Functioning and neurocognition in very early and early-life onset bipolar disorders: the moderating role of bipolar disorder type.

Defining homogeneous subgroups of bipolar disorder (BD) is a major goal in personalized psychiatry and research. According to the neurodevelopmental theory, age at onset may be a key variable. As potential trait markers of neurodevelopment, cognitive and functional impairment should be greater in the early form of the disease, particularly type 1 BD (BD I). The age at onset was assessed in a multicenter, observational sample of 4190 outpatients with BD. We used a battery of neuropsychological tests to assess six domains of cognition. Functioning was measured using the Functioning Assessment Short Test (FAST). We studied the potential moderation of the type of BD on the associations between the age at onset and cognitive and functioning in a subsample of 2072 euthymic participants, controlling for potential clinical and socio-demographic covariates. Multivariable analyses showed cognition to not be impaired in individuals with early (21-30 years) and very early-life (before 14 years) onset of BD. Functioning was equivalent between individuals with early and midlife-onset of BD II and NOS but better for individuals with early onset of BD I. In contrast, functioning was not worse in individuals with very early-onset BD I but worse in those with very early-onset BD II and NOS. Early-life onset BDs were not characterized by poorer cognition and functioning. Our results do not support the neurodevelopmental view that a worse cognitive prognosis characterizes early-life onset BD. This study suggests that functional remediation may be prioritized for individuals with midlife-onset BD I and very early life onset BD 2 and NOS.

Incidence and predictors of metabolic syndrome onset in individuals with bipolar disorders: A longitudinal study from the FACE-BD cohort.

INTRODUCTION: Metabolic syndrome (MetS) is a cluster of components including abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. MetS is highly prevalent in individuals with bipolar disorders (BD) with an estimated global rate of 32.6%. Longitudinal data on incident MetS in BD are scarce and based on small sample size. The objectives of this study were to estimate the incidence of MetS in a large longitudinal cohort of 1521 individuals with BD and to identify clinical and biological predictors of incident MetS. METHODS: Participants were recruited from the FondaMental Advanced Center of Expertise for Bipolar Disorder (FACE-BD) cohort and followed-up for 3 years. MetS was defined according to the International Diabetes Federation criteria. Individuals without MetS at baseline but with MetS during follow-up were considered as having incident MetS. A logistic regression model was performed to estimate the adjusted odds ratio and its corresponding 95% confidence interval (CI) for an association between each factor and incident MetS during follow-up. We applied inverse probability-of-censoring weighting method to minimize selection bias due to loss during follow-up. RESULTS: Among individuals without MetS at baseline (n = 1521), 19.3% developed MetS during follow-up. Multivariable analyses showed that incident MetS during follow-up was significantly associated with male sex (OR = 2.2, 95% CI = 1.7-3.0, p < 0.0001), older age (OR = 2.14, 95% CI = 1.40-3.25, p = 0.0004), presence of a mood recurrence during follow-up (OR = 1.91, 95% CI = 1.22-3.00, p = 0.0049), prolonged exposure to second-generation antipsychotics (OR = 1.56, 95% CI = 0.99, 2.45, p = 0.0534), smoking status at baseline (OR = 1.30, 95% CI = 1.00-1.68), lifetime alcohol use disorders (OR = 1.33, 95% CI = 0.98-1.79), and baseline sleep disturbances (OR = 1.04, 95% CI = 1.00-1.08), independently of the associations observed for baseline MetS components. CONCLUSION: We observed a high incidence of MetS during a 3 years follow-up (19.3%) in individuals with BD. Identification of predictive factors should help the development of early interventions to prevent or treat early MetS.

Comparative analysis of anticholinergic burden scales to explain iatrogenic cognitive impairment and self-reported side effects in the euthymic phase of bipolar disorders: Results from the FACE-BD cohort.

