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

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 (ConLi+Gen) 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

Données actuelles sur la compréhension et la prise en charge du trouble de la personnalité borderline

Le trouble de la personnalité borderline est un trouble fréquent, grave et invalidant, qui représente une file active importante des patients suivis en psychiatrie. Son pronostic est particulièrement assombri par leurs gestes suicidaires, et les coûts pour la société liés à ce trouble sont substantiels, avec des dépenses liées à l'utilisation importante des structures sociales et sanitaires. Ce trouble a connu des avancées significatives en seulement quelques décennies, depuis le concept essentiellement psychanalytique d' état limite , décrit notamment par O. Kernberg et J. Bergeret. Aujourd'hui, les descriptions cliniques, critériologiques et dimensionnelles du trouble correspondent à un état clinique bien particulier. Depuis les années 1980, l'approche théorique cognitivo-comportementale, avec A. Beck, J. Young et M. Linehan, a décrit les modes de pensée et les comportements dysfonctionnels de ces patients à partir de leurs expériences infantiles. Certains aspects du trouble peuvent également être éclairés à la lumière d'une approche développementale, via la théorie de l'attachement, conceptualisée à l'origine par J. Bowlby, et qui constitue une nouvelle piste de compréhension psychopathologie basée sur des interactions dysfonctionnelles lors de la petite enfance. Cette approche complémentaire semble indispensable pour mieux appréhender la prise en charge et donner du sens aux manifestations symptomatiques, en les replaçant dans la dynamique de la relation. Bateman et Fonagy se sont d ailleurs appuyés sur ce concept d'attachement pour développer une approche psychothérapique basée sur la mentalisation. Sur le plan étiologique, il semblerait que plusieurs facteurs de risque précipitants d'ordre socio-psycho-environnementaux interagissent de manière complexe avec des facteurs de prédisposition, génétiques et de tempérament. L'attachement désorganisé de l'enfant semble aussi constituer une vulnérabilité importante au développement du trouble de la personnalité borderline, en entraînant un déficit important en mentalisation.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Relapsing-remitting behavioural variant of frontotemporal dementia in a bipolar patient

We report the case of a bipolar I patient who was diagnosed with frontotemporal dementia at the age of 54 during a manic episode. Her neurological state improved when this episode ended. Each subsequent thymic relapse was associated with cognitive deficits which subsided when the patient became euthymic, even though SPECT continued to show the same frontal hypoperfusion. We here discuss the hypothesis that the cognitive reserve of this patient, a former journalist, may, except during her mood episodes, have provided her with sufficient resources to meet her life demands despite her underlying neurological disorder

Dynamics of depressive and psychomotor symptoms during electroconvulsive therapy in older depressive patients: A case series

International audienceObjective. Electroconvulsive therapy (ECT) is an effective treatment for patients suffering from a major depressive episode, especially older ones. Identification of specific responses within early ECT sessions remains an issue of debate, however. Hence, this pilot study prospectively examined the outcome in terms of depressive signs, symptom by symptom, throughout a course of ECT, concentrating particularly on psychomotor retardation symptoms. Methods. Nine patients were clinically evaluated several times during the ECT course, before the first session and then weekly (over 3 to 6 weeks, according to their evolution), by completing the Montgomery–Asberg Depression Rating Scale (MADRS), the Mini-Mental State Examination test, and the French Retardation Rating Scale for Depression (ERD) for assessing the severity of psychomotor retardation. Results. Non-parametric Friedman tests showed significant positive changes in mood disorders during ECT in older depressive patients (mean: -27.3% of initial MADRS total score). Fast improvement in ERD score was observed at t1 (i.e., after 3–4 ECT sessions), whereas a slightly delayed improvement in the MADRS scores was found at t2 (i.e., after 5–6 ECT sessions). Moreover, the scores for items linked to the motor component of psychomotor retardation (e.g., Gait, Postural control, Fatigability) were the first to significantly decrease during the first two weeks of the ECT course compared with the cognitive component. Conclusions. Interestingly, participants' concentration on daily functional activities, their interest and fatigability, and their reported state of sadness were the first to progress, representing possible precursor signs of positive patient outcomes following ECT

An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes

Objectives The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. Methods We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. Results The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. Conclusions This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies

An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes

Objectives The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. Methods We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. Results The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. Conclusions This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies

Clinical factors associated with lithium response in bipolar disorders

International audienceBackground: Bipolar disorder is a common chronic illness characterized by high levels of morbidity and all-cause mortality. Lithium is one of the gold standard mood stabilizer treatments, but the identification of good, partial and non-responders in clinical settings is inconsistent. Methods: We used an established rating scale (the Alda scale) to classify the degree of lithium response (good response, partial response, non-response) in a large, multicentre clinically representative sample of well-characterized cases of bipolar disorders I and II. Next, we examined previously reported clinical predictors of response to determine which factors significantly differentiated between the three response groups. Results: Of 754 cases, 300 received lithium, for at least 6 months, as a treatment for bipolar disorder (40%). Of these cases, 17% were classified as good response, 52% as partial response and 31% as non-response. Lifetime history of mixed episodes ( p = 0.017) and alcohol use disorders ( p = 0.015) both occurred in >20% of partial response and non-response groups but <10% of good response cases. Family history of bipolar disorder I was of borderline statistical significance, being more frequent in the good response group (38%) compared with the non-response group (18%). There was a trend ( p = 0.06) for bipolar disorder II to be associated with non-response. Conclusions: Only three factors previously identified as predictors of lithium response significantly differentiated the response groups identified in our sample. Interestingly, these factors have all been found to co-occur more often than expected by chance, and it can be hypothesized that they may represent a shared underlying factor or dimension. Further prospective studies of predictors and the performance of the Alda scale are recommended

Clinical factors associated with lithium response in bipolar disorders

International audienceBackground: Bipolar disorder is a common chronic illness characterized by high levels of morbidity and all-cause mortality. Lithium is one of the gold standard mood stabilizer treatments, but the identification of good, partial and non-responders in clinical settings is inconsistent. Methods: We used an established rating scale (the Alda scale) to classify the degree of lithium response (good response, partial response, non-response) in a large, multicentre clinically representative sample of well-characterized cases of bipolar disorders I and II. Next, we examined previously reported clinical predictors of response to determine which factors significantly differentiated between the three response groups. Results: Of 754 cases, 300 received lithium, for at least 6 months, as a treatment for bipolar disorder (40%). Of these cases, 17% were classified as good response, 52% as partial response and 31% as non-response. Lifetime history of mixed episodes ( p = 0.017) and alcohol use disorders ( p = 0.015) both occurred in >20% of partial response and non-response groups but <10% of good response cases. Family history of bipolar disorder I was of borderline statistical significance, being more frequent in the good response group (38%) compared with the non-response group (18%). There was a trend ( p = 0.06) for bipolar disorder II to be associated with non-response. Conclusions: Only three factors previously identified as predictors of lithium response significantly differentiated the response groups identified in our sample. Interestingly, these factors have all been found to co-occur more often than expected by chance, and it can be hypothesized that they may represent a shared underlying factor or dimension. Further prospective studies of predictors and the performance of the Alda scale are recommended

A study in the general population about sadness to disentangle the continuum from well-being to depressive disorders

International audienceSadness is both a common experience in general population and one of the main criteria of major depressive disorder (MDD). We tested the hypothesis of a depressive continuum using sadness as an intermediate experience between well-being and disorder.A French cross-sectional Mental Health survey in General Population interviewed 38,694 individuals. We examined prevalences and compared sociodemographic correlates and psychiatric disorders of individuals in 3 independent groups 1) MDD, 2) sadness without MDD, and 3) controls.The prevalence of sadness was of 29.8% in the whole sample and of 93% in subjects suffering from MDD (n = 4976). The "sadness" group shared the same sociodemographic patterns as the "MDD" group. All psychiatric disorders assessed (i.e. bipolar disorder, anxiety disorder, alcohol use disorder, psychotic disorder and suicide attempts) were significantly associated with both "sadness" and "MDD" groups compared to "controls". Individuals with sadness, compared to those with MDD, were significantly less likely to meet the criteria for all psychiatric disorders. MDD's sensitivity of sadness was 94,2%.Even though we used a quota sampling method, the sample was not strictly representative of the general population.Sadness validates the depressive continuum hypothesis, since it is more frequent in the general population than MDD itself and at the same time shares with MDD the same sociodemographic and clinical correlates. A gradual association from controls to MDD was observed for psychiatric comorbidities. Finally, the high sensitivity of sadness may suggest its use to screen at-risk individuals converting from well-being to full psychiatric disorders