Effects of web-based adapted physical activity on hippocampal plasticity, cardiorespiratory fitness, symptoms, and cardiometabolic markers in patients with schizophrenia: a randomized, controlled study.

Among the lifestyle interventions, the physical activity (PA) has emerged as an adjuvant non-pharmacological treatment improving mental and physical health in patients with schizophrenia (SZPs) and increasing the hippocampus (HCP) volume. Previously investigated PA programs have been face-to-face, and not necessary adapted to patients' physiological fitness. We propose an innovative 16-week adapted PA program delivered by real-time videoconferencing (e-APA), allowing SZPs to interact with a coach and to manage their physical condition. The primary goal was to demonstrate a greater increase of total HCP volumes in SZPs receiving e-APA compared to that observed in a controlled group. The secondary objectives were to demonstrate the greater effects of e-APA compared to a controlled group on HCP subfields, cardiorespiratory fitness, clinical symptoms, cognitive functions, and lipidic profile. Thirty-five SZPs were randomized to either e-APA or a controlled group receiving a health education program under the same conditions (e-HE). Variables were assessed at pre- and post-intervention time-points. The dropout rate was 11.4%. Compared to the e-HE group, the e-APA group did not have any effect on the HCP total volumes but increased the left subiculum volume. Also, the e-APA group significantly increased cardiorespiratory fitness (VO2max), improved lipidic profile and negative symptoms but not cognitive functions. This study demonstrated the high feasibility and multiple benefits of a remote e-APA program for SZPs. e-APA may increase brain plasticity and improve health outcomes in SZPs, supporting that PA should be an add-on therapeutic intervention. ClinicalTrial.gov on 25 august 2017 (NCT03261817).

[What antipsychotic drugs will be in the next decade?] / Les antipsychotiques de la future décade.

Antipsychotic drugs are one of the oldest drugs that can change the brain activity. These drugs are mainly used in schizophrenia and the first drug that was judged as efficacious in the treatment of psychosis has been chlorpromazine. This is a decade later that it has been shown that these drugs were antagonists at the dopamine transmission by blocking the dopamine D2/D3 receptors. Several other pharmacological targets have been tested during the last decades as glutamatergic, serotoninergic, cholinergic and neuropeptidergic agents but none has been shown to improve symptoms of schizophrenia. Three main issues could explain this failure: the exact causes of schizophrenia is still unknown, we still used the idea that one drug could improve all the symptoms of schizophrenia and it is clear that the group of schizophrenics disease could be different disease with different causes. We propose to review the different drugs that have been tested and we will discuss why the most recent genetic studies could help us to propose new pharmacological targets to treat schizophrenia.

Paris MEM: a study protocol for an effectiveness and efficiency trial on the treatment of traumatic stress in France after the 2015-16 terrorist attacks.

BACKGROUND: The Paris and Nice terrorist attacks affected a thousand of trauma victims and first-line responders. Because there were concerns that this might represent the first of several attacks, there was a need to quickly enhance the local capacities to treat a large number of individuals suffering from trauma-related disorders. Since Reconsolidation Therapy (RT) is brief, relatively easy to learn, well tolerated and effective, it appeared as the ideal first-line treatment to teach to clinicians in this context. METHODS: This study protocol is a two-arm non-randomized, multicenter controlled trial, comparing RT to treatment as usual for the treatment of trauma-related disorders. RT consists of actively recalling one's traumatic event under the influence of the ß-blocker propranolol, once a week, for 10-25 min with a therapist, over 6 consecutive weeks. This protocol evaluates the feasibility, effectiveness, and cost-utility of implementing RT as part of a large multi-center (N = 400) pragmatic trial with a one-year follow-up. DISCUSSION: Paris MEM is the largest trial to date assessing the efficiency of RT in the aftermath of a large-scale man-made disaster. RT could possibly reinforce the therapeutic arsenal for the treatment of patients suffering from trauma-related disorders, not only for communities in western countries but also worldwide for terror- or disaster-stricken communities. TRIAL REGISTRATION: Clinical Trials (ClinicalTrials.gov). June 3, 2016. NCT02789982.

[Validation of the French version of the self-evaluation of negative symptoms (SNS)]. / Validation de la version française de l'échelle autoévaluation des symptômes négatifs (SNS).

