OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs).
BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs.
METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days.
RESULTS: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen\'s d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen\'s d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86]).
CONCLUSIONS: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment.

Eptinezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), was recently approved in Europe for the prophylactic treatment of migraine in adults who have at least four migraine days a month. Eptinezumab is administered by intravenous infusion every 12 weeks. During recent months, a considerable amount of evidence from eptinezumab trials has been published. The aim of this review is to describe the existing evidence on the tolerability, safety and efficacy of eptinezumab in patients with migraine. Data from randomized (PROMISE-1, PROMISE-2, RELIEF and DELIVER) and open-label (PREVAIL) phase 3 clinical trials have demonstrated the favorable effect of eptinezumab in migraine symptoms from first day of treatment. These studies showed that eptinezumab results in an overall reduction in mean monthly migraine days (MMDs), increases in the ≥50% and ≥ 75% migraine responder rates (MRRs) and improvements in patient-reported outcome measures in both patients with episodic migraine (EM) and with chronic migraine (CM), including patients who failed previous preventive treatments. The RELIEF trial also showed that eptinezumab, within 2 h of administration, reduced headache pain, migraine-associated symptoms and acute medication use when administered during a migraine attack. Eptinezumab benefits manifested as early as day 1 after dosing and with the subsequent doses lasted up to at least 2 years. Treatment-emergent adverse events reported by ≥2% of patients included upper respiratory tract infection and fatigue. Current evidence demonstrates that eptinezumab has a potent, fast-acting, sustained migraine preventive effect in patients with EM and CM. Eptinezumab has also shown to be well tolerated, supporting its use in the treatment of patients with migraine and inclusion in the current migraine therapeutic options.

The current article reviews the latest information on epidemiology, clinical features, diagnosis, recent advancements in clinical management, current therapeutic novelties, and the prevention of migraines. In a narrative review, all studies as per developed MeSH terms published until February 2023, excluding those irrelevant, were identified through a PubMed literature search.
Overall, migraine affects more than a billion people annually and is one of the most common neurological illnesses. A wide range of comorbidities is associated with migraines, including stress and sleep disturbances. To lower the worldwide burden of migraine, comprehensive efforts are required to develop and enhance migraine treatment, which is supported by informed healthcare policy. Numerous migraine therapies have been successful, but not all patients benefit from them.
CGRP pathway-targeted therapy demonstrates the importance of translating mechanistic understanding into effective treatment. In this review, we discuss clinical features, diagnosis, and recently approved drugs, as well as a number of potential therapeutic targets, including pituitary adenylate cyclase-activating polypeptide (PACAP), adenosine, opioid receptors, potassium channels, transient receptor potential ion channels (TRP), and acid-sensing ion channels (ASIC).
In addition to providing more treatment options for improved clinical care, a better understanding of these mechanisms facilitates the discovery of novel therapeutic targets.

Objectives: We compared and ranked the efficacy and tolerability of multiple prophylactic treatments for vestibular migraine (VM), including β-blockers, calcium channel blockers, antiseizure medications, and antidepressants such as tricyclics and serotonin-noradrenaline reuptake inhibitors. Methods: PubMed, Web of Science, Embase, and Cochrane Center for Clinical Trials were systematically searched for relevant randomized clinical trials (RCTs) from March 2023 to May 2023. Studies on the efficacy and tolerability of prophylactic treatments for VM were included. Efficacy was measured using the average vertigo frequency per month and dizziness handicap inventory (DHI) improvement after 3-6 months of treatment. Tolerability was measured by the number of patients reporting at least one adverse event (AE). Network meta-analyses were performed according to a Bayesian framework and a random-effects model based on odds ratios or mean differences (MDs) and 95% confidence intervals (CIs). A sequence of ranking probability was calculated according to the surface under the cumulative ranking (SUCRA) curve. This network meta-analysis was previously registered with PROSPERO (CRD42023422258). Results: Five RCTs comprising 334 patients were analyzed by synthesizing the published evidence. Considering the examined prophylactic therapies, there is significant evidence that valproate acid (VPA) is superior to placebo or abortive treatment alone (MD = -4.12, 95% CI = -8.09, -0.15) in reducing the frequency of vertigo. Flunarizine (MD = 20.00, 95% CI = 10.90, 29.10), valproate acid (MD = 18.88, 95% CI = 10.42, 27.34), and venlafaxine (MD = 11.48, 95% CI = 9.84, 13.12) were significantly more effective than placebo or abortive treatment in reducing DHI. VPA most strongly reduced the frequency of vertigo according to SUCRA, but it ranked third-to-last in tolerability. Flunarizine ranked best in DHI improvement but worst in tolerability. Metoprolol ranked worst for efficacy but best for tolerability. Conclusion: VPA and flunarizine reduced the frequency of vertigo and improved DHI, but they had unfavorable tolerability. The effects of metoprolol on vertigo require further study. Given the low certainty and limited sample, additional head-to-head RCTs are warranted to further confirm efficacy. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/; Identifier CRD42023422258.

