We report a case of a new-onset, persistent tremor that developed during a clinical trial (NCT02927236) of intermittent theta burst stimulation [iTBS, a form of repetitive magnetic transcranial magnetic stimulation (rTMS)] for cocaine use disorder. Although the participant exhibited an exceptionally strong clinical response, subsequent unblinding revealed that they received sham iTBS. This case highlights the potential for strong functional neurological placebo responses in rTMS trials, and functional disorders might be a marker of a placebo response. Additionally, we note the possibility that the weak e-fields produced by some sham rTMS systems may induce clinically relevant effects.

The use of placebo in clinical practice has been the topic of extensive debate in the bioethics literature, with much scholarship focusing on concerns regarding deception. While considerations of placebo without deception have largely centred on open-label placebo, this paper considers a different kind of ethical quandary regarding placebo without an intent to deceive-one where the provider believes a treatment is effective due to a direct physiological mechanism, even though that belief may not be supported by rigorous scientific evidence. This is often the case with complementary and alternative medicine (CAM) techniques and also with some mainstream therapies that have not proven to be better than sham. Using one such CAM technique as a case study-electroencephalography (EEG) neurofeedback for attention-deficit/hyperactivity disorder (ADHD)-this paper explores the ethics of providing therapies that may have some beneficial effect, although one that is likely due to placebo effect. First, we provide background on EEG neurofeedback for ADHD and its evidence base, showing how it has proven to be equivalent to-but not better than-sham neurofeedback. Subsequently, we explore whether offering therapies that are claimed to work via specific physical pathways, but may actually work due to the placebo effect, constitute deception. We suggest that this practice may constitute unintentional deception regarding mechanism of action. Ultimately, we argue that providers have increased information provision obligations when offering treatments that diverge from standard of care and we make recommendations for mitigating unintentional deception.

Insomnia is a widespread symptom of many psychiatric and neurological disorders, but can also be a clinically relevant disorder of its own. The application of low-dose electricity as a treatment for both has had a long history, dating back to the 19th century, but has seen somewhat of a renaissance in therapies such as tDCS.
The aim of this publication was to identify and present original works from the second half of the 19th century as well as contemporary studies that investigated the therapeutic value of electricity in treating sleep disorders.
While the nine historical sources identified mostly presented impressive successes in treatment, the nine modern publications had much more heterogeneous and moderate results.
The discussion of these differences refers to the scientific discourse of the late 19th century about the placebo-effect and the role of suggestibility in the therapeutic process and outcome.
In conclusion profound parallels can be seen between treatment innovations and methodological discussions in the 1880-1890s and nowadays.

UNASSIGNED: Contextual factors, such as participant/experimenter sex may moderate the placebo effects. We tested whether the participant and experimenter sex modulated placebo effects on experimentally induced pain and associated stress.
UNASSIGNED: To investigate if (i) participant sex and (ii) experimenter sex influence placebo analgesia and subjective and physiological stress in two experiments employing a within-subjects and a mixed design, respectively. Placebo effects were investigated in pain reports, stress, and blood pressure.
UNASSIGNED: Participants received painful stimulations and a placebo cream. In Experiment One (N = 59) participants underwent a placebo condition (PC) and a natural history condition (NHC) in random order. A placebo cream was applied in the PC and then the heat stimulation temperature was surreptitiously lowered. Identical stimulations were administered in the NHC, but with no cream, no information, and no lowered temperature. In Experiment Two, participants (N = 93) were randomly assigned to three groups receiving either a placebo cream with surreptitiously lowered intensity of electric stimuli (Placebo, PG), a placebo cream (Cream-Control, CCG) without changing the stimuli, or lowered intensity, but with no cream (Pain-Control, PCG) in a mixed design. All participants in both experiments received the same stimuli in the post-test as in the pre-test. Four experimenters (two females) in Experiment One, and five experimenters (two females) in Experiment Two conducted the studies.
UNASSIGNED: No placebo effect was seen on pain. However, there were placebo effects on stress, moderated by participant and experimenter sex: in Experiment One males in the PC had lower diastolic blood pressure (DBP) compared to males in the NHC. Participants in the PC had lower DBP compared to the NHC when tested by a female. In Experiment Two, participants expected more cream effectiveness when a female experimenter administered it, and reported lower stress in the PG compared to the PCG when tested by females.
UNASSIGNED: Our findings highlight a distinction between placebo effects on pain and on associated stress. Secondly, female experimenters recorded lower physiological and subjective stress, higher effectiveness expectations, and lower pain from both sexes compared to male experimenters. Possible reasons for the failure to find a pain placebo effect are discussed.

It has been estimated that between 15% and 18% of patients who start antiretroviral therapy (ART) do not achieve a successful immune recovery despite complete virological suppression. In the literature this phenomenom is known as poor immune recovery or immunovirological discordance (IVD). Zinc has an immunomodulatory role associated with T lymphocytes and its supplementation could enhance immune recovery.
To determine if zinc supplementation on IVD patients prevents immune failure after 12 months of supplementation. Secondary objectives were to determine serum zinc levels in HIV patients with and without IVD and the frequency of hypozincemia in discordant patients.
We reviewed the historical record of patients under care at Arriarán Foundation. Following inclusion criteria were defined: 1) age ≥ 18 years, 2) standard ART (three effective drugs) for at least 18 months, 3) virologically suppressed for 12 months, 3) persistence of CD4 count ≤200 cells/mm3 and/or increase ≤ 80 cells/mm3 after one year of viral undetectability. A control group was assigned paired 1:1 by sex, age (± 2 years) that did achieved an increase of CD4> 350 cells/ mm3. In both groups plasma zinc levels were determined. In a later phase, patients with IVD were randomized to receive zinc (15 mg daily) versus placebo. Patients were followed for 12 months with CD4 count, viral load and zinc levels determinations every 4-6 months.
A total of 80 patients, 40 patients with IVD criteria and 40 controls were included. 92.5% were men, and age average was 47.5 years. The median baseline CD4 was 189 cells/mm3 (71-258) in the cases vs. 552.5 cells/ mm3 (317-400) in the control group with a median increase at the end of the study of 39 cell/mm3 and 19 cell/mm3 respectively. There was no difference in baseline plasma zinc levels between both groups (81.7 + 18.1 in cases versus 86.2 + 11.0 in controls). In the 40 patients with IVD, the median absolute increase in CD4 after annual zinc supplementation was 31.5 cells/mm3 in the treated group versus 50 cells/mm3 in the placebo group, this difference being statistically not significant (p = 0.382).
Patients with IVD have plasma zinc levels similar to those who achieve adequate immune recovery. Zinc supplementation in IVD patients showed a statistically non-significant difference in in CD4 levels between cases and controls. The results warrant a comparative study with a larger number of patients.

Chronic use of hypnotic medications such as benzodiazepines is associated with adverse consequences including increased risk of falls. Efforts to help patients discontinue these medications have had varying levels of success. We developed a blinded (masked) tapering protocol to help patients taper off hypnotics. In this blinded protocol, patients consented to a drug taper but agreed to forego knowledge about the specific tapering schedule or the actual dose each night until the end of the taper. Blinded tapering aims to reduce negative expectancies for withdrawal effects that may impair a patient\'s successful discontinuation of hypnotics. In preparation for a randomized trial, we tested the feasibility of adding a blinded tapering component to current best evidence practice [supervised hypnotic taper combined with cognitive behavioral therapy for insomnia (CBTI)] in 5 adult patients recruited from an outpatient mental health practice in Oregon. A compounding pharmacy prepared the blinded capsules for each patient. During the gradual blinded taper, each participant completed CBTI. Measures collected included feasibility/process (e.g., recruitment barriers), hypnotic use, the Dysfunctional Beliefs and Attitudes about Sleep Scale, Insomnia Severity Index, Epworth Sleepiness Scale, and Patient Health Questionnaire-9 (depressive symptoms). The intervention was feasible, and participants reported high satisfaction with the protocol and willingness to follow the same treatment again. All five participants successfully discontinued their hypnotic medication use post-treatment. Dysfunctional beliefs/attitudes about sleep and insomnia severity improved. Blinded tapering is a promising new method for improving hypnotic discontinuation among patients treated with a combination of hypnotic tapering plus CBTI.

