Delirium is a sudden and temporary state of disturbed consciousness or cognition that occurs due to underlying medical problems such as fever or alcohol withdrawal. It is most common in older, hospitalized adults aged 75 years or older, leading to an increased risk of falls, dementia, low life expectancy and high healthcare costs.
Nonpharmacological approaches to prevent or reduce delirium are time-consuming, difficult to implement, and partially effective. Pharmacological interventions therefore offer hope. Insomnia, a major risk factor for delirium, can be alleviated with sleep-promoting medications. However, not all medications are suitable. Some can make delirium worse. Interestingly, suvorexant (an orexin receptor antagonist) promotes sleep by blocking a neuropeptide called orexin that regulates wakefulness. This mechanism could prevent delirium, as many studies show.
Against this background, a team of researchers, involving Professor Kotaro Hatta from the Department of Psychiatry at Juntendo University Nerima Hospital in Tokyo, Japan, tested whether suvorexant reduce delirium in older adults at high risk for delirium after hospitalization. The research team consisted of Dr. Yasuhiro Kishi of Nippon Medical School Musashikosugi Hospital, Dr. Ken Wada of Hiroshima City Hiroshima Citizens Hospital, Dr. Takashi Takeuchi of Tokyo Medical and Dental University Hospital, Dr. Toshihiro Taira of Fukuyama City Hospital, Dr. Keiichi Uemura of Tonan Hospital, Dr. Asao Ogawa of National Cancer Center Hospital East, Ms. Kanae Takahashi, Ms. Asako Sato, Mr. Masayoshi Shirakawa and Dr. Ichiro Arano of MSD KK, Tokyo, Japan, and Dr. W. Joseph Herring of Merck & Co., Inc., Rahway, NJ, USA. Their research was published in JAMA network opened on August 16, 2024.
Looking back on the motivation behind the research, Prof. Hatta says: “When I worked as a psychiatric liaison in a general hospital, I was treating patients with delirium every day. So when an orexin receptor antagonist became available, we decided to use this drug to address sleep-wake cycle disturbances, a primary clinical manifestation of delirium.”
To this end, researchers conducted a double-blind, placebo-controlled, randomized Phase 3 clinical trial in 50 Japanese hospitals from October 2020 to December 2022. The study included 203 Japanese adults aged 65 to 90 who were at high risk for delirium and hospitalized for a sudden illness or planned surgery. Participants were randomly assigned to two groups, with 101 receiving suvorexant (15 mg) and 102 receiving a placebo every night for five to seven days. They were assessed daily for delirium based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Subtypes of delirium – namely hyperactive (characterized by agitation, hallucination and impulsivity), hypoactive (characterized by drowsiness and apathy) and mixed (shifts between hyperactive and hypoactive delirium) -;
were also recorded for those presenting with delirium. Researchers then compared both groups to assess whether suvorexant made a difference.
Consistent with expectations, suvorexant showed a trend toward reducing delirium, with only 16.8% of participants experiencing delirium, compared to 26.5% in the placebo group. However, the difference was not statistically significant. Both groups also experienced similar side effects, such as constipation and vomiting.
The incidence of hypoactive delirium was similar between the suvorexant (5.9%) and placebo groups (4.9%). However, in the post-hoc exploratory analysis, the incidence of hyperactive and mixed delirium was lower in the suvorexant group (10.9%) compared to placebo (21.6%). Delirium with a hyperactive component was considered because it interferes with surgery or treatment, making it burdensome for hospital staff.
As the results suggest, suvorexant may not have preventive effects on hypoactive delirium, but may benefit hyperactive and mixed delirium.
When explaining the results, Prof. Hatta emphasizes: “The lack of significant reduction in delirium after taking suvorexant was surprising given that previous studies reported positive findings. However, these studies did not distinguish between delirium subtypes, except in one study that excluded hypoactive delirium due to its irrelevance in postoperative management and another study that the primary outcome is delirium of any type. Thus, we believe that previous studies have focused more on hyperactive or mixed delirium and overlooked hypoactive delirium.”
Prof. Hatta says: “Addressing this problem could increase the life expectancy of older adults and reduce the burden on caregivers.”
Let’s hope these insights pave the way to discovering more effective pharmacological interventions to prevent delirium.
Source:
Magazine reference:
Hatta, K., et al. (2024). Suvorexant for reduction of delirium in older adults after hospital admission. JAMA network opened. doi.org/10.1001/jamanetworkopen.2024.27691.