The clinical spectrum of myotonic disorders is broad. Myotonic dystrophy type 1, or DM1, is the most common of them, with prevalence estimates based on clinical diagnosis ranging from one in six to ten thousand, although genetic screening data suggest as many as one in 2,100 people may be affected. DM1 results from an unstable expansion of CTG repeats in the DMPK gene on chromosome 19. The expanded transcripts exert a toxic gain of function, sequestering RNA-binding proteins and disrupting alternative splicing across the genome, which explains why the disease touches so many organ systems. Patients may develop progressive muscle wasting and weakness, cardiac conduction disease and cardiomyopathy, respiratory failure, cataracts, diabetes, thyroid dysfunction and cognitive impairment. Presentation varies enormously: some individuals live nearly normal lives and remain undiagnosed well into adulthood, while others lose ambulation and face shortened life expectancy from cardiorespiratory complications. Myotonic dystrophy type 2, caused by a CCTG expansion in the CNBP gene on chromosome 3, shares the same RNA-mediated spliceopathy mechanism but tends to produce a milder, proximal myopathy without the congenital forms or genetic anticipation seen in DM1.

Distinct from the dystrophies are the non-dystrophic myotonias, pure skeletal muscle channelopathies caused by variants in ion channel genes, with no systemic involvement and a normal life expectancy. Myotonia congenita, the most common with a prevalence of roughly two to seven per 100,000, stems from variants in CLCN1, the gene encoding the ClC-1 voltage-gated chloride channel essential for membrane repolarisation. It is the same channel whose function is secondarily disrupted in myotonic dystrophy. Paramyotonia congenita and sodium channel myotonia are allelic autosomal dominant disorders of SCN4A, the gene for the Nav1.4 sodium channel that generates the action potentials driving contraction. Paramyotonia is notorious for worsening with cold and repeated activity, and can be accompanied by episodic paralysis, while sodium channel myotonia may show both warm-up and paradoxical worsening. For many patients, pain and fatigue are as troublesome as the stiffness itself, and the visible normality of their appearance can make the condition a hidden disability.

The therapeutic mainstay for myotonia has long been sodium channel blockade. In paramyotonia and sodium channel myotonia the mechanism is direct, since the underlying SCN4A variants confer a gain of channel function that the drugs inhibit. In myotonia congenita and the dystrophies the effect is indirect: reducing persistent sodium current partially compensates for impaired chloride-mediated repolarisation. Mexiletine emerged as first-line therapy on the strength of clinical impression, and in 2012 the first randomised controlled trial confirmed its efficacy in non-dystrophic myotonia, with subsequent studies, including aggregated N-of-1 trials, consolidating the evidence. Secondary outcomes consistently showed benefits extending to quality of life, pain, fatigue, independence and emotional well-being. Lamotrigine joined the arsenal in 2017 when a phase 2 crossover trial in 22 patients demonstrated efficacy on the myotonia behaviour score, making these two drugs the only anti-myotonic agents with randomised trial evidence. A head-to-head phase 3 trial failed to show lamotrigine was non-inferior to mexiletine, but it still delivered considerable benefit, giving clinicians two credible options.

Both drugs have also shown efficacy in DM1, with favourable cardiac safety profiles in trials, though these studies were small, short and potentially subject to selection bias in a population where cardiac conduction defects are common. Evidence in DM2 remains far thinner, with no dedicated large randomised trials, forcing treatment strategies to be extrapolated from other populations. Cardiac caution has historically shadowed mexiletine because of its potential pro-arrhythmic properties, yet neither the trials nor 302.4 years of real-world follow-up in non-dystrophic myotonia demonstrated significant electrocardiographic changes, and observational data in myotonic dystrophy show no safety signal on conduction parameters. The FDA has issued a warning on lamotrigine based on in vitro class 1B sodium channel blocker activity, but this has not been replicated by other regulators, including the European Medicines Agency, and has not translated into observable effects on human cardiac conduction. A joint ILAE/AES task force now recommends baseline electrocardiography only for those over 60 or with multiple cardiovascular risk factors, with specialist review mandatory for known cardiac disease. Clinicians must also weigh the rare but serious risk of Stevens-Johnson syndrome with lamotrigine, which a 55-year review of the FDA adverse event database found accounted for nearly ten percent of reported cases.

