Identification and characterization of migraine in pregnancy: A Norwegian registry-based cohort study.

BACKGROUND: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care. METHODS: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified. RESULTS: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care. CONCLUSIONS: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication.

Trends and prescribing patterns of antimigraine medicines in nine major cities in China from 2018 to 2022: a retrospective prescription analysis.

BACKGROUND: The objective of this study was to investigate the trends and prescribing patterns of antimigraine medicines in China. METHODS: The prescription data of outpatients diagnosed with migraine between 2018 and 2022 were extracted from the Hospital Prescription Analysis Cooperative Project of China. The demographic characteristics of migraine patients, prescription trends, and corresponding expenditures on antimigraine medicines were analyzed. We also investigated prescribing patterns of combination therapy and medicine overuse. RESULTS: A total of 32,246 outpatients who were diagnosed with migraine at 103 hospitals were included in this study. There were no significant trend changes in total outpatient visits, migraine prescriptions, or corresponding expenditures during the study period. Of the patients who were prescribed therapeutic medicines, 70.23% received analgesics, and 26.41% received migraine-specific agents. Nonsteroidal anti-inflammatory drugs (NSAIDs; 28.03%), caffeine-containing agents (22.15%), and opioids (16.00%) were the most commonly prescribed analgesics, with corresponding cost proportions of 11.35%, 4.08%, and 19.61%, respectively. Oral triptans (26.12%) were the most commonly prescribed migraine-specific agents and accounted for 62.21% of the total therapeutic expenditures. The proportion of patients receiving analgesic prescriptions increased from 65.25% in 2018 to 75.68% in 2022, and the proportion of patients receiving concomitant triptans decreased from 29.54% in 2018 to 21.55% in 2022 (both P <  0.001). The most frequently prescribed preventive medication classes were calcium channel blockers (CCBs; 51.59%), followed by antidepressants (20.59%) and anticonvulsants (15.82%), which accounted for 21.90%, 34.18%, and 24.15%, respectively, of the total preventive expenditures. Flunarizine (51.41%) was the most commonly prescribed preventive drug. Flupentixol/melitracen (7.53%) was the most commonly prescribed antidepressant. The most commonly prescribed anticonvulsant was topiramate (9.33%), which increased from 6.26% to 12.75% (both P <  0.001). A total of 3.88% of the patients received combined therapy for acute migraine treatment, and 18.63% received combined therapy for prevention. The prescriptions for 69.21% of opioids, 38.53% of caffeine-containing agents, 26.61% of NSAIDs, 13.97% of acetaminophen, and 6.03% of triptans were considered written medicine overuse. CONCLUSIONS: Migraine treatment gradually converges toward evidence-based and guideline-recommended treatment. Attention should be given to opioid prescribing, weak evidence-based antidepressant use, and medication overuse in migraine treatment.

Acute Treatment of Migraine.

OBJECTIVE: Most patients with migraine require acute treatment for at least some attacks. This article reviews the approach to the acute treatment of migraine, migraine-specific and nonspecific treatment options, rescue treatment and options for management in the emergency department and inpatient settings, and treatment during pregnancy and lactation. LATEST DEVELOPMENTS: Triptans, ergot derivatives, and nonsteroidal anti-inflammatory drugs have historically been the main acute treatments for migraine. The development of new classes of acute treatment, including the small-molecule calcitonin gene-related peptide receptor antagonists (gepants) and a 5-HT1F receptor agonist (lasmiditan), expands available options. These new treatments have not been associated with vasospasm or increased cardiovascular risk, therefore allowing migraine-specific acute treatment for the more than 20% of adults with migraine who are at increased risk of cardiovascular events. Neuromodulation offers a nonpharmacologic option for acute treatment, with the strongest evidence for remote electrical neuromodulation. ESSENTIAL POINTS: The number of available migraine treatments continues to expand, although triptans are still the mainstay of migraine-specific acute treatment. There is no one-size-fits-all acute treatment and multiple treatment trials are sometimes necessary to determine the optimal regimen for patients. Switching within and between classes, using the maximum allowed dose, using combination therapy, and counseling patients to treat early are all strategies that may improve patient response to acute treatment.

