Most of the about 30 clinically approved antiseizure medications (ASMs) have been discovered using animal seizure models. Thus, such models are commonly considered highly predictive of clinical antiseizure efficacy. However, this has recently been questioned by the apparent dichotomy in clinical antiseizure efficacy between the novel ASMs padsevonil and the alkyl-carbamate cenobamate, both of which were highly potent in a battery of acute and chronic rodent models. In this review, we analyze and compare the preclinical and clinical data for cenobamate and padsevonil, along with their proposed mechanisms of action, to identify differences between the two drugs that might have predicted the contrasting clinical outcome, as well as another alkyl-carbamate, carisbamate, which was highly effective in preclinical models but failed in clinical trials. While padsevonil was more potent than cenobamate and carisbamate in suppressing seizures in most acute and chronic animal models, an important difference was observed in the amygdala kindling model of focal epilepsy. Cenobamate suppressed both focal and secondary generalized convulsive seizures, whereas padsevonil was less effective against focal versus generalized seizures, and carisbamate was only partially effectivein amygdala kindled rats. Padsevonil was developed in a target-based, rational drug design program that combined high affinity for synaptic vesicle glycoprotein 2 (SV2) with moderate affinity at the benzodiazepine binding site of the GABAA receptor, presuming that effects at these two targets would lead to a synergistic increase in antiseizure activity. However, it failed in human trials. In contrast, cenobamate, which was discovered by a chemocentric approach and phenotypic screening, exerted impressive clinical efficacy with a high rate of seizure freedom. The amygdala kindled rat was the only preclinical model that correctly predicted the successful and unsuccessful outcomes of clinical development of cenobamate, carisbamate, and padsevonil. Hopefully, the present analysis of three ASM discovery programs with largely diverging clinical outcomes will help to better understand the complexity and challenges of ASM development.

Risperidone has modest efficacy for behaviours and psychological symptoms of dementia and is associated with many adverse events. Current guidelines limit its use to no longer than 12-16 weeks. This study aims to evaluate adverse outcomes over time, identify key predictors, and examine high-risk subgroups to inform safer prescribing. A one-stage individual participant data meta-analysis of six randomised controlled trials (risperidone: n = 1009; placebo: n = 712) was conducted. Mixed-effect generalised linear models and proportional hazards mixed-effects models estimated treatment effects, predictors, and subgroup differences for adverse outcomes over varying time periods. Risperidone was associated with increased risks of cerebrovascular (hazard ratio [HR] 4.11; 95% confidence interval [CI] 1.77-9.51; p = 0.001) and major cardiovascular events (HR 2.00; 95% CI 1.23-3.26; p = 0.006), with median (interquartile range) onset at 4.3 (5.9) and 4.8 (6.8) weeks of treatment, respectively. Somnolence occurred consistently during treatment, whereas upper respiratory tract infections (odds ratio [OR] 2.31; 95% CI 1.24-4.32; p = 0.009) and extrapyramidal symptoms emerged (OR 2.93; 95% CI 1.68-5.08; p < 0.001) after week 4. Older age, male sex, and baseline cardiac pharmacotherapy use predicted serious adverse outcomes. Most adverse effects occur after 4 weeks of treatment. Attention to baseline risk factors is essential to minimise harm. Risk-benefit calculators may guide individualised prescribing.

The Argatroban Plus Recombinant Tissue-Type Plasminogen Activator for Acute Ischemic Stroke (ARAIS) trial did not show the benefit of argatroban as an adjunct in patients with acute ischemic stroke who received intravenous alteplase. This post hoc exploratory analysis aimed to determine whether the circadian rhythm can affect the efficacy of argatroban as an adjunct in this population. From the per-protocol population of the ARAIS trial, patients were divided into 2 groups based on the beginning time of intravenous thrombolysis: daytime (06:00-17:59) and nighttime (18:00-05:59) groups. Each group was divided into argatroban plus alteplase and alteplase alone groups. The primary outcome was excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days. The safety outcome was symptomatic intracerebral hemorrhage (sICH). Among 692 patients from the per-protocol analysis, 489 were in the daytime group, and 203 in the nighttime group. In the daytime group, the proportion of patients with an excellent functional outcome was 60.5% (144/238) in the argatroban plus alteplase group versus 66.9% (168/251) in the alteplase-alone group, respectively, without significant difference between two groups (adjusted odds ratio [aOR] = 1.19; 95% CI 0.80-1.78; p = 0.40). In the nighttime group, argatroban plus alteplase was significantly associated with higher proportion of excellent functional outcome compared with alteplase alone (75.9% vs 60.3%; aOR = 0.47; 95% CI 0.24-0.93; p = 0.03). An interaction effect was found between intervention (argatroban plus alteplase or alteplase only) by different treatment period on primary outcome (P for interaction = 0.02). For safety outcomes, no significant differences in sICH rates were observed between treatment groups within either time stratum. This is the first report that suggested a potential association between argatroban and a higher rate of excellent functional outcome in patients with acute ischemic stroke who received intravenous alteplase during the nighttime. This finding requires further validation in future studies. ClinicalTrials.gov Identifier: NCT03740958.

Evidence directly comparing ocrelizumab (OCR) and ofatumumab (OFA) after sphingosine-1-phosphate receptor modulators (S1PRMs) withdrawal is limited, even though this transition period carries an increased risk of disease reactivation and the two anti-CD20 agents differ in molecular properties that may influence post-S1PRM outcomes. We compared effectiveness, safety, and tolerability of OFA versus OCR in relapsing-remitting multiple sclerosis (RRMS) after S1PRM therapy. We retrospectively analyzed adult (> 18 years) patients with RRMS from 23 Italian centers who switched from S1PRMs to OCR or OFA (October 2016 to July 2024). Clinical outcomes included annualized relapse rate (ARR), cumulative relapse incidence, confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), and variation in the expanded disability status scale score (ΔEDSS) from baseline to last follow-up. Magnetic resonance imaging (MRI) outcomes included time to overall MRI activity, new/enlarging T2 lesions, and new T1 Gd-enhancing lesions. Persistence on anti-CD20 and safety were also assessed. We applied inverse probability of treatment weighting (IPTW) to balance baseline covariates, and used Cox, Andersen-Gill, and regression models, further adjusted for variables with residual imbalance, to compare outcomes. We included 225 subjects (mean age 43.3 ± 10.6 years; OCR = 131, OFA = 94), with a median follow-up of 33 months. After IPTW, groups were well balanced. Compared with OCR, OFA was associated with lower ARR (adjusted relative risk [aRR] 0.22, 95% CI 0.06-0.86, p = 0.030) and relapse hazard (adjusted hazard ratio [aHR] 0.21, 95% CI 0.05-0.83, p = 0.026). When restricting washout to ≤ 10 weeks and applying spline-based Andersen-Gill models, results remained consistent, with OFA showing a lower relapse risk than OCR across short-to-intermediate washout intervals. CDP hazard was lower (aHR 0.38, 95% CI 0.15-0.94, p = 0.038), while PIRA and CDI did not differ. ΔEDSS favored OFA (adjusted mean difference [aMD] -0.26, 95% CI -0.51 to -0.02, p = 0.046). OFA showed a lower hazard of overall MRI activity (aHR 0.41, 95% CI 0.19-0.92, p = 0.030), with similar risk for new T1 Gd+ lesions. A sensitivity analysis restricted to patients who switched to OFA or OCR during the same availability window yielded results consistent with the primary analysis. Treatment persistence was shorter on OFA, but absolute discontinuation rates were low in both groups. Severe AEs were rare and did not differ. In S1PRM-exposed RRMS, OFA was associated with reduced relapse risk, disability accumulation, EDSS worsening, and MRI activity compared with OCR, with overall good tolerability and safety.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disorder affecting the central nervous system, often misdiagnosed as multiple sclerosis. The identification of aquaporin-4-IgG (AQP4-IgG) has improved diagnostic precision and enabled targeted therapies. Given the unique regional challenges in healthcare delivery across the Middle East and North Africa (MENA) region, the Middle East and North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) convened an expert panel to develop evidence-based, region-specific consensus recommendations for diagnosis and management. These guidelines endorse the 2015 International Panel for NMO Diagnosis (IPND) criteria, emphasizing AQP4-IgG testing via cell-based assays. Differential diagnosis should consider multiple sclerosis, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and acute disseminated encephalomyelitis (ADEM). For acute treatment: initiate high-dose intravenous methylprednisolone promptly and use plasma exchange early for severe or steroid-refractory attacks. For long-term immunotherapy, monoclonal antibodies (rituximab, inebilizumab, eculizumab, ravulizumab, satralizumab, or tocilizumab) are recommended according to availability and patient factors; conventional immunosuppressants remain alternatives when biologics are inaccessible. Guidance is provided for pediatric patients and for pregnancy and breastfeeding, including planning after ≥ 12 months of disease stability and early postpartum treatment resumption. These MENACTRIMS guidelines aim to improve NMOSD outcomes across the region by promoting accurate diagnosis and timely, effective therapy.

