131 7 DELIRIUM | PART THREE review on antipsychotics for treatment of delirium in hospitalized non-ICU patients [9] included three studies comparing typical to atypical antipsychotics for the treatment of delirium in patients with advanced cancer [13-15]. Lin et al (n = 30; 100% with a cancer diagnosis) performed a single-center, open RCT, and compared the efficacy between haloperidol and olanzapine to treat delirium (DSM-IV criteria) in palliative and hospice center cancer patients [13]. Comparison of the scores of Delirium Rating Scale-Chinese (DRS-c) and Clinical Global Impression-Severity (CGI-S) between two groups showed no statistical difference. The study by Maneeton et al (n = 52; 38.5% with cancer diagnosis) was a single-center, prospective, double-blind RCT which compared quetiapine vs. haloperidol for the treatment of delirium (DSM-IV-TR and Confusion Assessment Method (CAM) criteria) [14]. The primary outcome measure was the DRS-R-98. They concluded that low-dose quetiapine and haloperidol were equally effective and safe. The 2018 ESMO clinical practice guideline on delirium in adult cancer patients [8] identified 15 studies, including three RCT’s [15, 26, 27]. Kim et al (n = 32; 72% with a cancer diagnosis) compared risperidone with olanzapine over a 7-day period [26]. The primary outcome measure was the DRS-R-98. There was no significant difference in either efficacy or adverse effects in this underpowered study. The second study by Hui et al (n = 90; 100% with a cancer diagnosis) was a single-center, double-blind, parallel group RCT conducted in adult patients with advanced cancer, comparing the effect of lorazepam vs. placebo as an adjuvant to haloperidol for persistent agitation (RASS score of≥+2) in patients with delirium (DSM-IV-TR criteria) [27]. This study was designed to assess a different primary research objective than our RCT. Recently, Agar et al [15] conducted a three-armed, multicenter, placebo-controlled study of antipsychotic treatment of delirium in patients receiving palliative care (n = 247, 88% with a cancer diagnosis). Treatment with either risperidone or haloperidol was associated with significantly greater delirium symptom severity scores and mean extrapyramidal effects than placebo. There was no comparison of haloperidol vs. risperidone in the Agar study. As a secondary outcome, haloperidol treatment was associated with poorer overall survival in long-term follow-up. However, there are some considerations that need to be addressed. First, although the therapeutic dose of haloperidol and the optimal dose titration schedule for delirium remain to be defined, starting and maintenance doses of haloperidol for patients >65 years of age (0.25 mg PO bid, increased to a maximum of 2 mg/day) used in the Agar study were low compared with doses reported in previous studies in the oncology / palliative care setting [28]. This may have underestimated the clinical effect of antipsychotic drugs to treat delirium in patients with advanced cancer. Furthermore, differences at baseline between the haloperidol and placebo arms in number of patients aged >65 years (90% vs. 80%, respectively), and the median dose of opioids (33 vs. 15 mg, respectively), are factors that may have affected study results. Other possible factors impacting on study results in the Agar study are older age and dementia/ cognitive impairment, which are predictors of poor response to antipsychotics in the treatment of delirium [20, 29-32]. In the study by Agar et al, mean age of the patients in the haloperidol arm was 76.5 years (21% diagnosed with cognitive impairment), and in the risperidone arm mean age was 74.5 years (22% with cognitive impairment). Median IQCODE (a structured questionnaire to detect individuals who may go on to develop
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