As with other psychiatric disorders, development of drugs to treat binge-eating disorder (BED) has been hampered by high placebo response and dropout rates in randomized controlled trials (RCTs). Although not approved for use in BED, several RCTs have suggested that topiramate is efficacious for BED in obese individuals. Using data from a positive investigator-initiated RCT of topiramate in 61 obese individuals with BED, the objective of the present study is (i) to develop a quantitative disease-drug-trial framework to inform future BED clinical trial designs, and (ii) to determine the optimal topiramate dose to achieve therapeutic efficacy. Disease-drug-trial models were developed separately for the two efficacy measures, namely, longitudinal normalized weekly binge-eating episode frequency (BEF) and binge day frequency (BDF). Model building consisted of (i) developing a placebo effect model that describes response from the placebo group, (ii) adding a drug effect to the placebo model to describe dose-response relationships, and (iii) developing a parametric time to event model to characterize patient dropout patterns. The placebo effect on normalized BEF and BDF over time demonstrated a maximum decrease of ~ 57% by 5 weeks. Participants had a higher dropout probability if no weight loss occurred during the trial period. The identified dose-response relationship demonstrated a daily dose of 125 mg was needed to exhibit a marked reduction in weekly BEF. The developed comprehensive disease-drug-trial model will be utilized to simulate different clinical trial designs to increase the success for future BED drug development programs.

The importance of adjusting for cross-study heterogeneity when conducting network meta-analyses (NMAs) was demonstrated using a case study of biologic therapies for moderate-to-severe plaque psoriasis.
Bayesian NMAs were conducted for Psoriasis Area and Severity Index 90 response. Several covariates were considered to account for cross-trial differences: baseline risk (i.e., placebo response), prior biologic use, body weight, psoriasis duration, age, race and baseline Psoriasis Area and Severity Index score. Model fit was evaluated.
The baseline risk-adjusted NMA, which adjusts for multiple observed and unobserved effect modifiers, was associated with the best model fit. Lack of adjustment for cross-trial differences led to different clinical interpretations of findings.
Failure to adjust for cross-trial differences in NMA can have important implications for clinical interpretations when studying the comparative efficacy of healthcare interventions.

The use of placebos in randomised controlled trials is a subject of considerable ethical debate. In this paper we present a set of considerations to evaluate the ethics of placebo controlled trials that includes: social value of the study; need for a randomised controlled trial and placebo; standards of care; risks of harm due to administration of placebo and the harm benefit balance; clinical equipoise; and double standards. We illustrate the application of these considerations using a case study of a large ongoing multicentre, placebo-controlled, double-blinded, randomised trial to determine primaquine anti-relapse efficacy in vivax malaria.
There is an urgent need for primaquine anti-relapse studies in order to rationalise the management of a potentially fatal disease. An ethical justification for the use of the placebo arm is provided on the grounds that the actual current applied standard of care in most endemic places does not include primaquine. It has also been argued that there is clinical equipoise among the primaquine study arms and that the risk of harms of being in the placebo arm is the risk of having relapse, which is no more than not being included in the trial, and that there are no double standards.
Based on our set of considerations, we conclude that a placebo arm is not only justified but imperative in this study. We propose that similar considerations should be prospectively applied to other placebo controlled trials and observational control arms where no treatment is offered.

The conventional statistical methodologies for evaluating treatment effect are based on hypothesis testing (P-value). Alternative measurements of treatment effect have been proposed for anti-infective treatments using the probability of target attainment. A general framework is proposed to extend this methodology to other therapeutic areas. A disease trial model is used for estimating the probability of reaching a treatment effect associated with relevant clinical benefits, in complement to the evaluation of the probability of rejecting the null hypothesis. A case study is presented in depression, where disease status is evaluated using bounded clinical scores (Hamilton Depression Rating Scale), and detectable treatment effect is inversely proportional to placebo response. The β-regression approach is used to model Hamilton scale scores, and a placebo-related criterion is proposed for determining the clinical benefit. The probability of reaching a clinical benefit represents a reliable criterion for replacing the P-value paradigm in the assessment of the outcomes of clinical trials.