Incidence, prevalence, and global burden of schizophrenia - data, with critical appraisal, from the Global Burden of Disease (GBD) 2019.

Schizophrenia substantially contributes to the burden of mental disorders. Schizophrenia's burden and epidemiological estimates in some countries have been published, but updated estimates of prevalence, incidence, and schizophrenia-related disability at the global level are lacking. Here, we present the data from and critically discuss the Global Burden of Diseases, Injuries, and Risk Factors Study data, focusing on temporal changes in schizophrenia's prevalence, incidence, and disability-adjusted life years (DALYs) globally. From 1990 to 2019, schizophrenia raw prevalence (14.2 to 23.6 million), incidence (941,000 to 1.3 million), and DALYs (9.1 to 15.1 million) increased by over 65%, 37%, and 65% respectively, while age-standardized estimates remained stable globally. In countries with high socio-demographic index (SDI), both prevalence and DALYs increased, while in those with low SDI, the age-standardized incidence decreased and DALYs remained stable. The male/female ratio of burden of schizophrenia has remained stable in the overall population over the past 30 years (i.e., M/F = 1.1), yet decreasing from younger to older age groups (raw prevalence in females higher than males after age 65, with males having earlier age of onset, and females longer life expectancy). Results of this work suggest that schizophrenia's raw prevalence, incidence, and burden have been increasing since 1990. Age-adjusted estimates did not reduce. Schizophrenia detection in low SDI countries is suboptimal, and its prevention/treatment in high SDI countries should be improved, considering its increasing prevalence. Schizophrenia sex ratio inverts throughout the lifespan, suggesting different age of onset and survival by sex. However, prevalence and burden estimates for schizophrenia are probably underestimated. GBD does not account for mortality from schizophrenia (and other mental disorders, apart from anorexia nervosa).

Sexual dysfunction among males and females with bipolar disorder and healthy subjects: The burden of illness severity.

OBJECTIVES: Sexual dysfunction has wide-ranging impacts on the person's functioning and quality of life, being associated with higher severity of psychiatric illnesses and poor therapeutic response. Given the paucity of data on this topic in bipolar disorder (BD), we investigated sexual functioning among males and females with BD and healthy controls (HCs) as well as whether illness severity markers and subthreshold mood symptoms were associated with sexual dysfunctions in BD patients. METHODS: The study included 80 BD outpatients and 70 HCs. Sexual functioning was evaluated using the validated, gender-specific Changes in Sexual Functioning Questionnaire (CSFQ-14). RESULTS: BD patients had a significantly poorer sexual functioning than HCs (p < 0.00001). The odds of sexual dysfunction doubled given a one-unit increase in the number of suicide attempts (adjusted OR = 2.01, 95% CI:1.23-3.55; p < 0.01) and increased by 60% for every additional hospitalization (p < 0.05). Greater illness duration was associated with arousal/orgasmic (p < 0.05) and overall sexual dysfunctions (p < 0.01). BD patients with more mixed or (hypo)manic episodes had a lower likelihood of libido loss and arousal/orgasmic disturbances (p < 0.01), respectively. Higher levels of subthreshold depressive symptoms increased by 20% the odds of sexual interest/frequency dysfunctions (p < 0.05), and up to 60% regarding orgasmic disturbances (p < 0.01). CONCLUSIONS: Sexual functioning may be a useful proxy of illness severity as well as a relevant dimension to more deeply characterize BD patients. Further studies are warranted to replicate our findings, to evaluate temporal associations between sexual dysfunctions and illness severity across the BD mood and treatment spectrums and to explore neurobiological underpinnings of these associations.

Allostatic load, emotional hyper-reactivity, and functioning in individuals with bipolar disorder.

