D. Ducasse

Antipsychotic drugs: Pro-cancer or anti-cancer? A systematic review

INTRODUCTION Important data was recently published on the potential genotoxic or carcinogenic effects of antipsychotics, as well as on their cytotoxic properties on cancer cells, that must be considered by psychiatrists in the benefit/risk ratio of their prescriptions. AIM OF THE STUDY To answer whether or not antipsychotics, as a class or only some specific molecules, may influence cancer risk among treated patients. METHODS ELIGIBILITY CRITERIA: All studies (in vitro, animal studies and human studies) concerning effects of antipsychotic drugs on cancer development were included. The search paradigm [neoplasms AND (antipsychotic agents OR neuroleptic OR phenothiazine)] was applied to Medline (1966-present) and Web of Science (1975-present). RESULTS Ninety-three studies were included in the qualitative synthesis. Results can be summarized as follows: (1) patients with schizophrenia may be less likely to develop cancer than the general population, (2) antipsychotics as a class cannot be considered at the moment as at risk for cancer, even if some antipsychotics have shown carcinogenic properties among rodents, (3) phenothiazines seem to have antiproliferative properties that may be useful in multidrug augmentation strategies in various cancer treatments, but their bad tolerance may decrease usage amongst non-psychotic patients, and (4) clozapine appears to have a separate status given that this molecule shows antiproliferative effects implied in agranulocytosis as well as a potential increased risk for leukemia. CONCLUSION Benefit/risk ratio regarding cancer risk is in favor of treating patients with schizophrenia with antipsychotic drugs. The practicing clinician should be reassuring on the subject of cancer risk due to antipsychotic drugs.

La thérapie d’acceptation et d’engagement

INTRODUCTION Acceptance and commitment therapy (ACT) is a third generation of cognitive-behavioral therapies. The point is to help patients to improve their psychological flexibility in order to accept unavoidable private events. Thus, they have the opportunity to invest energy in committed actions rather than struggle against their psychological events. OBJECTIVES OF THE STUDY (i) To present the ACT basic concepts and (ii) to propose a systematic review of the literature about effectiveness of this kind of psychotherapy. METHOD (i) The core concepts of ACT come from Monestès (2011), Schoendorff (2011), and Harris (2012); (ii) we conducted a systematic review of the literature using the PRISMAs criteria. The research paradigm was « acceptance and commitment therapy AND randomized controlled trial ». The bases of the MEDLINE, Cochrane and Web of science have been checked. RESULTS Overall, 61 articles have been found, of which, after reading the abstracts, 40 corresponded to the subject of our study. (I) Psychological flexibility is established through six core ACT processes (cognitive defusion, acceptance, being present, values, committed action, self as context), while the therapist emphasizes on experiential approach. (II) Emerging research shows that ACT is efficacious in the psychological treatment of a wide range of psychiatric problems, including psychosis, depression, obsessive-compulsive disorder, trichotillomania, generalized anxiety disorder, post-traumatic stress disorder, borderline personality disorder, eating disorders. ACT has also shown a utility in other areas of medicine: the management chronic pain, drug-dependence, smoking cessation, the management of epilepsy, diabetic self-management, the management of work stress, the management of tinnitus, and the management of multiple sclerosis. Meta-analysis of controlled outcome studies reported an average effect size (Cohens d) of 0.66 at post-treatment (n=704) and 0.65 (n=580) at follow-up (on average 19.2 weeks later). In studies involving comparison between ACT and active well-specified treatments, the effect size was 0.48 at post (n=456) and 0.62 at follow-up (n=404). In comparisons with waist list, treatment as usual, or placebo treatment, the effect sizes were 0.99 at post (n=248) and 0.71 at follow-up (n=176). Furthermore, ACT studies pointed out learning specific skills, such as decreasing experiential avoidance, increasing cognitive defusion, acceptance and contact with the present moment. Finally, all ACT studies showed an improved quality of life. DISCUSSION The loss of psychological flexibility is the origin of the pain caused by psychiatric disorders and chronic diseases. This is why other studies are needed to investigate ACTs full potential.

