Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach.

BACKGROUND: Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. AIMS: To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. METHOD: This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. RESULTS: The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. CONCLUSIONS: Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment.

Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

International multi-site survey on the use of online support groups in bipolar disorder.

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups. AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking. METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data. RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report.

OBJECTIVE: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. MATERIALS AND METHODS: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. RESULTS: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). CONCLUSIONS: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

[Post partum depression: future perspectives]. / Depressione post partum: prospettive future.

AIM: Post partum depression (PPD) is a psychiatric illness approximately affecting 10-20% of women after childbirth. The objective of this work is to update our knowledge of PPD giving particular emphasis to etiopathogenetic hypotheses. METHODS: An accurate search of the literature on this topic was conducted using free dedicated websites such as PubMed. RESULTS: The most recent studies reveal that PPD is a complex disease, whose pathogenesis is not yet clarified, determined by a mix of genetic, biological and environmental factors. Genetic studies have shown a possible involvement of polymorphisms of genes coding for serotonin transporter, 5HT2A and 5HT2C receptors, HMCN1 and METTL13 genes, D2 receptor and GABAA receptor (GABAAR). The involvement of these systems might provide an explanation of the relations among genetic alterations, hormonal fluctuations in the post partum, changes in neurotransmission and mood fluctuations typical of PPD. DISCUSSION: The results obtained so far are not exhaustive. However, there is a substantial evidence showing that patients with PPD may have a high genetic vulnerability, although we have not been able yet to pinpoint a specific biological marker of the disease. Recent research is focusing on the δ subunit of GABAAR and the possible role of selective agonists of this subunit, such as gaboxadol, in the treatment of PPD.

The PDLIM5 gene and lithium prophylaxis: an association and gene expression analysis in Sardinian patients with bipolar disorder.

A number of studies support the notion that lithium interacts with the protein kinase C (PKC) pathway, an important mediator of several intracellular responses to neurotransmitter signaling. PDLIM5 (PDZ and LIM domain 5; LIM) is an adaptor protein that selectively binds the isozyme PKC(epsilon) to N-type Ca(2+) channels in neurons. We tested for an association between three single nucleotide polymorphisms (SNPs) at the PDLIM5 gene and lithium prophylaxis in a Sardinian sample comprised of 155 bipolar patients treated with lithium. In order to evaluate whether PDLIM5 expression interacts with lithium response, we carried out gene expression analysis in lymphoblastoid cells of 30 bipolar patients. No association was shown between PDLIM5 polymorphisms and lithium response. When PDLIM5 expression was evaluated, no significant differences were detected between Full Responders to lithium (total score>or=7) and other patients (total score