Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin.

BACKGROUND: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period. METHODS: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466). FINDINGS: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge's g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline. CONCLUSIONS: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity. FUNDING: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.

Vitamin D serum concentration is prospectively associated with depressive symptoms in the EpiFloripa Aging Cohort Study: a structural equation modeling approach.

OBJECTIVE: To evaluate the direct, indirect, and total prospective effects of serum concentrations of [25(OH)D, 25-hydroxycolecalciferol] on depressive symptoms in older adults. METHODS: Data from the second (2013-2015) and third (2017-2019) waves of the EpiFloripa Aging Cohort Study (≥ 60 years) were analyzed. Depressive symptoms were assessed by the 15-item Geriatric Depression Scale (GDS-15). 25(OH)D levels were measured using the microparticle chemiluminescence method. A directed acyclic graph (DAG) was constructed to identify the minimum set of adjustments. Structural equation modeling (SEM) analysis was used to determine the effects of 25(OH)D on depressive symptoms. RESULTS: A total of 574 older adults' data were analyzed (63.1% female). In the follow-up (n=390), 16.2% of older adults presented high-severity of depressive symptoms (> or = 6 points). SEM analysis revealed a small direct and negative effect of 25(OH)D (ß=-0.11, P < 0.05), and a total negative effect (ß=-0.13; P < 0.05) on depressive symptoms on wave 3 (an increase of 25(OH)D led to a decrease on depressive symptoms). No direct effect on wave 2 and no indirect effect mediated by depressive symptoms in wave 2 were found. CONCLUSIONS: Findings indicate a prospective association between 25(OH)D and depressive symptoms, suggesting a long-term effect in older adults from southern Brazil.

Euthymic and depressed bipolar patients are characterized by different RNA editing patterns in blood.

Bipolar disorder (BD) is a worldwide leading cause of disability. Inflammation roles in this disease is well established. ADAR1-mediated RNA editing is one of the key mechanisms regulating the inflammatory response. We have identified a panel of RNA editing-based blood biomarkers which allowed to discriminate unipolar from BD depression with high accuracy. We confirmed here the diagnostic value of this panel in a new cohort of BD patients recruited in Brazil. We also identified new combinations which allow a clear discrimination of BD from healthy controls and among BD subgroups, confirming that RNA editing is a key mechanism in BD.

The effect of lifestyle interventions on depressive symptom severity in individuals with type-2 diabetes: A meta-analysis of randomized controlled trials.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a severe metabolic condition which is commonly comorbid with depression. Lifestyle factors are involved in the pathophysiology of both conditions; however, the role of lifestyle interventions remains unclear. OBJECTIVE: The objective of this study is to systematically review the literature on randomized controlled trials evaluating the effect of lifestyle interventions on depressive scores in patients with T2DM. METHODS: A systematic search was conducted in computerized databases before October 2022. A random-effects model was used to investigate the effect of lifestyle interventions on depression scores and meta-regression was conducted to assess the influence of age and disease onset. RESULTS: Six trials met the eligibility criteria for inclusion. A statistically significant reduction in depression scores was found for groups receiving lifestyle interventions compared to controls (SMD = -0.49 [95%CI -0.89 to -0.08]; p = 0.0269]). Interventions increased in efficacy with the age of the participants but no significant correlation was found with years since disease onset. Participants in a control group receiving a less intense lifestyle intervention demonstrated improved depression scores when compared to those who received standard care or no intervention at all. Trial design and outcome measurement tools were heterogeneous between studies and limited data on antidepressant use was available which may introduce bias into the results. CONCLUSION: Lifestyle interventions were effective at improving depressive symptom severity in patients with T2DM.

Does the Ranking Matter? A Retrospective Cohort Study Investigating the Impact of the 2018 CANMAT and ISBD Guidelines for the Management of Patients with Bipolar Disorder Treatment Recommendations for Acute Mania on Rehospitalization Rates.