INTRODUCTION: Schizophrenia is a disorder affecting 1% of the population and is associated with severe functional impairment. Negative symptoms are responsible for the majority of this impairment, and many patients with schizophrenia have negative symptoms. However, their evaluation is still a challenge. Thus, standardized assessments are needed to facilitate identification of these symptoms. Many tools have been developed, but most are based on observer ratings. Self-evaluation can provide an additional outcome measure and allow patients to be more engaged in their treatment. The Self-evaluation of Negative Symptoms (SNS) has been developed recently. This is a remarkably understandable instrument for patients with schizophrenia as it allows them to readily complete it without assistance, providing information with respect to their own perception of negative symptoms. The SNS is a self-assessment that permits patients to evaluate themselves in 5 dimensions of negative symptoms. This validation study for the SNS revealed good psychometric properties alongside satisfactory acceptance by patients. AIM: This study was to confirm the validation of the French version of the self-evaluation of negative symptoms (SNS). METHODS: Patients with schizophrenia or schizoaffective disorder according to the DSM-IV-R, with a stable regimen of anti-psychotic drugs for the last two months, aged more than 18 years old were eligible for the study. Symptoms were rated using the SNS, the Scale for the Assessment of Negative Symptoms (SANS), the Calgary Depression Scale for Schizophrenics (CDSS), the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression and Parkinsonism. Patients were asked to fulfill the SNS twice, 6 weeks apart. RESULTS: Sixty patients were evaluated. Cronbach's coefficient (α=0.8) showed good internal consistency. The SNS significantly correlated with the SANS (r=0.6), the negative sub-score of the BPRS (r=0.6) and the Clinician Global Impression on the severity of negative symptoms (r=0.7). SNS scores did not correlate with level of insight (r=0.08) or Brief Psychiatric Rating Scale positive sub-scores (r=0.2). SNS scores correlated with CDSS scores. However, we did not find correlation between the first item of the CDSS which evaluates depression and the "diminished emotional range" sub-score of SNS. The test-retest of SNS revealed no changes of scores at two evaluations 6 weeks apart. CONCLUSION: The acceptance by patients of the SNS was excellent. The French version of the SNS demonstrated a good internal consistency, good convergent validity and good discriminant validity. The study demonstrates the ability of patients with schizophrenia to accurately report their own experiences. Self-assessments of negative symptoms should be more widely employed in clinical practice because they may allow patients with schizophrenia to develop appropriate coping strategies.

[Association between the violence in the community and the aggressive behaviors of psychotics during their hospitalizations]. / Relation entre la violence intra-hospitalière des patients avec psychoses et la violence dans la communauté.

BACKGROUND: Violence is a common issue in psychiatry and has multiple determiners. The aim of this study is to assess the psychotic inpatients' violence in association with the violence of the neighborhood from which the patients are drawn and to estimate the impact of this environmental factor with regard to other factors. METHOD: A prospective multicenter study was led in nine French cities. Eligible patients were psychotic involuntary patients hospitalized in the cities' psychiatric wards. During their treatments, any kind of aggressive behavior by the patients has been reported by the Overt Aggression Scale (OAS). RESULTS: From June 2010 to May 2011, 95 patients have been included. Seventy-nine per cent of the patients were violent during their hospitalizations. In a bivariate analysis, inpatient violence was significantly associated with different factors: male gender, patient violence history, substance abuse, manic or mixed disorder, the symptoms severity measured by the BPRS, the insight degree and the city crime rate. In a multivariate analysis, the only significant factors associated with the patients' violence were substance abuse, the symptoms severity and the crime rates from the different patients' cities. CONCLUSION: These results suggest that violence within the psychotic patients' neighborhood could represent a risk of violence during their treatments.

[Pharmacological treatments in patients with pervasive developmental disorders: A review]. / Efficacité des traitements pharmacologiques dans les troubles envahissants du développement : une revue de la littérature.

BACKGROUND: Pervasive developmental disorders (PDD) are neurodevelepmental disorders that are characterized by severe deficits in socialisation and communication, and the existence of repetitive and stereotyped interests and behaviours. It is estimated more than 60/100,000 children are suffering from PDD. Comorbid disorders are common in people with PDD, including intellectual deficiency, symptoms of attention deficit-hyperactivity, aggression and disruption, and pervasive repetitive behaviours or thoughts. These symptoms have a negative impact on the outcome and quality of life of the patients and their caregivers. The first-line management of comorbid disorders in PDD is behavioural intervention, but sometimes this is not sufficient, and the use of pharmacological treatment is needed. METHOD: We conducted a review of studies of medical treatments used in patients with PDD to establish which treatments show good evidence of efficacy in PDD. We used the Medline database and the following keywords "pervasive development disorders" or "autism spectrum disorders" or "autistic disorder" and "therapy" or "treatment". RESULTS: The treatments that showed the best efficacy on irritability in well-designed studies are second generation antipsychotics, risperidone and aripiprazole. Some studies indicate that haloperidol is efficient as well, but the very high frequency of extra-pyramidal effects limits its use. Methylphenidate has shown some efficacy on impulsivity and hyperactivity in randomised placebo-controlled studies. First data concerning atomoxetine are promising but better-designed studies are needed. Selective serotonin re-uptake inhibitors: fluvoxamine and fluoxetine have shown some efficacy in the treatment of serious and pervasive repetitive behaviours. Alpha-adrenergic treatments, clonidine and guanfacine, can help in the management of disruptive behaviours in patients with PDD. Data concerning naltrexone are contradictory, indeed many case reports of its efficacy on aggressive (mostly auto-aggressive) behaviours are reported in the literature, but well-designed studies do not find any improvement in patients treated with naltrexone compared with patients treated with placebo. First data concerning ocytocin are promising, indeed, if they were to be confirmed, that would be the first treatment efficient on the core symptoms of PDD.

