The Placebo Effect in Psychosis: Why It Matters and How to Measure It.

Psychosis is characterized by unusual percepts and beliefs in the form of hallucinations and delusions. Antipsychotic medication, the primary treatment for psychosis, is often ineffective and accompanied by severe side effects, but research has not identified an effective alternative in several decades. One reason that clinical trials fail is that patients with psychosis tend to show a significant therapeutic response to inert control treatments, known as the placebo effect, which makes it difficult to distinguish drug effects from placebo effects. Conversely, in clinical practice, a strong placebo effect may be useful because it could enhance the overall treatment response. Identifying factors that predict large placebo effects could improve the future outlook of psychosis treatment. Biomarkers of the placebo effect have already been suggested in pain and depression, but not in psychosis. Quantifying markers of the placebo effect would have the potential to predict placebo effects in psychosis clinical trials. Furthermore, the placebo effect and psychosis may represent a shared neurocognitive mechanism in which prior beliefs are weighted against new sensory information to make inferences about reality. Examining this overlap could reveal new insights into the mechanisms underlying psychosis and indicate novel treatment targets. We provide a narrative review of the importance of the placebo effect in psychosis and propose a novel method to assess it.

Anti-satellite glia cell IgG antibodies in fibromyalgia patients are related to symptom severity and to metabolite concentrations in thalamus and rostral anterior cingulate cortex.

Recent translational work has shown that fibromyalgia might be an autoimmune condition with pathogenic mechanisms mediated by a peripheral, pain-inducing action of immunoglobulin G (IgG) antibodies binding to satellite glia cells (SGC) in the dorsal root ganglia. A first clinical assessment of the postulated autoimmunity showed that fibromyalgia subjects (FMS) had elevated levels of antibodies against SGC (termed anti-SGC IgG) compared to healthy controls and that anti-SGC IgG were associated with a more severe disease status. The overarching aim of the current study was to determine whether the role of anti-SGC IgG in driving pain is exclusively through peripheral mechanisms, as indirectly shown so far, or could be attributed also to central mechanisms. To this end, we wanted to first confirm, in a larger cohort of FMS, the relation between anti-SGC IgG and pain-related clinical measures. Secondly, we explored the associations of these autoantibodies with brain metabolite concentrations (assessed via magnetic resonance spectroscopy, MRS) and pressure-evoked cerebral pain processing (assessed via functional magnetic resonance imaging, fMRI) in FMS. Proton MRS was performed in the thalamus and rostral anterior cingulate cortex (rACC) of FMS and concentrations of a wide spectrum of metabolites were assessed. During fMRI, FMS received individually calibrated painful pressure stimuli corresponding to low and high pain intensities. Our results confirmed a positive correlation between anti-SGC IgG and clinical measures assessing condition severity. Additionally, FMS with high anti-SGC IgG levels had higher pain intensity and a worse disease status than FMS with low anti-SGC IgG levels. Further, anti-SGC IgG levels negatively correlated with metabolites such as scyllo-inositol in thalamus and rACC as well as with total choline and macromolecule 12 in thalamus, thus linking anti-SGC IgG levels to the concentration of metabolites in the brain of FMS. However, anti-SGC IgG levels in FMS were not associated with the sensitivity to pressure pain or the cerebral processing of evoked pressure pain. Taken together, our results suggest that anti-SGC IgG might be clinically relevant for spontaneous, non-evoked pain. Our current and previous translational and clinical findings could provide a rationale to try new antibody-related treatments in FMS.

Susceptibility to Nocebo Hyperalgesia, Dispositional Optimism, and Trait Anxiety as Predictors of Nocebo Hyperalgesia Reduction.

OBJECTIVES: The current paper explores the psychological predictors of nocebo hyperalgesia and whether the reduction of nocebo hyperalgesia can be predicted by susceptibility to nocebo hyperalgesia and psychological characteristics. METHODS: Nocebo effects on pressure pain were first experimentally induced in 83 healthy female participants through conditioning with open-label instructions about the pain-worsening function of a sham TENS device to assess susceptibility to nocebo hyperalgesia. Participants were then randomized to 1 out of 2 nocebo-reduction conditions (counterconditioning/extinction) or to continued nocebo-conditioning (control), each combined with open-label instructions about the new sham device function. Dispositional optimism, trait and state anxiety, pain catastrophizing, fear of pain, and body vigilance were assessed at baseline. RESULTS: The results showed that lower optimism and higher trait anxiety were related to a stronger induction of nocebo hyperalgesia. Moreover, a stronger induction of nocebo hyperalgesia and higher trait anxiety predicted a larger nocebo reduction across interventions. Also, nocebo hyperalgesia and optimism moderated the effects of the nocebo-reduction interventions, whereby larger nocebo hyperalgesia and lower optimism were associated with a larger nocebo reduction after counterconditioning, compared with control, and also extinction for larger nocebo hyperalgesia. DISCUSSION: Our findings suggest that open-label conditioning leads to stronger nocebo hyperalgesia when trait anxiety is high and dispositional optimism is low, while these psychological characteristics, along with larger nocebo hyperalgesia, also predict open-label counterconditioning to be an effective nocebo-reduction strategy. Susceptibility to nocebo hyperalgesia, trait anxiety, and dispositional optimism might be indicators of a flexible pain regulatory system.

Efficacy of open-label counterconditioning for reducing nocebo effects on pressure pain.

BACKGROUND: Nocebo effects can adversely affect the experience of physical symptoms, such as pain and itch. Nocebo effects on itch and pain have shown to be induced by conditioning with thermal heat stimuli and reduced by counterconditioning. However, open-label counterconditioning, in which participants are informed about the placebo content of the treatment, has not been investigated, while this can be highly relevant for clinical practice. Furthermore, (open-label) conditioning and counterconditioning has not been investigated for pain modalities relevant to musculoskeletal disorders, such as pressure pain. METHODS: In a randomized controlled trial, we investigated in 110 healthy female participants whether nocebo effects on pressure pain combined with open-label verbal suggestions can be (1) induced via conditioning and (2) reduced via counterconditioning. Participants were allocated to either a nocebo- or sham-conditioning group. Next, the nocebo group was allocated to either counterconditioning, extinction or continued nocebo conditioning; sham conditioning was followed by placebo conditioning. RESULTS: Nocebo effects were significantly larger after nocebo conditioning than sham conditioning (d = 1.27). Subsequently, a larger reduction of the nocebo effect was found after counterconditioning than after extinction (d = 1.02) and continued nocebo conditioning (d = 1.66), with effects similar to placebo conditioning (following sham conditioning). CONCLUSIONS: These results show that (counter)conditioning combined with open-label suggestions can modulate nocebo effects on pressure pain, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders, particularly for musculoskeletal disorders. SIGNIFICANCE: Few studies have investigated the efficacy counterconditioning to reduce nocebo effects. Whereas typically deceptive procedures are used, these are not ethically appropriate for use in clinical practice. The current study demonstrates that open-label counterconditioning in a pain modality relevant for many chronic pain conditions may be a promising new strategy for reducing nocebo effects in a non-deceptive and ethical manner, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders.

Placebo effects in children with autism spectrum disorder.

Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with neurodevelopmental disorders. Here, we review the placebo effect in autism spectrum disorder (ASD). Placebo responses are widely evident in ASD clinical trials and could partly operate via so-called placebo-by-proxy, whereby caregivers or clinicians indirectly shape patient outcomes. Understanding the role of placebo effects in ASD may help discern genuine treatment effects from contextual factors in clinical trials. The much less studied nocebo effect, or negative placebo, might contribute to the experience of side effects in ASD treatments but empirical data is missing. Better knowledge about placebo and nocebo mechanisms may contribute to the development of more effective research designs, such as three-armed designs that account for natural history, and improved treatments for ASD symptoms. At a clinical level, deeper knowledge about placebo and nocebo effects may optimize the delivery of care for individuals with ASD in the future. WHAT THIS PAPER ADDS: Placebo responses are evident in autism spectrum disorder (ASD) clinical trials. Placebo responses in ASD are likely dependent on a placebo-by-proxy mechanism.

Parental responses and catastrophizing in online cognitive behavioral therapy for pediatric functional abdominal pain: A mediation analysis of a randomized controlled trial.

