CPCP: Pharmacologic Management of Hypoactive Delirium

Luke Watson PharmD
Luke Watson, Pharm.D.

Today’s Clinical Problems in Consultation Psychiatry (CPCP) is about treatment of hypoactive delirium and it was led by clinical pharmacist, Luke Watson Pharm.D. By the way, Luke saw the new Star Wars movie recently and thought it was superb.

Over the years I’ve been asked to evaluate “depression” or “apathy” in many patients who were not participating in physical therapy, not eating, lethargic, and amotivated. However, when I do a simple bedside test such as the Mini-Cog, They are often unable to even recite the months of the year backward or complete the Clock Drawing Task, the latter of which produces a graphic image that is usually so disorganized I have no trouble persuading the critical care unit resident that depression is not the issue at all. I often find out that the patients suffer from hypoactive delirium, not depression. It’s not unusual for me to discover that, even before I arrive at the patient’s bedside, the primary medical team has already started an antidepressant–which I advise they stop.

The non-pharmacological methods for managing delirium are important ways to promote brain healing and general recovery, as pointed out in a recent American Delirium Society Blog Post by Dr. Joe Flaherty, MD.

However, sometimes I also find out the patients are suffering from frightening visual hallucinations or fragmented persecutory delusions. This raises the question of whether antipsychotic treatment is indicated. As Luke pointed out, there are few studies on which to base a firm opinion. Often enough there may be good reasons, though, to have an informed consent discussion with patients and families about the risks and benefits of allowing delirium (whether hypoactive or not) accompanied by frightening hallucinations and delusions to persist versus treating the psychotic symptoms with antipsychotics.

A few words about the data are in order. The precaution against cholinesterase inhibitors for treating agitation of delirium largely arises from the van Eijk et al paper on the effect of rivastigmine added to halperidol for delirium management, published in the Lancet in 2010 [1]. Rivastigmine might have increased mortality, so the trial was consequently halted early.

There are a handful of studies about medications in the management of hypoactive delirium which have been published between 1994-2015, ramelteon generating a bit of excitement [2]. In general, studies used pretty low doses of antipsychotic except for the Boettger et al study using 15 mg of aripiprazole as a comparator to haloperidol between which there were no significant differences [3].

The European survey Luke mentions indicates the majority of clinicians, (40% of whom were psychiatrists) prefer non-pharmacologic methods for managing hypoactive delirium, which is in accord with Dr. Flaherty’s approach. However, the most frequent challenge is remembering to look for the risk factors for delirium (the most frequent ones are being elderly and having impaired cognitive at baseline) and attempting to prevent it. As Luke reminds us, we’re better at preventing delirium than managing it after the dark side casts its long shadow over the brain.



  1. van Eijk, M. M., et al. (2010). “Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial.” Lancet 376(9755): 1829-1837.
    BACKGROUND: Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS: Patients (aged >/=18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0.75 mL (1.5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. FINDINGS: Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0.07). Median duration of delirium was longer in the rivastigmine group (5.0 days, IQR 2.7-14.2) than in the placebo group (3.0 days, IQR 1.0-9.3; p=0.06). INTERPRETATION: Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING: ZonMw, the Netherlands Brain Foundation, and Novartis.
  2. Hatta, K., et al. (2015). “Ramelteon for Delirium in Hospitalized Patients.” JAMA 314(10): 1071-1072.
  3. Boettger, S., et al. (2011). “Aripiprazole and haloperidol in the treatment of delirium.” Aust N Z J Psychiatry 45(6): 477-482.
    OBJECTIVE: To compare the efficacy and tolerability of aripiprazole and haloperidol in the amelioration of distressing symptoms of delirium and its motoric subtypes. METHODS: At Memorial Sloan-Kettering Cancer Center, we prospectively collected sociodemographic and medical data and systematically rated all patients diagnosed with delirium with the Memorial Delirium Assessment Scale (MDAS), Karnofsky Performance Scale (KPS) and the abbreviated Udvalg Kliniske Undersogelser Side Effect Rating Scale (UKU) at the initial diagnosis of delirium (T1), after 48-72 h (T2) and 7 days later (T3). All collected information was entered into a delirium database. For our analysis, we subsequently extracted data on aripiprazole (ARI) treated patients to compare to case-matched haloperidol (HAL) treated patients. RESULTS: We retrieved 21 patients treated with aripiprazole and 21 case-matched patients treated with haloperidol. Initial MDAS scores did not significantly differ between the groups. Over the course of treatment (T1 to T3), MDAS scores improved from 18.1 to 8.3 for ARI and 19.9 to 6.8 for HAL. The delirium resolution rate was 76.2% for ARI and 76.2% for HAL. For patients with hypoactive delirium, the MDAS scores improved from 15.6 to 5.7 for ARI and 18.8 to 8.1 for HAL. Delirium resolution rates for patients with hypoactive delirium were 100% for ARI and 77.8% for HAL. For patients experiencing hyperactive delirium, the MDAS scores improved from 19.9 to 6.8 for ARI and 20.8 to 5.8 for HAL. Delirium resolution rates for patients with hyperactive delirium were 58.3% for ARI and 75% for HAL. There were no significant differences in treatment results between ARI and HAL. Treatment with HAL caused more extrapyramidal side effects. CONCLUSION: From our secondary analysis, aripiprazole may be as effective as haloperidol in the management of delirium and its subtypes. Treatment with haloperidol resulted in more side effects.


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