OBJECTIVES: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available biomarkers. Allostatic load (AL) represents the strain that stress, including the effects of acute phases and inter-episode chronic mood instability, exerts on interconnected biological systems. This study aimed to operationalize an AL index and explore whether it could be relevant to better characterize BD patients with and without emotional hyper-reactivity particularly those at higher risk of immune-cardiometabolic dysregulation and functional impairment. METHODS: Levels of biomarkers of chronic inflammation (hsCRP and albumin), cardiovascular (systolic/diastolic blood pressure) and metabolic functions (fasting glucose, glycosylated hemoglobin, total cholesterol, LDL, HDL, and triglycerides) were measured in 1072 adult BD outpatients. Patients were classified in two groups (with/without emotional hyper-reactivity) assessed by the Multidimensional Assessment of Thymic States scale. An Allostatic Load Index for BD (BALLI), comprising six biomarkers, was constructed using data-driven biomarker selection. RESULTS: BALLI showed 81.1% accuracy with good sensitivity (81%) and specificity (81.2%) for characterizing BD patients presenting emotional hyper-reactivity, elevated risk of inflammation (increased hsCRP, hypoalbuminemia) and cardiometabolic disturbances (hypertension, hyperglycemia, and hypertriglyceridemia). Patients classified by the BALLI as presenting emotional hyper-reactivity had significantly lower global and cognitive functioning than those without emotional hyper-reactivity (P < .0001). CONCLUSIONS: A multidimensional approach based on a simple AL score (eg, BALLI) and dimensions of behavior (eg, emotional hyper-reactivity) alongside mood is clinically relevant. AL index could be a useful tool to detect multisystemic physiological dysregulations in BD patients with/without emotional hyper-reactivity particularly those at higher risk of immune-cardiometabolic disturbances and functional impairment.

Intracellular Pathogen Infections and Immune Response in Autism.

BACKGROUND/AIMS: Perinatal exposure to infections during critical developmental periods is a promising area of study in autism spectrum disorder (ASD). Epidemiological data has highlighted this relationship, pointing out significant correlations between perinatal exposure to pathogens and the occurrence of ASD. The aim of this review is to critically examine the present state of the art on intracellular pathogenic infection during pregnancy and postnatally, pointing out possible correlations with the development of ASD. METHODS: We reviewed and collected studies concerning potential associations between intracellular pathogens like viral, bacterial, and parasite infection and the risk of ASD. RESULTS: We included 14 publications, considering bacterial and/or viral infection that demonstrated the potential to trigger ASD. Nine case-control studies were included and 5 of them reported an association between infections and ASD. One of the 2 cohorts investigated demonstrated that maternal infection increased the risk of ASD in the offspring. Three cross-sectional studies demonstrated that ASD patients presented with chronic infections and active neuroinflammatory processes. Most of the reports suggest inflammatory response as a common factor, and interleukin 6 appears to be a key-player in this process. CONCLUSION: The immune responses generated by organisms that cause perinatal maternal infection, i.e., bacteria, viruses, or parasites, have been associated with the development of autism in offspring. Physiological changes transmitted from the mother during chronic or acute inflammation should be further investigated so that modulatory preventive measures can be developed.

Emotional reactivity, functioning, and C-reactive protein alterations in remitted bipolar patients: Clinical relevance of a dimensional approach.

OBJECTIVES: Inter-episode mood instability has increasingly been considered in bipolar disorder. This study aimed to investigate emotional reactivity as a major dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms and functional status. This study also aimed to investigate whether high-sensitivity C-reactive protein, a marker of low-grade inflammation, could be a biological marker of emotional dysregulation in bipolar disorder (BD). METHODS: Cross-sectional study of 613 subjects who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for BD recruited from the FondaMental Advanced Centers of Expertise in Bipolar Disorders cohort from 2009 to 2014. All patients had been in remission for at least 3 months before assessment. Patients were classified into three groups according to levels of emotional reactivity. Emotional reactivity was assessed by using the Multidimensional Assessment of Thymic States, and functional status was assessed by the Functioning Assessment Short Test. Clinical characteristics and blood sample were collected from all patients. RESULTS: In total, 415 (68%) patients had abnormal emotional reactivity. Independent of potential confounders, including age, gender and subthreshold mood symptoms, serum levels of high-sensitivity C-reactive protein were significantly higher in patients with emotional hyper-reactivity (median = 4.0 mg/L, interquartile range = 2.7-5.6), and with emotional hypo-reactivity (median = 3.0 mg/L, interquartile range = 1-4) compared with patients with normal emotional reactivity (median = 0.95 mg/L, interquartile range = 0.4-1.9, p < 0.001). Patients with emotional hyper-reactivity showed significant cognitive functioning impairment ( p < 0.001). CONCLUSIONS: Emotional reactivity appears to be a relevant dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms. Levels of high-sensitivity C-reactive protein may be an objective marker of emotional dysregulation in BD. Further studies are needed to confirm our findings.

Bipolar patients referred to specialized services of care: Not resistant but impaired by sub-syndromal symptoms. Results from the FACE-BD cohort.

OBJECTIVE: A national network of expert centers for bipolar disorders was set up in France to provide support, mainly for psychiatrists, who need help for managing bipolar disorder patients. The aims of this article are to present the main characteristics of the patients referred to an expert center in order to highlight the major disturbances affecting these patients and to understand the most significant difficulties encountered by practitioners dealing with bipolar disorder patients. METHODS: Patients were evaluated by trained psychiatrists and psychologists, with standardized and systematic assessment using interviews and self-report questionnaires. RESULTS: All patients (n = 839) met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for bipolar disorder I (48.4%), bipolar disorder II (38.1%) or bipolar disorder-not otherwise specified (13.5%). Mean illness duration was 17 years (±11.3), with 41.9% of patients having a history of suicide attempts. Lifetime comorbidities were 43.8% for anxiety disorders and 32.8% for substance abuse. At the point of inclusion, most patients (76.2%) were not in an acute phase, being considered to have a syndromal remission, but which still required referral to a tertiary system of care. Among these patients, 37.5% had mild to moderate residual depressive symptoms (Montgomery and Asberg Depression Rating Scale ranging from 7 to 19) despite 39% receiving an antidepressant. However, 47.8% were considered to be poorly adherent to medication; 55% showed evidence of sleep disturbances, with half being overweight; 68.1% of patients showed poor functioning (Functioning Assessment Short Test ⩾ 12) with this being linked to residual depressive symptoms, sleep disturbances and increased body mass index. CONCLUSIONS: It appears that bipolar disorder patients referred to an expert center in most cases do not suffer from a severe or resistant illness but they rather have residual symptoms, including subtle but chronic perturbations that have a major impact on levels of functioning. The longitudinal follow-up of these patients will enable a better understanding of the evolution of such residual symptoms.

Anxiety and depression comorbidities in irritable bowel syndrome (IBS): a systematic review and meta-analysis.

Irritable bowel syndrome (IBS) has been associated with high prevalence of psychological disorders. However, it remains unclear whether IBS and each of its subtypes (predominant diarrhea IBS-D, constipation IBS-C, mixed IBS-M) are associated with higher anxiety and depressive symptoms levels. This study aimed to determine the associations of IBS and each of its subtypes with anxiety and/or depression. We conducted a systematic review and meta-analysis using five electronic databases (PubMed, PsychINFO, BIOSIS, Science Direct, and Cochrane CENTRAL). We selected case-control studies comparing anxiety and depression levels of patients with IBS to healthy controls, using standardized rating scales. Outcomes were measured as random pooled standardized mean differences (SMD). Ten studies were included in our analysis (885 patients and 1,384 healthy controls). Patients with IBS had significant higher anxiety and depression levels than controls (respectively, SMD = 0.76, 95 % CI 0.47; 0.69, p < 0.01, I2 = 81.7 % and SMD = 0.80, 95 % CI 0.42; 1.19, p < 0.01, I2 = 90.7 %). This significant difference was confirmed for patients with IBS-C and -D subtypes for anxiety, and only in IBS-D patients for depression. However, other IBS subtypes had a statistical trend to be associated with both anxiety and depressive symptomatology, which suggests a lack of power due to the small number of studies included. Patients with IBS had significantly higher levels of anxiety and depression than healthy controls. Anxiety and depression symptomatology should be systematically checked and treated in IBS patients, as psychological factors are important moderators of symptom severity, symptom persistence, decisions to seek treatment, and response to treatment.

Staging and neuroprogression in bipolar disorder.

The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression.

Can olfactory dysfunction be a marker of trait or states of bipolar disorders? A comprehensive review.

BACKGROUND: Olfactory deficits (OD) are reported as markers for a large spectrum of neuro-psychiatric disorders. Alterations can concern perception, identification, discrimination and assignment of odour's valence of olfaction process. We propose a comprehensive review to summarize which kind of OD were reported in bipolar disorders (BD) and in which phase of the disease, to know if they could be a marker of state or trait. METHODS: A Systematic Literature Review was conducted using PRISMA guidelines to include all studies assessing olfaction with objective measures in BD. RESULTS: 9 studies were identified. All of them have assessed odour identification and 3 reported deficits mainly in patients with psychotic features or elements of illness severity in comparison to healthy subjects. There is no difference in threshold of perception between BD patients and controls and it is no possible to conclude for discrimination because only one study has assessed this dimension in comparison to control. We cannot conclude for hedonic value of odours regarding these studies. LIMITATIONS: These studies are very incomplete because only one has evaluated all the processes involved in olfaction process. CONCLUSIONS: In light of this review, evidence is still missing to unveil potential disturbances of olfactory process as a marker of BD. These new avenues of research could help to clarify the links between OD and BD and provide information on the pathophysiology of the disorder according to the impaired dimension.

An emotional-response model of bipolar disorders integrating recent findings on amygdala circuits.

Because of our classification system limitations for defining psychiatric disorders and understanding their physiopathology, a new research area based on dimensions has emerged. It consists of exploring domains derived from fundamental behavioral components linked to neurobiological systems. Emotional processing is among the most affected dimensions in bipolar disorders (BD), but is excluded from the definition criteria. The purpose of this review is to synthesize the emotional responses disruption during the different phases of BD, using intensity and valence as the two key characteristics of emotions. We integrate those emotional disruptions into an original, emotion-based model contrasting with the current diagnostic frame built on mood. Emotional processing is underpinned by cortico-limbic circuits involving the amygdala. Recent publications showed the crucial role of the amygdala in emotional processes triggered by stimuli of negative, but also positive valence. We show how these neuroscience data can provide physiological basis for emotional disturbances observed in BD. We conclude with translational perspectives to improve the current knowledge about neural substrates underlying altered emotional responses characterizing BD.

Toi Même, a Mobile Health Platform for Measuring Bipolar Illness Activity: Protocol for a Feasibility Study.

BACKGROUND: The diagnosis and management of bipolar disorder are limited by the absence of available biomarkers. Patients with bipolar disorder frequently present with mood instability even during remission, which is likely associated with the risk of relapse, impaired functioning, and suicidal behavior, indicating that the illness is active. OBJECTIVE: This research protocol aimed to investigate the correlations between clinically rated mood symptoms and mood/behavioral data automatically collected using the Toi Même app in patients with bipolar disorder presenting with different mood episodes. This study also aimed to assess the feasibility of this app for self-monitoring subjective and objective mood/behavior parameters in those patients. METHODS: This open-label, nonrandomized trial will enroll 93 (31 depressive, 31 euthymic, and 31 hypomanic) adults diagnosed with bipolar disorder type I/II (Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria) and owning an iPhone. Clinical evaluations will be performed by psychiatrists at the baseline and after 2 weeks, 1 month, 2 months, and 3 months during the follow-up. Rather than only accessing the daily mood symptoms, the Toi Même app also integrates ecological momentary assessments through 2 gamified tests to assess cognition speed (QUiCKBRAIN) and affective responses (PLAYiMOTIONS) in real-life contexts, continuously measures daily motor activities (eg, number of steps, distance) using the smartphone's motion sensors, and performs a comprehensive weekly assessment. RESULTS: Recruitment began in April 2018 and the completion of the study is estimated to be in December 2021. As of April 2019, 25 participants were enrolled in the study. The first results are expected to be submitted for publication in 2020. This project has been funded by the Perception and Memory Unit of the Pasteur Institute (Paris) and it has received the final ethical/research approvals in April 2018 (ID-RCB: 2017-A02450-53). CONCLUSIONS: Our results will add to the evidence of exploring other alternatives toward a more integrated approach in the management of bipolar disorder, including digital phenotyping, to develop an ethical and clinically meaningful framework for investigating, diagnosing, and treating individuals at risk of developing bipolar disorder or currently experiencing bipolar disorder. Further prospective studies on the validity of automatically generated smartphone data are needed for better understanding the longitudinal pattern of mood instability in bipolar disorder as well as to establish the reliability, efficacy, and cost-effectiveness of such an app intervention for patients with bipolar disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT03508427; https://clinicaltrials.gov/ct2/show/NCT03508427. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18818.

Adjunctive tianeptine treatment for bipolar disorder: A 24-week randomized, placebo-controlled, maintenance trial.

OBJECTIVE: The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression. METHODS: This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels. RESULTS: There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo. CONCLUSION: Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.