Associations between sleep quality and biomarkers for neurodegeneration - A longitudinal one-year case-control study of patients with bipolar disorder and healthy control individuals

Disturbed sleep during affective episodes may impact levels of cerebrospinal fluid (CSF)-amyloid-beta (Aβ)42 and other biomarkers of neurodegeneration in patients with bipolar disorder (BD). The study aimed to investigate the correlations between sleep and biomarkers for Alzheimer's disease (AD) and neurodegeneration in BD and healthy controls (HC). We present a prospective, longitudinal case-control study of euthymic patients with BD (N ​= ​86) and HC (N ​= ​44). All participants were evaluated with clinical assessments at baseline, and after a year. The patients’ affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. Patients were re-assessed during and after an episode if it occurred during follow-up. Total sleep scores based on three Hamilton-17 Depression Scale items were analyzed in relation to concentrations of CSF-Aβ42, CSF-Aβ40, CSF-Aβ38, CSF-Aβ42/40 and 42/38 ratios, CSF-soluble amyloid-precursor proteins α+β, plasma-Aβ42, plasma-Aβ40, CSF-phosphorylated-tau, CSF-total-tau, plasma-total-tau, CSF-neurofilament-light, plasma-neurofilament-light, CSF-neurogranin, serum-S100B, CSF-8-oxo-7,8-dihydro-guanosine, CSF-8-oxo-7,8-dihydro-2′-deoxyguanosine, urine-8-oxo-7,8-dihydro-guanosine, and urine-8-oxo-7,8-dihydro-2′-deoxyguanosine. The primary outcome was the association between total sleep scores and levels of CSF-Aβ42 at baseline and follow-up estimated by the regression coefficient in a linear mixed model. We found no statistically significant associations between sleep and CSF-Aβ42 (−2.307 ​pg/ml (95% CI: -9.525–4.911; p ​= ​0.523)) or any other biomarkers. However, higher sleep scores appeared to be associated with higher CSF-Aβ42/40 and CSF-Aβ42/38 ratios, and lower CSF-total-tau concentration, but were not statistically significant after correction for multiple testing. In conclusion attenuated sleep during an affective episode was not associated with changes in biomarkers for AD and neurodegeneration in BD, but larger prospective studies are needed

Asymmetric dimethylarginine in somatically healthy schizophrenia patients treated with atypical antipsychotics:a case-control study

BACKGROUND: Schizophrenia is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, and the L-arginine:ADMA ratio are markers of endothelial dysfunction that predict mortality and adverse outcome in a range of cardiovascular disorders. Increased ADMA levels may also lead to increased oxidative stress. We hypothesized that ADMA and the L-arginine:ADMA ratio are increased in somatically healthy schizophrenia patients treated with atypical antipsychotics (AAP), and that the ADMA and the L-arginine: ADMA ratio are positively correlated to measures of oxidative stress. METHODS: We included 40 schizophrenia patients treated with AAP, but without somatic disease or drug abuse, and 40 healthy controls. Plasma concentrations of ADMA and L-arginine were determined by high-performance liquid chromatography. Data were related to markers of systemic oxidative stress on DNA, RNA and lipids, as well as measures of medication load, duration of disease and current symptomatology. RESULTS: Plasma ADMA and the L-arginine:ADMA ratio did not differ between schizophrenia patients and controls. Furthermore, ADMA and the L-arginine:ADMA ratio showed no correlations with oxidative stress markers, medication load, or Positive and Negative Syndrome Scale scores. CONCLUSIONS: Schizophrenia and treatment with AAP was not associated with increased levels of plasma ADMA or the L-arginine:ADMA ratio. Furthermore, plasma levels of ADMA were not associated with levels of systemic oxidative stress in vivo

Effect of Chronic Escitalopram versus Placebo on Personality Traits in Healthy First-Degree Relatives of Patients with Depression: A Randomized Trial

The serotonergic neurotransmitter system is closely linked to depression and personality traits. It is not known if selective serotonin reuptake inhibitors (SSRI) have an effect on neuroticism that is independent of their effect on depression. Healthy individuals with a genetic liability for depression represent a group of particular interest when investigating if intervention with SSRIs affects personality. The present trial is the first to test the hypothesis that escitalopram may reduce neuroticism in healthy first-degree relatives of patients with major depressive disorder (MD).The trial used a randomized, blinded, placebo-controlled parallel-group design. We examined the effect of four weeks escitalopram 10 mg daily versus matching placebo on personality in 80 people who had a biological parent or sibling with a history of MD. The outcome measure on personality traits was change in self-reported neuroticism scores on the Revised Neuroticism-Extroversion-Openness-Personality Inventory (NEO-PI-R) and the Eysenck Personality Inventory (EPQ) from entry until end of four weeks of intervention.When compared with placebo, escitalopram did not significantly affect self-reported NEO-PI-R and EPQ neuroticism and extroversion, EPQ psychoticism, NEO-PI-R openness, or NEO-PI-R conscientiousness (p all above 0.05). However, escitalopram increased NEO-PI-R agreeableness scores significantly compared with placebo (mean; SD) (2.38; 8.09) versus (-1.32; 7.94), p = 0.046), but not following correction for multiplicity. A trend was shown for increased conscientiousness (p = 0.07). There was no significant effect on subclinical depressive symptoms (p = 0.6).In healthy first-degree relatives of patients with MD, there is no effect of escitalopram on neuroticism, but it is possible that escitalopram may increase the personality traits of agreeableness and conscientiousness.Clinicaltrials.gov NCT00386841

Escitalopram and Neuroendocrine Response in Healthy First-Degree Relatives to Depressed Patients – A Randomized Placebo-Controlled Trial

INTRODUCTION: The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD). METHODS: Eighty healthy first-degree relatives to patients with MDD were randomized to escitalopram 10 mg versus matching placebo daily for four weeks. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUC(total)) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention. RESULTS: Change in CorAUC(total) showed no statistically significant difference between the escitalopram and the placebo group, p = 0.47. There were large intra- and inter-individual differences in the results of the DEX-CRH test. There was statistically significant negative correlation between the plasma escitalopram concentration and change in CorAUC(total), rho = -0.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUC(total). CONCLUSION: The present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age. TRIAL REGISTRATION: ClinicalTrials.gov NCT00386841

Rationale and design of the participant, investigator, observer, and data-analyst-blinded randomized AGENDA trial on associations between gene-polymorphisms, endophenotypes for depression and antidepressive intervention: the effect of escitalopram versus placebo on the combined dexamethasone-corticotrophine releasing hormone test and other potential endophenotypes in healthy first-degree relatives of persons with depression

<p>Abstract</p> <p>Background</p> <p>Endophenotypes are heritable markers, which are more prevalent in patients and their healthy relatives than in the general population. Recent studies point at disturbed regulation of the hypothalamic-pituitary-adrenocortical axis as a possible endophenotype for depression. We hypothesize that potential endophenotypes for depression may be affected by selective serotonin re-uptake inhibitor antidepressants in healthy first-degree relatives of depressed patients. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test from baseline to the end of intervention.</p> <p>Methods</p> <p>The AGENDA trial is designed as a participant, investigator, observer, and data-analyst-blinded randomized trial. Participants are 80 healthy first-degree relatives of patients with depression. Participants are randomized to escitalopram 10 mg per day versus placebo for four weeks. Randomization is stratified by gender and age. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test at entry before intervention to after four weeks of intervention. With the inclusion of 80 participants, a 60% power is obtained to detect a clinically relevant difference in the primary outcome between the intervention and the placebo group. Secondary outcome measures are changes from baseline to four weeks in scores of: 1) cognition and 2) neuroticism. Tertiary outcomes measures are changes from baseline to four weeks in scores of: 1) depression and anxiety symptoms; 2) subjective evaluations of depressive symptoms, perceived stress, quality of life, aggression, sleep, and pain; and 3) salivary cortisol at eight different timepoints during an ordinary day. Assessments are undertaken by assessors blinded to the randomization group.</p> <p>Trial registration</p> <p>Local Ethics Committee: H-KF 307413</p> <p>Danish Medicines Agency: 2612-3162.</p> <p>EudraCT: 2006-001750-28.</p> <p>Danish Data Agency: 2006-41-6737.</p> <p>ClinicalTrials.gov: NCT 00386841</p