Practical considerations are also reshaping prescribing. Mexiletine, licensed as Namuscla for adults with non-dystrophic myotonia in several countries and used off-label in children and in myotonic dystrophy, typically requires dosing up to three times daily, which can undermine adherence. Prolonged-release once-daily formulations are now in phase 3 trials: the HERCULES study in DM1 and DM2 and the ACHILLES study in non-dystrophic myotonia. Meanwhile, basic science continues to probe alternative targets. No specific chloride channel activators exist, but intriguing work has shown that niflumic acid, which acutely blocks the ClC-1 channel in transfected cells, paradoxically acts as a pharmacological chaperone that increases channel protein expression when applied over 24 hours. Potassium channel openers such as retigabine, withdrawn from the market in 2017 over blue pigmentation concerns, have inspired next-generation compounds in development.

The most dramatic shift, however, is in DM1, where an era of molecularly targeted clinical trials is underway. Several companies are developing therapies designed to reduce the mutant DMPK transcript or to prevent the sequestration of muscleblind-like protein 1, the key splicing regulator whose loss drives the downstream transcriptional chaos. Delivery strategies range from naked oligonucleotides to targeted conjugates and adeno-associated virus vectors, with studies progressing from early-phase work to phase 3. The most advanced candidate is del-desiran, an antibody-oligonucleotide conjugate that hijacks the transferrin receptor to ferry the drug into muscle. In the phase 2 MARINA trial it demonstrated target engagement and amelioration of aberrant alternative splicing in some patients, a proof of principle that has electrified the field. None of these approaches is curative, and the extent of achievable molecular and clinical correction remains uncertain, but they represent the first credible assault on the underlying pathology rather than its symptoms.

Translational challenges loom large. Many trials use video hand opening time as the primary endpoint, a measure that captures skeletal muscle excitability and likely reflects modulation of MBNL-dependent mis-splicing of ion channel transcripts, making it a useful proof-of-mechanism marker, but its relevance to broader clinical benefit in a multisystem disease is debated. Effects on the heart and brain may not be established for years and will depend on post-marketing surveillance. Delivery poses further difficulties: repeated intravenous infusions at six- to eight-week intervals demand substantial healthcare infrastructure and may limit scalability and central nervous system penetration. Alongside the genetic approaches, repurposed small molecules are advancing. Metformin showed signals of efficacy on the six-minute walk test in the MYOMET phase 2 study, though the primary endpoint was missed in the intention-to-treat population, and the larger phase 3 METFORMYO trial is now underway with the MFM-32 as its primary measure. Tideglusib, a GSK3-beta inhibitor tested in congenital and childhood-onset DM1, showed signals in cognitive and neuromuscular ratings without significant safety concerns, and a phase 2/3 study in children is recruiting. Erythromycin, which modulates MBNL-dependent splicing preclinically, was well tolerated in a phase 2 trial with promising improvements in splicing biomarkers and creatine kinase levels.

Symptomatic care continues to evolve in parallel. Excessive daytime sleepiness affects the majority of people with DM1, yet randomised evidence for psychostimulants such as modafinil remains thin. A phase 2 trial of pitolisant in 30 participants suggested improvements in subjective sleepiness but was not powered for statistical significance, and a small study of intravenous flumazenil found no benefit over placebo. The overall picture that emerges from the review is not one of replacement but of layering: mechanism-based therapies are being built on top of a symptomatic framework that already works reasonably well for myotonia, even as it leaves progressive weakness and multisystem degeneration unaddressed. The recurring theme, the authors note, is the gap between molecular target engagement and clinically meaningful benefit, a gap that applies equally to established drugs and to the new genetic agents. Whether the emerging therapies will ultimately change disease trajectory remains uncertain, but for patients who have waited decades for anything more than symptomatic relief, the pipeline now offers genuine hope, and clinicians are being urged to prepare for a practice landscape that may look radically different within a few years.

Subject of Research: Treatment advances for myotonia in myotonic dystrophy and non-dystrophic muscle channelopathies

Article Title: Treatment updates in myotonic disorders

Article References: Matthews, E., Specterman, M. J., & Mul, K. (2026). Treatment updates in myotonic disorders. Journal of Neurology, 273(10), Article 562. https://doi.org/10.1007/s00415-026-14073-9

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14073-9

Keywords: myotonia, myotonic dystrophy type 1, myotonia congenita, sodium channel blockers, mexiletine, lamotrigine, RNA splicing, oligonucleotide therapy, clinical trials, muscle channelopathies, DMPK gene, disease-modifying therapy

Oxcarbazepine, often abbreviated OXC, is a chemical cousin of carbamazepine, one of the classic antiepileptic drugs that also established itself as a mainstay in the treatment of bipolar disorder. Structurally, oxcarbazepine is a keto analogue of carbamazepine, and it exerts its therapeutic effects primarily through its active metabolite, 10-hydroxycarbazepine, known as the monohydroxy derivative or MHD. This metabolite stabilizes hyperexcited neuronal membranes by blocking voltage-gated sodium channels, dampening the aberrant electrical firing that underlies both seizures and, in the psychiatric context, the pathological mood swings of mania. Because oxcarbazepine avoids some of the metabolic pitfalls of its parent compound, including the formation of reactive epoxide metabolites that have been implicated in carbamazepine hypersensitivity, clinicians have hoped it would offer a gentler profile. It is generally prescribed in selected clinical settings as an alternative or adjunctive option for patients with bipolar disorder who cannot tolerate first-line agents or who need additional mood stabilization.

Yet the skin remains a vulnerable organ system for this entire drug family. Antiepileptic drugs as a class are notorious for cutaneous adverse reactions, ranging from benign morbilliform rashes to the terrifying end of the spectrum occupied by severe cutaneous adverse reactions, or SCARs. These include Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms, known as DRESS. Stevens-Johnson syndrome and toxic epidermal necrolysis represent a continuum of the same disease process, in which an immune-mediated attack causes keratinocytes to die and the epidermis to separate from the dermis, producing blistering, skin sloughing, and mucosal involvement that can be life-threatening. Mortality in toxic epidermal necrolysis can reach double digits despite intensive care, and severity is often gauged with tools such as the SCORTEN score, while drug causality is assessed with instruments like the ALDEN algorithm and the RegiSCAR criteria. Against this backdrop, any report of skin reactions to oxcarbazepine deserves careful attention, particularly because reports describing OXC-associated cutaneous reactions specifically in patients with bipolar disorder have remained limited.

The Guangzhou team approached the problem with a retrospective descriptive design, combing through clinical records to identify twelve patients with bipolar disorder who had developed cutaneous reactions attributed to oxcarbazepine. The study was approved by the Medical Ethics Committee of the Affiliated Guangdong Second Provincial General Hospital of Jinan University, and written informed consent was obtained from all patients or their legal guardians. For each case, the researchers collected demographic characteristics, details of the medication regimen, the clinical features of the skin eruption, and the treatment outcomes. The diagnosis of bipolar disorder was established according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, ensuring a diagnostically homogeneous cohort in which the drug, rather than diagnostic heterogeneity, was the variable of interest.

