[Anticholinergic scales: Use in psychiatry and update of the anticholinergic impregnation scale]. / Les échelles anticholinergiques : usage en psychiatrie et mise à jour de l'échelle d'imprégnation anticholinergique.

Anticholinergic properties are well known to prescribers, notably in mental health, as a therapeutic strategy for i.e. extrapyramidal syndrome but also as a source of numerous adverse side effects. Herein, we propose a narrative literature review describing: (i) cholinergic pharmacology and anticholinergic properties; (ii) the importance of anticholinergic therapeutic properties in psychiatry; (iii) the existing anticholinergic drug scales and their usage limitations in Psychiatry and; last (iv) an update to the anticholinergic drug impregnation scale, designed for the French psychiatry practice. The anticholinergic side effects can appear both in the peripheral level (dry mouth, constipation, etc.) and in the central level (especially as cognitive deficits). Many of the so called « anticholinergic ¼ drugs are in fact entirely or mostly antimuscarinic and act essentially as parasympathetic system antagonists. Overall, anticholinergic/antimuscarinic side effects are usually attributed to psychotropic medications: to certain antipsychotics, notably classical neuroleptics such as phenothiazine and also to tricyclic antidepressants. In practice, the impact of anticholinergic toxicity treatments is often highlighted due to their excessively prolonged use in patients on antipsychotics. Interestingly, these antipsychotic treatments are better known for their anticholinergic side effects, especially cognitive ones, with an early onset specially in elder patients and/or in the case of polymedication. In order to evaluate anticholinergic side effects, metrics known as anticholinergic burden scales were created in the last few decades. Nowadays, 13 different scales are documented and accepted by the international academic community, but only three of them are commonly used: the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS) and the Anticholinergic Burden Scale (ACB). All of them are based on a similar principle, consisting of grading treatments individually, and they are normally scored from 0 - no presence of side effects - to 3 - anticholinergic effects considered to be strong or very strong. Using these scales enables the calculation of the so-called "anticholinergic burden", which corresponds to the cumulative effect of using multiple medications with anticholinergic properties simultaneously. The application of anticholinergic scales to patients with psychiatric disorders has revealed that schizophrenic patients seem to be especially sensitive to anticholinergic cognitive side effects, while elder and depressed patients were more likely to show symptoms of dementia when exposed to higher anticholinergic burden. Unfortunately, these tools appear to have a low parallel reliability, and so they might induce large differences when assessing side effects predictability. In addition, the capacity of these scales to predict central adverse effects is limited due to the fact they poorly or do not differentiate, the ability of treatments to cross the blood-brain barrier. Finally, one last limitation on the validity of these scales is prescription posology is not accounted for side effects considered to be dose dependent. Recently, the MARANTE (Muscarinic Acetylcholine Receptor ANTagonist Exposure) scale has incorporated an anticholinergic burden weighting by posology. Nevertheless, this new model can be criticized, due to the limited number of medications included and due to testing a limited number of potency ranges and dosages for each treatment. Herein, we propose an update to the Anticholinergic Impregnation Scale, developed specifically for the French Psychiatry practice. The scale validation was based on an evaluation of the prescriptions correcting anticholinergic peripheral side effects (constipation, xerostomia and xeropthalmia). This indirect evaluation allowed us to show patients with an anticholinergic impregnation score higher than 5 received significantly more treatments for constipation and xerostomia. This strategy bypasses the bias of a cognitive evaluation in patients with severe mental health disorders. Moreover, the relevance of a tool developed specifically for French psychiatry is justified by the fact that some highly prescribed treatments for mental illness in France (cyamemazine and tropatemine) are strong anticholinergics, and also by the fact they are rarely included in the existing anticholinergic scales. This update of the original scale, published in 2017, includes information whether prescribed drugs cross the blood-brain barrier and thus makes possible a more accurate assessment when evaluating anticholinergic central side effects. Finally, the anticholinergic impregnation scale will soon be integrated into a prescription help software, which is currently being developed to take into consideration dose dependent adverse effects.

[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.

Psychotropics and COVID-19: An analysis of safety and prophylaxis.

The use of psychotropics during the COVID-19 pandemic has raised two questions, in order of importance: first, what changes should be made to pharmacological treatments prescribed to mental health patients? Secondly, are there any positive side effects of these substances against SARS-CoV-2? Our aim was to analyze usage safety of psychotropics during COVID-19; therefore, herein, we have studied: (i) the risk of symptomatic complications of COVID-19 associated with the use of these drugs, notably central nervous system activity depression, QTc interval enlargement and infectious and thromboembolic complications; (ii) the risk of mistaking the iatrogenic impact of psychotropics with COVID-19 symptoms, causing diagnostic error. Moreover, we provided a summary of the different information available today for these risks, categorized by mental health disorder, for the following: schizophrenia, bipolar disorder, anxiety disorder, ADHD, sleep disorders and suicidal risk. The matter of psychoactive substance use during the pandemic is also analyzed in this paper, and guideline websites and publications for psychotropic treatments in the context of COVID-19 are referenced during the text, so that changes on those guidelines and eventual interaction between psychotropics and COVID-19 treatment medication can be reported and studied. Finally, we also provide a literature review of the latest known antiviral properties of psychotropics against SARS-CoV-2 as complementary information.