Objective: To test if decreased parental protective behaviors, monitoring behaviors, and parental catastrophizing mediate relief of gastrointestinal symptoms in children 8-12 years with functional abdominal pain disorders (FAPDs). The study uses secondary data analyses of a randomized controlled trial in which exposure-based online cognitive behavioral therapy (ICBT) was found superior to treatment as usual in decreasing gastrointestinal symptoms. Methods: The ICBT included 10 weekly modules for children and 10 weekly modules for parents. Treatment as usual consisted of any medication, dietary adjustments, and healthcare visits that the participants engaged in during 10 weeks. All measures were self-assessed online by parents. Biweekly assessments of the Adult Responses to Children's Symptoms (ARCS), Protect and Monitor subscales, and the Pain Catastrophizing Scale, parental version (PCS-P) were included in univariate and multivariate growth models to test their mediating effect on the child's gastrointestinal symptoms assessed with the Pediatric Quality of Life Gastrointestinal Symptoms Scale (PedsQL). Results: A total of 90 dyads of children with FAPDs and their parents were included in the study, of which 46 were randomized to ICBT and 44 to treatment as usual. The PCS-P was found to mediate change in the PedsQL ab = 0.639 (95% CI 0.020-2.331), while the ARCS Monitor ab = 0.472 (95% CI -1.002 to 2.547), and Protect ab = -0.151 (95% CI -1.455 to 0.674) were not mediators of change. Conclusions: To target parental catastrophizing in ICBT for pediatric FAPDs is potentially important to reduce abdominal symptoms in children.

Augmented pain inhibition and higher integration of pain modulatory brain networks in women with self-injury behavior.

Individuals who engage in nonsuicidal self-injury (NSSI) have demonstrated insensitivity to pain compared with individuals without NSSI. Yet, the neural mechanisms behind this difference are unknown. The objective of the present study was to determine which aspects of the pain regulatory system that account for this decreased sensitivity to pain. In a case-control design, 81 women, aged 18-35 (mean [SD] age, 23.4 [3.9]), were included (41 with NSSI and 40 healthy controls). A quantitative sensory testing protocol, including heat pain thresholds, heat pain tolerance, pressure pain thresholds, conditioned pain modulation (assessing central down-regulation of pain), and temporal summation (assessing facilitation of pain signals) was used. Pain-evoked brain responses were assessed by means of fMRI scanning during thermal pain. NSSI participants showed a more effective central down-regulation of pain, compared to controls, assessed with conditioned pain modulation. The neural responses to painful stimulation revealed a stronger relation between nociceptive and pain modulatory brain regions in NSSI compared to controls. In line with previous studies, pressure and heat pain thresholds were higher in participants with NSSI, however, there were no correlations between pain outcomes and NSSI clinical characteristics. The augmented pain inhibition and higher involvement of pain modulatory brain networks in NSSI may represent a pain insensitive endophenotype associated with a greater risk for developing self-injurious behavior.

Brain network segregation and integration during painful thermal stimulation.

The present study aimed to determine changes in brain network integration/segregation during thermal pain using methods optimized for network connectivity events with high temporal resolution. Participants (n = 33) actively judged whether thermal stimuli applied to the volar forearm were painful or not and then rated the warmth/pain intensity after each trial. We show that the temporal evolution of integration/segregation within trials correlates with the subjective ratings of pain. Specifically, the brain shifts from a segregated state to an integrated state when processing painful stimuli. The association with subjective pain ratings occurred at different time points for all networks. However, the degree of association between ratings and integration/segregation vanished for several brain networks when time-varying functional connectivity was measured at lower temporal resolution. Moreover, the increased integration associated with pain is explained to some degree by relative increases in between-network connectivity. Our results highlight the importance of investigating the relationship between pain and brain network connectivity at a single time point scale, since commonly used temporal aggregations of connectivity data may result in that fine-scale changes in network connectivity may go unnoticed. The interplay between integration/segregation reflects shifting demands of information processing between brain networks and this adaptation occurs both for cognitive tasks and nociceptive processing.

Genetic Influence on Nociceptive Processing in the Human Brain-A Twin Study.

Nociceptive processing in the human brain is complex and involves several brain structures and varies across individuals. Determining the structures that contribute to interindividual differences in nociceptive processing is likely to improve our understanding of why some individuals feel more pain than others. Here, we found specific parts of the cerebral response to nociception that are under genetic influence by employing a classic twin-design. We found genetic influences on nociceptive processing in the midcingulate cortex and bilateral posterior insula. In addition to brain activations, we found genetic contributions to large-scale functional connectivity (FC) during nociceptive processing. We conclude that additive genetics influence specific brain regions involved in nociceptive processing. The genetic influence on FC during nociceptive processing is not limited to core nociceptive brain regions, such as the dorsal posterior insula and somatosensory areas, but also involves cognitive and affective brain circuitry. These findings improve our understanding of human pain perception and increases chances to find new treatments for clinical pain.

The translocator protein gene is associated with endogenous pain modulation and the balance between glutamate and γ-aminobutyric acid in fibromyalgia and healthy subjects: a multimodal neuroimaging study.

ABSTRACT: A cerebral upregulation of the translocator protein (TSPO), a biomarker of glial activation, has been reported in fibromyalgia subjects (FMS). The TSPO binding affinity is genetically regulated by the Ala147Thr polymorphism in the TSPO gene (rs6971) and allows for a subject classification into high affinity binders (HABs) and mixed/low affinity binders (MLABs). The aim of the present multimodal neuroimaging study was to examine the associations of the TSPO polymorphism with: (1) conditioned pain modulation, (2) expectancy-modulated pain processing assessed during functional magnetic resonance imaging, and (3) the concentration and balance of glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex and thalamus using proton magnetic resonance spectroscopy in FMS (n = 83) and healthy controls (n = 43). The influence of TSPO on endogenous pain modulation presented in the form of TSPO HABs, as opposed to MLABs, displaying less efficient descending pain inhibition and expectancy-induced reduction of pain. Translocator protein HABs in both groups (FM and healthy controls) were found to have higher thalamic glutamate concentrations and exhibit a pattern of positive correlations between glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex, not seen in MLABs. Altogether, our findings point to TSPO-related mechanisms being HAB-dependent, brain region-specific, and non-FM-specific, although in FMS the disadvantage of an aberrant pain regulation combined with an HAB genetic set-up might hamper pain modulation more strongly. Our results provide evidence for an important role of TSPO in pain regulation and brain metabolism, thereby supporting the ongoing drug development targeting TSPO-associated mechanisms for pain relief.

Does Certainty of Genuine Treatment Increase the Drug Response in Alzheimer's Disease Patients: A Meta-Analysis and Critical Discussion.

BACKGROUND: Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer's disease (AD) is unknown. OBJECTIVE: The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients. METHODS: The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100%certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50%certainty). RESULTS: In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95%CI [-0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = -0.91, 95%CI [-1.43; -0.41], p < 0.001). There was a statistically significant difference between open-label and RCT trials (difference = 1.06, 95%CI [0.23; 1.90], p = 0.001). CONCLUSION: Patients with AD did not benefit from certainty of receiving genuine treatment. This could be due to the nature/progression of the disease, but it could also be related to an order effect in the practice of running AD trials, where RCTs are conducted prior to open label. These findings have implications for the understanding of non-specific treatment effects in AD patients as well as for the design of clinical trials that test pharmacological treatments in AD.

Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls.

The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5-HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5-HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5-HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5-HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5-HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.

Offset analgesia and onset hyperalgesia with different stimulus ranges.

INTRODUCTION: Offset analgesia (OA), a large reduction in pain after a brief increase in intensity of an otherwise stable painful stimulus, has been established by a large body of research. But the opposite effect, onset hyperalgesia (OH), a disproportional hyperalgesic response after a briefly decreased intensity of a painful stimulus, has only been investigated in one previous study. OBJECTIVES: The aim of this study was to induce OA and OH in healthy participants and explore the effects of different stimulus ranges (increase/decrease of temperature) on OA and OH. METHODS: A total of 62 participants were tested in 2 identical experiments. Offset analgesia and OH conditions included 2 different temperature deviations (±1°C/±2°C) from initial temperature and were compared with a constant temperature (control). RESULTS: Offset analgesia was successfully elicited in OA1°C in experiment 1, and in OA1°C and OA2°C in experiment 2. Results indicate a continuous stimulus-response relationship between the stimulus range and the resulting hypoalgesic response. Onset hyperalgesia was only elicited in OH2°C in experiment 1. Exploratory analysis showed that the lack of OH response in experiment 2 could be explained by sex differences, and that OA and OH responses were only weakly correlated. CONCLUSIONS: The asymmetry between pain responses after a brief temperature increase and decrease suggests that different mechanisms are involved in the pain responses to increasing and decreasing temperature. This asymmetry may also be explained by high temperatures in OA condition (+1°C/+2°C above baseline) that could be seen as salient "learning signals," which augment the response to following changes in temperature.

What Should Clinicians Tell Patients about Placebo and Nocebo Effects? Practical Considerations Based on Expert Consensus.

INTRODUCTION: Clinical and laboratory studies demonstrate that placebo and nocebo effects influence various symptoms and conditions after the administration of both inert and active treatments. OBJECTIVE: There is an increasing need for up-to-date recommendations on how to inform patients about placebo and nocebo effects in clinical practice and train clinicians how to disclose this information. METHODS: Based on previous clinical recommendations concerning placebo and nocebo effects, a 3-step, invitation-only Delphi study was conducted among an interdisciplinary group of internationally recognized experts. The study consisted of open- and closed-ended survey questions followed by a final expert meeting. The surveys were subdivided into 3 parts: (1) informing patients about placebo effects, (2) informing patients about nocebo effects, and (3) training clinicians how to communicate this information to the patients. RESULTS: There was consensus that communicating general information about placebo and nocebo effects to patients (e.g., explaining their role in treatment) could be beneficial, but that such information needs to be adjusted to match the specific clinical context (e.g., condition and treatment). Experts also agreed that training clinicians to communicate about placebo and nocebo effects should be a regular and integrated part of medical education that makes use of multiple formats, including face-to-face and online modalities. CONCLUSIONS: The current 3-step Delphi study provides consensus-based recommendations and practical considerations for disclosures about placebo and nocebo effects in clinical practice. Future research is needed on how to optimally tailor information to specific clinical conditions and patients' needs, and on developing standardized disclosure training modules for clinicians.

Polymorphisms of the µ-opioid receptor gene influence cerebral pain processing in fibromyalgia.

BACKGROUND: Dysregulation of the µ-opioid receptor has been reported in fibromyalgia (FM) and was linked to pain severity. Here, we investigated the effect of the functional genetic polymorphism of the µ-opioid receptor gene (OPRM1) (rs1799971) on symptom severity, pain sensitivity and cerebral pain processing in FM subjects and healthy controls (HC). METHODS: Symptom severity and pressure pain sensitivity was assessed in FM subjects (n = 70) and HC (n = 35). Cerebral pain-related activation was assessed by functional magnetic resonance imaging during individually calibrated painful pressure stimuli. RESULTS: Fibromyalgia subjects were more pain sensitive but no significant differences in pain sensitivity or pain ratings were observed between OPRM1 genotypes. A significant difference was found in cerebral pain processing, with carriers of at least one G-allele showing increased activation in posterior cingulate cortex (PCC) extending to precentral gyrus, compared to AA homozygotes. This effect was significant in FM subjects but not in healthy participants, however, between-group comparisons did not yield significant results. Seed-based functional connectivity analysis was performed with the seed based on differences in PCC/precentral gyrus activation between OPRM1 genotypes during evoked pain across groups. G-allele carriers displayed decreased functional connectivity between PCC/precentral gyrus and prefrontal cortex. CONCLUSIONS: G-allele carriers showed increased activation in PCC/precentral gyrus but decreased functional connectivity with the frontal control network during pressure stimulation, suggesting different pain modulatory processes between OPRM1 genotypes involving altered fronto-parietal network involvement. Furthermore, our results suggest that the overall effects of the OPRM1 G-allele may be driven by FM subjects. SIGNIFICANCE: We show that the functional polymorphism of the µ-opioid receptor gene OPRM1 was associated with alterations in the fronto-parietal network as well as with increased activation of posterior cingulum during evoked pain in FM. Thus, the OPRM1 polymorphism affects cerebral processing in brain regions implicated in salience, attention, and the default mode network. This finding is discussed in the light of pain and the opioid system, providing further evidence for a functional role of OPRM1 in cerebral pain processing.

Dynamic brain-to-brain concordance and behavioral mirroring as a mechanism of the patient-clinician interaction.

The patient-clinician interaction can powerfully shape treatment outcomes such as pain but is often considered an intangible "art of medicine" and has largely eluded scientific inquiry. Although brain correlates of social processes such as empathy and theory of mind have been studied using single-subject designs, specific behavioral and neural mechanisms underpinning the patient-clinician interaction are unknown. Using a two-person interactive design, we simultaneously recorded functional magnetic resonance imaging (hyperscanning) in patient-clinician dyads, who interacted via live video, while clinicians treated evoked pain in patients with chronic pain. Our results show that patient analgesia is mediated by patient-clinician nonverbal behavioral mirroring and brain-to-brain concordance in circuitry implicated in theory of mind and social mirroring. Dyad-based analyses showed extensive dynamic coupling of these brain nodes with the partners' brain activity, yet only in dyads with pre-established clinical rapport. These findings introduce a putatively key brain-behavioral mechanism for therapeutic alliance and psychosocial analgesia.

Placebo Responses Among Men With Erectile Dysfunction Enrolled in Phosphodiesterase 5 Inhibitor Trials: A Systematic Review and Meta-analysis.

Importance: Placebo responses in the treatment of erectile dysfunction (ED) are poorly described in the literature to date. Objective: To quantify the association of placebo with ED outcomes among men enrolled in placebo-controlled, phosphodiesterase 5 inhibitor (PDE5I) trials. Data Sources: For this systematic review and meta-analysis, a database search was conducted to identify double-blind, placebo-controlled studies using PDE5Is for the treatment of ED published from January 1, 1998, to December 31, 2018, within MEDLINE, Embase, Cochrane Library, and Web of Science. Only articles published in the English language were included. Study Selection: Double-blind, placebo-controlled randomized clinical trials of PDE5Is for ED were included. Studies were excluded if they did not provide distribution measures for statistical analysis. Study selection review assessments were conducted by 2 independent investigators. A total of 2215 studies were identified from the database search, and after review, 63 studies that included 12 564 men were analyzed. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in abstracting data and assessing validity. Data were extracted from published reports by 2 independent reviewers. Quality assessment was performed using the Jadad scale. Data were pooled using a random-effects model. Main Outcomes and Measures: The main outcome was improvement in the erectile function domain of the International Index of Erectile Function questionnaire in the placebo arm of the included studies. Effect size was reported as bias-corrected standardized mean difference (Hedges g). The hypothesis was formulated before data extraction. Results: A total of 63 studies that included 12 564 men (mean [SD] age, 55 [7] years; age range, 36-68 years) were included. Erectile function was significantly improved among participants in the placebo arm, with a small to moderate effect size (Hedges g [SE], 0.35 [0.03]; P < .001). Placebo effect size was larger among participants with ED associated with posttraumatic stress disorder (Hedges g [SE], 0.78 [0.32]; P = .02) compared with the overall analysis. No significant difference was found between placebo and PDE5Is for ED after prostate surgery or radiotherapy (Hedges g [SE], 0.30 [0.17]; P = .08). Conclusions and Relevance: In this study, placebo was associated with improvement of ED, especially among men with ED-related posttraumatic stress disorder. No difference was found between placebo and PDE5I among men treated for ED after prostate surgery.

Sickness behavior is not all about the immune response: Possible roles of expectations and prediction errors in the worry of being sick.

BACKGROUND: People react very differently when sick, and there are only poor correlations between the intensity of the immune response and sickness behavior. Yet, alternative predictors of the individual differences in sickness are under-investigated. Based on the predictive coding model of placebo responses, where health outcomes are function of bottom-up sensory information and top-down expectancies, we hypothesized that individual differences in behavioral changes during sickness could be explained by individual top-down expectancies and prediction errors. METHODS: Twenty-two healthy participants were made sick by intravenously administering lipopolysaccharide (2 ng/kg body weight). Their expectations of becoming sick were assessed before the injection. RESULTS: Participants having lower expectations of becoming sick before the injection reacted with more emotional distress (i.e., more negative affect and lower emotional arousal) than those with high expectations of becoming sick, despite having similar overall sickness behavior (i.e., a combined factor including fatigue, pain, nausea and social withdrawal). In keeping with a predictive coding model, the "prediction error signal", i.e., the discrepancy between the immune signal and sickness expectancy, predicted emotional distress (reduction in emotional arousal in particular). CONCLUSION: The current findings suggest that the emotional component of sickness behavior is, at least partly, shaped by top-down expectations. Helping patients having a realistic expectation of symptoms during treatment of an illness may thus reduce aggravated emotional responses, and ultimately improve patients' quality of life and treatment compliance. REGISTRATION: "Endotoxin-induced Inflammatory and Behavioral Responses and Predictors of Individual Differences", https://clinicaltrials.gov/ct2/show/NCT02529592, registration number: NCT02529592.

Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus.

BACKGROUND: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. METHODS: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. RESULTS: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. CONCLUSIONS: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice.