Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions.

INTRODUCTION: Generalized Anxiety Disorder (GAD) is a common psychiatric condition, characterized by the presence of general apprehensiveness and excessive worry. Current management consists of a range of pharmacological and psychological treatments. However, many patients do not respond to first-line pharmacological treatments and novel anxiolytic drugs are being developed. AREAS COVERED: In this review, the authors first discuss the diagnostic criteria and epidemiology of GAD. The effective pharmacological treatments for GAD and their tolerability are addressed. Current consensus guidelines for treatment of GAD are discussed, and maintenance treatment, the management of treatment resistance, and specific management of older adults and children/adolescents are considered. Finally, novel anxiolytics under development are discussed, with a focus on those which have entered clinical trials. EXPERT OPINION: A range of effective treatments for GAD are available, particularly duloxetine, escitalopram, pregabalin, quetiapine, and venlafaxine. There is a limited evidence base to support the further pharmacological management of patients with GAD who have not responded to initial treatment. Although many novel anxiolytics have progressed to clinical trials, translation from animal models has been mostly unsuccessful. However, the potential of several compounds including certain psychedelics, ketamine, oxytocin, and agents modulating the orexin, endocannabinoid, and immune systems merits further study.

Orexin Receptor Antagonists in the Treatment of Depression: A Leading Article Summarising Pre-clinical and Clinical Studies.

The orexin (hypocretin) system comprises two neuropeptides (orexin-A and orexin-B) and two G-protein coupled receptors (the orexin type 1 and the orexin type 2 receptor). The system regulates several biological functions including appetite, the sleep-wake cycle, the stress response, and motivation and reward processing. Dysfunction of the orexin system has been implicated in the pathophysiology of depression in human and animal studies, although the exact nature of this dysfunction remains unclear. Orexin receptor antagonists (ORAs) are a class of compounds developed for the treatment of insomnia and have demonstrated efficacy in this area. Three dual orexin receptor antagonists (DORAs) have received licences for treatment of primary insomnia and some ORAs have since been investigated as potential treatments for major depressive disorder (MDD). In this leading article, we summarise the existing literature on use of ORAs in depression, in pre-clinical and clinical studies. In rodent models of depression, investigated ORAs have included the DORA almorexant and TCS1102, the selective orexin 1 receptor antagonists SB334867 and SB674042 and the selective orexin 2 receptor antagonists LSN2424100, MK-1064 and TCS-OX2-29. These pre-clinical studies suggest a possible antidepressant effect of systemic DORA treatment, however the evidence from selective ORAs is conflicting. To date, four published RCTs (one with the DORA filorexant and three with the selective orexin 2 receptor antagonist seltorexant), have compared an ORA with placebo in the treatment of MDD. Only one of these demonstrated a statistically significant difference relative to placebo.

Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review.

BACKGROUND: The mechanisms underlying placebo effects of psychotropic drugs remain poorly understood. We carried out the first, to our knowledge, systematic review of functional neuroimaging correlates of placebo response in adults with anxiety/depressive disorders. METHODS: We systematically searched a large set of databases up to February 2021 based on a pre-registered protocol (PROSPERO CRD42019156911). We extracted neuroimaging data related to clinical improvement following placebo or related to placebo mechanisms. We did not perform a meta-analysis due to the small number of included studies and significant heterogeneity in study design and outcome measures. RESULTS: We found 12 relevant studies for depressive disorders and 4 for anxiety disorders. Activity in the ventral striatum, rostral anterior cingulate cortex and other default mode network regions, orbitofrontal cortex, and dorsolateral prefrontal cortex correlated with placebo antidepressant responses. Activity in regions of the default mode network, including posterior cingulate cortex, was associated with placebo anxiolysis. There was also evidence for possible involvement of the endogenous opioid, dopamine, and serotonin systems in placebo antidepressant and anxiolytic effects. CONCLUSIONS: Several brain regions and molecular systems may be involved in these placebo effects. Further adequately powered studies exploring causality and controlling for confounders are required.

Obsessive-compulsive symptoms and the Covid-19 pandemic: A rapid scoping review.

BACKGROUND: There has been much speculation about untoward effects of the Covid-19 pandemic on psychological symptoms. OCD may be expected to be especially impacted. Our aim was to distil the current evidence base on relationships between the pandemic and obsessive-compulsive symptoms, in patients, and general population samples. METHODS: We conducted a rapid scoping review, in the form of a systematic literature search, coupled with narrative review. 32 relevant papers were identified. RESULTS AND INTERPRETATION: (1) A sizable proportion of people with OCD (but not all) experienced/reported symptom worsening during the pandemic, especially during initial restrictions (approximately 20-65 % of cases in longitudinal studies); (2) contamination/washing symptoms appeared particularly susceptible; and (3) OCD symptoms in general population samples were associated with trait compulsivity and pandemic-related-stress. The literature was heterogeneous with various methodological issues being commonplace. FUTURE DIRECTIONS: The review identified important unaddressed issues: how should exposure based therapy be adapted during pandemics? How can we minimise harm from exacerbation of OCD in vulnerable individuals arising from public health messaging? Why do some but not all OCD patients experience worsening? And does Covid-19 infection affect (or lead to) OCD symptoms?

Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases.

Obesity is associated with changes in the secretome of adipose tissue (AT), which affects the vasculature through endocrine and paracrine mechanisms. Wingless-related integration site 5A (WNT5A) and secreted frizzled-related protein 5 (SFRP5), adipokines that regulate noncanonical Wnt signaling, are dysregulated in obesity. We hypothesized that WNT5A released from AT exerts endocrine and paracrine effects on the arterial wall through noncanonical RAC1-mediated Wnt signaling. In a cohort of 1004 humans with atherosclerosis, obesity was associated with increased WNT5A bioavailability in the circulation and the AT, higher expression of WNT5A receptors Frizzled 2 and Frizzled 5 in the human arterial wall, and increased vascular oxidative stress due to activation of NADPH oxidases. Plasma concentration of WNT5A was elevated in patients with coronary artery disease compared to matched controls and was independently associated with calcified coronary plaque progression. We further demonstrated that WNT5A induces arterial oxidative stress and redox-sensitive migration of vascular smooth muscle cells via Frizzled 2-mediated activation of a previously uncharacterized pathway involving the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) and the GTPase RAC1. Our study identifies WNT5A and its downstream vascular signaling as a link between obesity and vascular disease pathogenesis, with translational implications in humans.