Healthcare resource utilization and associated costs among patients with migraine in Finland: A retrospective register-based study.

Migraine is a common chronic brain disorder, characterized by recurring and often disabling attacks of severe headache, with additional symptoms such as photophobia, phonophobia and nausea. Migraine affects especially the working age population. The objective of this retrospective observational register-based study was to analyze the use of healthcare services and associated costs in Finnish migraine patients. Study was based on aggregate data from January 1st, 2020, to December 31st, 2021, from the Finnish Institute for Health and Welfare's national registries. Patients were grouped into nine patient groups according to medication prescriptions and diagnoses. Healthcare resource utilization in specialty, primary, and occupational healthcare was assessed and analyzed separately for all-cause and migraine related healthcare contacts from a one-year period. The total number of patients was 175 711, and most (45%) of the patients belonged to a group that had used only one triptan. Migraine related total healthcare resource utilization was greater for patients that had used two or more triptans compared to those that had used only one. The patients with three or more preventive medications had the highest total migraine related healthcare resource utilization of the studied patient cohorts. Of the total annual healthcare costs 11.5% (50.6 million €) was associated to be migraine related costs. Total per patient per year healthcare costs were highest with patients that had used three or more preventive medications (5 626 €) and lowest in those with only one triptan (2 257 €). Our findings are in line with the recent European Headache Federation consensus statement regarding the unmet need in patients who have had inadequate response to two or more triptans. When assessing the patient access and cost-effectiveness of novel treatments for the treatment of migraine within different healthcare systems, a holistic analysis of the current disease burden along with potential gains for patients and healthcare service providers are essential information in guiding decision-making.

Menstrually associated migraine.

Menstrually related migraine is a disabling condition affecting 35% to 54% females with migraine during their fertile years. The International Headache Classification distinguishes menstrually related migraine from pure menstrual migraine based on the occurrence of the attacks even outside the perimenstrual periods. Hormonal fluctuations are the main driver for the disease in subjects with genetic susceptibility and alterations of brain structures and connectivity. Menstrually related attacks are often particularly severe and disabling requiring proper management. Acute treatment mainly consists of nonsteroidal anti-inflammatory drugs (NSAIDs), recommended in patients also suffering from dysmenorrhea, and triptans. Prevention is specifically indicated in women with high monthly headache frequency or burdensome attacks during perimenstrual periods. Trials proved the efficacy of short-term prevention with triptans and NSAIDs but did not evaluate possible long-term effectiveness and tolerability. Evidence of prevention using hormonal treatments is poor, but extended-cycle treatments might be suitable for women requiring hormonal replacement for concomitant conditions. Few data are available on treatments targeting CGRP, among whom gepants are the most promising because of their utility both in migraine acute and preventive treatment. A greater recognition of disease and a deep knowledge of patients' comorbidities are essential to its proper management.

Update on gepants for the treatment of chronic migraine.

Chronic migraine (CM) is a profoundly debilitating condition that has detrimental clinical and social outcomes. Over the past two decades, novel small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, known as gepants, and CGRP monoclonal antibodies (mAbs) have been developed, ushering in a new era of migraine-specific treatment. In this review, we discuss the literature investigating the role of gepants for the treatment of CM. Numerous completed and ongoing clinical studies have conclusively demonstrated the safety, tolerability, and efficacy of several gepants for the acute treatment of migraine. However, preventive trials involving gepants have focused on patients with episodic migraine, with atogepant being the only gepant approved for CM prevention by the US Food and Drug Administration at the time of writing. Although some preliminary positive results have been reported, further research is still required to achieve additional advancements in the future. In summary, the effectiveness of gepants for treating individuals with CM are highly expected. This review highlights the development and current progress of gepants for the treatment of CM, focusing both on their role as acute abortive agents and preventive measures and on their concomitant use with other antimigraine medications, such as CGRP mAbs or triptans.

