Publications by authors named "Jean-Michel Aubry"

113 Publications

Is Coping with Stigma by Association Role-Specific for Different Family Members? A Qualitative Study with Bipolar Disorder Patients' Relatives.

Community Ment Health J 2021 Mar 9. Epub 2021 Mar 9.

Mood Disorder Unit, Psychiatric Specialties Service, Geneva University Hospital, Rue de Lausanne 20, 1201, Geneva, Switzerland.

Trying to cope with stigma by association (SBA) often results in behaviors leading to social isolation and withdrawal. This study aimed at exploring the stigma-related experiences of family members of persons living with bipolar disorder (PW-BD). A semi-structured interview was conducted with relatives of PW-BD. Open-ended questions addressed three issues: awareness of public stigma of bipolar disorder, experiences of associative stigma, and ways of coping with experiences of SBA. Data were collected from a purposive sample of 21 family members. Experiences of SBA were specifically related to the different family roles. Parents had to deal with responsibility, partners with the choice of staying or not, and siblings with "a sort of duty." These specific prejudices enhanced specific coping strategies. This is the first study to highlight specific issues and coping from the perspective of family members. Based on these findings, specific targeted interventions could be developed.
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http://dx.doi.org/10.1007/s10597-021-00809-6DOI Listing
March 2021

Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts.

Transl Psychiatry 2021 Feb 4;11(1):96. Epub 2021 Feb 4.

Institute of Primary Care and Public Health (Unisante), University of Lausanne, Lausanne, Switzerland.

Studies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23, p = 0.004), 0.77 (SE = 0.37, p = 0.036), and 1.11 (SE = 0.39, p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings.
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http://dx.doi.org/10.1038/s41398-021-01236-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862438PMC
February 2021

Prediction of lithium response using genomic data.

Sci Rep 2021 Jan 13;11(1):1155. Epub 2021 Jan 13.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.
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http://dx.doi.org/10.1038/s41598-020-80814-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806976PMC
January 2021

Maladaptive emotion regulation traits predict altered corticolimbic recovery from psychosocial stress.

J Affect Disord 2021 02 6;280(Pt A):54-63. Epub 2020 Oct 6.

Psychiatry Department, Faculty of Medicine, University of Geneva, Campus Biotech, 1202 Geneva, Switzerland; Mood Disorder Unit, Psychiatric Specialties Service, Geneva University Hospital, 1201 Geneva, Switzerland.

Background: Adaptive recovery from stress promotes healthy cognitive affective functioning, whereas maladaptive recovery is linked to poor psychological outcomes. Neural regions, like the anterior cingulate and hippocampus, play critical roles in psychosocial stress responding and serve as hubs in the corticolimbic neural system. To date, however, it is unknown how cognitive emotion regulation traits (cER), adaptive and maladaptive, influence corticolimbic stress recovery. Here, we examined acute psychosocial stress neural recovery, accounting for cER.

Methods: Functional neuroimaging data were collected while forty-seven healthy participants performed blocks of challenging, time-sensitive, mental calculations. Participants immediately received performance feedback (positive/negative/neutral) and their ranking, relative to fictitious peers. Participants rested for 90 seconds after each feedback, allowing for a neural stress recovery period. Collected before scanning, cER scores were correlated with neural activity during each recovery condition.

Results: Negative feedback recovery yielded increased activity within the dorsomedial prefrontal cortex and amygdala, but this effect was ultimately explained by maladaptive cER (M-cER), like rumination. Isolating positive after-effects (i.e. positive > negative recovery) yielded a significant positive correlation between M-cER and the anterior cingulate, anterior insula, hippocampus, and striatum.

Conclusions: We provide first evidence of M-cER to predict altered neural recovery from positive stress within corticolimbic regions. Positive feedback may be potentially threatening to individuals with poor stress regulation. Identifying positive stress-induced activation patterns in corticolimbic neural networks linked to M-cER creates the possibility to identify these neural responses as risk factors for social-emotional dysregulation subsequent to rewarding social information, often witnessed in affective disorders, like depression.
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http://dx.doi.org/10.1016/j.jad.2020.09.122DOI Listing
February 2021

TOP-ID: a Delphi technique-guided development of a prescription and deprescription tool for adults with intellectual disabilities.

