Modafinil Use for Hypoactive Delirium in the Intensive Care Unit

Delirium represents an acute confusional state, characterized by changes in attention, awareness, and other cognitive domains, often fluctuating and attributable to an underlying medical or physiologic cause.¹ Delirium is widely prevalent, affecting nearly one-third of patients aged 70 years or older,² often requiring pharmacologic and nonpharmacologic intervention tailored to motoric subtype.³ Although modafinil has been studied in select critical care populations, its use in managing delirium, particularly hypoactive delirium, has been described in only a handful of case reports. Here, we present a case of a 57-year-old woman with severe hypoactive delirium whose condition rapidly improved following a split-dosing strategy of modafinil. This report adds to the limited literature on modafinil in hypoactive delirium and highlights orexin-mediated arousal as a promising mechanistic target.

Case Report

A 57-year-old woman with idiopathic pulmonary fibrosis and no previous psychiatric history underwent bilateral lung transplantation for progressive respiratory failure. Her postoperative course was complicated by primary graft dysfunction, viral pneumonia, and profound deconditioning, resulting in more than 2 months of intensive care unit (ICU) hospitalization. By the time of psychiatric consultation, her medical status had begun to stabilize. She was hemodynamically steady, infection controlled, and no longer required high-level respiratory support, yet she remained profoundly disengaged. She had not participated in physical therapy for the previous 5 days and had shown inconsistent engagement even before that. Psychiatry was thus consulted for “worsening depression.”

On evaluation, she exhibited marked psychomotor slowing, minimal spontaneous speech, impaired attention, and fluctuating alertness without any overt sadness, rumination, or guilt. The months backward test (MBT), Luria motor sequence,⁴ and bedside go/no-go task were all grossly impaired. These findings were consistent with severe hypoactive delirium (Delirium Rating Scale-R-98 [DRS-R-98]⁵ score = 29). Given her pronounced hypoactivity and underarousal, modafinil 50 mg at 6 AM and 50 mg at 10 AM was initiated to promote wakefulness.

Within 24 hours after only 3 doses, she became alert, conversant, and actively engaged in physical therapy. Her DRS-R-98 score improved to 11 by day 2 and then 7 by day 3. She accurately performed the MBT and showed only mild residual deficits on the Luria and go/no-go tasks. Modafinil was continued for the remainder of her 10-day ICU stay, then tapered to 50 mg at 6 AM daily upon transfer to the general medical floor, and ultimately discontinued at discharge.

Discussion

Modafinil is a wakefulness-promoting agent whose effects stem from increased dopaminergic signaling via reuptake inhibition, with downstream activation of orexin neurons in the lateral hypothalamus.^6–8 This mechanism provides a biologically plausible rationale for its use in hypoactive delirium, a phenotype characterized by impaired arousal, attentional deficits, and psychomotor slowing. Orexin-mediated networks interact with acetylcholine, histamine, serotonin, and norepinephrine systems implicated in delirium pathophysiology.⁸ Unlike traditional psychostimulants such as methylphenidate, modafinil lacks prominent euphoric or sympathomimetic effects, potentially conferring a favorable side effect profile in medically fragile patients.^9–11

Several prior reports have documented improved wakefulness after modafinil initiation in delirious patients.^12–14 However, these cases were limited by the absence of validated delirium assessments, concomitant psychotropic use, and reliance on once-daily dosing. By contrast, our case employed a split-dosing strategy informed by modafinil pharmacokinetics, with peak plasma concentrations occurring 2–4 hours after administration.¹⁵ Morning split dosing may better sustain daytime wakefulness during periods critical for mobilization, rehabilitation, and delirium recovery. Modafinil has also demonstrated modest procognitive effects in healthy volunteers,^16,17 though its cognitive impact in critically ill populations remains uncertain.¹⁸ Identifying mechanism-informed agents that target arousal may be essential for addressing both acute hypoactive delirium and the persistent cognitive sequelae that follow critical illness.^19,20

In this case, split-dose modafinil was temporally associated with marked improvement in arousal, attention, and functional engagement in severe hypoactive ICU delirium, measured using validated delirium and bedside cognitive assessments. While causal inference is inherently limited by a single-case design, the rapidity and magnitude of improvement following initiation strengthen the observed signal. Given the paucity of effective pharmacologic options for hypoactive delirium, this case supports further investigation of arousal-targeted therapies. Modafinil, through orexin-mediated mechanisms, may represent a rational, phenotype-informed treatment strategy for carefully selected patients with underarousal-predominant delirium in critical care and general inpatient settings.

Article Information

Published Online: July 21, 2026. https://doi.org/10.4088/PCC.26cr04193
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(4):26cr04193
Submitted: January 23, 2026; accepted March 25, 2026.
To Cite: Eason AJ, Dorvault N, Bentley H, et al. Modafinil use for hypoactive delirium in the intensive care unit. Prim Care Companion CNS Disord. 2026;28(4):26cr04193.
Author Affiliations: College of Medicine, University of Florida, Gainesville, Florida (Eason, Dorvault); Department of Psychiatry, University of Florida, Gainesville, Florida (Bentley, Jiang); Department of Medicine, Stanford School of Medicine, Stanford, California (Gunther).
Corresponding Author: Austin J. Eason, MD, College of Medicine, University of Florida, Gainesville, Florida ([email protected]).
Financial Disclosure: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report, and information has been de identified to protect patient anonymity.
ORCID: Austin J. Eason: https://orcid.org/0009-0006-3150-3390