The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans.

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects.

5-HT1F agonists.

5-Hydroxytryptamine (HT)/serotonin receptor agonism has been a long-recognized property of triptan medications, and more recently, the study and development of medications with selective binding to the 1F receptor subtype have been explored. While the exact mechanism contributing to decreased symptoms of an acute migraine attack remains unclear, selective 5-HT1F agonists have demonstrated clinical efficacy with lasmiditan as the only approved medication from this class to date. Lasmiditan lacks vasoconstrictive properties, giving it utility in specific patient populations in whom triptans should be avoided. Availability, central nervous system (CNS) side effects, and 8-hour driving restriction may affect its clinical use.

Oxidative tryptamine dimers from Corynebacterium durum directly target survivin to induce AIF-mediated apoptosis in cancer cells.

Accumulating evidence indicates that microbial communities in the human body crucially affect health through the production of chemical messengers. However, the relationship between human microbiota and cancer has been underexplored. As a result of a biochemical investigation of the commensal oral microbe, Corynebacterium durum, we identified the non-enzymatic transformation of tryptamine into an anticancer compound, durumamide A (1). The structure of 1 was determined using LC-MS and NMR data analysis as bis(indolyl)glyoxylamide, which was confirmed using one-pot synthesis and X-ray crystallographic analysis, suggesting that 1 is an oxidative dimer of tryptamine. Compound 1 displayed cytotoxic activity against various cancer cell lines with IC50 values ranging from 25 to 35 µM. A drug affinity responsive target stability assay revealed that survivin is the direct target protein responsible for the anticancer effect of 1, which subsequently induces apoptosis-inducing factor (AIF)-mediated apoptosis. Inspired by the chemical structure and bioactivity of 1, a new derivative, durumamide B (2), was synthesized using another indole-based neurotransmitter, serotonin. The anticancer properties of 2 were similar to those of 1; however, it was less active. These findings reinforce the notion of human microbiota-host interplay by showing that 1 is naturally produced from the human microbial metabolite, tryptamine, which protects the host against cancer.

Clinical guidance for choosing the right pharmacotherapy for migraine attacks.

INTRODUCTION: Migraine as headache attacks with autonomic symptoms is a serious condition and it is important to treat a single attack effectively in order to improve not only the patient's quality of life at a given moment but also to prevent the migraine from becoming a chronic one. AREA COVERED: The article briefly presents the guidance in selecting the most appropriate pharmacological treatment of migraine attack, indicating a personalized approach to migraine patient. EXPERT OPINION: In this short paper, we show the implementation of new drugs into everyday clinical practice. Good cooperation between the physician and the patient and having the patient's trust is one of the elements of a personalized therapeutic approach and the key to achieving satisfaction of both the patient and the doctor.

Treatment patterns and characteristics of headache in patients in Japan: A retrospective cross-sectional and longitudinal analysis of health insurance claims data.

BACKGROUND: The present study aimed to investigate prescription patterns for patients aged over 17 years with headaches in the REZULT database. METHODS: We conducted a cross-sectional study (Study 1) of the proportion of over-prescription of acute medications (≥30 tablets/90 days for triptans, combination non-steroidal anti-inflammatory drugs (NSAIDs) and multiple types; ≥45 tablets/90 days for single NSAIDs) among patients with headache diagnosed in 2020. We longitudinally studied (Study 2) patients for >2 years from initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache was diagnosed in 200,055 of 3,638,125 (5.5%) patients: 13,651/200,055 (6.8%) received acute medication. Single NSAIDs were prescribed to 12,297/13,651 (90.1%) patients and triptans to 1710/13,651 (12.5%). Over-prescription was found in 2262/13,651 (16.6%) patients and 1200/13,651 (8.8%) patients received prophylactic medication. In Study 2, 408,183/6,840,618 (6.0%) patients were first diagnosed with headaches, which persisted for ≥2 years. Over time, the proportion of patients over-prescribed acute medications increased. Over 2 years, 37,617/408,183 (9.2%) patients were over-prescribed acute medications and 29,313/408,183 (7.2%) patients were prescribed prophylaxis at least once. CONCLUSIONS: According to real-world data, prophylaxis remains poorly prescribed, and both acute and prophylactic treatment rates for headaches have increased over time.

