Background Major depressive disorder (MDD) is a highly recurrent condition, and improving our understanding of the abnormalities that persist in remitted MDD (rMDD) may provide insight into mechanisms that contribute to relapse. MDD has been characterized by reward learning deficits linked to dysfunction in frontostriatal regions. Although initial behavioral evidence of reward learning deficits in rMDD has recently emerged, it is unclear whether these reflect impairments in neural reward processing that persist into remission. Methods We examined behavioral reward learning and 128-channel event-related potentials (ERP) during a well-validated probabilistic reward task in 26 rMDD individuals and 34 never-depressed controls. Temporo-spatial principal components analysis (PCA) was used to separate overlapping ERP components, and group differences in neural activity in a priori regions were examined using low-resolution electromagnetic tomography (LORETA). Results Individuals with rMDD displayed reduced behavioral reward learning, as well as blunted ERP amplitude to reward feedback. Importantly, the reduction in ERP amplitude occurred at a PCA factor that peaked during the time at which phasic reward feedback-related signaling – hypothesized to originate in the striatum and project to the anterior cingulate cortex (ACC) – are thought to modulate scalp-recorded activity. Consistent with this, LORETA analyses revealed reduced activity in the ACC in the rMDD group, and this blunting correlated with poorer reward learning. Conclusion These findings suggest that the reward learning impairment observed in acute MDD persists into full remission and that these impairments may be attributable to abnormalities in the neural processes that support reward feedback monitoring, particularly within the ACC.

IntroductionTactile stimulation during a placebo treatment could enhance its credibility and thereby boost positive treatment expectations and the placebo effect. This experimental study aimed to investigate the interplay between tactile stimulation, expectation, and treatment credibility for the placebo effect in nausea.MethodsNinety healthy participants were exposed to a 20-min vection stimulus on two separate days and were randomly allocated to one of three groups on the second day after the baseline period: Placebo transcutaneous electrical nerve stimulation (TENS) with tactile stimulation (n = 30), placebo TENS without tactile stimulation (n = 30), or no intervention (n = 30). Placebo TENS was performed for 20 min at a dummy acupuncture point on both forearms. Expected and perceived nausea severity and further symptoms of motion sickness were assessed at baseline and during the evaluation period. At the end of the experiment, participants in the placebo groups guessed whether they had received active or placebo treatment.ResultsExpected nausea decreased significantly more in the placebo groups as compared to the no treatment control group (interaction day × group, F = 6.60, p = 0.003, partial η2 = 0.20), with equal reductions in the two placebo groups (p = 1.0). Reduced expectation went along with a significant placebo effect on nausea (interaction day × group, F = 22.2, p < 0.001, partial η2 = 0.35) with no difference between the two placebo groups (p = 1.0). Twenty-three out of 29 participants in the tactile placebo group (79%) but only 14 out of 30 participants (47%) in the non-tactile placebo group believed that they had received the active intervention (p = 0.015). Bang’s blinding index (BI) indicated random guessing in the non-tactile placebo group (BI = 0; 95% CI, −0.35 to 0.35) and non-random guessing in the direction of an “opposite guess” in the tactile placebo group (BI = −0.52; 95% CI, −0.81 to −0.22).ConclusionTactile stimulation during placebo TENS did not further enhance positive treatment expectations and the placebo effect in nausea but increased the credibility of the intervention. Further trials should investigate the interaction between perceived treatment assignment, expectation, and the placebo effect during the course of a trial.

In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and (in females) gastric activity could be verified. Using label-free tandem mass spectrometry, 74 differentially regulated proteins were identified as correlates of the placebo effect. Gene ontology (GO) enrichment analyses identified acute-phase proteins and microinflammatory proteins to be involved, and the identified GO signatures predicted dayadjusted scores of nausea indices in the placebo group. We also performed GO enrichment analyses of specific plasma proteins predictable by the experimental factors or their interactions and identified 'grooming behavior' as a prominent hit. Finally, Receiver Operator Characteristics (ROC) allowed to identify plasma proteins differentiating placebo responders from non-responders, comprising immunoglobulins and proteins involved in oxidation reduction processes and complement activation. Plasma proteomics is a promising tool to identify molecular correlates and predictors of the placebo effect in humans.

BackgroundRecent studies indicate that the administration of open-label placebos (OLP) can improve symptoms in various medical conditions. The primary aim of this 3-week randomized controlled trial was to examine the effects of OLP treatments on pain, functional disability, and mobility in patients with arthritic knee pain.MethodsSixty patients (55% females; mean age, 66.9 ± 9.7 SD years) were randomized to one of two OLP treatments (n = 41) or no treatment (NT; n = 19). OLP treatments were accompanied by the verbal suggestion “to decrease pain” (OLP-pain, n = 20) or “to improve mood” (OLP-mood, n = 21). Pain and mood levels were monitored on 11-point Numeric Rating Scales (NRSs) in a patient diary, and global clinical improvement (CGI-I) was assessed at the end of the study. At baseline and after 21 days, patients filled in validated questionnaires to assess symptoms and functional disability of the knee (WOMAC), mental and physical quality of life (SF-36), state anxiety (STAI-state), perceived stress (PSQ-20), and self-efficacy (GSE). In addition, knee mobility (neutral zero-method), heart rate variability (HRV), and diurnal cortisol levels were evaluated before and after treatment.ResultsEvaluation of daily pain ratings indicated significant pain decrease in the OLP groups compared to NT (p = 0.013, d = 0.64), with no difference between the OLP-pain and the OLP-mood groups (p = 0.856, d = 0.05). OLP treatment also improved WOMAC pain (p = 0.036, d = 0.55), again with no difference between the two OLP groups (p = 0.65, d = 0.17). WOMAC function and stiffness, knee mobility, stress, state anxiety, quality of life, and self-efficacy did not change differently between groups.ConclusionOLP treatment improved knee pain in elderly patients with symptomatic knee osteoarthritis (OA), while functional disability and mobility of the knee did not change. The content of the verbal suggestion was of minor importance. OLP administration may be considered as supportive analgesic treatment in elderly patients with symptomatic knee OA.Trial RegistrationGerman Clinical Trials Register (https://www.drks.de/), DRKS00015191 (retrospectively registered).