Obstructive Sleep Apnea is Linked to Depression and Cognitive Impairment: Evidence and Potential Mechanisms

Obstructive sleep apnea (OSA) is highly prevalent but very frequently undiagnosed. OSA is an independent risk factor for depression and cognitive impairment/dementia. Herein the authors review studies in the literature pertinent to the effects of OSA on the cerebral microvascular and neurovascular systems and present a model to describe the key pathophysiologic mechanisms that may underlie the associations, including hypoperfusion, endothelial dysfunction, and neuroinflammation. Intermittent hypoxia plays a critical role in initiating and amplifying these pathologic processes. Hypoperfusion and impaired cerebral vasomotor reactivity lead to the development or progression of cerebral small vessel disease (C-SVD). Hypoxemia exacerbates these processes, resulting in white matter lesions, white matter integrity abnormalities, and gray matter loss. Blood-brain barrier (BBB) hyperpermeability and neuroinflammation lead to altered synaptic plasticity, neuronal damage, and worsening C-SVD. Thus, OSA may initiate or amplify the pathologic processes of C-SVD and BBB dysfunction, resulting in the development or exacerbation of depressive symptoms and cognitive deficits. Given the evidence that adequate treatment of OSA with continuous positive airway pressure improves depression and neurocognitive functions, it is important to identify OSA when assessing patients with depression or cognitive impairment. Whether treatment of OSA changes the deteriorating trajectory of elderly patients with already-diagnosed vascular depression and cognitive impairment/dementia remains to be determined in randomized controlled trials

A Model of Placebo Response in Antidepressant Clinical Trials

Abstract Placebo response in clinical trials of antidepressant medications is substantial and increasing. High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to more failed trials and delaying the delivery of new treatments to market. Media reports seize upon increasing placebo response and modest advantages for active drugs as reasons to question the value of antidepressant medication, which may further stigmatize treatments for depression and dissuade patients from accessing mental health care. Conversely, enhancing the factors responsible for placebo response may represent a strategy for improving available treatments for Major Depressive Disorder. A conceptual framework describing the causes of placebo response is needed in order to develop strategies for minimizing placebo response in clinical trials, maximizing placebo response in clinical practice, and talking with depressed patients about the risks and benefits of antidepressant medications. This review examines contributors to placebo response in antidepressant clinical trials and proposes an explanatory model. Research aimed at reducing placebo response should focus on limiting patient expectancy and the intensity of therapeutic contact in antidepressant clinical trials, while the optimal strategy in clinical practice may be to combine active medication with a presentation and level of therapeutic contact that enhances treatment response

Sertraline Treatment of Elderly Patients with Depression and Cognitive Impairment

Background There is little information on the efficacy and side effects of antidepressant treatment in elderly patients with combined depression and cognitive impairment without dementia (DEP-MCI), and it is unclear if cognitive performance improves with antidepressant response in these patients. Methods In 39 elderly DEP-MCI patients, changes in depression and cognitive impairment were evaluated with open sertraline treatment up to 200 mg/day for 12 weeks. Results Of the 26 completers, 17 were responders and nine were non-responders. Diagnostic subtype of depression was unrelated to response. ANCOVA on WAIS-R digit symbol percent change scores revealed a significant effect for responder status (F = 5.59, p < 0.03), and age (F = 0.24, p < 0.64) and education (F = 1.64, p < 0.22) were not significant covariates. From pre-trial to post-trial, responders improved in WAIS-R digit symbol percent change scores (Mean −10% SD 24) while non-responders declined (Mean 14% SD 18; t = 2.60, p < 0.02). Other neuropsychological measures were unrelated to response. Percent change in HRSD scores showed significant inverse correlations with percent change in several cognitive measures. Conclusions DEP-MCI patients showed moderate clinical response to sertraline treatment. When responders were compared to non-responders, cognitive improvement was limited to one measure of attention and executive function. Overall, there was little cognitive improvement with antidepressant treatment. The findings indirectly suggest that lack of improvement in cognition following treatment of depression in DEP-MCI patients may be associated with increased risk of meeting diagnostic criteria for dementia during follow-up

Not Just Nonspecific Factors: The Roles of Alliance and Expectancy in Treatment, and Their Neurobiological Underpinnings

Therapeutic factors such as alliance and expectancy have been found to greatly affect treatment outcome in both psychotherapy and psychopharmacotherapy. Often, these factors are referred to as nonspecific because of their common roles across treatment modalities. Here we argue that conceptualizing such factors as nonspecific is not accurate at best, misleading at worst and may undermine treatment outcome across various modalities. We argue that alliance and expectancy contain both a trait-like common factor component and a state-like specific effect, and that it is clinically, conceptually and methodologically critical to disentangle the two. In other words, both alliance and expectancy may also function as active ingredients of treatment, leading to better outcome. We review the literature regarding the neurobiological underpinnings of alliance and of the expectancy effect, and suggest how future studies on the neurobiological basis of these effects can shed further light on the potentially distinct mechanisms of the trait-like and state-like components of each therapeutic factor

Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study

Objectives: To evaluate the impact of obstructive sleep apnea (OSA) on neurocognitive function and brain morphology in older adults with depression and cognitive impairment. Methods: We prospectively screened OSA with the STOP-Bang questionnaire in the last 25 patients enrolled into the Donepezil Treatment of Cognitive Impairment and Depression (DOTCODE) trial. High and low probability of OSA were defined as a STOP-Bang score of ≥5 (h-OSA) and of <5 (l-OSA), respectively. Baseline magnetic resonance imaging (MRI) was used to evaluate brain morphology. The initial 16 weeks of antidepressant treatment were part of the DOTCODE trial. Results: After 16 weeks of antidepressant treatment, the h-OSA group performed significantly worse on the Selective Reminding Test delayed recall task than the l-OSA group, controlling for baseline performance (F = 19.1, df = 1,22, p < 0.001). In 19 of 25 participants who underwent brain MRI, the h-OSA group had significantly greater volumes of MRI hyperintensities in deep white matter, periventricular white matter, and subcortical gray matter compared with the l-OSA group. There was no significant association between OSA and hippocampal or entorhinal cortex volumes in our sample, even after controlling for intracranial volume. Conclusions: OSA is associated with impaired verbal episodic memory and microvascular damage in older adults with depression and cognitive impairment. One possibility is that by contributing to cerebral microvascular damage, OSA may exacerbate progressive memory decline

A Quality-Based Review of Randomized Controlled Trials of Psychodynamic Psychotherapy

Objective: The Ad Hoc Subcommittee for Evaluation of the Evidence Base for Psychodynamic Psychotherapy of the APA Committee on Research on Psychiatric Treatments developed the Randomized Controlled Trial Psychotherapy Quality Rating Scale (RCT-PQRS). The authors report results from application of the RCT-PQRS to 94 randomized controlled trials of psychodynamic psychotherapy published between 1974 and May 2010. Method: Five psychotherapy researchers from a range of therapeutic orientations rated a single published paper from each study. Results: The RCT-PQRS had good interrater reliability and internal consistency. The mean total quality score was 25.1 (SD=8.8). More recent studies had higher total quality scores. Sixty-three of 103 comparisons between psychodynamic psychotherapy and a nondynamic comparator were of "adequate" quality. Of 39 comparisons of a psychodynamic treatment and an "active" comparator, six showed dynamic treatment to be superior, five showed dynamic treatment to be inferior, and 28 showed no difference (few of which were powered for equivalence). Of 24 adequate comparisons of psychodynamic psychotherapy with an "inactive" comparator, 18 found dynamic treatment to be superior. Conclusions: Existing randomized controlled trials of psychodynamic psychotherapy are promising but mostly show superiority of psychodynamic psychotherapy to an inactive comparator. This would be sufficient to make psychodynamic psychotherapy an "empirically validated" treatment (per American Psychological Association Division 12 standards) only if further randomized controlled trials of adequate quality and sample size replicated findings of existing positive trials for specific disorders. We do not yet know what will emerge when other psychotherapies are subjected to this form of quality-based review

Effects of L-DOPA monotherapy on psychomotor speed and [11C] raclopride binding in high-risk older adults with depression

Background: A high-risk subgroup of older patients with depression has slowed processing and gait speeds. This study examined whether carbidopa/levodopa (L-DOPA) monotherapy increased dopamine availability, increased processing/gait speed, and relieved depressive symptoms. Methods: Adult outpatients with depression >59 years old underwent baseline [11C]raclopride positron emission tomography followed by open L-DOPA for 3 weeks (1 week each of 150 mg, 300 mg, and 450 mg). Generalized estimating equations tested the pre- and post-L-DOPA differences in processing and gait speed measures, depressive symptoms, and reported side effects. The decrease in binding potential between the pre- and posttreatment scans indexed enhanced synaptic dopamine availability induced by L-DOPA treatment. Results: Thirty-six subjects participated (age, 75.3 ± 7.5 years; 44.4% male). Significant, dose-dependent increases in processing and gait speed were observed with L-DOPA (450-mg dose: processing speed factor score effect size = 0.41, p = .001; dual-task gait speed effect size = 0.43, p = .002). [11C]raclopride decrease in binding potential was significantly different from 0 in sensorimotor (t24 = −4.85, p < .001) and associative striatum (t24 = −2.52, p = .019) but not in limbic striatum (t24 = 0.265, p = .793). Depressive symptoms decreased significantly on the Hamilton Rating Scale for Depression (effect size = −0.37, p = .002). Dropout rate was 8.3%, and nausea was the most frequently reported side effect. Conclusions: By enhancing availability of dopamine, L-DOPA improved processing and gait speed in older adults with depression and significantly decreased [11C]raclopride binding in selected striatal subregions

Neuroanatomical predictors of L-DOPA response in older adults with psychomotor slowing and depression: A pilot study

Background: Declining function in dopamine circuits is implicated in normal aging and late-life depression (LLD). Dopamine augmentation recently has shown therapeutic promise, but predictors of response are unknown. Methods: Depressed elders with slowed gait underwent baseline magnetic resonance imaging (MRI) and [11C]raclopride positron emission tomography (PET). Subjects then received open treatment with carbidopa/levodopa (L-DOPA) for three weeks. Linear regressions examined relationships between baseline MRI measures, [11C]raclopride binding, and behavioral outcomes. Results: Among N = 16 participants aged 72.5 ± 6.8 years, higher left superior temporal gyrus volume was associated with higher processing speed at baseline, while cortical thinning in a processing speed network was associated with greater improvement following L-DOPA. Greater volume and cortical thickness in brain regions associated with mobility were associated with higher baseline gait speed. Higher baseline white matter hyperintensity volume predicted less post-L-DOPA improvement on dual task gait speed and IDS-SR scores. Higher [11C]raclopride binding in the associative striatum was associated with cortical thickness in some, but not all, processing speed brain regions, while higher binding in sensorimotor striatum was significantly associated with left caudate volume. Limitations: Limiting the conclusions drawn from this pilot study are the small sample size and open administration of L-DOPA. Conclusions: Greater baseline brain volumes and cortical thickness in regions supporting cognition and gait were associated with higher behavioral performance, while lower structural integrity was associated with increased responsivity to L-DOPA. If substantiated in larger studies, these findings could facilitate the targeting of dopaminergic treatments to those LLD patients most likely to respond

Knowledge Hub on the Integrated Assessment of Chemical Contaminants and their Effects on the Marine Environment

In a time of environmental awareness, spurred on by the possibility that our world is threatened by climate change, it is important to remember that there are other anthropogenic pressures, which are also essential for addressing the protection of the marine and coastal environment. Pollution is a global, complex issue that contributes to biodiversity loss and poor environmental health and comes from the production and release of many of the synthetic chemicals that we use in our daily lives. Chemical contaminants are often underrepresented as a major contributor of environmental deterioration. The Joint Programming Initiative Healthy and Productive Seas and Oceans (JPI Oceans) established in 2018 the JPI Oceans Knowledge Hub on the integrated assessment of chemical contaminants and their effects on the marine environment. The purpose of the Knowledge Hub was to provide recommendations on how to improve the methodological basis for marine chemical status assessment. The work has resulted in the following policy paper which focuses on improving the efficiency and implementation of integrated assessment methodology of effects of chemicals of emerging concern. Substantial additional knowledge of biological effects is needed to achieve Good Environmental Status (GES) of our oceans and coastal areas. The Knowledge Hub is represented by highly skilled scientists and policy makers, appointed by the JPI Oceans Management Board, to ensure that the recommendations provided are useful for policy making

Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C

PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors