Combination of anti-CGRP/CGRP-R mAbs with onabotulinumtoxin A as a novel therapeutic approach for refractory chronic migraine: a retrospective study of real-world clinical evidence and a protocol for a double-blind, randomized clinical trial to establish the efficacy and safety.

Chronic migraine is a disabling neurovascular disorder that ranks amongst the top causes of years lived with disability worldwide. The duration and the frequency of migraine affect cognitive and affective domains, inducing worsening of memory, executive functions, orientation and causing anxiety. Population-based studies report a worrying level of resistance to treatments. Therefore, this study aims: 1) to assess efficacy of monoclonal antibodies (mAbs) directed towards the calcitonin gene-related peptide (CGRP) or its receptor (CGRP-R) for chronic migraine resistant to current preventatives; 2) to design a clinical trial protocol to evaluate the efficacy and safety of combination therapy utilizing anti-CGRP/CGRP-R together with onabotulinumtoxin A in patients suffering from resistant chronic migraine; 3) to provide a molecular rationale for combination therapy. A controlled trial is warranted as pooled analysis of real-world data from our group highlighted that combined treatment provides ≥50% reduction vs. baseline (onabotulinumtoxin A) of monthly headache days (MHDs) in up to 58.8% of patients, but there has been only sparse application of this combined therapy to date. The mAbs chosen are: erenumab, because its combination effect with onabotulinumtoxin A improved symptoms in 65% of patients; eptinezumab, due to its faster action. The results highlight that early diagnosis of migraine improves therapeutic outcomes with mAbs alone, confirming their effectiveness and the need for an adequately powered clinical trial evaluating the safety and potential superior effectiveness of eptinezumab/erenumab and onabotulinumtoxin A together.

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

Impaired cortisol awakening response in eating disorder women with childhood trauma exposure: evidence for a dose-dependent effect of the traumatic load.

BACKGROUND: Childhood trauma is a non specific risk factor for adult eating disorders (ED), and the hypothalamic-pituitary-adrenal (HPA) axis seems to mediate such a risk. Here we explored the impact of different types of childhood trauma and of traumatic load on the cortisol awakening response (CAR) of women with anorexia nervosa (AN) or bulimia nervosa (BN). METHODS: Saliva samples were collected at awakening and after 15, 30, 60 min to measure cortisol levels by 121 women (44 AN patients, 36 BN patients and 41 healthy women). Participants filled in the Childhood Trauma Questionnaire. RESULTS: AN and BN patients with childhood maltreatment exhibited an attenuated CAR compared with non-maltreated ones. In the whole ED patient group, the CAR showed a progressive impairment with the increasing number of reported trauma types. Although significant negative correlations emerged between the type or the number of traumas and the CAR, only the number of traumas remained significantly associated with the CAR in a stepwise multiple regression analysis. CONCLUSIONS: Present findings confirm that childhood trauma is associated with an impaired CAR in adult AN and BN patients and demonstrate for the first time a negative dose-dependent effect of the traumatic load on HPA axis activity.

Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity.

PURPOSE: Hedonic eating occurs independently from homeostatic needs prompting the ingestion of pleasurable foods that are typically rich in fat, sugar and/or salt content. In normal weight healthy subjects, we found that before hedonic eating, plasma levels of 2-arachidonoylglycerol (2-AG) were higher than before nonhedonic eating, and although they progressively decreased after food ingestion in both eating conditions, they were significantly higher in hedonic eating. Plasma levels of anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), instead, progressively decreased in both eating conditions without significant differences. In this study, we investigated the responses of AEA, 2-AG, OEA and PEA to hedonic eating in obese individuals. METHODS: Peripheral levels of AEA, 2-AG, OEA and PEA were measured in 14 obese patients after eating favourite (hedonic eating) and non-favourite (nonhedonic eating) foods in conditions of no homeostatic needs. RESULTS: Plasma levels of 2-AG increased after eating the favourite food, whereas they decreased after eating the non-favourite food, with the production of the endocannabinoid being significantly enhanced in hedonic eating. Plasma levels of AEA decreased progressively in nonhedonic eating, whereas they showed a decrease after the exposure to the favourite food followed by a return to baseline values after eating it. No significant differences emerged in plasma OEA and PEA responses to favourite and non-favourite food. CONCLUSION: Present findings compared with those obtained in our previously studied normal weight healthy subjects suggest deranged responses of endocannabinoids to food-related reward in obesity.

