Search

Aripiprazole may be viewed as the prototype of third-generation antipsychotics. This concept is based on the notion of D2 partial agonism, whereas all molecules of first-and second generation were D2 antagonists. After reviewing the basic pharmacological notions linked to such concepts, the mechanisms of action of these molecules are addressed, with a particular focus on functional selectivity and biased ligand. One of the essential pharmacological properties of D2 agonists, and particularity aripiprazole, is their ability to not induce D2 supersensitivity as well as to reverse this supersensitivity when it has been induced by D2 antagonists. In clinical practice, this impacts the choice of treatment in first episode psychosis as well as in refractory schizophrenia. Animal research shows that D2 supersensitivity could contribute to worsen addictive trends. The pharmacokinetic incidence of D2 supersensitivity tends to favour the long-acting forms of partial agonists. The notion of partial agonism could finally lead to design fourth-generation antipsychotics, on the basis on research focusing on functional selectivity., (Copyright © 2018. Published by Elsevier Masson SAS.)

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., (© 2018 L’Encéphale, Paris.)

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., (© L’Encéphale, Paris, 2016.)

Objectives: The first objective of this article is to summarize the history of electroconvulsive therapy (ECT) in psychiatry in order to highlight the transition from clinical level of evidence based on phenomenological descriptions to controlled trial establishing causal relationship. The second objective is to apply the criteria of causation for ECT, to focus on the dose-effect relationship criteria, and thus to analyze the conditions of application of these criteria for ECT., Methods: A literature review exploring the use of electricity, ECT and electroencephalography (EEG) in psychiatry was conducted. The publications were identified from the Pubmed and GoogleScholar electronic databases. The scientific literature search of international articles was performed in July 2016., Results: In 1784, a Royal commission established in France by King Louis XVI tested Mesmer's claims concerning animal magnetism. By doing that, the commission, including such prominent scientists as the chemist Anton Lavoisier and the scientist and researcher on electricity and therapeutics Benjamin Franklin, played a central role in establishing the criteria needed to assess the level of evidence of electrical therapeutics in psychiatry. Surprisingly, it is possible to identify the classical Bradford Hill criteria of causation in the report of the commission, except the dose-effect relationship criteria. Since then, it has been conducted blinded randomized controlled trials that confirmed the effectiveness of ECT against ECT placebos for the treatment of psychiatric disorders. At present, the dose-effect relationship criteria can be analyzed through an EEG quality assessment of ECT-induced seizures., Conclusions: EEG quality assessment includes several indices: TSLOW (time to onset of seizure activity ≤5Hz, seconds), peak mid-ictal amplitude (mm), regularity (intensity or morphology of the seizure (0-6)), stereotypy (global seizure patterning, 0-3) and post-ictal suppression (0-3). A manual rating sheet is needed to score theses indices. Such manual rating with example of EEG segments recording is proposed in this article. Additional studies are needed to validate this manual, to better establish the dose-response relationship for the ECT, and thus strengthen the position of the EEG as a central element for clinical good practice for ECT., (© L’Encéphale, Paris, 2016.)

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., (© L’Encéphale, Paris, 2016.)

Proving the efficacy of a psychotropic drug is a medical, scientific and ethical need. Psychotropic drug development is now a highly complex process, which takes several years and which is very expensive. It involves multiple steps of preclinical and clinical pharmacological refinement and testing. Methodology of studies to prove curative or preventive effect of psychotropic drugs is well codified. Preclinical studies include pharmacokinetic data, toxicology and performance in various animal models of pathology. Clinical phases are centered on randomized controlled double blind trials for demonstrating efficacy and safety/tolerability. This methodology follows strict criteria to avoid bias and to prove internal and external validity of the results. All the results from randomized controlled trials or RCTs lead to different levels of evidence of Evidence-Based Medicine (EBM): gold standard is RCTs while the lowest reference is clinical case or expert opinion. However, it is possible to level criticism at these data issued from RCTs. The main matter is that studies do not reflect the healthcare reality in daily life. For these reasons, a real debate between evaluation of efficacy and effectiveness is acute. Effectiveness refers to the overall effects of psychotropic drugs in naturalistic conditions. Furthermore, analysis of costs and financial benefits are more and more important from social and economic points of view. Official agencies and health insurances look after them very carefully. This article deals with these issues and provides examples using data from the international literature. These examples are drawn from RCTs, naturalistic studies, meta-analysis, pharmaco-economic studies and concern neuroleptics, antipsychotics, antidepressants, and mood-stabilizers., (© L’Encéphale, Paris, 2016.)