Bipolar disorders (BD) are characterized by cognitive impairment during the euthymic phase, to which treatments can contribute. The anticholinergic properties of medications, i.e., the ability of a treatment to inhibit cholinergic receptors, are associated with cognitive impairment in elderly patients and people with schizophrenia but this association has not been well characterized in individuals with remitted BD. Moreover, the validity of only one anticholinergic burden scale designed to assess the anticholinergic load of medications has been tested in BD. In a literature review, we identified 31 existing scales. We first measured the associations between 27 out of the 31 scales and objective cognitive impairment in bivariable regressions. We then adjusted the bivariable models with covariates: the scales significantly associated with cognitive impairment in bivariable and multiple logistic regressions were defined as having good concurrent validity to assess cognitive impairment. In a sample of 2,031 individuals with euthymic BD evaluated with a neuropsychological battery, two scales had good concurrent validity to assess cognitive impairment, whereas chlorpromazine equivalents, lorazepam equivalents, the number of antipsychotics, or the number of treatments had not. Finally, similar analyses with subjective anticholinergic side-effects as outcome variables reported 14 scales with good concurrent validity to assess self-reported peripheral anticholinergic side-effects and 13 to assess self-reported central anticholinergic side-effects. Thus, we identified valid scales to monitor the anticholinergic burden in BD, which may be useful in estimating iatrogenic cognitive impairment in studies investigating cognition in BD.

[French Expert advice on the management of valproate in childbearing and pregnant women with bipolar disorder]. / Avis d'experts français sur la prise en charge des femmes en âge de procréer et enceintes souffrant d'un trouble bipolaire traitées par valproate.

INTRODUCTION: The perinatal period is associated with high risk of relapses in women with untreated bipolar disorder (BD) and can have significant consequences on foetal and child development. Valproate is an effective mood stabilizer in BD but it is also the anticonvulsant associated to the highest risks of neurodevelopmental disorders and congenital malformations. The National Agency for the Safety of Medicines and Health Products (ANSM) changed the conditions of use and prescription of valproate in France in 2015. Its prescription is now contraindicated (i.e., not to be prescribed) in women able to have children unless alternative treatments are ineffective or not tolerated. Moreover, valproate could only be prescribed if the protocol of a specific pregnancy prevention program is followed. METHODS: A panel of experts from the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) provided consensus-based recommendations for switching and discontinuation of valproate in women with BD. The development of these recommendations consisted of an adaptation to French clinical practice based on a European expert opinion published in 2019. The experts discussed five real-world clinical situations in light of the scientific evidence and their clinical experience (a. Stable BD patient with valproate monotherapy who is planning pregnancy, b. Stable BD patient with valproate polytherapy who is planning pregnancy, c. Unstable BD patient with frequent relapses and valproate polytherapy who is planning pregnancy, d. Stable BD patient treated with valproate and unexpected pregnancy, e. Unstable BD patient treated with valproate and unexpected pregnancy) and developed, through several rounds of exchange drafts, a French version of clinical recommendations. RESULTS: First of all, some factors need to be considered for establishing personalized practical recommendations for a safe and effective switching or discontinuation of valproate in any clinical situations: planned pregnancy or unplanned pregnancy or current pregnancy, the existence or not of a pregnancy risk minimization program and a complete treatment history. Other factors that should be considered are the predominant polarity, the severity, the stability, the comorbidities associated with BD, the beliefs toward treatments, the family situation and the preference of the patient. The modalities for switching or discontinuation of valproate in women with BD were related to the clinical situation. First-line therapeutic alternatives such as lithium, lamotrigine, quetiapine, olanzapine or aripiprazole were preferred for patients suffering from a clinically stable BD considering pregnancy or pregnant. In patients suffering from clinically unstable BD, to reach stability was considered first. A shared decision-making should be systematically implemented and the patient must be fully informed of the risks related to an in-utero exposure to valproate, and the risks of the discontinuation/switch that is considered. CONCLUSION: Although the adaptation to French practice of the recommendations from the European expert opinion highlighted some differences in the criteria taken into consideration to guide the therapeutic decision, this expert advice will guide the clinician for switching and discontinuation of valproate in BD women able to have children or pregnant.