Cortisol awakening response in patients with anorexia nervosa or bulimia nervosa: relationships to sensitivity to reward and sensitivity to punishment.

BACKGROUND: Sensitivity to punishment (SP) and sensitivity to reward (SR) are personality characteristics that may have relevance for the pathophysiology of eating disorders (EDs). Moreover, personality characteristics are known to modulate the activity of the hypothalamus-pituitary-adrenal (HPA) axis, which is the main component of the endogenous stress response system. As stress has been implicated in the aetiology and the maintenance of EDs, we aimed to study the HPA axis activity in relation to SP and SR, as conceptualized by Gray's reinforcement sensitivity theory (RST), in patients with anorexia nervosa (AN) or bulimia nervosa (BN). METHOD: Twenty-five women with AN, 23 women with BN and 19 healthy women volunteered for the study. HPA axis activity was assessed by measurement of the salivary cortisol awakening response (CAR). The subjects' SP and SR were measured by the behavioural inhibition system (BIS)/behavioural approach system (BAS) scales. RESULTS: The CAR was significantly enhanced in AN patients, but not in BN patients, compared to healthy women. The CAR correlated significantly with BAS measures, negatively in healthy controls and positively in binge-purging AN patients and BN women. SP, measured by the BIS scale, was higher in patients than in controls. CONCLUSIONS: These findings confirm the occurrence of an enhanced activity of the HPA axis in symptomatic AN, but not in symptomatic BN, and show for the first time that the CAR is associated with SR, as conceptualized by the RST, negatively in healthy subjects but positively in binge-purging ED patients.

Asymmetry of salivary cortisol and α-amylase responses to psychosocial stress in anorexia nervosa but not in bulimia nervosa.

BACKGROUND: The stress response involves the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). As a role for stress in determining of the onset and the natural course of eating disorders (EDs) has been proposed, the study of the psychobiology of the stress response in patients with anorexia nervosa (AN) and bulimia nervosa (BN) should be helpful in understanding the pathophysiology of these disorders. The two neurobiological components of the stress response can be easily explored in humans by the measurement of salivary cortisol and α-amylase response to a stressor. Therefore, we assessed salivary cortisol and α-amylase responses to the Trier Social Stress Test (TSST) in symptomatic patients with AN and BN compared to healthy controls. METHOD: Seven AN women, eight BN women and eight age-matched healthy females underwent the TSST between 1530 and 1700 h. Salivary cortisol and α-amylase levels were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to healthy women, AN patients showed a normal cortisol response to the TSST, although this occurred at significantly increased hormone levels, and an almost complete absence of response of α-amylase. BN women, however, exhibited enhanced pre-stress levels of salivary α-amylase but a normal response of the enzyme and cortisol to the TSST. CONCLUSIONS: These findings demonstrate, for the first time, the occurrence of an asymmetry between the HPA axis and SNS components of the stress response in the acute phase of AN but not in BN. The pathophysiological significance of this asymmetry remains to be determined.

New strategies for the prevention and treatment of allergic rhinitis in children.

Allergic rhinitis (AR) is a very common disease in children, often underdiagnosed and with underestimated complications. Its prevalence has increased during the last years, due to changes in environmental factors. The therapeutic strategy will include prevention by identification and eviction of the main allergens, associated to pharmacological therapy. Among antirhinitic drugs, the new generation of non-sedative specific antihistamines represent the main choice. We report our own experience with astemizole, one of these new antihistamines which confirms that astemizole is an effective and safe drug for the management of AR in children.

Evaluation of new test (Phadiatop) for the screening of respiratory allergic disorders in children.

The present study investigated the sensitivity, specificity, and predictive value of a new in vitro test, the Phadiatop, which detects the presence in serum of specific IgE to a balanced mixture of the most frequent inhalant allergens. Ninety-eight children (63 males, 35 females) 2-12 years old (median age = 6), suffering from rhinitis and/or conjunctivitis and/or asthma were studied. Our data show that Phadiatop has an 87% sensitivity, a 100% specificity, a 92% efficiency, a 100% positive predictive value, and an 86% negative predictive value. These results indicate that Phadiatop is very effective in diagnosing atopy (no false positive). However, a negative Phadiatop does not exclude the diagnosis of atopy.