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)., (© L’Encéphale, Paris, 2016.)

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., (© L’Encéphale, Paris, 2016.)

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 » 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., (© L’Encéphale, Paris, 2016.)

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., (© L’Encéphale, Paris, 2016.)

Adverse effects of psychotropic medications must be systematically assessed during a clinical trial. This systematic and mandatory evaluation, for the patient safety first, will also allow to establish for the tested molecule, an efficiency/tolerance ratio which could be compared to preexisting medications, and guide the clinician prescriptions. These side effects are closely related to the pharmacological profile of the tested molecule, in particular its monoamine binding profile. Antipsychotics are taken as an example, with a focus on classical clinical side effects related to each monoamine transmission blocking., (© L’Encéphale, Paris, 2016.)

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., (© L’Encéphale, Paris, 2016.)

Extensive evidence demonstrates that psychotherapy can be an efficacious and effective health care service for a wide range of mental health and health conditions. Recently, an important distinction between efficacy research and effectiveness research has been made within research focused on the outcome of psychotherapy. Data from both efficacy and effectiveness studies are fundamental to a complete understanding of the potential impact of a psychotherapy and the way to carry successful psychotherapeutics interventions to routine clinical practice. Efficacy studies, using randomized controlled trials, maximize the internal validity of a study by the use of design features, such as random assignment to a psychotherapeutic intervention and control conditions, training of therapists to a specified level of competence in providing the treatment, and ensuring that all participants have the condition that the treatment was designed to address. The randomized controlled trials allowed to objectify the efficacy of the psychotherapies in multiple pathological contexts, as we will see with the example of bipolar disorders. On the other hand, effectiveness studies strive to maximize external validity (while maintaining an adequate level of internal validity) by locating the study within clinical service sites that provide ongoing health services, using clinicians who are routinely providing psychological services and patients who have been referred to the clinical settings. These studies do not allow understanding changes and psychotherapeutic processes in real practice. A solution might be found in using pragmatic case studies in a systematic manner to constitute ecologically valid samples and measure change and psychotherapeutic processes during clinically significant periods of time., (© L’Encéphale, Paris, 2016.)

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., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The management of negative symptoms appears to be a major challenge because of functional disability induced by these symptoms and their relative resistance to treatments currently on the market. The aim of this article is to review new approaches that may enable optimal management of these symptoms. First, we describe the methodological difficulties that hindered the development and evaluation of specific treatment, and objectives currently defined to enable the development of new pharmacological approaches. Then we present the monotherapy and adjuvant therapies that have been assessed, including first and second generation antipsychotics, psychostimulants, antidepressants, cholinergic and glutamatergic agents, the oxytocin, hormones and more invasive therapies such as transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT). Other molecules are under development and evaluation such alpha-7 nicotinic receptor agonists., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Treating negative symptoms of schizophrenia is a major issue and a challenge for the functional and social prognosis of the disease, to which they are closely linked. First- and second-generation antipsychotics allow a reduction of all negative symptoms. The hope of acting directly on primary negative symptoms with any antipsychotic is not supported by the literature. However, the effectiveness of first- and second-generation antipsychotics is demonstrated on secondary negative symptoms., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The history of negative symptoms of schizophrenia rises early days of medicine in clinical and pathophysiological differences between positive and negative and their complex joint. Forming a set of typical core of symptoms, and some feature of a syndrome belonging to a specific pathophysiological mechanism, negative symptoms of schizophrenia emerge from old descriptions of clinical pictures, related to the overall look of madness, the heart of alienation, a central sign of early dementia, gradually more precisely describing the strange nature of the autistic withdrawal and schizophrenic apragmatism. At therapeutic era, negative symptoms have taken over the positive symptoms to establish an operational criteria whose importance lies in the progressive severity of this clinical type and in their contribution to therapeutic resistance. Despite the efforts of modern typological classifications, this work rehabilitates the old concept of "unitary psychosis" by defining a common symptomatic core to multiple clinical forms of psychosis, combining deficit of emotional expression and avolition, meaning a native psychopathology and a pathophysiology possibly in a common final way, and calling the arrival of new treatment strategies., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The aim of this review of the literature is to summarize the state of the knowledge concerning the relationship between negative symptoms in schizophrenia, electrophysiology and electrotherapy. The scientific literature search of international articles was performed during August and September 2015 using the PubMed electronic database. We used the following MeSH terms: "Negative symptoms", "Schizophrenia", "Electrophysiology", "Neurophysiology", "EEG power", "Alpha rhythm", "Transcranial magnetic stimulation", "Transcranial direct current stimulation", "Electroconvulsive therapy", "Neurofeedback", "Vagus Nerve Stimulation", "Deep Brain Stimulation", and "State dependent". Negative symptoms in schizophrenia are associated with altered activity in prefrontal cortex in functional neuroimaging studies. This is in line with electrophysiological measurements that found a change in EEG spectral power in the alpha frequency band over prefrontal brain regions. The notion of functional hypofrontality has led to hypotheses that electrotherapy applied to the prefrontal cortex may be an effective treatment of negative symptoms in schizophrenia. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were used to increase cortical activity in schizophrenia and achieve a clinical effect on negative symptoms. Three meta-analyses confirmed, with a moderate effect size, that rTMS is an effective treatment option for negative symptoms in schizophrenia. The two subsequently published prospective multicenter studies, however, found opposite results from each other. Two randomized controlled studies suggested that tDCS is an effective treatment option for negative symptoms. There is no study on the efficacy of neurofeedback, vagal nerve stimulation or deep brain stimulation on negative symptoms in schizophrenia. Additional studies are needed to confirm the efficacy of rTMS and tDCS on negative symptoms in schizophrenia. Influencing factors, related to clinical and stimulation parameters, of rTMS and tDCS on negative symptoms should be better investigated. Effects related to electrophysiological brain activity of the patient, especially in the alpha band, during the stimulation should also be better investigated. The action of electrotherapy may be state dependent, and a better understanding of electrophysiological effects of electrotherapy techniques could enable their optimization., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

For a long time, treatment of schizophrenia has been essentially focussed on positive symptoms managing. Yet, even if these symptoms are the most noticeable, negative symptoms are more enduring, resistant to pharmacological treatment and associated with a worse prognosis. In the two last decades, attention has shift towards cognitive deficit, as this deficit is most robustly associated to functional outcome. But it appears that the modest improvement in cognition, obtained in schizophrenia through pharmacological treatment or, more purposely, by cognitive enhancement therapy, has only lead to limited amelioration of functional outcome. Authors have claimed that pure cognitive processes, such as those evaluated and trained in lots of these programs, may be too distant from real-life conditions, as the latter are largely based on social interactions. Consequently, the field of social cognition, at the interface of cognition and emotion, has emerged. In a first part of this article we examined the links, in schizophrenia, between negative symptoms, cognition and emotions from a therapeutic standpoint. Nonetheless, investigation of emotion in schizophrenia may also hold relevant premises for understanding the physiopathology of this disorder. In a second part, we propose to illustrate this research by relying on the heuristic value of an elementary marker of social cognition, facial affect recognition. Facial affect recognition has been repeatedly reported to be impaired in schizophrenia and some authors have argued that this deficit could constitute an endophenotype of the illness. We here examined how facial affect processing has been used to explore broader emotion dysfunction in schizophrenia, through behavioural and imaging studies. In particular, fMRI paradigms using facial affect have shown particular patterns of amygdala engagement in schizophrenia, suggesting an intact potential to elicit the limbic system which may however not be advantageous. Finally, we analysed facial affect processing on a cognitive-perceptual level, and the aptitude in schizophrenia to manipulate featural and configural information in faces., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

During the past ten years, research on schizophrenia has witnessed a clear emphasis on studies based on negative symptoms. This interest can be explained in terms of diagnosis, specific treatment, functional prognosis and outcome issues. However, main current approaches consider negative symptoms from an operationalist view, which implies objective and atheoretical descriptions of clinical criteria, observed from a third person perspective. And the understanding of negative symptoms in schizophrenia, still a crucial issue of mental health, remains only partial. From a different perspective, psychopathology - and notably psychiatric phenomenology -, can provide a conceptual and clinical framework, taking into account subjective experience (first person perspective), based on a global understanding of the clinical situation lived by patients with schizophrenia. In the present review, we give a brief survey on the historical aspects of the description of negative symptoms. Then, we introduce the clinical contributions raised by clinical phenomenology. We principally develop Minkowski's notion of loss of vital contact, and Blankenburg's notion of loss of natural evidence. Then we highlight the current debates which are discussed and explored in contemporary psychopathology. In conclusion, we discuss the possible articulation between objective and subjective approaches, in order to better understand pauci-symptomatic forms of schizophrenia., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Negative symptoms account for a clinical dimension of schizophrenia. They are partly the cause of functional disability of this disease. Clinical experience shows that antipsychotics have little or no effect on these symptoms. The aim of this review is to gather existing data on the treatment of negative symptoms with antidepressants. The combination of antipsychotics with antidepressants is a therapeutic strategy commonly used for the treatment of these symptoms. The pro-dopaminergic effects of antidepressants explain their effectiveness on negative symptoms. There are many comparative, randomized, controlled studies evaluating the efficacy of antidepressant associated with antipsychotic for the treatment of negative symptoms. Furthermore three meta-analyses have been conducted. The overall results suggest that the use of antidepressants may contribute to clinical improvement of negative symptoms in schizophrenia. The limitations of these studies are the small number of patients included and the definition and assessment of negative symptoms. The existing scales are not sufficiently discriminating. Further research using new measurement tools should help refine these results., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Recent investigations performing exploratory and confirmatory factor analysis have suggested that negative symptoms are multidimensional, including evidence for at least two distinct negative symptom subdomains: diminished expression and amotivation. Guidance for selection of instruments for measurement of negative symptoms is rapidly evolving. As there are continuing advances in the description of negative symptoms, new instruments are under development, and new data on the performance of instruments emerge from clinical trials. The Scale for Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), and the Negative Symptom Assessment-16 (NSA-16) are considered to be reliable and valid measures for negative symptom trials but differ with respect to their domain coverage, use of informants, integration of global scores, administration time and comprehensiveness of their structured interviews. In response to the 2005 NIMH - MATRICS consensus statement, work groups are field testing and refining two new measures, the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Brief Negative Symptom Scale (BNSS). Both address the five currently recognized domains of negative symptoms, differentiate appetitive from consummatory aspects of anhedonia and address desire for social relationships. Thus far, both have exhibited promising psychometric properties., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Getting and keeping a job are not only one of the criteria of recovery from schizophrenia, but are also one of its main means. Indeed, recovery is partly defined by the ability to work. Despite the lack of data in France about employment of people with schizophrenia, it is widely acknowledged that the employment rate of people with schizophrenia remains quite low, and frequently it is only an employment in sheltered workshops, not on the regular work market. International research data show that it is possible to improve significantly this employment rate, with an appropriate support, that is precisely defined by the current researches, and that is quickly spreading in most developed countries. The aim of this paper is to present, on the basis of a broad current literature review, the key predictive factors of the return to work for people with schizophrenia, and the strategies to optimize vocational services. It will appear that there are several ways to improve practices and interventions in France to support work integration. To begin with individual factors of work integration, dependant on each person, the clinical state and the cognitive skills (in a broad sense, including social cognition and metacognition) are to be taken into account, and optimized by means of the association of a finely tuned pharmacological treatment and psychosocial interventions such as cognitive remediation adjusted to the person's specific needs. The other main kind of factors is environmental factors, particularly the kind of vocational support, which turns out to have a major impact not only on job acquisition, but importantly also on job tenure. The most effective vocational services are based on the "Place and train" model, and even more precisely on the Individual Placement and Support (IPS) model, that allows to the majority of people with a severe mental illness (more than 50%) to obtain a competitive employment after 6 to 18 months of individualized support. This approach is now widely recommended as "an evidence-based practice" of rehabilitation. It is important to promote in France the development of this kind of practice, already implemented as an experiment by few militant and involved associations. This development remains in France slow and delayed (compared to the practices in the