[Chlorpromazine-induced agranulocytosis: a case report]. / Toxicité médullaire des phénothiazines : à propos d'un cas d'agranulocytose sous chlorpromazine.

CASE REPORT: We report the case of a 50-year-old man, treated with chlorpromazine for schizophrenia, who developed an agranulocytosis. Three mechanisms of drugs-induced agranulocytosis have been reported: toxic, genetic and immune. Phenothiazines are responsible for drug-induced agranulocytosis. This patient had been treated with first and second generation antipsychotic drugs during his life and had already been exposed to chlorpromazine or other phenotiazines without any signs of toxicity. However, two months after the introduction of chlorpromazine he presented an agranulocytosis (leukocytes 1.4G/L and neutrophils 0.2G/L). After discontinuation of chlorpromazine, blood count returned to normal. The role of chlorpromazine in inducing toxic agranulocytosis was based on: (i) normal blood count before the introduction of chlorpromazine; (ii) occurrence of agranulocytosis within the first weeks of chlorpromazine treatment; (iii) normal bone marrow and blood count after discontinuation of chlorpromazine; (iv) chlorpromazine was the only new drug prescribed to this patient at the time the agranulocytosis occurred. Risk factors for toxic agranulocytosis in this patient were: old age, association of phenothiazine with other drugs known to be able to induce agranulocytosis, and past history of use of high doses of chlorpromazine. DISCUSSION: This case report highlights the risk of chlorpromazine in inducing agranulocytosis, a risk underestimated in regard of the clozapine risk to induce agranulocytosis or neutropenia. For this reason, it seems reasonable to recommend performing a blood count before introduction of phenothiazine in patients with risk factors for toxic drug-induced agranulocytosis (old age, female, receiving other drugs with a high potential to induce agranulocytosis and having received high doses of phenothiazine for a long time).

[Confusion and delusions occurring during interferon-alpha treatment]. / Syndrome confuso-délirant sous IFN alpha.

A number of side effects occurring during IFN therapy have been described. Psychiatric side effects include cognitive, behavioural and affective changes, confusion and, less commonly, psychotic symptoms. We report the case of a 52-year-old patient who had been treated for almost three years with IFN alpha for a chronic myelogenous leukemia and who presented an acute confusional episode with delusions, following the reintroduction of IFN alpha after a therapy suspension of 2 weeks. Clinical improvement occurred quite rapidly after cessation of the IFN treatment; this evolution and the normality of the biological tests, EEG and cerebral imagery suggest a causal relationship between this treatment and the psychiatric symptoms.

[Validation of the French translation and factorial structure of the Tiffany and Drobes Smoking Urge Questionnaire]. / Validation de la traduction française et de la structure factorielle du Questionnaire sur l'urgence à fumer de Tiffany et Drobes (QSU).

UNLABELLED: Over the past 10 years researches and clinicians have made substantial progress in understanding and treating nicotine dependence. To demonstrate the effectiveness of these treatments, reliable and sensitive measures of change and outcome must be used. In the nicotine dependence treatment literature numerous outcome have been used: frequencies drug use, problems associated with substance use, psychiatric comorbidity, withdrawal severity, and craving. The term craving reflects the subjective reports of addicts regarding their attempts to abstain from drug use and the state of their minds at the point at which they attempt to fail. Exposure to cues previously associated with nicotine play a role in precipitating relapse in eliciting a conditioned craving/withdrawal response and can be measures by the Questionnaire of Smoking Urge (QSU). OBJECTIVE OF THE STUDY: Validation in a French translated version of the QSU published in 1991 by Tiffany and Drobes. METHODOLOGY: 42 male and 62 female participated in the study with the translated questionnaire: mean age was 36.7 years, mean age at starting and mean duration of tobacco consumption was respectively 20.2 years old and 16.5 years, daily consumption was 16.6 cigarettes per day. The French translation of the QSU was administered to smokers instructed to abstain from smoking one hour and a half to three hours. RESULTS: The back translation has been accepted by Tiffany because more than 85% of the items are similar to the original questionnaire. We founded the same factor analysis with two factors, "desire to smoke" and "intention to smoke" accounting for 34% and 11% of the items variance, respectively. These two factors were the same than those of the original questionnaire. CONCLUSION: The validation of the French translation of the QSU gives the opportunity to use a sensitive instrument to assess craving.

The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders.

The role of the D(3) receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D(3) receptor. The D(3) receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D(3) receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D(3) receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D(3) receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.

BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization.

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.

Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia.

Schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities or physical anomalies supports a neurodevelopmental etiology, especially in early onset schizophrenia. Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse. In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression. In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166-174 bp) between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172-176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 Ball gene polymorphism in the same population. These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia.