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Lucas Spanemberg,1,2 Marco Antonio Caldieraro,1 Edgar Arrua Vares,1 Bianca Wollenhaupt-Aguiar,3,4 Márcia Kauer-Sant’Anna,3,4 Sheila Yuri Kawamoto,1 Emily Galvão,3–5 Gordon Parker,6,7 Marcelo P Fleck1,8 1Mood Disorders Program, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2Department of Psychiatry, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, 3INCT Translational Medicine, Hospital de Clínicas de Porto Alegre, 4Bipolar Disorders Program and Laboratory of Molecular Psychiatry, Universidade Federal do Rio Grande do Sul, 5Centro Universitário Metodista, Porto Alegre, Brazil; 6School of Psychiatry, University of New South Wales, 7Black Dog Institute, Sydney, NSW, Australia; 8Neuromodulation Research Clinic, Douglas Mental Health University Institute, Montréal, ON, Canada Background: The purpose of this study was to compare melancholic patients rated by the CORE measure of observable psychomotor disturbance with nonmelancholic and control subjects across a set of biomarkers.Methods: Depressed patients were classified as melancholic or nonmelancholic by using the CORE measure. Both groups of patients, as well as control subjects, were compared for a set of clinical and laboratory measures. Serum levels of brain-derived neurotrophic factor, of two markers of oxidative stress (protein carbonyl content [PCC] and thiobarbituric acid reactive substances [TBARS]), and of several immunity markers (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-alpha, and interferon-gamma) were analyzed. Results: Thirty-three depressed patients and 54 healthy controls were studied. Depressive patients showed higher IL-4, IL-6, and PCC values than healthy controls. Thirteen (39%) of the depressed patients were assigned as melancholic by the CORE measure. They generated lower interferon-gamma (compared with nonmelancholic depressed patients) and TBARS (compared with both the nonmelancholic subset and controls) and returned higher IL-6 levels than controls. Both depressive groups generated higher PCC scores than controls, with no difference between melancholic and nonmelancholic subsets. Conclusion: A sign-based measure to rate melancholia was able to replicate and extend biological findings discriminating melancholic depression. Signs of psychomotor disturbance may be a useful diagnostic measure of melancholia. Keywords: melancholic depression, oxidative stress, inflammatory cytokines, brain-derived neurotrophic factor

Objective To investigate the association between peripheral biomarkers and child psychopathology in a large community sample. Method A total of 625 aged 6- to 13-year old subjects were recruited from a community school-based study. Psychopathology was assessed using the Child Behaviour Checklist ( CBCL). Psychiatric diagnosis was evaluated using the Development and Well-Being Assessment. The following biomarkers were examined in peripheral blood: brain-derived neurotrophic factor, cytokines ( IL-2, IL-4, IL-6, IL-10, IL-17, IFN-g, and TNF-α), chemokines (eotaxin/ CCL11, IP-10, MCP-1), cytokine receptors ( sTNFR1 and sTNFR2), and the oxidative stress marker TBARS. Results We found significant associations between sTNFR2, eotaxin/ CCL11 and CBCL total score, as well as with specific dimensions of psychopathology. There were different patterns of association between these biomarkers and psychological and behavioural symptoms in children with and without a mental disorder. TBARS, IL-6 and MCP-1 were more specific to some clusters of symptoms in children with a psychiatric diagnosis. Conclusion Our data support the potential use of biomarkers, especially those involved in immune-inflammatory pathways, in investigating neurodevelopmental psychopathology. Their association with different dimensions of symptoms might be of useful when analyzing illness severity and clusters of symptoms within specific disorders. [ABSTRACT FROM AUTHOR]

Objective We examined the relationship between biological rhythms and severity of depressive symptoms in subjects with bipolar disorder and the effects of biological rhythms alterations on functional impairment. Method Bipolar patients ( n = 260) and healthy controls ( n = 191) were recruited from mood disorders programs in three sites (Spain, Brazil, and Canada). Parameters of biological rhythms were measured using the Biological Rhythms Assessment in Neuropsychiatry ( BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity. Results Multivariate analyses of covariance showed significant intergroup differences after controlling for potential confounders (Pillai's F = 49.367; df = 2, P < 0.001). Depressed patients had the greatest biological rhythms disturbance, followed by patients with subsyndromal symptoms, euthymic patients, and healthy controls. Biological rhythms and HAMD scores were independent predictors of poor functioning ( F = 12.841, df = 6, P < 0.001, R2 = 0.443). Conclusion Our study shows a dose-dependent association between the severity of depressive symptoms and degree of biological rhythms disturbance. Biological rhythms disturbance was also an independent predictor of functional impairment. Although the directionality of this relationship remains unknown, our results suggest that stability of biological rhythms should be an important target of acute and long-term management of bipolar disorder and may aid in the improvement of functioning. [ABSTRACT FROM AUTHOR]

Objective The impact of childhood trauma ( CT) on brain-derived neurotrophic factor ( BDNF) and cytokines levels remains unclear. We investigated the association between CT and changes in BDNF and cytokines plasma levels in children. Method We recruited 36 children with trauma ( CT+) and 26 children without trauma ( CT-). The presence of CT was based on a clinical interview and by Criteria A of DSM- IV criteria for PTSD. Blood samples were drawn from all children to assess BDNF and cytokines. ancova was performed with psychiatric symptoms and BMI as covariates to evaluate group differences in plasma levels. Results CT+ showed increased levels of BDNF and TNF-α after excluding children with history of inflammatory disease ( P < 0.05) when compared with those CT-. IL-12p70, IL-6, IL-8, IL-10, and IL-1β levels were not statistically different between groups. Conclusion CT+ showed increased BDNF and proinflammatory cytokines levels. The increase in BDNF levels may be an attempt to neutralize the negative effects of CT, while an increase in TNF-a levels be associated with a proinflammatory state after CT. How these changes associated with trauma relate to other biological changes and illness trajectory later in life remain to be further studied. [ABSTRACT FROM AUTHOR]

BACKGROUND: There has been an increasing interest in the role of oxidative stress in the pathophysiology of bipolar disorder. To explore this further, we evaluated the activity of glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST), as well as 3-nitrotyrosine levels and carbonyl content in patients in the early (within 3 years of illness onset) and late (a minimum of 10 years of illness) stages of bipolar disorder. METHODS: We matched 30 patients in the early stage and 30 patients in the late stage of bipolar disorder, diagnosed according to DSM-IV criteria, with 60 healthy controls (30 matched for each group of patients). We measured symptomatic status using the Hamilton Rating Scale for Depression and the Young Mania Rating Scale. RESULTS: We found a significant increase in 3-nitrotyrosine levels among patients in the early (p < 0.010) and late (p < 0.010) stages of bipolar disorder. The activity of GR and GST was increased only among patients in the late stage of illness. Glutathione peroxidase activity and carbonyl content did not differ among the groups. LIMITATIONS: Limitations of our study include its cross-sectional design, which did not allow us to examine direct causative mechanisms or the effects of progression of illness, and the potential environmental bias introduced by comparing patient groups recruited from different regions of the world. CONCLUSION: Our data indicate a possible tyrosine nitration-induced damage in patients with bipolar disorder that is present from the early stage of illness. Our data also indicate that patients in the late stage of illness demonstrate enhanced activity of GR and GST, which could suggest the involvement of a compensatory system in bipolar disorder. [ABSTRACT FROM AUTHOR]

Objective: Rational therapeutic development in bipolar is hampered by a lack of pathophysiological model. However, there is a wealth of converging data on the role of dopamine in bipolar disorder. This paper therefore examines the possibility of a dopamine hypothesis for bipolar disorder. Method: A literature search was conducted using standard search engines Embase, PyschLIT, PubMed and MEDLINE. In addition, papers and book chapters known to the authors were retrieved and examined for further relevant articles. Results: Collectively, in excess of 100 articles were reviewed from which approximately 75% were relevant to the focus of this paper. Conclusion: Pharmacological models suggest a role of increased dopaminergic drive in mania and the converse in depression. In Parkinson's disease, administration of high-dose dopamine precursors can produce a 'maniform' picture, which switches into a depressive analogue on withdrawal. It is possible that in bipolar disorder there is a cyclical process, where increased dopaminergic transmission in mania leads to a secondary down regulation of dopaminergic receptor sensitivity over time. This may lead to a period of decreased dopaminergic transmission, corresponding with the depressive phase, and the repetition of the cycle. This model, if verified, may have implications for rational drug development. [ABSTRACT FROM AUTHOR]

