What is the evidence for or against using methylphenidate or modafinil in hypoactive delirium?

Comment by InpharmD Researcher

Evidence evaluating the use of methylphenidate or modafinil in hypoactive delirium is limited. However, available data suggest consistent support for the use of methylphenidate in patients with hypoactive delirium, particularly in terminally ill and geriatric populations. Methylphenidate has been associated with symptomatic benefits, including improvements in alertness, communication, and daily functioning, with some studies also reporting improvements in Mini-Mental State Examination (MMSE) scores. In contrast, modafinil’s use is supported only by a few isolated case reports, which have described improvements in daytime alertness and oral intake; accordingly, more rigorous, controlled trials are necessary to conclusively establish its safety, efficacy, and appropriate role in the treatment of hypoactive delirium.

Background

A 2023 systematic review evaluated the use of methylphenidate in the treatment of hypoactive delirium, focusing specifically on terminally ill patients. The review analyzed data from 17 patients with advanced cancer, drawing on three studies: a prospective clinical study, a case series, and a case report. All patients exhibited hypoactive delirium and were treated with methylphenidate at starting doses of 5 mg/day, titrated to 10 to 30 mg/day. Across all studies, patients demonstrated notable symptomatic improvements, including increased alertness, enhanced communication, improved ability to perform daily activities, and resolution of delirium. In the largest study, cognitive function improved from a median Mini-Mental State Examination (MMSE) score of 21 to 27 following the initial dose. Despite these encouraging findings, the review emphasized that all available evidence is limited to small, uncontrolled studies in palliative care settings. Notably, no studies on modafinil were identified. Overall, the authors concluded that while methylphenidate may be beneficial for hypoactive delirium in terminally ill patients, larger controlled trials are necessary to establish its safety and efficacy. [1]

Several literature reviews and clinical reports have evaluated the potential role of psychostimulants, including methylphenidate and modafinil, in the management of hypoactive delirium. A 2010 literature review evaluated the use of psychostimulants in end-of-life patients with hypoactive delirium and cognitive disorders unrelated to dementia or hyperactive/mixed delirium. The review included five studies on methylphenidate and one on caffeine, among which three specifically addressed hypoactive delirium. Of the methylphenidate studies, one prospective trial (n= 14) in patients with hypoactive delirium of unknown irreversible cause reported significant improvement in Mini-Mental State Examination (MMSE) scores after administration of methylphenidate, with most patients achieving optimal results on daily doses between 20 to 30 mg. Another case report described symptom improvement but no MMSE score change in a patient with paraneoplastic encephalitis-related hypoactive delirium treated with 15 mg of methylphenidate. A separate double-blind, placebo-controlled crossover trial in opioid-treated patients without specified delirium type demonstrated significant cognitive and alertness improvements with 10 mg of methylphenidate. Regarding caffeine, a double-blind, placebo-controlled crossover study in 12 cancer patients found that 200 mg of intravenous caffeine improved psychomotor test scores (T10 and T30), but not other cognitive measures. Notably, modafinil was not directly studied, though it was cited as potentially promising based on findings from non-delirium contexts. Another 2024 review provides suggestive evidence for methylphenidate on hypoactive delirium, citing a prospective study (Gagnon et al.) in advanced cancer patients that observed improved alertness and psychomotor activity; however, replication is lacking. Modafinil is also suggested as a theoretical candidate based on its pharmacological profile, but the authors caution that such an intervention may increase agitation. Overall, authors note methodological limitations across studies, including small sample sizes and the absence of randomized controlled trials specifically targeting hypoactive delirium, which may limit the ability to draw definitive conclusions regarding the efficacy and safety of these interventions. [2], [3]

