Patterns of executive functions and theory of mind in adults with a family history of alcohol use disorder: Combined group and single-case analyses.

BACKGROUND: Impairments in executive function and social cognition are highly prevalent in individuals with an alcohol use disorder (AUD). Some studies show that similar difficulties are displayed by individuals with a positive family history of AUD (FH+) compared with individuals with a negative family history (FH-). Yet, no studies have jointly investigated cognitive and affective theory of mind at the behavioral level. Moreover, some studies show preserved executive and socioemotional functioning in FH+ participants. One possible explanation for these divergent results is that FH+ individuals are cognitively heterogeneous. In this study, we examined the frequency and co-occurrence of difficulties in executive function and social cognition among FH+ individuals at the individual level. METHODS: Sixty FH+ and 60 FH- participants matched on age, sex, and education level were included. They completed tasks assessing executive functions (Stroop, Trail Making Test) and affective and cognitive theory of mind (Movie for the Assessment of Social Cognition). They also completed self-report questionnaires measuring impulsivity, alexithymia, and empathy. Single-case analyses assessed the proportion of FH+ participants with difficulties in executive function and/or theory of mind. RESULTS: FH+ individuals exhibited difficulties in response inhibition and made more errors during theory of mind processing, indicating an absence of mental state representation, compared with FH- individuals. In the FH+ sample, 53.33% had executive function and/or theory of mind difficulties. Those with lower theory of mind scores reported higher alexithymia and lower empathy on self-report measures. CONCLUSIONS: FH+ individuals display heterogeneous executive function and theory of mind abilities. Given that they mostly occur independently of one another, executive function and theory of mind difficulties may be distinct vulnerability markers in AUD.

Neural activations during cognitive and affective theory of mind processing in healthy adults with a family history of alcohol use disorder.

BACKGROUND: Social cognition impairments are a common feature of alcohol use disorders (AUD). However, it remains unclear whether these impairments are solely the consequence of chronic alcohol consumption or whether they could be a marker of vulnerability. METHODS: The present study implemented a family history approach to address this question for a key process of social cognition: theory of mind (ToM). Thirty healthy adults with a family history of AUD (FH+) and 30 healthy adults with a negative family history of AUD (FH-), matched for age, sex, and education level, underwent an fMRI cartoon-vignette paradigm assessing cognitive and affective ToM. Participants also completed questionnaires evaluating anxiety, depressive symptoms, childhood trauma, and alexithymia. RESULTS: Results indicated that FH+ individuals differed from FH- individuals on affective but not cognitive ToM processing, at both the behavioral and neural levels. At the behavioral level, the FH+ group had lower response accuracy for affective ToM compared with the FH- group. At the neural level, the FH+ group had higher brain activations in the left insula and inferior frontal cortex during affective ToM processing. These activations remained significant when controlling for depressive symptoms, anxiety, and childhood trauma. CONCLUSIONS: These findings highlight difficulties during affective ToM processing among first-degree relatives of AUD patients, supporting the idea that some of the impairments exhibited by these patients may already be present before the onset of AUD and may be considered a marker of vulnerability.

Differential semantic processing in patients with schizophrenia versus bipolar disorder: an N400 study.

OBJECTIVE: Both bipolar disorder (BD) and schizophrenia (SZ) are associated with language and thought symptoms that probably reflect a semantic memory-related impairment. We conducted a preliminary study to explore the nature of semantic processing in these disorders, using event-related potentials (ERPs). METHODS: Twelve patients with BD, 10 patients with SZ and a matched group of 21 healthy controls (HC) underwent EEG recording while they heard sentences containing homophones or control words and performed a semantic ambiguity resolution task on congruent or incongruent targets. RESULTS: Mean N400 amplitude differed between groups for homophones. Patients with SZ made more resolution errors than HC and exhibited a greater N400 congruity effect in ambiguous conditions than BD. In BD, the opposite N400 congruity effect was observed in ambiguous conditions. CONCLUSION: Results indicated differences in semantic processing between BD and SZ. Further studies with larger populations are needed in order to develop neurophysiological markers of these disorders. SIGNIFICANT OUTCOMES: In ambiguous conditions, patients with SZ exhibited a greater N400 difference between congruent and incongruent conditions than patients with BD.In ambiguous conditions, patients with SZ exhibited greater N400 amplitude in incongruent conditions than in congruent ones, whereas patients with BD exhibited the opposite N400 congruity effect.Ambiguity resolution results suggest that patients with SZ have difficulty considering the context, while patients with BD overactivate the dominant meaning of homophones and have difficulty inhibiting it.

[Is the orientation of patients suffering from depressive disorder to the psychiatric emergencies by a general practitioner associated with the decision to hospitalize?] / L'orientation des patients souffrant d'un trouble dépressif aux urgences psychiatriques par le médecin traitant est-elle associée à la décision d'hospitalisation : étude observationnelle.

INTRODUCTION: Depressive disorders affect nearly 350 million people worldwide and are the world's leading cause of incapacity. Patients who are depressed preferentially approach their general practitioner (GP), who is their first point of contact, in 50-60% of cases. The aim of our study is to assess whether the orientation of patients suffering from anxiety-depressive disorder towards a GP in a general emergency is a factor associated with hospitalization when compared to patients who present themselves spontaneously for the same disorders. Our secondary objective was to identify the different profiles of patients who were hospitalized for these disorders as an emergency. MATERIALS AND METHODS: We conducted a cross-sectional study for the year 2015, targeting patients who presented as general emergencies at the centre hospitalier de Troyes and who had received a psychiatric diagnosis in the context of an anxiety or depressive disorder. RESULTS: Five hundred and twenty four patients were included. A univariate analysis showed that referral by the attending physician was associated with hospitalization in 57.9% vs. 42.1% cases (P=0.007), at an odds ratio at 1.98 [1.22-3.21] by multivariate analysis. Analysis by ascending hierarchical classification made it possible to identify 3 profiles for hospitalized patients: 1) patients with a known psychiatric history, a history of past or current follow-ups directed by a psychiatrist, with at least one psychotropic treatment, the presence of psychotic symptoms and a low suicidal risk compared to the rest of the study population; 2) patients without a psychiatric history, or a history of past or ongoing psychiatric follow-up and the absence of ongoing psychotropic treatment. These patients were referred by a GP (67% vs 23%, P<0.001) and their suicidal risk was higher (59% vs 26%, P<0.001); 3) patients about whom the psychiatrist had little information at the time of the emergency consultation. CONCLUSIONS: The relevance of GPs in orientation towards emergencies pleads in favor of a partnership and an early exchange between treating physicians and the psychiatrists.

Factors associated with deaths from suicide in a French nationwide HIV-infected cohort.

OBJECTIVES: People living with HIV (PLHIV) are at a higher risk of dying by suicide than the general population. Epidemiological data regarding determinants of suicide in PLHIV are scarce. The aim of this study was thus to study demographic, socio-economic, psychiatric history and immunovirological characteristics associated with death from suicide in the French multicenter Dat'AIDS cohort, from January 2000 to July 2013. METHODS: This was a nested case-control study. All deceased PLHIV during the study period who died by suicide and whose medical files could be checked were included as cases. Controls were selected using incidence density sampling. For each case, up to four controls were selected among all actively followed PLHIV at the index date (date of death of cases). Controls were matched for time from HIV diagnosis (5-year periods) and clinical centre. RESULTS: Seventy cases and 279 controls were included in the study. By multivariable analysis, the factors significantly associated with death from suicide were: not having children, active or substituted drug consumption, alcohol intake > 20 g/day or history of alcohol abuse, history of depressive disorder and/or of attempted suicide, and psychotropic drug intake. Conversely, age, gender, country of birth, positive HCV serology and HIV-related factors, such as AIDS status, use of combination antiretroviral therapy (cART), nadir and current CD4 counts and HIV viral load, were not significantly associated with the risk of death from suicide. CONCLUSIONS: In the cART era, HIV-related factors are not associated with a higher risk of suicide mortality. Suicide prevention measures should target PLHIV with the psychological morbidities observed in our cohort.

Setup for high-temperature surface Brillouin light scattering: Application to opaque thin films and coatings.

A setup combining surface Brillouin light scattering with a high-temperature chamber has been developed. The temperature of the sample is controlled with a Bühler HDK chamber for optical measurements (maximum temperature of 1600 °C), in controlled atmospheres or high vacuum (10-6 mbar). This setup allows the study of sound velocity of surface acoustic waves and of the elastic constants of opaque thin films and coatings in situ as a function of temperature from surface Brillouin light scattering, by analyzing the backscattered light from the sample at a fixed angle of incidence. In this paper, we will demonstrate the applications of this setup for metallic glass thin films devitrification study and evaluation of high temperature elastic properties of hard nitride coatings. This kind of study using surface acoustic waves is rare, in contrast to those made on transparent bulk materials.

[How may practitioners interpret the results of clinical trials?] / Comment le praticien doit-il interpréter les résultats d'un essai clinique ?

