Immunoinflammatory and oxidative alterations in subjects with schizophrenia under clozapine: A meta-analysis.

Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced by clozapine and its relationship with the drug's clinical response and compare it with other antipsychotics. Our systematic review has selected nineteen studies meeting the inclusion criteria, from which eleven were included in the meta-analysis, totalizing 689 subjects distributed over three different comparisons. The results revealed that clozapine treatment activates the compensatory immune-regulatory system (CIRS) (Hedges's g = +1.049; CI +0.62 - +1.47, p < 0.001) but has no effects on the immune-Inflammatory Response System (IRS) (Hedges's g= -0.27; CI -1.76 - +1.22, p = 0.71), M1 macrophage (Hedges's g= -0.32; CI -1.78 - +1.14, p = 0.65) and Th1 (Hedge's g = 0.86; CI -0.93 - +1.814, p = 0.07) profiles. Comparing clozapine-treated patients with other anti-psychotics-treated, plasma levels of interleukin (IL)-6 were greater in the clozapine group (Hedge's g = 0.75; CI 0.35 - 1.15, p<0.001). In addition, higher IL-6 plasma levels after four weeks of clozapine treatment were related to the development of clozapine-induced fever; however, IL-6 levels recovered to baseline in 6-10 weeks due to an unexplained compensatory mechanism. In conclusion, our results show that clozapine treatment causes a time-dependent mixed immune profile characterized by increased IL-6 levels and CIRS activation, which may contribute to this drug mechanism of action and adverse effects. Future studies must be designed to investigate the relationship between clozapine-induced immune alterations and symptom remission, treatment resistance, and adverse effects, given the importance of this drug for treating resistant schizophrenia.

Clozapine prescription trends in Brazil in the last decade

Objective: Clozapine is a second-generation antipsychotic indicated for treatment-resistant schizophrenia. Studies in several countries have shown a low rate of clozapine use despite the fact that approximately 30% of schizophrenia cases are treatment-resistant. In Brazil, few studies have addressed the frequency and variety of antipsychotic use in individuals diagnosed with schizophrenia (ICD F20). The objective of this study was to measure the rates of clozapine use in this population in the last decade using Brazilian Ministry of Health data. Methods: Prescriptions made between 2010 and 2020 in all 26 states and the Federal District registered at the Outpatient Information System Database from the Brazilian Health System (SIASUS) were evaluated. Results: A total of 25,143,524 prescriptions were recorded in this period, with clozapine representing 8.86% of all antipsychotics. The most frequently prescribed antipsychotic for patients with schizophrenia was olanzapine (35.8%), followed by quetiapine (27.5%). From 2010 to 2020, the rate of clozapine prescriptions in Brazil increased from 7.2% to 10.9%. Conclusions: Despite a slight increase in prescriptions in the last decade, clozapine is still underutilized in Brazil.

Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls

Objective: To test the hypothesis that genetic variations of cannabinoid receptors contribute to the pathophysiology of cognitive deficits in schizophrenia. Methods: In this genetic association case-control study, cannabinoid receptor polymorphisms CNR1 rs12720071 and CNR2 rs2229579 were tested for association with neurocognitive performance in 69 patients with schizophrenia and 45 healthy controls. Neurocognition was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS). Results: We found a consistent association between CNR1 rs12720071 polymorphism and the cognitive performance of patients in several cognitive domains. Patients with C/C polymorphism presented significantly worse performance in motor speed, verbal fluency, attention/processing speed and reasoning/problem solving. Conclusion: Although limited, our data support the hypothesis that CNR1 variations may be associated with the pathogenesis of cognitive deficits of schizophrenia.

Heterogeneous trajectories in schizophrenia: insights from neurodevelopment and neuroprogression models

The notion that schizophrenia is a neuroprogressive disorder is based on clinical perception of cumulative impairments over time and is supported by neuroimaging and biomarker research. Nevertheless, increasing evidence has indicated that schizophrenia first emerges as a neurodevelopmental disorder that could follow various pathways, some of them neuroprogressive. The objective of this review is to revisit basic research on cognitive processes and neuroimaging findings in a search for candidate keys to the intricate connections between neurodevelopment and neuroprogression in schizophrenia. In the complete panorama, schizophrenia is a neurodevelopmental disorder, possibly associated with an additional burden over the course of the disease through pathologically accelerated aging, and cognitive heterogeneity may explain the different trajectories of each patient.

