Is Obesity A Determinant Of Success With Pharmacological Treatment For Depression? A Systematic Review, Meta-Analysis And Meta-Regression.

BACKGROUND: The bidirectional association between Major Depressive Disorder (MDD) and obesity suggests that body mass index (BMI) at the baseline could influence remission rates (RR) with pharmacological treatment. We evaluated the influence of baseline BMI on the chances of remission among patients with MDD administered antidepressants. METHODS: Based on the guidelines of the PRISMA statement, we conducted a systematic review on PubMed, Cochrane and Embase databases with subsequent meta-analysis and meta-regression. We included only randomized controlled trials evaluating the efficacy of antidepressants of different classes (monotherapy and combined therapies) that evidenced baseline BMI assessment. We created a model to describe the linear relationship between baseline BMI and RR. RESULTS: Our systematic review yielded 70 studies with a total of 9,779 patients in the active group and 7,136 patients in the placebo group. In placebo controlled studies, BMI influenced the RR of patients randomized to active treatment. The RR for antidepressants in monotherapy was higher in normal weight to overweight patients rather than obese patients (33% vs 12%, respectively). Also in monotherapy, the RR is higher when the study is conducted on patients with a lower baseline BMI (p=0.029). For combined therapies, the pooled RR was higher in obese patients rather than in normal weight to overweight patients (75% vs 17%, respectively). LIMITATIONS: BMI provides no information about body composition and obesity can be related to several potential confounders that potentially influence RR. CONCLUSION: The RR with antidepressant therapy seems to be associated with baseline BMI in patients with MDD, although this simple variable was insufficiently explored so far.

Comprehensive review of the current literature on impact of ambient air pollution and sleep quality.

Air pollution is associated with increasing morbidity, mortality and decreasing health and life span. Accumulating epidemiological and experimental evidence has shown that exposure to ambient air pollutants such as particulate matters (PM) and gaseous components [eg, nitrogen dioxide (NO2), ozone (O3)] has detrimental effects on sleep quality. We conducted this comprehensive review to explore the association between ambient air pollution and sleep quality. A systematic search was conducted with the databases of PubMed and Web of Science from inception to November 2019. Overall, 15 studies with 133,695 subjects that evaluated the association between ambient air pollution and sleep quality were conducted in 10 different countries (ie, USA, Brazil, Canada, Chile, China, Egypt, Germany, Iran, Mexico, and Turkey). Most included studies in the current review have shown that one or more air pollutants have negative influences on sleep quality. Air pollutants might be one of the triggers for poor sleep quality via disparate mechanisms including but not limited to the central ventilator control centers, central nervous system, allergic and non-allergic mechanisms. The possible association between air pollution and select chronic diseases (eg, mental illnesses, cardiovascular diseases) and behaviors (eg, impulsivity) may also play important roles in explaining the association between ambient air pollution and sleep quality. The associations and underlying mechanisms between ambient air pollutants and sleep quality need to be clarified with long-term, multi-centered cohort studies.

Caloric restriction, resting metabolic rate and cognitive performance in Non-obese adults: A post-hoc analysis from CALERIE study.

Physical activity (PA) has been proposed as a determinant of cognitive function and is one component of energy balance (EB). EB is the difference between energy intake (EI) and the total daily energy expenditure (TDEE). TDEE is a combination of resting metabolic rate (RMR), thermic effect of food and PA. The potential role of each of these components on cognitive function has not yet been systemically investigated. We aim to evaluate the association between each component of EB on cognition, using baseline and longitudinal data from a clinical trial of caloric restriction (CR). This is a parallel-group, randomized clinical trial comparing two years of 25% CR with two years of ad libitum diet (AL), with 220 healthy volunteers of both sex, aged between 21 and 50 years and initial BMI ≥ 22 kg/m2 and <28 kg/m2. Body weight, fat mass (FM), fat-free mass (FFM), and bone mineral content were evaluated, as well as RMR, TDEE, cognitive performance and baseline energy intake. A 30 min/day of a moderate level on a minimum of 5 days/week was advised as PA measure. Longitudinal analysis demonstrated that the influence of CR in the improvement of cognitive performance was moderated by changes in RMR, suggesting that in individuals submitted to CR, the cognitive performance and the RMR improved proportionally, independently of changes in EI and body mass. EB and homeostasis are crucial to modulate the RMR. Moreover, RMR presents an important influence on cognitive function in individuals submitted to CR in a long term.

Mental, emotional, and behavioral effects of ketogenic diet for non-epileptic neuropsychiatric conditions.

Ketogenic diet (KD) is comprised of a distinct macronutrient combination: i.e. 90% fat, 8% of protein and 2% of carbohydrates, typically characterized as a high-fat low-carbohydrate diet. KD's efficacy was largely established for treatment resistant epilepsy in children, but its mental, emotional and behavioral effects remain largely unknown. Nevertheless, the efficacious effects of KD in childhood epilepsy provide rationale for repurposing this approach for other brain-based disorders. Consequently, clinicians and researchers should be aware of the evidence regarding efficacy, as well as the benefits and risks of adopting this diet. Results from animals and humans studies provide equivocal evidence across multiple domains of psychopathology. Conceptually, KD shows promise to serve as an efficacious treatment for mental disorders.

The effect of caloric restriction on working memory in healthy non-obese adults.

OBJECTIVE: We aim to evaluate the effect of caloric restriction (CR) in cognition by comparing performance in neuropsychological tests for working memory between a group of non-obese healthy subjects doing CR for 2 years with another consuming ad libitum diet (AL). METHODS: This study was part of a larger multicenter trial called CALERIE that consisted of a randomized clinical trial with parallel-group comparing 2 years of 25% CR and AL in 220 volunteers with a BMI between 22 and 28 kg/m2, across 3 sites. The cognitive tests used were the Cambridge Neuropsychological Tests Automated Battery (CANTAB) for Spatial Working Memory (SWM) including the total number of errors (SWMTE) and strategy (SWMS). Included as possible moderators were sleep quality, mood states, perceived stress, and energy expenditure. Analyses were performed at baseline and months 12 and 24. RESULTS: After adjustments, there was a significantly greater improvement in working memory assessed by the SWM for CR individuals, compared to AL. At month 24, it was related mostly to lower protein intake, compared to other macronutrients. Changes in SWM were moderated by changes in sleep quality, physical activity, and energy expenditure. CONCLUSION: On the long term, CR in healthy individuals seems to have a slightly positive effect on working memory. The study of brain CR targets opens new possibilities to prevent and treat cognitive deficits.

Machine learning and big data analytics in bipolar disorder: A position paper from the International Society for Bipolar Disorders Big Data Task Force.

OBJECTIVES: The International Society for Bipolar Disorders Big Data Task Force assembled leading researchers in the field of bipolar disorder (BD), machine learning, and big data with extensive experience to evaluate the rationale of machine learning and big data analytics strategies for BD. METHOD: A task force was convened to examine and integrate findings from the scientific literature related to machine learning and big data based studies to clarify terminology and to describe challenges and potential applications in the field of BD. We also systematically searched PubMed, Embase, and Web of Science for articles published up to January 2019 that used machine learning in BD. RESULTS: The results suggested that big data analytics has the potential to provide risk calculators to aid in treatment decisions and predict clinical prognosis, including suicidality, for individual patients. This approach can advance diagnosis by enabling discovery of more relevant data-driven phenotypes, as well as by predicting transition to the disorder in high-risk unaffected subjects. We also discuss the most frequent challenges that big data analytics applications can face, such as heterogeneity, lack of external validation and replication of some studies, cost and non-stationary distribution of the data, and lack of appropriate funding. CONCLUSION: Machine learning-based studies, including atheoretical data-driven big data approaches, provide an opportunity to more accurately detect those who are at risk, parse-relevant phenotypes as well as inform treatment selection and prognosis. However, several methodological challenges need to be addressed in order to translate research findings to clinical settings.

Association between diabetes and mood disorders and the potential use of anti-hyperglycemic agents as antidepressants.