A 2021 systematic review assessed the efficacy of pharmacologic interventions for hypoactive delirium in adult and geriatric patients. After detailed screening and application of inclusion and exclusion criteria based on study design, patient demographics, and relevance to hypoactive delirium, only three studies met the final eligibility criteria. These included one prospective cohort study using methylphenidate, and two randomized controlled trials comparing aripiprazole and haloperidol, and ziprasidone and haloperidol, respectively. A 2005 cohort study enrolled 14 patients with advanced cancer and hypoactive delirium and reported a statistically significant improvement in Mini-Mental State Examination (MMSE) scores from 21 to 27 (p<0.001) after a single dose of methylphenidate, with further improvement to 28 (p= 0.02) following a stable dose. A randomized controlled trial evaluated 42 patients, including 18 with hypoactive delirium, comparing aripiprazole versus haloperidol. Complete resolution of hypoactive delirium was reported in 100% of patients treated with aripiprazole versus 77.8% in the haloperidol group (p<.001), alongside greater improvement in Memorial Delirium Assessment Scale (MDAS) scores. Conversely, a 2018 multicenter randomized controlled trial evaluated 566 critically ill patients, of whom 504 had hypoactive delirium, and found no statistically significant differences in delirium duration, survival, or other outcomes between haloperidol, ziprasidone, and placebo groups. Overall, these findings suggest that aripiprazole and methylphenidate may be promising therapeutic options for hypoactive delirium, while traditional antipsychotics such as haloperidol and ziprasidone demonstrated limited efficacy in this population. [4]

References:

[1] Bachu A, Kotapati P, Kainth T, et al. Use of methylphenidate for hypoactive delirium: a comprehensive systematic review. Psychoactives. 2023;2(4):337-345. doi:10.3390/psychoactives2040021
[2] Elie D, Gagnon P, Gagnon B, Giguère A. Utilisation des psychostimulants chez les patients en fin de vie atteints de delirium hypoactif et de troubles cognitifs : revue de la littérature [Using psychostimulants in end-of-life patients with hypoactive delirium and cognitive disorders: A literature review]. Can J Psychiatry. 2010;55(6):386-393. doi:10.1177/070674371005500608
[3] Rosen JH, Bieber E, Matta SE, et al. Hypoactive Delirium: Differential Diagnosis, Evaluation, and Treatment. Prim Care Companion CNS Disord. 2024;26(1):23f03602. Published 2024 Feb 8. doi:10.4088/PCC.23f03602
[4] Lodewijckx E, Debain A, Lieten S, Bravenboer B, Mets T. Pharmacologic treatment for hypoactive delirium in adult patients: a brief report of the literature. Journal of the American Medical Directors Association. 2021;22(6):1313-1316.e2. doi:10.1016/j.jamda.2020.12.037
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence for or against using methylphenidate or modafinil in hypoactive delirium?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

Methylphenidate hydrochloride improves cognitive function in patients with advanced cancer and hypoactive delirium: a prospective clinical study
Design

Prospective clinical study

N= 14
Objective

To investigate the clinical improvement observed in patients with advanced cancer and hypoactive delirium after the administration of methylphenidate hydrochloride
Study Groups

All patients (N= 14)
Inclusion Criteria

Cognitive failure documented by the Mini-Mental State Examination (MMSE); sleep–wake pattern disturbances; psychomotor retardation; absence of delusions or hallucinations; absence of an underlying cause to explain the delirium
Exclusion Criteria

Signs of hyperactivity, opioid toxicity, severe myoclonus, hallucinations and delusions, or reversible identifiable underlying causes for the delirium
Methods

Patients were administered a 10-mg test dose of methylphenidate orally, followed by a regimen of 10 mg orally twice a day (8 am and noon). MMSE was repeated 1 hour after administration and at each follow-up visit. Doses were increased in 5-mg increments to reach resolution of delirium or maximum tolerable dose
Duration

March 1999 to August 2000
Outcome Measures

Improvement in cognitive function as measured by MMSE and improvement in psychomotor activities
Baseline Characteristics Patient no. Sex Age, yr Cancer type Brain metastases* Type of opioid Daily dose of opioid, mg Other psychoactive drugs (and oral daily dose)
1 M 46 Lung Yes Morphine 30

Phenytoin (500 mg), famotidine (40 mg), dexamethasone (12 mg)
2 M 51 Lung Yes — —

Dexamethasone (4 mg)
3 F 62 Colon — Codeine 300

Prednisone (5 mg)
4 M 80 Testicular — — —

—
5 M 65 Lung Yes Morphine 90

Celecoxib (200 mg), phenytoin (300 mg), omeprazole (20 mg), dexamethasone (8 mg), metoclopramide (10 mg)
6 F 44 Rectal — Morphine 90

Sertaline (50 mg), omeprazole (20 mg), prednisone (25 mg)
7 M 65 Lung — Morphine 280

—
8 M 80 Lung — — —

Methotrimeprazine (5 mg), dexamethasone (4 mg)
9 M 64 Prostate — Methadone 75

Methotrimeprazine (10 mg), dexamethasone (16 mg), metoclopramide (40 mg)
10 M 66 Lung — — —

Methotrimeprazine (5 mg), metoclopramide (30 mg)
11

F

 61 Lung — — — —
12 F 41 Cervix — Morphine 120

Metoclopramide (60 mg)
13 F 79 Breast Yes — —

Dexamethasone (16 mg)
14 M 57 Prostate — — —

Methotrimeprazine (25 mg), dexamethasone (2 mg)
Results

All 14 patients showed improvement in cognitive function, as measured by the MMSE. The median pretreatment MMSE score was 21 (mean 20.9 ± 4.9), which improved to a median of 27 (mean 24.9 ± 4.7) after the first dose of methylphenidate (p < 0.001, matched, paired Wilcoxon signed rank test). One patient died before reaching a stable dose of methylphenidate. In the remaining 13 patients, the median MMSE score further improved to 28 (mean 27.8 ± 2.4), which was significantly higher compared to the median MMSE score recorded 1 hour after the first dose (p = 0.02). All patients showed improvement in psychomotor activities.
Adverse Events

No distressing side effects reported; increased side effects such as nervousness at higher doses
Study Author Conclusions

Hypoactive delirium in patients with advanced cancer appears to be a specific syndrome that could be improved by the administration of methylphenidate.
Critique

The study is limited by its small sample size and lack of a control group. The prospective design is a strength, but the absence of randomization and blinding may introduce bias. Further studies are needed to confirm these findings and explore the underlying mechanisms.
References:

Gagnon B, Low G, Schreier G. Methylphenidate hydrochloride improves cognitive function in patients with advanced cancer and hypoactive delirium: a prospective clinical study. J Psychiatry Neurosci. 2005;30(2):100-107.

 

Use of Modafinil in Two Patients with Hypoactive Delirium

Design

 Case series

Case presentation 1

An 85-year-old man with multiple health issues, including three-vessel coronary artery disease, systolic heart failure, severe aortic regurgitation, and moderate aortic stenosis, was admitted for an upper gastrointestinal bleed four days before a scheduled aortic valve replacement. Gastric ulcers were found during an esophagogastroduodenoscopy, and after receiving packed red blood cell transfusions, his melena stopped. He later underwent transcatheter aortic valve replacement (TAVR). Post-procedure, he developed daytime somnolence, lethargy, restlessness, and agitated behaviors at night, with minimal oral intake.

A geriatric consultant initially recommended evening trazodone and melatonin for sleep, and removal of the urinary catheter. When no improvement was seen after one day, the consultant suggested daytime modafinil at 100 mg daily for alertness and discontinuing nighttime olanzapine. This led to slight improvements in his daytime alertness and nighttime sleep. The modafinil dose was increased to 200 mg for the remainder of his hospitalization, with further improvement in both alertness and oral intake. Modafinil was stopped before discharge to a skilled nursing facility.

Case presentation 2

An 86-year-old woman with moderate-to-advanced Alzheimer’s dementia was admitted after a fall resulting in head trauma. A head CT showed a large subdural hematoma, which was surgically evacuated, followed by a second evacuation three days later. Postoperatively, she developed hypoactive delirium with daytime somnolence, poor appetite, and agitated behaviors in the evenings. The hospital team managed these symptoms with as-needed oral evening trazodone and quetiapine. Despite poor oral intake, she was hydrated with intravenous fluids. During a goals of care discussion, her daughter expressed a preference against feeding tubes.


In the three days before discharge, methylphenidate was started at 5 mg twice a day, which was increased to 10 mg twice a day. Over this period, her daytime alertness improved, and she began eating a few bites of food daily. Upon discharge to a skilled nursing facility, her daughter requested a change in methylphenidate due to anxiety and jitteriness. Modafinil 100 mg daily was substituted, and escitalopram was started for anxiety and depression. By the time of her discharge to home, her oral intake improved to 25-50% of meals. Modafinil was discontinued before her hospital discharge, and she continued taking escitalopram at home.

Study Author Conclusions

 We observed two patients with mixed forms of delirium in whom the use of a stimulant was associated with increased daytime alertness, improved oral intake, and a decrease in agitated nighttime behaviors. The evidence is still too scant to recommend the use of stimulants in patients with hypoactive or mixed delirium, but more studies are forthcoming to help clarify their utility in this population. 
References:

Eskildsen MA. Use of modafinil in two patients with hypoactive delirium. Proc UCLA Health. 2020;23(1).