The association of blood biomarkers with cerebral white matter and myelin content in bipolar disorder: a systematic review.

OBJECTIVES: Evidence from diffusion tensor imaging (DTI) and postmortem studies has demonstrated white-matter (WM) deficits in bipolar disorder (BD). Changes in peripheral blood biomarkers have also been observed; however, studies evaluating the potential relationship between brain alterations and the periphery are scarce. The objective of this systematic review is to investigate the relationship between blood-based biomarkers and WM in BD. METHODS: PubMed, Embase, and PsycINFO were used to conduct literature searches. Cross-sectional or longitudinal studies reporting original data which investigated both a blood-based biomarker and WM (by neuroimaging) in BD were included. RESULTS: Of 3,750 studies retrieved, 23 were included. Several classes of biomarkers were found to have a significant relationship with WM in BD. These included cytokines and growth factors (interleukin-8 [IL-8], tumor necrosis factor alpha [TNF-a], and insulin-like growth factor binding protein 3 [IGFBP-3]), innate immune system (natural killer cells [NK]), metabolic markers (lipid hydroperoxidase, cholesterol, triglycerides), the kynurenine (Kyn) pathway (5-hydroxyindoleacetic acid, kynurenic acid [Kyna]), and various gene polymorphisms (serotonin-transporter-linked promoter region). CONCLUSION: This systematic review revealed that blood-based biomarkers are associated with markers of WM deficits observed in BD. Longitudinal studies investigating the potential clinical utility of these specific biomarkers are encouraged.

Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy.

Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker.

Lifestyle Behaviors, Depression, and Anxiety Among Individuals Living in Canada During the COVID-19 Pandemic.

The aim of our study was to investigate the association between lifestyle behaviors and symptoms of depression and anxiety during the COVID-19 pandemic in Canada. A web survey was conducted between July 3-August 3, 2020, across Canada. The main outcomes considered were a positive screening for depression, as evaluated by the PHQ-2 and positive screening for anxiety, as evaluated by the GAD-7. Lifestyle behaviors were assessed using the Short Multidimensional Lifestyle Inventory Evaluation-Confinement (SMILE-C), an instrument adapted for lifestyle behaviors during the COVID-19 pandemic. The total sample size included 404 participants, of which 24.3% had a positive screen for depression, 20.5% for anxiety, and 15.5% for both. We found significant differences in SMILE-C scores between individuals with a positive and individuals with a negative screen for depression (P < .001). Likewise, there were significant differences in SMILE-C scores between individuals with a positive and individuals with a negative screen for anxiety (P < .001). We found an association between unhealthy lifestyle behaviors and symptoms of depression and anxiety during the COVID-19 lockdown in Canada. The findings highlight the importance of lifestyle medicine (LM) education and targeted lifestyle interventions to promote healthy behaviors and help reduce the burden of mental disorders.

Biomarkers of neuroprogression and late staging in bipolar disorder: A systematic review.

BACKGROUND: Bipolar disorder may undertake a progressive course in a subset of patients, and research efforts have been made to understand the biological basis underlying this process. This systematic review examined the literature available on biological markers associated with illness progression in bipolar disorder. METHODS: Peer-reviewed articles were assessed using Embase, PsycINFO and PubMed, as well as from external sources. After initial screening, a total of 871 citations from databases and other sources were identified. Participants with a diagnosis of bipolar disorder were included in our systematic review; however, studies with participants younger than 15 or older than 65 were excluded. All studies were assessed using the Newcastle-Ottawa Scale assessment tool, and data pertaining to the results were extracted into tabular form using Google Sheets and Google Documents. The systematic review was registered on PROSPERO international prospective register of systematic reviews (ID Number: CRD42020154305). RESULTS: A total of 35 studies were included in the systematic review. Increased ventricular size and reduction of grey matter volume were the most common brain changes associated with illness progression in bipolar disorder. Among the several biomarkers evaluated in this systematic review, findings also indicate a role of peripheral inflammatory markers in this process. DISCUSSION: The studies evaluating the biological basis of the illness progression in bipolar disorder are still scarce and heterogeneous. However, current evidence supports the notion of neuroprogression, the pathophysiological process related to progressive brain changes associated with clinical progression in patients with bipolar disorder. The increase in peripheral inflammatory biomarkers and the neuroanatomical changes in bipolar disorder suggest progressive systemic and structural brain alterations, respectively.

