Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine.

BACKGROUND: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. AIM: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). METHODS: Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. RESULTS: M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. CONCLUSION: These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

Effects of Paradoxical Sleep Deprivation on Oxidative Parameters in the Serum and Brain of Mice Submitted to the Animal Model of Hyperglycemia.

The present study aimed to investigate the effects of paradoxical sleep deprivation (PSD) on behavioral and oxidative stress parameters in the brain and serum of mice submitted to the animal model of hyperglycemia induced by alloxan, mimicking the main symptom of diabetes mellitus (DM). Adults C57BL/6 male and female mice received an injection of alloxan, and ten days later, the animals were submitted to the PSD for 36hr. The animals' behavioral parameters were evaluated in the open-field test. Oxidative stress parameters [Diacetyldichlorofluorescein (DCF), Thiobarbituric acid reactive substances (TBARS), Superoxide dismutase (SOD), and Glutathione] were assessed in the frontal cortex, hippocampus, striatum, and serum. The PSD increased the male and female mice locomotion, but the alloxan's pre-administration prevented the PSD-induced hyperactivity. In addition, the male mice receiving alloxan and submitted to the PSD had elevated latency time in the first quadrant and the number of fecal boli, demonstrating increased anxiety-like behavior. The HPA-axis was hyperactivating in male and female mice pre-administered alloxan and/or PSD-submitted animals. The oxidative stress parameters were also increased in the serum of the animals administered alloxan and/or sleep-deprived mice. Despite alloxan or PSD leading to behavioral or biochemical alterations, the one did not potentiate the other in mice. However, more studies are necessary to identify the link between sleep and hyperglycemia.

Opportunities and challenges for the use of deep brain stimulation in the treatment of refractory major depression.

Major Depressive Disorder continues to remain one of the most prevalent psychiatric diseases globally. Despite multiple trials of conventional therapies, a subset of patients fail to have adequate benefit to treatment. Deep brain stimulation (DBS) is a promising treatment in this difficult to treat population and has shown strong antidepressant effects across multiple cohorts. Nearly two decades of work have provided insights into the potential for chronic focal stimulation in precise brain targets to modulate pathological brain circuits that are implicated in the pathogenesis of depression. In this paper we review the rationale that prompted the selection of various brain targets for DBS, their subsequent clinical outcomes and common adverse events reported. We additionally discuss some of the pitfalls and challenges that have prevented more widespread adoption of this technology as well as future directions that have shown promise in improving therapeutic efficacy of DBS in the treatment of depression.

Prevalence of cognitive impairment and associated factors in older people.

BACKGROUND: Older people are the fastest-growing age group, with the highest risk of cognitive impairment. This study assessed the prevalence and associated factors with cognitive impairment in community-dwelling older people. METHODS: Older people were interviewed and accomplished through sociodemographic and health questionnaires. The quantitative variables were described by mean and standard deviation or median and interquartile range. The significance level adopted was 5 % (p < 0.05). The association between the quantitative variables was evaluated using the Pearson or Spearman correlation coefficients. RESULTS: The research population comprised 165 long-lived adults aged ≥80. The youngest one was 80, and the oldest one was 94 years old. The participants were 84.8 ± 3.6 years old, female (63 %) with a mean of education of 2.9 ± 1.8 years. A poor performance in the Mini-Mental State Examination (MMSE) was found in 58 (35.2 %) individuals when adjusted for educational level. After adjustment for confounding factors, body mass index (BMI) (p = 0.09), total older adults' income (up to 1 minimum wage [mw], p = 0.023; over 1 to 2 mw, p = 0.023), functional disability (Moderate dependence 75 %, p = 0.038; Moderate dependence 50 %, p = 0.081; Moderate dependence 25 %, p = 0.054), and the anxiety scale (p = 0.032), remained associated with cognitive impairment. CONCLUSIONS: This study showed that BMI, total older adults' income, functional disability, and anxiety are related to cognitive impairment in long-lived adults. This study has some limitations, such as the fact that it is a cross-sectional study, the reduced number of individuals, and the fact that there were no comparisons among different ages and populations.

Abbreviated Suicidal Narrative Inventory: Factor Structure, Internal Consistency, and Validity in a Brazilian Sample.

AIM: To investigate the factor structure, reliability, and validity of the Brazilian version of the Abbreviated Suicidal Narrative Inventory (SNI-38). METHODS: We used an anonymous online questionnaire of the SNI-38 and self-report measures administered between November 2020 and October 2021 in the Brazilian community. Participants were recruited through social media advertisements. Confirmatory factor analysis was carried out to test the factor structure of the SNI-38. In addition, we examined internal consistency, and convergent validity against stressful life events, the suicide crisis syndrome, suicidal ideation, and suicide attempts. RESULTS: 2660 participants were included. The eight-factor model SNI-38 had a good model fit (χ2[637] = 7,473.98, p < .001, CFI = .99, TLI = .99, RMSEA = .07, SRMR = .06); all items were significantly and positively loaded onto their respective factors (factor loadings ≥ .45). Reliability was good to high in all subscales except goal disengagement. Additionally, all subscales - except goal disengagement - were correlated positively which the suicide crisis syndrome, stressful life events, lifetime/past-month suicidal ideation, and lifetime suicide attempts. CONCLUSIONS: These findings provide preliminary support for the validity of the Brazilian version of the SNI-38, being an appropriate and valid tool for measuring suicidal narrative among Brazilian samples.

The Revised Suicide Crisis Inventory (SCI-2): Factor Structure, Internal Consistency, and Validity in a Brazilian Sample.

OBJECTIVE: To examine the factor structure, reliability, and validity of the Brazilian version of the Suicide Crisis Inventory (SCI-2) among Brazilian adults. METHODS: The SCI-2 was cross-culturally adapted into Portuguese and administered to 2,265 individuals in the Brazilian community. Confirmatory factor analyses, internal consistency, and convergent and criterion validity against the suicidal narrative, stressful life events, suicidal ideation, and suicide attempts were examined. RESULTS: The revised one-factor model of the SCI-2 resulted in adequate, but not optimal, model fit (χ2[1539] = 31,442.79, p < .001, CFI = .99, TLI = .99, RMSEA = .09, SRMR = .05). The revised five-factor model, on the other hand, demonstrated good fit (χ2[1529] = 14,174.86, p < .001, CFI = 1.00, TLI = 1.00, RMSEA = .06, SRMR = .04). Comparison of these two models indicated that the five-factor exhibited a superior model fit to the one-factor model. The SCI-2 total and subscales showed strong internal consistency, good convergent, and criterion validity in relation to stressful life events, suicidal narrative (except goal disengagement subscale), suicidal ideation, and suicide attempts. CONCLUSIONS: These findings indicate that the Brazilian version of the SCI-2 is a valid tool for measuring symptoms of the Suicide Crisis Syndrome.

Antidepressant Effect of Sodium Butyrate is Accompanied by Brain Epigenetic Modulation in Rats Subjected to Early or Late Life Stress.

BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. RESULTS: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. CONCLUSION: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Suicide Risk Moderates the Relationship Between Stressful Life Events, the Suicidal Narrative, and the Suicide Crisis Syndrome: A Brazilian Cross-Sectional Study.

BACKGROUND: Stressful life events are associated with higher odds of suicidal thoughts and behaviors. Furthermore, stressful life events can trigger specific symptoms, including the suicidal narrative and suicide crisis syndrome, resulting in an increased risk of suicidal thoughts and behaviors. This study examined the moderating role of suicide risk in the relationship between stressful life events, the suicidal narrative, and the suicide crisis syndrome. METHODS: 2,260 adults completed an online survey recruited through advertisements on social media. The level of emotional distress was assessed through the Suicide Narrative Inventory, Suicide Crisis Inventory-2, Stressful Life Events Questionnaire, and Mini International Neuropsychiatric Interview. The PROCESS macro (Hayes) was used to analyze the moderation models. RESULTS: Stressful life events were positively correlated with the suicidal narrative and suicide crisis syndrome. The effects of stressful life events on suicidal narrative and suicide crisis syndrome were strongest when suicide risk was low and weakest when suicide risk was high. CONCLUSIONS: These findings suggest that including stressful life events as part of suicide risk assessment in general and clinical settings is critical to managing treatment for suicidal thoughts and developing adaptive coping.

COVID-19, Anxiety, and Body Mass Index Increase Leptin Levels: a Cross-sectional Multicentric Study.

Although many efforts have been made to understand the pathophysiological mechanisms of COVID-19, critical gaps remain to be explored. This study aimed to investigate potential alterations in adipokine levels (specifically adiponectin, leptin, and resistin) among individuals with COVID-19. Within this population, we further assessed the association between these markers with both, body mass index (BMI) and psychiatric symptoms. This cross-sectional study included an age- and sex-matched sample of adults with COVID-19 (cases) and without COVID-19 (controls). We evaluated the severity of psychiatric symptoms, BMI, and adipokines. Individuals with COVID-19 presented greater BMI, stress levels, and leptin levels when compared to controls. Leptin levels were greater in individuals with moderate/severe COVID-19 as compared to individuals with COVID-19 who were asymptomatic or having mild symptoms. Leptin levels were positively correlated with BMI, severity of depressive and anxiety symptoms, and stress levels in the total sample. Leptin levels were also positively correlated with BMI, severity of anxiety symptoms, and stress levels in controls. In cases, there was a positive correlation between adiponectin and the severity of depressive symptoms and stress levels and leptin/resistin with BMI. A linear regression model revealed that BMI, severity of anxiety symptoms, and the diagnosis of COVID-19 are independently associated with increased leptin levels. Thus, leptin levels seem to be impacted by the COVID-19 infection, anxiety, and BMI.

Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities.

Notwithstanding advances in understanding the pathophysiology of major depressive disorder (MDD), no single mechanism can explain all facets of this disorder. An expanding body of evidence indicates a putative role for the inflammatory response. Several meta-analyses showed an increase in systemic peripheral inflammatory markers in individuals with MDD. Numerous conditions and circumstances in the modern world may promote chronic systemic inflammation through mechanisms, including alterations in the gut microbiota. Peripheral cytokines may reach the brain and contribute to neuroinflammation through cellular, humoral, and neural pathways. On the other hand, antidepressant drugs may decrease peripheral levels of inflammatory markers. Anti-inflammatory drugs and nutritional strategies that reduce inflammation also could improve depressive symptoms. The present study provides a critical review of recent advances in the role of inflammation in the pathophysiology of MDD. Furthermore, this review discusses the role of glial cells and the main drivers of changes associated with neuroinflammation. Finally, we highlight possible novel neurotherapeutic targets for MDD that could exert antidepressant effects by modulating inflammation.

Potential mechanisms of action of resveratrol in prevention and therapy for mental disorders.

There is a growing body of evidence about the potential of diet and nutrients to improve the population's mental health and the treatment of psychiatric disorders. Some studies have suggested that resveratrol has therapeutic properties in mental disorders, such as major depressive disorder, bipolar disorder, Alzheimer's disease, and autism. In addition, resveratrol is known to induce several benefits modulated by multiple synergistic pathways, which control oxidative stress, inflammation, and cell death. This review collects the currently available data from animal and human studies and discusses the potential mechanisms of action of resveratrol in prevention and therapy for psychiatric disorders.

Mitochondrial health index correlates with plasma circulating cell-free mitochondrial DNA in bipolar disorder.

Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. In this study, 14 BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. Ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. After adjusting for confounding variables, such as age, sex, body mass index (BMI), and smoking status, patients with BD presented lower MHI compared to non-psychiatry controls, as well as higher ccf-mtDNA levels that negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, MHI and ccf-mtDNA were also examined in relation to several MQC-related proteins, such as Fis-1, Opa-1, and LC3. Our results showed that MHI correlated negatively with Fis-1 and positively with Opa-1 and LC3. Accordingly, ccf-mtDNA had a positive correlation with Fis-1 and a negative correlation with Opa-1 and LC3. Furthermore, we found a noteworthy inverse correlation between illness severity and MHI, with lower MHI and higher ccf-mtDNA levels in subjects with a longer illness duration, worse functional status, and higher depressive symptoms. Our findings indicate that mitochondrial allostatic load contributes to BD, suggesting mitochondria represent a potential biological intersection point that could contribute to impaired cellular resilience and increased vulnerability to stress and mood episodes. Ultimately, by linking mitochondrial dysfunction to disease progression and poor outcomes, we might be able to build a predictive marker that explains how mitochondrial function and its regulation contribute to BD development and that may eventually serve as a treatment guide for both old and new therapeutic targets.