BMJ Open 2020 11 4;10(11):e039208. Epub 2020 Nov 4.

Unit for Intellectual Disabilities and Autism in Adults, Division of Psychiatric Specialties, Department of Psychiatry, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.

Objectives: Adults with an intellectual disability (AWID) are often polymedicated because of somatic and psychiatric health problems. Besides, they may display challenging behaviours, leading to off-label prescription of psychotropic drugs, without efficacy and with numerous adverse effects. In this context, a prescription/deprescription tool (Tool for Optimising Prescription in Intellectual Disability/TOP-ID) was developed to improve the care of AWID. This paper describes how TOP-ID was designed.

Design: Four-step consensus-based process involving a review of the literature, eight semistructured interviews and a two-round Delphi process.

Setting: Seventeen general practices and university and general hospitals from Belgium, France and Switzerland.

Participants: Eighteen French-speaking physicians from different domains of expertise participated in the Delphi process.

Primary And Secondary Outcome Measures: For the Delphi iteration process, consensus was defined as at least a 65% agreement between the experts.

Results: Two rounds were needed for the Delphi process. Eighty-one items of the tool were submitted to 18 out of 35 recruited French-speaking experts during the first round. Sixty-nine per cent of the items reached a rate of agreement of 65% or more in that round. Thirteen questions were reformulated and resubmitted for the second Delphi iteration round. All of the statements reached a rate of agreement of 65% or more in the second round.

Conclusion: TOP-ID is the first prescription-deprescription tool developed specifically for AWIDs in French. It is intended to help prescribers document patient care in order to reduce prescription errors and to improve safety. The next steps of the project include the development of an electronic version of TOP-ID and a utility study.
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http://dx.doi.org/10.1136/bmjopen-2020-039208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643515PMC
November 2020

Effect of Ketamine on Rumination in Treatment-Resistant Depressive Patients.

J Clin Psychopharmacol 2020 Nov/Dec;40(6):607-610

From the Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.

Background: A rapid antidepressant effect of ketamine has repeatedly been documented in the literature, and identifying clinical features associated with a better response to this treatment is currently an essential question. Considering the relationship between rumination and depression and the need to identify potential predictors of response to ketamine, we analyzed the effect of a single injection of ketamine 0.5 mg/kg on rumination in treatment-resistant depressive (TRD) patients and explored whether baseline ruminative style and early improvements of rumination would predict a greater antidepressant effect of ketamine.

Methods: Ten TRD outpatients who participated in a 4-week open study on the antidepressant effect of ketamine also completed the Ruminative Response Scale the day before, the day after, and a week after ketamine administration.

Results: We found that in our patients, a single rapid 1-minute intravenous injection of ketamine 0.5 mg/kg was efficacious in reducing rumination, but neither severity of rumination at baseline nor early improvements of rumination after ketamine injection predicted antidepressant response.

Conclusions: Our preliminary data suggest that a single injection of ketamine 0.5 mg/kg can be efficacious in reducing rumination in TRD patients but rumination does not seem to be a useful clinical predictor of response to ketamine. Larger studies are necessary to confirm these results.
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http://dx.doi.org/10.1097/JCP.0000000000001305DOI Listing
October 2020

[Light - darkness and bipolar disorder].

Rev Med Suisse 2020 Sep;16(707):1745-1747

Service des spécialités psychiatriques, Département de psychiatrie, HUG, 1211 Genève 14.

Circadian rhythmicity generated by the biological clock structures the functioning of human beings over a period of almost 24 hours. This clock is entrained daily by internal and external cues among which light is the most powerful. Several disturbances, whether clinical or biological, observed in bipolar disorders are suggestive of a disruption of the circadian rhythm. Thus, treatments that modulate the biological clock have been developed. So far, the results of light therapy are not unanimous and invite us to better specify the treatment modalities. Dark therapy is a promising intervention that is still not much studied nowadays and therefore opens up great prospects for research in the future.
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September 2020

Covid-19 et santé mentale.

Rev Med Suisse 2020 09;16(707):1731

Institut de psychiatrie légale, Département de psychiatrie, CHUV, Lausanne.

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September 2020

Psychopathological precursors of the onset of mood disorders in offspring of parents with and without mood disorders: results of a 13-year prospective cohort high-risk study.

J Child Psychol Psychiatry 2021 Apr 25;62(4):404-413. Epub 2020 Aug 25.

Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Background: There is still limited evidence from prospective high-risk research on the evolution of specific disorders that may emerge early in the development of mood disorders. Moreover, few studies have examined the specificity of mood disorder subtypes among offspring of parents with both major subtypes of mood disorders and controls based on prospective tracking across the transition from childhood to adulthood. Our specific objectives were to (a) identify differences in patterns of psychopathological precursors among youth with (hypo)mania compared to MDD and (b) examine whether these patterns differ by subtypes of parental mood disorders.

Methods: Our data stem from a prospective cohort study of 449 directly interviewed offspring (51% female, mean age 10.1 years at study intake) of 88 patients with BPD, 71 with MDD, 30 with substance use disorders and 60 medical controls. The mean duration of follow-up was 13.2 years with evaluations conducted every three years.

Results: Within the whole cohort of offspring, MDE (Hazard Ratio = 4.44; 95%CI: 2.19-9.02), CD (HR = 3.31;1.55-7.07) and DUD (HR = 2.54; 1.15-5.59) predicted the onset of (hypo)manic episodes, whereas MDD in offspring was predicted by SAD (HR = 1.53; 1.09-2.15), generalized anxiety (HR = 2.56; 1.05-6.24), and panic disorder (HR = 3.13; 1.06-9.23). The early predictors of (hypo)mania in the whole cohort were also significantly associated with the onset of (hypo)mania among the offspring of parents with BPD.

Conclusions: The onset of mood disorders is frequently preceded by identifiable depressive episodes and nonmood disorders. These precursors differed by mood subtype in offspring. High-risk offspring with these precursors should be closely monitored to prevent the further development of MDD or conversion to BPD.
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http://dx.doi.org/10.1111/jcpp.13307DOI Listing
April 2021

Self-Destigmatization Process? Experiences of Persons Living with Bipolar Disorder: A Qualitative Study.

Community Ment Health J 2020 08 7;56(6):1160-1169. Epub 2020 Apr 7.

Mood Disorder Unit, Psychiatric Specialties Service, Geneva University Hospital, Rue de Lausanne 20, 1201, Geneva, Switzerland.

This qualitative study investigated subjective experiences of self-stigmatization and self-destigmatization among people living with bipolar disorder (BD). We conducted in-depth interviews focusing on self-stigmatization and self-destigmatization with 22 individuals living with BD. The interview transcripts were thematically analyzed using a mixed inductive and deductive approach. Thirty-six codes were extracted and organized into six themes: language, behaviors, relationships, personal experience, identity, and healthcare. Each theme was characterized by an evolution process, and the codes were distributed in a step-by-step order as landmarks. The process begins with the experience of self-stigmatization, and develops toward self-destigmatization. This study presents a new six-dimension process called the "self-destigmatization process" (SDP), a personal and interrelational process that deconstructs self-stigmatization. Clinicians can use the landmarks of the process for clinical assessment and therapeutic interventions to increase recovery orientation.
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http://dx.doi.org/10.1007/s10597-020-00614-7DOI Listing
August 2020

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Mol Psychiatry 2020 Mar 16. Epub 2020 Mar 16.

Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
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http://dx.doi.org/10.1038/s41380-020-0689-5DOI Listing
March 2020

Pain interventions in adults with intellectual disability: A scoping review and pharmacological considerations.

Eur J Pain 2020 05 9;24(5):875-885. Epub 2020 Mar 9.

Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Psychopharmacology Unit, Geneva University Hospitals, Geneva, Switzerland.

Background And Objective: Having to deal on a daily routine with prescriptions in adults with intellectual disability (ID), we systematically reviewed the literature on the specificities of pain interventions in that population, focusing on medication and trying to gather practical information on appropriate pain treatments. Given the scarcity of the literature on the topic, we also discussed the pharmacological considerations to be taken into account when prescribing analgesic drugs in that vulnerable population.

Databases And Data Treatment: Articles on pain and ID were searched in the Medline and Google scholar electronic databases using the key words "Intellectual Disability," "Developmental Disability" and specific keywords for pharmacological and non-pharmacological pain interventions. Preset outcomes about pharmacological treatment specificity, efficacy and safety were then collected.

Results: One hundred and fifty-two articles were found and 16 were retained based on our inclusion and exclusion criteria. Of the 16 articles, five were topical reviews. Among the 11 remaining articles, five discussed pharmacological interventions, four considered non-pharmacological interventions and two discussed both. As anticipated, the literature matching our specific outcomes about the pharmacological treatment of pain was scarce and for the most part not designed to answer the questions of specificity, efficacy and safety of pain treatment in adults with ID.

Conclusion: The specificity of analgesic treatments in adults with ID is a totally unexplored domain. In the absence of clinical guidelines, pharmacological facts-such as inter-individual variability in drug response, pharmacokinetic and pharmacodynamic interactions, frequent co-morbidities and ease of administration-must be systematically integrated, when prescribing in the population of adults with ID.

Significance: This review synthesizes the state of research on pain interventions in adults with ID and is one of the rare articles addressing the specificities of analgesic prescriptions in this population.
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http://dx.doi.org/10.1002/ejp.1547DOI Listing
May 2020

Linking alpha oscillations, attention and inhibitory control in adult ADHD with EEG neurofeedback.

Neuroimage Clin 2020 24;25:102145. Epub 2019 Dec 24.

Department of Psychiatry, University of Geneva, Geneva, Switzerland.

Abnormal patterns of electrical oscillatory activity have been repeatedly described in adult ADHD. In particular, the alpha rhythm (8-12 Hz), known to be modulated during attention, has previously been considered as candidate biomarker for ADHD. In the present study, we asked adult ADHD patients to self-regulate their own alpha rhythm using neurofeedback (NFB), in order to examine the modulation of alpha oscillations on attentional performance and brain plasticity. Twenty-five adult ADHD patients and 22 healthy controls underwent a 64-channel EEG-recording at resting-state and during a Go/NoGo task, before and after a 30 min-NFB session designed to reduce (desynchronize) the power of the alpha rhythm. Alpha power was compared across conditions and groups, and the effects of NFB were statistically assessed by comparing behavioral and EEG measures pre-to-post NFB. Firstly, we found that relative alpha power was attenuated in our ADHD cohort compared to control subjects at baseline and across experimental conditions, suggesting a signature of cortical hyper-activation. Both groups demonstrated a significant and targeted reduction of alpha power during NFB. Interestingly, we observed a post-NFB increase in resting-state alpha (i.e. rebound) in the ADHD group, which restored alpha power towards levels of the normal population. Importantly, the degree of post-NFB alpha normalization during the Go/NoGo task correlated with individual improvements in motor inhibition (i.e. reduced commission errors) only in the ADHD group. Overall, our findings offer novel supporting evidence implicating alpha oscillations in inhibitory control, as well as their potential role in the homeostatic regulation of cortical excitatory/inhibitory balance.
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http://dx.doi.org/10.1016/j.nicl.2019.102145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948256PMC
December 2020

Altered Electroencephalographic Resting-State Large-Scale Brain Network Dynamics in Euthymic Bipolar Disorder Patients.

Front Psychiatry 2019 15;10:826. Epub 2019 Nov 15.

Functional Brain Mapping Laboratory, Campus Biotech, Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland.

Neuroimaging studies provided evidence for disrupted resting-state functional brain network activity in bipolar disorder (BD). Electroencephalographic (EEG) studies found altered temporal characteristics of functional EEG microstates during depressive episode within different affective disorders. Here we investigated whether euthymic patients with BD show deviant resting-state large-scale brain network dynamics as reflected by altered temporal characteristics of EEG microstates. We used high-density EEG to explore between-group differences in duration, coverage, and occurrence of the resting-state functional EEG microstates in 17 euthymic adults with BD in on-medication state and 17 age- and gender-matched healthy controls. Two types of anxiety, state and trait, were assessed separately with scores ranging from 20 to 80. Microstate analysis revealed five microstates (A-E) in global clustering across all subjects. In patients compared to controls, we found increased occurrence and coverage of microstate A that did not significantly correlate with anxiety scores. Our results provide neurophysiological evidence for altered large-scale brain network dynamics in BD patients and suggest the increased presence of A microstate to be an electrophysiological trait characteristic of BD.
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http://dx.doi.org/10.3389/fpsyt.2019.00826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873781PMC
November 2019

Bipolar spectrum disorder: What evidence for pharmacological treatment? A systematic review.

Psychiatry Res 2019 12 31;282:112627. Epub 2019 Oct 31.

Mood disorder unit, Psychiatric specialties service, Geneva University Hospital, Rue de Lausanne 20, CH-1201 Geneva, Switzerland. Electronic address:

Background And Objectives: Bipolar spectrum disorder (BSD) is an extended concept of bipolar disorder (BD) that includes conditions that do not fulfill the criteria. There is no recommendation today about its treatment. We reviewed relevant literature focusing on pharmacological treatments, looking for high-strength evidence leading to guidelines.

Methodology: A literature search was conducted using MedLine / PubMed database and Google Scholar up to September 2018. Search words were related to BSD and pharmacological treatment.

Results: The literature search yielded 621 articles. Out of these, 35 articles met our selection criteria. There was limited high quality data. Only one randomized control trial (RCT) and one randomized open label trial were found. Most studies used different definition of BSD.

Conclusions: There is a considerable lack of data and no evidence supporting efficacy of pharmacological treatment for BSD. There is a need for a consensus on the definition of BSD and more evidence studies to evaluate drug's effectiveness in this condition.
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http://dx.doi.org/10.1016/j.psychres.2019.112627DOI Listing
December 2019

Consultation spécialisée pour les troubles bipolaires au Rwanda.

Rev Med Suisse 2019 Sep;15(663):1675-1677

Service des spécialités psychiatriques, Département de psychiatrie, HUG, Rue de Lausanne 20bis, 1201 Genève.

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September 2019

Vérités et Fake News.

Rev Med Suisse 2019 Sep;15(663):1647-1648

Chef de département, Service des spécialités psychiatriques, Département de santé mentale et de psychiatrie, HUG, Genève.

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September 2019

Eye-gaze processing in the broader bipolar phenotype revealed by electrical neuroimaging.

Psychiatry Res Neuroimaging 2019 09 31;291:42-51. Epub 2019 Jul 31.

Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Department of Mental Health and Psychiatry, Service of Psychiatric Specialties, Mood disorders unit University Hospitals of Geneva, Switzerland.

Previous studies have documented atypical brain responses to faces in individuals with bipolar disorder (BD) and in their relatives. In view of previous findings of atypical face processing in youths at risk for BD, the aim of this study was to examine whether BD patients and offspring would show differential activation in networks of the social brain when processing eye-gaze. Data from 18 euthymic BD patients and 18 offspring, as well as 36 age-matched healthy controls, were collected using a delayed face-matching paradigm, event related potentials and electrical neuroimaging methods. The P200 component, which is implicated in facial cues decoding, differentiated the BD groups from their age-matched controls. P200 source reconstruction indicates impairments conveyed by eye-contact in a network involved in experiencing others' social intentions in BD patients (supplementary motor cortex, precentral gyrus, inferior parietal lobe), and the engagement of compensatory prefrontal mechanisms for modulating these functions in BD offspring. When viewing faces that had an averted gaze, BD patients and offspring showed a hypo-activation, compared to controls, particularly in regions involved in experiencing others' feelings (post-central gyrus in BD patients / ventral premotor cortex in offspring). Therefore, the neural mechanism for decoding shifts in eye-gaze may be a familial characteristic of BD.
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http://dx.doi.org/10.1016/j.pscychresns.2019.07.007DOI Listing
September 2019

Psychiatric disorders among offspring of patients with Bipolar and Borderline Personality Disorder.