To correctly interpret the results of a randomised controlled trial (RCT), practitioners have to spot bias and other potential problems present in the trial. Internal as well as external validity of the trial are linked to the presence of such bias. The internal validity is ensured by a clear definition of the objectives of the trial. The number of patients to be included in the trial is calculated on the basis of the main objective of the trial and more precisely on the basis of the primary endpoint selected to assess the efficacy of treatment. This is the best way to ensure that the statistical significance of the result may have a clinical relevance. Internal validity depends also on the process of patients selection, the methods used to ensure comparability of groups and treatments, the criteria employed to assess efficacy, and the methods for the analysis of data. External validity refers to subjects that have been excluded from the trial, limitations of RCTs, as well as the coherence and clinical relevance of the trial. Internal validity has to be fueled by external validity.

[Evaluating the efficacy of long acting injectable antipsychotics through clinical trials]. / Comment évaluer l'efficacité d'un antipsychotique d'action prolongée au moyen d'un essai clinique ?

After reminding the various phases of the development of molecules, this article will state the stages of commercialisation of treatments, underlining the FDA (Food and Drug Administration) and the EMA (European Medicine Agency) requirements. Like all the other treatments available in Europe and in the United States, the long acting injectable antipsychotics (LAI) have to prove their efficacy compared to placebo and their non-inferiority compared to a treatment of reference, usually the same molecule in the oral form. These criteria of efficacy have evolved over time. If initially classical criteria of symptomatic intensity (score on scale PANSS) were considered, criteria more adequate from a clinical perspective, such as relapse, but also related to functioning, quality of life and, more recently, costs-effectiveness have appeared. This evolution is probably due to several factors: vision on mental illness, progress in patient's rights and aspirations, but also the pregnant place of health costs recently taken in the evaluation of treatments. These modifications are also based on the indications of L.A.I., i.e. stabilized patients for whom the challenge is rehabilitation care more than the control of symptoms.

[What role for paraclinical investigations within clinical trials conducted in psychiatric patients?] / Quel est le rôle des tests et examens complémentaires dans un essai clinique en psychiatrie ?

As in the usual care of patients, paraclinical investigations have today only a very modest role in clinical trials in psychiatry, mainly to complete the pre-therapeutical assessments prior to inclusion of subjects or to monitor treatment tolerance. Yet, the accumulation of data in neurosciences suggests the next emergence of biomarkers, whose interest is that they are closely associated to the biological disturbances underlying psychiatric illnesses, and that they are accessible by means of technological tools such as imaging devices. These tools allow to explore the effects on brain of psychotropic medications, such as antidepressants, antipsychotics, or mood stabilizers, in relation to their therapeutic action. The obtained results allow to consider the use of such biomarkers in clinical trials in addition to more conventional approaches. In particular, they could be used as targets to measure brain response to treatment in association with clinical response, to predict a therapeutic response from the neurofunctional characteristics of patients, or to establish the safety profile of drugs on the nervous system. The use of such biomarkers in clinical trials would help to better define the explored populations and their characteristics, as well as the variables to assess, and to better measure the impact of the treatments and their potential harmful effects on the nervous system.

[Modeling for clinical trial in psychiatry: rationale, benefits and limitations]. / Quelle place pour la modélisation dans les essais cliniques en psychiatrie ?

Drug development of new compounds implies to define the dosage as well as the conditions of their use (indication, treatment duration, drug interactions, warnings …). This information requires the identification of the time course response. The decisions made during the clinical phases are now based on mathematical models. These models are continuously described and improved during all phases of the drug development using data collected in healthy volunteers and patients. Their objectives are to describe the most precisely, the link between the compound characteristics (pharmacology), the patient demographics and the effects. Further, the natural history of the disease, the placebo effect and the probability of dropping out will be integrated into the model to optimize the evaluation of the compound. These technical improvements are not only statistical, in the sense that they allow a better understanding of the advantages and pitfalls of the new drug. This article presents these methods used in psychiatry and which will become the new standard of drug evaluation.

[Negative symptoms and cerebral imaging]. / Symptômes négatifs et imagerie cérébrale.

A number of neuroanatomical and neurofonctional abnormalities have been evidenced by cerebral imaging studies in patients suffering from schizophrenia. Nevertheless, those specifically associated with the negative symptoms of this disease are still insufficiently known. This work is a review of selected studies that have assessed the brain correlates of negative symptoms in schizophrenia. Approaches using structural imaging have highlighted reduction of gray matter density or cortical thickness associated with negative symptoms, which is rather sparsely distributed within the frontal and temporal regions, localized nevertheless more particularly in the frontal medial and orbitofrontal areas, as well as the amygdalo-hippocampic complex. These deficits are concurrent with a loss of integrity of the principal paths of white matter tracts between frontal and limbic regions. On the other hand, neurofonctional abnormalities associated with negative symptoms involve especially the frontal areas and limbic striatum. A disturbed functioning within the fronto-striatal loops, related to a striatal dopaminergic deficit, may represent a potential explanatory hypothesis of the negative symptoms of schizophrenia, as suggested by studies using Positron Emission Tomography on this topic or neuroimaging studies on the effects of antipsychotics. A better identification of the cerebral abnormalities associated with the negative dimension of schizophrenia, with regard to the lateralization of these abnormalities or to their changes during the course of the disease, could offer new therapeutic modalities for the treatment of this dimension which, until now, remains few responsive to conventional pharmacological treatments.

[Negative symptoms in schizophrenia: psychotherapeutic approaches]. / Symptômes négatifs de la schizophrénie: approches psychothérapeutiques.

Although negative symptoms are recognized as a central feature of schizophrenia, their definition as well as phenomenology have long been a vexing issue. During these last years, a major progress has been made with the delineation of two underlying subdomains of negative symptoms: diminished expression and anhedonia-avolition-apathy. As current guidelines are not always in accord on the efficacy of treatments on negative symptoms, it may be tempting to re-interpret the findings of clinical trials by looking at the effects of treatments on these two subdomains. This could concern both psychotropic treatments and psychotherapeutic interventions. Furthermore, neuroimaging as well as emotional response studies have permitted to better understand the mechanism which could be at the root of diminished expression and anhedonia in schizophrenia. On this basis, new psychotherapeutic methods have been devised which, by specifically targeting these two subdomains, are likely to be more efficient on negative symptoms. Further research is warranted to test their efficacy in randomized controlled trials.

[Affective disorders and anxiety comorbidities]. / Troubles affectifs et comorbidités anxieuses.

Anxiety disorders are frequently associated with affective disorders and represent one of the most important comorbidity in patients with bipolar disorder. Their prevalence is high, whatever the anxiety disorder, with nevertheless higher rates for generalized anxiety disorder (18.4 to 19.9% for lifetime prevalence). Such high frequencies raise essential questions about the link between these groups of disorders, and if it is necessary to distinguish them or to consider their phenomenological overlap as resulting of common disease processes. The existence of comorbid anxiety disorder in bipolar disorder significantly worsens its evolution, inducing more severe episodes, shortening remission periods, favoring relapses and suicide as well as substance use, and reducing quality of life in comparison to bipolar patients without anxiety. The mechanisms that link the anxious symptomatology to mood dysregulation are still poorly understood, although it is likely that genetic factors play a key role, combined with other factors of vulnerability, including those involved in coping strategy to address ongoing distress. Despite the high impact of anxiety on the severity of bipolar disorder course, few randomized controlled trials examined treatments of comorbid anxiety disorders and only recent recommendations offer useful therapeutic perspectives. In this context, it seems necessary to better understand the features associated with the occurence of anxiety disorders in affective disorders, in order to better identify the mechanisms underlying such comorbidity, together with working to develop therapeutics that efficiently target them.

[Co-occuring mood and substance use disorders]. / Troubles affectifs et comorbidités addictives en dehors de l'alcool.

Mood and substance use disorders commonly co-occur, yet there is little evidence-based research to guide the pharmacologic management of these comorbid disorders. The authors review the existing empirical findings including current clinical pharmacotherapy practices for treating co-occurring mood and substance use disorders and call into question current clinical practices. The specific mood disorders reviewed are bipolar and major depressive disorders (either one co-occurring with a substance use disorder). The authors also highlight knowledge gaps that may serve as a basis for future research. Findings from the relatively small amount of available data indicate that pharmacotherapy for managing mood symptoms might be effective in patients with substance dependence, although results have not been consistent across all studies. In most studies, medications for managing mood symptoms did not appear to have an impact on the substance use disorder. Research has only begun to address optimal pharmacologic management of co-occurring disorders. In addition, current clinical treatment for drug dependence often exclude new pharmacotherapies approved by the French Haute Autorité de Santé for treating certain types of addiction. With new data becoming available, it appears that we need to revisit current practice in the pharmacological management of co-occurring mood and substance use disorders.

[Neurocognitive fuctioning in pure mania and mixed mania]. / Fonctionnement neurocognitif dans la manie pure et la manie mixte.

Neurocognitive dysfunction is increasingly recognized as a prominent feature of bipolar disorder. Cognitive function seems to be impaired across different states of bipolar illness. Nervertheless, research that studies neuropsychological functioning in acute phases is scarce. Acutely ill patients have shown dysfunctions in several cognitive areas. We reviewed the literature on neuropsychological studies of acute phases to highlight neurocognitive deficits in mixed and pure mania. The results show dysfunctions in sustained attention that are significantly more important in mixed mania rather than in pure mania. Impulsive pattern of responding seems to characterize pure manic state. We also found impairments in processing speed, verbal and spatial learning/memory and executive functions, including cognitive flexibility, inhibitory control, conceptual reasoning, planning and problem solving. Disturbance in executive functioning seems to be more important in pure mania rather than mixed mania.

[Mixed states and neuroimaging]. / États mixtes et neuroimagerie.

Despite the growing number of neuroimaging studies in bipolar disorder over the past years, the brain regions involved in mood dysregulation in this disease are still poorly understood. If some neurofunctional abnormalities seem to be independent of mood state, others were preferentially associated with mania or depression, involving the amygdala and other limbic regions as well as ventral frontal regions, with a likely hemispheric lateralization of these abnormalities according to the thymic state that was examined. Very few imaging studies became interested in bipolar patients in a mixed state, making it harder to connect brain malfunction to a given mood state. However, data obtained so far support the hypothesis of a lateralization of brain abnormalities in relation to bipolar symptomatology, suggesting that neurofonctional abnormalities preferentially located in the right ventral frontal and limbic areas may underlie the depressive component, associated with abnormalities of the left similar regions for the manic component. Identification of brain dysfunctions that may explain the emergence of mixed symptoms will likely provide useful information to better understand the respective roles of each hemisphere in the pathophysiology of bipolar disorder.

[Pathophysiological models of mixed states]. / Modèles physiopathologiques des états mixtes.

Mixed states are complex manifestations of bipolar disorders. Pathophysiology of mixed states remains unclear. Several models have been proposed to understand the mechanisms underlying these mood states. These models describe mixed state either as a combinaison of depression and mania, as well as a transition between mania and depression, or mixed state as a severe type of depression or mania. Pathophysiological hypotheses involve temperaments or some personality disorders, psychiatric comorbidities as well as substance use disorders, or thyroid dysfunction. However, the formal demonstration of any specific genetic vulnerability to mixed state has not yet been provided.

[Antimanic treatments in bipolar mixed states]. / Traitements anti- maniaques dans les états mixtes.

INTRODUCTION: Mixed states present nosologic and diagnostic challenges with a relative paucity of evidence to guide treatment. Mixed bipolar states are difficult to treat and are associated with a high neuropsychiatric morbidity, a high risk of suicide and a poor outcome. In DSM- 5, the definition of mixed episode has been removed (in DSM- IV TR: "juxtaposed full manic and depressive episodes"). Mixed symptoms are captured under a broader concept called "mixed features" that is applied to mania and depression. The classification of mixed states as defined in DSM- 5 is less restrictive than in DSM- IV TR and challenges us at methodological and therapeutic levels. OBJECTIVE: The aim of this paper was to conduct an overview of the literature to ascertain the efficacy of pharmacotherapy of mixed states. METHOD: A systematic review of the literature was conducted using PubMed. RESULTS: Manic symptoms of mixed episodes seem to show a good response to second generation antipsychotics and to divalproate. There is no evidence of differential efficacy for second generation of antipsychotics (SGAs). Lithium and carbamazepine may be effective in mixed states in monotherapy and perhaps benefit in combination with SGAs as second line. Combination pharmacological treatment of SGAs and moodstabilizers are common in mixed states. This pattern has the best literature evidence. CONCLUSIONS: There is a few evidence to help us to choose the right treatment for patients with mixed state. In light with the DSM 5, more drugs specifically designed to treat mixed state are needed.

[Treatment of depressive mixed states]. / Le traitement des dépressions mixtes.

Mixed states are a frequent mood state characterized by the mixture of manic and depressive symptoms. Their clinical description has been studied for centuries but has known a renewal of interest recently. Several authors intend to redefine its diagnostic criteria to develop an appropriate therapeutic strategy. Current recommendations suggest to treat mixed depression as a mixed state whatever the dominant polarity is, and therefore according to the rules of therapeutic management of the manic state. Mood stabilizers and antipsychotic medications are indicated and have proven their effectiveness. Lithium, which was considered controversial, now appears to have some therapeutic value, especially in the prevention of suicidal behavior. The depressive component of mixed states, even pronounced, should not be an argument for a prescription of antidepressants, at the risk of aggravating clinical components such as irritability and impulsivity and increasing the danger of suicide attempt. Furthermore, electroconvulsivetherapy represents a real alternative ; psychotherapies have their place in relapse prevention and psychoeducation, but not during acute phases. Finally, an accurate assessment and appropriate management of suicide risk should be a constant concern for the clinicians.