Can Pharmacological Conditioning as an Add-On Treatment Optimize Standard Pharmacological Treatment in Patients with Recent-Onset Rheumatoid Arthritis? A Proof-of-Principle Randomized Clinical Trial.

Medication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce. This proof-of-principle double-blind randomized clinical trial examined whether treatment effects in recent-onset rheumatoid arthritis (RA) can be optimized through pharmacological conditioning. After four months of standardized treatment (n = 46), patients in clinical remission (n = 19) were randomized to the Control group (C), continuing standardized treatment (n = 8), or the Pharmacological Conditioning (PC) group, receiving variable treatment according to conditioning principles (n = 11). After eight months, treatment was tapered and discontinued linearly (C) or variably (PC). Standard treatment led to large improvements in disease activity and HRQoL in both groups. The groups did not differ in the percentage of drug-free clinical remission obtained after conditioning or continued standard treatment. The PC group did show a larger decrease in self-reported disease activity (Cohen's d = 0.9) and a smaller increase in TNF-α levels (Cohen's d = 0.7) than the C group. During all phases, more differences between groups were found for the patients who followed protocol than for the intention-to-treat sample. Although the results are not conclusive, pharmacological conditioning may have some advantages in terms of disease progression and stability, especially during the conditioning phase, compared with standard clinical treatment. The effects may be particularly beneficial for patients who show a good initial response to increased medication dosages.

Pharmacological conditioning in the treatment of recent-onset rheumatoid arthritis: a randomized controlled trial study protocol.

BACKGROUND: In pharmacological conditioning associations are formed between the effects of medication and contextual factors related to the medication. Pharmacological conditioning with placebo medication can result in comparable treatment effects and reduced side effects compared to regular treatment in various clinical populations, and may be applied to achieve enhanced drug effects. In the current study protocol, pharmacological conditioning is applied to achieve enhanced treatment effects in patients with recent-onset rheumatoid arthritis (RA). The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness for patients with inflammatory conditions, such as recent-onset RA. METHODS: A multicenter, randomized controlled clinical trial is conducted in patients with recent-onset RA. Participants start on standardized pharmacological treatment for 16 weeks, which consists of methotrexate (MTX) 15 mg/week and a tapered schedule of prednisone 60 mg or 30 mg. After 4 months, participants in clinical remission (based on the rheumatologist's opinion and a targeted score below 1.6 on a 44-joint disease activity score (DAS44)) are randomized to 1 of 2 groups: (1) the control group (C), which continues with a standardized treatment schedule of MTX 15 mg/week or (2) the pharmacological conditioning group (PC), which receives an MTX treatment schedule in alternating high and low dosages. In the case of persistent clinical remission after 8 months, treatment is tapered and discontinued linearly in the C group and variably in the PC group. Both groups receive the same cumulative amount of MTX during each period. Logistic regression analysis is used to compare the proportion of participants with drug-free clinical remission after 12 months between the C group and the PC group. Secondary outcome measures include clinical functioning, laboratory assessments, and self-reported measures after each 4-month period up to 18 months after study start. DISCUSSION: The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness in patients with inflammatory conditions, such as recent-onset RA. TRIAL REGISTRATION: Netherlands Trial Register, NL5652. Registered on 3 March 2016.

Editor's choice: Optimizing healthy food preferences by serious gaming.

Objective: Serious gaming is an upcoming and promising tool in prevention and health promotion. The aim of this experimental study was to examine whether health-related serious gaming could optimize food-related outcomes and physical activity.Design: Eighty-one healthy participants (80% female) were randomly allocated to an experimental condition, in which participants played serious games based on transferring information, priming and evaluative conditioning, for half an hour, or a control condition, in which participants played non-health-related computer games.Main outcome measures: The primary study outcome was self-reported food preference and self-reported food choice, assessed by the Food Choice Task with food pairs differing in healthiness, or in both healthiness and attractiveness. Secondary outcomes were actual food choice and physical activity.Results: A significantly healthier food preference for pairs differing in healthiness was found on the Food Choice Task in the experimental compared to the control condition. No significant differences were found on the other outcomes.Conclusions: This study provides preliminary support for the effects of serious gaming based on optimizing food preferences. More research is needed to confirm the present findings and to further elucidate and optimize the effects of serious gaming on health behaviours.

How to prevent, minimize, or extinguish nocebo effects in pain: a narrative review on mechanisms, predictors, and interventions.

Nocebo effects, such as side effects due to negative expectations regarding the pain treatment, are a concern for health care providers and come with significant costs. This narrative review focuses on underlying mechanisms and possible factors that contribute to the susceptibility to the nocebo effect on pain and related outcomes and suggests strategies that can prevent, minimize, or extinguish nocebo effects in clinical settings. Nocebo effects are the result of psychological (eg, conditioning, verbal suggestions, and observational learning) and neurobiological (eg, cholecystokinin and dopamine regulation) mechanisms. Evidence from clinical and experimental studies lead to various recommendations and strategies to alter the nocebo effect in order to optimize pain treatments, such as providing patients with enhanced information, optimizing patient-physician communication and relationships, and offering psychoeducation on coping skills in order to manage patient expectations. The current literature from both clinical and experimental studies provides a better understanding of the nocebo effect and possible factors that modulate its strength on treatment outcomes. This allows for the development of evidence-based strategies aimed at the prevention, minimization, and treatment of the nocebo effect in pain conditions and possible other somatic disorders.

Can verbal suggestions strengthen the effects of a relaxation intervention?

Short stress management interventions such as relaxation therapy have demonstrated preliminary effectiveness in reducing stress-related problems. A promising tool to strengthen the effectiveness of relaxation-based interventions is the use of verbal suggestions, as previous research provided evidence that verbal suggestions can induce positive outcome expectancies, facilitate adaptive responses to stress and improve health outcomes. The present experimental proof-of-concept study aimed to investigate the effects of a brief relaxation intervention and specifically the role of verbal suggestions on stress-related outcomes assessed by self-report questionnaires and psychophysiological data. 120 participants (mean age = 22.1 years) were randomized to one of four intervention conditions: a brief relaxation intervention plus verbal suggestions condition, a brief relaxation intervention only condition, a verbal suggestions only condition, and a control condition. Afterwards, participants were subjected to a psychosocial stress challenge to assess reactivity to a stressful event. Immediately after both relaxation interventions (with and without verbal suggestions), lower self-reported state anxiety was found compared to the control condition, but no differences were observed in response to the stressor. The verbal suggestions only condition did not impact state anxiety. No significant effects were found for verbal suggestion interventions on cortisol, alpha amylase, heart rate and skin conductance. This is the first study investigating the role of verbal suggestions in the effectiveness of a brief relaxation intervention. Although this experimental proof-of-concept study provides support for the effectiveness of a brief relaxation intervention in lowering state anxiety directly after the intervention, the effects did not impact the response to a subsequent stressor and we did not observe any evidence for the add-on effectiveness of verbal suggestions. The effectiveness of brief relaxation interventions on stress responses should be investigated further in future research by incorporating interventions that are tailored to the specific stress challenge and various types of verbal suggestions.

Mineralocorticoid receptor haplotype moderates the effects of oral contraceptives and menstrual cycle on emotional information processing.