Childhood trauma increases vulnerability to attempt suicide in adulthood through avoidant attachment.

BACKGROUND: Childhood trauma and affective disorders are known risk factors for adult suicidal behavior. Studies have shown a mediating effect of insecure attachment on the effect of childhood trauma and suicidal behavior but so far it is not clear whether this effect is related to an attachment dimension (anxiety, avoidance). AIM: The present study sought to examine the mediating effect of attachment anxiety and avoidance on suicidal behavior. METHODS: We analyzed data on childhood trauma, attachment style, depression severity, presence of prior suicide attempts and current suicide ideation from 96 patients diagnosed with an affective disorder. Two mediation analyses were conducted to assess the effect of childhood trauma on 1) prior suicide attempts and 2) current suicidal ideation through its effect on attachment. RESULTS: We found that childhood trauma had a complete mediated effect on the presence of prior suicide attempts through its effect on avoidant attachment (a1b1 = 0.0120, 95%-CI [0.0031, 0.0276]). However, only emotional abuse had a direct influence on suicidal ideation (c' = 0.0273, p < 0.01) without any indirect effect of anxious or avoidant attachment. LIMITATIONS: Variables were not assessed in a prospective way and sample size was small. CONCLUSIONS: Our findings suggest that individuals with avoidant attachment and childhood trauma are likely to present a high suicide risk. Since avoidant attachment is associated with altered perceptions and eventual rejection of social support, we recommend to screen for attachment early and to engage patients in therapeutical approaches focusing on the client-therapist alliance.

Key findings on bipolar disorders from the longitudinal FondaMental Advanced Center of Expertise-Bipolar Disorder (FACE-BD) cohort.

BACKGROUND: The FACE-BD cohort is an observational cohort of individuals with bipolar disorders (BD) who benefited from a systematic evaluation with evidence-based treatment recommendations and who were followed-up every year for 3 years in France. The objectives were to describe the lifetime course of BD, associated psychiatric and somatic comorbidities, and cognition profile. This cohort aims to identify clinical/biological signatures of outcomes, trajectories of functioning and transition between clinical stages. This article summarizes 10 years of findings of the FACE-BD cohort. METHOD & RESULTS: We included 4422 individuals, all having a baseline assessment, among which 61.2% had at least one follow-up visit at either one, two or three years. A subsample of 1200 individuals had at least one biological sample (serum, plasma, DNA). Assessments include family history of psychiatric disorders, psychiatric diagnosis, current mood symptoms, functioning, hospitalizations, suicidal attempts, physical health, routine blood tests, treatment history, psychological dimensions, medico-economic data and a cognitive assessment. Studies from this cohort illustrate that individuals with BD display multiple coexistent psychiatric associated conditions including sleep disturbances, anxiety disorders, substance use disorders and suicide attempts as well as a high prevalence of metabolic syndrome. During follow-up, we observed a 55% reduction of the number of days of hospitalization and a significant improvement in functioning. CONCLUSIONS: The FACE-BD cohort provides a strong research infrastructure for clinical research in BD and has a unique position among international cohorts because of its comprehensive clinical assessment and sustainable funding from the French Ministry of Health.

Influence of childhood maltreatment on prevalence, onset, and persistence of psychiatric comorbidities and suicide attempts in bipolar disorders.