J Clin Psychol 2019 10 10;75(10):1810-1819. Epub 2019 Jun 10.

Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Objective: As part of a larger study investigating biological risk factors for bipolar disorder (BD) and borderline personality disorder (BPD), we investigated the prevalence of psychiatric diagnoses presented by young BD or BPD offspring. With respect to the scarcity of studies interested in psychiatric disorders among BPD offspring, we have chosen to report these results despite the small sample size for a prevalence study.

Method: We recruited 21 BD and 22 BPD offspring and 23 control subjects. All subjects were assessed with a structured interview.

Results: Our main finding suggests that BPD offspring present a higher rate of psychiatric disorders compared to BD offspring. Attention deficit and hyperactivity disorder was the most prevalent disorder.

Conclusion: Our results contribute to the evidence that offspring of patients with BPD, are at high risk with regard to their mental health and deserve both more research and special attention at the clinical level.
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http://dx.doi.org/10.1002/jclp.22817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771911PMC
October 2019

Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder.

Anesthesiology 2019 06;130(6):923-935

From the Department of Neuroscience, Faculty of Medicine (V.S., J.H., D.W., A.D., S.S., L.V.) Geneva Neuroscience Center (V.S., J.H., D.W., A.D., S.S., L.V.) Swiss Center for Affective Sciences (V.S., J.H., D.W., S.S.), University of Geneva, Geneva, Switzerland Department of Mental Health and Psychiatry, Service of Psychiatric Specialties (S.V., G.M., V.B., A.D., J.-M.A., M.K.) Department of Anesthesiology, Pharmacology, and Intensive Care (L.V.), University Hospitals of Geneva, Geneva, Switzerland Faculty of Medicine, University of Namur, Namur, Belgium (M.D.).

What We Already Know About This Topic: The antidepressant effect of ketamine is associated with increased activity in the reward circuitry of the brain and a suppression of circuitry that mediates perceptual processing of negative emotions. The duration of ketamine effect on these brain structures remains to be defined.

What This Article Tells Us That Is New: As expected, ketamine administration led to an improvement in mood and global vigilance. The improvement in mood was accompanied by an increased recruitment of the orbitofrontal cortex, ventral striatum, medial substantial nigra and ventral tegmental area, structures that are part of the reward circuitry.Responses in the mesolimbic structures (amygdala, medial substantial nigra and ventral tegmental area, orbitofrontal cortex) to negative stimuli were decreased after ketamine administration.The data are consistent with the premise that ketamine induces sustained changes in the mesolimbic neural circuits to reset pathological reward and emotional processing.

Background: Ketamine rapidly improves maladaptive mood states in major depressive disorder, and some of the neural substrates underlying this therapeutic effect have been identified. This study aimed to identify functional changes within neural networks that may underlie the impact of ketamine on both reward and emotional processing in patients with treatment-resistant major depression.

Methods: Ten adult patients with a Montgomery-Åsberg Depression Rating Scale score above 25 were enrolled to receive a single intravenous administration of ketamine (0.5 mg/kg). Patients' performance along with related neural network activations were analyzed in a game-like reward task and in an emotional judgment task using functional magnetic resonance imaging 1 day before and 1 and 7 days after ketamine administration.

Results: A significant correlation (R = 0.46, P = 0.03) between the improvement of depression scores and the enhanced reaction time for positive items was found in the game-like reward task 1 day after ketamine administration. This enhanced sensitivity for rewarded items was accompanied by increased activity of reward-related brain regions, including the orbitofrontal cortex, ventral striatum, and the ventral tegmental area, an effect that persisted up to 1 week after ketamine injection. In the emotional judgment task, it was found that ketamine rapidly modified local brain activities in response to emotionally negative, positive, or neutral stimuli in the amygdala, insula, anterior cingulate cortex, and in the ventral tegmental area.

Conclusions: Single bolus ketamine administration rapidly triggers lasting changes in mesolimbic neural networks to improve pathologic reward and emotional processing in patients with major depressive disorder.
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http://dx.doi.org/10.1097/ALN.0000000000002667DOI Listing
June 2019

Rumination related activity in brain networks mediating attentional switching in euthymic bipolar patients.

Int J Bipolar Disord 2019 Jan 12;7(1). Epub 2019 Jan 12.

Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Introduction: Mood disorder patients have a tendency to be more internally oriented, with difficulties in switching attentional focus, which might result in the generation of negative thoughts, such as rumination. The present study explored self-referential neural activity correlating with rumination tendency and attentional switching capacity in bipolar disorder.

Methods: Twenty euthymic bipolar patients and twenty matched healthy controls underwent a novel introspection task of switching between internally and externally focused attention during a word processing task, while their brain activity was assessed using functional MRI.

Results: During internal focus, higher activity in self-related regions (mPFC, PCC) was found in euthymic bipolar patients as compared to controls, verifying the hypothesis of exaggerated recruitment of self-referential processes in bipolar subjects. Switching from internal to external focus revealed higher parahippocampal activity in patients as compared to controls, additionally more pronounced when switching away from negative as compared to positive self-referential information. Furthermore, rumination traits correlated with activity in PCC, subgenual and pregenual ACC, and bilateral anterior insula during repetition of internal focus, specifically when evaluating negative words. Finally, we used ACC subregions that correlated with tendency to ruminate as seeds for a whole brain connectivity analysis. Patients showed stronger connectivity between sgACC (seed), pgACC, dPFC, and anterior insula during internal focus, whereas pgACC (seed) was more strongly connected to parahippocampal gyrus when switching from internal to external focus.

Conclusions: These findings reveal an overactive rumination-related network whose activity is enhanced by negative information in euthymic bipolar patients, which could possibly contribute to impaired switching of thoughts away from internal attention.
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http://dx.doi.org/10.1186/s40345-018-0137-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330377PMC
January 2019

Rumination related activity in brain networks mediating attentional switching in euthymic bipolar patients.

Int J Bipolar Disord 2019 Jan 12;7(1). Epub 2019 Jan 12.

Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Introduction: Mood disorder patients have a tendency to be more internally oriented, with difficulties in switching attentional focus, which might result in the generation of negative thoughts, such as rumination. The present study explored self-referential neural activity correlating with rumination tendency and attentional switching capacity in bipolar disorder.

Methods: Twenty euthymic bipolar patients and twenty matched healthy controls underwent a novel introspection task of switching between internally and externally focused attention during a word processing task, while their brain activity was assessed using functional MRI.

Results: During internal focus, higher activity in self-related regions (mPFC, PCC) was found in euthymic bipolar patients as compared to controls, verifying the hypothesis of exaggerated recruitment of self-referential processes in bipolar subjects. Switching from internal to external focus revealed higher parahippocampal activity in patients as compared to controls, additionally more pronounced when switching away from negative as compared to positive self-referential information. Furthermore, rumination traits correlated with activity in PCC, subgenual and pregenual ACC, and bilateral anterior insula during repetition of internal focus, specifically when evaluating negative words. Finally, we used ACC subregions that correlated with tendency to ruminate as seeds for a whole brain connectivity analysis. Patients showed stronger connectivity between sgACC (seed), pgACC, dPFC, and anterior insula during internal focus, whereas pgACC (seed) was more strongly connected to parahippocampal gyrus when switching from internal to external focus.

Conclusions: These findings reveal an overactive rumination-related network whose activity is enhanced by negative information in euthymic bipolar patients, which could possibly contribute to impaired switching of thoughts away from internal attention.
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http://dx.doi.org/10.1186/s40345-018-0137-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330377PMC
January 2019

Rumination related activity in brain networks mediating attentional switching in euthymic bipolar patients.

Int J Bipolar Disord 2019 Jan 12;7(1). Epub 2019 Jan 12.

Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Introduction: Mood disorder patients have a tendency to be more internally oriented, with difficulties in switching attentional focus, which might result in the generation of negative thoughts, such as rumination. The present study explored self-referential neural activity correlating with rumination tendency and attentional switching capacity in bipolar disorder.

Methods: Twenty euthymic bipolar patients and twenty matched healthy controls underwent a novel introspection task of switching between internally and externally focused attention during a word processing task, while their brain activity was assessed using functional MRI.

Results: During internal focus, higher activity in self-related regions (mPFC, PCC) was found in euthymic bipolar patients as compared to controls, verifying the hypothesis of exaggerated recruitment of self-referential processes in bipolar subjects. Switching from internal to external focus revealed higher parahippocampal activity in patients as compared to controls, additionally more pronounced when switching away from negative as compared to positive self-referential information. Furthermore, rumination traits correlated with activity in PCC, subgenual and pregenual ACC, and bilateral anterior insula during repetition of internal focus, specifically when evaluating negative words. Finally, we used ACC subregions that correlated with tendency to ruminate as seeds for a whole brain connectivity analysis. Patients showed stronger connectivity between sgACC (seed), pgACC, dPFC, and anterior insula during internal focus, whereas pgACC (seed) was more strongly connected to parahippocampal gyrus when switching from internal to external focus.

Conclusions: These findings reveal an overactive rumination-related network whose activity is enhanced by negative information in euthymic bipolar patients, which could possibly contribute to impaired switching of thoughts away from internal attention.
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http://dx.doi.org/10.1186/s40345-018-0137-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330377PMC
January 2019

Quid de la prévention pour la santé mentale ?

Rev Med Suisse 2018 Sep;14(619):1635

Institut de psychiatrie légale, Département de psychiatrie, CHUV, Lausanne.

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September 2018

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

Bipolar Disord 2019 02 28;21(1):68-75. Epub 2018 Jun 28.

Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.

Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.

Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.

Results: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.

Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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http://dx.doi.org/10.1111/bdi.12659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585855PMC
February 2019

Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder.

Front Psychiatry 2018 31;9:207. Epub 2018 May 31.

Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset ( = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with showing the strongest association with the continuous trait ( = 9.80E-04) and with the dichotomous phenotype ( = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
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http://dx.doi.org/10.3389/fpsyt.2018.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991073PMC
May 2018

Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder.

Front Psychiatry 2018 31;9:207. Epub 2018 May 31.

Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset ( = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with showing the strongest association with the continuous trait ( = 9.80E-04) and with the dichotomous phenotype ( = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
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http://dx.doi.org/10.3389/fpsyt.2018.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991073PMC
May 2018

Phenotypic Assessment of Drug Metabolic Pathways and P-Glycoprotein in Patients Treated With Antidepressants in an Ambulatory Setting.

J Clin Psychiatry 2018 Mar/Apr;79(2)

Psychopharmacology Unit, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Gabrielle Perret-Gentil 4, 1211 Genève 4, Switzerland.

Objective: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach.

Methods: From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5.

Results: We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent.

Conclusions: The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients.

Trial Registration: ClinicalTrials.gov identifier: NCT02438072.
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http://dx.doi.org/10.4088/JCP.16m11387DOI Listing
August 2019

Early changes of blood lipid levels during psychotropic drug treatment as predictors of long-term lipid changes and of new onset dyslipidemia.

J Clin Lipidol 2018 Jan - Feb;12(1):219-229. Epub 2017 Oct 16.

Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. Electronic address:

Background: Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels.

Objective: This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development.

Methods: Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment.

Results: Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (≥5%) for TC, LDL-C, TG, and non-HDL-C and decrease (≥5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (≥30% TC, ≥40% LDL-C, ≥45% TG, ≥55% non-HDL-C increase, and ≥20% HDL-C decrease; sensitivity 70%-100%, specificity 53%-72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort (P ≤ .03) as well as in a replication cohort (n = 79; P ≤ .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others (P ≤ .01).

Conclusion: Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia.
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http://dx.doi.org/10.1016/j.jacl.2017.10.002DOI Listing
July 2019

Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.

JAMA Psychiatry 2018 01;75(1):65-74

Douglas Mental Health University Institute, McGill University, Montreal, Canada.

Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).

Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.

Design, Setting, And Participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.

Main Outcomes And Measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.

Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.

Conclusions And Relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.3433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833535PMC
January 2018