Overview of the PRN

The Central Nervous System Practice and Research Network (CNS PRN) provides a forum to encourage networking among pharmacists, trainees, and other health science professionals with clinical and/or research interest in CNS disorders. Its membership includes individuals with expertise in neurology, psychiatry, and neurocritical care. In addition, the CNS PRN has dedicated committees, which trainees are highly encouraged to participate in, responsible for educational programming, recognition and nominations, social media communication, and research and grants.

Membership Overview

Total Members: 192

Student Members: 45

Resident/Fellow Members: 7

Current CNS PRN Officers (2023–2024)

Chair: Jason Chau

Chair-Elect: Roxana Dumitru

Secretary-Treasurer: Brittany Vickery

Current Committee Chairs (2023–2024)

Communications: Craig Furnish

Education: Emily Laswell

Recognition and Nominations: Bridget Bradley and Susan Hamblin

Research and Grant: Brent Sokola

Student and Trainee: Adam Gummersheimer

Opportunities for Student, Resident, and Fellow Members

The CNS PRN highly encourages the participation of students, residents, and fellows in all facets of the PRN. One of the easiest ways to get involved is to serve on one of its committees. Trainees can share their interest in joining a committee by completing the Call for Interest sent out annually in late August or reaching out to the CNS PRN chair (https://www.accp.com/prns/officers.aspx).

The CNS PRN has five committees available for member involvement: Recognition and Nominations, Education, Research and Grant, Communications, and Student and Trainee. Each committee welcomes and encourages trainee input. The Recognition and Nominations Committee focuses on highlighting PRN members’ achievements throughout the year. The Education Committee supports educational programming regarding topics of interest in the CNS space; this past year, the topics included status epilepticus, insomnia, circadian rhythm disorders, and restless legs syndrome. The Research and Grant Committee supports members hoping to conduct studies related to CNS disorders and promotes student involvement in research. The Communications Committee puts together the Spring and Fall newsletters and runs the CNS PRN social media accounts (currently twitter/X [@accpcnsprn] and Instagram [@cns_prn]). Finally, the Student and Trainee Committee supports all levels of trainees with a mentor/mentee program and journal club/case presentation opportunities.

The CNS PRN usually offers multiple trainee travel awards each year. Awardees usually receive a monetary award to help support attendance to the ACCP Annual Meeting/Global Conference as well as an opportunity to present their research or a clinically related project at the CNS PRN Business Meeting and Networking Forum.

With its 192 members, the CNS PRN is very accessible for networking. The CNS PRN Business Meeting and Networking Forum welcomes student, resident, and fellow members, which, in the PRN’s experience, provides an excellent opportunity for trainees to get to know current members.

Current Clinical Issue

New Drug Update: Xanomeline/Trospium (KarXT)

By: P. Brittany Vickery, Pharm.D., BCPS, BCPP, CPP

Associate Editor, High-Yield Med Reviews

Xanomeline/Trospium: A Pipeline Medication for Schizophrenia and Psychosis Associated with Alzheimer Disease

Introduction

Xanomeline/trospium is a novel muscarinic antipsychotic that is being researched for the treatment of schizophrenia and psychosis related to Alzheimer disease. Xanomeline/trospium exhibits its mechanism of action through dual M₁ and M₄ muscarinic acetylcholine receptor orthosteric agonism in the CNS with peripheral antagonism at the M₂ and M₃ receptors. It binds in the same area that acetylcholine binds. M₄ agonism in the hindbrain and striatum prevents activation of mesolimbic dopaminergic neurons and reduces positive symptoms while limiting extrapyramidal symptoms. M₁ agonism in the frontal cortex blocks excessive stimulation of dopamine release by glutamate in the mesolimbic pathway, reducing positive symptoms while also increasing dopamine release in the mesocortical pathway and improving negative and cognitive symptoms. Hence, this avoidance of direct dopamine receptor inhibition or blockade is postulated to improve hallmark symptoms of schizophrenia across positive symptoms, negative symptoms, and cognitive symptom domains. Trospium is combined with xanomeline as a peripheral anticholinergic agent to offset the anticholinergic effects of xanomeline, but trospium has central anticholinergic effects itself, including somnolence, dizziness, hallucinations, and confusion. The EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials have been conducted with several subgroup analyses as well.