The timing of the reactions emerged as one of the most striking patterns in the data. Onset of cutaneous reactions occurred mainly within the first two weeks of treatment, a temporal signature that mirrors what is known about hypersensitivity reactions to aromatic antiepileptic drugs generally. This early window matters enormously for clinical practice, because it defines the period during which patients and their families need to be most vigilant. A rash appearing in the first fortnight of oxcarbazepine therapy should never be dismissed as a trivial irritation; it demands prompt evaluation and, in many cases, immediate discontinuation of the drug. The two-week signal also aligns with the immunology of delayed-type drug hypersensitivity, in which sensitization to a drug or its metabolites typically requires days to weeks before T-cell-mediated pathology becomes clinically visible on the skin.

In terms of presentation, the most common form was a generalized eruption, meaning a rash spreading across large areas of the body, followed by localized eruptions confined to specific regions. One patient among the twelve was diagnosed with Stevens-Johnson syndrome, the severe blistering disorder that constitutes a dermatological emergency. That single case is the most sobering element of the series, a reminder that even a drug marketed partly on its improved tolerability can, in susceptible individuals, trigger the full machinery of a severe cutaneous adverse reaction. The patient with Stevens-Johnson syndrome was among three patients in the series who were receiving lamotrigine concurrently, and the authors note that mixed drug attribution could not be excluded in these cases. Lamotrigine itself carries a well-known risk of severe skin reactions, particularly when titrated rapidly, so the presence of both drugs complicates the causal picture and illustrates a perennial challenge in psychopharmacology: patients with bipolar disorder frequently take combinations of medications, and disentangling which agent is responsible for an adverse event requires careful pharmacovigilance.

The good news from the series is that the outcomes were favorable. Clinical improvement was observed after discontinuation of oxcarbazepine and supportive management, a pattern consistent with the natural history of most drug-induced cutaneous reactions, which typically resolve once the offending agent is cleared. Supportive management for severe reactions can involve wound care, fluid and electrolyte management, pain control, and in the most serious cases interventions such as intravenous immunoglobulin, though the source material does not specify which supportive measures were used in individual patients. The essential clinical algorithm, however, is clear: early recognition, immediate drug withdrawal, and supportive care form the backbone of treatment for antiepileptic-induced skin reactions, and the Guangzhou experience reinforces that approach in the specific context of bipolar disorder.

The authors are appropriately cautious about what their study can and cannot show. With only twelve patients, a retrospective design, and no comparison group, the findings must be interpreted descriptively. They cannot be used to estimate the true incidence of oxcarbazepine-associated skin reactions, to establish causality with certainty, or to identify independent risk factors for developing them. Retrospective case series are hypothesis-generating by nature; they map the terrain of a clinical problem without quantifying its frequency. The researchers explicitly call for larger prospective studies to further characterize these reactions, work that would ideally include systematic skin assessment at defined time points, pharmacogenomic testing, and comparison groups of patients taking oxcarbazepine without reactions. Such studies could eventually clarify whether known genetic risk factors for carbamazepine hypersensitivity, such as certain human leukocyte antigen alleles, also predispose patients to oxcarbazepine reactions, a question of intense interest given the structural relationship between the two drugs.

For clinicians treating bipolar disorder, the practical takeaways are nonetheless actionable today. Oxcarbazepine remains a legitimate option in selected patients, but prescribers should counsel patients explicitly about skin symptoms before the first prescription, emphasizing that any rash, blistering, mucosal ulceration, or fever with skin changes in the first weeks of therapy warrants urgent medical contact. The first two weeks deserve heightened vigilance, and concomitant lamotrigine should prompt extra caution in attribution and monitoring. For patients, the study is a reminder that psychiatric medications, like all drugs, carry physical as well as psychological side effects, and that the skin can serve as an early warning system. For researchers, the twelve cases from Guangzhou provide a descriptive foundation on which larger, prospective investigations can now build, moving the field from anecdote toward the incidence estimates and risk-factor profiles that would allow truly personalized prescribing decisions in bipolar disorder.

Subject of Research: Cutaneous adverse reactions associated with oxcarbazepine treatment in patients with bipolar disorder

Article Title: Clinical features of oxcarbazepine-associated cutaneous reactions in patients with bipolar disorder: a retrospective case series

Article References: Huang, Y., Xue, K., Fan, C., Ren, X., & Zeng, X. (2026). Clinical features of oxcarbazepine-associated cutaneous reactions in patients with bipolar disorder: a retrospective case series. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08621-w

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08621-w

Keywords: oxcarbazepine, bipolar disorder, cutaneous reactions, Stevens-Johnson syndrome, antiepileptic drugs, severe cutaneous adverse reactions, lamotrigine, drug hypersensitivity, case series, psychopharmacology, drug safety, dermatology

The research team, led by Nesrin Yilmaz of Erzincan Binali Yıldırım University in Turkey together with colleagues across several Turkish institutions, set out to answer a question that had never been directly addressed. Previous studies had shown that lamotrigine can alter intracellular ATP levels in a dose-dependent manner, and that this energetic disturbance promotes the generation of reactive oxygen species, the unstable molecules that chew through lipids, proteins, and DNA. What remained unknown was whether the ovary, an organ exquisitely sensitive to oxidative stress because of its finite pool of follicles, suffers the same fate, and whether supplementing ATP from outside the cell could counteract the damage.

To find out, the investigators divided forty-two female Wistar albino rats into seven groups of six animals each. One group served as a healthy control. A second received a low oral dose of lamotrigine, ten milligrams per kilogram of body weight, roughly comparable to standard therapeutic exposure. A third received a high oral dose of thirty milligrams per kilogram. The remaining four groups received either ATP at five milligrams per kilogram intraperitoneally or melatonin at ten milligrams per kilogram orally, each paired with either the low or the high lamotrigine dose. Crucially, both protective agents were administered one hour before lamotrigine every day for thirty days, a pre-treatment design intended to ensure that the antioxidants were already on board when the drug hit the tissue.

At the end of the thirty-day period, the researchers assembled an unusually comprehensive picture of ovarian health. They quantified oxidant and antioxidant biomarkers in ovarian tissue, measured serum levels of anti-Mullerian hormone, or AMH, a widely used clinical marker of the ovarian follicle reserve, graded histopathological injury under the microscope, and deployed a double-immunofluorescence technique to visualize, cell by cell, the accumulation of 8-hydroxy-2′-deoxyguanosine, a signature of oxidative DNA damage, along with dityrosine, a marker of protein oxidation, and the inflammatory enzymes cyclooxygenase-1 and cyclooxygenase-2.

The results drew a sharp line between the two doses. Low-dose lamotrigine produced no detectable oxidative, histopathological, or immunofluorescence alterations at all, a reassuring finding for patients on standard regimens, at least in this animal model. High-dose lamotrigine, by contrast, told a very different story. Oxidant markers climbed significantly, antioxidant defenses fell, and serum AMH dropped, all accompanied by severe follicular degeneration visible in the tissue sections. The immunofluorescence work added molecular texture to the damage: pronounced immunopositivity for 8-OHdG and dityrosine signaled that both DNA and proteins had taken an oxidative beating, while cyclooxygenase-2, the inducible inflammatory enzyme, lit up strongly even as cyclooxygenase-1, its constitutive counterpart, was suppressed.

That COX-1/COX-2 imbalance is more than a technical footnote. Cyclooxygenase enzymes convert arachidonic acid into prostaglandins that participate in ovulation, luteal function, and inflammatory signaling within the ovary. A simultaneous rise in the inducible COX-2 and fall in the constitutive COX-1 suggests a shift from homeostatic prostaglandin production toward an inflammatory program, the kind of shift that can disrupt follicular development and impair the delicate hormonal crosstalk between the ovary and the rest of the reproductive axis. Combined with the decline in AMH, which reflects a shrinking or damaged follicle pool, the picture is one of genuine reproductive vulnerability, not merely incidental biochemical noise.

The most striking result, however, concerned the two protective strategies. When ATP was given before high-dose lamotrigine, it attenuated the oxidant surge, restored antioxidant levels, preserved AMH, reduced histopathological injury, and dampened the abnormal 8-OHdG, dityrosine, and COX-2 immunopositivity more effectively than melatonin did. This is a noteworthy result precisely because melatonin is something of a benchmark in oxidative-stress research, a hormone with a long track record of protecting reproductive tissues in animal models. For ATP to outperform it suggests that the mechanism of lamotrigine-induced injury is not simply an excess of free radicals but something more fundamental: a collapse of cellular energy homeostasis that melatonin, however capable a radical scavenger, cannot fully correct.

The authors propose that exogenous ATP works by restoring cellular energy balance and modulating inflammatory signaling, thereby addressing the injury at its energetic root rather than mopping up radicals downstream. The idea has an elegant logic. If lamotrigine perturbs intracellular ATP levels and that perturbation drives reactive oxygen species generation, then replenishing ATP supplies the cell with the resources it needs to run its own antioxidant machinery, including the energy-dependent repair enzymes that excise oxidized DNA bases and refold or degrade damaged proteins. In this framing, melatonin treats the symptom while ATP treats the cause, which would explain the superior outcomes across the biochemical, histological, and immunofluorescence readouts.

Several caveats deserve emphasis before anyone extrapolates these findings to the clinic. The study was conducted in rats over thirty days, with doses and routes of administration that do not map one-to-one onto human pharmacology. The high lamotrigine dose of thirty milligrams per kilogram exceeds typical human therapeutic exposure on a body-weight basis, and the ATP was delivered intraperitoneally, raising questions about how exogenous ATP would reach ovarian tissue in patients. The pre-treatment design, in which protection was given an hour before the drug, also differs from the real-world scenario in which a patient is already taking lamotrigine before any protective agent is considered. Whether ATP remains protective when given alongside or after the drug is unknown.

Even so, the study opens a genuinely novel therapeutic direction. If the findings hold up in translational work, cellular bioenergetic restoration could become an adjunctive strategy for protecting the ovary during chronic high-dose lamotrigine exposure, and perhaps during other drug treatments known to disturb cellular energy metabolism. For the many young women who must take antiseizure medications for years, the prospect of a fertility-sparing intervention is compelling. The Turkish team’s demonstration that a molecule as fundamental as ATP can shield the ovary more effectively than a celebrated antioxidant reframes drug-induced reproductive injury as, at least in part, an energy problem, and energy problems may have energy solutions. Further studies in larger animal models and, eventually, carefully designed clinical trials will determine whether this laboratory insight can be translated into a practical therapy for patients.

Subject of Research: The protective effects of exogenous adenosine triphosphate against lamotrigine-induced oxidative ovarian injury in rats

Article Title: ATP mitigates high-dose lamotrigine-induced oxidative ovarian injury in rats more effectively than melatonin: insights from biochemical parameters, histopathology, and 8-OHdG, dityrosine, and COX-1/COX-2 double immunofluorescence

Article References: Yilmaz, N., Paltaci, S. I., Yavuzer, B., Sarigul, C., Ozkaraca, M., Gungor, A., Suleyman, B., Mammadov, R., & Suleyman, H. (2026). ATP mitigates high-dose lamotrigine-induced oxidative ovarian injury in rats more effectively than melatonin: insights from biochemical parameters, histopathology, and 8-OHdG, dityrosine, and COX-1/COX-2 double immunofluorescence. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02273-w

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02273-w

Keywords: lamotrigine, adenosine triphosphate, melatonin, oxidative stress, ovary, ovarian injury, anti-Mullerian hormone, 8-OHdG, dityrosine, cyclooxygenase, rats, reproductive toxicology