Rivastigmine as an Antidote for Clozapine and Other Anticholinergic-Induced CNS Depression and Delirium: A Study of 100 Cases

Efficacy of Rivastigmine in the Management of Toxic Anticholinergic Delirium: A Prospective Study at Alexandria Poison Center

This study aims to evaluate the clinical efficacy and safety of rivastigmine in reversing the full spectrum of anticholinergic delirium including hypoactive delirium which is presented with CNS depression and hyperactive or agitated delirium.

The study was conducted on 100 patients at the Poison Control Center of Alexandria University Main Hospital. The primary objective is to assess the effectiveness of rivastigmine in restoring consciousness and improving cognitive function in patients presenting with delirium and depressed mental status using GCS and RASS score.

Study Overview

• Status: Completed
• Conditions: Clozapine Poisoning; Hypoactive Delirium; Tricyclic Antidepressant Poisoning; Anticholinergic Delirium; Antipsychotic Toxicity; CNS Depression; Procyclidine Induced Delirium
• Intervention / Treatment: Drug: Rivastigmine

Detailed Description

This prospective clinical study assess the efficacy of rivastigmine in reversing the full spectrum of anticholinergic delirium. The study encompasses both hyperactive (agitated) and hypoactive (depressed mental status/CNS depression) presentations, with a specific focus on the hypoactive variant. While anticholinergic toxicity is traditionally associated with agitation, this research highlights its role in causing hypoactive delirium and assesses how rivastigmine facilitates the recovery of consciousness and cognitive function.

Participants:

The study includes 100 patients (aged ≥18 years) with Anticholinergic delirium-induced by exposure to drugs with anticholinergic properties-manifests either as agitated delirium (characterized by confusion, agitation, disorientation, and hallucinations) or hypoactive delirium (characterized by CNS depression). Patient status was assessed using the Glasgow Coma Scale (GCS) and the Richmond Agitation-Sedation Scale (RASS) upon admission to the Poison Control Center of Alexandria University Main Hospital (AUMH).

Intervention Protocol:

Administration: An initial enteral dose of 6 mg is administered orally or by nasogastric tube. Transdermal patch was administered when nasogastric route was non-feasible.

Dosing: Additional 6 mg doses are administered every 2 hours until achieving GCS 15 /RASS 0

Assessment & Resolution:

Awareness, cognition, consciousness, and the level of agitation or sedation were evaluated using the Glasgow Coma Scale (GCS) and the Richmond Agitation-Sedation Scale (RASS). These assessments were performed at baseline, 2 hours, and 6 hours for both the oral and transdermal groups, and at 12 hours exclusively for the transdermal group. Clinical success was defined as achieving a GCS score of 15 and a RASS score of 0.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Alexandria, Egypt, 21131
    • Poison Control Center (PCC), Alexandria University Main Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Exposure: acute exposure to anticholinergic agents (e.g., clozapine, tricyclic antidepressants).

Clinical Presentation: Presence of anticholinergic delirium either hyperactive/agitated or hypoactive/CNS depression/coma).

Exclusion Criteria:

1. Non-Toxic Delirium: Delirium of multifactorial origin or other medical causes (e.g., sepsis, hepatic encephalopathy, alcohol withdrawal, or metabolic disturbances).
2. Cardiac Contraindications: Baseline bradycardia, Atrioventricular (AV) block, or significant QTc prolongation.
3. Patients who experienced pulmonary aspiration as a complication of overdose, necessitating endotracheal intubation and mechanical ventilation
4. Severe Organ Impairment: Known severe renal or hepatic impairment.
5. Neurological Conditions: History of pre-existing seizure disorders or epilepsy.
6. Respiratory Conditions: Severe asthma or Chronic Obstructive Pulmonary Disease (COPD) due to the risk of bronchoconstriction.
7. Obstructions: Mechanical bowel obstruction or urinary tract obstruction.
8. Hypersensitivity: Known history of hypersensitivity to rivastigmine or other carbamates.
9. Pregnancy/Lactation: Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rivastigmine Treatment Group; A total of 100 patients presenting with anticholinergic delirium (including both hyperactive and hypoactive variants) were enrolled. Each participant received rivastigmine according to the established clinical titration protocol.