OBJECTIVE: There is limited data about the impact of mood disorders treatment guidelines on clinical outcomes. The objective of this study was to investigate the impact of prescribers' adherence to the 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) treatment guidelines recommendations on the readmission rates of patients hospitalized for mania. METHOD: A retrospective cohort of all individuals admitted due to acute mania to Kingston General Hospital, Kingston, ON, from January 2018 to July 2021 was included in this study. Patient variables and data regarding index admission and subsequent hospitalizations were extracted from medical records up to December 31, 2021. Treatment regimens were classified as first-line, second-line, noncompliant, or no treatment. We explored the associations between treatment regimens and the risk of readmissions using univariate, multivariate, and survival analysis. RESULTS: We identified 211 hospitalizations related to 165 patients. The mean time-to-readmission was 211.8 days (standard deviation [SD] = 247.1); the 30-day rehospitalization rate was 13.7%, and any rehospitalization rate was 40.3%. Compared to no treatment, only first-line treatments were associated with a statistically significant decreased risk of 30-day readmission (odds ratio [OR] = 0.209; 95% CI, 0.058 to 0.670). The risk of any readmission was reduced by first-line (OR = 0.387; 95% CI, 0.173 to 0.848) and noncompliant regimens (OR = 0.414; 95% CI, 0.174 to 0.982) compared to no treatment. On survival analysis, no treatment group was associated with shorter time-to-readmission (log-rank test, p = 0.014) and increased risk of readmission (hazard ratio = 2.27; 95% CI, 1.30 to 3.96) when compared to first-line medications. CONCLUSIONS: Treatment with first-line medications was associated with lower 30-day rehospitalization rates and longer time-to-readmission. Physicians' adherence to treatments with higher-ranked evidence for efficacy, safety, and tolerability may improve bipolar disorder outcomes.

Practices, knowledge, and attitudes about lithium treatment: Results of online surveys completed by clinicians and lithium-treated patients.

BACKGROUND: Lithium remains the gold-standard medication for acute and prophylactic treatment of bipolar disorder. Understanding clinicians' practices and patients' experiences, knowledge and attitudes about lithium may improve its clinical use. METHODS: Online anonymous surveys collected information about clinician's practices and level of confidence in managing lithium and patients' experiences with lithium treatment and information received about benefits and side effects. Knowledge and attitudes regarding lithium were assessed with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ). RESULTS: Among 201 clinicians, 64.2% endorsed often treating patients with lithium and reported high levels of confidence in assessing and managing lithium. Practices concerning clinical indications, drug titration, and serum levels were guideline-concordant, but compliance with monitoring recommendations was less frequent. Practitioners were interested in receiving more education about lithium. The patients' survey recruited 219 participants with 70.3% being current lithium users. Most patients (68%) found lithium helpful and 71% reported experiencing any kind of side effect. Most responders did not receive information about side effects or other benefits of lithium. Patients with higher scores on the LKT were more likely to have positive attitudes about lithium. LIMITATIONS: Cross-sectional design with predominantly English-speaking participants from Brazil and North America. CONCLUSIONS: There is a discrepancy between guidelines, clinician confidence and knowledge of lithium use and practice. A deeper understanding of how to monitor, prevent and manage long-term side effects and which patients are most likely to benefit from lithium may narrow the gap between knowledge and use.

Psilocybin-Assisted Psychotherapy as a Potential Treatment for Eating Disorders: a Narrative Review of Preliminary Evidence.

Eating disorders (ED) are a group of potentially severe mental disorders characterized by abnormal energy balance, cognitive dysfunction and emotional distress. Cognitive inflexibility is a major challenge to successful ED treatment and dysregulated serotonergic function has been implicated in this symptomatic dimension. Moreover, there are few effective treatment options and long-term remission of ED symptoms is difficult to achieve. There is emerging evidence for the use of psychedelic-assisted psychotherapy for a range of mental disorders. Psilocybin is a serotonergic psychedelic which has demonstrated therapeutic benefit to a variety of psychiatric illnesses characterized by rigid thought patterns and treatment resistance. The current paper presents a narrative review of the hypothesis that psilocybin may be an effective adjunctive treatment for individuals with EDs, based on biological plausibility, transdiagnostic evidence and preliminary results. Limitations of the psychedelic-assisted psychotherapy model and proposed future directions for the application to eating behavior are also discussed. Although the literature to date is not sufficient to propose the incorporation of psilocybin in the treatment of disordered eating behaviors, preliminary evidence supports the need for more rigorous clinical trials as an important avenue for future investigation.

Association between adiposity and emergent depressive symptoms in a 10-years prospective cohort of older adults: The EpiFloripa Aging study.

BACKGROUND: The association between obesity and depressive symptoms has been described in the literature, but there is a scarcity of longitudinal data. This study aimed to verify the association between body mass index (BMI) and waist circumference and the incidence of depressive symptoms over a 10-year follow-up in a cohort of older adults. METHODS: Data from the first (2009-2010), second (2013-2014), and third (2017-2019) waves of the EpiFloripa Aging Cohort Study were used. Depressive symptoms were assessed by the 15-item Geriatric Depression Scale (GDS-15) and classified in significant depressive symptoms for those with ≥6 points. The Generalized Estimating Equations model was used to estimate the longitudinal association between BMI and waist circumference and depressive symptoms across a 10-year follow-up. RESULTS: The incidence of depressive symptoms (N = 580) was 9.9 %. The relationship between BMI and the incidence of depressive symptoms in older adults followed a U-shaped curve. Older adults with obesity had an incidence relative ratio of 76 % (IRR = 1.24, p = 0.035) for increasing the score of depressive symptoms after 10 years, compared to those with overweight. The higher category of waist circumference (Male: ≥102; Female: ≥88 cm) was associated with depressive symptoms (IRR = 1.09, p = 0.033), only in a non-adjusted analysis. LIMITATIONS: Relatively high follow-up dropout rate; Few individuals in the underweight BMI category; BMI must be considered with caution because it does not measure only fat mass. CONCLUSIONS: Obesity was associated with the incidence of depressive symptoms when compared with overweight in older adults.

Understanding and navigating the repercussions of the politically polarized climate in mental health.

The world is experiencing a moment of political polarization between liberal and conservative ideas, which has aggravated since the arrival of the Covid-19. Many countries (Brazil included) have been experiencing the generalized occurrence of people fighting over politics, in contexts including family, workplace, friendships, and romantic relationships. Over the past 2 years, it has been possible to observe an unexpected and overwhelming effect of the political climate on psychotherapy patients, some of whom have started to actively look for therapists who share their convictions. Brazil is experiencing a moment of severe sanitary, economic, social, and political crisis, which is directly affecting our patients. Nevertheless, the impact of the political climate on our population has not been systematically investigated. However, as the political environment is an inherent part of the social component of the psychosocial model, it is important that mental health professionals be prepared to have this conversation with their patients. This highlights the need to address these difficulties in supervision, rounds, and clinical discussions.

Nutrition and bipolar disorder: a systematic review.

INTRODUCTION: Individuals with bipolar disorder (BD) have higher rates of unhealthy lifestyles and risk for medical comorbidities Research currently suggests that dietary factors may play a role in the development of depression and anxiety. Therefore, nutritional approaches are potential strategies for the treatment of BD. The aim of this review is to summarize the available evidence on nutrition and BD. MATERIALS AND METHODS: The paper was developed based on PRISMA 2020 guidelines. The search was conducted in Sep-2021 using PubMed and Cochrane Library, augmented by manually checked references lists. The search found 986 studies, of which 47 were included, combined with 13 from reference lists, totaling 60 studies. RESULTS: There were 33 observational trials, of which 15 focused on fatty acids, 9 on micronutrients, 5 on specific foods, 4 on macro and micronutrients. The 27 interventional studies mainly focused on fatty acids, micronutrients and N-acetylcysteine (NAC). DISCUSSION: Dietary intake or supplementation of unsaturated fatty acids, mainly Omega-3 seems to be associated with improved BD symptoms, along with seafood, folic acid and zinc. Studies found variable, mainly non-significant impacts of creatine, carnitine, vitamin D, inositol or NAC supplementation on BD. There are promising results associated with Coenzyme Q10 (Coq10) and probiotics. Taken together, these preliminary findings suggest that dietetic approaches might be included as part of BD treatment. Also considering the high risk of metabolic disorders in individuals with BD, they should be encouraged to choose healthy dietary lifestyles, including daily intake of fruits, vegetables, seafood and whole grains.

Effects of nutritional interventions on the severity of depressive and anxiety symptoms of women in the menopausal transition and menopause: a systematic review, meta-analysis, and meta-regression.

IMPORTANCE: Depression and anxiety may significantly affect women during the menopausal transition. In addition to traditional treatment strategies such as hormone therapy, antidepressants, and psychotherapy, nutritional interventions have been increasingly studied, but there is no consensus about their role in this patient population. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the effect of nutritional interventions on the severity of depressive (DS) and anxiety (AS) symptoms in women during the menopausal transition or menopausal years. EVIDENCE REVIEW: Electronic search using databases PubMed, Cochrane, and Embase to identify articles indexed until January 31, 2021, focusing on randomized placebo-controlled trials documenting the effect of diet, food supplements, and nutraceuticals on DS and AS. FINDINGS: Thirty-two studies were included (DS, n = 15; AS, n = 1; DS and AS combined, n = 16). We found two studies that demonstrated data combined with other interventions: one with lifestyle interventions (vitamin D plus lifestyle-based weight-loss program) and another with exercise (omega 3 plus exercise). The pooled effect size favored the intervention group over placebo for both DS and AS (DS: standardized mean difference, -0.35 [95% confidence interval, -0.68 to -0.03; P = 0.0351]; AS: standardized mean difference, -0.74 [95% CI, -1.37 to -0.11; P = 0.0229]). There was significant heterogeneity in the pooled results, which can be attributed to differences in assessment tools for depression and anxiety as well as the variety of nutritional interventions studied. The subgroup analysis showed a statistically significant effect of menopausal status (perimenopausal or menopausal) but not the type or duration of nutritional intervention. Older age was the only significant predictor of the effect size of nutritional interventions in the meta-regression. CONCLUSIONS AND RELEVANCE: Nutritional interventions are promising tools for the management of mood/anxiety symptoms in women during the menopausal transition and in postmenopausal years. Because of significant heterogeneity and risk of bias among studies, the actual effect of different approaches is still unclear.

The concept of "metabolic jet lag" in the pathophysiology of bipolar disorder: implications for research and clinical care.

Bipolar disorder (BD) is a potentially chronic mental disorder marked by recurrent depressive and manic episodes, circadian rhythm disruption, and changes in energetic metabolism. "Metabolic jet lag" refers to a state of shift in circadian patterns of energy homeostasis, affecting neuroendocrine, immune, and adipose tissue function, expressed through behavioral changes such as irregularities in sleep and appetite. Risk factors include genetic variation, mitochondrial dysfunction, lifestyle factors, poor gut microbiome health and abnormalities in hunger, satiety, and hedonistic function. Evidence suggests metabolic jet lag is a core component of BD pathophysiology, as individuals with BD frequently exhibit irregular eating rhythms and circadian desynchronization of their energetic metabolism, which is associated with unfavorable clinical outcomes. Although current diagnostic criteria lack any assessment of eating rhythms, technological advancements including mobile phone applications and ecological momentary assessment allow for the reliable tracking of biological rhythms. Overall, methodological refinement of metabolic jet lag assessment will increase knowledge in this field and stimulate the development of interventions targeting metabolic rhythms, such as time-restricted eating.

Effects of the ketogenic diet on cognition: a systematic review.

INTRODUCTION: Ketogenic diet (KD) therapy has been used as a dietary intervention in drug-resistant epilepsy for several years. Research currently suggests that KD therapy may carry neuroprotective and cognition enhancing effects for individuals with non-epileptic conditions as well as for healthy individuals. Therefore, KD may have potential as a non-invasive, nutritional treatment approach for difficult to manage conditions such as neurodegenerative illnesses or mood disorders. The aim of this review is to summarize the available evidence on ketogenic interventions and the resulting cognitive outcomes. MATERIALS AND METHODS: The paper was based on PRISMA 2020 guidelines. The search was conducted in June 2021 on the following databases: CENTRAL, PubMed, EMBASE, PsycInfo, Web of Science. The search yielded 2014 studies, of which 49 were included. RESULTS: There were 22 animal studies assessing murine models and 27 studies on humans. The primary indications in these studies were epileptic conditions, neurodegenerative disorders, cognitive impairment, and healthy populations. DISCUSSION: Administration of KD seems to confer cognitive-enhancing effects in areas such as working memory, reference memory and attention. Studies found that KD treatment in animals has the potential to alleviate age-related cognitive decline. Over 80% of the 27 human studies reported a favourable effect of intervention, and none reported a detrimental effect of KD. While these findings suggest that KD may improve the functioning of certain cognitive domains, definitive conclusions were limited by studies with small sample sizes, the absence of controls and randomization, and the lack of objective measures of cognition.

The Interactions Between Vulnerabilities for HIV and Syphilis among Cisgender and Transgender People Who Use Drugs.

In Brazil, transgender people are most affected by HIV, and crack cocaine addiction may contribute to social vulnerability and exposure to sexual and violence-related risks. This cross-sectional study comprised 2393 individuals seeking addiction treatment, consisting of 43 trans women, 1995 cisgender men, and 355 cisgender women. Records of rapid test results for HIV and syphilis and screening responses of trans women were compared to both cisgender groups using a logistic regression model to identify associated risk factors. HIV prevalence was higher in the transgender group (39.5%) than in cis women and men (5.9% and 3.6%, respectively). Our study showed an eightfold higher chance of a positive HIV test among transgender individuals who used drugs (OR: 8.79, p < .01, 95% CI: 3.90-19.78) compared to cisgender people who used drugs. A lifetime history of syphilis infection was more common in transgender people (60.0%) and cis women (32.8%) than in cis men (9.5%). Active syphilis was also more common in the transgender population (OR: 5.46, p < .01, 95% CI: 2.63 11.32). In our sample, 44.2% of transgender individuals had a history of at least one suicide attempt in their lifetime. Our results showed that transgender women were at higher risk of crack cocaine use (OR: 5.51, p < .01, 95% CI: 2.16-14.06) than cisgender men and women. The study showed that trans women had a higher prevalence of syphilis and HIV, and a greater chance of being homeless. The synergy of these vulnerabilities may have led to our findings of high psychotic symptoms and a history of suicide attempts in transgender individuals.

Understanding and navigating the repercussions of the politically polarized climate in mental health

Abstract The world is experiencing a moment of political polarization between liberal and conservative ideas, which has aggravated since the arrival of the Covid-19. Many countries (Brazil included) have been experiencing the generalized occurrence of people fighting over politics, in contexts including family, workplace, friendships, and romantic relationships. Over the past 2 years, it has been possible to observe an unexpected and overwhelming effect of the political climate on psychotherapy patients, some of whom have started to actively look for therapists who share their convictions. Brazil is experiencing a moment of severe sanitary, economic, social, and political crisis, which is directly affecting our patients. Nevertheless, the impact of the political climate on our population has not been systematically investigated. However, as the political environment is an inherent part of the social component of the psychosocial model, it is important that mental health professionals be prepared to have this conversation with their patients. This highlights the need to address these difficulties in supervision, rounds, and clinical discussions.

Effects of transcranial direct current stimulation associated with hypocaloric diet on glucose homeostasis in obesity.

OBJECTIVE: The aim of this study was to test the effects of repetitive active transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (rDLPFC) associated with a hypocaloric diet on glucose homeostasis in people with excessive weight. METHODS: Adults with overweight or obesity were selected in a randomized, double-blind pilot study to complete 4 weeks (20 sessions) of fixed-dose tDCS (2 mA, 20 minutes) delivered over the rDLPFC and associated with a standard hypocaloric diet. Participants were randomly assigned (1:1) and stratified by sex to the active tDCS group (active) or the sham tDCS group (sham). Changes in glucose homeostasis were assessed in a 4-hour liquid meal tolerance test, performed before and after the intervention. RESULTS: Twenty-eight participants were randomized (79% with obesity; mean [SD] age 37.6 [5.8] years). After the intervention, fasting plasma glucose (mean [95% CI], -7.8 mg/dL [-14.0 to -1.6]) and insulin levels (-7.7 µIU/mL [-13.9 to -1.6]) decreased in the active compared with the sham. Similarly, the Matsuda insulin sensitivity index increase in the active (4.7 pmol-1  × mmol-1 [1.6 to 7.8]) compared with the sham (0.6 pmol-1  × mmol-1 [-1.4 to 3.2]). CONCLUSIONS: Repetitive, active tDCS over the rDLPFC could be a promising noninvasive technique to improve glucose homeostasis in individuals with overweight or obesity on a low-calorie diet, highlighting the importance of investigating this intervention modality in individuals with type 2 diabetes mellitus.

Long-term Effect of Lifestyle Interventions on the Cardiovascular and All-Cause Mortality of Subjects With Prediabetes and Type 2 Diabetes: A Systematic Review and Meta-analysis.

BACKGROUND: Lifestyle interventions improve the metabolic control of individuals with hyperglycemia. PURPOSE: We aimed to determine the effect of lifestyle interventions on cardiovascular and all-cause mortality in this population. DATA SOURCES: Searches were made through MEDLINE, Cochrane CENTRAL, Embase, and Web of Science (no date/language restriction, until 15 May 2022). STUDY SELECTION: We included randomized clinical trials (RCTs) of subjects with prediabetes and type 2 diabetes, comparing intensive lifestyle interventions with usual care, with a minimum of 2 years of active intervention. DATA EXTRACTION: Data from the 11 RCTs selected were extracted in duplicate. A frequentist and arm-based meta-analysis was performed with random-effects models to estimate relative risk (RR) for mortality, and heterogeneity was assessed through I2 metrics. A generalized linear mixed model (GLMM) was used to confirm the findings. DATA SYNTHESIS: Lifestyle interventions were not superior to usual care in reducing cardiovascular (RR 0.99; 95% CI 0.79-1.23) or all-cause (RR 0.93; 95% CI 0.85-1.03) mortality. Subgroup, sensitivity, and meta-regression analyses showed no influence of type of intervention, mean follow-up, age, glycemic status, geographical location, risk of bias, or weight change. All of these results were confirmed with the GLMM. Most studies had a low risk of bias according to the RoB 2.0 tool and the certainty of evidence was moderate for both outcomes. LIMITATIONS: Most studies had a low risk of bias according to the RoB 2.0 tool, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach resulted in moderate certainty of evidence for both outcomes. Differences in lifestyle programs and in usual care between the studies should be considered in the interpretation of our results. CONCLUSIONS: Intensive lifestyle interventions implemented so far did not show superiority to usual care in reducing cardiovascular or all-cause mortality for subjects with prediabetes and type 2 diabetes.