BACKGROUND: Psychiatric comorbidities and suicide attempts are highly prevalent in Bipolar Disorders (BD). We examined the associations between childhood maltreatment, psychiatric comorbidities, and suicide attempts, in terms of lifetime prevalence, sequence of onset, and current symptoms. METHODS: We assessed 3,047 individuals with BD for suicide attempts, anxiety disorders, substance use disorders, and eating disorders. Participants completed a self-report for the assessment of childhood maltreatment. Associations between childhood maltreatment and characteristics of comorbidities (lifetime prevalence, current symptoms, and age at onset) were examined using logistic regressions and network analyses. RESULTS: Psychiatric comorbidities were frequent with a mean number per individual of 1.23 (SD = 1.4). Most comorbidities occurred prior to the onset of BD. Participants who reported higher levels of childhood maltreatment had more frequent and multiple comorbidities, which were also more currently active at inclusion. Childhood maltreatment did not decrease the age of onset of comorbidities, but was associated with a faster accumulation of comorbidities prior to the onset of BD. Logistic regression and network analyses showed that emotional abuse and sexual abuse might play a prominent role in the lifetime prevalence of psychiatric comorbidities and suicide attempts. CONCLUSIONS: Childhood maltreatment was associated with suicide attempts, and with frequent, multiple, and persistent psychiatric comorbidities that accumulated more rapidly prior to the onset of BD. Hence, childhood maltreatment should be systematically assessed in individuals with BD, in particular when the course of the disorder is characterized by a high comorbid profile or by a high suicidality.

Clinical predictors of recurrences in bipolar disorders type 1 and 2: A FACE-BD longitudinal study.

OBJECTIVE: To examine which characteristics predict the time to a first mood recurrence at three years in Bipolar Disorder type I (BD-I) and type II (BD-II). METHODS: Individuals with BD were followed up to 3 years. Turbull's extension of the Kaplan-Meier analysis for interval-censored data was used to estimate the cumulative probability of recurrence over time. Separate models were performed according to BD subtype to determine which baseline factors were predictive of recurrences and were adjusted for age, gender and educational level. RESULTS: We included 630 individuals with BD-I and 505 with BD-II. The first recurrence of any polarity occurred earlier in BD-II (p = 0.03). The first depressive recurrence occurred earlier in BD-II (p < 0.0001), whereas the first (hypo)manic recurrence occurred earlier in BD-I (p = 0.0003). In BD-I, the clinical variables that were associated to the time to a first mood recurrence were depressive symptoms, lifetime rapid cycling, global activation and the number of psychotropic medications at baseline. In BD-II, the time to a first recurrence was associated with a younger age at onset of BD and a higher number of lifetime mood episodes. The Areas Under the Curve for both models were moderate. CONCLUSION: Predictors of recurrences showed few specificities to BD-I or BD-II. The ability to predict recurrences in BD based on socio-demographic and clinical variables remained too moderate for a transfer in daily practice. This study highlights the need for further studies that would include other types of predictors, such as molecular, cognitive or neuro-imaging ones, to achieve an accurate level of prediction of recurrences in BD.

Evolution and characteristics of the use of valproate in women of childbearing age with bipolar disorder: Results from the FACE-BD cohort.

BACKGROUND: Valproate is associated with teratogenic and neurodevelopmental effects. Several agencies have restricted the conditions of its prescription in bipolar disorders (BD). We aimed to assess the evolution of valproate prescription and the clinical profile of BD women of childbearing age receiving valproate. METHODS: Based on a large national cohort, we included all BD women 16-50 years old. Sociodemographic, clinical and pharmacological data were recorded. Logistic regression analyses were used to describe variables associated with valproate prescription. RESULTS: Of the 1018 included women 16-50 years old, 26.9% were treated with valproate with a mean daily dosage of 968 mg. The prevalence of BD women using valproate was 32.6% before May 2015 and 17.3% after May 2015 (p<0.001), the date of French regulatory publication of restriction of valproate prescription. The multivariate analysis revealed that the inclusion period after May 2015 (OR=0.54, CI 95% 0.37-0.78, p=0.001), the age lower than 40 years (OR=0.65, CI 95% 0.43-0.98, p=0.040) and the number of lifetime mood episodes (OR=0.98, CI 95% 0.95-0.99, p=0.040) were the variables negatively associated with the use of valproate. LIMITATIONS: Study could be underpowered to determine a clinical profile associated with valproate prescription. CONCLUSIONS: The regulatory change in BD women of childbearing age had a significant impact on valproate prescription, even if the prescription rate remains high. Important efforts are needed to help clinicians and patients to improve quality of care in BD women of childbearing age.

Functional neuroimaging in patients presenting with somatoform disorders: A model for investigating persisting symptoms after tick bites and post-treatment Lyme disease syndrome?

Approximately 10% of patients presenting with Lyme disease experience fatigue, musculoskeletal pain, concentration disorders, or short-term memory deficits in the six months following treatment. This entity has been defined as post-Lyme disease syndrome or post-treatment Lyme disease syndrome. The pathophysiology of this syndrome is unknown, but neither persistence of the bacterium nor effectiveness of antibiotics are currently reported in the literature. The French High Council for Public Health (French acronym HCSP) has recently defined a new entity called "persistent polymorphic symptoms after a tick bite" allowing for designing studies to better understand these subjective presentations, for which objective biomarkers are currently lacking. This entity encompasses patients experiencing fatigue and generalized pain in the months following a tick bite and can be associated with several subjective symptoms with major impact on the quality of life. In the field of somatoform disorders, this article reviews functional neuroimaging studies in patients presenting with subjective complaints and discusses potential clinical implications for persisting symptoms after tick bites and post-treatment Lyme disease syndrome.

Association between hypovitaminosis D and cognitive inhibition impairment during major depression episode.

BACKGROUND: Major depressive episode (MDE) has been associated with cognitive functioning alteration and hypovitaminosis D (hypoVD), but the relationship between hypoVD, depression, and cognition is not well understood. We aimed to compare patient with MDE with or without hypoVD in regard of cognitive functioning. METHODS: 91 patients (38.5 years old, 65.9% female) with MDE were included in a cross-sectional study and were evaluated with a complete cognitive battery. None of the participants were medicated at the time of the inclusion. Serum 25-hydroxyvitamin D was measured using LC-MS/MS method, and hypovitaminosis was defined as 25OHD < 50nmol/L. Covariates were gender, season of dosage, first MDE onset, age, body mass index and depression severity RESULTS: Patients with hypoVD demonstrated a higher stroop intereference index time underscoring that means low cognitive inhibition ability. Mutiple logistic regression confirmed that hypoVD was significantly associated with high stroop interference time index after controlling by gender, season of dosage, first MDE onset, age, body mass index and depression severity. CONCLUSION: Our results suggest that patient with MDE having hypoVD may be more prone to cognitive impairment.

Affect lability predicts occurrence of suicidal ideation in bipolar patients: a two-year prospective study.

OBJECTIVE: The aim of our study was to investigate, in bipolar patients, whether affect lability was associated with suicidal ideation incidence during 2-year follow-up, and which subtype of affect lability was associated with suicidal ideation. METHOD: A total of 319 euthymic or mildly depressed bipolar outpatients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups according to the occurrence of suicidal ideation during a 2-year follow-up. Affect lability was assessed by the French version of the Affect Lability Scale. RESULTS: Bipolar patients with high affect lability were more likely to report suicidal ideation during follow-up, even after adjustment for age, study level, rapid cycling, current depression level, anxiety disorder, and lifetime history SA (OR = 2.47; 95% CI [1.15-5.30], P = 0.01). The risk of suicidal ideation increased with the level of affect lability. More specifically, the propensity to switch from neutral to elation affect, from anxious to depressive affect (or inversely), and from neutral to anger affect predicted suicidal ideation. CONCLUSION: Reducing affective lability could become a new therapeutic target of suicidal prevention in bipolar disorder.

Anticonvulsants and suicide attempts in bipolar I disorders.

OBJECTIVE: To identify risk factors for suicide attempts (SA) in individuals commencing treatment for a manic or mixed episode. METHOD: A total of 3390 manic or mixed cases with bipolar disorder (BD) type I recruited from 14 European countries were included in a prospective, 2-year observational study. Poisson regression models were used to identify individual and treatment factors associated with new SA events. Two multivariate models were built, stratified for the presence or absence of prior SA. RESULTS: A total of 302 SA were recorded prospectively; the peak incidence was 0-12 weeks after commencing treatment. In cases with a prior history of SA, risk of SA repetition was associated with younger age of first manic episode (P = 0.03), rapid cycling (P < 0.001), history of alcohol and/or substance use disorder (P < 0.001), number of psychotropic drugs prescribed (P < 0.001) and initiation of an anticonvulsant at study entry (P < 0.001). In cases with no previous SA, the first SA event was associated with rapid cycling (P = 0.02), lifetime history of alcohol use disorder (P = 0.02) and initiation of an anticonvulsant at study entry (P = 0.002). CONCLUSION: The introduction of anticonvulsants for a recent-onset manic or mixed episode may be associated with an increased risk of SA. Further BD studies must determine whether this link is causal.

Effect of early trauma on the sleep quality of euthymic bipolar patients.

OBJECTIVE: Poor quality of sleep is frequent in euthymic bipolar patients and conveys worse clinical outcomes. We investigated the features of euthymic bipolar patients associated with poor sleep quality, with a focus on the effect of childhood trauma. METHOD: 493 euthymic patients with DSM-IV-defined bipolar disorders were recruited in FondaMental Advanced Centers of Expertize for Bipolar Disorders (FACE-BD) between 2009 and 2014. Clinical variables were recorded. Subjective sleep quality and history of childhood trauma were respectively measured by the Pittsburgh Sleep Quality Index (PSQI) and the Childhood Trauma Questionnaire (CTQ). RESULTS: Poor sleepers were older, less professionally active, had significantly higher anxiety levels, took more anxiolytic drugs and did endorse more suicide attempts and suicidal ideas than good sleepers after adjusting for anxiety levels and age. Emotional abuse was associated with poor sleep quality after adjustment for BMI, age, professional activity, and bipolar disorders (BD) type (OR=1.83; 95% CI [1.30; 3.10]; p=0.02). However, this association was lost after adjustment for anxiety levels, anxiolytic treatment and suicide ideation/attempts. LIMITATIONS: The main limitation was the type of sleep assessment, which only measured the subjective part of sleep complaints. CONCLUSION: A history of emotional abuse might underlie sleep problems in many bipolar patients but anxiety seems to act as a confounding factor in this relationship. New studies are needed to elucidate the role of childhood maltreatment on poor sleep among bipolar patients.

Characteristics of depressive patients according to family history of affective illness: Findings from a French national cohort.

BACKGROUND: Literature is scarce about the characteristics of mood disorder patients with a family history (FH) of affective illness. The aim of the current study was to compare the prominent features of depressive patients with a FH of mania (FHM), those of depressive patients with a FH of depression (FHD), and those of depressive patients with no FH of affective illness (FHO). METHODS: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 45 (9.1%) were classified as FHM, 210 (42.6%) as FHD, and 238 (48.3%) as FHO. RESULTS: The main characteristics of FHM patients were a cyclothymic temperament, the presence of mixed features and diurnal variations of mood during depression, early sexual behaviour, a high number of mood episodes and hypomanic switches, high rates of suicide attempts and rapid cycling; diagnosis of bipolar disorder was more frequent in this group as well as comorbid obsessive compulsive disorder, posttraumatic stress disorder, bulimia, attention deficit/hyperactivity disorder and impulse control disorders. The FHD patients had more depressive temperament, generalized anxiety disorder, and anorexia nervosa. Compared to FHO, FHM and FHD showed an earlier age at onset, more comorbid anxiety disorders, as well as more psychotic features. LIMITATIONS: The following are the limitations of this study: retrospective design, recall bias, and preferential enrolment of bipolar patients with a depressive predominant polarity. CONCLUSIONS: In light of genetic studies conducted in affective disorder patients, our findings may support the hypothesis of genetic risks factors common to affective disorders and dimensions of temperament, that may extend to comorbid conditions specifically associated with bipolar or unipolar illness.

[Inclusion criteria and rating scales for RCTs in Psychiatry. The future of qualitative studies]. / Quels patients inclure et quelles échelles utiliser dans un essai clinique ? Les études qualitatives en perspective.

An inventory on the two critical dimensions that structure the Randomized Controlled Trial in Psychiatry, namely the definition of inclusion criteria for eligible patients for testing and the choice of psychometric methods of pathology assessment and its evolution during the experiment, considers the importance of increasingly numerous and precise international recommendations. Taking into account the formal constraints of industrial, questioning the cultural differences of the methodological approach of the tests, meeting the requirements of feasibility and ever increasing security, frequent cumbersome procedure often contrasts with the modest nature of the results. A better definition to include patients in randomized trials is desirable and it asks to return to the clinic studying the expectations of patients and their response to the therapeutic situation. Excessive standardization otherwise required for ensuring the objective nature of the assessment hampers the collection of original and varied clinical features of importance in the further definitions of indications. On the way to a resumption of the single case study, we can expect from qualitative methods applied to small groups of subjects, optimization principles of patient selection for the upcoming randomized trial and greater chance to address the relevant details of clinical response to the therapeutic situation. This is what has led to the discovery of psychotropic drugs and which is involved in the various modalities of the qualitative approach. For example, and beyond the exploration of clinical drug effects, the study of the experience of psychiatric inpatient care in the Healing Garden, conducted on a small group and on the basis of the narrative analysis of their experience, notes several operating thematic dimensions: a reduction in the perception of symptoms of the disease, the impression of regaining a foothold into reality, the interest of a differently perceived doctor-patient relationship, the advantage of renewed power to act and the recognition of the importance of support from others, patients recovering somehow « vitality ¼ of touch with reality. This suggests the possibility to establish an appropriate rating scale for such a specific therapeutic situation and to provide a more accurate and efficient recruitment for a comparative objective demonstration. Moreover, this construction of meaning reinforces the therapeutic benefit of treatment in Healing Garden and offers new dimensions for research.

[What place for placebo in clinical trials conducted on psychiatric patients?] / Quelle place pour le placebo dans les essais cliniques en psychiatrie ?

Placebo effect remains a crucial issue in current clinical trials. Most clinical trials rely on the hypothesis of equivalent placebo response rates in both placebo and specific drug arms ("additive model"). But contrary to this dominant and rarely questioned hypothesis, several aspects may influence placebo response. A few recent meta-analyses and reviews have shown evidence for several clinical and methodological factors, which are able to modulate placebo response. In psychiatry research, placebo response has been mainly explored through antidepressant trials. In early clinical trials, drug-placebo differences were initially significant and robust. However, more recent clinical trials have not yielded similar results, and rather show narrowed antidepressant-placebo differences. Several factors may be involved in this absence of comparability: intrinsic properties of new antidepressants, changes in clinical criteria and classifications, symptomatic remission rather than global remission criteria, industrial and institutional constraints. Moreover, results from antidepressant trials (laboratory conditions) remain hardly fully transposable to clinical routine (ecological conditions).

[What can we expect from clinical trials in psychiatry?] / Que peut-on attendre des essais cliniques en psychiatrie ?

Clinical trials in psychiatry allow to build the regulatory dossiers for market authorization but also to document the mechanism of action of new drugs, to build pharmacodynamics models, evaluate the treatment effects, propose prognosis, efficacy or tolerability biomarkers and altogether to assess the impact of drugs for patient, caregiver and society. However, clinical trials have shown some limitations. Number of recent dossiers failed to convince the regulators. The clinical and biological heterogeneity of psychiatric disorders, the pharmacokinetic and pharmacodynamics properties of the compounds, the lack of translatable biomarkers possibly explain these difficulties. Several breakthrough options are now available: quantitative system pharmacology analysis of drug effects variability, pharmacometry and pharmacoepidemiology, Big Data analysis, brain modelling. In addition to more classical approaches, these opportunities lead to a paradigm change for clinical trials in psychiatry.