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Objective:To assess efficacy and tolerability of 1-year erenumab treatment in patients with episodic migraine.Methods:Patients were randomized (n=955; 1:1:1) during the 24-week double-blind treatment phase (DBTP) to monthly subcutaneous placebo, erenumab 70 or 140mg. At Week 24, 845 patients were re-randomized (1:1) to erenumab 70 or 140mg during the 28-week dose-blinded active-treatment phase (ATP). Monthly migraine days (MMD), achieving ≥50%, ≥75% and 100% reduction in MMD, and safety/tolerability were assessed.Results:Mean MMD at DBTP baseline was 8.3. At Week 52, mean changes (SE) from pre-DBTP baseline/Week 24 (pre-ATP baseline) in MMD were −4.2 (0.2)/−1.1 (0.2) (70mg) and −4.6 (0.2)/−1.8 (0.2) (140mg) irrespective of treatment during the DBTP. For patients reducing dose from 140 (DBTP) to 70mg (ATP), change in MMD from Week 24 to 52 was −0.1 (0.3), and for those increasing from 70 (DBTP) to 140mg (ATP) was −1.8 (0.3). At Week 52, 61.0%, 38.5% and 19.8% of patients on erenumab 70mg, and 64.9%, 40.8% and 21.2% on erenumab 140mg, achieved ≥50%, ≥75% and 100% reduction in MMD from DBTP baseline, respectively. Among erenumab-treated patients in DBTP who showed ≥50% reduction in MMD during the last 3 months of DBTP and completed ATP, 86% showed sustained responses at ≥50% during the last 3 months of ATP. Safety of erenumab in the ATP was similar to the DBTP; exposure-adjusted incidence rates of adverse events were similar for either dose.Conclusion:Over 52 weeks, erenumab provided sustained efficacy in episodic migraine; the safety profiles were similar between erenumab dose groups in the presence of dose blinding.Clinicaltrials.gov identifier:NCT02456740Classification of evidence:Class II evidence that 52 weeks of treatment with erenumab 70 and 140mg subcutaneously monthly results in sustained reductions in monthly migraine days and similar dose tolerability for patients with episodic migraine.

One of the proposed mechanisms of action for the anxiolytic effects of the benzodiazepines is via a decrease in central serotonergic neurotransmission. The aim of this study was to combine in vivo microdialysis in the rat with behaviour on the elevated X-maze to determine changes in 5-HT release in the ventral hippocampus with concomitant measurement of behaviour. Twenty minutes exposure to the elevated X-maze resulted in an increase in extracellular 5-HT in the ventral hippocampus with no change in extracellular 5-HIAA. Restricting the rat to either the open or the closed arms produced an increase in extracellular 5-HT, however the increase in 5-HT when restricted to the open arms was not significantly greater than that on the closed arms. Forty minutes pretreatment with diazepam (2.5 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus and had an anxiolytic profile over 5 min and 20 min exposures of the rats to the X-maze. Diazepam had no effect on basal 5-HT levels before exposure to the X-maze but reduced extracellular 5-HT levels when the animal was returned to the holding cage. Forty minutes pretreatment with the .5-HT1A receptor partial agonist ipsapirone (1 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus but did not produce behaviour different from vehicle controls after 5 or 20 min periods on the X-maze.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of rearing hooded Lister rats either in groups of seven or singly on 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the frontal cortex were investigated using in vivo voltammetry together with Nafion coated carbon fibre micro-electrodes. The selective detection of basal extracellular levels of 5-HT with this technique (Peak B) was confirmed with parallel experiments using intracranial microdialysis to measure 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in vivo. The DA voltammetric signal (Peak A) was observed in vivo only following pharmacological or electrical stimulation of DA release. Enhanced efflux of cortical DA and 5-HT in response to local application of KCl and that of 5-HT following parentelar fenfluramine were selectively detected by the association: differential pulse voltammetry (DPV)-Nafion coated microbiosensors, supporting the capability of this electrochemical method to selectively monitor release of these amine neurotransmitters in vivo and in situ. The locomotor behaviour data indicated that isolation rearing resulted in augmented locomotor activity in a novel environment. In addition, the in vivo voltammetric results showed that following KCl or fenfluramine treatment cortical 5-HT release is prolonged while that of DA is increased in rats reared in isolation when compared with socially reared rats. This imbalance between extracellular levels of DA and 5-HT recorded in the frontal cortex of rats exposed to isolated housing conditions may contribute to the behavioural differences reported between isolation and group reared rats.

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