Epidemiological and mechanistic studies support the association between Diabetes Mellitus and mood disorders, such as Major Depressive Disorder and Bipolar Disorder. This association is especially relevant in specific domains of depressive psychopathology, such as disturbances in reward systems and cognitive functions. Several anti-hyperglycemic agents have demonstrated effects on depressive symptoms and cognitive decline and this efficacy is probably the result of an action in shared brain targets between these two groups of conditions. These medications include subcutaneous insulin, intranasal insulin, metformin, and liraglutide. The study of the mechanisms involved in the relationship between Diabetes Mellitus and mood disorders offers a new avenue of investigation, and this understanding can be applied when examining whether antidiabetic agents can be repurposed as antidepressants and mood stabilizers. The objective of this narrative review is to critically appraise the literature surrounding drugs commonly used as anti-hyperglycemic agents and their effects on the brain, while discussing their potential as a new treatment for mental illnesses, and specifically, mood disorders.

Hypersomnia and Bipolar Disorder: A systematic review and meta-analysis of proportion.

BACKGROUND: Hypersomnia is a common problem amongst individuals with Bipolar Disorder (BD). The objective of this meta-analysis is to estimate the frequency of hypersomnia in individuals with BD, and identify associated factors METHODS: Our search focused on articles documenting the frequency of hypersomnia among individuals with BD indexed in PubMed database and in the Cochrane Library, following the recommendations from the Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) Group. A meta-analysis of proportion was conducted; funnel plot and Egger's test were used for the assessment of publication bias. Subgroups analyses were performed in order to evaluate possible confounders and associated factors. RESULTS: We identified 10 studies, which included 1824 patients with BD. The overall estimate of the proportion of BD cases that reported hypersomnia was 29.9% [95% confidence interval (CI): 25.8 - 34.1%, I2 = 59.2%; p < .05]. The funnel plot and the Egger's test suggest a low risk of publication bias (p = .527). The polarity of mood state, Bipolar Disorder type, use of medication, age, diagnostic criteria and hypersomnia criteria were not significantly related to hypersomnia. LIMITATIONS: There is a possibility that smaller cross-sectional studies were not included. The high heterogeneity between studies is frequent in meta-analysis of both interventional and observational studies. Hypersomnia was not the primary outcome in some of the included studies. CONCLUSIONS: To our knowledge, this is the first systematic review and meta-analysis of hypersomnia prevalence in patients with BD. Further studies focused on clinical correlates and implications for health outcomes in BD are warranted.

Oligopeptidases activity in bipolar disorder: Ndel1 and angiotensin I converting enzyme.

BACKGROUND: Abnormal activity of two enzymes relevant to neurodevelopment, namely nuclear-distribution element-like 1 (Ndel1) and angiotensin I-converting enzyme (ACE), was reported in individuals with schizophrenia; to our knowledge, these oligopeptidases were never measured in bipolar disorder (BD). AIMS: Evaluate the enzyme activity of Ndel1 and ACE in euthymic individuals with BD type 1 which was compare to healthy control (HC) group. METHODS: Ndel1 and ACE activities were assessed in the serum of individuals with BD type 1 according to DSM-IV criteria (n = 70) and a HC group (n = 34). The possible differences between BD type 1 and HC groups were evaluated using Analysis of Covariance (ANCOVA), and the results were adjusted for age, gender and body mass index. RESULTS: We observed a positive correlation between Ndel1 activity and the total YMRS score in BD group (p = 0.030) and a positive correlation between ACE activity and Ham-D score (p = 0.047). ANCOVA analysis showed lower Ndel1 activity in BDs compared to HCs. Interestingly, we did not observe between-groups differences in ACE activity, despite the recognized correlation of ACE activity levels with cognitive functions, also described to be worsened in psychiatric patients. CONCLUSION: Oligopeptidases, especially Ndel1, which has been strongly correlated with neurodevelopment and brain formation, are potentially a good new target in the study of the neurobiology of BD. LIMITATIONS: The relatively small sample size did not permit to examine the cause-effect relationship of clinical dimensions of BD and the enzymatic activity.

The effect of paroxetine, venlafaxine and bupropion administration alone and combined on spatial and aversive memory performance in rats.

BACKGROUND: The use of antidepressants in combination is common practice following non-response to single antidepressant agents. Nevertheless, the scientific literature lacks preclinical studies regarding the combined administration of antidepressants across multiple behavioral measures including, but not limited to, cognition. Hence, we aimed to determine the effects of paroxetine (PAR), venlafaxine (VEN) and bupropion (BUP) alone or combined (PAR+BUP or VEN+BUP) on spatial and affective memory tasks to advance the knowledge about the combined use of antidepressants in cognition. METHODS: Adult rats received daily injections (15 days) of PAR (20mg/kg, ip), VEN (20mg/kg, ip), BUP (20mg/kg, ip) alone or combined and were submitted to behavioral measures of spatial memory (radial-arm maze - RAM), aversive memory (passive avoidance - PA), open field (OF) and forced swimming (FST) tests. RESULTS: In the RAM, VEN or VEN+BUP impaired learning, while short-term memory (STM) was impaired by PAR, BUP and their combination. VEN+BUP improved STM as compared to BUP. PAR impaired long-term memory (LTM). VEN or BUP alone impaired STM and long-term fear memory, whilst PAR+BUP or VEN+BUP did not induce significant alterations. CONCLUSIONS: The effects of VEN, PAR or BUP alone and in combination on measures of memory are variable and vary as a function of the pharmacodynamics profile of each drug as well as the specific memory paradigm.

Differential Impact of Obesity on CD69 Expression in Individuals with Bipolar Disorder and Healthy Controls.

Preliminary evidence suggests that premature immunosenescence is involved in bipolar disorder (BD) pathophysiology. The cellular marker CD69 is expressed in T lymphocyte surface during their activation and its expression is negatively correlated with age. The objective of this study was to assess the moderating effects of obesity on the reduction of expression of CD69, a marker of immunosenescence. Forty euthymic patients with BD type I, aged 18-65 years, were included in this study. The healthy comparison group consisted of 39 volunteers who had no current or lifetime history of mental disorders, no use of psychotropic medications, and no known family history of mood disorders or psychosis. Peripheral blood mononuclear cells from BD patients and healthy controls were collected and isolated. The cells were allowed to grow in culture and stimulated for 3 days. CD69 was marked and read in flow cytometry. We found that the lower expression of CD69 in BD patients was moderated by body mass index (BMI) in both CD4+ (RR = 0.977, 95% CI 0.960-0.995, p = 0.013) and CD8+ cells (RR = 0.972, 95% CI 0.954-0.990, p = 0.003). Our findings indicate that BMI could potentially influence the process of premature aging in BD.

The differential association between history of childhood sexual abuse and body mass index in early and late stages of bipolar disorder.

BACKGROUND: History of distal stressors such as childhood trauma is a well-established, non-specific vulnerability factor for multiple mental illnesses. The objective of this study was to investigate the possible association between history of childhood trauma and body mass index (BMI) in individuals in early and late stages of bipolar disorder (BD) and to verify is there was any difference in the association of sexual abuse history and obesity in early versus late stages of BD. METHODS: Seventy-one euthymic BD-type I patients and eighty-one healthy controls were evaluated using the Childhood Trauma Questionnaire (CTQ) and body mass index (BMI). The association between BMI and CTQ total and subscores were evaluated dividing BD population in early-stage BD-I (less than 10 years since onset of disease) or late-stage BD (more than 10 years). RESULTS: BD individuals had higher rates of history of childhood trauma than HC, especially sexual and emotional abuse, after adjusting for confounders. We observed a moderating effect of group on the association between BMI and sexual abuse (SA), but not on other modalities of childhood trauma, after adjustments for age, gender, ethnicity, education, alcohol and tobacco use. LIMITATIONS: Our sample included a predominance of female individuals. The study cross-sectional design does not allow concluding a cause-effect relationship. In dividing the BD subgroups in relation with the time since the onset, we supposed that the natural course of BD is linear. The CTQ is subject to recall bias. CONCLUSION: There is a relationship between childhood sexual abuse and BMI, but the direction of the association varies across the different stages of BD-I.

Food addiction: Prevalence, psychopathological correlates and associations with quality of life in a large sample.

OBJECTIVE: To determine the prevalence of food addiction in a large Brazilian non-clinical sample. Sociodemographic and psychopathological correlates of food addiction as well as associations with quality (QoL) domains were also investigated. METHODS: This cross-sectional study obtained data from a Brazilian anonymous web-based research platform (N = 7639; 71.3% females). Participants provided sociodemographic data and completed the modified Yale Food Addiction Scale 2.0, PHQ-9, hypomania checklist (HCL-32), Fagerström Test for Nicotine Dependence, AUDIT, modified Skin picking-Stanford questionnaire, Minnesota impulsive disorders interview, Symptom Checklist-90-Revised inventory (SCL-90R), early trauma inventory self report-short form, and the WHO Quality of Life instrument-Abbreviated version (WHOQOL-Bref). Associations were adjusted to potential confounders through multivariable models. RESULTS: The prevalence of food addiction was 4.32% (95%CI: 3.89-4.80%), and was more common among females. Food addiction was associated with a positive screen for a major depressive episode (OR = 4.41; 95%CI: 3.46-5.62), bipolar spectrum disorder (OR = 1.98; 95%CI: 1.43-2.75), and skin picking disorder (OR = 2.02; 95%CI: 1.31-3.09). Food addiction was also independently associated with exposure to early life psychological and sexual abuse (P = 0.008) as well as with reduced physical, psychological, social, and environment QoL (all P < 0.001). CONCLUSIONS: Food addiction may be common in low and middle-income countries, though possibly less prevalent than in the US. Food addiction was associated with co-occurring mood disorders and skin picking disorder as well as with early life psychological and sexual abuse. Finally, food addiction was independently associated with broad reductions in QoL. Public health efforts towards the early recognition and management of food addiction are warranted.

Plasma copeptin and metabolic dysfunction in individuals with bipolar disorder.

AIM: This study aimed to compare plasma copeptin levels, the c-terminal of provasopressin, between individuals with bipolar disorder (BD) and healthy controls and to assess the relation between copeptin and metabolic parameters. METHODS: We measured plasma levels of copeptin in individuals with BD (n = 55) and healthy controls (n = 21). Information related to psychiatric/medical history, as well as to metabolic comorbidities and laboratorial parameters was also captured. Insulin resistance and ß-cell function in basal state were calculated from fasting plasma glucose and C-peptide using the HOMA2 calculator. Impaired glucose metabolism was defined as pre-diabetes or type 2 diabetes mellitus. Copeptin, adiponectin, and leptin plasma levels were determined by enzyme-linked immunosorbent assay. RESULTS: Plasma copeptin levels were lower in individuals with BD, relative to healthy controls (P < 0.001). There were significant interactions between BD and plasma copeptin on ß-cell function (rate ratio [RR] = 1.048; P = 0.030) and on leptin levels (RR = 1.087; P = 0.012), indicating that there was a positive correlation between these markers in the BD group, but a negative one in healthy controls. Finally, in individuals with BD only, the association between ß-cell function, body mass index (RR = 1.007; P < 0.001), and insulin resistance (RR = 1.001; P = 0.037) was moderated by copeptin levels. CONCLUSION: Copeptin levels were lower in individuals with BD than in healthy controls. There were differential associations between copeptin and metabolic parameters within the BD and healthy control subgroups, suggesting an association between abnormal copeptin and metabolic dysregulation only in the BD population.

Medical comorbidity in bipolar disorder: The link with metabolic-inflammatory systems.

BACKGROUND: Bipolar disorder (BD) is associated with chronic low-grade inflammation, several medical comorbidities and a decreased life expectancy. Metabolic-inflammatory changes have been postulated as one of the main links between BD and medical comorbidity, although there are few studies exploring possible mechanisms underlying this relationship. Therefore, the aims of the current narrative review were 1) synthesize the evidence for metabolic-inflammatory changes that may facilitate the link between medical comorbidity and BD and 2) discuss therapeutic and preventive implications of these pathways. METHODS: The PubMed and Google Scholar databases were searched for relevant studies. RESULTS: Identified studies suggested that there is an increased risk of medical comorbidities, such as autoimmune disorders, obesity, diabetes and cardiovascular disease in patients with BD. The association between BD and general medical comorbidities seems to be bidirectional and potentially mediated by immune dysfunction. Targeting the metabolic-inflammatory-mood pathway may potential yield improved outcomes in BD; however, further study is needed to determine which specific interventions may be beneficial. LIMITATIONS: The majority of identified studies had cross-sectional designs, small sample sizes and limited measurements of inflammation. CONCLUSIONS: Treatment and prevention of general medical comorbidities in mood disorders should include preferential prescribing of metabolically neutral agents and adjunctive lifestyle modifications including increased physical activity, improved diet and decreased substance abuse. In addition, the use of anti-inflammatory agents could be a relevant therapeutic target in future research.