BACKGROUND: Contacts of patients with multidrug-resistant tuberculosis (MDR-TB) are at risk of developing TB disease. Tuberculosis preventive treatment (TPT) is an intervention that can potentially reduce this risk.
OBJECTIVE: To evaluate the effectiveness and safety of TPT for contacts of patients with MDR-TB.
METHODS: EMBASE, PubMed, Web of Science, and the Cochrane Library were searched for eligible studies on 24 July 2023, without start date restrictions.
METHODS: We included studies that compared TPT with no treatment in contacts of patients with MDR-TB and reported outcomes of progression to TB disease.
METHODS: Contacts of patients with MDR-TB.
METHODS: TPT.
UNASSIGNED: A modified version of the Newcastle-Ottawa Scale was used.
UNASSIGNED: Random-effects meta-analysis was utilized to calculate the relative risk for disease progression to TB in contacts of patients with MDR-TB who received TPT compared to those who did not. Additionally, completion, adverse effect, and discontinued rates were assessed.
RESULTS: Involving 1105 individuals from 11 studies, the pooled relative risk for disease progression in contacts receiving TPT versus those without treatment was 0.34 (95% CI: 0.16-0.72). Subgroup analysis indicated a lower pooled relative risk for regimens based on the drug-resistance profile of the index patients with TB compared to uniform treatment regimens (0.22 [95% CI: 0.06-0.84] vs. 0.49 [95% CI: 0.17-1.35]), although not statistically significant. The pooled completed rate was 83.8%, adverse effect rate was 22.9%, and discontinued rate was 6.5%. After excluding the levofloxacin and pyrazinamide regimen study, the completed rate increased to 88.0%, and adverse effects and discontinued rates decreased to 8.0% and 4.0%, respectively.
CONCLUSIONS: TPT reduces TB disease progression risk in contacts of patients with MDR-TB. Tailored TPT regimens based on drug-resistance profiles may offer additional benefits. Furthermore, efforts to improve completed rates and manage adverse effects are essential for optimizing effectiveness and safety.

Post-stroke depression (PSD), one of the most common complications following stroke, affects approximately one-third of stroke patients and is significantly associated with increased disability and mortality as well as decreased quality of life, which makes it an important public health concern. Treatment of PSD significantly ameliorates depressive symptoms and improves the prognosis of stroke.
The authors discuss the critical aspects of the clinical application of prediction and preventive treatment of PSD. Then, the authors update the biological factors associated with the onset of PSD. Furthermore, they summarize the recent progress in pharmacological preventive treatment in clinical trials and propose potential treatment targets. The authors also discuss the current roadblocks in the preventive treatment of PSD. Finally, the authors put postulate potential directions for future studies so as to discover accurate predictors and provide individualized preventive treatment.
Sorting out high-risk PSD patients using reliable predictors will greatly assist PSD management. Indeed, some predictors not only predict the incidence of PSD but also predict prognosis, which indicates that they might also aid the development of an individualized treatment scheme. Preventive application of antidepressants may also be considered.

BACKGROUND: Migraine affects 1.1 billion people globally and is the second leading cause of disability worldwide. In clinical trials, treatment efficacy is evaluated by comparing the differential responses in the treatment and placebo arms. Although placebo response in preventive migraine trials has been studied, there is limited research examining temporal trends. This study evaluates the trend of placebo response over thirty years in migraine prevention trials and investigates the association of potential confounders, such as patient, treatment, and study characteristics on placebo response using meta-analysis with regression.
METHODS: We conducted literature searches from January 1990 to August 2021 in bibliographical databases (PubMed, Cochrane Library, and EMBASE). Studies were selected according to PICOS criteria and included randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adult patients diagnosed with episodic or chronic migraine, with or without aura. The protocol was registered with PROSPERO (CRD42021271732). Migraine efficacy outcomes included were either continuous (e.g., monthly migraine days) or dichotomous (e.g., ≥ 50% responder rate (yes/no)). We assessed the correlation of the change in outcome from baseline in the placebo arm, with the year of publication. The relationship between placebo response and year of publication was also assessed after accounting to confounders.
RESULTS: A total of 907 studies were identified, and 83 were found eligible. For the continuous outcomes, the change from baseline in mean placebo response showed an increase over the years (rho = 0.32, p = 0.006). The multivariable regression analysis also showed an overall increase in placebo response over the years. The correlation analysis of dichotomous responses showed no significant linear trend between publication year and mean placebo response (rho = 0.08, p = 0.596). Placebo response also varied by route of administration.
CONCLUSIONS: Placebo response increased over the past 30 years in migraine preventive trials. This phenomenon should be considered when designing clinical trials and conducting meta-analyses.