Comparative retention and effectiveness of migraine preventive treatments: A nationwide registry-based cohort study.

BACKGROUND AND PURPOSE: Little is known about the comparative effects of migraine preventive drugs. We aimed to estimate treatment retention and effectiveness of migraine preventive drugs in a nationwide registry-based cohort study in Norway between 2010 and 2020. METHODS: We assessed retention, defined as the number of uninterrupted treatment days, and effectiveness, defined as the reduction in filled triptan prescriptions during four 90-day periods after the first preventive prescription, compared to a 90-day baseline period. We compared retention and efficacy for different drugs against beta blockers. Comparative retention was estimated with hazard ratios (HRs), adjusted for covariates, using Cox regression, and effectiveness as odds ratios (ORs) using logistic regression, with propensity-weighted adjustment for covariates. RESULTS: We identified 104,072 migraine patients, 81,890 of whom were female (78.69%) and whose mean (standard deviation) age was 44.60 (15.61) years. Compared to beta blockers, botulinum toxin (HR 0.43, 95% confidence interval [CI] 0.42-0.44) and calcitonin gene-related peptide pathway antibodies (CGRPabs; HR 0.63, 95% CI 0.59-0.66) were the least likely to be discontinued, while clonidine (HR 2.95, 95% CI 2.88-3.02) and topiramate (HR 1.34, 95% CI 1.31-1.37) were the most likely to be discontinued. Patients on simvastatin, CGRPabs, and amitriptyline were more likely to achieve a clinically significant reduction in triptan use during the first 90 days of treatment, with propensity score-adjusted ORs of 1.28 (95% CI 1.19-1.38), 1.23 (95% CI 0.79-1.90), and 1.13 (95% CI 1.08-1.17), respectively. CONCLUSIONS: We found a favorable effect of CGRPabs, amitriptyline, and simvastatin compared with beta blockers, while topiramate and clonidine were associated with poorer outcomes.

The history and rationale of the development of new drugs for migraine treatment.

Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers,: flunarizine,: valproic acid,: topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.

A migrânea é uma das doenças mais prevalentes e incapacitantes do mundo. O tratamento da crise de migrânea e o tratamento profilático da doença são essenciais para diminuir o seu impacto individual, social e econômico. Este é um artigo de revisão narrativa. Revisamos as principais drogas usadas para a migrânea e os modelos experimentais e referenciais teóricos que levaram ao seu desenvolvimento. Foram abordados os derivados do ergot, triptanas, anti-inflamatórios não hormonais, antidepressivos tricíclicos, betabloqueadores, flunarizina, ácido valproico, topiramato, toxina onabotulínica do tipo A, os ditans, anticorpos monoclonais contra o CGRP e seu receptor e os gepants. Também foram abordados possíveis alvos terapêuticos para o desenvolvimento de novas drogas e drogas que estão em desenvolvimento para o tratamento da migrânea. Muitas das drogas usadas atualmente foram desenvolvidas para o tratamento de outras doenças e se mostraram efetivas para o tratamento da migrânea. Essas ajudaram a ampliar o conhecimento sobre a doença. Com o melhor entendimento da fisiopatologia da migrânea, novas drogas foram e estão sendo desenvolvidas especificamente para o tratamento dessa doença.

Simultaneous Comparisons of 25 Acute Migraine Medications Based on 10 Million Users' Self-Reported Records From a Smartphone Application.

BACKGROUND AND OBJECTIVES: Many acute treatment options exist for migraine. However, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking. METHODS: This is a retrospective analysis of 10,842,795 migraine attack records extracted from an e-diary smartphone application between June 30, 2014, and July 2, 2020. We analyzed 25 acute medications among 7 classes-acetaminophen, nonsteroid anti-inflammatory drugs (NSAIDs), triptans, combination analgesics, ergots, antiemetics, and opioids. Gepants and ditan were not included in this analysis. Different doses and formulations of each medication, according to the generic names, were combined in this analysis. We used a 2-level nested logistic regression model to analyze the odds ratio (OR) of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user. Subgroup analyses were conducted for users in the United States, the United Kingdom, and Canada. RESULTS: Our final analysis included 4,777,524 medication-outcome pairs from 3,119,517 migraine attacks among 278,006 users. Triptans (mean OR 4.8), ergots (mean OR 3.02), and antiemetics (mean OR 2.67) were the top 3 classes of medications with the highest effectiveness, followed by opioids (mean OR 2.49), NSAIDs (other than ibuprofen, mean OR 1.94), combination analgesics (acetaminophen/acetylsalicylic acid/caffeine) (OR 1.69, 95% CI 1.67-1.71), others (OR 1.49, 95% CI 1.47-1.50), and acetaminophen (OR 0.83, 95% CI 0.83-0.84), using ibuprofen as the reference. Individual medications with the highest ORs were eletriptan (OR 6.1, 95% CI 6.0-6.3), zolmitriptan (OR 5.7, 95% CI 5.6-5.8), and sumatriptan (OR 5.2, 95% CI 5.2-5.3). The ORs of acetaminophen, NSAIDS, combination analgesics, and opioids were mostly around or less than 1, suggesting similar or lower reported effectiveness compared with ibuprofen. The ORs for 24 medications, except that of acetylsalicylic acid, achieved statistical significance with p < 0.0001, and our nested logistic regression model achieved an area under the curve (AUC) of 0.849. Country-specific subgroup analyses revealed similar ORs of each medication and AUC (United States 0.849, United Kingdom 0.864, and Canada 0.842), demonstrating the robustness of our analysis. DISCUSSION: Using a big data approach, we analyzed patient-generated real-time records of 10 million migraine attacks and conducted simultaneous head-to-head comparisons of 25 acute migraine medications. Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with migraine, selected acute medications (e.g., triptans, ergots, antiemetics) are associated with higher odds of user-rated positive response than ibuprofen.

[Sumatriptan-naproxen sodium fix-dose combination for acute migraine treatment, a review]. / Szumatriptán­naproxén-nátrium fix dózisú kombinációja a migrén akut kezelésében ­ irodalmi áttekintés.

Migraine as a common primary headache disorder has a significant negative effect on quality of life of the patients. Its pharmacotreatment includes acute and preventative therapies. Based on the shared therapeutic guideline of the European Headache Federation and the European Academy of Neurology for acute migraine treatment a combination of triptans and non-steroidal anti-inflammatory drugs is recommended for acute migraine treatment in triptan-nonresponders. In this short review we summarized the results of the randomized controlled clinical trials evaluating the effectiveness and safety of sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination. It was revealed that the fix-dose combination was better than placebo for the primary outcomes of exemption of pain and headache relief at 2 hours. Furthermore the combination showed beneficial effect on accompanying symptoms of migraine attack (i.e. nausea, photo- and phonophobia). Adverse events were mild or moderate in severity and rarely led to withdrawal of the drug.
It can be concluded that sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination is effective, safe and well-tolerated in the acute treatment of migraine. 

Triptan non-response in specialized headache care: cross-sectional data from the DMKG Headache Registry.

