Parkinson's disease (PD) is a heterogeneous, chronic neurodegenerative disorder. Once the diagnosis is made, symptomatic dopamine substituting therapy is initiated. This narrative review discusses exemplary past and recent failed attempts. The diagnosis of PD at the onset of motor symptoms is already late in terms of disease progression. An easy-to apply, reliable, sensitive diagnostic biomarker for predictive screening is currently outstanding. Nevertheless, the ability to delay progression and/or cure of the disease is currently the greatest unmet need. Chronic neurodegenerative processes arise from various distinct yet interconnected metabolic and pathological cascade sequences that work together. The translation of promising treatments concepts for beneficial disease modification has failed once they were tested in levodopa-naive patients. Microbiome alteration with short fatty acids or acetyl-DL-leucine supplementation, only enhance levodopa efficacy, But do not modify disease progression in a benefical way. Presently, there is also a lack of real innovation in terms of dopamine substitution. While sufficient symptomatic therapies for patients with Parkinson’s disease exist, the delay of progression or even better cure remains an unmet need. Experimental and neuropathological research provides extensive insights into the mechanisms of chronic neurodegeneration of dopamine generating neurons in the affected basal ganglia of the nigrostriatal system. Accordingly, concepts for disease modifying therapies have been developed and were positive in uniform experimental models of Parkinson’s disease. Regrettably, the translation of these treatment concepts into reliable clinical study results has failed due to the heterogenous nature of Parkinson’s disease. This is compounded by important misconceptions such as the consideration of levodopa as the therapeutic gold standard, which impacts aging mechanisms and neuronal degeneration or euphoric discussed therapies that only improve symptomatic levodopa effects because of a metabolic delay.
Bipolar disorder is often treatable with conventional psychopharmacology. Despite the availability of numerous established treatments for bipolar disorder, cases of treatment resistance persist. The identification of optimal therapies proves challenging, as the term treatment resistance lacks a clear, standardized definition. Ambiguity in defining frequency, duration, and number of medication failures across the different subtypes of refractory bipolar disorder contributes to an inconsistent framework which negatively impacts both clinical decision making and clinical outcomes. This review article surveys updated novel treatments for the subtypes of refractory bipolar disorder in adult and pediatric populations. Treatment-resistant acute mania, rapid cycling, and bipolar depression in adult populations are reviewed, and studies in pediatric treatment-resistant bipolar disorder are overviewed. A literature search was conducted using MEDLINE and focused on studies published between 2015 and 2025 to highlight the latest research findings in this area of interest. Future directions offer optimism through precision medicine, but a comprehensive conclusive survey of treatment-resistant bipolar disorder remains premature in its current state of research. Current challenges underscore the importance of creating a clearly defined classification system to improve diagnostic clarity and the consistency of research and clinical outcomes.
Social anxiety disorder (SAD) is a common and disabling mental disorder that follows a chronic course unless it is treated with effective treatments. This systematic review examines randomized controlled trials (RCTs) of pharmacological treatments for adults with SAD published since 2015. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Search was conducted on PubMed, Scopus, Web of Science, and PsycINFO. Risk of bias of the included studies was assessed using the Cochrane risk of bias tool for randomized trials. Eighteen RCTs were included. Selective serotonin reuptake inhibitors (SSRIs) were the most investigated pharmacological intervention, either as monotherapy or in combination with cognitive behavioral therapy (CBT). More recent drugs show promising results include cannabidiol and d-cycloserine. When CBT is unavailable, SSRIs are the first-line pharmacological treatment for SAD based on current evidence. However, response rates vary substantially. We recommend a personalized approach that includes patient preference and treatment accessibility.
