Lymphocyte glucocorticoid receptor resistance and depressive symptoms severity: a preliminary report

OBJECTIVE: Assessment of the temporal interrelationship of neuropsychiatric parameters requires technologies allowing frequent biological measurements. We propose glucocorticoid receptor (GR) function of lymphocytes to assess the temporal relationship between glucocorticoid resistance and the course of major depressive disorder. METHOD: Dexamethasone suppression of lymphocyte proliferation was in vitro assessed via 5-bromo-2' deoxyuridine (BrdU) incorporation in DNA. Optimal conditions were determined using blood of healthy volunteers. Thereafter the relation between depression severity (Hamilton Depression Rating Scale, HDRS, scores), lymphocyte proliferation and morning cortisol levels in blood was studied in thirteen depressed patients, mostly with a history of treatment resistance. RESULTS: Recovery from depression was not directly associated with changes in lymphocyte glucocorticoid resistance. However, a negative correlation was observed between HDRS and BrdU incorporation and a positive correlation between morning cortisol and BrdU incorporation. No significant correlation was found between cortisol and HDRS. Regression analyses showed that HDRS was related to both suppression of BrdU incorporation (beta -0.508, p<0.001) and cortisol levels (beta 0.364, p=0.001) in a highly significant model (F2,60=14,244, p<0.001) Except for one case, such relation could not be found within patients. CONCLUSION: Our preliminary results suggest a mutual relation between lymphocyte GR function, morning cortisol levels and MDD symptom severity. A direct relation between glucocorticoids resistance and recovery may not exist, but glucocorticoid resistance might attenuate or prevent recovery. It is clear that additional studies using larger and more homogenous groups of MDD patients are required to support our findings.     

TNF-alpha as a molecular target in bipolar disorder

The pathophysiology of bipolar disorder (BD) is poorly understood. An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-alpha may play a critical role in this process. In the present review we examine the evidence suggesting that TNF-alpha regulates apoptotic cascades which may be related to neuronal and glial loss in BD. Current evidence suggests that an increase in serum levels of TNF-alpha takes place during manic and depressive episodes. The present article reviews the therapeutic implications of TNF-alpha signaling pathways involvement in the pathophysiology of BD.     

Interleukin-6 levels and HPA axis activation in breast cancer patients with major depressive disorder

An association or a casual link has been proposed between the neuroendocrinological and neuroimmunological changes attributed to either depression or cancer. This study investigated whether breast cancer patients with and without major depression exhibit plasma interleukin-6 abnormalities and dexamethasone suppression test results. Four groups, each consisting of 30 women (1--healthy women, 2--patients with major depression, 3--breast cancer patients without major depression, 4--breast cancer patients with major depression), were compared to each other. Psychiatric evaluations were made by structured clinical interview for DSM-IV. Severity of depression was measured with the Hamilton Depression Rating Scale. Plasma levels of interleukin-6 were measured. A dexamethasone suppression test was applied. Breast cancer patients with major depression had markedly higher plasma levels of interleukin-6 than the other group. All breast cancer patients with depression had abnormal dexamethasone suppression test results. These findings suggest a hypothalamo-pituitary-adrenal axis activation and plasma levels of interleukin-6 and plasma interleukin-6 elevation and plasma levels if interleukin-6 and plasma levels of post cortisol concentrations. Evidence for a casual link or association of major depression with immune and endocrinological activation needs to be investigated further.     

The type 2 corticotrophin-releasing hormone receptor mediates orexin A-induced luteinising hormone suppression in ovariectomised rats

Orexins are thought to be regulatory factors of the arousal and sleep patterns. They also affect immune, feeding, autonomic and neuroendocrine systems. We have previously shown that intracerebroventricular (i.c.v.) injection of orexin decreases pulsatile luteinising hormone (LH) secretion in ovariectomised (OVX) rats. However, the details of this mechanism have not been fully examined. Intracerebroventricular injection of orexin A also stimulates corticotrophin-releasing hormone (CRH) systems, which have been implicated in the stress-induced suppression of reproductive function. In the present study, we investigated the role of CRH systems in orexin-induced LH suppression. OVX rats were implanted with i.c.v. and intravenous (i.v.) cannulae. After i.c.v. injection of orexin and/or CRH receptor antagonists, blood samples were collected through the i.v. cannula at 6-min intervals for 120 min for LH measurement. Intracerebroventricular injection of orexin A or B (3 nmol/2.5 microl) suppressed pulsatile LH secretion. Coadministration of orexin A and alpha-helical corticotrophic-releasing factor (CRF), a nonselective CRH receptor antagonist (13 nmol/2.5 microl), or astressin(2)B, a selective type2 (CRH-R2) CRH receptor antagonist (28 nmol/2.5 microl), partly restored pulsatile LH secretion. Orexin B-induced LH suppression was not restored by alpha-helical CRF. In addition, i.c.v. injection of orexin A increased CRH and urocortin II (UcnII), but not Ucn mRNA levels, in the hypothalamus. These findings suggest that CRH-R2 mediates orexin A-induced LH suppression and it is possible that CRH and UcnII in the hypothalamus are involved in this pathway.     

Postnatal development in vasopressin deficient Brattleboro rats with special attention to the hypothalamo-pituitary–adrenal axis function: the role of maternal genotype

Anomalies in hormonal and neurotransmitter status during perinatal period can lead to lifespan alterations in the central nervous system. Vasopressin is present early in the brain and has various mitogenic, metabolic and physiological actions, e.g. in water homeostasis or in the regulation of the hypothalamo-pituitary–adrenal (HPA) axis. Therefore we examine the possible role of vasopressin in perinatal development with special attention to the influence of maternal genotype and to the HPA axis regulation. We compared homozygous vasopressin deficient (di/di) Brattleboro rats to their heterozygous (di/+) littermates both from di/+ and di/di mother. Higher locomotion due to reduced adaptation was present at preweaning. During the first 10 days of life the di/di pups from di/di mother were the smallest, while in the later perinatal period the genotype of the pups became the more important determinant of the somatic development, namely the di/di pups from both mothers had reduced weight gain. Generally the lack of vasopressin in the pups fastened the somatic development (pinna detachment, eye and ear opening, incisor eruption) however the neurobehavioral development (palmar grasp reflex, righting reflex, negative geotaxis, etc.) was not influenced profoundly by either the mother's or the pup's genotype. The lack of vasopressin in pups abolished the 24 h maternal separation induced adrenocorticotrop hormone (ACTH) elevation while the accompanying corticosterone rises were even higher. The vasopressin deficiency of the mother reduced the resting ACTH and all corticosterone levels in all pups. So we can conclude that the lack of vasopressin speeds up the development, probably there is a greater drive for self-sufficiency in these animals. The mother's vasopressin deficiency reduced the HPA axis reactivity of the pups. The role of vasopressin in the HPA axis regulation is important during the perinatal period independently from the mother's genotype. The large discrepancy between ACTH and corticosterone regulation requires further studies.     

Epilepsy and autism spectrum disorders: Are there common developmental mechanisms?

Autistic spectrum disorders (ASD) and epilepsies are heterogeneous disorders that have diverse etiologies and pathophysiologies. The high rate of co-occurrence of these disorders suggest potentially shared underlying mechanisms. A number of well-known genetic disorders share epilepsy and autism as prominent phenotypic features, including tuberous sclerosis, Rett syndrome, and fragile X. In addition, mutations of several genes involved in neurodevelopment, including ARX, DCX, neuroligins and neuropilin2 have been identified in children with epilepsy, ASD or often both. Finally, in animal models, early-life seizures can result in cellular and molecular changes that could contribute to learning and behavioral disabilities as seen in ASD. Increased understanding of the common genetic, molecular and cellular mechanisms of ASD and epilepsy may provide insight into their underlying pathophysiology and elucidate new therapeutic approaches of both conditions.     

Measuring corticotropin-releasing hormone in pregnant women - comparing blood collection protocols for epidemiological studies

We describe a pilot study to determine the effect of delays in blood sample processing under simulated field conditions on measurement of corticotropin-releasing hormone (CRH) levels in pregnant women. CRH, a peptide secreted by the placenta into the maternal blood, is of interest in epidemiological studies of gestational duration. Many investigators suspected that CRH might break down quickly after collection, and believed the optimal treatment of blood samples for CRH must include immediate processing under chilled conditions and quick freezing of plasma. Epidemiological studies often have logistical constraints that make such rapid processing unfeasible. To examine how delays in the processing of blood samples might affect the level of measured CRH, we collected whole blood samples from 33 pregnant women attending a prenatal clinic in Boston. We compared CRH levels measured following three different processing delays with the levels of samples that were processed immediately after blood collection, the 'gold standard'. The delayed strategies involved placing the freshly collected whole blood in a cooler or refrigerator for up to 22 h prior to processing. Correlation coefficients comparing delayed with gold standard processing exceeded 0.96. These results suggest that CRH may be measured in blood samples that were spun and frozen up to 22 h after blood collection.     

Simultaneous use of thyrotropin-releasing hormone test and combined dexamethasone/corticotropine-releasing hormone test for severity evaluation and outcome prediction in patients with major depressive disorder

We performed a prospective study designed to examine whether or not evaluation of the severity and prediction of treatment outcome in major depressive disorder would be enabled by simultaneous use of the thyrotropin-releasing hormone (TRH) test and the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test. We studied consecutive patients hospitalized for major depressive disorder. The patients received the TRH test and the DEX/CRH test on the 4th through the 7th hospital days and at the time of improvement. None of the indices in these tests at the time of admission correlated with the Hamilton rating scale for depression (HRSD) or the Global Assessment for Function (GAF). However, since the DeltaMAXACTH, ACTHAUC, DeltaMAXcortisol, and CortisolAUC showed significant decreases at the time of improvement compared with the time of admission, suggesting that the DEX/CRH test can be a state marker. DeltaMAXTSH showed no significant change. Prediction of improvement within 3 months after admission was not possible with either test alone. However, the quotient which divided DeltaMAXACTH by DeltaMAXTSH was predictive of clinical improvement with a sensitivity of 50% and a specificity of 100%. The simultaneous use of the TRH test and the DEX/CRH test seems to provide a more useful biological marker than the separate use of either test alone in patients with major depressive disorder.