The HPA axis in bipolar disorder: Systematic review and meta-analysis.

OBJECTIVES: To provide a quantitative and qualitative synthesis of the available evidence on the role of Hypothalamic-Pituitary-Adrenal (HPA) axis in the pathophysiology of Bipolar Disorder (BD). METHODS: Meta-analysis and meta-regression of case-control studies examining the levels of cortisol, ACTH, CRH levels. Systematic review of stress reactivity, genetic, molecular and neuroimaging studies related to HPA axis activity in BD. RESULTS: Forty-one studies were included in the meta-analyses. BD was associated with significantly increased levels of cortisol (basal and post-dexamethasone) and ACTH, but not of CRH. In the meta-regression, case-control differences in cortisol levels were positively associated with the manic phase (p=0.005) and participants' age (p=0.08), and negatively with antipsychotics use (p=0.001). Reviewed studies suggest that BD is associated with abnormalities of stress-related molecular pathways in several brain areas. Variants of HPA axis-related genes seem not associated with a direct risk of developing BD, but with different clinical presentations. Also, studies on unaffected relatives suggest that HPA axis dysregulation is not an endophenotype of BD, but seems related to environmental risk factors, such as childhood trauma. Progressive HPA axis dysfunction is a putative mechanism that might underlie the clinical and cognitive deterioration of patients with BD. CONCLUSIONS: BD is associated with dysfunction of HPA axis activity, with important pathophysiological implications. Targeting HPA axis dysfunctions might be a novel strategy to improve the outcomes of BD.

HPA axis and aging in depression: systematic review and meta-analysis.

One of the most consistent findings in the biology of depression is an altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, data concerning this issue have never been examined with a focus on the older population. Here we present a systematic review and meta-analysis, based on studies investigating levels of cortisol, adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) in depressed participants older than 60 and compared with healthy controls. We found 20 studies, for a total of 43 comparisons on different indices of HPA axis functioning. Depression had a significant effect (Hedges' g) on basal cortisol levels measured in the morning (0.89), afternoon (0.83) and night (1.39), but a smaller effect on cortisol measured continuously (0.51). The effect of depression was even higher on post-dexamethasone cortisol levels (3.22), whereas it was non-significant on morning ACTH and CRH levels. Subgroup analyses indicated that various methodological and clinical factors can influence the study results. Overall, older participants suffering from depression show a high degree of dysregulation of HPA axis activity, with differences compared with younger adults. This might depend on several mechanisms, including physical illnesses, alterations in the CNS and immune-endocrinological alterations. Further studies are needed to clarify the implications of altered HPA axis activity in older patients suffering from depression. Novel pharmacological approaches might be effective in targeting this pathophysiological feature, thus improving the clinical outcomes.

Clinical, psychological and environmental predictors of prospective suicide events in patients with Bipolar Disorder.

Patients with Bipolar Disorder (BD) have high rates of suicide compared to the general population. The present study investigates the predictive power of baseline clinical, psychological and environmental characteristics as risk factors of prospective suicide events (attempts and completions). Data was collected from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. 3083 bipolar patients were included in this report, among these 140 (4.6%) had a suicide event (8 died by suicide and 132 attempted suicide). Evaluation and assessment forms were used to collect clinical, psychological and socio-demographic information. Chi-square and independent t-tests were used to evaluate baseline characteristics. Potential prospective predictors were selected on the basis of prior literature and using a screening analysis of all risk factors that were associated with a history of suicide attempt at baseline and were tested using a Cox regression analysis. The strongest predictor of a suicide event was a history of suicide attempt (hazard ratio = 2.60, p-value < 0.001) in line with prior literature. Additional predictors were: younger age, a high total score on the personality disorder questionnaire and a high percentage of days spent depressed in the year prior to study entry. In conclusion, the present findings may help clinicians to identify patients at high risk for suicidal behavior upon presentation for treatment.

Neuroimmune endocrine effects of antidepressants.

Antidepressant pharmacotherapy is to date the most often used treatment for depression, but the exact mechanism of action underlying its therapeutic effect is still unclear. Many theories have been put forward to account for depression, as well as antidepressant activity, but none of them is exhaustive. Neuroimmune endocrine impairment is found in depressed patients; high levels of circulating corticosteroids along with hyperactivation of the immune system, high levels of proinflammatory cytokines, low levels of melatonin in plasma and urine, and disentrainment of circadian rhythms have been demonstrated. Moreover, antidepressant treatment seems to correct or at least to interfere with these alterations. In this review, we summarize the complex neuroimmune endocrine and chronobiological alterations found in patients with depression and how these systems interact with each other. We also explain how antidepressant therapy can modify these systems, along with some possible mechanisms of action shown in animal and human models.

Age-related changes in an antioxidant defense system in elderly patients with essential hypertension compared with healthy controls.

BACKGROUND AND AIMS: Oxidative stress has been reported to increase with aging. Oxidative stress is also associated with hypertension, and antioxidant treatment has been shown to enhance antioxidant defense system. We therefore aimed to analyze the relationship between aging and some markers of oxidative stress in elderly patients with essential hypertension compared with healthy controls. MATERIAL AND METHODS: Blood was collected from 18 patients with essential hypertension and 21 age- and sex-matched healthy controls aged over 65. Patients were on their usual medications while participating in the study. Oxidative stress parameters were investigated by measuring the concentration of glutathione (GSH) in whole blood and activities of glutathione peroxidase (GPx-1), glutathione reductase (GR), catalase (CAT), and Cu-Zn superoxide dismutase (CuZn SOD, SOD-1) in erythrocytes. GSH, GPx-1, GR, CAT, and CuZn SOD correlations with age were expressed as Pearson product-moment correlation coefficient r. Independent-samples T test was used to compare mean values of parameters between groups. RESULTS: (1) Among all parameters analyzed herein, the activity of SOD-1 showed the most explicit decrease in relation to age, both in healthy controls and hypertensive subjects with r values of -0.54 (P = 0.05) and -0.68 (P < 0.01), respectively. (2) Age-related changes in parameters of oxidative stress did not differ significantly between groups. (3) Mean activity of SOD-1 was significantly higher (P < 0.05) in elderly hypertensives (2341.7 ± 213.71 U/g Hb) when compared with healthy controls (2199.7 ± 213.66 U/g Hb). (4) Mean GSH level was significantly higher (P < 0.01) in patients (3.1 ± 0.29 mmol/l) than in controls (2.8 ± 0.37 mmol/l). (5) Increased level of GSH in hypertension was followed by significantly (P < 0.01) higher activity of GR in this group when compared with controls (83.4 ± 15.25 and 64.1 ± 9.40 U/g Hb, respectively). CONCLUSIONS: (1) The antioxidant barrier changes in elderly subjects with senescence. (2) CuZn SOD activity is negatively correlated with age and this association is not altered by factors that modulate the enzyme activity, such as hypertension and antihypertensive treatment. (3) Significantly higher concentration of GSH and significantly higher GR activity in patients may suggest a significant role of GSH metabolism in the pathogenesis of hypertension, as well as its contribution to the effect of antihypertensive treatment.