Mirela Paiva Vasconcelos-Moreno

Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression

BACKGROUND Studies investigating inflammatory markers in post-traumatic stress disorder (PTSD) have yielded mixed results. The aim of our study was to compare concentrations of inflammatory markers in patients with PTSD compared with healthy controls. METHODS We did a meta-analysis and meta-regression of studies comparing inflammatory markers between patients with PTSD and healthy controls by searching PubMed, Embase, Scopus, Web of Science, and PsycINFO for articles published between Jan 1, 1960, and April 7, 2015. From eligible studies (ie, cross-sectional studies or baseline data from longitudinal studies of peripheral blood cytokine concentrations that compared adults with PTSD with healthy controls), we extracted outcomes of interest, such as mean and SD of peripheral blood cytokines, the time of day blood was collected, whether the study allowed patients with comorbid major depressive disorder in the PTSD group, whether patients were medication free, and severity of PTSD symptoms. We undertook meta-analyses whenever values of inflammatory markers were available in two or more studies. A random-effects model with restricted maximum-likelihood estimator was used to synthesise the effect size (assessed by standardised mean difference [SMD]) across studies. FINDINGS 8057 abstracts were identified and 20 studies were included. Interleukin 6 (SMD 0.88; p=0.0003), interleukin 1β (SMD 1.42; p=0.045), and interferon γ (SMD 0.49; p=0.002) levels were higher in the PTSD group than in healthy controls. Subgroup meta-analysis of patients who were not given medication showed higher tumour necrosis factor α (TNFα; SMD 0.69, 95% CI 0.35-1.02; p<0.0001) in the PTSD group than the control group in addition to the aforementioned cytokines. TNFα (SMD 1.32, 0.13-2.50; p=0.003), interleukin 1β (SMD 2.35, 0.01-4.68; p=0.048), and interleukin 6 (SMD 1.75, 0.97-2.53; p<0.0001) levels remained increased in the PTSD group in a subgroup meta-analysis of studies that excluded comorbid major depressive disorder. Illness duration was positively associated with interleukin 1β levels (b=0.33, p<0.0001) and severity with interleukin 6 (b=0.02, p=0.042). A model composed of several variables-presence of comorbid major depressive disorder, use of psychotropic medications, assay used, and time of day blood was collected-explained the large amount of heterogeneity between interleukin 1β, interleukin 6, and C-reactive protein studies. Eggers linear regression test revealed a potential publication bias for interleukin 1β. Additionally, for most inflammatory markers, study heterogeneity was reported to be high (I(2)>75%). INTERPRETATION PTSD is associated with increased interleukin 6, interleukin 1β, TNFα, and interferon γ levels. This information might be useful for consideration of chronic low-grade inflammation as a potential target or biomarker in PTSD treatment. Use of psychotropic medication and presence of comorbid major depressive disorder were important moderators that might explain the inconsistency between results of previous studies. Our search strategy used a range of databases and we made exhaustive effort to acquire data by contacting the authors. Notably, high levels of between-study heterogeneity were recorded for most cytokine variables measured in our analysis. However, meta-regression analysis could explain a large amount of this heterogeneity. FUNDING None.

Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder.

Background: Impaired stress resilience and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients. Methods: Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR). Results: Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels. Conclusions: Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness.

Exercise and severe major depression: Effect on symptom severity and quality of life at discharge in an inpatient cohort

BACKGROUND Exercise is a potential treatment for depression. However, few studies have evaluated the role of adjunct exercise in the treatment of severely major depressed inpatients. The goal of this study was to evaluate the effects of add-on exercise on the usual treatment of severely depressed inpatients. METHODS Fifty participants were randomized to an exercise (exercise + usual treatment) or a control (usual treatment) group. Twenty-five patients were randomly allocated to each group. The participants in the exercise group performed three sessions per week throughout the hospitalization period, with a goal dose of 16.5 kcal/kg/week plus the usual pharmacological treatment. Depressive symptoms and the Quality of Life (QoL) of the participants were assessed at the baseline, the second week, and discharge. RESULTS A significant group × time interaction was found for depressive symptoms and the physical and psychological domains of QoL. Differences between groups occurred at the second week and discharge with respect to depressive symptoms and the physical and psychological domains of QoL. There was no difference in the remission rate at discharge (48% and 32% for the exercise and control group, respectively). An NNT of 6.25 was found. No significant baseline characteristics predict remission at discharge. CONCLUSION Add-on exercise is an efficacious treatment for severely depressed inpatients, improving their depressive symptoms and QoL. Initial acceptance of exercise remains a challenge.

Early apoptosis in peripheral blood mononuclear cells from patients with bipolar disorder

BACKGROUND The pathophysiology of bipolar disorder (BD) includes several systemic alterations, such as inflammatory markers, oxidative stress, and DNA damage. Most of these parameters may be related to dysfunctions in cellular resilience mechanisms reported in patients, such as endoplasmic reticulum stress and mitochondrial damage. As a consequence, these impairments can ultimately lead to cell death. Therefore, the aim of this study was to assess cell death and viability in peripheral blood mononuclear cells (PBMCs) from patients with BD and controls. METHODS Ten euthymic patients with BD type I and seven age- and sex-matched healthy controls were recruited and had peripheral blood collected by venipuncture in heparine tubes. PBMCs were isolated from total blood, followed by measurement of cell viability by trypan blue exclusion, and apoptosis and necrosis by anexin V/propidium iodide (PI) staining. RESULTS Cell viability did not significantly differ between groups, as well as the percentage of cells in necrosis or in late apoptosis/necrosis. However, the percentage of cells in early apoptosis was higher in patients when compared with controls (p=0.002). LIMITATIONS This is a preliminary study with relatively small sample size. CONCLUSIONS The systemic toxicity along with dysfunctional cell resilience mechanisms reported in patients with BD may be inducing apoptosis in PBMCs. A deeper look into the clinical relevance of such findings is warranted.

Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging

Abstract Background: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls. Methods: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-α, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Results: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers. Conclusions: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.

Verbal memory impairment in healthy siblings of patients with schizophrenia

Cognitive deficits have been recognized as a core feature of schizophrenia (SZ) and are present in most patients. Verbal memory (VM), working memory (WM), and executive function (EF) are domains commonly impaired in patients with SZ. These latter domains have been related to the genetic risk of the disorder characterizing as possible endophenotypes. In order to study neurocognitive endophenotypes in a Brazilian population with elevated genetic risks to develop SZ, we measured VM (Hopkins Verbal Learning Test Revised), WM (Letter-Number Sequencing and Digit Span) and EF (Stroop Test) in 90 subjects (45 unaffected siblings of patients with SZ and 45 matched healthy controls). No differences were found in EF and WM (Letter-Number Sequencing and Digit Span). However, in VM, siblings of patients performed worse than controls on the immediate recall and delayed recall. Our results suggest that VM impairment could be considered an endophenotype of SZ.

Improvement of behavioural and manic-like symptoms secondary to herpes simplex virus encephalitis with mood stabilizers : a case report

Herpes simplex encephalitis (HE) is one of the most common aetiologies of fatal sporadic encephalitis (Whitley, 1990). Although acyclovir has greatly decreased mortality, HE is still associated with significant mortality (19–28%) and morbidity with rates of complete recovery less than 50% (Skoldenberg et al. 1984; Taira et al. 2009). Behavioural and cognitive symptoms are common sequelae of HE, even when appropriate antiviral therapy is administered in the acute stage of the illness (McGrath et al. 1997). Therefore, there is a need for novel therapeutic regimens for HE, given that current available treatment is not fully effective and the scarce available literature suggests benefit with alternative treatments. The effect of drugs on neuroplasticity has received greater attention in psychopharmacology, with recent studies showing that neurotrophic properties may be important for the behavioural and symptomatic effect of mood stabilizers such as valproate and lithium (Frey et al. 2006). Therefore, it could be hypothesized that these pharmacological properties may be useful in the treatment of HE, given that it is often associated with neuronal damage and behavioural symptoms. Here, we report on a 20-yr-old woman with HE and prominent secondary behavioural and manic-like symptoms. To the best of our knowledge this is the first report of HE that was responsive to pharmacotherapy which is the first-line treatment for acute mood episode. Ms. X, a 20-yr-old woman, was admitted to the emergency room with headache, vomiting, cough and dyspnoea; these had gradually developed within the previous 2 wk. Within the first 48 h, Ms. X showed a gradual …

Cognitive performance and psychosocial functioning in patients with bipolar disorder, unaffected siblings, and healthy controls

Objective: To assess cognitive performance and psychosocial functioning in patients with bipolar disorder (BD), in unaffected siblings, and in healthy controls. Methods: Subjects were patients with BD (n=36), unaffected siblings (n=35), and healthy controls (n=44). Psychosocial functioning was accessed using the Functioning Assessment Short Test (FAST). A sub-group of patients with BD (n=21), unaffected siblings (n=14), and healthy controls (n=22) also underwent a battery of neuropsychological tests: California Verbal Learning Test (CVLT), Stroop Color and Word Test, and Wisconsin Card Sorting Test (WCST). Clinical and sociodemographic characteristics were analyzed using one-way analysis of variance or the chi-square test; multivariate analysis of covariance was used to examine differences in neuropsychological variables. Results: Patients with BD showed higher FAST total scores (23.90±11.35) than healthy controls (5.86±5.47; p < 0.001) and siblings (12.60±11.83; p 0.001). Siblings and healthy controls also showed statistically significant differences in FAST total scores (p = 0.008). Patients performed worse than healthy controls on all CVLT sub-tests (p < 0.030) and in the number of correctly completed categories on WCST (p = 0.030). Siblings did not differ from healthy controls in cognitive tests. Conclusion: Unaffected siblings of patients with BD may show poorer functional performance compared to healthy controls. FAST scores may contribute to the development of markers of vulnerability and endophenotypic traits in at-risk populations.

Post-traumatic stress disorder and interleukin 6 - Authors' reply.

Lebanon is a small, middle-income country with a total population estimated at 4 million including 400 000 Palestinian refugees. The recent hosting of more than 1·2 million Syrian refugees has placed an enormous strain on the health system. However, both public and private health care institutions have remained functional and able to respond to the increase in demand. In 2014, the Lebanese Ministry of Public Health, in collaboration with WHO, UNICEF, and the International Medical Corps, launched the first National Mental Health Programme to reform the mental health system and scale up services. The programme has been making steady progress, including coordination of the work of more than 62 organisations working in Mental Health and Psychosocial Support (MHPSS) in response to the Syrian crisis. In May 2015, the Ministry launched the first National Mental Health and Substance Use strategy. One of the main concerns is to strengthen the national system while avoiding the building of a parallel system for the persons affected by the Syrian crisis. Working within the framework of the national strategy, 106 members of staff including nurses, social workers, and general practitioners at 50 primary health care centres have been trained on the mental health Gap Action ProgramIntervention Guide with the aim of integrating mental health into primary care. Staff at a further 30 primary health care centres have been trained in psychological fi rst aid. Furthermore, after finalizing a 4Ws (Who’s doing What, Where, and until When) assessment to map the existing resources, we have delivered a series of training modules on suicide risk management for frontline healthcare staff , established regional MHPSS task forces in the south and north of Lebanon, and strengthened the links with the Bekaa task force. The Ministry of Public Health has fi nalised an online platform for the 4Ws, with the support of the United Nations development programme to deliver information about available resources, and is working on building Authors’ reply Nilsonne and colleagues expressed some concerns related to our meta-analysis, which showed increased levels of interleukin-6 in patients with posttraumatic stress disorder (PTSD). We disagree with Nilsonne and colleagues’ criticism, as we selected several analytic strategies to explore heterogeneity and bias, namely: subgroup meta-analysis, meta-regression, leave-one-out, Egger’s test, and trim and fi ll. We decided not to exclude potential outliers, because only a small number of studies were included for each interleukin. In this scenario, the exclusion of a study that appeared to be an outlier could neglect a true pattern. To the best of our knowledge, the decision to exclude outliers should be based on specifi c measures available in the metafor package and not by means of visual inspection of the funnel plot. In addition, we performed Duval and Tweedie’s trim and fi ll method, as Egger’s linear regression test revealed a potential publication bias in the scenario proposed by Nilsonne and colleagues (ie, removing Guo and colleagues from the meta-analysis), and the result for interleukin 6 is still robust (standard mean diff erence 0·58, 95% CI 0·23 to 0·93; p=0·0012—one study was estimated on the left side). In regards to the sample size, we analysed it as a potential moderator of the effect size, and the result was not significant (b=–0·0018; 95% CI –0·0122 to 0·0086; p=0·7385). Moreover, the significance of the effect size remained robust when leave-one-out models were used for interleukin 6. Lastly, we would like to emphasise that studies that included patients with severe medical illness, autoimmune or infl ammatory disease, or use of anti-infl ammatory or immunomodulatory drugs were excluded from our meta-analysis. In light of the above, we believe that the association between interleukin 6 and PTSD is robust in our meta-analysis. However, it is important to highlight that non-measured confounders of the included studies might have overestimated the eff ect sizes reported.