RATIONALE: The processing of emotional information is affected by menstrual cycle phase and by the use of oral contraceptives (OCs). The stress hormone cortisol is known to affect emotional information processing via the limbic mineralocorticoid receptor (MR). OBJECTIVES: We investigated in an exploratory study whether the MR-genotype moderates the effect of both OC-use and menstrual cycle phase on emotional cognition. METHODS: Healthy premenopausal volunteers (n=93) of West-European descent completed a battery of emotional cognition tests. Forty-nine participants were OC users and 44 naturally cycling, 21 of whom were tested in the early follicular (EF) and 23 in the mid-luteal (ML) phase of the menstrual cycle. RESULTS: In MR-haplotype 1/3 carriers, ML women gambled more than EF women when their risk to lose was relatively small. In MR-haplotype 2, ML women gambled more than EF women, regardless of their odds of winning. OC-users with MR-haplotype 1/3 recognised fewer facial expressions than ML women with MR-haplotype 1/3. CONCLUSION: MR-haplotype 1/3 carriers may be more sensitive to the influence of their female hormonal status. MR-haplotype 2 carriers showed more risky decision-making. As this may reflect optimistic expectations, this finding may support previous observations in female carriers of MR-haplotype 2 in a naturalistic cohort study.

Dose-dependent effects of cannabis on the neural correlates of error monitoring in frequent cannabis users.

Cannabis has been suggested to impair the capacity to recognize discrepancies between expected and executed actions. However, there is a lack of conclusive evidence regarding the acute impact of cannabis on the neural correlates of error monitoring. In order to contribute to the available knowledge, we used a randomized, double-blind, between-groups design to investigate the impact of administration of a low (5.5 mg THC) or high (22 mg THC) dose of vaporized cannabis vs. placebo on the amplitudes of the error-related negativity (ERN) and error positivity (Pe) in the context of the Flanker task, in a group of frequent cannabis users (required to use cannabis minimally 4 times a week, for at least 2 years). Subjects in the high dose group (n=18) demonstrated a significantly diminished ERN in comparison to the placebo condition (n=19), whereas a reduced Pe amplitude was observed in both the high and low dose (n=18) conditions, as compared to placebo. The results suggest that a high dose of cannabis may affect the neural correlates of both the conscious (late), as well as the initial automatic processes involved in error monitoring, while a low dose of cannabis might impact only the conscious (late) processing of errors.

Cannabis and creativity: highly potent cannabis impairs divergent thinking in regular cannabis users.

RATIONALE: Cannabis users often claim that cannabis has the potential to enhance their creativity. Research suggests that aspects of creative performance might be improved when intoxicated with cannabis; however, the evidence is not conclusive. OBJECTIVE: The aim of this study was to investigate the acute effects of cannabis on creativity. METHODS: We examined the effects of administering a low (5.5 mg delta-9-tetrahydrocannabinol [THC]) or high (22 mg THC) dose of vaporized cannabis vs. placebo on creativity tasks tapping into divergent (Alternate Uses Task) and convergent (Remote Associates Task) thinking, in a population of regular cannabis users. The study used a randomized, double-blind, between-groups design. RESULTS: Participants in the high-dose group (n = 18) displayed significantly worse performance on the divergent thinking task, compared to individuals in both the low-dose (n = 18) and placebo (n = 18) groups. CONCLUSIONS: The findings suggest that cannabis with low potency does not have any impact on creativity, while highly potent cannabis actually impairs divergent thinking.

Preferred, but not objective temperature predicts working memory depletion.

The present study investigated the relationship between objective temperature and subjective temperature preferences in predicting performance in simple and complex cognitive tasks. We assessed the impact of room temperature (warm and cold) on the ability to "update" (and monitor) working memory (WM) representations in two groups of participants, who differed in their subjective temperature preferences (warm-preferred vs. cold-preferred). Participants performed an N-back task in which conditions (1-back and 2-back) differ in their WM load and cognitive demands. Results showed that the preferred, but not the objective temperature predicts WM performance in the more resource-demanding (the 2-back) condition. We propose that subjective preferences are more reliable predictors of performance than objective temperature and that performing under the preferred temperature may counteract "ego-depletion" (i.e., reduced self-control after an exhausting cognitive task) when substantial cognitive control is required. Our findings do not only favor a cognitive approach over the environmental/physical approaches dominating the research on cognition-environment interactions, but they also have important, straightforward practical implications for the design of workplaces.