Risk of neutropenia among clozapine users and non-users: results from 5,847 patients

Objective: Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those on continuous treatment for > 1 year who have never had an absolute neutrophil count (ANC) < 2,000/µL has been proposed as a monitoring strategy; however, there are no South American data to support this recommendation. This study sought to investigate whether clozapine use and other variables could explain the occurrence of ANC < 1,000/µL in patients with severe mental disorders. Methods: A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox regression considering the outcome as ANC < 1,000/µL at any time point. Predictors were sex, age, ethnicity, clozapine use, ANC > 2,000/µL during the first year of blood monitoring, and presence of a severe medical condition. Results: In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99, p < 0.05) and ANC > 2,000/µL (HR 0.04; 95%CI 0.01-0.10, p < 0.001) were protective factors, while presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p < 0.001) was a risk factor for ANC < 1,000/µL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI 0.74-2.39, p > 0.05). Conclusions: These findings suggest that clozapine does not increase the risk of neutropenia in subjects with ANC > 2,000/µL during the first year of use and in the absence of a severe medical condition. These results could help guide clinical and public-health decisions regarding clozapine blood monitoring guidelines.

Sex influences in the preventive effects of N-acetylcysteine in a two-hit animal model of schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology. AIMS: We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model. METHODS: Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5-7. On PND30-59 they received saline or NAC 220 mg/kg and between PND40-48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), α7-nAChR and parvalbumin were also evaluated. RESULTS: NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, α7-nAChR and parvalbumin, were prevented by NAC. CONCLUSION: Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.

White matter volume is decreased in bipolar disorder at early and late stages / O volume da substância branca está reduzido tanto nos estágios iniciais quanto nos estágios avançados do transtorno bipolar

Abstract Introduction: Bipolar disorder (BD) is a debilitating mood condition that affects approximately 1.3% of people worldwide, although some studies report up to 3.9% lifetime prevalence and 4-6% in adults when broad diagnostic criteria are applied. Objective: To compare differences in total white matter (WM), corpus callosum (CC) and total gray matter (GM) volumes in patients with type I BD at early and late stages compared with controls. Methods: Fifty-five subjects were enrolled in this study protocol. The double case-control design included 14 patients with BD at early stage; 15 patients at late stage; and their respective matched controls (14 and 12 subjects). Results: CC and total WM volumes were significantly smaller in patients with BD at early and late stages vs. controls. There was no difference for total GM volume in the early stage group, but in patients at late stage total GM volume was significantly smaller than in controls. The total GM volume reduction in patients at late stage is in agreement with the neuroprogression theory of BD. The reduction of WM volumes in total WM and in the CC at early and late stages supports the possibility that an early demyelination process could occur underlying the clinical manifestation of BD. Conclusion: Our findings may direct to the investigation of WM abnormalities in populations at high risk to develop BD, perhaps as early biomarkers before the overt syndrome.