Acceptance and Commitment Therapy for Management of Suicidal Patients: A Pilot Study

(6) pharmacological treatment and number of visits for psychiatric emergencies in the previous 3 months. Self-assessments included: (1) suicidal ideation on a visual analogue scale from 0 (none) to 10 (maximum), currently and during the last 15 days; (2) depressive intensity using Beck Depression Inventory-II (BDI); (3) psycho-logical pain on a visual analogue scale from 0 (none) to 10 (maxi-mum); (4) anxiety state using the State-Trait Anxiety Inventory (STAI); (5) hopelessness during the last month using the Beck Hopelessness Scale; (6) quality of life using the World Health Or-ganization Quality of Life measure, and (7) acceptance using the Acceptance and Action Questionnaire (AAQ) [10] . Considering the small sample size and skewed distribution of most continuous variables, median (min–max) and non-paramet-ric tests were used. Friedman’s tests for quantitative variables and Cochran’s Q test for categorical variables were used to globally compare the three time points. If the global p value was p < 0.05, two-by-two comparisons were run (signed rank, McNemar’s and kappa tests) and corrected for multiple comparisons (Bonferroni correction). Spearman’s rank order correlations were applied to measure associations between continuous variables. Statistical analyses were performed using SAS software, version 9.2 (SAS In-stitute, Cary, N.C., USA). Two patients did not start the programme; 78.8% attended all sessions. ACT was reported to be helpful by 96.9% patients. One patient (suffering from borderline personality disorder) commit-ted suicide during the first month of the study, without any clear association with intervention. Sociodemographic characteristics were as follows: 57.1% males, median age 38.4 years (min–max: 18–60), 48.6% single, 60% fully employed. The majority of patients were currently depressed (94.3%), having attempted suicide the month preceding the inclu-sion (93.9%). Psychiatric disorders were unipolar (37.1%), bipolar (57.1%), anxiety (97.1%), addictive (28.6%), eating (17.1%), and/or borderline personality (20%) disorders. All participants were on psychotropic medications. There were significant differences for all scores between the three visits (p < 0.001). Between inclusion and the 1-week follow-up, there was a significant reduction of the C-SSRS ‘suicidal ide-ation’ subscore [20 (0–30) vs. 0 (0–20), respectively; p < 0.001], SSI score [7 (0–22) vs. 0 (0–10); p < 0.001] as well as intensity of current and previous suicidal ideations during the last 15 days [1 (0–10) vs. 0 (0–3), 2 (0–9) vs. 0 (0–5), respectively; both p < 0.001]. Of note, reduction in the C-SSRS ‘suicidal ideation’ subscore was cor-related to the AAQ score (p = 0.04, r = –0.37), but not to BDI and STAI scores. Between inclusion and 3-month follow-up, the re-duction of all suicidal ideation scores remained significant. There were no suicide reattempts during the follow-up period. With one million deaths every year, suicide is a major health problem worldwide. Recently, suicidal behaviour disorder (SBD) has been included in DSM-5 as an independent clinical entity [1] . It highlights the need to address the suicidal process as a primary target of concern and to identify corresponding transnosographic preventive strategies, including psychotherapy. Acceptance and Commitment Therapy (ACT), a ‘third-wave’ behavioural therapy, targets experiential avoidance (tendency to avoid unwanted thoughts or emotions) at the core of psychiatric disorders. Of note, suicidal subjects report intrusive mental images of suicide that they try to suppress, increasing in their intensity and frequency, inde-pendently from depressive symptoms [2] . Indeed, experiential avoidance would predict suicidal behaviours [3] . Moreover, two case reports have suggested the preventive role of ACT on suicidal reattempts at 1 year [4] . Thus, we aimed at examining the useful-ness of an add-on ACT group programme to decrease suicidal ide-ation in high-risk patients. The study was conducted in the Department of Psychiatric Emergency and Acute Crisis, Academic Hospital of Montpellier, France. Thirty-five outpatients suffering from a current SBD ac-cording to DSM-5 [1] (history of suicidal attempt in the past year) were included in an ACT programme ( table 1 ) [5–7] . Exclusion criteria were current mania or depressive episode with mixed fea-tures, and schizophrenia. Patients were assessed at inclusion (1 week before the pro-gramme, T0) and 1 week (T1) and 3 months (T2) after programme completion. Psychiatrists assessed: (1) suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS) [8] (suicidal ide- ation subscore = severity and intensity items) and the Scale for Suicidal Ideation (SSI score) [9]; (2) psychiatric disorders using the French version of the Mini International Neuropsychiatric Inter-view; (3) borderline personality disorder using the Screening In-terview for Axis II Disorder; (4) depressive symptomatology using the Inventory of Depressive Symptomatology (IDS-C30); (5) glob-al functioning using the Functioning Assessment Short Test, and

Burning mouth syndrome: current clinical, physiopathologic, and therapeutic data.