other European countries) because of the lack of public funding. It implies an evolution of the social and medico-social practices, taking into account current research data, and assessing the outcomes of their practices in order to improve them. The employment specialist (sometimes called also the "job coach") turns out to play a key role, emphasized by current research, implying, among many other tasks, to coordinate the net of people supporting the work integration, including the clinical team, the employer and the colleagues of the workplace., (Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Dual diagnosis of schizophrenia and substance-related disorders is common in psychiatric practice. Epidemiologic studies and report have established that the risk of a substance-related disorder was 4 to 5 times higher in a population of psychiatric patients than in the general population. However, little is known on the reason of this relationship and the treatments required. It's well known that a family history of psychosis is a risk factor of schizophrenia. Similarly a family history of substance use disorders increases the risk of using substances. Because the two disorders often occurred together, it could be hypothesized that a genetic risk factor is common. However, recent studies did not confirm this hypothesis and it seems that their genetic risks factor would be unrelated. Evidence now exists describing the different profiles of patients whether they used substance or not. Concerning negative symptoms clinical studies and meta-analyses have described fewer symptoms in schizophrenia patients with a substance use disorder. Among the different explanations that have been addressed, it seems that a lower capability of obtaining the substance could partly explain this relationship. Perhaps because patients with social withdrawal have more difficulties to find and spend the time required to obtain abused substances. At the opposite some products such as cocaine may relieve some symptoms especially anhedonia and alogia. However the link between substance-related disorders and negative symptoms is weak and decreases in more recent studies, probably because negative symptoms as well as addiction disorders are better characterized. Considering that treating psychiatric symptoms may not always lead to a decrease in the substance-related disorders but that patients who give up substances improve their psychotic symptoms, a therapeutic strategy should be planned for these dual disorders patients combining psychiatry and addiction interventions., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Drug manufacturer seeking authorization to bring a newly medicinal compound to the market (Market Authorization Application) have to undertake various studies, each of them providing a specific report. It is however essential to know how to pool results in order to understand the behavior of the drug in all the situations likely to be encountered in clinical practice. The exploitation of these data is now carried out through pharmacometric analyzes which aim at quantifying the exposure and the response of a drug over time. These methods (named "population approach") are based on non-linear mixed effects model and therefore, on the identification of a mathematical model. A first step is to model the variations in concentrations over time by integrating the physio-pathological characteristics of the patients. At this stage, the Bayesian analysis is essential to identify and select the factors of interindividual variability. This pharmacokinetic (PK) modeling allows us to obtain the prescribed dose for each patient, but also their exposure. The second step consists in defining the relationship between exposure and effect: pharmacodynamic (PD) modeling. In psychiatry, the response can be the receptors' occupancy rate or the evolution of a clinical score (BPRS, PANSS…) over time. The final PK-PD model defines the target exposure, that is to say, the concentration values required to achieve maximum effect on the score studied without risking over-exposure. Ultimately, a Monte Carlo simulation will be conducted which will test the expected response for different doses and will facilitate a rational choice in dosage. Assessing the process behind the transition from an oral to a long-acting injectable form of an active ingredient such as aripiprazole can be done by following the same protocol. A 10- to 30-mg per day therapeutic range has thus been identified. The model incorporates all the identified factors of variability of aripiprazole (drug interactions and genetic polymorphism of the P450 2D6 cytochrome) and showed that with an injectable sustained release form, a monthly dose of 400mg would allow 90% of patients to gain exposure in the therapeutic range. In case of a drug inhibition and/or of a slow metabolizing profile, dosage adjustment is necessary., (Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Epidemiologic studies show a frequent co-occurence of affective and eating disorders. The incidence of one disorder in patients suffering from the other disorder is well over the incidence in the general population. Several causes could explain this increased comorbidity. First, the iatrogenic origin is detailed. Indeed, psychotropic drugs, and particularly mood stabilizers, often lead to modification in eating behaviors, generally inducing weight gain. These drugs can increase desire for food, reduce baseline metabolism or decrease motor activity. Also, affective and eating disorders share several characteristics in semiology. These similarities can not only obscure the differential diagnosis but may also attest of conjoint pathophysiological bases in the two conditions. However, genetic and biological findings so far are too sparse to corroborate this last hypothesis. Nonetheless, it is noteworthy that comorbidity of affective and eating disorders worsens patients'prognosis and is associated with more severe forms of affective disorders characterized by an earlier age of onset in the disease, higher number of mood episodes and a higher suicidality. Lastly, psychotropic drugs used in affective disorders (lithium, antiepileptic mood stabilizers, atypical antipsychotics, antidepressants) are reviewed in order to weigh their efficacy in eating disorders. This could help establish the best therapeutic option when confronted to comorbidity., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

Links between affective and endocrine-metabolic disorders are numerous and complex. In this review, we explore most frequent endocrine-metabolic comorbidities. On the one hand, these comorbidities imply numerous iatrogenic effects from antipsychotics (metabolic side-effects) or from lithium (endocrine side-effects). On the other hand, these comorbidities are also associated with affective disorders independently from medication. We will successively examine metabolic syndrome, glycemic disturbances, obesity and thyroid disorders among patients with affective disorders. Endocrinemetabolic comorbidities can be individually encountered, but can also be associated. Therefore, they substantially impact morbidity and mortality by increasing cardiovascular risk factors. Two distinct approaches give an account of processes involved in these comorbidities: common environmental factors (iatrogenic effects, lifestyle), and/or shared physiological vulnerabilities. In conclusion, we provide a synthesis of important results and recommendations related to endocrine-metabolic comorbidities in affective disorders : heavy influence on morbidity and mortality, undertreatment of somatic diseases, importance of endocrine and metabolic side effects from main mood stabilizers, impact from sex and age on the prevalence of comorbidities, influence from previous depressive episodes in bipolar disorders, and relevance of systematic screening for subclinical (biological) disturbances., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

The comorbidity of affective disorders with alcohol use disorder remains insufficiently taken into account. In spite of the well-known frequency of the addict comorbidity in most psychiatric disorders, the level of association between affective disorders and alcohol is still underestimated and poorly understood. The label of "double diagnosis" relates to a simple addition of two independent pathologies. It is suggested to consider a "dual psychopathology" combining the effects of one disorder on the other. Interactions between the two disorders commit a complex state calling a new clinical reading, an adapted therapeutic strategy through a necessary integration of care. Association of alcohol use disorder and affective disorder, particularly in bipolar disorders, is correlated with severity, unstable course, treatment resistance and a greater risk of suicide. Alcohol aggravates depression and hampers therapeutics. Alcohol and mania remain a dreaded danger. The mechanism of the comorbid association does not only refer to a behavioral strategy of compensation but seems strongly based on a shared and crossed vulnerability, related to the genetics of the 5HT carrier and gene Clock. Therapeutic limitations do suggest the implementation of an "integrated" device which supposes a new organization of care and facilitation of collaborations between Addiction and Psychiatry., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

Impulsivity is a complex and important phenomenon in mood disorders. Impulse control disorders, as defined in DSM, are more frequent in mood disorders especially in Bipolar Disorder type I, and are associated with a more severe course of illness. Dimensional studies demonstrate that impulsivity is a core manifestation of bipolar disorder both as state- and trait-dependent markers in patients. Comorbid substance use disorders are often associated with a higher level of impulsivity whereas the relation between suicidal behaviors and higher impulsivity remains uncertain. Moreover, neuropsychological tests were used to study correlation between clinical impulsivity and laboratory measurements of impulsivity. Level of correlation remains weak and several explanations are proposed in the literature., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

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., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

Mood disorders occupy a vast area in the field of psychiatry. Advances in the study of the brain, but also epidemiology and genetics allow us to make more solid connections between these disorders and neurological disorders, resuming a process of reconciliation between both specialties. The purpose of this short review is to draw the attention of the psychiatrist to these links, especially with a brief presentation of the psychiatric manifestations of a number of neurodegenerative diseases and more particularly frontotemporal dementia., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

The phenomenology of dissociative disorders may be complex and sometimes confusing. We describe here two cases who were initially misdiagnosed. The first case concerned a 61 year-old woman, who was initially diagnosed as an isolated dissociative fugue and was actually suffering from severe major depressive episode. The second case concerned a 55 year-old man, who was suffering from type I bipolar disorder and polyvascular disease, and was initially diagnosed as dissociative fugue in a mooddestabilization context, while it was finally a stroke. Yet dissociative disorders as affective disorder comorbidity are relatively unknown. We made a review on this topic. Dissociative disorders are often studied through psycho-trauma issues. Litterature is rare on affective illness comorbid with dissociative disorders, but highlight the link between bipolar and dissociative disorders. The later comorbidity often refers to an early onset subtype with also comorbid panic and depersonalization-derealization disorder. Besides, unipolar patients suffering from dissociative symptoms have more often cyclothymic affective temperament. Despite the limits of such studies dissociative symptoms-BD association seems to correspond to a clinical reality and further works on this topic may be warranted., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

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., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

Coexistence in an individual of an affective disorder and a personality disorder is very common and there is an abundant literature on it. Articles are numerous and heterogeneous ; the results are sometimes imprecise or discordant. Some data are, despite these reserves, shared by the scientific community. The main consensus is first on a bad prognosis, with a high rate of all DSM axes comorbidities, secondly on the trap of a same phenomenology for different underlying mechanisms. A review is presented., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

The attention deficit disorder and the bipolar disorder maintain a complex relation. Indeed, these two syndromes share numerous symptoms that engender numerous diagnostic difficulties. According to several studies, it seems that these two disorders are really different with significant differences at the functional and anatomical level. However, there are common cognitive deficits as well as relatively frequent co-morbidity which is necessary to know in order to adjust the treatment., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: The aim of this review is to summarize the state of knowledge concerning the relationship between cardiovascular risk, sleep abnormalities, and emotional reactivity in patients with bipolar disorder (BD)., Method: A scientific literature search of international articles was performed during August and September 2014 using the PubMed electronic database. We used the following MeSH terms : "Bipolar Disorders", "Cardiovascular risk", "Emotional reactivity", "Sleep apnea", and "Sleep disorder"., Results: Obstructive sleep apnea (OSA) is a sleep disorder strongly associated with BD, which tends to fragment sleep. OSA is associated with an increased cardiovascular risk. Furthermore, emotional hyper-reactivity is favored by "hostility" temperaments, BD and sleep deprivation. The combination of these factors interacts and also results in an increased cardiovascular risk. Taken as a whole, both sleep disorders and emotional hyper-reactivity seem to increase the risk of cardiovascular diseases in BD., Conclusion: These data emphasize the central role of sleep abnormalities and emotional reactivity in the vulnerability of BD to express cardiovascular diseases. From a clinical point of view, these data also emphasize the importance of identifying and care for sleep abnormalities in BD in order to improve BD outcome., (Copyright © 2014 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