This investigation explores the efficacy of subcutaneous ketamine for mitigating depressive symptoms and suicidal ideation, addressing a crucial need for rapid-onset treatments in severe depression cases. It introduces an innovative approach to administering an NMDA receptor antagonist, significantly advancing psychopharmacological methods for treating suicidal behaviors as distinct entities, even within depressive episodes. The study's objective is to assess the impact of subcutaneous ketamine on diminishing suicidal thoughts and mood symptoms during depressive episodes through a naturalistic, prospective observational design. Conducted at Hospital de Clínicas de Porto Alegre, Brazil, between 2021 and 2023, the study involved 26 patients undergoing a current depressive episode. Of these, 23 completed the acute phase of treatment, and 18 were followed up for 6 months. The treatment regimen commenced with a ketamine dose of 0.5 mg/kg, which was adjusted according to individual responses under psychiatric supervision. The findings revealed substantial decreases in Columbia Suicide Severity Rating Scale scores following multiple ketamine sessions, with most patients achieving remission after approximately eight sessions. A notable reduction in depressive symptoms was also observed. A clear dose-response relationship was established, indicating that higher doses of ketamine were associated with more significant improvements in depressive symptoms, suicidal ideation, and overall functionality. Follow-up assessments suggested that these improvements were sustained over time. The subcutaneous administration of ketamine was generally well-tolerated, with minor and short-lived side effects. The study posits that subcutaneous ketamine may present a promising solution for treating severe depression accompanied by suicidal tendencies, particularly considering its positive influence on patient functionality and well-being. This method could offer a cost-effective and accessible treatment alternative, especially relevant in settings with limited resources. Given its potential in reducing long-term disability and economic viability, the study advocates for its broader application and further validation through larger, controlled trials. Trial Registration: ClinicalTrials.gov NCT05249309., Competing Interests: Declaration of competing interest All of the researchers declare not to have any conflict of interest. In the last 5 years, Dr. Kauer-Sant'Anna has received grant or research support from CAPES, CNPq, CNPq-Produtividade FIPE-HCPA and INCT-TM-CNPq; has been a speaker for Daiichi-Sankyo, Lundbeck, Prati-Donaduzzi., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available; thus, developing newer treatments that are effective and well tolerable is an urgent unmet need. The objective of the present trial was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression., Method: A randomized, double-blind, placebo-controlled pilot study to assess the efficacy of adjunctive cannabidiol in bipolar depression was used. Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 8. Secondary outcomes included response and remission rates, changes in anxiety and psychotic symptoms, and changes in functioning. Patients continued double-blind treatment until week 12 to monitor for adverse effects, laboratory analysis, and manic symptoms. Study registry: NCT03310593., Results: A total of 35 participants were included. MADRS scores significantly decreased from baseline to the endpoint (placebo, -14.56; cannabidiol, -15.38), but there was no significant difference between the groups. Similarly, there were no other significant effects on the secondary outcomes. However, an exploratory analysis showed a significant effect of cannabidiol 300 mg/day in reducing MADRS scores from week 2 to week 8 (placebo, -6.64; cannabidiol, -13.72). There were no significant differences in the development of manic symptoms or any other adverse effects., Conclusion: Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE)—National Health and Medical Research Council (NHMRC). JAC and JEH have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm in the past. JAC, JEH, FK, FSG, and AWZ are coinventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; 29 July 2015; INPI on 19 August 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC, JEH, FSG, ACC, and AWZ are coinventors of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on 16 September 2016 (BR 112018005423-2). MKS reports research grants from SMRI, from the National Council for Scientific and Technological Development, Ministry of Science and Technology, Brazil (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq), and Coordination of Superior Level Staff Improvement (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES), and personal fees from SHIRE and Daichii-Sankyo, from FIPE-HCPA (Fundo de Incentivo à Pesquisa e Eventos – HCPA), and from CNPq Produtividade em Pesquisa outside of the submitted work. LNY is a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding from Abbvie, Alkermes, Allergan, Canadian Network for Mood and Anxiety Treatments (CANMAT), Canadian Institutes of Health Research (CIHR), Dainippon Sumitomo Pharma, Gedeon Richter, Intracellular Therapies, Lundbeck, Merck, Otsuka, Sanofi and Sunovion over the past 3 years. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To evaluate relative expression of genes with the potential to translate environmental stimuli into long-term alterations in the brain - namely Early Growth Response (EGR)1, EGR3, and Cryptochrome Circadian Regulator 2 (CRY2) - in peripheral blood from patients with Bipolar Disorder (BD), Schizophrenia (SZ), Major Depressive Disorder (MDD) and healthy controls (HC)., Methods: Thirty individuals ranging from 18 to 60 years were recruited for each group (BD, SZ, MDD or HC) from a Brazilian public hospital. Therefore, individuals' peripheral blood was collected and EGR1, EGR3 and CRY2 gene expression analyzed by PCR Real Time., Results: EGR1 mRNA levels are significantly lower in psychiatric patients when compared to HC, but there is no difference for EGR3 and CRY2. Exploring the findings for each diagnosis, there is a significant difference between each diagnosis group only for EGR1, which was lower in BD, MDD and SZ as compared to HC. No significant correlations were found between gene expression and clinical features., Conclusions: EGR1 is downregulated in psychiatric patients, regardless of the diagnosis and may be a potential common target in major psychiatric disorders. EGR1, as a transcription factor, modulates many other genes and participates in crucial neuronal and synaptic processes, such as plasticity, neurotransmitters metabolism, vesicular transport and signaling pathways. The study of EGR1 and its upstream regulators in psychiatry might lead to potential new therapeutic targets., Competing Interests: No conflicts of interest declared concerning the publication of this article.

Objective: Bipolar disorder (BD) is a major cause of disability-adjusted life years in young adults. Pregnancy complications have previously been associated with BD. The current study aimed to examine the association between perinatal factors and BD., Methods: We included 3,794 subjects from the 1993 Pelotas population-based birth cohort study. We assessed 27 variables at birth and modeled BD onset at 18 and 22 years. Bivariate analysis was performed by means of binomial logistic regression models. The variables with p-values less than 0.05 were included in a multiple regression with confounders., Results: Maternal smoking was associated with a 1.42-fold increased risk of BD at 18 or 22 years old (95%CI 1.091-1.841), and maternal passive exposure to tobacco with a 1.43-fold increased risk (95%CI 1.086-1.875). No association was found between other perinatal factors and BD after controlling for confounders., Conclusion: The results of the present cohort study corroborate previous reports in the literature indicating a negative effects of maternal smoking during pregnancy. These findings can be further tested and support the development of strategies to prevent the onset development of BD., Competing Interests: ICP receives authorship royalties from Springer Nature and ArtMed; has served as consultant, advisor, or continuing medical education speaker for Janssen, LundBeck, Libbs, Daiichi Sankyo, EMS, and Pfizer. The other authors report no conflicts of interest.

Background: Psychiatric disorders are associated with more than 90% of reported suicide attempts worldwide, but few treatments have demonstrated a direct effect in reducing suicide risk. Ketamine, originally an anesthetic, has been shown anti-suicide effects in clinical trials designed to treat depression. However, changes at the biochemical level were assessed only in protocols of ketamine with very limited sample sizes, particularly when the subcutaneous route was considered. In addition, the inflammatory changes associated with ketamine effects and their correlation with response to treatment, dose-effect, and suicide risk warrant further investigation. Therefore, we aimed to assess whether ketamine results in better control of suicidal ideation and/or behavior in patients with depressive episodes and whether ketamine affects psychopathology and inflammatory biomarkers., Materials and Methods: We report here the design of a naturalistic prospective multicenter study protocol of ketamine in depressive episodes carried out at Hospital de Clínicas de Porto Alegre (HCPA) and Hospital Moinhos de Vento (HMV). The study was planned to recruit adult patients with Major depressive disorder (MDD) or Bipolar disorder (BD) types 1 or 2, who are currently in a depressive episode and show symptoms of suicidal ideation and/or behavior according to the Columbia-Suicide Severity Rating Scale (C-SSRS) and have been prescribed ketamine by their assistant psychiatrist. Patients receive ketamine subcutaneously (SC) twice a week for 1 month, but the frequency can be changed or the dose decreased according to the assistant physician's decision. After the last ketamine session, patients are followed-up via telephone once a month for up to 6 months. The data will be analyzed using repeated measures statistics to evaluate the reduction in suicide risk as a primary outcome, as per C-SSRS., Discussion: We discuss the need for studies with longer follow-ups designed to measure a direct impact on suicide risk and that additional information about the safety and tolerability of ketamine in particular subset of patients such as those with depression and ideation suicide. In line, the mechanism behind the immunomodulatory effects of ketamine is still poorly understood., Trial Registration: https://clinicaltrials.gov/, identifier NCT05249309., Competing Interests: In the last 5 years, MK-S has received grant or research support from CAPES, CNPq, CNPq-Produtividade FIPE-HCPA and INCT-TM-CNPq; has been a speaker for Daiichi-Sankyo. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Anzolin, Goularte, Pinto, Belmonte-de-Abreu, Cruz, Cordova, Magalhaes, Rosa, Cereser and Kauer-Sant’Anna.)

Background: Emerging evidence indicates that inflammation plays an important role as a mechanism underlying mental disorders. However, most of the research on inflammatory mechanisms focuses on serum levels of interleukins and very few studies have investigated molecules that initiate and expand innate immune pathways such as damage-associated molecular patterns (DAMPs)., Objectives: This study investigated the levels of DAMPs among patients diagnosed with major depressive disorder (MDD), bipolar disorder (BD) I and II, schizophrenia (SCZ), and generalized anxiety disorder (GAD). We quantified serum levels of heat shock proteins (HSPs) 70 and 60 and of S100 calcium-binding protein B (S100B)., Methods: Serum levels of HSP70, HSP60, and S100B were assessed in a sample of participants with psychiatric disorders (n = 191) and a control group (CT) (n = 59) using enzyme-linked immunosorbent assay (ELISA)., Results: Serum HSP70 concentrations were significantly higher in the MDD group compared to the CT, SCZ, and BD groups. The GAD group had higher concentrations of HSP70 than the SCZ group. Exploring associations with medications, lithium (p = 0.003) and clozapine (p = 0.028) were associated with lower HSP70 levels. Approximately 64% of the sample had DAMPs levels below the limits of detection indicated by the respective ELISA kit., Conclusion: This was the first study to assess DAMPs levels in a transdiagnostic sample. Our preliminary findings suggest that HSP70 may be associated with MDD pathophysiology. Medications such as lithium and clozapine were associated with lower HSP70 levels in BD and SCZ groups, respectively. Therefore, it is worth mentioning that all participants were medicated and many psychotropic drugs exert an anti-inflammatory effect, possibly reducing the signs of inflammation., Competing Interests: Marcia Kauer-Sant’Anna has received personal fees from Novartis, Shire, EMS, and Daichi-Sankyo. Marco Antonio Caldieraro has received research grants from Janssen Pharmaceutical. No other conflicts of interest declared concerning the publication of this article.

Objectives: Veterans are at increased risk for exposure to trauma, developing serious mental illnesses, and death by suicide. History of trauma correlates with worsening outcomes in patients with bipolar disorder. This study investigated associations between trauma exposure (type and timing) and suicide attempt in Veterans with bipolar disorder., Methods: One hundred six Veterans with a diagnosis of bipolar disorder and 815 Veterans with no psychiatric history (age rage = 20-72 years old) completed a clinical questionnaire, the Beck Scale for Suicide Ideation, and the Traumatic Live Events Questionnaire. Multinomial logistic regressions investigated correlations between diagnosis, time of trauma (before, during, or after the military), trauma type (attack, illness, accident, child violence, child sexual abuse, and adult sexual abuse), and suicide attempt., Results: Seventy-five Veterans with bipolar disorder had comorbid PTSD. Controlling for PTSD, Veterans with bipolar disorder had a higher prevalence of trauma including physical assault [odds ratio (OR) = 2.85; 95% confidence interval (CI) = 1.39-5.86] and child sexual trauma (OR = 2.89; CI = 1.38-6.05). Veterans with bipolar disorder who endorsed previous suicide attempts (n = 42) had significantly higher levels of exposure to childhood trauma (OR = 5.69; CI = 1.84-17.62)., Conclusions: Results support incorporating history of previous trauma exposure when assessing Veterans at risk for bipolar disorder. Especially, trauma characterized as attack and childhood sexual abuse. Particular attention should be given to Veterans with bipolar disorder and exposure to trauma during childhood, which may be associated with increased risk of suicidality., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier Ltd.)