Monoamine oxidase inhibitors (MAOIs) remain an important option for patients with treatment-resistant depression (TRD) and other psychiatric conditions, despite potentially serious drug-drug interactions and associated dietary tyramine restrictions. However, they are rarely prescribed in patients with comorbid substance use disorders (SUDs) due to concerns about potential drug interactions and limited research in these populations. This narrative review investigates the use of MAOIs in patients who use psychoactive substances, exploring potential interactions while summarizing the relatively scant literature on using MAOIs as treatments for SUDs. It synthesizes data from 219 peer-reviewed publications investigating MAOI/psychoactive substance interactions or the use of MAOIs to treat SUDs or psychiatric conditions in patients with comorbid SUDs, including 20 randomized controlled trials, 18 non-randomized interventional trials, 32 observational studies/case series, 56 case reports, 85 preclinical studies, and 8 reviews, with publication years spanning from 1955 to 2025. Data from 28 non-peer-reviewed user-submitted reports from drug use/harm reduction forums are also included. Suspected cases of serotonin toxicity have been reported for MAOIs in combination with amphetamine, dextromethorphan, 3,4-methylenedioxymethamphetamine (MDMA), meperidine (pethidine), methadone, and tramadol. Hypertensive urgency/emergency has been reported for MAOIs in combination with alcohol (varieties containing significant amounts of tyramine), amphetamine, cocaine, dextroamphetamine, khat, methamphetamine, and psilocybin mushrooms. Other notable adverse events associated with MAOIs in combination with psychoactive substances include agitation (4-bromo-2,5-dimethoxyphenethylamine [2C-B] 5-methoxy-N,N-dimethyltryptamine [5-Meo-DMT]), N,N-dimethyltryptamine [DMT]), delirium/confusion (DMT, propoxyphene, and tramadol), edema (chlordiazepoxide), intracranial hemorrhage (amphetamine, khat, and methamphetamine), mania/psychosis (DMT), rhabdomyolysis (5-MeO-DMT, DMT, and propoxyphene), and sedation/stupor/loss of consciousness (amobarbital, amphetamine, cocaine, dextroamphetamine, and propoxyphene). Fatalities have been reported for MAOIs in combination with 5-MeO-DMT, amphetamine, dextroamphetamine, dextromethorphan (in overdose), MDMA, methamphetamine, meperidine, and tramadol (in overdose). Based on our findings, some substances, such as alcoholic beverages containing significant tyramine quantities (uncommon today), amphetamines, opioids with significant serotonergic reuptake inhibition, and some hallucinogens such as the empathogen/entactogen MDMA, can pose potentially fatal risks in combination with MAOIs. However, MAOI treatment of patients who use alcoholic beverages low in tyramine, caffeine, cannabis, nicotine, sedatives, some (primarily classic) hallucinogens, and some other substances can likely be appropriately managed with careful monitoring, although psychoactive substance dose and route of administration are important safety considerations. While there was initially hope MAOIs might effectively treat some SUDs, there are no robust human data to support their efficacy in this context. Given growing levels of substance use and an increasing number of novel illicit compounds being produced, more research on MAOI safety in patients with psychiatric conditions and comorbid psychoactive substance use/misuse is essential to determining their appropriateness in this complex patient population.

Bipolar disorder affects approximately 40 million individuals worldwide, with depression being the most prominent phase of the illness. Owing to limited treatment options, bipolar depression remains a major public health concern, often causing significant functional impairment and increased suicide risk. Current therapies frequently lack rapid effectiveness, highlighting the need for novel approaches. Psilocybin, a psychedelic compound receiving growing interest for its potential rapid antidepressant effects, is under investigation in clinical trials combined with psychotherapy. Early studies in bipolar II disorder (n = 19) show encouraging results, but evidence is still limited, and important safety concerns such as affective switching and pharmacokinetic interactions persist. Additional challenges include regulatory restrictions, infrastructure demands, and uncertainties about the role of the psychedelic experience, especially given possible interference by common bipolar medications. Cautious, rigorous research is essential to determine psilocybin's safety, efficacy, and practical application in bipolar depression, particularly for bipolar I disorder and long-term outcomes.