Henriët van Middendorp

The hormone cortisol is involved in bodily functions varying from stress to metabolism and the circadian rhythm, and is therefore a relevant clinical target. Cortisol effects can be manipulated through medication, and theoretically these effects are subject to conditioning. However, existing studies show variable results of cortisol conditioning. We explored a novel paradigm, based on studies showing the circadian rhythm can be conditioned non-pharmacologically in animals and that learning is possible during sleep. The target of the conditioning procedure was the cortisol awakening response, part of naturally-occurring morning rise in cortisol. Participants (40 males) followed a two-week protocol, with baseline measures taking place in the first week and conditioning and evocation in the second. A scent was used as the conditioned stimulus, presented in the 30 minutes before awakening for three mornings. In the final night of the study, participants awoke 4 hours earlier than normal, after exposure to the conditioned stimulus (experimental group) or a different scent (control group) in the 30 minutes before awakening. Results showed no differences between the control and experimental groups in the 45 minutes after awakening in the final night on cortisol levels or self-report outcomes (positive and negative affect, vitality, fatigue). Heart rate variability also did not show differences in the period from 30 minutes before to 45 minutes after awakening. Therefore, it seems that our novel design did not lead to results that support conditioning of the cortisol awakening response. Future studies might instead focus on replications of previous effective designs.

To evaluate the cost-effectiveness of the 'Plants for Joints' intervention for rheumatoid arthritis (RA) and metabolic syndrome-associated osteoarthritis (MSOA) patients over 16 weeks. Data from two randomized controlled trials were analysed. The first included 77 RA patients (intervention = 40; control = 37) and the second 64 MSOA patients (intervention = 32; control = 32). The intervention comprised a 16 week lifestyle programme including a whole-food plant-based diet, exercise, and stress management; control participants received usual care. Data from both trials were analysed together and separately. Costs were measured from societal and healthcare perspectives. Effects were expressed in quality-adjusted life-years (QALYs). The intervention cost €886/patient. Intervention group participants gained more QALYs than the control group (0.009; 95% confidence interval -0.004 to 0.023), equivalent to 3.3 additional days in 'perfect health' (0.009 × 365). Healthcare costs were higher in the intervention group, while societal costs were lower. None of these differences was statistically significant. From a societal perspective, the intervention had a moderate to high probability of being cost-effective compared with usual care, while the probability was low from a healthcare perspective. Stratified analyses indicated that the probability of cost-effectiveness was higher in RA than in MSOA patients. This difference became less pronounced after excluding outliers. The Plants for Joints intervention demonstrated a relatively high probability of cost-effectiveness from a societal perspective, although this was lower from a healthcare perspective. If these benefits are sustained in the long term, this intervention may reduce the disease and economic burden of arthritic conditions.

S-ketamine and midazolam are frequently used to provide sedation while maintaining spontaneous respiration. However, the effects of these agents on respiratory variability, which reflects the adaptability of the respiratory system, have not been thoroughly explored. We evaluated these effects in a randomized controlled pilot trial. This study was conducted as part of a randomized controlled trial originally designed to assess the effects of s-ketamine conditioning on pain sensitivity in patients with fibromyalgia syndrome. Participants were randomly assigned to receive an infusion of either s-ketamine (0.3 mg kg^-1 h^-1), midazolam (0.05 mg kg^-1 h^-1), or saline in a blinded fashion. Mean respiratory rate, variability of respiratory rate (VRR), and variability of tidal volume (VTV) were measured continuously and non-invasively with a bio-impedance method. Changes during drug infusion were compared in a linear mixed model to assess the effects of s-ketamine and midazolam compared to saline. Data were analyzed for 57 experiments in 28 participants. Their median baseline variabilities of respiratory rate and tidal volume were 0.19 (IQR: 0.16–0.25) and 0.23 (0.19–0.34), respectively. While mean respiratory rate was not affected, midazolam resulted in a significant decrease in both VRR (ß = −0.071, 95% CI: −0.120 to −0.021) and VTV (ß = −0.117, 95% CI: −0.170 to −0.062). In contrast, s-ketamine appeared to produce a smaller decrease in VTV (ß = −0.062, 95% CI: −0.118 to −0.003) with VRR remaining unaffected (ß = −0.036, 95% CI: −0.092 to 0.019). In conclusion, our study demonstrates that midazolam reduces respiratory variability, potentially impairing the adaptability of the respiratory system. In contrast, s-ketamine largely preserved respiratory variability, suggesting it may be a safer alternative for sedation in patients with impaired spontaneous breathing. Further studies are needed to assess the clinical implications of these observations in patients undergoing sedation.

