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

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

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

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

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

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

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

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

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

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

[How to evaluate side effects in a clinical trial?] / Comment évaluer les effets indésirables au cours d'un essai clinique ?

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.

[How to assess curative and/or preventive effects of psychotropic drugs?] / Comment évaluer l'effet curatif et/ou préventif des psychotropes ?

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.

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

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

[Electroconvulsive therapy and level of evidence: From causality to dose-effect relationship]. / Électroconvulsivothérapie et niveau de preuve : de la causalité à la relation dose-effet.

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.

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

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

[Can we assess the efficacy of psychotherapies in a clinical trial?] / Peut-on évaluer l'efficacité des psychothérapies à l'aide d'un essai clinique ?

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.

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

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

Predominant polarity in bipolar disorders: Further evidence for the role of affective temperaments.

BACKGROUND: Literature suggests bipolars may differ in several features according to predominant polarity, but the role of temperaments remains controversial. METHODS: The EPIDEP study was designed to identify bipolar patients among a large sample of major depressives. Only bipolars were included in the current study. Patients were subtyped as predominantly depressive (PD) and predominantly manic and hypomanic (PM) according to a broad (more episodes of a given polarity) and a narrow (2/3 of episodes of one polarity over the other) definition, and compared on their characteristics. RESULTS: Among 278 bipolars, 182 (79.8%) could be subtyped as PD and 46 (20.2%) as PM (broad definition); the respective proportions were of 111 (81.6%) and 25 (18.4%) using narrow definition. Expanding the definition added little in detecting differences between groups. Compared to PDs, PMs showed more psychosis, rapid cycling, stressors at onset, family history of affective illness, and manic first episode polarity; they also received more antipsychotics and lithium. The PDs showed more chronic depression, comorbid anxiety, and received more antidepressants, anticonvulsants and benzodiazepines. The following independent variables were associated with manic/hypomanic predominant polarity: cyclothymic temperament, first hospitalization≤25 years, hyperthymic temperament, and alcohol use (only for broad definition). LIMITATION: Cross-sectional design, recall bias. CONCLUSIONS: Study findings are in accord with literature except for suicidality and mixicity which were related to predominant mania, and explained by higher levels of cyclothymic and hyperthymic temperaments. Temperaments may play a key role in the subtyping of bipolar patients according to predominant polarity, which warrants confirmation in prospective studies.

[Negative symptoms: clinical and psychometric aspects]. / Symptômes négatifs: clinique et psychométrie.

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.

[Negative symptoms, emotion and cognition in schizophrenia]. / Symptômes négatifs, émotions et cognition dans la schizophrénie.

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.

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

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