Abstract Primary burning mouth syndrome (BMS) is defined as an “intraoral burning for which no medical or dental cause was found.” Lifetime prevalence ranges from 3.7% to 18% – 40% in the elderly. There is no consensus among experts on the diagnostic criteria of BMS, the etiology is poorly understood, and there are no existing clinical guidelines. Therefore, BMS is often underdiagnosed and its management complex. For patients with BMS, this lack of clinical expertise may result in decreased quality of life and increased psychological distress. We conducted a systematic review to identify clinical features, pathophysiology, and therapeutic strategies for BMS. We discuss the multifactorial origin, involving peripheral nerve dysfunction and hormonal dysfunction, as well as psychological traits. We also describe the results of randomized clinical trials for each treatment through a pathophysiologic approach. This review should help clinicians recognize BMS, understand its pathophysiology, and gain an enhanced scientific understanding of therapeutic alternatives.

A meta-analysis of cytokines in suicidal behavior

BACKGROUND We conducted the first meta-analysis of studies comparing the plasma and CSF concentrations of cytokines in suicidal patients vs. non-suicidal patients or healthy controls. METHODS We searched Medline, Web of Science, and PsycINFO from 1965 to November 2014 for relevant studies. Manual searches of references and unpublished data were also included. Suicidal patients included severe suicide ideators and suicide attempters. RESULTS Eleven articles were available for the meta-analysis, for a total sample size of 494 suicidal patients, 497 non-suicidal patients and 398 healthy controls. Levels of 6 independent plasma cytokines (IL2, IL6, TNFalpha, IFNgamma, IL4, TGFbeta) were meta-analyzed for plasma studies comparing suicidal vs. both controls. IL8 level was meta-analyzed for cerebrospinal fluid studies comparing suicidal patients with healthy controls. We reported with medium effect size, that suicidal patients had: (1) lower IL2 plasma levels than both non-suicidal patients and healthy controls (medium effect size); (2) lower IL4 and higher TGFbeta plasma levels than healthy controls. CONCLUSION Our results promote the hypothesis of altered inflammatory markers in suicidal patients, for both pro-inflammatory (IL2) and anti-inflammatory (IL4 and TGFbeta) cytokines.

Increased risk of suicide attempt in bipolar patients with severe tobacco dependence

BACKGROUND The aim of our study was to investigate, in bipolar patients, the association between tobacco status (use and dependence) and history of suicide attempt, and to assess the possible role of inflammation as a missing link in the association between smoking status and history of suicide attempt. METHODS A total of 453 adult bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups: 274 patients without past history of suicide attempt (non-SA), and 179 patients with a past history of suicide attempt (SA). Tobacco use and dependence, psychiatric and somatic comorbidities, history of childhood abuse, family history of suicide were assessed. Fasting blood tests yielded samples collected for the measurement of high sensitivity (hs-)CRP. RESULTS The risk of suicide attempt increased with smoking dependence. Notably, bipolar patients with a history of suicide attempt were three times more likely to have severe tobacco dependence, independently of confounding factors. However, we failed to find arguments promoting the hypothesis of inflammatory markers (through hs-CRP measure) in the link between tobacco dependence and suicidal behavior. CONCLUSIONS We found a significant association between severe tobacco dependence and history of suicide attempt, but not with level of CRP, independently of confusing factors. Longitudinal studies taken into account all these potential confusing factors are needed to confirm our results.

D2 and D3 dopamine receptor affinity predicts effectiveness of antipsychotic drugs in obsessive-compulsive disorders: a metaregression analysis

Rationale and objectiveThe relationship between clinically effective antipsychotic drugs in obsessive–compulsive disorders (OCD) and binding affinities to cloned dopamine and serotonin receptor subtypes was analyzed in an effort to clarify the contribution of individual receptor subtypes to medication response.MethodsMeta-analysis was used to update previous meta-analyses of effectiveness data of add-on antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) in OCD. Twelve previously analyzed randomized controlled trials (RCTs) and one new RCT were included. We performed a metaregression using a mixed-effect model to examine the association between antipsychotic’s effectiveness and receptor affinity.ResultsA total of 5 treatment arms obtained from 13 RCTs (431 patients) were included in our study. The results of our metaregression showed a significant association between D2 and D3 dopamine receptor affinities and effectiveness in OCD (respectively, slope = −0.36, p = 0.01; and slope = −0.50, p = 0.01) whereas other dopamine receptors and serotonin receptors were not significantly associated.ConclusionsThese observations suggest that increasing D2 and D3 dopamine receptor binding affinities enhances antipsychotics’ effectiveness in obsessive–compulsive disorders.