Fibromyalgia is a chronic pain syndrome characterized by widespread nociplastic pain, fatigue, sleep disturbances, and mood symptoms. Conventional treatments often yield limited benefits, prompting interest in noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS). This review synthesizes evidence from 31 randomized controlled trials (RCTs) evaluating the efficacy, safety, and tolerability of tDCS in fibromyalgia. A systematic search of Embase and Medline were conducted without date or language restrictions. Most studies assessed anodal tDCS targeting the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC), with outcomes spanning pain, global symptom burden, psychological symptoms, fatigue, and sleep quality. Ten of 14 sham-controlled trials reported significant pain reductions with M1 stimulation. Seven trials showed improvements in overall symptom severity (FIQ/FIQR), though most did not meet the minimal clinically important difference. Outcomes for fatigue, sleep, and mood were less consistent and often underreported. While tDCS appears safe and effective for fibromyalgia-related pain, variability in protocols and limited reporting of non-pain outcomes hinder broader conclusions. As an adjunctive therapy, its role may be enhanced through protocol standardization, longer-term follow-up, and combination strategies such as pairing with repetitive transcranial magnetic stimulation (rTMS) to address the full spectrum of fibromyalgia symptoms.
Effectiveness and tolerability of anti-seizure medications (ASM) vary widely among individuals with epilepsy. Genetic polymorphisms may influence pharmacokinetic and pharmacodynamic responses, yet available evidence is heterogeneous and inconsistently translated into clinical practice. A systematic search of eight databases (2000-2024) identified observational studies assessing associations between genetic variants and ASM response or adverse drug reactions. The review protocol was registered in PROSPERO (CRD420251237140). Two reviewers independently performed screening, data extraction and quality assessment using the Newcastle-Ottawa Scale. Owing to methodological heterogeneity, a narrative synthesis was conducted. A total of 168 studies were eligible. The strongest and most consistent associations involved HLA-B*15:02 and HLA-A*31:01 as predictors of severe cutaneous adverse reactions to carbamazepine, oxcarbazepine and phenytoin. CYP2C9 variants showed reproducible links to phenytoin toxicity. Associations involving ABCB1, SCN1A, SCN2A, GABRA1 and UGT2B7 for treatment response were reported, but findings varied across ASM classes and populations. Substantial ethnic variability was observed, particularly in Asian cohorts. Only a limited number of genetic polymorphisms currently demonstrate sufficient consistency for clinical translation, mainly HLA alleles predicting severe cutaneous reactions and CYP2C9 variants associated with phenytoin toxicity. Larger multiethnic studies with standardized outcome definitions are needed to clarify the therapeutic role of additional markers and support broader pharmacogenomic implementation.
New-onset or worsening bipolar disorder is common after childbirth and is associated with increased risk of psychiatric hospitalization, along with safety concerns for the mother and newborn. Despite the availability of several medications, preventing postpartum bipolar mood episodes remains difficult. This narrative review outlines findings of a search of MEDLINE/PubMed, PsycINFO, and the Cochrane Database of Systematic Reviews in November 2025. The author examines the challenges of preventing postpartum mood episodes in women with bipolar disorder and discusses opportunities for early detection and treatment of symptoms during and after pregnancy. Continuation of optimized maintenance treatment to mitigate the risk of recurrence associated with weaning and resumption of menstruation is emphasized. This review also highlights research gaps, particularly the lack of treatment studies. Efforts to prevent postpartum episodes of bipolar disorder should include timely identification of at-risk individuals, confirming diagnosis and psychiatric comorbidities, reviewing illness course, and analyzing risk and protective factors, psychoeducation, mitigating risk factors, vigilant monitoring for emerging symptoms of relapse or recurrence, tailoring treatment, assessing breastfeeding safety and compatibility, and addressing safety concerns. Follow-up should continue for several months, as mothers remain at risk of relapse during weaning, resumption of menstruation, and the return to work after maternity leave.
Neuropathic pain is considered the most difficult to manage, with many patients getting inadequate relief from the current pharmacotherapy. While many drugs have been added to the regimen, Lacosamide has emerged as a promising therapeutic option. This systematic review focuses on the efficacy and safety of lacosamide in adult patients with neuropathic pain. Databases such as PubMed, Embase, Scopus, Web of Science, and Cochrane were searched thoroughly for Randomized Controlled Trials (RCTs) published in English through November 2025. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in the included studies. Eight RCTs involving 976 participants with different neuropathic pain conditions met the inclusion criteria. Across the included studies, Lacosamide (200-600 mg/day) provided a modest reduction in their pain scores. However, it didn't have much of a positive impact on quality of life, limited function, adverse effects were common, and a high dropout rate was observed in several trials. Lacosamide might provide a modest analgesic benefit across multiple neuropathic conditions. But its extensive, long-term use requires more research to confirm its benefits, particularly the optimum dosing protocols.
Status epilepticus is a neurological emergency in which rapid treatment is essential to reduce morbidity and mortality. Delays in establishing intravenous access frequently hinder timely benzodiazepine administration, creating a critical need for fast, reliable, and user-friendly non-IV rescue therapies. The midazolam 10 mg autoinjector was developed to address these operational barriers and improve prehospital seizure management. This review examines the pharmacology, clinical efficacy, safety, and regulatory status of the midazolam autoinjector, drawing on published studies of intramuscular midazolam, pharmacokinetic evaluations of autoinjector formulations, and regulatory documents supporting its approval. The midazolam autoinjector offers a meaningful advance in the treatment of status epilepticus by enabling rapid, consistent intramuscular delivery without preparation. Its design directly addresses the practical limitations of existing therapies and is likely to encourage adoption in prehospital and other time-critical settings. As emergency care increasingly prioritizes early intervention, autoinjector-based benzodiazepines are poised to play an expanding role in modern seizure-rescue strategies.
Medication-overuse headache (MOH) affects 1-2% of the population and imposes substantial burden. Corticosteroids are often used as bridge therapy during withdrawal, although their effectiveness remains uncertain. This study aims to evaluate the effectiveness of corticosteroids as a withdrawal strategy in MOH. A systematic review with meta-analysis was conducted in accordance with PRISMA guidelines. The protocol was registered in PROSPERO (ID: 1161824). Searches were performed in PubMed, MEDLINE, EMBASE, the Cochrane Library, Web of Science, SciELO, and LILACS through June 2025. Randomized, placebo-controlled trials assessing corticosteroids during withdrawal therapy in adults with MOH were included. Random-effects meta-analyses were performed when feasible using RevMan 7.2.0. Of 4,483 records identified, four trials comprising 250 participants met eligibility criteria. Two studies presented high risk of bias, two raised some concerns. Considerable heterogeneity in design, dosing regimens, follow-up duration, and outcome definitions limited comparability and precluded a unified pooled analysis. Across studies, results consistently failed to show benefit. Meta-analytic findings demonstrated no advantage of corticosteroids over placebo regarding early withdrawal headache, withdrawal symptoms or reversal of medication overuse. The available evidence does not support corticosteroids as effective withdrawal therapy for MOH. Medication-overuse headache is a disabling condition caused by frequent use of pain medications. Stopping these drugs can temporarily worsen headaches. In this systematic review, the authors assessed all of the high-quality clinical trials that compared corticosteroids with placebo during medication withdrawal, analyzing data from international databases and including 250 patients. The results showed that corticosteroids did not reduce withdrawal headaches, symptoms, or improve recovery.
Serotonin Reuptake Inhibitors (SRIs) are the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), but they are effective in only 40-60% of the patients. We performed meta-analyses of predictors of resistance to SRIs in OCD. The systematic review was conducted as per PRISMA guidelines and registered in PROSPERO (ID: CRD42024568797). Multiple random-effects meta-analyses were performed for each predictor, depending on the type of the predictor variable and the outcome (continuous vs categorical). Pooled outcomes were reported as odds ratios (OR), mean differences (MD), standardized mean differences (SMD), Fisher's r-to-z transformed correlation coefficient, along with their 95% confidence intervals (CI). Out of 10,688 studies screened, 46 met our eligibility criteria, including a total of N = 4860 subjects. Analysis of categorical outcomes showed that earlier age at onset (SMD = 1.9 [0.79-2.99]), longer duration of illness (SMD = 2.78 [0.77-4.79]), greater OCD severity at baseline (MD = 2.50 [1.53-3.46]), poorer insight (OR = 0.24 [0.08-0.68]), contamination obsessions (OR = 0.61 [0.43-0.85]), and comorbid tics (OR = 0.44 [0.29-0.67]) predicted non-response to SRIs. Baseline OCD severity (Z = 0.56 [0.21-0.92]), poorer insight (SMD = 1.33 [0.42-1.33]), and presence of comorbid tics (SMD = 0.67 [0.01-1.36]) predicted poor response in continuous outcome analyses. Baseline severity, insight, and comorbid tics were consistent predictors of poor treatment response.
