Longitudinal assessment of serum anticholinergic activity in delirium of the elderly

Background: Delirium, a frequently occurring, devastating disease, is often underdiagnosed, especially in dementia. Serum anticholinergic activity (SAA) was proposed as a disease marker as it may reflect delirium's important pathogenetic mechanism, cholinergic deficiency. We assessed the association of serum anticholinergic activity with delirium and its risk factors in a longitudinal study on elderly hip fracture patients. Method: Consecutive elderly patients admitted for hip fracture surgery (n = 142) were assessed longitudinally for delirium, risk factors, and serum markers (IL-6, cortisol, and SAA). Using a sophisticated statistical design, we evaluated the association between SAA and delirium in general and with adjustments, but also the temporal course, including the events fracture, surgery, and potential delirium, individual confounders, and a propensity score. Results: Among elderly hip fracture patients 51% developed delirium, these showed more risk factors (p <0.001), and complications (p <0.05). Uncontrolled SAA levels (463 samples) were significantly higher in the delirium group (4.2 vs. 3.4 pmol/ml) and increased with delirium onset, but risk factors absorbed the effect. Using mixed-modeling we found a significant increase in SAA concentration (7.6% (95%CI 5.0-10.2, p <0.001)) per day, which was modified by surgery and delirium, but this effect was confounded by cognitive impairment and IL-6 values. Confounder control by propensity scores resulted in a disappearance of delirium-induced SAA increase. Conclusions: Delirium-predisposing factors are closely associated with changes in the temporal profile of serum anticholinergic activity and thus neutralize the previously documented association between higher SAA levels and delirium. An independent relationship of SAA to delirium presence is highly questionable. (C) 2012 Elsevier Ltd. All rights reserve

Exposure to a dysfunctional glucocorticoid receptor from early embryonic life programs the resistance to experimental autoimmune encephalomyelitis via nitric oxide-induced immunosuppression

Glucocorticoid (GC) hormones play a central role in the bidirectional communication between the neuroendocrine and the immune systems and exert, via GC receptors (GR), potent immunosuppressive and anti-inflammatory effects. In this study, we report that GR deficiency of transgenic mice expressing GR antisense RNA from early embryonic life has a dramatic impact in programming the susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. GR deficiency renders mice resistant to myelin oligodendrocyte glycoprotein-induced EAE, and such mice do not develop clinical or histological signs of disease compared with EAE-susceptible wild-type mice. Resistance to EAE in GR-deficient mice is associated not with endogenous GC levels, but with a significant reduction in spleen and lymph node cell proliferation. The use of NO inhibitors in vitro indicates that NO is the candidate immunosuppressor molecule. GR-deficient mice develop 3- to 6-fold higher nitrite levels in the periphery and are resistant to NO inhibition by GCs. Specific inhibition of NO production in vivo by treatment with the inducible NO synthase inhibitor, L-N(6)-(1-iminoethyl)-lysine, suppressed circulating nitrites, increased myelin oligodendrocyte glycoprotein-specific cell proliferation, and rendered GR-deficient mice susceptible to EAE. Thus, life-long GR deficiency triggers inducible NO synthase induction and NO generation with consequent down-regulation of effector cell proliferation. These findings identify a novel link among GR, NO, and EAE susceptibility and highlight NO as critical signaling molecule in bidirectional communication between the hypothalamic-pituitary-adrenocortical axis and the immune system

Triiodothyronine addition to paroxetine in the treatment of major depressive disorder

There is evidence that thyroid hormone T-3 increases serotonergic neurotransmission. Therefore, T-3 addition to antidepressants may improve treatment response in major depression. In nonrefractory depression, T-3 addition to tricyclic antidepressants indeed accelerates treatment response. Current therapeutic practice favors selective serotonin reuptake inhibitors. This is the first study to investigate the efficacy of T-3 addition to paroxetine in major depression. One hundred thirteen patients with major depressive disorder were randomly assigned to 8 wk of double-blind outpatient treatment with low-dose T-3 (25 mug), high-dose T-3 (25 mug twice daily), or placebo in addition to paroxetine 30 mg daily. A total of 106 patients started treatment and were included in the outcome analysis. Response rate after 8 wk ( reduction of Hamilton Rating Scale for Depression score greater than or equal to 50%) was 46% in all three treatment arms (P = 0.99). T-3 addition did not accelerate clinical response to paroxetine, nor was an effect of T-3 found when only women were analyzed. Patients on T-3 addition reported more adverse events than patients on placebo comedication. In conclusion, these results do not support a role for T-3 addition to selective serotonin reuptake inhibitors in the treatment of nonrefractory major depressive disorder. On the contrary, more adverse reactions occurred in T-3-treated patient

Glucocorticoids and relapse of major depression (dexamethasone/corticotropin-releasing hormone test in relation to relapse of major depression)