Drug: Rivastigmine; Initial Dose: A starting dose of 6 mg is administered either orally or via a Nasogastric Tube (NGT) for patients with impaired swallowing or depressed consciousness. Titration: Additional 6 mg doses are repeated every 2 hours based on clinical need until the resolution of delirium. Alternative Route: Transdermal patches (9.5 mg/24h) are applied in cases where enteral administration is not feasible or based on clinical judgment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glasgow Coma Scale (GCS) Score.	The Glasgow Coma Scale (GCS) is a clinical scale used to assess a patient's level of consciousness. The total score was recorded for all participants at baseline and subsequent intervals to evaluate the clinical response to rivastigmine. The GCS score ranges from a minimum of 3 to a maximum of 15, where higher scores indicate a better neurological outcome (improved consciousness). For the oral/NGT group, assessments were performed 2 hours after the initial dose and after each supplemental dose. For the transdermal group, monitoring included a 6 to 8-hour window and at 12 hours. Clinical resolution is defined as reaching a GCS score of 15 and a RASS score of 0.	Baseline (0 hour), 2 hours post-administration (all patients), 6-8 hours, and 12 hours (transdermal group). For patients receiving additional oral/NGT doses, assessments were repeated 2 hours after each supplemental dose up to 6 hours after resolution.
Change in Richmond Agitation-Sedation Scale (RASS) Score	The Richmond Agitation-Sedation Scale (RASS) is used to evaluate the clinical response to rivastigmine. The RASS is a 10-point scale ranging from a minimum value of -5 (denoting unarousable/deep sedation) to a maximum value of +4 (denoting combative/extreme agitation). A score of 0 represents an alert and calm state, which indicates the best clinical outcome for this study. Scores were recorded for all participants at baseline and 2 hours to evaluate the initial response. For the oral/NGT group, additional assessments were performed 2 hours after each supplemental dose. For the transdermal group, monitoring focused on the 6 to 8-hour window and at 12 hours. Clinical resolution is defined as reaching a RASS score of 0 and a GCS score of 15.	Baseline, 2h (all), 6-8h & 12h (patch group), and up to 6h post-resolution (both groups)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-Resolution Clinical Stability and Safety Profile.	Monitoring for potential adverse effects related to rivastigmine, including cardiac complications (e.g., bradycardia, arrhythmias) and cholinergic side effects (e.g., excessive secretions, vomiting). Safety is further assessed by the absence of relapse during a mandatory 6-hour observation period following the resolution of delirium and CNS depression. Patients are deemed clinically stable if they remain symptom-free throughout this period prior to discharge.	From initial administration up to 6 hours post-resolution of delirium.
Resolution of Peripheral Antimuscarinic Features.	Monitoring the normalization of heart rate and the resolution of urinary retention (without the requirement for catheterization) in patients presenting with these features at baseline.	From initial administration up to the point of CNS manifestation resolution (variable, typically within 2-12 hours).
The requirement for Additional Interventions	The percentage of patients requiring rescue therapy or escalation of care after receiving rivastigmine. This includes the need for benzodiazepines for sedation, the use of physical restraints, or clinical escalation to endotracheal intubation and intensive care unit (ICU) admission.	From Initiation of Rivastigmine Treatment Until 6 Hours After Recovery of Consciousness
Time to Clinical Resolution.	The duration (measured in hours) elapsed from the initial dose of rivastigmine until the patient achieves clinical resolution, defined as reaching a Glasgow Coma Scale (GCS) score of 15 and a Richmond Agitation-Sedation Scale (RASS) score of 0.	From the time of initial administration until the achievement of clinical resolution.

Collaborators and Investigators

• Sponsor: Alexandria University
• Investigators: Study Chair: Naima A Sherif, Professor of Forensic Medicine, University of Alexandria; Study Chair: Ragaa T Darwish, Professor of Forensic Medicine, University of Alexandria; Study Chair: Sahar Y Issa, Assoc Prof Forensic Med, University of Alexandria

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2025
• Primary Completion (Actual): April 15, 2026
• Study Completion (Actual): April 15, 2026

Study Registration Dates

• First Submitted: April 15, 2026
• First Submitted That Met QC Criteria: April 21, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 16, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Clozapine; Rivastigmine; Quetiapine; Carbamazepine; Cyproheptadine; Procyclidine; Acetylcholinesterase Inhibitors; CNS depression; Hypoactive dilirium; Anticholinergic delirium
• Additional Relevant MeSH Terms: Organic Chemicals; Acids, Acyclic; Carboxylic Acids; Carbamates; Phenylcarbamates; Rivastigmine
• Other Study ID Numbers: 0202283

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The individual patient data are part of a PHD's thesis and are currently protected by institutional policies at Alexandria University. The data may be available upon reasonable request from the principal investigator after the final publication of the study results and in accordance with the hospital's ethical committee guidelines."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No