may accelerate telomere shortening and aging in patients with affective disorders.

Heart rate variability is associated with disease severity in psychosis spectrum disorders.

While a growing literature links cardiac autonomic dysregulation to a variety of psychiatric disorders, the relationship between cardiac autonomic functioning and specific symptoms in schizophrenia (SZ) and bipolar disorder (BD) remains elusive. Thus, we investigated heart rate variability (HRV), a proxy for vagal activity, as a biological marker for symptom severity in patients with SZ and BD. HRV was calculated in 35 patients with SZ and 52 patients with BD, as well as in 149 healthy controls. In the patient groups, symptom severity and function were measured by the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale. Results showed that HRV was significantly lower in both clinical groups compared to the healthy controls, with no significant HRV differences between patient groups. PANSS general psychopathology scores, GAF symptom scores, and GAF function scores showed statistically significant associations with HRV across groups. These results suggest that disease severity is associated with autonomic dysfunction and that HRV may provide a potential biomarker of disease severity in SZ and BD.

Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative.

BACKGROUND: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. STRUCTURE: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. CONCLUSIONS: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.