Resumo Introdução: O transtorno do humor bipolar (THB) é uma condição debilitante que afeta aproximadamente 1,3% das pessoas em todo o mundo, embora alguns estudos relatem uma prevalência acumulada de até 3,9% e de 4-6% em adultos quando os critérios diagnósticos mais abrangentes são aplicados. Objetivo: Comparar as diferenças nos volumes totais de substância branca (SB), corpo caloso (CC) e volume total de substância cinzenta (SC) em pacientes com THB tipo I em estágios iniciais e tardios em comparação com controles. Métodos: Cinquenta e cinco sujeitos foram incluídos neste protocolo de estudo. O desenho de caso com duplo controle incluiu 14 pacientes com THB em estágio inicial; 15 pacientes com THB em fase tardia; e seus respectivos controles correspondentes (14 e 12 sujeitos). Resultados: Os volumes do CC e total de SB foram significativamente menores nos pacientes com THB nos estágios iniciais e tardios vs. controles. Não houve diferença para o volume total de SC no grupo em estágio inicial, mas em pacientes em fase tardia o volume total de SC foi significativamente menor do que nos controles. A redução do volume total de SC em pacientes em fase tardia está de acordo com a teoria da neuroprogressão do THB. A redução dos volumes de SB em SB total e no CC em fases precoces e tardias suporta a possibilidade de que um processo de desmielinização precoce poderia ocorrer subjacente à manifestação clínica de THB. Conclusão: Nossos achados podem direcionar a investigação de anormalidades da SB em populações de alto risco para o desenvolvimento de THB, talvez como biomarcadores precoces antes da síndrome aberta.

The Relationship between Cytokines and Verbal Memory in Individuals with Schizophrenia and Their Unaffected Siblings.

BACKGROUND: Verbal memory impairment may be considered an endophenotype in schizophrenia (SZ), also affecting the siblings of SZ subjects. Furthermore, the immune-inflammatory system response has an important modulatory effect on brain processes, especially on memory circuits. OBJECTIVE: Investigating the relationship between TNF-α and IL-6 and memory performance in patients with SZ, their unaffected siblings (SB) and healthy controls (HC). METHODS: 35 subjects with SZ, 36 SB, and 47 HC underwent a neurocognitive assessment for verbal memory by means of the revised Hopkins Verbal Learning Test (HVLT-R) in addition to serum cytokines analyses. RESULTS: SZ patients performed worse in HVLT-R than SB and HC, but SB and HC were not different. Regarding the biomarker levels, we found significant results of TNF-α for both groups. However, we did not find differences between groups after multiple-comparisons analysis. There were no significant correlations between episodic verbal memory, TNF-α, and IL-6. CONCLUSION: The results are compatible with the hypothesis that deficits in verbal memory of individuals with SZ could be secondary to inadequate functioning of cognitive processing areas, such as proactive cognitive control.

Cardiovascular risk and bipolar disorder: factors associated with a positive coronary calcium score in patients with bipolar disorder type 1

Objective: Cardiovascular disease is the leading cause of death in patients with bipolar disorder. The aim of this study was to evaluate the factors associated with positive coronary calcium score (CCS) in individuals with bipolar disorder type 1. Methods: Patients from the Bipolar Disorder Program at Hospital de Clínicas de Porto Alegre, Brazil, underwent computed tomography scanning for calcium score measurement. Clinical and sociodemographic variables were compared between patients according to their CCS status: negative (CCS = 0) or positive (CCS > 0). Poisson regression analysis was used to examine the association of CCS with number of psychiatric hospitalizations. Results: Out of 41 patients evaluated, only 10 had a positive CCS. Individuals in the CCS-positive group were older (55.2±4.2 vs. 43.1±10.0 years; p = 0.001) and had more psychiatric hospitalizations (4.7±3.0 vs. 2.6±2.5; p = 0.04) when compared with CCS- negative subjects. The number of previous psychiatric hospitalizations correlated positively with CCS (p < 0.001). Conclusion: Age and number of psychiatric hospitalizations were significantly associated with higher CCS, which might be a potential method for diagnosis and stratification of cardiovascular disease in bipolar patients. There is a need for increased awareness of risk assessment in this population.

Effects of N-acetylcysteine on amphetamine-induced sensitization in mice

Objective: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. Methods: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. Results: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. Conclusion: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.

Effects of N-acetylcysteine on amphetamine-induced sensitization in mice.

OBJECTIVE: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. METHODS: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. RESULTS: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. CONCLUSION: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.

Serum concentrations of brain-derived neurotrophic factor in patients diagnosed with gender dysphoria undergoing sex reassignment surgery.

INTRODUCTION:: Transsexualism (ICD-10) is a condition characterized by a strong and persistent dissociation with one's assigned gender. Sex reassignment surgery (SRS) and hormone therapy provide a means of allowing transsexual individuals to feel more congruent with their gender and have played a major role in treatment over the past 70 years. Brain-derived neurotrophic factor (BDNF) appears to play a key role in recovery from acute surgical trauma and environmentally mediated vulnerability to psychopathology. We hypothesize that BDNF may be a biomarker of alleviation of gender incongruence suffering. OBJECTIVES:: To measure preoperative and postoperative serum BDNF levels in transsexual individuals as a biomarker of alleviation of stress related to gender incongruence after SRS. METHODS:: Thirty-two male-to-female transsexual people who underwent both surgery and hormonal treatment were selected from our initial sample. BDNF serum levels were assessed before and after SRS with sandwich enzyme linked immunosorbent assay (ELISA). The time elapsed between the pre-SRS and post-SRS blood collections was also measured. RESULTS:: No significant difference was found in pre-SRS or post-SRS BDNF levels or with relation to the time elapsed after SRS when BDNF levels were measured. CONCLUSION:: Alleviation of the suffering related to gender incongruence after SRS cannot be assessed by BDNF alone. Surgical solutions may not provide a quick fix for psychological distress associated with transsexualism and SRS may serve as one step toward, rather than as the conclusion of, construction of a person's gender identity.

Serum concentrations of brain-derived neurotrophic factor in patients diagnosed with gender dysphoria undergoing sex reassignment surgery / Concentração sérica de fator neurotrófico derivado do cérebro em pacientes diagnosticados com disforia de gênero que realizaram cirurgia de redesignação sexual

Abstract Introduction: Transsexualism (ICD-10) is a condition characterized by a strong and persistent dissociation with one's assigned gender. Sex reassignment surgery (SRS) and hormone therapy provide a means of allowing transsexual individuals to feel more congruent with their gender and have played a major role in treatment over the past 70 years. Brain-derived neurotrophic factor (BDNF) appears to play a key role in recovery from acute surgical trauma and environmentally mediated vulnerability to psychopathology. We hypothesize that BDNF may be a biomarker of alleviation of gender incongruence suffering. Objectives: To measure preoperative and postoperative serum BDNF levels in transsexual individuals as a biomarker of alleviation of stress related to gender incongruence after SRS. Methods: Thirty-two male-to-female transsexual people who underwent both surgery and hormonal treatment were selected from our initial sample. BDNF serum levels were assessed before and after SRS with sandwich enzyme linked immunosorbent assay (ELISA). The time elapsed between the pre-SRS and post-SRS blood collections was also measured. Results: No significant difference was found in pre-SRS or post-SRS BDNF levels or with relation to the time elapsed after SRS when BDNF levels were measured. Conclusion: Alleviation of the suffering related to gender incongruence after SRS cannot be assessed by BDNF alone. Surgical solutions may not provide a quick fix for psychological distress associated with transsexualism and SRS may serve as one step toward, rather than as the conclusion of, construction of a person's gender identity.

Resumo Introdução: O transexualismo (CID-10) é uma condição caracterizada por forte e persistente dissociação com o gênero atribuído. A cirurgia de redesignação sexual (CRS) e a terapia hormonal (TH) permitem que indivíduos transexuais se sintam mais congruentes com seu gênero e, por isso, têm desempenhado papel importante nos últimos 70 anos. O fator neurotrófico derivado do cérebro (BDNF) parece desempenhar um papel fundamental na recuperação do trauma cirúrgico agudo e vulnerabilidade ambiental à psicopatologia. Nós hipotetizamos que o BDNF pode ser um biomarcador de alívio do sofrimento de incongruência de gênero pós-CRS. Objetivos: Mensurar os níveis séricos de BDNF no pré e pós-operatório em indivíduos transexuais como biomarcador de alívio de estresse relacionado à incongruência de gênero após a CRS. Métodos: Trinta e duas pessoas transexuais masculino para feminino submetidas a cirurgia e tratamento hormonal foram selecionadas de nossa amostra inicial. O nível sérico de BDNF foi avaliado antes e depois da CRS pela técnica ELISA. O tempo decorrido entre as coletas de sangue pré e pós-CRS foi medido. Resultados: Não houve diferença significativa nos níveis de BDNF pré e pós-CRS ou em relação ao tempo decorrido entre a CRS e a coleta. Conclusão: O alívio do sofrimento relacionado à incongruência de gênero pós-CRS não pode ser avaliado apenas pelo BDNF. Soluções cirúrgicas podem não fornecer uma solução rápida para o sofrimento associado ao transexualismo, e a CRS pode servir como um passo em direção à, em vez de conclusão da, construção da identidade de gênero de uma pessoa.

Carnosic Acid Protects Mitochondria of Human Neuroblastoma SH-SY5Y Cells Exposed to Paraquat Through Activation of the Nrf2/HO-1Axis.

Carnosic acid (CA; C20H28O4), which is also called salvin, is a major phenolic diterpene found in Rosmarinus officinalis L. and exhibits antioxidant, anti-inflammatory, and antiproliferative properties. CA activates the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, leading to the upregulation of antioxidant and phase II detoxification enzymes, such as heme oxygenase-1 (HO-1), glutathione reductase (GR), γ-glutamate-cysteine ligase (γ-GCL), and glutathione S-transferase (GST), among others. We have previously demonstrated that CA upregulates the total and mitochondrial synthesis of glutathione (GSH), causing mitochondrial protection against paraquat (PQ) and methylglyoxal (MG). Nonetheless, the complete mechanism by which CA prevented mitochondrial dysfunction was not clear yet. Here, we examine whether HO-1 would be involved in the CA-induced mechanism of mitochondrial protection in SH-SY5Y-treated cells. SH-SY5Y cells were pretreated with CA (1 µM) for 12 h prior to a challenge with PQ at 100 µM for additional 24 h. Zinc protoporphyrin IX (ZnPP IX; a specific inhibitor of HO-1; 10 µM) was utilized prior to exposure to CA in order to investigate whether HO-1 was involved in the cytoprotective effects elicited by CA. We found that the CA-induced Nrf2-dependent HO-1 upregulation ameliorated, at least in part, the mitochondrial function in PQ-treated cells. Therefore, CA protected mitochondria of SH-SY5Y cells and exerted anti-apoptotic effects by activating the Nrf2/HO-1 axis.

Anxiolytic properties of N-acetylcysteine in mice.

Anxiety disorders are highly prevalent and often result in poor quality of life. Available anxiolytics show significant adverse effects as well as partial efficacy in a sizable part of patients. Innovative treatments with more favorable risk-benefit ratio are sorely needed. A growing body of clinical data indicates the benefits of N-acetylcysteine (NAC) in psychiatric conditions. NAC modulates antioxidant, glutamatergic, inflammatory and neurotrophic pathways in the central nervous system, all of which are relevant to anxiety pathology. We evaluated the effects of NAC in mice models commonly used to characterize anxiolytic compounds. Male adult CF1 or BALB/c mice were treated (i.p.) acutely or subacutely (4 consecutive days) with NAC (60-150mg/kg) 60min before open field, light/dark, hole-board, social interaction, elevated T-maze or stress-induced hyperthermia tests. Diazepam (2mg/kg) was used as positive control. We found that NAC presents anxiolytic effects in all models, except for the elevated T-maze. Subacute treatments resulted in lower effective doses in comparison to acute treatment. The anxiolytic effects of NAC were comparable to diazepam. NAC is a safe and low cost medicine with suggested benefits in psychiatric conditions often presenting co-morbidity with anxiety. This study contributes evidence to support the validity of clinical trials with NAC in the context of anxiety disorders, especially considering the safety profile in comparison to the limitations of diazepam for long term treatment.

Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease

Objective: Bipolar disorder (BD) has been associated with increased rates of age-related diseases, such as type II diabetes, metabolic syndrome, osteoporosis, and cardiovascular disorders. Several biological findings have been associated with age-related disorders, including increased oxidative stress, inflammation, and telomere shortening. The objective of this study was to compare telomere length among participants with BD at early and late stages and age- and gender-matched healthy controls. Methods: Twenty-six euthymic subjects with BD and 34 healthy controls were recruited. Genomic DNA was extracted from peripheral blood and mean telomere length was measured using real-time quantitative polymerase chain reaction. Results: Telomere length was significantly shorter in both the early and late subgroups of BD subjects when compared to the respective controls (p = 0.002 and p = 0.005, respectively). The sample size prevented additional subgroup analyses, including potential effects of medication, smoking status, and lifestyle. Conclusion: This study is concordant with previous evidence of telomere shortening in BD, in both early and late stages of the disorder, and supports the notion of accelerated aging in BD.

Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease.

OBJECTIVE:: Bipolar disorder (BD) has been associated with increased rates of age-related diseases, such as type II diabetes, metabolic syndrome, osteoporosis, and cardiovascular disorders. Several biological findings have been associated with age-related disorders, including increased oxidative stress, inflammation, and telomere shortening. The objective of this study was to compare telomere length among participants with BD at early and late stages and age- and gender-matched healthy controls. METHODS:: Twenty-six euthymic subjects with BD and 34 healthy controls were recruited. Genomic DNA was extracted from peripheral blood and mean telomere length was measured using real-time quantitative polymerase chain reaction. RESULTS:: Telomere length was significantly shorter in both the early and late subgroups of BD subjects when compared to the respective controls (p = 0.002 and p = 0.005, respectively). The sample size prevented additional subgroup analyses, including potential effects of medication, smoking status, and lifestyle. CONCLUSION:: This study is concordant with previous evidence of telomere shortening in BD, in both early and late stages of the disorder, and supports the notion of accelerated aging in BD.

Cognition and functioning in bipolar depression

Objectives: Depressive symptoms are associated with worse outcomes in patients with bipolar disorder (BD). However, scarce data are available regarding neurocognitive profiles across different areas of functioning among BD patients with moderate and severe depression. Our objective was to assess cognition and global functioning in a group of patients with bipolar depression. Methods: Data were available for 100 patients with bipolar depression (78% female) and 70 controls (64% female) paired by age and education level. Cognitive function was assessed with a neuropsychological test battery. Functioning was assessed with the Functioning Assessment Short Test. Results: In patients, severe depression was associated with poorer cognitive performance on measures of executive function. Patients with severe depression showed worse global functioning than those with moderate depression (z = 2.54, p = 0.011). In patients with severe depression, lower global functioning was associated with lower scores in working memory (r = -0.200, p = 0.010), and executive function (r = -0.210, p = 0.007; and r = 0.293, p < 0.001). Conclusion: Our findings suggest cognitive impairment and global functioning impairment are associated with the severity of depressive symptoms in bipolar depression. Intensive treatment of depressive symptoms in patients with BD is crucial to improve cognitive functioning and, consequently, functional outcomes.

Neurobiological underpinnings of bipolar disorder focusing on findings of diffusion tensor imaging: a systematic review

Objective: To review the available data on diffusion tensor imaging (DTI) of subjects with bipolar disorder (BD), with a particular focus on fractional anisotropy (FA) in white matter (WM) tracts. Methods: The PubMed/MEDLINE database was searched for relevant articles, which were included in a systematic review of the literature. FA reductions and WM abnormalities were divided anatomically into three groups: commissural tracts, association tracts, and projection tracts. Results: Eighteen studies met the inclusion criteria. The corpus callosum was the main impaired commissural tract as demonstrated by FA reductions. Five studies reported FA reductions in the cingulum. Two studies reported decreased FA in the anterior thalamic radiation, and one in the corticospinal tract. Conversely, three studies found increased FA values in WM tracts involved in BD pathophysiology. Conclusion: Despite considerable heterogeneity, these results indicate a direct link between executive cognitive functioning and abnormal WM microstructural integrity of fronto-limbic tracts in patients with remitted BD, providing further evidence of the neuronal disruption that underlies BD symptomatology.