Clinical Evidence

EMERGENT-1 was a 5-week randomized, double-blind, placebo-controlled, phase II trial that assessed the efficacy and safety of xanomeline/trospium in 182 enrolled (250 screened) adults 18–60 years of age who were experiencing an acute exacerbation of schizophrenia requiring hospitalization. A total of 12 inpatient sites in the United States enrolled participants between September 2018 and August 2019. The study excluded patients who had a primary diagnosis other than schizophrenia, a history of antipsychotic treatment resistance, or a Positive and Negative Syndrome Scale (PANSS) total score decrease of 20% or more between screening and baseline. Eligible patients were randomly assigned in a 1:1 ratio to receive twice-daily dosing of oral xanomeline/trospium (50 mg/20 mg was the initial dose, and the maximum was 125 mg/30 mg flexible dosing or placebo).

Of the patients enrolled, 179 received at least one dose. Baseline characteristics were divided by those younger than 44 years and those 44 and older. Most of the participants were male. The most commonly reported adverse effects included nausea, vomiting, constipation, dyspepsia, dry mouth, and sedation. Two patients (2.2%) in the xanomeline/trospium group and five (5.6%) in the placebo group experienced a greater than 7% change in body weight. There were no significant or clinically meaningful changes in cholesterol, blood glucose, or triglyceride concentrations from baseline to week 5. At the end of the 5 weeks, the treatment group had a -17.4 change in the PANSS score from baseline compared with a -5.9 change in the placebo arm (p<0.001). Secondary outcomes of the PANSS positive symptom subscore, Clinical Global Impression-Severity (CGI-S) scale, and negative symptom subscore were also superior in the active arm (p<0.001).

EMERGENT-2 was a 5-week, randomized, placebo-controlled, double-blind, flexible-dose, inpatient, phase III trial of people with schizophrenia. Participants were adults 18–65 years of age with a diagnosis of schizophrenia who had a recent worsening of psychosis that required hospital admission. In addition, participants must have had a PANSS score of 80 or higher and a CGI-S score of 4 or higher. Participants were recruited from 22 inpatient sites in America and randomly assigned in a 1:1 fashion to xanomeline/trospium or placebo twice daily. Participants randomly assigned to xanomeline/trospium received 50 mg of xanomeline and 20 mg of trospium twice per day for the first 2 days, which was then increased to 100 mg of xanomeline and 20 mg of trospium twice per day for the next 5 days. On day 8, xanomeline/trospium dosing was flexible with the option to either increase to 125 mg of xanomeline and 30 mg of trospium twice per day or decrease back to 100 mg of xanomeline and 20 mg of trospium depending on tolerability. The primary end point was the change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population.

From December 16, 2020, to April 13, 2022, of the 407 people who were screened, the 252 participants who met the enrollment criteria were randomly assigned to xanomeline/trospium (n=126) or placebo (n=126). Baseline PANSS total scores were 98.3 (xanomeline/trospium; n=126) and 97.9 (placebo; n=125). The trial met the primary end point with a mean change from baseline to week 5 in PANSS total score that favored xanomeline/trospium (-21.2 points, SE 1.7) versus placebo (-11.6 points, SE 1.6; least-squares mean difference -9.6; 95% CI, -13.9 to -5.2; p<0.0001, Cohen’s d effect size 0.61). All secondary end points were also met, favoring xanomeline/trospium versus placebo (p<0.05).

The most common adverse events with xanomeline/trospium versus placebo were constipation (21% vs. 10%), dyspepsia (19% vs. 8%), headache (14% vs. 12%), nausea (19% vs. 6%), vomiting (14% vs. 1%), hypertension (10% vs. 1%), dizziness (9% vs. 4%), gastroesophageal reflux disease (6% vs. 0%), and diarrhea (6% vs. 3%). Treatment-emergent adverse event rates of extrapyramidal motor symptoms were reported at 0% in both groups. Akathisia, weight gain, and somnolence were similar between the xanomeline/trospium and placebo groups, as were adverse event–related discontinuation rates (7% vs. 6%).

In the EMERGENT-2 trial, xanomeline/trospium reduced positive and negative symptoms and was generally well tolerated. These results support the potential for xanomeline/trospium to represent a new class of effective and well-tolerated antipsychotic medicines based on activating muscarinic receptors, instead of the D₂ dopamine receptor-blocking mechanism of most current antipsychotic medications. Results from additional trials, such as the EMERGENT-3 and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of xanomeline/trospium in people with schizophrenia. An FDA decision should be made before the beginning of October 2024 regarding approval of this agent in the treatment of schizophrenia. If approved, it will be the first agent with a novel mechanism of action to the market in decades.

References

Brannan SK, Sawchak S, Miller AC, et al. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med 2021;384:717-26.

Correll CU, Angelov AS, Miller AC, et al. Safety and tolerability of KarXT (xanomeline–trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. Schizophrenia 2022(8):Article 109. Available at https://doi.org/10.1038/s41537-022-00320-1.

Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet 2024;403:160-70.

Kidambi N, Elsayed OH, El-Mallakh RS. Xanomeline-trospium and muscarinic involvement in schizophrenia. Neuropsychiatr Dis Treat 2023;19:1145-51.

Sauder C, Allen LA, Baker E, et al. Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Transl Psychiatry 2022;12:491.

Singh A. Xanomeline and trospium: a potential fixed drug combination (FDC) for schizophrenia – a brief review of current data. Innov Clin Neurosci 2022;19:43-7.

Stahl SM. Upstream with a Paddle: Regulating Dopamine via Trace Amine, Acetylcholine, and Glycine Modulation. Neuroscience Education Institute, 2023. Available at https://cdn.neiglobal.com/content/congress/2023/pdf-slides/23cg/C04_Upstream_Stahl_Slides.pdf.

Clinical Pearl: Management of Traumatic Brain Injury

By: Roxana Dumitru, Pharm.D., BCCCP, BCPS

Clinical Pharmacy Manager – Neurosciences ICU, Columbia University Irving Medical Center/NewYork-Presbyterian

Traumatic brain injury (TBI) is characterized according to the Glasgow Coma Scale (GCS) score and divided into mild (GCS 13–15), moderate (GCS 9–12), and severe (GCS 3–8) forms. After the initial insult is sustained, subsequent therapies in the treatment of these patients aim to minimize the risk of secondary brain injury. The Emergency Neurological Life Support algorithm outlines standard therapies that should be used in all patients with TBI, which include maintaining adequate analgesia and sedation, normothermia (while avoiding hypo/hyperthermia), euglycemia, and head of bed elevation to 30 degrees. Hypotension, hypoxemia, and hyponatremia should be avoided, and elevated intracranial pressures (ICPs) (sustained greater than 22 mm Hg for more than 5 minutes) should be treated. Coagulopathies should be corrected, including the reversal of antithrombotic medications, and seizure prophylaxis should be considered.¹ Table 1 summarizes specific recommendations as they apply to patients with severe TBI as outlined by the Brain Trauma Foundation (BTF) guidelines.²

Table 1. Summary of the BTF Recommendations for Management of Severe TBI²

^aRecommendations from a prior version of guidelines that are no longer supported by current evidence standards.

CPP = cerebral perfusion pressure; CSF = cerebrospinal fluid; EEG = electroencephalogram; EVD = external ventricular drain; ICP = intracranial pressure; LMWH = low-molecular-weight heparin; SBP = systolic blood pressure; TBI = traumatic brain injury; UFH = unfractionated heparin; VTE = venous thromboembolism.

Hyperosmolar Therapy

Hyperosmolar therapies lower ICP by acutely increasing blood osmolality, which creates a gradient facilitating fluid shift out of the brain.³ Although the BTF guidelines fail to recommend a specific hyperosmolar agent because of lack of data, the Neurocritical Care Society (NCS) guidelines suggest hypertonic saline (HTS) over mannitol for initial management of elevated ICP while also noting that mannitol is an effective alternative, particularly in patients with hypernatremia or volume overload.⁴ Although data suggest that both HTS and mannitol reduce ICP to similar degrees, neither has shown an improvement in neurologic outcomes in clinical trials.⁵ Hypertonic saline may have the added benefits of a quicker onset of action, a more durable ICP reduction, and retained efficacy in patients for whom mannitol treatment has failed.⁴ Mannitol is dosed at 0.5–1 g/kg intravenously and may be repeated every 4–6 hours as needed, with a duration of effect of 90 minutes to 6 hours.⁶ An osmolar gap greater than 20 mOsm/kg is often used as the threshold at which the risk of acute kidney injury increases, though some data suggest a higher limit can be used. Because of the risk of accumulation, mannitol should be used cautiously in patients with renal impairment. Although mannitol may be administered peripherally, 23.4% HTS requires central line administration. The anticipated duration of effect of HTS is 90 minutes to 4 hours, and doses may be repeated every 4–6 hours as needed if serum sodium is maintained at 160 mEq or less.⁶ Although 30 mL of 23.4% HTS is often administered for ICP crisis, various other concentrations of HTS such as 2% or 3% may be infused depending on the circumstance. Serum electrolytes should be routinely monitored with hyperosmolar therapies.

Sedation

After ensuring adequate analgesia and sedation, increased doses of propofol may be used to aid with ICP management because of propofol’s ability to reduce cerebral metabolic demand and cerebral blood flow. However, higher doses may worsen hypotension as well as increase the risk of hypertriglyceridemia and propofol infusion syndrome. Neuromuscular blockers may be considered in refractory intracranial hypertension, particularly when ICP elevations are associated with ventilator dysynchrony.⁷ Use of a paralytic infusion is recommended once a bolus test dose has shown efficacy.⁸ Barbiturates may be used to manage ICP elevations that are refractory to standard medical and surgical therapies. By decreasing brain metabolism, barbiturates can subsequently lead to reductions in cerebral blood flow and volume, which lowers ICP. Therapy is titrated to goal ICP or burst suppression on electroencephalogram, with a usual duration of administration of 24–96 hours. Adverse effects associated with barbiturates include loss of a neurologic examination, hypotension, immunosuppression, respiratory depression, and paralytic ileus. Pentobarbital may be dosed as a bolus of 5–15 mg/kg over 30–120 minutes, followed by a continuous infusion of 1–4 mg/kg/hour.⁹

Coagulopathy

Prompt antithrombotic reversal should be prioritized in an anticoagulant- or antiplatelet-associated intracranial hemorrhage to minimize further hematoma expansion, increased mortality, and poor long-term outcomes. Guidelines may be referenced for specific recommendations for reversal agents such as prothrombin complex concentrates, idarucizumab, andexanet alfa, and desmopressin.^10-12 Interest in antifibrinolytics such as tranexamic acid to reduce fibrinolysis and minimize intracranial hemorrhage expansion prompted the CRASH-3 study in isolated TBI. Tranexamic acid administered as a 1-g intravenous bolus followed by a 1-g intravenous infusion over 8 hours did not lead to a significant difference in 28-day head injury–related in-hospital mortality among patients randomized within 3 hours of injury when compared with placebo. Subgroup analysis suggested that patients with mild-moderate, but not severe TBI have a mortality benefit.¹³ The BTF guidelines do not comment on the use of antifibrinolytic therapy.²

Seizure Prophylaxis

Posttraumatic seizures can be divided into those occurring early (7 days or less) or late (more than 7 days) after injury. The concern that seizures may worsen secondary brain damage and lead to poor outcomes merits consideration for prophylaxis, particularly in patients with severe TBI. Early evidence suggested a benefit with phenytoin in decreasing the incidence of early, but not late posttraumatic seizures in patients with serious head trauma.¹⁴ The BTF guidelines acknowledge the adverse effects associated with phenytoin administration and recommend its use when the benefit outweighs the risk.² The evidence supporting levetiracetam was not sufficiently robust at the time of guideline publication; however, many institutions have transitioned to its use preferentially. Data suggest levetiracetam is as efficacious as phenytoin for prophylaxis against early seizures,¹⁵ with the advantage of fewer adverse effects, fewer drug interactions, and a more predictable pharmacokinetic profile. Most recently, the NCS Guidelines on Seizure Prophylaxis in Moderate to Severe Traumatic Brain Injury suggest either use of antiseizure prophylaxis or no prophylaxis, given the lack of any identified positive (or negative) effects on outcomes.¹⁶ Ineffective seizure prophylaxis may be a result of subtherapeutic drug concentrations from use of low doses combined with augmented renal clearance that is commonly seen in the neurocritical care patient population. Accordingly, the NCS guidelines state that antiseizure medications should be titrated to therapeutic concentrations to avoid underdosing. If an antiseizure medication is selected for prophylaxis, levetiracetam is suggested over phenytoin.¹⁶ In patients who do not develop a seizure, the use of prophylaxis should not continue beyond 7 days.

Fluids

Crystalloids are recommended as the preferred intravenous fluid in patients with TBI. The European Society of Intensive Care Medicine recommends against colloids or hypotonic solutions as maintenance or resuscitative fluids in neurocritical care patients. However, because of limited data, a recommendation was not given regarding the choice between normal saline and buffered solutions.¹⁷ The specific agent will depend on the patient’s goal sodium while aiming to avoid hyponatremia and hyperchloremia. Most patients can receive 0.9% sodium chloride or Plasma-Lyte while minimizing the use of lactated Ringer solution, which is more hypotonic than plasma. Albumin was associated with increased mortality in the SAFE-TBI study.¹⁸

Conclusion

The care of patients with TBI centers on preventing secondary brain injury. Pharmacists can play an important role by providing recommendations on ICP control, seizure prophylaxis, and reversal of underlying coagulopathies.

References

1. Zimmerman LL, Tran DS, Lovett ME, et al. Emergency Neurological Life Support: Traumatic Brain Injury Protocol. Version 5.0. Neurocritical Care Society, 2022. Available at https://www.neurocriticalcare.org/Portals/0/ENLS%205.0/ENLS%205.0%20Protocol%20-%20TBI.pdf.
2. Carney N, Totten AM, O’Reilly C, et al. Guidelines for the management of severe traumatic brain injury. Fourth edition. Neurosurgery 2017;80:6-15.
3. Hamblin SE. Acute traumatic brain injury management. In: Boucher BA, Haas CE, eds. Critical Care Self-Assessment Program, 2021 Book 2. Acute Organ Dysfunction and Special Populations. American College of Clinical Pharmacy, 2021:103-32.
4. Cook AM, Morgan Jones G, Hawryluk GWJ, et al. Guidelines for the acute treatment of cerebral edema in neurocritical care patients. Neurocrit Care 2020;32:647-66.
5. Wiles MD. Management of traumatic brain injury: a narrative review of current evidence. Anaesthesia 2022;77(suppl 1):102-12.
6. Tesoro E, Pajoumand M, Peacock S, et al. Emergency Neurological Life Support: Pharmacotherapy Protocol. Version 5.0. Neurocritical Care Society, 2022. Available at https://www.neurocriticalcare.org/Portals/0/Docs/ENLS/ENLS_5_Protocol_Pharm.pdf.
7. May CC, Smetana KS. Treatment of elevated intracranial pressure. In: Flannery AH, Zimmerman LH, eds. Critical Care Self-Assessment Program, 2022 Book 1. Neurocritical Care. American College of Clinical Pharmacy, 2022:7-34.
8. Hawryluk GWJ, Aguilera S, Buki A, et al. A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med 2019;45:1783-94.
9. Morrison C, Bhalla P, Ruzas CM, et al. Emergency Neurological Life Support: Intracranial Hypertension and Herniation. Version 5.0. Neurocritical Care Society [registration required]. Available at https://learn.neurocriticalcare.org/courses/6587.
10. Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24:6-46.
11. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants. J Am Coll Cardiol 2017;70:3042-67.
12. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulant therapy. Blood Adv 2018;2:3257-91.
13. CRASH-3 Trial Collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomized, placebo-controlled trial. Lancet 2019;394:1713-23.
14. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497-502.
15. Wilson CD, Burks JH, Rodgers RB, et al. Early and late posttraumatic epilepsy in the setting of traumatic brain injury: a meta-analysis and review of antiepileptic management. World Neurosurg 2018;110:e901-6.
16. Frontera JA, Gilmore EJ, Johnson EL, et al. Guidelines for seizure prophylaxis in adults hospitalized with moderate-severe traumatic brain injury: a clinical practice guideline for healthcare professionals from the Neurocritical Care Society. Neurocrit Care 2024;40:819-44.
17. Oddo M, Poole D, Helbok R, et al. Fluid therapy in neurointensive care patients: ESCIM consensus and clinical practice recommendations. Intensive Care Med 2018;44:449-63.
18. SAFE Study Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group; Australian Red Cross Blood Service; George Institute for International Health; Myburgh J, Cooper DJ, et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 2007;357:874-84.

Submitted by:

Craig Furnish, Pharm.D., BCCCP

Roxana Dumitru, Pharm.D., BCCCP, BCPS

Jason Chau, Pharm.D., BCPS, BCACP, MSCS