Pascale Mazzola-Pomietto

Remission from mania is associated with a decrease in amygdala activation during motor response inhibition.

OBJECTIVES Neuroimaging studies of bipolar disorder (BD) have provided evidence of brain functional abnormalities during both the states of mania and remission. However, the differences in brain function between these two states are still poorly known. In the current study, we aimed to use a longitudinal design to examine the functional changes associated with symptomatic remission from mania within the brain network underlying motor response inhibition. METHODS Using event-related functional magnetic resonance imaging (fMRI), 10 BD patients and 10 healthy subjects were imaged twice while performing a Go/NoGo task. Patients were in a manic state when they underwent the first scan and fully remitted during the second scan. A mixed-effect ANOVA was used to identify brain regions showing differences in activation change over time between the two groups. RESULTS The left amygdala was the only brain region to show a time-dependent change in activation that was significantly different between BD patients and healthy subjects. Further analyses revealed that this difference arose from the patient group, in which amygdala activation was decreased between mania and subsequent remission. CONCLUSIONS This finding suggests that a decrease in left amygdala responsiveness is a critical phenomenon associated with remission from mania. It emphasizes the relevance of longitudinal approaches for identifying neurofunctional modifications associated with mood changes in BD.

Relation between lymphocyte β-adrenergic responsivity and the severity of depressive disorders

Basal level and isoproterenol-induced response of cyclic adenosine monophosphate (cAMP) were determined in mononuclear leucocytes from 17 drug-free patients with major depressive (n = 9) or dysthymic disorders (n = 8) and 20 normal controls. No significant difference was observed between basal cAMP levels from depressed and control subjects. The cAMP production in response to maximal stimulation by isoproterenol (ISO), a beta-agonist, was significantly lower (-34.7%) in depressed patients than in controls, and was significantly negatively correlated to the severity of the depression as assessed by the Hamilton depression rating scale score (r = -0.62; p < 0.003). When the depressed group was subdivided on the basis of the DSM-III-R (APA 1987) diagnosis criteria into major depressive and dysthymic disorders, the ISO-stimulated cAMP levels in the two groups were indistinguishable. When evaluated at the same time than the density of beta-adrenoreceptors in eight depressed patients, the ISO-stimulated cAMP levels were highly significantly correlated with the Bmax values (r = 0.89; p < 0.003). The results indicate that the decrease in beta-adrenergic responsiveness of mononuclear leukocytes can be present in depressed patients whatever the nosographical subtype of the depressive disorder and is quantitatively related to the depression severity. Based on these data, it seems that the blunted beta-adrenergic sensitivity observed in mononuclear leukocytes (MNL) cells of depressed patients is closely associated with a loss of beta-adrenoceptors.

Stroop and emotional Stroop interference in unaffected relatives of patients with schizophrenic and bipolar disorders: distinct markers of vulnerability?

Reduced inhibition has been demonstrated in both schizophrenic and bipolar patients through the findings of increased interference on the Stroop Colour-Word Task (SCWT) and increased emotional interference on specific versions of the Emotional Stroop Task (EST). Despite previous findings of enhanced interference in unaffected relatives of schizophrenic and bipolar patients, it remains unclear whether interference might be a candidate endophenotype to both disorders. Moreover, data regarding emotional interference in unaffected relatives are critically lacking. In the present study, we aimed to compare unaffected relatives of patients with schizophrenia (SZ-rel, N = 30) and bipolar disorder (BD-rel, N= 30) with normal controls (N = 60) when performing the SCWT and an EST designed with neutral, depressive, paranoid and manic words. SZ-rel exhibited greater interference effect on both the SCWT and the EST as compared to either BD-rel or normal controls. BD-rel, and by contrast to SZ-rel and controls, showed increased emotional interference effect on the EST that was specifically associated to the disease-related words. The findings support the hypothesis of different markers of vulnerability to schizophrenic and bipolar disorders; impairment in cognitive inhibition could characterize high-risk individuals for schizophrenia whereas an emotional bias towards mood-related information could be a trait marker of bipolar disease.