The benign dermatological hair condition Alopecia Areata (AA) is known to impair Quality of Life (QoL), especially mental and social health, due to the accompanying visible appearance changes. Previous studies have identified demographic, clinical, social, and psychological variables related to QoL. Yet, the novelty of this study lies in examining how QoL differences in AA relate to (combinations of) these variables. The aim of the current study is to identify and characterize subgroups of AA persons with less or more QoL impairment by means of (combinations of) demographic, clinical, psychological, and social factors, including both potential risk (perceived stigmatization, avoidant coping, physical identity definition) and protective factors (disclosure, social support, emotion-focused coping and non-physical identity definition). An online questionnaire was filled out by 322 persons with AA, including the Dermatology Life Quality Index (DLQI) as QoL measure, Perceived Stigmatization Questionnaire (FSQ), brief COPE, Social Support Survey, a newly developed identity-definition measure, clinical characteristics, and demographics. Classification and Regression Tree (CART) analysis identified subgroups based on QoL outcome. Lowest QoL impairment was found in persons with low feelings of being flawed combined with low secretiveness. Low QoL impairment was also found in persons feeling flawed combined with low avoidant coping, low sensitivity to others' opinions and older age. QoL impairment was intermediate in persons perceiving more social support in those with a younger age, and defining identity less on physical appearance in those sensitive to others' opinions. Highest QoL impairment was characterized by feeling flawed combined with an avoidant coping style. Current findings provide indications for the identification of risk and protective profiles for QoL impairment and which factors to address in interventions to improve QoL in AA.

Attitudes towards medication can affect treatment outcomes and adherence through mechanisms such as placebo and nocebo effects. Questionnaires assessing both negative and positive attitudes towards medication in general, which can be used across a variety of settings and in both patient and non-patient samples, are however lacking. To fill this gap, we developed and validated the General Attitude towards Medication Questionnaire (GAMQ). Items were selected and adapted from existing questionnaires by a group of experts. Validation of the original Dutch version took place in 4 samples: 2 recruited from the general population (n = 508; n = 279) and 2 patient samples (patients with rheumatoid arthritis, n = 121; patients with atopic dermatitis, n = 70). We evaluated the psychometric properties of the GAMQ by determining the factor structure and its stability across samples, internal consistency, and convergent validity. The GAMQ contains 6 positive and 6 negatively worded items. A factor structure was observed with three subscales, representing ‘Trust in medication’, ‘Concerns about medication’, and ‘Reluctance to use medication’. The fit of the factor structure was satisfactory across samples, considering classic cut-offs, with an adequate or close to adequate fit. The total scale showed good internal consistency, good convergent validity with related scales (i.e., Beliefs about Medicines Questionnaire - General and a single medication attitude scale), and concurrent validity as reflected in associations with expectations about pain- and itch-relieving medication. It was not consistently or strongly associated with demographic or health-related characteristics. The newly developed GAMQ showed satisfactory psychometric properties in a variety of populations, although limitations should be considered. The GAMQ is the first scale to assess both positive and negative attitudes towards medication in general, providing indicators of Trust, Concerns, and Reluctance regarding medication. The scale may be an informative measure for predicting treatment outcomes and adherence, as well as placebo and nocebo effects in diverse samples.

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.

Objective: Expectancies are known to shape pain experiences, but it remains unclear how different types of expectancies contribute to daily pain fluctuations in fibromyalgia. This combined experimental and diary study aims to provide insights into how experimentally-derived nocebo hyperalgesia and other, diary-derived, expectancy-related factors are associated with each other and with daily pain in fibromyalgia. Methods: Forty-one female patients with fibromyalgia first participated in a lab procedure measuring nocebo hyperalgesia magnitude, then filled out an electronic diary 3 times a day over 3 weeks regarding the expectancy-related factors of pain expectancy, anxiety, optimism, and pain-catastrophizing thoughts, and current pain intensity. Results: Our results indicate that experimentally-induced nocebo hyperalgesia was unrelated to diary-assessed expectancy-related factors and did not predict daily fibromyalgia pain. Higher levels of the self-reported expectancy-related factors pain expectancy and pain catastrophizing, but not anxiety and optimism, predicted moment-to-moment pain increases in fibromyalgia, after controlling for current pain, moment-of-day and all other expectancy-related factors. Conclusion: Our findings indicate that self-reported expectancy-related factors, particularly pain expectancy and pain catastrophizing, are potentially more relevant for predicting daily pain experience than experimentally-induced nocebo hyperalgesia. Further translation of nocebo hyperalgesia is needed from experimental to Ecological Momentary Assessment research. Our findings imply that targeting the decrease in pain expectancy and catastrophizing thoughts e.g., via Cognitive Behavioral Therapy, have potential for improving daily pain levels in fibromyalgia.