Migraine is a highly prevalent and disabling neurological disorder whose diagnosis remains clinical. However, overlap with secondary headache disorders represents a major diagnostic challenge, particularly in patients with atypical features or changes in headache pattern, making neuroimaging crucial in selected cases. This review provides an updated overview of the differential diagnosis of migraine in adults, focusing on the role of clinical assessment, red flags, and neuroimaging in identifying secondary causes. A comprehensive, narrative review of the literature was conducted, integrating current guidelines and recent evidence on imaging indications and modalities. We discuss key conditions that may mimic migraine, including vascular, neoplastic, infectious, cerebrospinal fluid pressure-related, and cervicogenic disorders, highlighting their clinical and radiological features. Attention is given to the concept of pretest probability to guide imaging decisions and to the limitations of red flags in clinical practice. Neuroimaging should not be routinely performed in patients with typical migraine and normal neurological examination but rather tailored to the individual clinical context. An integrated approach combining clinical judgment, awareness of red flags, and targeted imaging is essential to avoid both underdiagnosis of secondary headaches and overuse of unnecessary investigations.
The ketogenic diet as a potential treatment for Alzheimer's disease (AD) has been investigated in several controlled trials. This topic is significant because of the limited nature of current interventions for AD, and the increasing recognition that lifestyle interventions may be important for reducing the risk of AD. The ketogenic diet is one of the few lifestyle interventions that has the potential to be beneficial after diagnosis. In this narrative review, the authors discuss the biological plausibility of how a ketogenic diet may improve amyloid burden and reduce neuroinflammation by providing an alternative energy source. They review relevant meta-analyses, systematic reviews, and controlled trials to investigate this diet in people diagnosed with AD. To this end, the authors used PubMed to search for appropriate systematic reviews and human trials, and closely examined the bibliographies of these papers to find trials potentially missed in their initial search. More research is needed before a ketogenic diet could be broadly recommended in patients diagnosed with AD. However, to the extent a treatment effect has been demonstrated, it is comparable to some pharmaceutical interventions in AD. Challenges that remain include demonstrating improvement in quality of life, improving adherence, and standardizing ketogenic therapies.
Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes mellitus and is frequently assumed to be the sole cause of neuropathic symptoms in patients with diabetes. This diagnostic simplification may lead to misdiagnosis, delayed treatment of alternative etiologies, and preventable neurological disability. Accurate differentiation between DPN and non-diabetic neuropathies remains a major clinical challenge. This narrative review examines the principal differential diagnoses of generalized DPN, integrating clinical presentation, disease tempo, electrophysiological patterns, and targeted laboratory evaluation. A structured literature search of PubMed, Scopus, and Web of Science (2015 2025) was conducted, focusing on inflammatory, nutritional, toxic, hereditary, amyloid, autoimmune, and systemic causes of peripheral neuropathy. Emerging diagnostic tools, including biomarkers and advanced neurophysiological techniques, are also discussed, and a practical diagnostic algorithm is proposed to support real-world clinical decision-making. DPN should be regarded as a diagnosis of exclusion rather than a default explanation in patients with diabetes. A phenotype-driven and structured diagnostic approach is essential to reduce diagnostic anchoring, prevent iatrogenic harm, and enable early identification of treatable neuropathies, ultimately improving neurological outcomes and precision medicine strategies.
Daridorexant is a dual orexin receptor antagonist with optimized pharmacokinetics to improve sleep and daytime functioning, without residual effects. This review summarizes the evidence for daridorexant in the management of insomnia disorder. This article gives a brief overview of insomnia disorder and the mechanism of action for dual orexin receptor antagonists; it also gives coverage to the distinct pharmacokinetics of daridorexant. Evidence evaluating daridorexant in the management of insomnia disorder is summarized, based on a narrative literature search of PubMed and Embase. All full-length publications reporting original research of Phase 1-4 clinical trials and observational studies of daridorexant were considered. Consistent nightly treatment with daridorexant showed significant and clinically meaningful improvements in both sleep and daytime functioning at the 50 mg dose. In clinical trials, daridorexant demonstrated efficacy across objective and patient-reported sleep measures in a broad adult population, including older adults, and efficacy was maintained for up to 1 year. Reduced wakefulness throughout the entire night with daridorexant was associated with improvement in daytime functioning. Head-to-head comparisons with standard insomnia hypnotics are limited to a Phase 2 dose-finding study. Its favorable safety profile makes daridorexant appropriate for many patients, including older adults.
In spinal muscular atrophy (SMA), irreversible loss of spinal motor neurons and progressive skeletal muscle atrophy cause continuous weakness and loss of motor function. Treatments that increase levels of survival motor neuron (SMN) protein in motor neurons have greatly improved prognoses for patients, but significant unmet needs remain. Myostatin is a protein secreted by skeletal muscle that acts as a negative regulator of muscle growth. Inhibition of the myostatin signaling pathway may improve motor function in SMA and other neuromuscular diseases. This article reviews the role of muscle in SMA and the potential for treatments that inhibit the myostatin signaling pathway in neuromuscular diseases. Preclinical and clinical trial data are discussed for these muscle-targeted treatments in development for SMA. SMN-targeted disease-modifying treatments focus on motor neuron survival rather than muscle. Treated individuals nonetheless experience a range of persistent muscle weakness. Treatments that inhibit myostatin signaling represent a potential complementary pathway for direct muscle enhancement. In the evolving SMA treatment landscape, understanding how muscle-targeted treatment can be incorporated into clinical practice will facilitate individualized treatment decisions and identify outcomes that best encapsulate maintenance or improvement of motor function across the phenotypic spectrum of SMA.
Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is the commonest autosomal dominant ataxia worldwide. It is a progressive neurodegenerative disorder with a complex and heterogeneous phenotype that extends far beyond ataxia. Motor and non-motor manifestations lead to a negative impact on quality of life. Despite this, many of these manifestations are amenable to pharmacological interventions. The current review addresses both disease-modifying and symptomatic therapies for SCA3/MJD. We discuss data on pharmacological and non-pharmacological treatment options for motor and non-motor symptoms of the disease. This narrative review is based on identified literature related to SCA3/MJD and is available on PubMed, Scopus and LILACS. There is no currently approved disease-modifying therapy for SCA3/MJD, albeit some recent clinical trials have disclosed encouraging results. The mainstay of clinical care currently relies upon management of symptoms, either using pharmacological or non-pharmacological strategies. Symptomatic treatments for some SCA3/MJD-related manifestations, such as dystonia and cramps, have been tested in controlled studies. For other manifestations, pharmacotherapy is chosen based on empirical evidence and/or experts' opinion. Therefore, better understanding of the natural history of the disease should pave the way for therapeutic discoveries.
Depression is one of the most frequent and disabling neuropsychiatric syndromes in Alzheimer's disease (AD), yet antidepressant use is still largely extrapolated from late‑life depression and is poorly aligned with emerging evidence on 'neurodegenerative depression' and disease‑modifying therapies. This article critically re‑examines the clinical value and risks of antidepressants in AD. Drawing on a narrative search of PubMed/MEDLINE and Embase (January 2000-December 2025) and targeted review of recent guidelines and anti‑amyloid trials, the article synthesizes randomized and observational data on efficacy and safety across antidepressant classes, highlighting modest and inconsistent benefits alongside adverse outcomes such as falls, hyponatremia, bleeding, mortality and possible acceleration of cognitive decline. It integrates mechanistic work on synaptic loss, neuroinflammation and network disruption, discusses the exclusion of depressed patients from anti‑amyloid trials, and reviews rapid‑acting, neuromodulatory and psychosocial strategies within a proposed precision‑prescribing framework based on biomarkers, vascular burden and symptom dimensions. Monoaminergic antidepressants in AD should not be abandoned but repositioned as time‑limited, closely monitored options for clearly defined, functionally impairing depressive syndromes, embedded in multimodal care rather than used as default, long‑term treatment for non‑specific distress. Future priorities include biomarker‑stratified AD depression trials, evaluation of interactions with anti‑amyloid therapies and rigorous testing of non‑monoaminergic interventions.
Chromosome 16p11.2 deletion syndrome is a genetic syndrome that includes difficulties in speech, language, and motor coordination. Arbaclofen, a selective GABA-B receptor agonist, has improved motor functioning and memory in mouse models. Prior clinical trials of arbaclofen in fragile X syndrome and autism spectrum disorder suggested benefit for social communication. L16hthouse (NCT04271332) is a multi-site, double-blind, randomized, placebo-controlled phase 2 trial to evaluate safety, efficacy, and tolerability of arbaclofen compared in 60 youths with 16p11.2 deletion syndrome (5 to 17:11 years) randomized on a 1:1 ratio. Primary outcomes included speech articulation, measured by the Goldman Fristoe Test of Articulation 3 (GFTA-3). Secondary outcomes included objective dysarthria indices, memory, motor control, and cognitive function, assessed with both standardized clinical measures and novel, computer-based assessments with automated scoring. Exploratory outcomes included attention, autism traits, and electrophysiological responses. L16hthouse is the first randomized trial in 16p11.2 deletion syndrome and uses an array of novel outcome measures to assess potential benefit in this population. In addition to providing potential insights about the safety, efficacy, and tolerability of arbaclofen, L16hthouse will provide an initial assessment of how these developmental outcome measures perform in a clinical trial across a broad age range.Clinical trial registration number: NCT04271332; 2020-02-13. The methods are described for a multi-site, double-blind, randomized controlled Phase 2 trial to evaluate the safety, efficacy, and tolerability of arbaclofen for youth with 16p11.2 deletion syndrome. The primary outcome measure was speech articulation, a key difficulty for youth with 16p11.2 deletion syndrome. The outcomes of this trial, combined with the parallel Canadian ARBA and European AIMS-CT-01 trials, will contribute to the evidence base of arbaclofen as a treatment for neurological and psychiatric conditions.
Over recent decades, research has identified both overlapping and distinct characteristics, risk factors, and genetic as well as neurobiological correlates associated with Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). This expanding body of evidence is increasingly informing the clinical management of individuals with comorbid ADHD and ASD. Based on a targeted PubMed search conducted up to March 24,2025,24.03.25, prioritizing meta-analyses or umbrella reviews over primary studies (whenever relevant), with terms encompassing autism, assessment, and treatment, this review addresses: 1) Shared and distinct phenotypic characteristics, neuropsychological features, and genetic and neuroimaging correlates of ADHD and ASD; 2) The assessment of individuals presenting with both ASD and ADHD symptoms; 3) Pharmacological and non-pharmacological strategies for the management for individuals with comorbid ASD and ADHD. The comorbidity of ADHD and ASD should not be overlooked. Nevertheless, before diagnosing comorbid ASD and ADHD, clinicians should perform a thorough differential diagnosis, ensuring that ADHD symptoms are not better explained by ASD. Regarding treatment, further research is warranted to develop personalized approaches, support long-term management strategies, and evaluate real-world outcomes such as quality of life, which are often underrepresented in clinical trials.
Traditional open-loop SCS is confronted by several major challenges. Variable inconsistent activation of the intended target results in the inconsistency of treatment outcomes and the programming of fixed-output devices below the sensation threshold may not activate dorsal column axons. Closed-loop SCS (CL-SCS) using evoked compound action potential (ECAP) has overcome these limitations with the ability to measure spinal cord activation and accurately administer therapeutic doses despite the dynamic physiologic processes that affect SCS therapy delivery. The authors present a comprehensive review of CL-SCS treatment and ECAP controlled effects demonstrating long-term benefits and cost-effectiveness compared to fixed output SCS for patients with chronic intractable trunk and limb pain. Several studies have been highlighted by the authors demonstrating superiority in both pain relief and universal treatment responses of ECAP- controlled CL-SCS in comparison to fixed-output open-loop SCS. ECAP dose-controlled CL-SCS delivers promising clinical benefits by providing precise, objective control of SCS dosing, aligning with outcomes observed in both RCT and real-world settings. The incorporation of neural metrics into the programming process offers a transparent and reproducible framework for optimizing therapy, enhancing pain relief, and improving universal patient outcomes.