Philippe Persoons

Determinants of symptoms in functional dyspepsia: gastric sensorimotor function, psychosocial factors or somatisation?

Background: Gastric sensorimotor dysfunction, psychosocial factors and somatisation are all implicated in symptom generation in functional dyspepsia (FD). Aim: To determine the relative contribution of each of these factors to overall dyspeptic symptom severity and weight loss in FD. Methods: In 201 consecutive tertiary care patients with FD (mean age 40.1 (SD 12.6) years), gastric sensorimotor function was studied using barostat (sensitivity, compliance and accommodation). Psychosocial factors (depression and anxiety disorders, positive and negative affect, perceived stress, alexithymia and history of abuse), somatisation and co-morbid irritable bowel syndrome (IBS) and chronic fatigue symptoms were assessed using self-report questionnaires. Variables were correlated with dyspepsia symptom severity (DSS) and weight loss. Hierarchical multiple linear regression was used to identify determinants of DSS and weight loss. Results: Multiple linear regression identified the following determinants of DSS: gastric sensitivity (β = 0.77, p = 0.25), depression (β = 0.12, p = 0.06) and somatisation (β = 0.48, p<0.0001) (controlling for age and occupation, R2 = 0.29, p<0.0001). The effect of depression on DSS is partially mediated by somatisation. Gastric sensitivity (β = 2.87, p = 0.08), history of childhood sexual abuse (β = 9.37, p = 0.0006), depression (β = 0.19, p = 0.24) and somatisation (β = 0.67, p = 0.01) are independent determinants of weight loss (controlling for gender and occupation, R2 = 0.42, p<0.0001). The effect of depression on weight loss is fully mediated by somatisation. Conclusion: Symptom severity and weight loss in FD are determined by psychosocial factors (depression, abuse history) and somatisation, and only to a lesser extent by gastric sensorimotor function. The importance of psychosocial factors and somatisation compared to gastric sensorimotor function is most pronounced in hypersensitive patients.

Relationship between anxiety and gastric sensorimotor function in functional dyspepsia.

Objective: To investigate the relationship between anxiety and gastric sensorimotor function in patients with (hypersensitive) functional dyspepsia (FD). Comorbidity between FD and anxiety disorders is high. In FD, epigastric pain is associated with gastric hypersensitivity and neuroticism, a personality trait related to anxiety. Experimentally induced anxiety in healthy volunteers is associated with changes in sensorimotor function of the proximal stomach. Methods: A total of 139 patients with FD (n = 102 women) underwent a barostat investigation to determine gastric compliance, meal accommodation, and thresholds for discomfort and pain. Anxiety was measured by the State-Trait Anxiety Inventory (STAI) scale (anxiety as a stable personality trait) and the STAI-State scale (momentary anxiety). The anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A) was filled out to detect comorbid anxiety disorders. Results: Hyper- and normosensitive patients had similar anxiety scores, but gastric compliance was significantly lower in hypersensitive patients (11.4 versus 32.8 ml/mm Hg; p < .001). In the whole patient group, no significant correlations between STAI scores and gastric sensorimotor function were found. In hypersensitive patients (n = 53, 43 women), state anxiety was negatively correlated with discomfort threshold (&rgr; = −.49; p = .001), pain threshold (&rgr; = −.48; p = .02), and gastric compliance (&rgr; = −.46; p = .002). These results were confirmed by multiple linear and logistic regression analyses. Conclusion: In hypersensitive patients with FD, state anxiety is significantly and negatively correlated with discomfort threshold, pain threshold, and compliance. These results strengthen the hypothesis that anxiety is important in FD, especially in hypersensitive patients. FD = functional dyspepsia; STAI = State-Trait Anxiety Inventory; HADS-A = Hospital Anxiety and Depression Scale-Anxiety subscale; FGID = functional gastrointestinal disorders; IBS = irritable bowel syndrome; CNS = central nervous system; MDP = minimal distending pressure; WMW test = Wilcoxon Mann-Whitney test; OR = odds ratio; ANS = autonomic nervous system; EMS = emotional motor system; PAG = periaqueductal grey; LC = locus coeruleus; HPA-axis = hypothalamo-pituitary-adrenal axis; ASI = anxiety sensitivity index; VSI = visceral sensitivity index.

Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study

PURPOSE Chronic fatigue syndrome has been associated with decreased function of the hypothalamic-pituitary-adrenal axis. Although neurally mediated hypotension occurs more frequently in patients with chronic fatigue syndrome than in controls, attempts to alleviate symptoms by administration of hydrocortisone or fludrocortisone have not been successful. The purpose of this study was to investigate the effect of combination therapy (5 mg/d of hydrocortisone and 50 microg/d of 9-alfa-fludrocortisone) on fatigue and well-being in chronic fatigue syndrome. METHODS We performed a 6-month, randomized, placebo-controlled, double-blind, crossover study in 100 patients who fulfilled the 1994 Centers for Disease Control and Prevention criteria for chronic fatigue syndrome. Between-group differences (placebo minus treatment) were calculated on a 10-point visual analog scale. RESULTS Eighty patients completed the 3 months of placebo and 3 months of active treatment in a double-blind fashion. There were no differences between treatment and placebo in patient-reported fatigue (mean difference, 0.1; 95% confidence interval [CI]: -0.3 to 0.6) or well-being (mean difference, -0.4; 95% CI: -1.0 to 0.1). There were also no between-group differences in fatigue measured with the Abbreviated Fatigue Questionnaire, the Short Form-36 Mental or Physical Factor scores, or in the Hospital Anxiety and Depression Scale. CONCLUSION Low-dose combination therapy of hydrocortisone and fludrocortisone was not effective in patients with chronic fatigue syndrome.

Dyspeptic patients with visceral hypersensitivity: sensitisation of pain specific or multimodal pathways?

Background and aims: Patients with functional dyspepsia who have hypersensitivity to gastric distension have more prevalent pain, suggesting the presence of hyperalgesia. It is unclear whether this reflects activation of pain specific afferent pathways or multimodal afferent pathways that also mediate non-painful sensations. In the former case, hyperalgesia should occur when intensity of non-painful sensations is still low. The aim of the study was to analyse whether the symptom profile during gastric dissentions in functional dyspepsia patients with hyperalgesia reflects sensitisation of pain specific or multimodal pathways. Methods: Forty eight consecutive dyspeptic patients (35 female) underwent gastric sensitivity testing with a barostat balloon using a double random staircase protocol. At the end of every distending step, patients scored perception of upper abdominal sensations on a graphic 0–6 rating scale and completed visual analogue scales (VAS 0–100 mm) for pain, nausea, satiety, and fullness. The end point was a rating scale of 5 or more. Results: Hypersensitivity was present in 20 patients (40%); gastric compliance did not differ between normo- and hypersensitive patients. At maximal distension (score 5 or more), hypersensitive patients had significantly lower distending pressures and intra-balloon volumes, but similar VAS scores for pain, nausea, satiety, and fullness compared with normosensitive patients. In both normosensitive and hypersensitive patients, elevation of pain VAS scores with increasing distending pressures paralleled the elevation in VAS scores for nausea, satiety, and fullness. Conclusions: Hypersensitive dyspeptic patients reach the same intensity of painful and non-painful sensations as normosensitive patients but at lower distending pressures. Hyperalgesia occurs in hypersensitive dyspeptic patients at distending pressures that also induce intense non-painful sensations. These findings argue against isolated upregulation of pain specific afferents in functional dyspepsia patients with visceral hypersensitivity.

Evaluation of short-term responsiveness and cutoff values of inflammatory bowel disease questionnaire in Crohn's disease.