Increased CRP levels may be a trait marker of suicidal attempt

Suicide is a leading cause of death worldwide. Identifying biomarkers will help enhance our understanding of suicidal pathophysiology and improve its prevention. Therefore, we investigated CRP levels in 600 depressed inpatients: 520 patients had a lifetime history of suicide attempts and 80 patients did not have any history of suicide attempts. For all patients, we assessed socio-demographic features, lifetime Axis I DSM-IV diagnoses, depression intensity, suicidal ideation, characteristics of suicidal history, and history of childhood trauma. The day following admission, fasting blood tests yielded samples collected for the measurement of high sensitivity hs-CRP. CRP levels were associated with a history of suicide attempts. The risk of suicide attempts increased with higher levels of CRP in a dose-response way before and after adjustments for age, gender, chronic diseases, addiction and anxiety comorbidities, antidepressants use, smoking status and sexual abuse. Noteworthy, the association between CRP levels and history of suicide attempts remained significant after having excluded patients with chronic diseases. There was no significant difference in CRP levels between patients who attempted suicide more or less than a week before plasma sampling, and no significant difference in CRP levels was evidenced between high vs low suicidal ideation. In conclusion, this is the first study suggesting that CRP may be a trait marker for suicidal vulnerability by associating CRP levels and a lifetime history of suicide attempts in depressed inpatients. Therefore, determining the inflammatory marker profile of individuals exhibiting suicidal behaviors could be relevant for anticipating behaviors and refining new therapeutic opportunities.

Neuroinflammation in suicide: Toward a comprehensive model

Objectives. Suicidal behaviour (SB) entered the DSM-5, underlying a specific biological vulnerability. Then, recent findings suggested a possible role of the immune system in SB pathogenesis. The objective of this review is to present these main immune factors involved in SB pathogenesis. Methods. We conducted a review using Preferred Reporting Items for Systematic reviews and Meta-Analysis criteria, and combined (“Inflammation”) AND (“Suicidal ideation” OR “Suicidal attempt” OR “suicide”). Results. Post mortem studies demonstrated associations between suicide and inflammatory cytokines in the orbitofrontal cortex, a brain region involved in suicidal vulnerability. Also, microgliosis and monocyte–macrophage system activation may be a useful marker of suicide neurobiology. Kynurenine may influence inflammatory processes, and related molecular pathways may be involved in SB pathophysiology. Few recent studies associated inflammatory markers with suicidal vulnerability: serotonin dysfunction, impulsivity and childhood trauma. Interestingly, the perception of threat that leads suicidal individuals to contemplate suicide may activate biological stress responses, including inflammatory responses. Conclusions. Translational projects would be crucial to identify a specific marker in SB disorders, to investigate its clinical correlations, and the interaction between inflammatory cytokines and monoamine systems in SB. These researches might lead to new biomarkers and novel directions for therapeutic strategies.

Treating patients with schizophrenia deficit with erythropoietin

This systematic review summarizes and critically appraises the literature on the effect of erythropoietin (EPO) in schizophrenia patients and the pathophysiological mechanisms that may explain the potential of its use in this disease. EPO is mainly known for its regulatory activity in the synthesis of erythrocytes and is frequently used in treatment of chronic anemia. This cytokine, however, has many other properties, some of which may improve the symptoms of psychiatric illness. The review follows the preferred reporting items for systematic reviews and meta‐analysis (PRISMA) statement guidelines. Three databases (Medline, Web of Science, and Cochrane) were searched combining the search terms ‘erythropoietin AND (psychotic disorders OR schizophrenia)’. Seventy‐eight studies were included in qualitative synthesis, a meta‐analytic approach being prohibited. The findings suggest that several EPO cerebral potential properties may be relevant for schizophrenia treatment, such as neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood–brain barrier permeability, effects on oxidative stress and neurogenesis. Several potentially detrimental side‐effects of EPO therapy, such as increased risk of thrombosis, cancer, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO. Overall, because the available data are inconclusive, further efforts in this field are warranted.