BACKGROUND: Knowledge of pathogenic mechanisms and predictors of relapse in major depressive disorder is still limited. Hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation is thought to be related to the development and course of depression. METHODS: We investigated whether dexamethasone/corticotropin-releasing hormone (DEX/CRH) test parameters were related to the occurrence of relapse in 45 outpatients with clinically remitted major depression. The DEX/CRH test was administered before and after 8 weeks of antidepressant treatment. RESULTS: Posttreatment maximal adrenocorticotropic hormone (ACTH) and maximal cortisol levels, as well as delta ACTH and delta cortisol levels, were significantly higher (all p < .05) among patients who relapsed (n = 22) compared with patients in whom no relapse occurred (n = 23). Higher posttreatment maximal cortisol response on the DEX/CRH test was associated with shorter "relapse-free survival" (p = .05). CONCLUSIONS: In outpatients with clinically remitted major depression, higher posttreatment maximal cortisol levels on the DEX/CRH test were associated with relapse of major depressio

Thyroid and adrenal axis in major depression: a controlled study in outpatients

Objective: Major depressive disorder has been associated with changes in the hypothalamus - pituitary-thyroid (HPT) axis and with hypercortisolism. However, the changes reported have been at variance, probably related to in- or outpatient status, the use of antidepressant medication and the heterogeneity of depression. We therefore conducted a controlled study in unipolar depressed outpatients who had been free of antidepressants for at least 3 months. Design: We assessed endocrine parameters in 113 depressed outpatients and in 113 sex- and age-matched controls. Methods: Patients were included if they had a major depression according to a Structural Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (DSM), fourth edition (SCID-IV) and if they had a 17-item Hamilton rating scale for depression (HRSD) score of greater than or equal to16. Endocrine parameters contained serum concentrations of TSH, (free) thyroxine, tri-iodothyronine, cortisol, thyroid peroxidase (TPO) antibody titre and 24-h urinary excretion of cortisol. Results: The serum concentration of TSH was slightly higher in depressed patients as compared with controls (P <0.001), independent of the presence of subclinical hypothyroidism and/or TPO antibodies (n = 28). All other HPT axis parameters were similar in both groups. The 24-h urinary cortisol excretion was similar in patients and controls. In atypical depression, serum cortisol was lower than in non-atypical depression (P = 0.01). Patients with neither melancholic depression nor severe depression (HRSD greater than or equal to 23) had altered endocrine parameters. Finally, serum TSH values could not be related to cortisol values. Conclusion: When compared with matched control subjects, outpatients with major depression had slightly higher serum TSH, while urinary cortisol levels were similar. Furthermore, we observed lower serum cortisol in atypical depression than in non-atypical depressio

The value of nonoperative versus operative treatment of frail institutionalized elderly patients with a proximal femoral fracture in the shade of life (FRAIL-HIP); protocol for a multicenter observational cohort study

Background: Proximal femoral fractures are strongly associated with morbidity and mortality in elderly patients. Mortality is highest among frail institutionalized elderly with both physical and cognitive comorbidities who consequently have a limited life expectancy. Evidence based guidelines on whether or not to operate on these patients in the case of a proximal femoral fracture are lacking. Practice variation occurs, and it remains unknown if nonoperative treatment would result in at least the same quality of life as operative treatment. This study aims to determine the effect of nonoperative management versus operative management of proximal femoral fractures in a selected group of frail institutionalized elderly on the quality of life, level of pain, rate of complications, time to death, satisfaction of the patient (or proxy) and the caregiver with the management strategy, and health care consumption. Methods: This is a multicenter, observational cohort study. Frail institutionalized elderly (70 years or older with a body mass index < 18.5, a Functional Ambulation Category of 2 or lower pre-trauma, or an American Society of Anesthesiologists score of 4 or 5), who sustained a proximal femoral fracture are eligible to participate. Patients with a pathological or periprosthetic fractures and known metastatic oncological disease will be excluded. Treatment decision will be reached following a structured shared decision process. The primary outcome is quality of life (Euro-QoL; EQ-5D-5 L). Secondary outcome measures are quality of life measured with the QUALIDEM, pain level (PACSLAC), pain medication use, treatment satisfaction of patient (or proxy) and caregivers, quality of dying (QODD), time to death, and direct medical costs. A cost-utility and cost-effectiveness analysis will be done, using the EQ-5D utility score and QUALIDEM score, respectively. Non-inferiority of nonoperative treatment is assumed with a limit of 0.15 on the EQ-5D score. Data will be acquired at 7, 14, and 30 days and at 3 and 6 months after trauma. Discussion: The results of this study will provide insight into the true value of nonoperative treatment of proximal femoral fractures in frail elderly with a limited life expectancy. The results may be used for updating (inter)national treatment guidelines. Trial registration: The study is registered at the Netherlands Trial Register (NTR7245; date 10-06-2018)