[Early intervention in bipolar affective disorders: Why, when and how]. / Intervenir précocement dans les stades débutants du trouble bipolaire : pourquoi, quand et comment.

OBJECTIVES: Bipolar disorder (BD) is a chronic and severe psychiatric disease. There are often significant delays prior to diagnosis, and only 30 to 40 % of patients will experience complete remission. Since BD occurs most often at a young age, the disorder can seriously obstruct future socio-professional development and integration. Vulnerability-stress model of BD is considered to be the result of an interaction between vulnerability genes and environmental risk factors, which leads to the onset of the disorder most often in late adolescence or early adulthood. The clinical "staging" model of BD situates the subject in a clinical continuum of varying degrees of severity (at-risk status, first episode, full-blown BD). Given the demonstrated effectiveness of early intervention in the early stages of psychotic disorder, we posit that early intervention for early stages of BD (i.e. at-risk status and first episode mania or hypomania) would reduce the duration of untreated illness and optimize the chances of therapeutic response and recovery. METHODS: We conducted a narrative review of the literature to gather updated data on: (1) features of early stages: risk factors, at-risk symptoms, clinical specificities of the first manic episode; (2) early screening: targeted populations and psychometric tools; (3) early treatment: settings and therapeutic approaches for the early stages of BD. RESULTS: (1) Features of early stages: among genetic risk factors, we highlighted the diagnosis of BD in relatives and affective temperament including as cyclothymic, depressive, anxious and dysphoric. Regarding prenatal environmental risk, we identified peripartum factors such as maternal stress, smoking and viral infections, prematurity and cesarean delivery. Later in the neurodevelopmental course, stressful events and child psychiatric disorders are recognized as increasing the risk of developing BD in adolescence. At-risk symptoms could be classified as "distal" with early but aspecific expressions including anxiety, depression, sleep disturbance, decreased cognitive performance, and more specific "proximal" symptoms which correspond to subsyndromic hypomanic symptoms that increase in intensity as the first episode of BD approaches. Specific clinical expressions have been described to assess the risk of BD in individuals with depression. Irritability, mixed and psychotic features are often observed in the first manic episode. (2) Early screening: some individuals with higher risk need special attention for screening, such as children of people with BD. Indeed, it is shown that children with at least one parent with BD have around 50 % risk of developing BD during adolescence or early adulthood. Groups of individuals presenting other risk factors, experiencing an early stage of psychosis or depressive disorders should also be considered as targeted populations for BD screening. Three questionnaires have been validated to screen for the presence of at-risk symptoms of BD: the Hypomanic Personality Scale, the Child Behavior Checklist-Paediatric Bipolar Disorder, and the General Behavior Inventory. In parallel, ultra-high risk criteria for bipolar affective disorder ("bipolar at-risk") distinguishing three categories of at-risk states for BD have been developed. (3) Early treatment: clinical overlap between first psychotic and manic episode and the various trajectories of the at-risk status have led early intervention services (EIS) for psychosis to reach out for people with an early stage of BD. EIS offers complete biopsychosocial evaluations involving a psychiatric examination, semi-structured interviews, neuropsychological assessments and complementary biological and neuroimaging investigations. Key components of EIS are a youth-friendly approach, specialized and intensive care and client-centered case management model. Pharmaceutical treatments for at-risk individuals are essentially symptomatic, while guidelines recommend the use of a non-antipsychotic mood stabilizer as first-line monotherapy for the first manic or hypomanic episode. Non-pharmacological approaches including psychoeducation, psychotherapy and rehabilitation have proven efficacy and should be considered for both at-risk and first episode of BD. CONCLUSIONS: EIS for psychosis might consider developing and implementing screening and treatment approaches for individuals experiencing an early stage of BD. Several opportunities for progress on early intervention in the early stages of BD can be drawn. Training first-line practitioners to identify at-risk subjects would be relevant to optimize screening of this population. Biomarkers including functional and structural imaging measures of specific cortical regions and inflammation proteins including IL-6 rates constitute promising leads for predicting the risk of transition to full-blown BD. From a therapeutic perspective, the use of neuroprotective agents such as folic acid has shown particularly encouraging results in delaying the emergence of BD. Large-scale studies and long-term follow-up are still needed to achieve consensus in the use of screening and treatment tools. The development of specific recommendations for the early stages of BD is warranted.

[Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic]. / Informations relatives aux psychotropes et à leurs adaptations éventuelles pour les patients souffrant de troubles psychiques en France pendant l'épidémie à SARS-CoV-2.

The 2019-20 coronavirus pandemic (SARS-CoV-2; severe acute respiratory syndrome coronavirus 2) has dramatic consequences on populations in terms of morbidity and mortality and in social terms, the general confinement of almost half of the world's population being a situation unprecedented in history, which is difficult today to measure the impact at the individual and collective levels. More specifically, it affects people with various risk factors, which are more frequent in patients suffering from psychiatric disorders. Psychiatrists need to know: (i) how to identify, the risks associated with the prescription of psychotropic drugs and which can prove to be counterproductive in their association with COVID-19 (coronavirus disease 2019), (ii) how to assess in terms of benefit/risk ratio, the implication of any hasty and brutal modification on psychotropic drugs that can induce confusion for a differential diagnosis with the evolution of COVID-19. We carried out a review of the literature aimed at assessing the specific benefit/risk ratio of psychotropic treatments in patients suffering from COVID-19. Clinically, symptoms suggestive of COVID-19 (fever, cough, dyspnea, digestive signs) can be caused by various psychotropic drugs and require vigilance to avoid false negatives and false positives. In infected patients, psychotropic drugs should be used with caution, especially in the elderly, considering the pulmonary risk. Lithium and Clozapine, which are the reference drugs in bipolar disorder and resistant schizophrenia, warrant specific attention. For these two treatments the possibility of a reduction in the dosage - in case of minimal infectious signs and in a situation, which does not allow rapid control - should ideally be considered taking into account the clinical response (even biological; plasma concentrations) observed in the face of previous dose reductions. Tobacco is well identified for its effects as an inducer of CYP1A2 enzyme. In a COVID+ patient, the consequences of an abrupt cessation of smoking, particularly related with the appearance of respiratory symptoms (cough, dyspnea), must therefore be anticipated for patients receiving psychotropics metabolized by CYP1A2. Plasma concentrations of these drugs are expected to decrease and can be related to an increase risk of relapse. The symptomatic treatments used in COVID-19 have frequent interactions with the most used psychotropics. If there is no curative treatment for infection to SARS-CoV-2, the interactions of the various molecules currently tested with several classes of psychotropic drugs (antidepressants, antipsychotics) are important to consider because of the risk of changes in cardiac conduction. Specific knowledge on COVID-19 remains poor today, but we must recommend rigor in this context in the use of psychotropic drugs, to avoid adding, in patients suffering from psychiatric disorders, potentially vulnerable in the epidemic context, an iatrogenic risk or loss of efficiency.

[Decision-making and schizophrenia]. / Prise de décision et schizophrénie.

Abnormalities involving the prefrontal cortex (PFC) have long been postulated to underpin the pathophysiology of schizophrenia. Investigations of PFC integrity have focused mainly on the dorsolateral PFC (DLPFC) and abnormalities in this region have been extensively documented. However, defects in schizophrenia may extend to other prefrontal regions, including the ventromedial PFC (VMPFC), and evidence of VMPFC abnormalities comes from neuropathological, structural and functional studies. Patients with acquired brain injury to the VMPFC display profound disruption of social behaviour and poor judgment in their personal lives. The Iowa Gambling Task (IGT) was developed to assess decision-making in these neurological cases : it presents a series of 100 choices from four card decks that differ in the distribution of rewarding and punishing outcomes. Whilst healthy volunteers gradually develop a preference for the two "safe" decks over the course of the task, patients with VMPFC lesions maintain a preference for the two "risky" decks which are associated with high reinforcement in the short term, but significant long-term debt. Interestingly, damage to VMPFC may cause both poor performance on the IGT and lack of insight concerning the acquired personality modification. Recently, our group reported a trait-related decisionmaking impairment in the three phases of bipolar disorder. In a PET study, VMPFC dysfunction was shown in bipolar manic patients impaired on a decision-making task and an association between decision-making cognition and lack of insight was described in mania. A quantitative association between grey matter volume of VMPFC and memory impairment was previously reported in schizophrenia. Research suggests that lack of insight is a prevalent feature in schizophrenia patients, like auditory hallucinations, paranoid or bizarre delusions, and disorganized speech and thinking. Because schizophrenia is associated with significant social or occupational dysfunction, previous research assessed decision-making function but indicates conflicting results. Thirteen studies have reported impaired IGT performance in patients with schizophrenia and, in seven reports, no significant differences in IGT performance between patient and healthy control groups were found. Those discrepancies may relate to multiple factors. First, most of the studies included small sample size and negative findings may be due to the large variance of net scores. Second, as suggested by Rodríguez-Sánchez et al., there is a wide disparity in performance by control subjects across studies. Third, intelligence quotient (IQ) score and level of education may be correlated with IGT performance, which may explain IGT performance differences in studies that did not control for educational or IQ score. Fourth, only two studies have systematically controlled for substance use disorder, a potential confounder. Fifth, only two studies assessed the impact of antipsychotic (AP) class on performance. Sixth, to our knowledge, no study assessed the impact of AP dosage on decision-making ability, while AP dose-reduction and dopamine increase, might lead to improvements, in cognitive functions in schizophrenia and in IGT performance in bipolar disorder, respectively. Finally, discrepancies between studies may be related to the heterogeneity of diagnostic groups. Two of the negative studies included schizophrenia and schizoaffective disorder while positive studies have generally included only patients with schizophrenia. Nevertheless, some studies that included only patients with schizophrenia failed to find differences between groups. Thus, further research should assess decision-making in schizophrenia by testing a large group of patients with homogeneity of diagnostic, in comparison with a large group of control subjects. Authors should control for IQ or level of education, substance use disorder and smoking status. While it is now accepted that DLPFC defects in schizophrenia may extend to VMPFC, future investigations should test for an association between memory, insight ability and IGT performance and assess the impact of antipsychotic dosage upon performance.

[Gene-environment interactions in affective disorders]. / Interaction gènes-environnement dans les troubles affectifs.

Kindling and behavioural sensitization were probably the first among the animal models of affective disorders, to suggest that genes-environment interactions were likely to be involved in the pathophysiology of these disorders. Cross-sensitization among stressors, drugs of abuse and illness episodes was deemed to be supported by the induction of a series of transcription factors, such as the proto-oncogene c-fos that subsequently alter gene expression by binding at DNA sites and inducing mRNAs for substances that may exert effects over long time periods. This was an anticipation of epigenetics which is currently defined as a functional modification to the DNA that does not involve an alteration of sequence. Epigenetic modifications are most commonly regulated by DNA methylation and histone acetylation which are usually associated with the silencing and activation of gene transcription, respectively. In animal models, it was shown that parents can actively remodel epigenetic marks, and thus affect patterns of gene expression in the offspring, whereas environmental adversity decreases parental investment in the offspring and thus alters phenotypic development. In line with this, some laboratories have sought to identify changes in gene expression in post mortem brain samples of humans with affective disorders. Finally, gene-environment interactions have been directly studied, both in animals and humans, by testing how a functional polymorphism in candidate genes would moderate the influence of stressful life events on behavioural expression. Interesting results have been found and replicated for unipolar depression, however date are scarce for bipolar disorder. Findings from these studies allow the building of more sophisticated models for unipolar and bipolar genetics.