Future targets for migraine treatment beyond CGRP.

BACKGROUND: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. FINDINGS: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. CONCLUSION: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

Subjective Sleep Quality and Sleep Architecture in Patients With Migraine: A Meta-analysis.

BACKGROUND AND OBJECTIVES: Sleep disturbance is often associated with migraine. However, there is a paucity of research investigating objective and subjective measures of sleep in patients with migraine. This meta-analysis aims to determine whether there are differences in subjective sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) and objective sleep architecture measured using polysomnography (PSG) between adult and pediatric patients and healthy controls. METHODS: This review was preregistered on PROSPERO (CRD42020209325). A systematic search of 5 databases (Embase, MEDLINE, Global Health, APA PsycINFO, and APA PsycArticles, last searched on December 17, 2020) was conducted to find case-control studies that measured PSG or PSQI in patients with migraine. Pregnant participants and those with other headache disorders were excluded. Effect sizes (Hedges g) were entered into a random effects model meta-analysis. Study quality was evaluated with the Newcastle Ottawa Scale and publication bias with the Egger regression test. RESULTS: Thirty-two studies were eligible, of which 21 measured PSQI or Migraine Disability Assessment Test in adults, 6 measured PSG in adults, and 5 measured PSG in children. The overall mean study quality score was 5/9; this did not moderate any of the results and there was no risk of publication bias. Overall, adults with migraine had higher PSQI scores than healthy controls (g = 0.75, p < 0.001, 95% confidence interval [CI] 0.54-0.96). This effect was larger in those with a chronic rather than episodic condition (g = 1.03, p < 0.001, 95% CI 0.37-1.01; g = 0.63, p < 0.001, 95% CI 0.38-0.88, respectively). For polysomnographic studies, adults and children with migraine displayed a lower percentage of rapid eye movement sleep (g = -0.22, p = 0.017, 95% CI -0.41 to -0.04; g = -0.71, p = 0.025, 95% CI -1.34 to -0.10, respectively) than controls. Pediatric patients displayed less total sleep time (g = -1.37, p = 0.039, 95% CI -2.66 to -0.10), more wake (g = 0.52, p < 0.001, 95% CI 0.08-0.79), and shorter sleep onset latency (g = -0.37, p < 0.001, 95% CI -0.54 to -0.21) than controls. DISCUSSION: People with migraine have significantly poorer subjective sleep quality and altered sleep architecture compared to healthy individuals. Further longitudinal empirical studies are required to enhance our understanding of this relationship.

Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.

Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis, but this has not been tested directly in vivo.  Here, we investigated synaptic vesicle glycoprotein 2A (SV2A) levels and their relationship to symptoms and structural brain measures using [11C]UCB-J positron emission tomography in 18 patients with schizophrenia and 18 controls. We found significant group and group-by-region interaction effects on volume of distribution (VT). [11C]UCB-J VT was significantly lower in the frontal and anterior cingulate cortices in schizophrenia with large effect sizes (Cohen's d = 0.8-0.9), but there was no significant difference in the hippocampus. We also investigated the effects of antipsychotic drug administration on SV2A levels in Sprague-Dawley rats using western blotting, [3H]UCB-J autoradiography and immunostaining with confocal microscopy, finding no significant effects on any measure. These findings indicate that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for them.