Marathon runners, subjected to intense training regimens and prolonged, exhaustive exercises, often experience a compromised immune response. Probiotic supplementation has emerged as a potential remedy to mitigate the impact of prolonged exercise on athletes. Consequently, this study sought to assess the influence of probiotic supplementation on monocyte functionality both before and after the official marathon race. Twenty-seven runners were randomly and double-blindly assigned to two groups: placebo (n 13) and probiotic (PRO) (n 14). Over 30 d, both groups received supplements – placebo sachets containing maltodextrin (5 g/d) and PRO sachets containing 1 × 1010 colony-forming unit Lactobacillus acidophilus and 1 × 1010 colony-forming unit Bifidobacterium bifidum subsp. lactis. Blood samples were collected, and immunological assays, including phagocytosis, hydrogen peroxide production, cytokine levels and monocyte immunophenotyping, were conducted at four different intervals: baseline (start of supplementation/30 d pre-marathon), 24 h-before (1 d pre-marathon), 1 h-after (1 h post-marathon) and 5 d-after (5 d post-marathon). Monocyte populations remained consistent throughout the study. A notable increase in phagocytosis was observed in the PRO group after 30 d of supplementation. Upon lipopolysaccharide stimulation, both PRO and placebo groups exhibited decreased IL-8 production. However, after the marathon race, IL-15 stimulation demonstrated increased levels of 5 d-after, while IL-1-β, IL-8, IL-10, IL-15 and TNF-α varied across different intervals, specifically within the PRO group. Probiotic supplementation notably enhanced the phagocytic capacity of monocytes. However, these effects were not sustained post-marathon.

Postmenopausal women have augmented pressure wave responses to low-intensity isometric handgrip exercise (IHG) due to an overactive metaboreflex (postexercise muscle ischaemia, PEMI), contributing to increased aortic systolic blood pressure (SBP). Menopause-associated endothelial dysfunction via arginine (ARG) and nitric oxide deficiency may contribute to exaggerated exercise SBP responses. L-Citrulline supplementation (CIT) is an ARG precursor that decreases SBP, pulse pressure (PP) and pressure wave responses to cold exposure in older adults. We investigated the effects of CIT on aortic SBP, PP, and pressure of forward (Pf) and backward (Pb) waves during IHG and PEMI in twenty-two postmenopausal women. Participants were randomised to CIT (10 g/d) or placebo (PL) for 4 weeks. Aortic haemodynamics were assessed via applanation tonometry at rest, 2 min of IHG at 30 % of maximal strength, and 3 min of PEMI. Responses were analysed as change (Δ) from rest to IHG and PEMI at 0 and 4 weeks. CIT attenuated ΔSBP (−9 ± 2 v. −1 ± 1 mmHg, P = 0·006), ΔPP (−5 ± 2 v. 0 ± 1 mmHg, P = 0·03), ΔPf (−6 ± 2 v. −1 ± 1 mmHg, P = 0·01) and ΔPb (−3 ± 1 v. 0 ± 1 mmHg, P = 0·02) responses to PEMI v. PL. The ΔPP during PEMI was correlated with ΔPf (r = 0·743, P < 0·001) and ΔPb (r = 0·724, P < 0·001). Citrulline supplementation attenuates the increase in aortic pulsatile load induced by muscle metaboreflex activation via reductions in forward and backward pressure wave amplitudes in postmenopausal women.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

It is estimated that electroconvulsive therapy is still administered to approximately a million people a year. It involves passing enough electric current through the human brain, eight to twelve times, to cause convulsions, in the hope of somehow alleviating emotional suffering, primarily depression. There have only ever been 11 placebo-controlled studies (where general anaesthesia is administered but the electric shock is withheld), all of which were pre-1986, had very small sample sizes and were seriously methodologically flawed. Five of these studies found no difference between the two groups at the end of treatment, four found ECT produced better outcomes for some patients, and two produced mixed results, including one where psychiatrists' ratings produced a difference, but the ratings of nurses and patients did not. In the 80 years since the first ECT no studies have found any evidence that ECT is better than placebo beyond the end of treatment. Nevertheless, all five meta-analyses relying on these studies have somehow concluded that ECT is more effective than placebo despite the studies' multiple failings. Meanwhile, evidence of persistent or permanent memory loss in 12% to 55% of patients has accumulated. Attempts to highlight this failure of ECT proponents to provide robust evidence that their treatment is effective and safe are routinely dismissed, diminished, denied and denounced. This paper responds to one such attempt, by Drs Meechan, Laws, Young, McLoughlin and Jauhar, to discredit two systematic reviews of the eleven pre-1986 studies, in 2010 and 2019, the latter of which also reviewed five meta-analyses that had ignored the studies' failings. The criticisms and claims of the recent crtiique of the two systematic reviews are examined in detail, by the first author of both reviews, for accuracy, relevance and logic. The critique is found to include multiple errors, misrepresentations, omissions, inconsistencies and logical flaws. It is concluded that Meechan et al. fail to make a fact-based, coherent argument against suspending ECT pending a series of large, carefully designed placebo-controlled studies to establish whether ECT does have any beneficial effects against which to weigh the significant established adverse effects.

The dominant view within mental health services and research suggests that feeling depressed is a kind of medical illness, partially caused by various biological deficits which are somehow corrected by physical interventions. This article critically appraises evidence for the effectiveness and value of antidepressant drugs and electroconvulsive therapy (ECT), the two principle physical treatments recommended for depression. It also describes the negative effects of these interventions and raises concerns about how they impact the brain. We propose an alternative understanding that recognises depression as an emotional and meaningful response to unwanted life events and circumstances. This perspective demands that we address the social conditions that make depression likely and suggests that a combination of politics and common sense needs to guide us in providing help for one another when we are suffering in this way. This alternative view is increasingly endorsed around the world, including by the United Nations, the World Health Organization and service users who have suffered negative consequences of physical treatments that modify brain functions in ways that are not well-understood.

A recent review of research in electroconvulsive therapy (ECT) for depression, for which I was the first author, found that only 11 placebo-controlled studies have even been conducted, all pre-1986. Our review concluded that they were so flawed that the meta-analyses that relied on them were wrong to conclude that ECT is effective. This commentary responds to a critique of the review by Ian Anderson. Some valuable comments are acknowledged and several errors or misunderstandings rectified.

l-Citrulline (l-Cit) is a non-essential amino acid that stimulates nitric oxide (NO) production and improves exercise performance by reducing muscle damage indices; however, the direct benefits of l-Cit on antioxidant markers are unclear. The aim of this study was to examine antioxidant responses to high-intensity interval exercise following acute l-Cit supplementation. Nine young men (21 (sd 1) years) participated in a double-blind crossover study in which they received 12 g of l-Cit and placebo (PL) an hour prior to high-intensity interval exercise on two occasions, separated by a 7-d washout period. Blood samples were obtained before (PRE), immediately after (IP), 10 (10P) and 30 min after exercise (30P) from the cubital vein using standard procedures. Serum concentrations of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and NO metabolites (NOx) were measured. The exercise protocol significantly elevated SOD (P = 0·01) and GPx (P = 0·048) from PRE to 10P in the l-Cit group with greater changes than the PL group. CAT concentrations increased IP (P = 0·014) and remained elevated at 10P (P = 0·03) and 30P (P = 0·015) in both the l-Cit and PL conditions. NOx concentrations increased IP (P = 0·05) in the l-Cit group with greater changes than PL group in PRE to IP, PRE to 10P and PRE to 30P (P < 0·05). Our data indicate that l-Cit supplementation (single 12 g dose pre-exercise) induces improvements in antioxidant markers following a session of high-intensity interval exercise in young men.