Differential Responses to Emotional Interference in Paranoid Schizophrenia and Bipolar Mania

Background: Studies on emotional biases towards threat-related stimuli in schizophrenia and bipolar disorder have provided, so far, inconsistent results. The aim of the present study was to investigate emotional interference in acute schizophrenic and manic patients and its clinical correlates by using a card version of the Emotional Stroop Task designed with neutral, paranoid, depressive and manic words. Methods: Thirty paranoid schizophrenia patients, 30 manic patients and 60 healthy controls were compared on the Emotional Stroop Test. Response times (RT) were collected for each card. Interference indices were calculated by subtracting the RT for the neutral card from the RT for the depressive, paranoid and manic cards. Results: The schizophrenic and manic patient groups showed an increased interference effect when the emotional valence was relating to the disorder-specific psychopathology. In addition, the paranoid interference index correlated with positive symptoms in schizophrenic patients. By contrast, no correlation was evidenced between interference indices and mood symptoms in the manic group. Conclusions: Among schizophrenic patients, paranoid interference might be a state-related emotional abnormality associated with persecutory delusions. In mania, we suggest that emotional biases towards depressive as well as manic information might be trait features of the emotional hyperreactivity involved in the vulnerability to bipolar disorder.

Les anomalies structurales observées en imagerie cérébrale dans le trouble bipolaire

Resume Les etudes de neuroimagerie structurale montrent, dans le trouble bipolaire, la presence d’un certain nombre d’anomalies cerebrales. Les anomalies les plus souvent retrouvees sont des hyperintensites de la substance blanche dans les regions periventriculaires et sous-corticales profondes, un elargissement modere des ventricules cerebraux touchant surtout le ventricule lateral droit, des alterations de la substance grise et de la substance blanche dans les regions frontale, cingulaire et temporale, ainsi que des changements de volume des structures sous-corticales, comprenant en particulier l’amygdale, le thalamus et les ganglions de la base. Il existe une grande heterogeneite des changements morphometriques observes dans ces travaux, qui peut s’expliquer en particulier par la variabilite des methodes utilisees et des caracteristiques cliniques des patients etudies. Neanmoins, l’ensemble des resultats de ces etudes, associes a ceux obtenus grâce aux approches lesionnelles, tend a montrer une distribution non symetrique des anomalies cerebrales, et qui touche en particulier les regions frontales et sous-corticales impliquees dans le traitement des informations emotionnelles. Confirmant cette lateralisation, les anomalies d’activation cerebrale observees en neuroimagerie fonctionnelle permettent en outre de preciser le role particulier de certains circuits fronto-limbiques dans l’expression symptomatique du trouble bipolaire.

Adherence to medication is associated with non-planning impulsivity in euthymic bipolar disorder patients

BACKGROUND Adherence to medication is a major issue in bipolar disorder. Non-planning impulsivity, defined as a lack of future orientation, has been demonstrated to be the main impulsivity domain altered during euthymia in bipolar disorder patients. It was associated with comorbidities. METHODS To investigate relationship between adherence to medication and non-planning impulsivity, we included 260 euthymic bipolar patients. Adherence to medication was evaluated by Medication Adherence Rating Scale and non-planning impulsivity by Barrat Impulsiveness Scale. Univariate analyses and linear regression were used. We conducted also a path analysis to examine whether non-planning impulsivity had direct or indirect effect on adherence, mediated by comorbidities. RESULTS Adherence to medication was correlated with non-planning impulsivity, even after controlling for potential confounding factors in linear regression analysis (Beta standardized coefficient = 0.156; p = 0.015). Path analysis demonstrated only a direct effect of non-planning impulsivity on adherence to medication, and none indirect effect via substance use disorders and anxiety disorders. LIMITATIONS Our study is limited by its cross-sectional design and adherence to medication was assessed only by self-questionnaire. CONCLUSIONS Higher non-planning impulsivity is associated with low medication adherence, without an indirect effect via comorbidities.

Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode

The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; η2=0.008; ICC=0.91, 95% CI [0.87-0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340-0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2nd week (β=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2nd and 8th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438-83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice.