Cognitive remediation and professional insertion of people with schizophrenia: RemedRehab, a randomized controlled trial.

BACKGROUND: People suffering from schizophrenia cannot easily access employment in European countries. Different types of vocational programs coexist in France: supported employment, sheltered employment (ShE), and hybrid vocational programs. It is now acknowledged that the frequent cognitive impairments constitute a major obstacle to employment for people with schizophrenia. However, cognitive remediation (CR) is an evidence-based nonpharmacological treatment for these neurocognitive deficits. METHODS: RemedRehab was a multicentric randomized comparative open trial in parallel groups conducted in eight centers in France between 2013 and 2018. Participants were recruited into ShE firms before their insertion in employment (preparation phase). They were randomly assigned to cognitive training Cognitive Remediation for Schizophrenia (RECOS) or Treatment As Usual (TAU). The aim of the study was to compare with the benefits of the RECOS program on access to employment and work attendance for people with schizophrenia, measured by the ratio: number of hours worked on number of hours stipulated in the contract. RESULTS: Seventy-nine patients were included in the study between October 2018 and September 2019. Fifty-three patients completed the study. Hours worked / planned hours equal to 1 or greater than 1 were significantly higher in the RECOS group than in the TAU group. CONCLUSIONS: Participants benefited from a RECOS individualized CR program allows a better rate of work attendance in ShE, compared to the ones benefited from TAU. Traditional vocational rehabilitation enhanced with individualized CR in a population of patients with schizophrenia is efficient on work attendance during the first months of work integration.

[Health professionals facing the coronavirus disease 2019 (COVID-19) pandemic: What are the mental health risks?] / Les professionnels de santé face à la pandémie de la maladie à coronavirus (COVID-19) : quels risques pour leur santé mentale ?

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has caused major sanitary crisis worldwide. Half of the world has been placed in quarantine. In France, this large-scale health crisis urgently triggered the restructuring and reorganization of health service delivery to support emergency services, medical intensive care units and continuing care units. Health professionals mobilized all their resources to provide emergency aid in a general climate of uncertainty. Concerns about the mental health, psychological adjustment, and recovery of health care workers treating and caring for patients with COVID-19 are now arising. The goal of the present article is to provide up-to-date information on potential mental health risks associated with exposure of health professionals to the COVID-19 pandemic. METHODS: Authors performed a narrative review identifying relevant results in the scientific and medical literature considering previous epidemics of 2003 (SARS-CoV-1) and 2009 (H1N1) with the more recent data about the COVID-19 pandemic. We highlighted most relevant data concerning the disease characteristics, the organizational factors and personal factors that may contribute to developing psychological distress and other mental health symptoms. RESULTS: The disease characteristics of the current COVID-19 pandemic provoked a generalized climate of wariness and uncertainty, particularly among health professionals, due to a range of causes such as the rapid spread of COVID-19, the severity of symptoms it can cause in a segment of infected individuals, the lack of knowledge of the disease, and deaths among health professionals. Stress may also be caused by organizational factors, such as depletion of personal protection equipment, concerns about not being able to provide competent care if deployed to new area, concerns about rapidly changing information, lack of access to up-to-date information and communication, lack of specific drugs, the shortage of ventilators and intensive care unit beds necessary to care for the surge of critically ill patients, and significant change in their daily social and family life. Further risk factors have been identified, including feelings of being inadequately supported, concerns about health of self, fear of taking home infection to family members or others, and not having rapid access to testing through occupational health if needed, being isolated, feelings of uncertainty and social stigmatization, overwhelming workload, or insecure attachment. Additionally, we discussed positive social and organizational factors that contribute to enhance resilience in the face of the pandemic. There is a consensus in all the relevant literature that health care professionals are at an increased risk of high levels of stress, anxiety, depression, burnout, addiction and post-traumatic stress disorder, which could have long-term psychological implications. CONCLUSIONS: In the long run, this tragic health crisis should significantly enhance our understanding of the mental health risk factors among the health care professionals facing the COVID-19 pandemic. Reporting information such as this is essential to plan future prevention strategies. Protecting health care professionals is indeed an important component of public health measures to address large-scale health crisis. Thus, interventions to promote mental well-being in health care professionals exposed to COVID-19 need to be immediately implemented, and to strengthen prevention and response strategies by training health care professionals on mental help and crisis management.