BACKGROUND: There is a need to identify alternative biomarkers to predict tuberculosis (TB) preventive treatment response because observing the incidence decline renders a long follow-up period.
METHODS: We searched PubMed, Embase and Web of Science up to 9 February 2023. The biomarker levels during preventive treatment were quantitatively summarized by means of meta-analysis using the random-effect model.
RESULTS: Eleven eligible studies, published during 2006-2022, were included in the meta-analysis, with frequently heterogeneous results. Twenty-six biomarkers or testing methods were identified regarding TB preventive treatment monitoring. The summarized standard mean differences of interferon-γ (INF-γ) were -1.44 (95% CI: -1.85, -1.03) among those who completed preventive treatment (τ2 = 0.21; I2 = 95.2%, p < 0.001) and -0.49 (95% CI: -1.05, 0.06) for those without preventive treatment (τ2 = 0.13; I2 = 82.0%, p < 0.001), respectively. Subgroup analysis showed that the INF-γ level after treatment decreased significantly from baseline among studies with high TB burden (-0.98, 95% CI: -1.21, -0.75) and among those with a history of Bacillus Calmette-Guérin vaccination (-0.87, 95% CI: -1.10, -0.63).
CONCLUSIONS: Our results suggested that decreased INF-γ was observed among those who completed preventive treatment but not in those without preventive treatment. Further studies are warranted to explore its value in preventive treatment monitoring due to limited available data and extensive between-study heterogeneity.

We conducted a systematic review examining the cost effectiveness of a 3-month course of isoniazid and rifapentine, known as 3HP, given by directly observed treatment, compared to 9 months of isoniazid that is directly observed or self-administered, for latent tuberculosis infection. 3HP has shown to be effective in reducing progression to active tuberculosis and like other short-course regimens, has higher treatment completion rates compared to standard regimens such as 9 months of isoniazid. Decision makers would benefit from knowing if the higher up-front costs of rifapentine and of the human resources needed for directly observed treatment are worth the investment for improved outcomes.
We searched PubMed, Embase, CINAHL, LILACS, and Web of Science up to February 2022 with search concepts combining latent tuberculosis infection, directly observed treatment, and cost or cost-effectiveness. Studies included were in English or French, on human subjects, with latent tuberculosis infection, provided information on specified anti-tubercular therapy regimens, had a directly observed treatment arm, and described outcomes with some cost or economic data. We excluded posters and abstracts, treatment for multiple drug resistant tuberculosis, and combined testing and treatment strategies. We then restricted our findings to studies examining directly-observed 3HP for comparison. The primary outcome was the cost and cost-effectiveness of directly-observed 3HP.
We identified 3 costing studies and 7 cost-effectiveness studies. The 3 costing studies compared directly-observed 3HP to directly-observed 9 months of isoniazid. Of the 7 cost-effectiveness studies, 4 were modelling studies based in high-income countries; one study was modelled on a high tuberculosis incidence population in the Canadian Arctic, using empiric costing data from that setting; and 2 studies were conducted in a low-income, high HIV-coinfection rate population. In five studies, directly-observed 3HP compared to self-administered isoniazid for 9 months in high-income countries, has incremental cost-effectiveness ratios that range from cost-saving to $5418 USD/QALY gained. While limited, existing evidence suggests 3HP may not be cost-effective in low-income, high HIV-coinfection settings.
Cost-effectiveness should continue to be assessed for programmatic planning and scale-up, and may vary depending on existing systems and local context, including prevalence rates and patient expectations and preferences.

BACKGROUND: Preventive treatment for refractory chronic cluster headache (rCCH) is challenging and many therapies have been tried.
OBJECTIVE: To study what could be considered the therapy of choice in rCCH through a systematic review and meta-analysis.
METHODS: This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in PROSPERO (ID CRD42021290983). A systematic search was performed in MEDLINE, Embase, Cochrane, clinicaltrials.gov, and the WHO\'s-International-Clinical-Trials-Registry-Platform. Studies on the preventive treatment for rCCH as defined by the European Headache Federation consensus statement were included. A meta-analysis of the pooled response rate was conducted for the different therapies.
RESULTS: Of 336 results, 45 were eligible for inclusion. Most articles studied the effect of neuromodulation as a preventive treatment for rCCH. The most studied neuromodulation technique was occipital nerve stimulation (ONS), with a pooled response rate in the meta-analysis of 57.3% (95% CI 0.481-0.665). Deep brain stimulation (DBS) was the second most studied treatment with a pooled response rate of 77.0% (95% CI 0.594-0.957). DBS results were more heterogeneous than ONS, which could be related to the different stimulation targets in DBS studies, and reported more serious adverse events than in ONS studies. The remaining therapies (anti-CGRP pathway drugs, warfarin, ketamine-magnesium infusions, serial occipital nerve blocks, clomiphene, onabotulinum toxin A, ketogenic diet, sphenopalatine ganglion radiofrequency or stimulation, vagus nerve stimulation, percutaneous bioelectric current stimulation, upper cervical cord stimulation, and vidian neurectomy) present weaker results or have less quality of evidence.
CONCLUSIONS: The results of this systematic review and meta-analysis suggest that ONS could be the first therapeutic strategy for patients with rCCH based on the current evidence.