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 purpose of the present study was to compare next-morning responses of RMR and appetite to pre-sleep consumption of casein protein (CP) in pre- and postmenopausal women. The study was a randomised, crossover, double-blind, placebo-controlled trial. Seven sedentary premenopausal (age: 19·9 (sd 1·2) years; BMI: 23·1 (sd 2·6) kg/m2) and seven sedentary postmenopausal (age: 56·4 (sd 4·9) years; BMI: 26·3 (sd 3·5) kg/m2) women participated. During visit one, anthropometrics and body composition were measured. Following visit one, subjects consumed either CP (25 g) or placebo (PL) ≥2 h after their last meal and ≤30 min prior to sleep on the night before visits two and three. Visits two and three occurred ≥1 week after visit one and were 48 h apart. During visits two and three, RMR (VO2), RER and appetite were measured via indirect calorimetry and visual analogue scale, respectively. Anthropometrics and body composition were analysed by one-way ANOVA. RMR and measures of appetite were analysed using a 2 × 2 (menopause status × CP/PL) repeated-measures ANOVA. Significance was accepted at P ≤ 0·05. RMR was significantly lower in postmenopausal compared with premenopausal women under both conditions (P = 0·003). When consumed pre-sleep CP did not alter RMR, RER or appetite compared with PL when assessed next morning in pre- and postmenopausal women. These data contribute to growing evidence that pre-sleep consumption of protein is not harmful to next-morning metabolism or appetite. In addition, these data demonstrate that menopause may not alter next-morning RMR, RER or appetite after pre-sleep consumption of CP.

The onset of action of antidepressant drugs was investigated on the basis of two independent multicenter, double-blind efficacy studies comparing amitriptyline (n = 120), oxaprotiline (n = 120), imipramine (n = 506) and moclobemide (n = 580) with placebo (n = 189 + 191). The samples consisted of in- and outpatients diagnosed, according to Diagnostic and Statistical Manual (DSM)-III criteria, as suffering from major depressive disorder. Measures of efficacy criteria were the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A) and the Zung Self-Rating Depression scale. By using the Sustained Relative Improvement (SRI) criterion, onset of action was determined in each individual patient as that time point in the 30 day observation period at which a 20% baseline score reduction was achieved without subsequent deterioration. Analogously, a response to treatment was defined as a 50% baseline score reduction. As expected, highly significant differences between active drugs and placebo were found with respect to the total number of improvers and responders. Significant differences between treatment modalities surfaced in the percentage rate as well as the time distribution of premature withdrawals. Yet, unexpectedly, among improvers, the time spans to onset of improvement were found to be independent of treatment modality as indicated by virtually identical cumulative percentages of improvers throughout the whole observation period. The picture was essentially the same for the HAM-A and Zung assessments, except for a significant time lag between observer- and self-ratings. In particular, our analyses revealed no evidence for a delayed onset of action under various antidepressants with large biochemical and pharmacological differences in comparison to placebo. Moreover, the early onset of improvement was highly predictive of later outcome: on average, 70% of the patients showing improvement within the first 14 days became responders. Applying survival-analytical methods, we found that differences between active treatments and placebo emerged within the first 5 days and reached a point of maximum distinction around day 14. After this time point, differences between treatment modalities remained constant until the end of the observation period. According to our data, 20–25% of the patients were, on average, ‘true’ drug responders, thus suggesting that the therapeutic qualities of antidepressants do not lie in the suppression of symptoms, but rather are related to their ability to elicit and maintain certain conditions which allow recovery in a subgroup of patients who would otherwise remain non-responders.

The use of a placebo control group in the evaluation of a new product is today considered by most as a necessary condition of experimental drug research. Placebo response is an essential consideration in all clinical trials. If not properly controlled, incorrect and dangerous conclusion may be inferred for a product efficacy and safety profile. However, the inclusion of a placebo group in clinical trials in neuropsychiatric research raises several ethical and scientific questions. Whereas in certain indications, such as suicidal patients and severe and psychotic depression, the use of a placebo is generally not accepted, it is difficult to assess drug efficacy. This article discusses the concept of placebo in clinical trials, the occurrence of adverse events after placebo treatment and the high response rate of placebo in neuropsychiatric clinical research. The experimental methodology to adequately control all the factors involved is also analysed and discussed.

There is a tension between the need for scientifically valid trials of new psychotropic drugs and concern about conducting placebo-controlled trials, the trials psychopharmacologists consider the gold standard trial, when this requires that some patients be denied existing effective therapy. This paper will review the scientific principles supporting the need for placebo-controlled trials in depression and schizophrenia, and will provide preliminary data on failure rates of placebo-controlled trials for these disorders, as illustrations of the application of these principles. Next, the ethical issues pertinent to the conduct of placebo-controlled trials for these two serious psychiatric disorders will be reviewed. Preliminary data on suicides in placebo-controlled depression and schizophrenia trials will be presented to argue for the ethical acceptability of the conduct of placebo-controlled trials in these two conditions.