[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.

The clinical and economic impact of three-monthly long-acting formulation of paliperidone palmitate versus the one-monthly formulation in the treatment of schizophrenia in France: A cost-utility study.

OBJECTIVES: Schizophrenia entails a considerable humanistic and economic burden. Improved treatment continuity to antipsychotic therapy is paramount to reduce the risk of relapse. The novel three-monthly paliperidone palmitate treatment (PP3M) offers the longest dosing interval currently available in France. This study assesses its cost-effectiveness, versus the currently available one-monthly long-acting treatment (PP1M) in French schizophrenic patients. METHODS: A Markov model with monthly cycles was developed and adapted. It encompassed [a] administration of PP3M or PP1M in first-line, [b] a period where the patient does not receive any active treatment, and [c] a follow-up treatment line consisting of a treatment mix reflecting French clinical practice. Relapse rates in first-line were based on a pivotal non-inferiority head-to-head trial, and treatment discontinuation rates were based on French real-world data. Accounting for differences in drug exposure, time-dependent monthly relapse rates were applied following discontinuation to first line. The impact of a less frequent injection schedule for PP3M in QoL was accounted for through the application of a utility differential. The collective perspective was adopted throughout a 5-year time horizon. Four percent discount rates were applied on costs and outcomes. RESULTS: PP3M was dominant when compared to PP1M, featuring an incremental QALY of 0.123 and a cost saving effect (-669€) resulting from reduced therapy costs (drug acquisition, administration and monitoring) and relapse-related costs. Sensitivity analysis supported the robustness of the results. CONCLUSION: With slightly better QALY outcomes and a cost-saving effect when compared to PP1M, introducing PP3M is an improvement to the current treatment in France.

[First-episode psychosis as primary manifestation of medical disease: An update]. / Premier épisode psychotique révélant une affection médicale générale : mise au point pour l'interniste.

A huge variety of medical diseases may potentially present with isolated psychotic symptoms, and disease-specific treatment or management is available for a significant part of them. The initial medical work-up of a first-episode psychosis (FEP) is of crucial importance. This literature review aimed to identify medical conditions potentially revealed by FEP, to list the warning signs of secondary psychosis, and to discuss a screening strategy. Underlying organic conditions may be drugs and medications, neurologic diseases, infections, inflammatory and/or autoimmune pathologies, and metabolic disorders whether of hereditary origin. Each patient presenting with a first-episode psychosis should be evaluated with a precise anamnesis, a careful clinical examination, and routine laboratory tests. Brain imaging and tests (depending on the context) should be performed in the presence of atypical clinical features or "red flags", leading to suspect an organic disease.

[Interest of extrahospital multidisciplinary unit of neuro-psycho-geriatric intervened in nursing home: Analysis of 288 interventions]. / Intérêt d'une unité mobile multidisciplinaire extra-hospitalière de neuro-psychogériatrie intervenant en EHPAD : analyse de 288 interventions.

INTRODUCTION: Geriatrics Mobile Units are a new organisation operating in nursing homes. Their mission is to propose globally oriented neuro-psychiatric and geriatric care. The purpose of the study is to assess their activity and impact over a 21-month period. METHOD: A prospective single center study of UMNPG's data including intervention characteristics, patient characteristics, recommendations and reassessment after intervention. The Neuropsychiatric Inventory Nursing Home version (NPI-NH) was measured during intervention and reassessed after 30 days (Student's t-test). RESULTS: From March 2014 to December 2015, UMNPG conducted 288 interventions mainly for medical advices (81%), clinical assessments (54%) and health care team support (46%). The average age was 84.6±7.3years, 73.3% of whom were women. The patients were dependent (62% of GIR 1 or 2) with dementia (60%) and under several medications (83.7%). The symptoms were mainly agitation/aggression (76.4%), anxiety (75%), depression (66.7%), irritability (60.4%), aberrant motor behaviour (55.9%) and delusions (48.6%). The main proposals of UMNPG were a change in treatment (79.5%), a health care team support (85.4%) and hospitalization (8.4%). The rate of follow-up on recommendation was 83% on the 15th day and 80% on the 30th day. The rate of avoided hospitalizations was 16%. The average NPI-NH decreased (on day 0 NPI=50±19.2; on day 30 NPI=33.9±19.6, p<0.001). CONCLUSION: UMNPG-EHPAD intervenes for frail elderly residents with multiple disorders in crisis situations. Medical recommendations help to support people in nursing homes and decrease NPI-NH. UMNPG-EHPAD is part of geriatric network strengthening the city/hospital connection.

Quantitative System Pharmacology (QSP): An Integrative Framework for paradigm change in the treatment of the first-episode schizophrenia.

Despite the lack of progress in the curative treatment of mental illness, especially schizophrenia, the accumulation of neuroscience data over the past decade suggests the re-conceptualization of schizophrenia. With the advent of new biomarkers and cognitive tools, new neuroscience technologies such as functional dynamic connectivity and the identification of subtle clinical features; it is now possible to detect early stages at risk or prodromes of a first psychotic episode. Current concepts reconceptualizes schizophrenia as a neurodevelopmental disorder at early onset, with polygenic risk and only symptomatic treatment for positive symptoms at this time. The use of such technologies in the future suggests new diagnostic and therapeutic options. Next steps include new pharmacological perspectives and potential contributions of new technologies such as quantitative system pharmacology brain computational modeling approach.

Atypical permanent neurological sequelae after an acute intoxication with lithium and aripiprazole.

OBJECTIVES: The aim of the present case report was to describe atypical neurological sequelae after a lithium and aripiprazole co-intoxication in a suicide attempt. METHODS: We report the case of a 31-year-old patient with bipolar disorder who developed, after lithium and aripiprazole massive ingestion, a severe pseudobulbar dysarthria and motor disorders suggestive of basal ganglia micro lesions. We review literature on neurological sequelae due to acute lithium intoxications. RESULTS: Acute lithium intoxication can cause permanent neurological sequelae, the most frequent clinical feature being a permanent cerebellar syndrome. Moreover, the widely-prescribed combination of lithium with antipsychotics increases the neurotoxicity in lithium intoxications. In this case, both atypical neurological syndrome and normal paraclinical investigations lead first to misdiagnose the lithium neurological damages. CONCLUSIONS: This case illustrates that acute lithium intoxications can result in serious and potentially permanent neurological deficits, which remain difficult to diagnose. Imaging abnormalities are not constant, and neurological presentation can be atypical.

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.

[How to treat and manage unsatisfactory response?]. / Réponse non suffisante : quelle prise en charge ?

Only one third of patients suffering from depression will achieve a satisfactory response with first line treatments and more than half of patients will fail to obtain at least 50 % reduction in their symptoms after 3 months of treatment. This article presents a review of the scientific arguments supporting the various therapeutic strategies when confronted to a first treatment failure after an adequate drug trial. Several pharmacological approaches are possible. A first and classical approach is adjusting the drug dosage (optimization). This strategy is coherent with the pharmacological profile of some antidepressant drugs (tricyclic antidepressants, tetracyclic antidepressants, venlafaxine). There is no scientific basis to a dose-effect relationship with the selective serotonin reuptake inhibitors (SSRIs), as minimal doses of these drugs correspond to a high ratio of serotonin transporter occupation; however increasing doses of SSRIs constitutes a usual practice, endorsed by several experts. A second classic strategy is changing an inefficient antidepressant drug to another antidepressant drug (switch). Theoretically, a different pharmacological class should have more chances to be successful; however, in the case of a failure with an SSRI, an inter-class switch has not consistently proven to be superior to an intra-class switch. In some cases, association of antidepressant drugs can also be an advantageous strategy (combination), particularly in the case of partial response with the first prescribed drug. Due to its particular mechanism of action, mirtazapine is often a drug of choice in the case of such an association. Finally, another approach to recommend in case of partial response is associating an antidepressant drug to another class of drugs, such as lithium, atypical antipsychotics or thyroid hormones (potentiation). Lithium has unfailingly proven its efficacy in case of resistance, but the utilization of atypical antipsychotics, at low-doses, has become increasingly common, certainly, because they are easier to handle. Aside from the pharmacological options, we can consider a number of other strategies, first among them is psychotherapy. Most studies assessing the efficacy of psychotherapy were conducted with this therapy as a first-line treatment. More studies of psychotherapy in depression after unsatisfactory response are distinctly needed. Available data seem to indicate that psychotherapy constitutes an efficient alternative, regardless of the type of psychotherapy (results are more robust in cognitive and behavioural therapies and brief interpersonal psychotherapy, in relation with the greater number of studies using these therapies), with effect sizes comparable to the ones obtained with pharmacological options. Among other strategies, physical exercise has been getting more attention lately, even though evidence in this indication remains deceiving for the moment. Lastly, neuromodulation techniques have an unquestionable place. The rTMS has been largely tested with interesting results. Given the time and staff necessary to conduct this therapy, the question has now switched to how precisely select the patients who will most benefit from rTMs, and how long and at what pace should the sessions take place. ECT is undoubtedly the most efficient treatment, but, apart from life-threatening melancholia and other restricted exceptions, it is usually indicated in multi-resistant depression. Some authors suggest using this therapy earlier, as chronicity of the disease is itself a factor of poor response. Finally, this article reviews also the most recent French and International guidelines in managing patients having showed an unsatisfactory response to a first-line treatment.

[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.