BACKGROUND: Triptans are effective for many migraine patients, but some do not experience adequate efficacy and tolerability. The European Headache Federation (EHF) has proposed that patients with lack of efficacy and/or tolerability of ≥ 2 triptans ('triptan resistance') could be considered eligible for treatment with the novel medications from the ditan and gepant groups. There is little data on the frequency of 'triptan resistance'. METHODS: We used patient self-report data from the German Migraine and Headache Society (DMKG) Headache Registry to assess triptan response and triptan efficacy and/or tolerability failure. RESULTS: A total of 2284 adult migraine patients (females: 85.4%, age: 39.4 ± 12.8 years) were included. 42.5% (n = 970) had failed ≥ 1 triptan, 13.1% (n = 300) had failed ≥ 2 triptans (meeting the EHF definition of 'triptan resistance'), and 3.9% (n = 88) had failed ≥ 3 triptans. Compared to triptan responders (current use, no failure, n = 597), triptan non-responders had significantly more severe migraine (higher frequency (p < 0.001), intensity (p < 0.05), and disability (p < 0.001)), that further increased with the level of triptan failure. Responders rates were highest for nasal and oral zolmitriptan, oral eletriptan and subcutaneous sumatriptan. CONCLUSION: In the present setting (specialized headache care in Germany), 13.1% of the patients had failed ≥ 2 triptans. Triptan failure was associated with increased migraine severity and disability, emphasizing the importance of establishing an effective and tolerable acute migraine medication. Acute treatment optimization might include switching to one of the triptans with the highest responder rates and/or to a different acute medication class. TRIAL REGISTRATION: The DMKG Headache Registry is registered with the German Clinical Trials Register (DRKS 00021081).

Tryptamine: A privileged scaffold for the management of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disease associated with aging. It is characterized by the progressive loss of memory and other cognitive functions. Although the exact etiology of AD is not well explored, several factors, such as the deposition of amyloid-ß (Aß) plaques, hyperphosphorylation of tau protein, presence of low levels of acetylcholine, and generation of oxidative stress, are key mediators in the progression of AD. Currently, the clinical treatment options for AD are limited and are based on cholinesterase (ChE) inhibitors (e.g., donepezil, rivastigmine, and galantamine), N-methyl- d-aspartic acid receptor antagonists (e.g., memantine), and the recently approved Aß modulator (e.g., aducanumab). Tryptamine (2-(1H-indol-3-yl)ethan-1-amine) is a small molecule that contains an indole nucleus and an ethylamine side chain. It is also the active metabolite of tryptophan. It possesses a wide range of biological activities related to neurodegenerative disorders, such as ChE inhibition, Aß aggregation inhibition, antioxidant effects, monoamine-oxidase inhibition, and neuroprotection. Several tryptamine-based hybrid analogs are currently being investigated as multifunctional agents for the development of novel hybrids for AD treatment. Thus, this review article aims to provide in-depth insights into the research progress and strategies for designing multifunctional agents used in Alzheimer's therapy.

Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article.

AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.

Towards precision medicine in migraine: Recent therapeutic advances and potential biomarkers to understand heterogeneity and treatment response.

After 35 years since the introduction of the International Classification of Headache Disorders (ICHD), we are living in the era of the second great revolution in migraine therapies. First, discoveries of triptans provided a breakthrough in acute migraine treatment utilizing bench-to-bedside research results on the role of serotonin in migraine. Next, the discovery of the role of neuropeptides, more specifically calcitonin gene-related peptide (CGRP) in migraine attack led to the development of anti-CGRP therapies that are effective both in acute and preventive treatment, and are also able to reduce migraine-related burden. Here, we reviewed the most recent clinical studies and real-world data on available migraine-specific medications, including triptans, ditants, gepants and anti-CGRP monoclonal antibodies. Novel drug targets, such as PACAP and amylins were also discussed. To address the main challenges of migraine therapy, the high heterogeneity of people with migraine, the prevalent presence of various comorbid disorders, and the insufficient medical care of migraine patients were covered. Promising novel approaches from the fields of omics, blood and saliva biomarker, imaging and provocation studies might bring solutions for these challenges with the potential to identify further drug targets, distinguish more homogeneous patient subgroups, contribute to more optimal drug selection strategies, and detect biomarkers in association with headache features or predicting treatment efficacy. In the future, the combined analysis of data of different biomarker modalities with machine learning algorithms may serve precision medicine in migraine treatment.

Multi-omic analyses of triptan-treated migraine attacks gives insight into molecular mechanisms.

Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.