Exploring the psychoneurobiology of the placebo response in gambling, depressive, and anxiety disorders

The discovery of new therapeutic agents for psychiatric disorders is potentially hindered by the large placebo responses seen in psychotropic drug trials. Through improved understanding of the placebo response, we might understand how to better design clinical trials and identify novel therapeutic targets. However, the placebo response in psychiatric disorders has been scarcely explored. Trial-level variables, such as duration of the trial or number of centres, appear to influence placebo response rate. Within-patient factors, such as previous experience of treatment, expectations, and neurobiology, are also likely to influence placebo response. Which factors matter, and how they influence placebo response in psychiatric disorders, remains unknown.There are large placebo response rates in clinical trials of gambling disorder (sometimes exceeding 70%). I aimed to identify predictors of placebo and medication response in gambling disorder through a pooled analysis of individual patient data from six treatment studies. Multiple linear regression models demonstrated that baseline severity and number of weeks completed in the trial were predictors of medication response (p’s < 0.01). By contrast, predictors of placebo response included increased baseline depressive symptoms, reduced baseline anxiety symptoms, and non-Caucasian ethnicity (p’s < 0.05). These results were robust to choices made in the analysis.It was noteworthy that symptoms of anxiety and depression were predictors of placebo response in gambling disorder. It is possible that biomarkers associated with placebo effects on anxiety or depressive symptoms might be relevant in other psychiatric disorders. I carried out a systematic review of the functional neuroimaging literature to identify neural correlates of placebo response in patients with anxiety or depression. Due to a small number of included studies and significant heterogeneity in study design, I was not able to carry out a formal meta-analysis. The rostral anterior cingulate cortex and default mode network, the ventral striatum, orbitofrontal cortex, and dorsolateral frontal cortex appeared to be key anatomical nodes in placebo antidepressant or anxiolytic effects. Important neurotransmitters might include endogenous opioids, dopamine, and serotonin.The review highlighted a relative lack of research into placebo anxiolysis. This could be due to a lack of convenient experimental paradigms free of confounders. I developed and tested two experimental paradigms designed to induce placebo anxiolysis in healthy volunteers. The first combined verbal suggestions of improvement and a conditioning procedure with administration of a placebo nasal spray in the 7.5% CO2 inhalational model of anxiety. The conditioning procedure induced significant expectations of improvement (p < 0.001) but this did not translate into reduced anxiety compared with a control group who did not undergo conditioning (p’s > 0.350). In the second, volunteers with symptoms of social anxiety disorder were shown a placebo abstract video accompanied by suggestions that it would reduce their anxiety before completing a novel online social interaction task (InterneT-based Stress test for Social Anxiety Disorder, ITSSAD). The placebo again did not reduce anxiety compared with a control group who did not receive verbal suggestions of improvement (p’s > 0.236). An exploratory analysis suggested that expectations did not influence outcomes. Acute anxiety is associated with nocebo effects, and it is possible that such experimental models are not conducive to inducing placebo effects.My findings highlight several gaps in the literature for future study, as well as a few challenges. Further research is needed to explore whether application of knowledge regarding predictors of placebo response improves detection of medication efficacy in clinical trials, to understand how to optimise prospective neuroimaging study design into placebo effects in mental disorders, and to explore the interaction between autonomic arousal and placebo conditioning

Anxiety disorders

Anxiety is a normal phenomenon that represents an ‘alarm system’, which allows preparation of physical and psychological responses to a perceived threat or danger (the ‘fight-or-flight’ response). Anxiety is usually appropriate, short-lived and controllable. When anxiety is present inappropriately, and its symptoms are abnormally severe, persistent and impair physical, social or occupational functioning, an ‘anxiety disorder’ can be diagnosed. In this section, we summarise what is known about the aetiology and neurobiology of the anxiety disorders included in the International Classification of Diseases, 11th edition (ICD-11) classification of mental disorders: generalised anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social anxiety disorder and separation anxiety disorder [1]. As there is significant overlap in the neurobiology of these disorders, we discuss the anxiety disorders as a whole, highlighting specific aspects where relevant. Characteristic features of the anxiety disorders are shown in Table 9.4.1

Dataset in support of the Southampton Doctoral Thesis 'Exploring the psychoneurobiology of the placebo response in gambling, depressive, and anxiety disorders'

This dataset supports the thesis entitled &#39;Exploring the Psychoneurobiology of the Placebo Response in Gambling, Depressive, and Anxiety Disorders&#39; All data are stored as plain text .csv files. Data supporting Chapter 5 are stored in enasal dataset chapter5.csv. This file includes raw baseline questionnaire trait and personality measures, and raw subjective and autonomic CO2 outcome measures. Data supporting Chapter 6 are stored in itssad dataset chapter6.csv. This file includes baseline questionnaire trait and personality scores, and calculated scores for subjective mood and anxiety measures for the ITSSAD task. Data supporting Chapter 4 (systematic review into functional neuroimaging correlates of placebo antidepressant and anxiolytic effects) can be found on [OSF](https://osf.io/fvb3a/). Date of data collection: 01/01/2020 - 30/10/2022 Funders: Medical Research Council (Grant number MR/T000902/1) </span

Protocol for conducting the InterneT-based Stress test for Social Anxiety Disorder (ITSSAD)

Social anxiety disorder (SAD) is very common and can be significantly disabling. New treatments are needed as the remission rate for SAD is the lowest of all the anxiety disorders. Experimental medicine models, in which features resembling a clinical disorder are experimentally induced, are a cost-effective and timely approach to explore potential novel treatments for psychiatric disorders. Following the emergence of SARS-CoV-2, there is a need to develop experimental medicine models that can be carried out remotely. We developed a novel procedure to investigate SAD (the InterneT-based Stress test for Social Anxiety Disorder; ITSSAD) that can be carried out entirely online by a single investigator, potentially reducing costs and maximising internal reliability. The procedure involves an anticipatory period followed by a naturalistic social interaction task

Why we need more research into the placebo response in psychiatry

Placebos are not inert, but exert measurable biological effects. The placebo response in psychiatric illness is important and clinically relevant, but remains poorly understood. In this paper, we review current knowledge about the placebo response in psychiatric medicine and identify research directions for the future. We argue that more research is needed into the placebo response in psychiatric medicine for three broad reasons. First, awareness of factors that cause placebo response, for whom, and when, within clinical trials will allow us to better evidence efficacy of new treatments. Second, by understanding how placebo mechanisms operate in the clinic, we can take advantage of these to optimise the effects of current treatments. Finally, exploring the biological mechanisms of placebo effects might reveal tractable targets for novel treatment development

The role of the orexin system in the neurobiology of anxiety disorders: potential for a novel treatment target

Anxiety disorders constitute the most common group of psychiatric disorders with a lifetime prevalence of 14.5–33.7%. Despite efficacious pharmacological and psychological treatments, first line treatment is often not effective, and development of new therapies is needed. One area of interest is the orexin system, a neurotransmitter system centred in the lateral hypothalamus with widespread projections throughout the brain, including to several key areas involved in the modulation of fear and anxiety. In this article, we summarise findings from pre-clinical and clinical investigations of the potential role of the orexin system in the neurobiology of fear and anxiety. Pre-clinical studies in rodents generally indicate that orexin signalling promotes fear and anxiety-related behaviour, particularly in response to aversive stimuli. Orexin signalling in the amygdala, bed nucleus of the stria terminalis, paraventricular nucleus of thalamus, locus coeruleus and prefrontal cortex has been specifically implicated. Human studies are limited, with some evidence that orexin receptor antagonists are anxiolytic in experimental medicine models of anxiety, some indications from clinical populations of altered orexin signalling, and a molecular genetic study associating a non-synonymous variant in the orexin 1 receptor (HCRTR1) with panic disorder and agoraphobia. Given this emerging body of evidence, further human studies are required to fully assess the orexin system as a potential novel anxiolytic target

GAD: experimental medicine models, emerging targets: Pharmacotherapy in generalized anxiety disorder: novel experimental medicine models and emerging drug targets

Many pharmacological and psychological approaches have been found efficacious in patients with generalized anxiety disorder (GAD), but many treatment-seeking patients will not respond and others will relapse despite continuing with interventions which initially had beneficial effects. Other patients will respond, but then stop treatment early because of untoward effects such as sexual dysfunction, drowsiness and weight gain. There is much scope to develop novel approaches, which could have greater overall effectiveness or acceptability than currently available interventions, or which have particular effectiveness in specific clinical sub-groups. �Experimental medicine� studies in healthy volunteers model disease states and represent a �proof-of-concept� approach for the development of novel therapeutic interventions: they determine whether to proceed to pivotal efficacy studies, and so can reduce delays in translating innovations into clinical practice. Investigations in healthy volunteers challenged with the inhalation of air �enriched� with 7.5% carbon dioxide (CO2) indicate this technique provides a validated and robust experimental medicine model, mirroring the subjective, autonomic and cognitive features of GAD. The anxiety response during CO2 challenge probably involves both central noradrenergic neurotransmission and effects on acid-base sensitive receptors, and so may stimulate development of novel agents targeted at central chemosensors. Increasing awareness of the potential role of altered cytokine balance in anxiety and the interplay of cytokines with monoaminergic mechanisms may also encourage the investigation of novel agents with modulating effects on immunological profiles. Although seemingly disparate, these two approaches to treatment development may pivot on a shared mechanism in exerting anxiolytic-like effects through pharmacological effects on acid-sensing ion channelsKey Points� Generalized anxiety disorder (GAD) is a common and impairing condition for which currently available pharmacological and psychological treatments are not ideal, having sub-optimal efficacy and acceptability problems in both short-term and long-term treatment.� �Experimental medicine� studies in healthy volunteers provide useful �proof-of-concept� approaches in the development of novel pharmacological and psyschological interventions: two promising avenues include the development of novel agents targeted at central chemosensors, or at modulating immunological responses.� Investigations in healthy volunteers challenged with the inhalation of air �enriched� with 7.5% carbon dioxide (CO2) indicate this technique provides a validated and robust experimental medicine model, mirroring the subjective, autonomic and cognitive features of GAD