Lucas B. Rizzo

The role of oxidative and nitrosative stress in accelerated aging and major depressive disorder

Major depressive disorder (MDD) affects millions of individuals and is highly comorbid with many age associated diseases such as diabetes mellitus, immune-inflammatory dysregulation and cardiovascular diseases. Oxidative/nitrosative stress plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative/neuropsychiatric disorders including MDD. In this review, we critically review the evidence for an involvement of oxidative/nitrosative stress in acceleration of aging process in MDD. There are evidence of the association between MDD and changes in molecular mechanisms involved in aging. There is a significant association between telomere length, enzymatic antioxidant activities (SOD, CAT, GPx), glutathione (GSH), lipid peroxidation (MDA), nuclear factor κB, inflammatory cytokines with MDD. Major depression also is characterized by significantly lower concentration of antioxidants (zinc, coenzyme Q10, PON1). Since, aging and MDD share a common biological base in their pathophysiology, the potential therapeutic use of antioxidants and anti-aging molecules in MDD could be promising.

Effects of Risperidone on Cytokine Profile in Drug-Naïve First-Episode Psychosis

Background: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. Methods: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. Results: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms. Conclusions: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions.

Peripheral interleukin-2 level is associated with negative symptoms and cognitive performance in schizophrenia.

Although several studies have pointed to a possible role of interleukin 2 (IL-2) in schizophrenia (SZ), association between IL-2 and the different groups of symptoms has not been explored. The objective of this study was to investigate a possible correlation of peripheral IL-2 levels with symptoms and cognitive performance in patients with SZ. In addition, we compared the plasma levels of IL-2 between patients with SZ and healthy controls. Twenty-nine chronically medicated outpatients with SZ according to DSM-IV were compared with twenty-six healthy controls. The patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF). All the participants had blood collected into EDTA tubes by venipuncture between 9:00 and 10:00AM. Plasma concentrations of IL-2 were determined by cytometric bead array. A computerized neuropsychological battery assessed verbal learning, verbal fluency, working memory, set shifting, executive function, inhibition and intelligence. Patients with SZ had lower levels of IL-2 than healthy controls (p<0.001). In the SZ group, IL-2 levels were positively correlated with scores in the digit span test (rho=0.416, P=0.025) and intelligence (rho=0.464, P=0.011). We also found a negative correlation between IL-2 and total score in the negative subscale of PANSS (rho=-0.447, p=0.015). Our findings suggest that IL-2 may be involved in the mechanisms related to cognitive deterioration and negative symptomatology in schizophrenia.

Effects of depression on the cytokine profile in drug naïve first-episode psychosis

Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n=55) versus healthy controls (n=57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.

Targeting the inflammatory pathway as a therapeutic tool for major depression.

In the last decades convergent findings from several lines of evidence has revealed a robust association between major depressive disorder (MDD) and inflammatory pathways. Despite this, the translation of these findings into new and better treatments for MDD has not occurred. The objective of this study is to comprehensively review what is already known with reasonable certainty on inflammatory pathways in MDD, to clarify some points that have been insufficiently studied and to discuss the implications of these findings for future studies targeting inflammatory pathways as a therapeutic tool for individuals with MDD.

Selfish brain and selfish immune system interplay: A theoretical framework for metabolic comorbidities of mood disorders

HIGHLIGHTSThe brain and the immune system are energy consumptive and are the highest hierarchical priority in energy distribution.Psychological stress and immune dysfunction in mood disorders may contribute to malfunctioning of the mechanisms of the “selfish” brain and immune system.Such malfunctioning may result in comorbidities in mood disorders. ABSTRACT According to the “selfish brain” theory, the brain regulates its own energy supply influencing the peripheral metabolism and food intake according to its needs. The immune system has been likewise “selfish” due to independent energy consumption; and it may compete with the brain (another high energy‐consumer) for glucose. In mood disorders, stress in mood episodes or physiological stress activate homeostasis mechanisms from the brain and the immune system to solve the imbalance. The interaction between the selfish brain and the selfish immune system may explain various conditions of medical impairment in mood disorders, such as Metabolic Syndrome (MetS), obesity, type 2 diabetes mellitus (T2DM) and immune dysregulation. The objective of this study is to comprehensively review the literature regarding the competition between the brain and the immune system for energy substrate. Targeting the energetic regulation of the brain and the immune system and their cross‐talk open alternative treatments and a different approach in the study of general medical comorbidities in mood disorders, although more investigation is needed.

Peripheral immuno-inflammatory abnormalities in ultra-high risk of developing psychosis

BACKGROUND Immuno-inflammatory imbalances have been documented in schizophrenia, but very little is known about the immunological changes prior to the onset of disease. OBJECTIVE This work aimed to compare serum levels of pro- and anti-inflammatory cytokines in young subjects at ultra-high risk (UHR) of developing psychosis with age- and sex-matched healthy controls. METHODS A total of 12 UHR and 16 age- and sex-matched healthy controls (HC) subjects were enrolled in this study. Clinical profile was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS), Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I) or Kiddie-SADS-Present and Lifetime Version (K-SADS-PL), and Global Assessment of Functioning (GAF) scale. Serum interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, IFN-γ, and IL-17 were measured by flow cytometry using the Th1/Th2/Th17 cytometric bead array. RESULTS Compared with the healthy control group, patients in UHR showed increased IL-6 levels (Z=-2.370, p=0.018) and decreased IL-17 levels in serum (Z=-1.959, p=0.050). Levels of IL-17 positively correlated to the values in GAF symptoms (rho=0.632, p=0.028). CONCLUSION Our results suggest that immunological imbalances could be present in the early stages of psychosis, including in at-risk stages. Future studies should replicate and expand these results.

Crack cocaine addiction, early life stress and accelerated cellular aging among women

BACKGROUND Early life stress (ELS) and addiction are related to age-related diseases and telomere shortening. However, the role of telomere length (TL) in crack cocaine addiction remains unknown. The purpose of this study was to investigate the TL in a sample of crack cocaine dependent-women who reported an ELS history and in a community-based sample of elderly women as a reference group for senescence. METHODS This study included treatment seeking crack cocaine dependents women (n=127) and elderly women without a psychiatric diagnosis (ELD, n=49). The crack cocaine sample was divided in two groups according to their Childhood Trauma Questionnaire (CTQ) scores: presence of history of childhood abuse and neglect (CRACK-ELS) and absence of ELS history (CRACK). TL was assessed by T/S ratio obtained from peripheral blood DNA using quantitative PCR assay. RESULTS CRACK and CRACK-ELS subjects exhibited shortened TL in comparison to the ELD group, despite their younger age. Among crack cocaine sample, CRACK-ELS group had significantly shorter telomeres than the CRACK group. Correlation analysis within crack cocaine group indicated that TL was negatively correlated with emotional abuse scores. CONCLUSIONS These results support previous findings associating telomere shortening with both ELS and drug addiction. This study suggests new evidence of a distinct biological phenotype for drug-dependent women with ELS. The results support the biological senescence hypothesis underpinning ELS experience.

Impaired glucose metabolism moderates the course of illness in bipolar disorder

BACKGROUND The longitudinal course of bipolar disorder (BD) is highly heterogeneous, and is moderated by the presence of general medical comorbidities. This study aimed to investigate the moderating effects of impaired glucose metabolism (IGM) on variables of illness course and severity in a BD population. METHODS Fifty-five patients with BD were evaluated. All subjects were evaluated with respect to current and past psychiatric and medical disorders, as well as lifetime use of any medication. Body mass index (BMI) and metabolic parameters were obtained. IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. RESULTS Thirty (54.5%) individuals had IGM. After adjustment for age, gender, ethnicity, alcohol use, smoking, BMI and past and current exposure to psychotropic medications, individuals with IGM, when compared to euglycemic participants, had an earlier age of onset (RR: 0.835, p=0.024), longer illness duration (RR: 1.754, p=0.007), a higher number of previous manic/hypomanic episodes (RR: 1.483, p=0.002) and a higher ratio of manic/hypomanic to depressive episodes (RR: 1.753, p=0.028). Moreover, we observed a moderating effect of IGM on the association between number of mood episodes and other variables of illness course, with the correlation between lifetime mood episodes and frequency of episodes being significantly greater in the IGM subgroup (RR: 1.027, p=0.029). All associations observed herein remained significant after adjusting for relevant confounding factors (e.g. age, alcohol and tobacco use, exposure to psychotropic agents, BMI). LIMITATIONS Cross-sectional design, small sample size. CONCLUSIONS Comorbid IGM may be a key moderator of illness progression in BD.

Brain‐derived neurotrophic factor, impaired glucose metabolism, and bipolar disorder course

OBJECTIVES The neurotrophin brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker in bipolar disorder (BD). However, current evidence is limited and results have been highly heterogeneous. This study aimed to assess the moderating effect of impaired glucose metabolism (IGM) on plasma levels of BDNF in individuals with BD, and on the relationship between BDNF and variables of illness course. METHODS We measured and compared the plasma levels of BDNF in individuals with BD (n=57) and healthy controls (n=26). IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. Information related to current and past psychiatric/medical history, as well as prescription of pharmacological treatments was also captured. RESULTS Individuals with BD had lower levels of BDNF, relative to healthy controls, after adjustment for age, gender, current medications, smoking, alcohol use, and IGM (P=.046). There was no effect of IGM (P=.860) and no interaction between BD diagnosis and IGM (P=.893). Peripheral BDNF levels were positively correlated with lifetime depressive episodes (P<.001), psychiatric hospitalizations (P=.001) and suicide attempts (P=.021). IGM moderated the association between BDNF and the number of previous mood episodes (P<.001), wherein there was a positive correlation in euglycemic participants and a negative correlation in individuals with IGM. CONCLUSIONS BD is independently associated with lower levels of BDNF; IGM may modify the relationship between BDNF and BD course, suggesting an interactive effect of BDNF with metabolic status on illness progression.