Psychostimulants such as methylphenidate (MPH) and modafinil (MOD) are effective in attention-deficit/hyperactivity disorder and narcolepsy but may induce behavioral activation, anxiety-like responses, and cognitive alterations, particularly under stress. Buspirone (BUS), a nonsedative anxiolytic acting as a partial 5-HT1A receptor agonist, may influence stimulant-related behavioral effects. This study evaluated whether BUS modifies behavioral outcomes induced by chronic MPH and MOD administration in rats exposed to repeated restraint stress. Adult male Sprague-Dawley rats received oral MPH (10 mg/kg), MOD (75 mg/kg), BUS (10 mg/kg), or their combinations for 35 days under restrained or nonrestrained conditions. Behavioral assessments included locomotor activity, exploratory performance (open-field and head-dip tests), and memory evaluation using passive avoidance and Morris water maze paradigms. MPH and MOD alone increased locomotor activity and altered exploratory behavior, with effects influenced by stress conditions. BUS coadministration attenuated stimulant-induced hyperactivity and modulated exploratory responses. BUS alone reduced passive avoidance latency, which may reflect anxiolytic effects rather than impaired memory, while combined treatment indicated modulation of stimulant-associated cognitive outcomes. BUS may reduce stimulant-induced behavioral activation under stress, suggesting its potential as an adjunct to improve the behavioral tolerability of psychostimulant therapy.

Idiopathic hypersomnia (IH) is a chronic central disorder of hypersomnolence characterized by excessive daytime sleepiness despite adequate or prolonged sleep, with potentially substantial effects on occupational functioning, cognition, and driving safety. Pharmacologic management may be challenging when treatment is limited by inadequate efficacy or adverse effects. We report a young woman with severe hypersomnolence and a diagnosis of IH supported by clinical history and objective sleep testing. Multiple sleep latency testing demonstrated a mean sleep latency of one minute and 22 seconds, with no sleep-onset rapid eye movement periods (SOREMPs). Her Epworth Sleepiness Scale (ESS) score was 18/24, and symptoms included prolonged sleep duration, extended daytime naps, occupational impairment, and drowsy driving. Modafinil initially produced substantial benefit but subsequently lost efficacy despite dose escalation. Sequential trials of armodafinil, solriamfetol, mixed amphetamine salts, and methylphenidate were limited by tachycardia, inadequate efficacy or poor tolerability, paranoia, and persistent late-day sleepiness, respectively. Lower-sodium oxybate was subsequently initiated at 3 g once nightly but was reduced to 2.25 g because of significant nausea. With slower, individualized titration to 5.5 g once nightly, the patient reported substantial improvement in daytime sleepiness and functioning. Her ESS score decreased from 18/24 to 4/24, scheduled methylphenidate and caffeine were no longer required, and daytime napping was markedly reduced. This case illustrates the challenges of longitudinal pharmacologic management of IH and highlights the importance of individualized treatment selection, tolerability-guided oxybate titration, and assessment of functional outcomes beyond standardized sleepiness scores.

The coexistence of multiple primary sleep disorders in a single patient is uncommon and poses significant diagnostic and therapeutic challenges. We report a 45-year-old woman with severe mixed sleep apnea (OSA/CSA), NREM parasomnia (night terrors), sleep-related eating disorder (SRED), nightmare disorder (with RBD like behavior but no REM atonia on PSG), and central hypersomnolence phenotype minimally affected with PAP optimization and delayed sleep-wake phase disorder. Symptoms began more than two decades earlier and included violent dream-enactment behaviors, hypnopompic hallucinations, sleep inertia, and chronic excessive daytime sleepiness (EDS). Treatment required multi-modal therapy. Positive airway pressure therapy successfully treated sleep disordered breathing while pitolisant and solriamfetol produced the most durable improvement in daytime sleepiness. Together melatonin plus clonazepam reduced parasomnia frequency and severity. Several other agents (including prazosin, sodium oxybate, paroxetine, and modafinil) were tried and discontinued for limited benefit or adverse effects. Notably, GLP-1 receptor agonist (GLP-1 RA) therapy for obesity was followed by a substantial weight loss and coincided with resolution of SRED. Because this occurred alongside improved sleep stability, PAP adherence, behavioral adaptation, and medication changes, causality cannot be inferred. The observation may justify further study of metabolic and incretin-related pathways in sleep-related eating behaviors. Overall, this case highlights the complexity of overlapping sleep-wake disorders, the need for individualized pharmacologic sequencing, and a potential emerging role for GLP-1 agonists in SRED.

Obstructive sleep apnea (OSA) is a common disorder whose clinical expression and daytime sleepiness may evolve over time, particularly in the presence of coexisting sleep disorders. We report a nine-year longitudinal case of a 29-year-old man presenting initially with severe excessive daytime sleepiness (EDS) (Epworth Sleepiness Scale (ESS) score: 19/24) and mild OSA (apnea-hypopnea index (AHI): 10 events/h), who represented nine years later with disabling sleepiness, weight gain (body mass index: 30.2 kg/m[2]), and typical cataplexy. No documented sleep medicine follow-up or OSA treatment was available during the intervening nine-year period. Repeat polysomnography demonstrated moderate, rapid eye movement (REM)-predominant OSA (AHI: 20.4 events/h; REM-AHI: 52.9 events/h; non-REM (NREM)-AHI: 9.4 events/h; REM-AHI/NREM-AHI ratio: 5.6), with increased sleep fragmentation. The Multiple Sleep Latency Test (MSLT), performed after diagnostic polysomnography and before continuous positive airway pressure (CPAP) optimization, showed severe objective sleepiness (mean sleep latency: 3.7 minutes) with sleep-onset REM periods in all five nap opportunities. In the setting of typical cataplexy, these findings strongly supported a diagnosis of narcolepsy type 1; however, untreated OSA and sleep fragmentation at the time of testing were acknowledged as potential confounders in the interpretation of the MSLT. Management included fixed-pressure CPAP at 8 cm H2O, sertraline for cataplexy, and modafinil for EDS. At 30-day follow-up, CPAP downloads showed use on 60% of nights, with a residual AHI of 3.1 events/h and mean leak of 35 L/min, indicating effective control of respiratory events when therapy was used, but suboptimal adherence and mask leak likely limiting clinical benefit. This case highlights three key clinical messages: EDS disproportionate to OSA severity should prompt evaluation for a coexisting central disorder of hypersomnolence; REM-predominant OSA can coexist with narcolepsy type 1 without implying a causal relationship between the two disorders; and their relative contributions to sleepiness may change over time. When MSLT is required in a patient with OSA, effective treatment of OSA and adequate documentation of prior sleep are important for reliable interpretation. Management should address both OSA and narcolepsy and include periodic reassessment as the clinical phenotype evolves.

Persistent excessive daytime sleepiness (EDS) following aneurysmal subarachnoid hemorrhage (SAH) is an underrecognized complication that may impair quality of life and patient safety. We report a 60-year-old man with EDS that had been present for approximately one year and progressively worsened following aneurysmal SAH despite adequately treated obstructive sleep apnea. Overnight polysomnography (PSG) demonstrated well-controlled sleep-disordered breathing, while the multiple sleep latency test (MSLT) revealed severe objective hypersomnolence, supporting a diagnosis of secondary central hypersomnia. Alternative causes of EDS were excluded through clinical evaluation and objective sleep testing. The patient experienced meaningful improvement following treatment with modafinil. This case highlights the importance of considering secondary central hypersomnia in patients with persistent EDS after aneurysmal SAH. It demonstrates the value of PSG followed by MSLT in establishing the diagnosis and guiding management.

This study aimed to elucidate the dynamic impact of acute hypobaric hypoxia (HH) on the pharmacokinetics of modafinil (MOD) and its association with liver injury and regulation of the key metabolizing enzyme Cyp3a11. A mouse model combining acute HH (simulating 5000 m) with 24 hours sleep deprivation was established. MOD was administered by gavage. Assessments included the Morris water maze test, high-performance liquid chromatography pharmacokinetic analysis, serum alanine aminotransferase/aspartate aminotransferase measurement, hepatic H&E staining, and analysis of Cyp3a11 expression via quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry assays. HH exacerbated cognitive deficits, which were ameliorated by MOD. It induced biphasic pharmacokinetic alterations: accelerated absorption (higher early plasma concentration) but impeded elimination (increased area under the plasma concentration-time curve, prolonged mean residence time, and decreased apparent clearance). These changes correlated with time-dependent liver responses: after 1 hour HH, alanine aminotransferase/aspartate aminotransferase transiently decreased with compensatory Cyp3a11 upregulation but no significant histopathological damage; after 24 hours HH, progressive liver injury (inflammation, vacuolation, and necrosis) developed alongside significant suppression of Cyp3a11 expression. While MOD retains cognitive-enhancing efficacy under HH, its pharmacokinetics are markedly altered. The shift from accelerated absorption to delayed elimination is closely associated with HH-induced biphasic regulation of hepatic Cyp3a11 and progressive liver injury, indicating a need for optimized dosing strategies in HH scenarios. SIGNIFICANCE STATEMENT: This study reveals how high-altitude hypoxia alters modafinil's pharmacokinetics and efficacy via hepatic Cyp3a11 regulation, offering critical insights for optimizing drug use in hypobaric hypoxia environments.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability worldwide and is frequently associated with persistent impairments in consciousness, cognition, mood, and functional independence. Despite advances in acute neurocritical care, effective therapies that enhance neurological recovery remain limited. Neuromodulation has emerged as a promising strategy to augment neuroplasticity and improve recovery through both pharmacologic and non-pharmacologic approaches. This narrative review summarizes current evidence supporting pharmacologic neuromodulatory therapies, including central nervous system stimulants (methylphenidate and modafinil), dopaminergic agents (amantadine and bromocriptine), acetylcholinesterase inhibitors (donepezil and rivastigmine), and selective serotonin reuptake inhibitors (sertraline and fluoxetine). Mechanisms of action, clinical efficacy, adverse effects, and practical considerations across the acute, subacute, and chronic phases of TBI recovery are discussed. Emerging non-pharmacologic neuromodulation techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, vagus nerve stimulation, and deep brain stimulation, are also reviewed. Although amantadine remains the only neuromodulator supported by moderate-quality guideline recommendations for accelerating recovery in disorders of consciousness, accumulating evidence suggests that several additional pharmacologic and non-pharmacologic neuromodulation interventions may improve attention, executive function, fatigue, mood, and rehabilitation participation in carefully selected patients. However, current evidence is limited by heterogeneous study populations, small sample sizes, inconsistent outcome measures, and a paucity of long-term randomized controlled trials. Future research should prioritize adequately powered comparative studies, standardized outcome measures, biomarker-guided patient selection, and multimodal treatment strategies to optimize neurological recovery following TBI.

Dopamine signaling dysregulation is an important feature of numerous central nervous system (CNS) diseases and disorders including psychostimulant use disorder (PUD). Atypical dopamine transporter (DAT) inhibitors have been developed as potential candidates for PUD treatment. Herein, we develop eight new pH sensitive chemical probes with potential of an atypical DAT inhibition profile by incorporating fluorescent anthracene units into the pharmacophore of either modafinil or benztropine. Five new anthracene analogues showed significantly higher affinity for wildtype DAT compared to the outward-facing biased DAT mutant Y156F, which is a characteristic of atypical inhibitors. Additionally, the compounds generally showed higher affinities for DAT over the serotonin transporter (SERT). These novel probes may be used to assess the degree of amine protonation upon protein binding, hence the de facto pH in the active site and consequently if a pH difference between classical and atypical binding exists.

Sodium oxybate (SO) is an effective therapy for narcolepsy type 1 (NT1) but has been infrequently linked to complex sleep-related behaviors. We describe a case of NT1 who developed sleep-related eating disorder (SRED) after progressive gradual titration of SO. A 15-year-old female was diagnosed with NT1. Symptoms remained disabling despite high doses of modafinil and venlafaxine, and thus SO was initiated and titrated over months. After increasing to a dose of 4 g twice per night, the family reported episodes of partial arousal with altered consciousness beginning 1-2 h after the first dose, where the patient left the bed, ate large quantities of calorie-dense foods, and appeared unresponsive, before returning to bed again with complete amnesia. These episodes contributed to significant distress for the patient and her family, and notable weight gain. Gradual dose reduction to 7 g/night combined with structured behavioral interventions (dietary modification, bedside snacks, and environmental safety measures) successfully resolved SRED while maintaining excellent cataplexy control, demonstrating that combined management strategies can avoid medication discontinuation.

Pharmacological management has been the backbone of treatment for disorders of central hypersomnolence despite challenges in drug administration due to intolerable side effects, development of tolerance, and addiction potential. Recent advances in drug therapies for central hypersomnolence disorders, namely sodium oxybate and orexin agonists, have either changed or increased the potential to significantly improve the quality of life of individuals with narcolepsy and idiopathic hypersomnia. Mechanisms of action, pharmacodynamics and pharmacokinetics of previously and commonly used medications, along with the evidence behind their use, are discussed. In addition, oveporexton, an orexin receptor 2 agonist (OX2R) will be discussed as it marks an important first step in directly counteracting the pathology behind narcolepsy with cataplexy and has completed Phase 2 trials with Phase 3 underway. Early clinical data is promising; however, its long term efficacy and safety data is insufficient to garner US Food & Drug Administration approval, though additional trials are ongoing in narcolepsy with cataplexy, and non-orexin deficient central hypersomnolence disorders as well. Regardless, new drug developments may lead expanded treatment options and may have the potential to decrease or potentially eliminate the need for polypharmacy in the treatment algorithm for narcolepsy and idiopathic hypersomnia.