Background: The inflammatory bowel disease questionnaire (IBDQ) is a frequently used outcome parameter in clinical trials. Whereas the validity and reproducibility of the IBDQ have been extensively studied, there are limited data on its short‐term responsiveness and cutoff values for remission and partial clinical response. Methods: The IBDQ score and its bowel (BD), systemic (SysD), emotional (ED), and social (SocD) dimensions were tested for responsiveness in a cohort of 224 patients with Crohns disease (CD) treated with infliximab for refractory luminal disease. Changes in the IBDQ score and its dimensions 4 weeks after therapy were analyzed and correlated with changes in the Crohns Disease Activity Index (CDAI). The responsiveness ratios of the IBDQ and its dimensions were analyzed. Using regression line with &Dgr;CDAI, the cutoff values for the IBDQ remission and response were calculated. Results: Overall, there was a good correlation between the CDAI and IBDQ at week 0 (correlation coefficient, 0.69; P < .001) and week 4 (−0.76; P < .001) and change after 4 weeks (0.74; P < .001). The correlation coefficients for &Dgr;CDAI and changes in BD, SysD, ED, and SocD were 0.753, 0.552, 0.620, and 0.631, respectively; all P < 0.001. The responsiveness ratios for &Dgr;IBDQ, BD, SysD, ED, and SocD were 2.6, 2.1, 1.9, 1.7, and 1.9, respectively. Regression line for the IBDQ (r = −0.76, P < .001) resulted in a cutoff value for remission of 168 points and for &Dgr;IBDQ resulted in a cutoff value of 22 and 27 points for clinical improvement based on &Dgr;CDAI ≥−70 and ≥−100 points. Conclusions: The IBDQ is a responsive instrument for reflecting quick change in the quality of life of patients with CD. Cutoff values for the IBDQ remission and partial response were 168 and ≥27 points.

In vivo type 1 cannabinoid receptor availability in Alzheimer's disease

The endocannabinoid system (ECS) is an important modulatory and potentially neuroprotective homeostatic system in the brain. In Alzheimers disease (AD), the role of type 1 cannabinoid receptor (CB₁R) is unclear, with contradictory findings in post-mortem studies showing upregulation, downregulation or unchanged CB₁R status. We have investigated CB₁R availability in vivo in patients with AD, in relation to amyloid deposition, cognitive functioning and apolipoprotein E (ApoE) genotype. Eleven AD patients and 7 healthy volunteers (HV) underwent combined [¹⁸F]MK-9470 PET and [¹¹C]PIB PET scans to assess CB₁R availability and amyloid deposition, respectively, and T1 volumetric MRI for partial volume correction. We found no difference in CB₁R availability between AD and HV, VOI-based fractional uptake values (FUR) were 0.043±0.01 for AD and 0.045±0.01 for controls (p=0.9). CB₁R availability did not correlate with neuropsychological test scores and was not modulated by ApoE genotype. As expected, global [¹¹C]PIB SUVR (standardized uptake value ratio) was increased in AD (SUVR 1.9±0.3) compared to HV (1.2±0.1) with p<0.001, but no correlation was found between amyloid β (Aβ) deposition and CB₁R availability. In conclusion, we found no in vivo evidence for a difference in CB₁R availability in AD compared to age-matched controls. Taken together with recently reported in vivo CB₁R changes in Parkinsons and Huntingtons disease, these data suggest that the CB₁R is differentially involved in neurodegenerative disorders.

Attachment in old age: theoretical assumptions, empirical findings and implications for clinical practice.

Contemporary theoretical models that conceptualize attachment as a biologically-based behavioral system that is activated under threat offer a heuristic theoretical framework to understand processes involved in aging and particularly individual differences in coping with the inevitable losses associated with aging and age-related disease, including dementia. This paper provides a systematic qualitative review of research concerning attachment in old age published between 1983 and June 2012. Four major findings emerged. First, studies suggest age-related changes with regard to the number and type of attachment figures, with older adults, compared to younger adults, having less attachment relations. Moreover, so-called symbolic attachments (e.g., to God or a deceased loved one) become more prominent in old age. Second, the quality of attachment changes with increasing age, with significant decreases in attachment anxiety, but not in attachment avoidance. Third, late-life attachment is in theoretically predicted ways associated with indices of intraindividual and interindividual functioning. Finally, insecure attachment has a negative impact on subjective caregiver burden and behavior of patients with dementia. There is some evidence suggesting that attachment-based interventions show positive effects in treating problem behaviors associated with dementia. However, these conclusions need to be interpreted within the context of important methodological limitations, stressing the need for future research in this domain. Guidelines for future research are outlined.

Long-term methylphenidate intake in chronic fatigue syndrome

Objective: Concentration disturbances are frequent in chronic fatigue syndrome (CFS). In a placebo-controlled double-blind crossover study, methylphenidate over 4 weeks was superior to placebo in the relief of fatigue and concentration disturbance. This observational study describes the effect of long-term methylphenidate intake on fatigue, concentration, and daily life activities, as reported by the patients themselves. Methods: A questionnaire was sent to all CFS patients who were prescribed methylphenidate at the general internal medicine department of a university hospital between August 2004 and February 2007, for possible improvement of concentration difficulties and fatigue. Results: Out of 194 consecutive patients, 149 (76.8%) sent the questionnaire back. At the time of the questionnaire, 65.3% had stopped the intake of methylphenidate, 34.7% still took it daily or occasionally. Among the patients who continued methylphenidate, 48% reported an at least 50% improvement of fatigue, and 62% reported an at least 50% improvement of concentration difficulties. This continued intake of methylphenidate resulted in more working hours in these patients. Side effects (agitation, palpitations, and dry mouth) were reported significantly more in patients who had stopped methylphenidate than in those who still took it. Conclusion: The long-term intake of methylphenidate by CFS patients with concentration difficulties has a positive effect in about one out of three patients.

Perception of induced dyspnea in fibromyalgia and chronic fatigue syndrome

OBJECTIVE Dyspnea perception is distorted in patients with medically unexplained dyspnea. The goals of this study were 1) to replicate these results in patients with fibromyalgia and/or chronic fatigue syndrome (CFS), and 2) to investigate predictors of distorted symptom perception within the patient group, with a focus on negative affectivity (NA), psychiatric comorbidity and somatic symptom severity. METHODS Seventy-three patients diagnosed with fibromyalgia and/or CFS and 38 healthy controls (HC) completed a rebreathing paradigm, consisting of a baseline (60s of room air), a rebreathing phase (150s, gradually increasing ventilation, partial pressure of CO2 in the blood, and self-reported dyspnea), and a recovery phase (150s of room air). Dyspnea, respiratory flow and FetCO2 levels were measured continuously. RESULTS Patients reported more dyspnea than HC in the recovery phase (p=0.039), but no differences between patients and HC were found in the baseline (p=0.07) or rebreathing phase (p=0.17). No significant differences between patients and HC were found in physiological reactivity. Within the patient group, the effect in the recovery phase was predicted by somatic symptom severity (p=0.046), but not by negative affectivity or by the number of psychiatric comorbidities. CONCLUSION This study extended earlier findings in patients with medically unexplained dyspnea to patients with fibromyalgia and CFS. This suggests that altered symptom perception is a non-symptom-specific mechanism underlying functional somatic syndromes in general, particularly in patients with high levels of somatic symptom severity. The results are discussed in a predictive coding framework of symptom perception.

Probability of major depression diagnostic classification using semi-structured versus fully structured diagnostic interviews

BACKGROUND Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics. METHOD Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit. RESULTS A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15-3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98-10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) (OR = 0.96; 95% CI = 0.56-1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26-0.97). CONCLUSIONS The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.