Troubles affectifs et impulsivité

Resume L’impulsivite est une composante complexe et importante de la phenomenologie des troubles de l’humeur. Les troubles impulsifs tels qu’ils sont definis dans le DSM sont frequemment associes aux troubles de l’humeur, surtout le trouble bipolaire de type I, et ils definissent une pathologie psychiatrique plus severe. Les approches dimensionnelles soulignent que l’impulsivite peut etre une manifestation intrinseque du trouble de l’humeur, a la fois liee a l’etat mais aussi persistante en tant que trait permanent chez les patients. Si les conduites addictives comorbides sont associees de facon robuste a une impulsivite plus marquee chez les patients souffrant de troubles bipolaires, le lien entre les antecedents de tentative de suicide et le niveau d’impulsivite reste incertain. Par ailleurs, dans l’hypothese d’un processus neuropsychologique qui sous-tend ces phenomenes cliniques, les liens entre impulsivite observable en clinique et tests neuropsychologiques restent tenus et plusieurs explications ont ete proposees pour faire face a cette discordance.Impulsivity is a complex and important phenomenon in mood disorders. Impulse control disorders, as defined in DSM, are more frequent in mood disorders especially in Bipolar Disorder type I, and are associated with a more severe course of illness. Dimensional studies demonstrate that impulsivity is a core manifestation of bipolar disorder both as state- and trait-dependent markers in patients. Comorbid substance use disorders are often associated with a higher level of impulsivity whereas the relation between suicidal behaviors and higher impulsivity remains uncertain. Moreover, neuropsychological tests were used to study correlation between clinical impulsivity and laboratory measurements of impulsivity. Level of correlation remains weak and several explanations are proposed in the literature.

Les variations de la neuro-anatomie structurale cérébrale sont-elles des endophénotypes candidats prometteurs dans le trouble bipolaire ?

Resume Le trouble bipolaire est une pathologie complexe ayant une composante heritable indeniable. Les etudes epidemiologiques soulignent la contribution de facteurs genetiques a cette composante hereditaire. Neanmoins, les travaux de biologie moleculaire utilisant des approches de genetique classique n’ont pas permis d’identifier ces facteurs. Pour pallier cette difficulte, plusieurs strategies sont mises en oeuvre. La recherche d’endophenotype est l’une d’entre elles. Son objectif est d’identifier des phenotypes biologiques dont l’expression repond a des mecanismes genetiques plus simples que ceux impliques dans la manifestation de la maladie. Les endophenotypes representent, donc, des marqueurs intermediaires entre genes et etats pathologiques, et leur utilisation devrait faciliter l’identification de loci genetiques associes a la pathologie. Dans cet article, nous decrirons les principaux phenotypes de la neuro-imagerie structurale cerebrale qui sont utilises en recherche et rapporteront leur heritabilite en population generale. Puis nous nous centrerons sur les resultats des etudes realisees dans les familles de patients souffrant de trouble bipolaire. Les donnees qui, sont encore peu nombreuses, suggerent que de discretes anomalies de la neuro-anatomie cerebrale, en particulier au niveau des faisceaux de fibres de la matiere blanche, sont des endophenotypes candidats prometteurs dans le cadre de cette pathologie.Bipolar disorder is a complex pathology which has a strong heritability component. Epidemiologic studies have pinpointed the contribution of genetic factors to the heritability component. The molecular studies, that have used classical genetic approaches, have been inconclusive at indentifying genes involved in the etiology of this disorder. To overcome these difficulties, a number of strategies have been developed. One of them is the endophenotypic approach. Its main scope is to identify biological markers that are influenced by genetic factors that are less complex than those involved in the clinical expression of the disorder. Thus, it is likely these markers will be more readily linked to specific genetic loci. In this article, we describe the main phenotypes of neuro-anatomic measurements that are widely used in research, and report data on their heritability in the general population. Then, we focus on the results of the few structural neuro-imaging studies that have been carried out in families of patients suffering of bipolar disorders. The current data converge to indicate that subtle structural abnormalities, particularly at the level white matter tracts, seem to be promising endophenotype candidates for bipolar disorder.