Epidemiological studies of major depressive episodes (MDE) highlighted the frequent association of symptoms or signs of mania or hypomania with depressive syndrome. Beyond the strict definition of DSM-IV, epidemiological recognition of a subset of MDE characterized by the presence of symptoms or signs of the opposite polarity is clinically important because it is associated with pejorative prognosis and therapeutic response compared to the subgroup of "typical MDE". The development of DSM-5 took into account the epidemiological data. DSM-5 opted for a more dimensional perspective in implementing the concept of "mixed features" from an "episode" to a "specification" of mood disorder. As outlined in the DSM-5: "Mixed features associated with a major depressive episode have been found to be a significant risk factor for the development of bipolar I and II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring of response to therapeutic". However, the mixed features are sometimes difficult to identify, and neurophysiological biomarkers would be useful to make a more specific diagnosis. Two neurophysiological models make it possible to better understand MDE with mixed features : i) the emotional regulation model that highlights a tendency to hyper-reactive and unstable emotion response, and ii) the vigilance regulation model that highlights, through EEG recording, a tendency to unstable vigilance. Further research is required to better understand relationships between these two models. These models provide the opportunity of a neurophysiological framework to better understand the mixed features associated with MDE and to identify potential neurophysiological biomarkers to guide therapeutic strategies., (Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

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., (Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

DSM-IV mixed states have become the mixed mania and mixed depression in the new DSM-5. One noticeable point is the introduction of nine cations, among which the "with mixed features" specification. These non exclusive specifications may contribute to a more precise identification of mixed clinical pictures, and therefore to offer a more efficient therapeutic answer. Different dimensional approaches are widely documented. They allow the isolation of a mixed factor which is clinically associated with two other specifications: anxious distress and psychotic features. These severity markers may encourage clinicians to be alert about the risk of misdiagnosis, and cautious in the management of these clinical situations., (Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

Because of their compilation of contrasted symptoms and their variable clinical presentation, mixed episodes have been withdrawn from the DSM. However, mixed states question not only the bonds between depression and mania, but also the distinction between bipolar disorders and schizophrenia. Indeed, doubts about the dichotomy introduced by Kraepelin between bipolar disorders and schizophrenia is as old as the nosolgy itself, as attest the later works of this author revealing his hesitations on his own classification. But findings here reviewed issued from recent technical advances, particularly in the imaging and genetic fields, offer a better understanding of the boundaries between these two disorders. Yet, when confronted to an acute episode, clinicians may find it challenging to distinguish a mixed state from a schizophrenic relapse. Indeed, there is no pathognomonic manifestation allowing to retain a diagnosis with confidence. The physician will therefore have to identify a pattern of signs, which will orient his assessment with no certainty. Thus, negative rather than affective or psychotic symptomatology appears to be useful in discriminating schizophrenia (or schizoaffective) disorders from mixed mania. However, a conclusion during this acute stage appears in definitive a formal exercise, first because the final diagnosis will only be ascertained once the symptoms are amended, and second because, according to our classifications, a mood episode, including mania and mixed mania, can be observed without ruling out the diagnosis of schizophrenia., (Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

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., (Copyright © 2013 Sociedade Brasileira de Farmacognosia. Published by Elsevier Masson SAS.. All rights reserved.)

The nosological position of mixed states has followed the course of classifying methods in psychiatry, the steps of the invention of the clinic, progress in the organization of care, including the discoveries of psychopharmacology. The clinical observation of a mixture of symptoms emerging from usually opposite clinical conditions is classical. In the 70s, a syndromic specification fixed the main symptom combinations but that incongruous assortment failed to stabilize the nosological concept. Then stricter criteriology was proposed. To be too restrictive, a consensus operates a dimensional opening that attempts to meet the pragmatic requirements of nosology validating the usefulness of the class system. This alternation between rigor of categorization and return to a more flexible criteriological option reflects the search for the right balance between nosology and diagnosis. The definition of mixed states is best determined by their clinical and prognostic severity, related to the risk of suicide, their lower therapeutic response, the importance of their psychiatric comorbidities, anxiety, emotional lability, alcohol abuse. Trying to compensate for the lack of categorical definitions and better reflecting the clinical field problems, new definitions complement criteriology with dimensional aspects, particularly taking into account temperaments., (Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.)

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., (Copyright © 2013 Sociedade Brasileira de Farmacognosia. Published by Elsevier Masson SAS.. All rights reserved.)