Suicidal Risk in Women with Premenstrual Syndrome and Premenstrual Dysphoric Disorder: A Systematic Review and Meta-Analysis.

Purpose: Women with premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS) experience substantial functional impairment and decreased quality of life. While previous research has highlighted a relationship between premenstrual disturbances and suicide risk, no meta-analysis has been conducted to quantitatively assess the findings. Methods: A systematic review and meta-analysis was conducted by searching the literature in three databases (Pubmed, PsycINFO, and EMBASE) on July 15, 2020. Studies that assessed the relationship between suicidality (attempt, ideation, and/or plan) and premenstrual disturbance (PMDD, PMS, and/or premenstrual symptoms) were included. Results: Thirteen studies were included in the qualitative review (n = 10 included in meta-analysis). Results revealed that women with PMDD are almost seven times at higher risk of suicide attempt (OR: 6.97; 95% CI: 2.98-16.29, p < 0.001) and almost four times as likely to exhibit suicidal ideation (OR: 3.95; 95% CI: 2.97-5.24, p < 0.001). Similarly, women with PMS are also at increased risk of suicidal ideation (OR: 10.06; 95% CI: 1.32 to -76.67, p = 0.03), but not for suicide attempt (OR: 1.85; 95% CI: 0.77 to -4.46, p = 0.17). Conclusions: Women with PMDD and PMS are at higher risk of suicidality compared with women without premenstrual disturbances. These findings support routine suicidal risk assessments for women who suffer from moderate-to-severe premenstrual disturbance. Furthermore, psychosocial treatments for women diagnosed with PMS/PMDD should consider and target suicidality to minimize risk and improve well-being.

Biological Pathways Associated with Neuroprogression in Bipolar Disorder.

There is evidence suggesting clinical progression in a subset of patients with bipolar disorder (BD). This progression is associated with worse clinical outcomes and biological changes. Molecular pathways and biological markers of clinical progression have been identified and may explain the progressive changes associated with this disorder. The biological basis for clinical progression in BD is called neuroprogression. We propose that the following intertwined pathways provide the biological basis of neuroprogression: inflammation, oxidative stress, impaired calcium signaling, endoplasmic reticulum and mitochondrial dysfunction, and impaired neuroplasticity and cellular resilience. The nonlinear interaction of these pathways may worsen clinical outcomes, cognition, and functioning. Understanding neuroprogression in BD is crucial for identifying novel therapeutic targets, preventing illness progression, and ultimately promoting better outcomes.

Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal

Objective: To evaluate the association between childhood trauma (CT) and serum levels of brain-derived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crack-cocaine withdrawal. Method: Thirty-three male crack-cocaine users were recruited at admission to a public addiction treatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Information about drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reported throughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on a latent analysis model that divided the sample into low-, medium-, and high-level trauma groups. Results: There was a significant increase in BDNF levels from admission to discharge, which did not differ across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction (F2,28 = 6.357, p = 0.005,ηp 2 = 0.312). In participants with low trauma level, TBARS decreased, while in those with a high trauma level, TBARS increased during early withdrawal. Conclusion: TBARS levels showed opposite patterns of change in crack-cocaine withdrawal according to baseline CT. These results suggest that CT could be associated with more severe neurological impairment during withdrawal.

Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal.

OBJECTIVE: To evaluate the association between childhood trauma (CT) and serum levels of brain-derived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crack-cocaine withdrawal. METHOD: Thirty-three male crack-cocaine users were recruited at admission to a public addiction treatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Information about drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reported throughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on a latent analysis model that divided the sample into low-, medium-, and high-level trauma groups. RESULTS: There was a significant increase in BDNF levels from admission to discharge, which did not differ across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction (F2,28 = 6.357, p = 0.005,ηp 2 = 0.312). In participants with low trauma level, TBARS decreased, while in those with a high trauma level, TBARS increased during early withdrawal. CONCLUSION: TBARS levels showed opposite patterns of change in crack-cocaine withdrawal according to baseline CT. These results suggest that CT could be associated with more severe neurological impairment during withdrawal.

Differential biomarker signatures in unipolar and bipolar depression: A machine learning approach.

OBJECTIVE: This study used machine learning techniques combined with peripheral biomarker measurements to build signatures to help differentiating (1) patients with bipolar depression from patients with unipolar depression, and (2) patients with bipolar depression or unipolar depression from healthy controls. METHODS: We assessed serum levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumor necrosis factor-α, interferon-γ, interleukin-17A, brain-derived neurotrophic factor, lipid peroxidation and oxidative protein damage in 54 outpatients with bipolar depression, 54 outpatients with unipolar depression and 54 healthy controls, matched by sex and age. Depressive symptoms were assessed using the Hamilton Depression Rating Scale. Variable selection was performed with recursive feature elimination with a linear support vector machine kernel, and the leave-one-out cross-validation method was used to test and validate our model. RESULTS: Bipolar vs unipolar depression classification achieved an area under the receiver operating characteristics (ROC) curve (AUC) of 0.69, with 0.62 sensitivity and 0.66 specificity using three selected biomarkers (interleukin-4, thiobarbituric acid reactive substances and interleukin-10). For the comparison of bipolar depression vs healthy controls, the model retained five variables (interleukin-6, interleukin-4, thiobarbituric acid reactive substances, carbonyl and interleukin-17A), with an AUC of 0.70, 0.62 sensitivity and 0.7 specificity. Finally, unipolar depression vs healthy controls comparison retained seven variables (interleukin-6, Carbonyl, brain-derived neurotrophic factor, interleukin-10, interleukin-17A, interleukin-4 and tumor necrosis factor-α), with an AUC of 0.74, a sensitivity of 0.68 and 0.70 specificity. CONCLUSION: Our findings show the potential of machine learning models to aid in clinical practice, leading to more objective assessment. Future studies will examine the possibility of combining peripheral blood biomarker data with other biological data to develop more accurate signatures.

Evaluation of BDNF levels in patients hospitalized for physical trauma at an emergency hospital in Porto Alegre, southern Brazil / Avaliação dos níveis de BDNF em pacientes hospitalizados por trauma físico em um hospital de emergência de Porto Alegre, sul do Brasil

Abstract Objective To assess the association between brain-derived neurotrophic factor (BDNF) levels and acute stress disorder (ASD) in patients who have suffered physical trauma. Methods Data were collected at an emergency hospital in Porto Alegre, state of Rio Grande do Sul, southern Brazil. Participants were over 18 years of age, victims of physical trauma, and had been hospitalized for a minimum of 48 hours. A total of 117 hospitalized patients who agreed to participate in the research were grouped according to the shift in which blood was collected (38 subjects from the morning shift and 79 from the afternoon shift), had their BDNF levels measured and responded to other questionnaires. Respondents were further grouped by age into three ranges: 18-30, 31-50 and 51-70 years. Results We found a significant difference in the distribution of BDNF between the two shifts in which blood samples were collected, with the afternoon group having higher BDNF levels (U = 1906.5, p = 0.018). A difference was observed only between the 18-30 group and the 51-70 group in the afternoon shift (Umorning = 1107, pmorning = 0.575; Uafternoon = 7175, pafternoon = 0.028). Conclusions The population whose blood samples were collected in the afternoon showed significantly higher values of BDNF compared to those of the morning shift. This same population presented lower BDNF levels when associated with ASD subtypes A1, A2, and A. We hypothesize that the lower values of BDNF measured in the morning shift were due to a response to the circadian cycle of cortisol, whose action inhibits the expression of serum neurotrophins.

Resumo Objetivo Verificar a associação entre os níveis de fator neurotrófico derivado do cérebro (brain-derived neurotrophic factor [BDNF]) e transtorno de estresse agudo (TEA) em pacientes que sofreram trauma físico. Métodos Os dados foram coletados em um hospital de emergência de Porto Alegre, Rio Grande do Sul, Brasil. Os participantes eram maiores de 18 anos, vítimas de trauma físico e estavam hospitalizados por um período mínimo de 48 horas. Um total de 117 pacientes hospitalizados que concordaram em participar da pesquisa foram agrupados de acordo com o turno de realização da coleta de sangue (38 sujeitos no turno da manhã e 79 sujeitos no turno da tarde), tiveram seus níveis de BDNF medidos e responderam a outros questionários. Os entrevistados também foram agrupados por idade em três faixas etárias: 18-30, 31-50 e 51-70 anos. Resultados Encontramos uma diferença significativa na distribuição de BDNF entre os turnos, sendo que o grupo da tarde apresentou níveis maiores de BDNF (U = 1906,5, p = 0,018). Houve diferença entre o grupo de 18-30 anos e o de 51-70 anos no turno da tarde (Umanhã = 1107, pmanhã = 0,575; Utarde = 7175, ptarde = 0,028). Conclusões A população cuja coleta ocorreu à tarde apresentou valores significativamente maiores de BDNF em relação à coleta do turno da manhã. Esta mesma população apresentou menores níveis dessa neurotrofina quando associada com os subtipos A1, A2 e A de TEA. É possível hipotetizar que os menores valores de BDNF aferidos na coleta do turno da manhã se devam a uma resposta ao ciclo circadiano do cortisol, cuja ação inibe a expressão de neurotrofinas séricas.

Evaluation of BDNF levels in patients hospitalized for physical trauma at an emergency hospital in Porto Alegre, southern Brazil.

OBJECTIVE: To assess the association between brain-derived neurotrophic factor (BDNF) levels and acute stress disorder (ASD) in patients who have suffered physical trauma. METHODS: Data were collected at an emergency hospital in Porto Alegre, state of Rio Grande do Sul, southern Brazil. Participants were over 18 years of age, victims of physical trauma, and had been hospitalized for a minimum of 48 hours. A total of 117 hospitalized patients who agreed to participate in the research were grouped according to the shift in which blood was collected (38 subjects from the morning shift and 79 from the afternoon shift), had their BDNF levels measured and responded to other questionnaires. Respondents were further grouped by age into three ranges: 18-30, 31-50 and 51-70 years. RESULTS: We found a significant difference in the distribution of BDNF between the two shifts in which blood samples were collected, with the afternoon group having higher BDNF levels (U = 1906.5, p = 0.018). A difference was observed only between the 18-30 group and the 51-70 group in the afternoon shift (Umorning = 1107, pmorning = 0.575; Uafternoon = 7175, pafternoon = 0.028). CONCLUSIONS: The population whose blood samples were collected in the afternoon showed significantly higher values of BDNF compared to those of the morning shift. This same population presented lower BDNF levels when associated with ASD subtypes A1, A2, and A. We hypothesize that the lower values of BDNF measured in the morning shift were due to a response to the circadian cycle of cortisol, whose action inhibits the expression of serum neurotrophins.

Cholinergic Differentiation of Human Neuroblastoma SH-SY5Y Cell Line and Its Potential Use as an In vitro Model for Alzheimer's Disease Studies.

Cholinergic transmission is critical to high-order brain functions such as memory, learning, and attention. Alzheimer's disease (AD) is characterized by cognitive decline associated with a specific degeneration of cholinergic neurons. No effective treatment to prevent or reverse the symptoms is known. Part of this might be due to the lack of in vitro models that effectively mimic the relevant features of AD. Here, we describe the characterization of an AD in vitro model using the SH-SY5Y cell line. Exponentially growing cells were maintained in DMEM/F12 medium and differentiation was triggered by the combination of retinoic acid (RA) and BDNF. Both acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) enzymatic activities and immunocontent were determined. For mimicking tau and amyloid-ß pathology, RA + BDNF-differentiated cells were challenged with okadaic acid (OA) or soluble oligomers of amyloid-ß (AßOs) and neurotoxicity was evaluated. RA + BDNF-induced differentiation resulted in remarkable neuronal morphology alterations characterized by increased neurite density. Enhanced expression and enzymatic activities of cholinergic markers were observed compared to RA-differentiation only. Combination of sublethal doses of AßOs and OA resulted in decreased neurite densities, an in vitro marker of synaptopathy. Challenging RA + BDNF-differentiated SH-SY5Y cells with the combination of sublethal doses of OA and AßO, without causing considerable decrease of cell viability, provides an in vitro model which mimics the early-stage pathophysiology of cholinergic neurons affected by AD.

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

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

Agmatine as a potential therapeutic intervention in bipolar depression: the preclinical landscape.

INTRODUCTION: Present antidepressant treatments are only helpful in a quarter of patients with bipolar depression, and new strategies are warranted. Increasing evidence suggests that accelerated polyamine metabolism is associated with the pathophysiology of depression. Polyamines regulate stress responses, inflammation, and neuronal signaling in the central and enteric nervous system. Agmatine is a promising target of altered polyamine metabolism considering its unique ability to regulate intracellular polyamine content and neuroprotective effects. Areas covered: This review discusses the polyamine system and its relationship to the central and enteric nervous system, focusing on results from preclinical studies supporting the relationship between agmatine and the pathophysiology of depression. We also discussed the main mechanisms underlying the antidepressant and neuroprotective effects of agmatine. Expert opinion: Our review points out the possible relationship between polyamines and the pathophysiology of depression. It discusses the efficacy of agmatine in several models of depressive-like behaviour, and suggests that it may prove to be an efficacious adjunctive treatment in bipolar depression. Furthermore, it discusses a proposed pathway linking systemic inflammation, observed in a subset of bipolar disorder patients, to abnormal polyamine metabolism and associated changes in the epithelial gut barrier and blood-brain barrier.

Illness severity and biomarkers in depression: Using a unidimensional rating scale to examine BDNF.

BACKGROUND: Numerous studies have reported reduced peripheral brain-derived neurotrophic factor (BDNF) in major depression (MD). However, most of these studies used multidimensional depression rating scales, and failed to identify a relationship between BDNF levels and depression severity. Unidimensional scales are a more valid measure of syndrome severity. In these scales, items are ordered in increasing severity, so that as scores increase, syndrome severity increases; thus, each item adds unique information, and items can be totaled to a meaningful sum. The current study used the HAM-D6, a unidimensional measure of depression, to examine if it could identify a correlation between serum BDNF and depression severity. METHODS: Serum BDNF levels and symptom severity were assessed in 163 depressed patients, including those with both unipolar (84.0%) and bipolar (16.0%) depression. The evaluation of depression severity included the total HAM-D17 and 3 subscales, including the HAM-D6. RESULTS: On average, patients presented moderate to severe depression (HAM-D17=21.2±5.5). Overall BDNF levels were 60.4±22.6ng/mL. The correlation between serum BDNF and depression severity was modest and not different when assessed by the HAM-D6 subscale or the HAM-D17 as a whole (z=0.951; p=0.341), despite being statistically significant for the HAM-D6 (r=-0.185; p=0.019; 95% CI: -0.335 to -0.033), but not for the entire HAM-D17 (r=-0.127; p=0.108; 95% CI: -0.272 to 0.027). CONCLUSION: We could not identify a strong relationship between serum BDNF levels and depression severity using the HAM-D6. This is in concordance with results of previous studies that reported no correlation between these variables, and indicates that the properties of the clinical measures used cannot explain the results these studies.

Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia - A controlled cross-sectional study.

OBJECTIVES: Previous studies measuring serum levels of biomarkers of inflammation/oxidative stress and neurotrophins levels in fibromyalgia (FM) have rendered inconsistent results. In the present study, our aim was to explore the levels of interleukins, oxidative stress markers and brain-derived neurotrophic factor (BDNF) in patients with FM in relation to depression and severity of disease. METHODS: In a prospective controlled cross-sectional study, serum concentrations of IL-6, IL-8, IL-10, TNF-α, thiobarbituric acid reactive substances (TBARS), protein carbonyl and BDNF were measured in 69 FM patients and 61 healthy controls (all women). In the FM group, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS) were applied. Mann Whitney's and Spearman correlation tests were used for statistical analysis. RESULTS: The FM patients demonstrated a significant impact of the disease on quality of life (FIQ 70.2±17.8) and most of them had depression at some level (82.6% and 87.0% as assessed by BDI and HDRS, respectively). Most biomarkers (IL-6, IL-8, TNF-α, TBARS and protein carbonyl) and BDNF did not differ significantly between patients and controls, but the IL-10 levels were higher in FM patients (adjusted p=0.041). Among FM patients, there was no correlation of HDRS, FIQ, and BDI scores with any biomarker tested here. CONCLUSION: We observed no significant differences in biomarkers between FM patients and controls, except for higher levels of IL-10 (an anti-inflammatory cytokine) in patients. The levels of biomarkers were not correlated with parameters of disease and depression severity.

Reduced Neurite Density in Neuronal Cell Cultures Exposed to Serum of Patients with Bipolar Disorder.

BACKGROUND: Increased inflammatory markers and oxidative stress have been reported in serum among patients with bipolar disorder (BD). The aim of this study is to assess whether biochemical changes in the serum of patients induces neurotoxicity in neuronal cell cultures. METHODS: We challenged the retinoic acid-differentiated human neuroblastoma SH-SY5Y cells with the serum of BD patients at early and late stages of illness and assessed neurite density and cell viability as neurotoxic endpoints. RESULTS: Decreased neurite density was found in neurons treated with the serum of patients, mostly patients at late stages of illness. Also, neurons challenged with the serum of late-stage patients showed a significant decrease in cell viability. CONCLUSIONS: Our findings showed that the serum of patients with bipolar disorder induced a decrease in neurite density and cell viability in neuronal cultures.