Acute laryngeal dystonia (ALD) is a rare but potentially fatal extrapyramidal adverse effect of high-dose antipsychotic medications like haloperidol. It presents with sudden contraction of laryngeal muscles that causes narrowing of the airway, which rapidly progresses to respiratory failure if not promptly recognized. We report a 45-year-old male patient with schizophrenia who developed respiratory distress and inspiratory stridor within 15 minutes of receiving haloperidol for postoperative agitation following emergent abdominal surgery. Initial management with epinephrine failed to improve symptoms. Given the temporal association with haloperidol administration, an acute dystonic reaction was suspected, and the patient was promptly treated with intravenous diphenhydramine and benztropine, resulting in immediate improvement of respiratory distress. Anticholinergic therapy was continued for one week with no recurrence of symptoms. This case highlights the importance of early recognition of ALD in postoperative and critical care settings, as timely administration of anticholinergic agents can be life-saving and may prevent unnecessary endotracheal intubation. It is recommended to continue anticholinergic agents for a prolonged period of time, even after haloperidol discontinuation, to prevent the recurrence of symptoms that have been reported in many cases in the past.

Background and Clinical Significance: Withdrawal symptoms from an abrupt discontinuation or rapid dose reduction in amantadine has been documented as early as 1987. Symptoms can align with several diagnoses, including but not limited to infection, fever, worsening of Parkinson's disease, seizures, and an altered mental status. In the case described, the timely diagnosis of amantadine withdrawal was delayed due to its nonspecific presentation. Case Presentation: A man in his 60s presented with lethargy, confusion, and delayed responses. His past medical history included parkinsonism, a seizure, type 2 diabetes, and schizoaffective disorder. Outpatient medications included amantadine, benztropine, divalproex, levetiracetam, paliperidone, risperidone, and semaglutide. He was admitted for an altered mental status, and home medications were held when he became NPO. A nasogastric tube was placed, and amantadine was restarted. Following the amantadine reinitiation, the patient returned to baseline and, after ruling out other causes, was diagnosed with amantadine withdrawal. He ultimately completed a 20-day admission and was discharged to a nursing home. Conclusions: The timely diagnosis of amantadine withdrawal was delayed due to its nonspecific presentation. For patients taking amantadine, clinicians should include amantadine withdrawal in their list of differential diagnoses, and in cases of altered mentation, a careful review of the medication list is essential.

Myelination is essential for rapid axonal conduction and neuronal integrity, and its loss in demyelinating diseases such as multiple sclerosis (MS) leads to progressive neurological impairment. Despite advances in immunomodulatory therapies, effective strategies that promote remyelination remain limited. Here, we identify Morusin, a prenylated flavonoid natural compound, as a potent enhancer of oligodendrocyte (OL) differentiation and myelination-associated outcomes. Using a fluorescence-based screen of diverse flavonoids in primary rat oligodendrocyte progenitor cells (OPCs), it was found that Morusin markedly increased myelin basic protein (MBP) expression. To enable cross-species validation, we established a SOX10-inducible human OPC differentiation system, which shortened differentiation time and allowed functional screening in human cells. In this platform, Morusin enhanced OL maturation and induced a transcriptional profile enriched for myelination- and axon ensheathment-related genes, including MBP, PLP1, MAG, and SIRT2. Furthermore, in myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) mice, Morusin improved myelination-associated histological features and functional recovery, comparable to the benchmark compound Benztropine. Collectively, these findings identify Morusin as a promising natural compound with pro-myelinating activity across multiple experimental systems and highlight the potential of rationally guided natural compound screening for regenerative therapy in demyelinating diseases.

This study reports a case of tardive dyskinesia (TD) and depression in a patient with long-term use of antipsychotic and anticholinergic drugs, through the tapering and discontinuation of anticholinergic drugs and the concurrent use of deutetrabenazine combined with modified electroconvulsive therapy (MECT). Her TD symptoms have completely improved. The score on the Hamilton Depression Rating Scale (HAMD-17) has dropped from 20 points to eight points, and the depressive symptoms have improved by 60%. A 31-year-old woman with a mood disorder, treated with risperidone (dose range: 4 mL/day, duration: 11 months), olanzapine (dose range: 10 mg/day, duration: 11 months), and benztropine (dose range: 6 mg/day, duration: four months) for recurrent depression, developed lip twitching, bradykinesia, and worsened depression. Upon admission on February 4, benztropine was tapered and discontinued by February 22. A new regimen of deutetrabenazine combined with MECT was initiated on February 7. Following 15 days of this combined treatment, the patient's TD symptoms completely resolved. The HAMD-17 score dropped from 20 to eight, and the Brief Psychiatric Rating Scale (BPRS) score initially fluctuated but then stabilized and improved. No recurrence was observed during a 10-day follow-up post-discharge. This case study indicates that stopping anticholinergic drugs and using vesicular monoamine transporter 2 (VMAT2) inhibitors with MECT can quickly alleviate symptoms in patients with TD and mood disorders. Clinicians should be aware of the long-term motor disorder risks of antipsychotics, perform regular screenings, and focus on multi-target interventions. Future research should increase sample sizes to confirm the treatment's general applicability and long-term safety.

Anticholinergic medications (ACMs) prescribed for the treatment of antipsychotic-associated extrapyramidal symptoms (EPSs) are frequently prescribed for durations that exceed expert guidelines and are associated with significant side-effect burden. Evidence suggests that education with regard to the risks of long-term prescribing of ACMs for resolved EPSs may be lacking in the health care community, and no best practices exist for deprescribing ACMs. This review discusses EPSs and their treatment with two ACMs, benztropine and trihexyphenidyl, and it presents evidence of the risks of chronic ACM prescribing, including serious side effects such as cognitive impairment, dry mouth, blurred vision, and risk for delirium, as well as sequelae of severe constipation and urinary retention. It is pertinent to remember that many psychotropic agents, including several antipsychotics, as well as other commonly prescribed medications have moderate to strong anticholinergic properties. Each ACM, when prescribed with other medications concomitantly, compounds ACM burden and associated side effects. Informed by the authors' extensive experience with quality improvement projects on deprescribing ACMs, this review examines both the benefits and risks of ACM deprescribing, with an emphasis on choosing appropriate patients and engaging in shared decision making while utilizing patient-facing assessments and decision-support tools. ACM tapering schedules are suggested, along with recommendations for closer patient monitoring during the deprescription process. Barriers to deprescription at the patient, prescribing clinician, and system level are then reviewed, along with relevant ethical considerations inherent to any medication changes, including ACM deprescribing.

Stress-related emotional disorders, such as post-traumatic stress disorder (PTSD) and major depression, increase alcohol relapse risk. PTSD, depression, and alcohol use phenotypes associate with gene variants of FKBP prolyl isomerase 5 (FKBP5), a chaperone modulator of glucocorticoid receptors (GR). FKBP51 inhibitors can decrease ethanol intake, but FKBP51's role in recurrence of post-stress ethanol drinking is unknown. We tested the hypotheses that expression of Fkbp5 and immediate early genes (IEGs) in the central nucleus of the amygdala (CeA) is increased in rats with a history of defeat or foot-shock stress and associates with faster submission and increased reacquisition of ethanol self-administration. We tested if benztropine mesylate, an FDA-approved drug that inhibits FKBP51-GR binding, reduces reacquisition of ethanol self-administration in rats with a history of foot-shock stress. Wistar rats were studied after resident-intruder social defeat (n = 32) or in an ethanol self-administration reacquisition model, with or without repeated foot-shock history (n = 62). Acute social defeat stress increased CeA IEG expression within 1 h Fkbp5 expression by 6 h. CeA IEG activation correlated with Fkbp5 expression, and both correlated with faster submission to defeat. CeA Fkbp5 expression also associated with greater ethanol intake and blood ethanol concentration during reacquisition of ethanol self-administration. Benztropine (i.p., 5, 10 mg/kg) dose-dependently reduced relapse-like ethanol reacquisition, and sex-specific analyses suggest a more robust effect in males than females. The results warrant the study of CeA FKBP51 in passive stress coping and of drug-like selective FKBP51 inhibitors to reduce ethanol relapse after histories of repeated stress.

Drug-induced Parkinsonism (DIP) is a recognized extrapyramidal side effect (EPS) associated with prolonged antipsychotic therapy, and typically occurs early in antipsychotic initiation. We present a rare case of late-onset DIP in a 64-year-old previously incarcerated male veteran with schizophrenia, who had been maintained on risperidone for nearly 40 years without regular psychiatric follow-up. The patient presented with a one-month progression of rigidity, dysarthria, and dysphagia. Upon admission, neurological evaluation revealed significant cogwheel rigidity, slow speech, flat affect, and dysdiadochokinesia consistent with DIP. Treatment involved gradual tapering of risperidone, introduction of benztropine for symptomatic relief, and initiation of aripiprazole to maintain psychiatric stability. Symptoms markedly improved, reaffirming the diagnosis of DIP over idiopathic Parkinson's disease. This case emphasizes the importance of regular medication review and follow-up in managing antipsychotic therapy to prevent severe EPS complications, particularly in vulnerable populations such as incarcerated individuals and military veterans.

Intellectual disability (ID) arises from complex pathogenic mechanisms. Although myelin dysfunction and white matter damage have been implicated, the cellular and molecular mechanisms linking impaired myelination to cognitive deficits remain largely unknown. Here, we identify a de novo heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) variant, c.638C>T (p.Pro213Leu), in patients with ID. The Hnrnph2[P213L] knock-in mice display spatial learning deficits, representing a partial phenotypic overlap with HNRNPH2-related neurodevelopmental disorder. Notably, Hnrnph2[P213L] mice exhibit significant myelination defects, primarily due to the impaired differentiation of oligodendrocyte progenitor cells. Furthermore, the myelin-enhancing drug benztropine rescues myelination, restores myelin-related gene expression, and ameliorates cognitive deficits, highlighting the role of hnRNPH2 P213L-induced myelin abnormalities in the pathogenesis of ID. Mechanistically, the P213L mutation disrupts the interaction between hnRNPH2 and its target transcripts, leading to the downregulation of myelination-related genes. Collectively, these findings reveal a critical mechanistic connection between myelin dysfunction and ID, thereby offering potential therapeutic insights for X-linked neurodevelopmental disorders.

Parkinson's disease is considered a neurodegenerative brain affection where the substantia nigra, a group of dopamine producer neurons are eliminated and hence, dopamine levels go to dangerous lower levels. With this molecule limited, an imbalance in neurotransmitters is set, a decreased neurological activity is set affecting the motion and several communication pathways. The most recognized outcome lies in the motor cortex, which is characterized by different motor symptoms such as bradykinesia, rigidity, uncontrollable tremors, imbalance, stiffness, and sudden slowness for several corporal movements. Since this is an incurable disease, pharmacological studies focus on the symptom's elimination and palliative care, researching on dopaminergic transporters (DAT) blockage to enhance the action of exogenous dopamine by stopping dopamine reabsorption and allowing correct neurotransmission. Several chemical structures have been evaluated and one of the most popular, benztropine, recently has been synthetically and biologically studied by several research groups. In this document we briefly discuss the disease to guide the reader in the journey of several research groups that have selected dopamine receptors and channels as targets for drug development, broadly focused on the synthesis and action mechanism of benztropine and analogs for Parkinson's disease treatment, in order to showcase the potential of molecules that seem obsolete when chemical modification is on reach and the power of the chemical tools for their modification.

Drug-induced non-ischemic priapism is a rare but critical condition in children. Aripiprazole, an atypical antipsychotic, has been associated with priapism, mostly in adults. Prompt recognition is essential to prevent permanent sequelae. An 8-year-old boy, with a complex past medical history including prior dystonic reactions, presented with acute dystonia and subsequent priapism following inadvertent administration of Aripiprazole. The erection persisted for approximately five hours, partially responsive to Diphenhydramine and Benztropine. Urologic evaluation confirmed ischemic priapism. Conservative management was successful, and no surgical intervention was needed. Doppler ultrasound of the penis showed normal flow without thrombosis. The patient remained clinically stable, experiencing only brief, intermittent episodes of erection, each of which resolved with conservative management. This case underscores the potential for Aripiprazole-induced priapism in the pediatric population, despite its generally favorable safety profile. Early recognition and timely urologic consultation are essential for optimal outcomes. When identified promptly, conservative management may be effective in avoiding invasive intervention.

Managing multiple sclerosis (MS), a chronic, neuroinflammatory and demyelinating disease, remains an unmet medical need. A great obstacle to developing therapeutic interventions altering the disease process is the lack of a suitable disease model recapitulating its core pathologies, especially the process of myelin damage and regeneration against the backdrop of persistent neuroinflammation. Now we report the generation and characterization of a new demyelination/remyelination model with key pathological features of MS through repeated ablations of Tmem10+ oligodendrocytes. Using the Tmem10-Cre driver that targets expression of diphtheria toxin receptor (DTR) in Tmem10+ (mature myelin-forming) oligodendrocytes, we conducted 3 rounds of Tmem10+ oligodendrocyte ablations over the span of 9 weeks in young adult mice by injecting diphtheria toxin (DT). Three rounds of the oligodendrocyte ablation caused prolonged demyelination and axonal injury in the backdrop of chronic neuroinflammation, including gliosis and lymphocyte infiltration. In response to the oligodendrocyte ablations, the proliferation and differentiation of OPCs were accelerated for the regeneration of myelin-forming oligodendrocytes, leading to spontaneous remyelination. This de-/re-myelination model presents a wide "time window" between the onset of demyelination and spontaneous remyelination, which makes it suitable for assessing the efficacy of therapeutic pro-remyelinating agents, as demonstrated by administering Benztropine to this demyelination model.

Serotonin syndrome is a life-threatening condition characterized by neuromuscular hyperactivity, autonomic dysregulation and altered mental status. Polypharmacy in older adults with multiple comorbidities is associated with increased risk of serotonin syndrome. We report a woman in her 50s with diabetes, hypertension and chronic kidney disease recently misdiagnosed with Parkinsonism. She presented with confusion, hyperreflexia, myoclonus and autonomic instability. Her medications included supratherapeutic paroxetine (40mg two times per day), aripiprazole and benztropine. Symptoms improved with cyproheptadine and cessation of serotonergic agents. However, persistent motor findings prompted further evaluation. Cervical spine MRI showed C4-C5 disc protrusion with ventral cord compression, while brain imaging revealed cerebral atrophy. Cautious administration of haloperidol did not worsen symptoms, suggesting drug-induced or structural Parkinsonism. This case highlights the risk of uncoordinated pharmacotherapy and premature diagnostic closure. The presentation of serotonin syndrome may obscure underlying neurologic pathology, making thorough medication review and multidisciplinary evaluation essential in complex geriatric presentations.