[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.

[Affective disorders and impulsivity]. / Troubles affectifs et impulsivité.

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.

[Short history of mixed states]. / Une approche historique des états mixtes.

The notion of mixed states is classically associated with descriptions and categories inherited from Kraepelin. However, simultaneous descriptions of depressive and manic manifestations can be traced back to ancient times. Semiology and definitions of these clinical associations have evolved across the times. We provide here a short insight on four distinct periods: Greek authors from ancient times, pre-Kraepelinian psychiatry (18th and 19th centuries), Kraepelin's conceptualization, and contemporary psychiatry (20th and 21st centuries).

[Mixed states and schizophrenia]. / États mixtes et schizophrénie.

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.

[Clinical description of mixed mania]. / Clinique des manies mixtes.

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.

[Pathophysiological models of mixed states]. / Modèles physiopathologiques des états mixtes.

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.

[Treatment of depressive mixed states]. / Le traitement des dépressions mixtes.

Mixed states are a frequent mood state characterized by the mixture of manic and depressive symptoms. Their clinical description has been studied for centuries but has known a renewal of interest recently. Several authors intend to redefine its diagnostic criteria to develop an appropriate therapeutic strategy. Current recommendations suggest to treat mixed depression as a mixed state whatever the dominant polarity is, and therefore according to the rules of therapeutic management of the manic state. Mood stabilizers and antipsychotic medications are indicated and have proven their effectiveness. Lithium, which was considered controversial, now appears to have some therapeutic value, especially in the prevention of suicidal behavior. The depressive component of mixed states, even pronounced, should not be an argument for a prescription of antidepressants, at the risk of aggravating clinical components such as irritability and impulsivity and increasing the danger of suicide attempt. Furthermore, electroconvulsivetherapy represents a real alternative ; psychotherapies have their place in relapse prevention and psychoeducation, but not during acute phases. Finally, an accurate assessment and appropriate management of suicide risk should be a constant concern for the clinicians.

[Recommendations for the treatment of mixed episodes in current guidelines]. / Recommandations sur le traitement des épisodes mixtes dans les guidelines actuels.

A literature search on the pharmacological treatment of acute bipolar mixed episodes in current guidelines shows that only seven of them address the acute management of mixed episodes as a separate condition, whereas the vast majority of these guidelines include the treatment of mixed episodes in the chapter of mania. As a general rule, most guidelines advise to stop antidepressant treatment and mention the superiority of valproate over lithium. Specific recommendations for the treatment of "mixed states" can be found in two guidelines, while specific recommendations for that of "mixed mania" are present in five of them. Recommendations for the treatment of "mixed depression" exist in only three guidelines. If some consensus may be found for the treatment of "mixed states" as a whole, recommendations for the treatment of "mixed mania" appear to be variable, whereas those for the treatment of "mixed depression" seem to be limited.

[Psychotherapeutic and psychosocial interventions and endophenotypes in bipolar disorders]. / Interventions psychothérapeutiques et psychosociales et endophénotypes dans les troubles bipolaires.

Diseases with complex determinism, bipolar disorders, involve at the same time environmental and genetic factors of vulnerability. The characterization of these vulnerabilities would allow a better knowledge of their etiology and envisage the development of therapeutics, more specialized, even preventive. The research in genetic psychiatry allowed to highlight endophenotype candidates associated to bipolar disorders. They are endogenous clinical or biological features, biologically more elementary than phenotypes and more directly bound to the physiological consequences of genes and their polymorphisms. Targeting some of them with specific psychotherapy and psychosocial interventions could reduce the consequences of their expression and so have an action on the course of the disease and also preventive.

[Temperamental endophenotypes]. / Les endophénotypes tempéramentaux.

Temperament has been defined as the heritable biologically determined core of personality that remains stable throughout the life span and establishes the baseline level of reactivity, mood, and energy of a person. If the link between temperament and mental disorder goes back to the Greco-Roman medicine, Kraepelin was among the first authors to pay attention to the temperamental bases of bipolar disorder. He proposed four temperamental types that he described in the premorbid histories of the majority of manic-depressive patients, and found overrepresented in the biologic relatives of these patients. Building on this ancestry, Akiskal formulated the modern concept of affective temperament, and described five temperaments: depressive, hyperthymic, cyclothymic, irritable, and anxious. According to Akiskal's model, bipolar disorder lies along a continuum from temperament to full-blown episodes of affective illness. A series of recent studies have shown the role played by temperaments in the outbreak of bipolar episodes, their clinical presentation, as well as the illness course and comorbidities. Furthermore modern familial and genetic studies have confirmed the first observations of Kraepelin. It has been recently proposed that affective temperaments may carry distinct evolutionary advantages on the individual or a group level, so that affective disorders would be genetic reservoirs for adaptative temperaments and the price to be paid for the chance of exceptionality. Apart from these theoretical perspectives, paying attention to temperamental components may have important implications for the treatment of bipolar disorder. Finally recent studies confirmed as well, that the concept of affective temperament fulfilled the criteria required to be considered as an endophenotype.

[Schizophrenia and/or bipolar disorder: the neurocognitive endophenotypes]. / Schizophrénie et/ou trouble bipolaire : les endophénotypes neurocognitifs.

Although Kraepelinian dichotomous conceptualization of psychosis was historically beneficial, modern studies do not support the existence of a sub-typing of psychotic illnesses into schizophrenic and affective psychoses. Years of intensive investigation on the genetic bases of schizophrenia and bipolar disorder suggest that these disorders, rather than being wholly distinct disorders, share common genetic risks. However, one of the most serious difficulties for genetic research in these illnesses is their enormous phenotypic heterogeneity. A response to this problem is the use of neurocognitive functions as endophenotypes or intermediate phenotypes. A review of the literature suggests that in both schizophrenia and bipolar disorder, neurocognitive functions are influenced by genetic factors and that there exists neuropsychological deficits in the nonaffected relatives of probands. However, it is unclear whether or not patterns of performance on neurocognitive tasks across probands as well as unaffected family members offer potential for identifying shared and illness-specific neurocognitive phenotypes for schizophrenia and bipolar disorder. Overlapping and unique neurocognitive endophenotypic signatures of the two psychoses are comprehensively described.

[Emotion endophenotypes in bipolar and schizophrenic disorders]. / Les endophénotypes émotionnels dans les troubles bipolaires et la schizophrénie.

Because of its proximity to the vulnerability model hypotheses and its correlation to functional outcome, emotional processing has emerged as a major topic of research in bipolar as well as schizophrenia disorders. By experimental necessity, the somewhat vague notion of emotion has been parceled into several dimensions. Thus, the aptitude to perceive and decrypt emotional stimuli has been artificially differentiated between the emotional feelings reported by subjects and the concomitant physiological changes. A large literature has been built to characterize a singular emotional profile combining a deficit in facial affect recognition with preserved or even enhanced emotional experience of negative emotions. Even though emotional disturbances tend to be intuitively associated with bipolar disorders, this latter profile is far better documented in schizophrenia. Furthermore, several studies of high-risk individuals or of relatively healthy populations allow for selecting some of these emotional disturbances as endophenotypes. Conversely, functional imaging works have explored the cortico-limbic circuit underlying these functions in both the acute and stabilized phases of these illnesses. Here again, a fairly common pattern seems to emerge in both disorders with hyperactivity of the limbic system and failure to activate the modulating regions of the prefrontal cortex. However, inconsistencies in results need to be addressed, and neuroimaging works on healthy relatives or high-risk individuals are still very scarce. These results are discussed in light of the models of shared genetic vulnerability between schizophrenia and bipolar disorders.

[Schizophrenia and/or bipolar disorder: neurobiological endophenotypes]. / Schizophrénie et/ou trouble bipolaire : les endophénotypes neurobiologiques.

BACKGROUND: The term endophenotype was used by Gottesman (1991) to describe a trait that may be intermediate on the chain of causality from genes to diseases. Some family relatives of affected patients also carry the endophenotype, although not the disease phenotype. The increased penetrance of the endophenotype, and its closer relationship to the gene than that of the phenotype proper, are expected to help genetic studies. An endophenotype may be neuropathological, neurocognitive, emotional, neurophysiological or neurobiological in nature. OBJECTIVE: We aim at identifying neurobiological endophenotypes for schizophrenia and bipolar disorder. METHODS: We used a survey of neurobiological studies to select and evaluate endophenotype candidates for schizophrenia and for bipolar disorder. RESULTS: Neurobiological endophenotype candidates for schizophrenia include lateral ventricles enlargement, grey matter atrophy in frontal lobe and insula, decreased levels of N-acetyl-aspartate in the hippocampus and niacin-induced flushing. Neurobiological endophenotype candidates for bipolar disorder include tryptophan depletion-induced planning impairment, abnormalities of reward system, psychostimulants-induced behavioural differences, hypersensitivity to cholinergic REM induction test and abnormalities of immune and hypothalamus-pituitary-adrenergic system. CONCLUSIONS: More studies to evaluate endophenotype candidates with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged in schizophrenia and bipolar disorder.

[What perspectives for cognitive remediation in schizophrenia?]. / Quelles perspectives pour la remédiation cognitive dans la schizophrénie?

Cognitive deficits are routinely evident in schizophrenia, and are of sufficient magnitude to influence functional outcomes in work, social functioning and illness management. Cognitive remediation is an evidenced-based non-pharmacological treatment for the neurocognitive deficits seen in schizophrenia. Narrowly defined, cognitive remediation is a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning, but from the vantage of the psychiatric rehabilitation field, cognitive remediation is a therapy which engages the patient in learning activities that enhance the neurocognitive skills relevant to their chosen recovery goals. Cognitive remediation programs vary in the extent to which they reflect these narrow or broader perspectives but a metaanalytic study reports moderate range effect sizes on cognitive test performance, and daily functioning. Reciprocal interactions between baseline ability level, the type of instructional techniques used, and motivation provide some explanatory power for the heterogeneity in patient response to cognitive remediation. Recent studies indicate that intrinsic motivation mediates the relationship between neurocognition and functional outcomes. Results of these studies suggest that intrinsic motivation should be a viable treatment target in cognitive remediation intervention. In this perspective, NEAR (Neuropsychological Educational Approach to Remediation) program was created to enhance intrinsic motivation by employing more engaging and interesting software packages for cognitive practice, involving consumers in choosing the focus of training and having the NEAR leader serve as a coach to engage the consumers in active guidance of their own treatment program.

[Schizophrenia, executive control and memory]. / Schizophrénie, fonctions exécutives et mémoires.

Schizophrenia affects 1% of the general population. In addition to disabling clinical symptoms, cognitive deficits have also been updated. It has further been proposed that the well-known diversity of schizophrenia in terms of functional outcome and recovery from acute episode is best characterized by cognitive deficits, but not by its classical symptoms. DSM-V acknowledges the importance of cognition in schizophrenia, and could recommend a formal neuropsychological assessment in individuals with psychosis. Schizophrenic patient's cognitive functioning has been studied extensively in the domain of memory and executive control. To date, the studies highlight important deficits in both of these domains. However, within the memory systems, some of them remain unaffected. Altogether, the data invalidate the hypothesis of a global damage and are in favor of specific cognitive deficits. The observed deficits would depend on the dominant symptoms and pre-morbid functioning. The interest of these results was to give impulse to the development of comprehensive assessment battery designed to evaluate the cognitive profiles of each patient and develop a personalized program of cognitive remediation.