In the Journals

Antipsychotics worsen delirium symptoms

Patients receiving palliative care who were treated with risperidone and haloperidol displayed significantly greater distressing symptoms of delirium relative to those who were treated with placebo, according to clinical trial results published in JAMA Internal Medicine.

“Delirium is highly prevalent in patients receiving palliative care, with up to four in 10 people having delirium on admission to a palliative care unit, and higher rates seen at the end of life,” Meera R. Agar, PhD, of the discipline, palliative and supportive services at Flinders University in Australia, and colleagues wrote. “Symptom relief is important to reduce the known distress associated with delirium; thus, effective, evidence-based management strategies that optimally balance benefits and risks are needed.”

Between Aug. 13, 2008 and April 2, 2014, Agar and colleagues conducted a double-blind, parallel-arm clinical trial to investigate the efficacy of antipsychotic medications (risperidone and haloperidol) compared with placebo for mitigating symptoms of delirium related to distress, such as inappropriate behavior and/or communication, as well as illusions or hallucinations. Patients receiving care at one of 11 Australian inpatient hospice or hospital palliative care services for a life-limiting illness such as cancer who also a delirium symptoms score of 1 or more (sum of Nursing Delirium Screening Scale behavioral, communication and perceptual items) were enrolled in the trial. The researchers randomly assigned 247 participants (mean age, 74.9 years; 85 women [34.4%]; 218 with cancer [88.3%]) to age-adjusted titrated doses of either oral risperidone (n = 82), haloperidol (n =81) or placebo (n = 84) every 12 hours for 72 hours. When necessary, individualized treatment of delirium symptoms, supportive care and subcutaneous midazolam hydrochloride were used as additional treatments to help manage cases of severe distress or safety concerns.

Primary intention-to-treat analysis indicated that participants in both the risperidone and haloperidol groups had significantly higher delirium symptom scores with an average of 0.48 and 0.24 units higher, respectively, than those in the placebo group. Similarly, extrapyramidal effects were greater in the risperidone (0.73; 95% CI, 0.09-1.37; P = 0.03) and haloperidol (0.79; 95% CI, 0.17-1.41; P = .01) groups compared with the placebo group. Overall survival was better in the placebo group than both antipsychotic drug groups — 29% and 73% of patients in the risperidone and haloperidol groups, respectively, were more likely to die than those in the placebo group.

“Antipsychotic drugs should not be added to manage specific symptoms of delirium that are known to be associated with distress in patients receiving palliative care who have mild to moderately severe delirium,” Agar and colleagues wrote. “Rather, management relies on ensuring systematic screening (given that two-thirds of people with delirium are not diagnosed on referral to palliative care), reversing the precipitants of delirium, and providing supportive interventions. Further studies are needed to understand how to tailor, implement, and embed screening for delirium and multicomponent supportive interventions into palliative care settings.”

In a related editorial, Donovan T. Maust, MD, MS, and Helen C. Kales, MD, both from the department of psychiatry at the University of Michigan, wrote that the suggestions of Agar and colleagues to reduce the use of antipsychotic medications for delirium in patients receiving palliative care should be immediately implemented into current practice. However, while the investigators offer alternatives to relieve distress in these patients, “such alternatives can be time-consuming and are not incentivized in the current reimbursement systems in the United States;” therefore, the change that is advocated in the findings of this study is unlikely, Maust and Kales argue.

“Choosing to not prescribe an antipsychotic should not mean not providing support and treatment,” they conclude. “Physicians need training and resources so that they are equipped to provide environmental or biopsychosocial interventions in place of a prescription. But to fully engage in such training and shift the treatment paradigm, physicians need to let go of the idea that dopamine receptor blockade is the answer to treating distress in these patients. Some distress cannot be medicated away.” – by Alaina Tedesco

Disclosure: Agar and colleagues report receiving study funding by the Australian Government’s Department of Health under the National Palliative Care Strategy, as well as the National Health and Medical Research Council in Australia. Maust and Kales do not report any relevant financial disclosures.

 

Patients receiving palliative care who were treated with risperidone and haloperidol displayed significantly greater distressing symptoms of delirium relative to those who were treated with placebo, according to clinical trial results published in JAMA Internal Medicine.

“Delirium is highly prevalent in patients receiving palliative care, with up to four in 10 people having delirium on admission to a palliative care unit, and higher rates seen at the end of life,” Meera R. Agar, PhD, of the discipline, palliative and supportive services at Flinders University in Australia, and colleagues wrote. “Symptom relief is important to reduce the known distress associated with delirium; thus, effective, evidence-based management strategies that optimally balance benefits and risks are needed.”

Between Aug. 13, 2008 and April 2, 2014, Agar and colleagues conducted a double-blind, parallel-arm clinical trial to investigate the efficacy of antipsychotic medications (risperidone and haloperidol) compared with placebo for mitigating symptoms of delirium related to distress, such as inappropriate behavior and/or communication, as well as illusions or hallucinations. Patients receiving care at one of 11 Australian inpatient hospice or hospital palliative care services for a life-limiting illness such as cancer who also a delirium symptoms score of 1 or more (sum of Nursing Delirium Screening Scale behavioral, communication and perceptual items) were enrolled in the trial. The researchers randomly assigned 247 participants (mean age, 74.9 years; 85 women [34.4%]; 218 with cancer [88.3%]) to age-adjusted titrated doses of either oral risperidone (n = 82), haloperidol (n =81) or placebo (n = 84) every 12 hours for 72 hours. When necessary, individualized treatment of delirium symptoms, supportive care and subcutaneous midazolam hydrochloride were used as additional treatments to help manage cases of severe distress or safety concerns.

Primary intention-to-treat analysis indicated that participants in both the risperidone and haloperidol groups had significantly higher delirium symptom scores with an average of 0.48 and 0.24 units higher, respectively, than those in the placebo group. Similarly, extrapyramidal effects were greater in the risperidone (0.73; 95% CI, 0.09-1.37; P = 0.03) and haloperidol (0.79; 95% CI, 0.17-1.41; P = .01) groups compared with the placebo group. Overall survival was better in the placebo group than both antipsychotic drug groups — 29% and 73% of patients in the risperidone and haloperidol groups, respectively, were more likely to die than those in the placebo group.

“Antipsychotic drugs should not be added to manage specific symptoms of delirium that are known to be associated with distress in patients receiving palliative care who have mild to moderately severe delirium,” Agar and colleagues wrote. “Rather, management relies on ensuring systematic screening (given that two-thirds of people with delirium are not diagnosed on referral to palliative care), reversing the precipitants of delirium, and providing supportive interventions. Further studies are needed to understand how to tailor, implement, and embed screening for delirium and multicomponent supportive interventions into palliative care settings.”

In a related editorial, Donovan T. Maust, MD, MS, and Helen C. Kales, MD, both from the department of psychiatry at the University of Michigan, wrote that the suggestions of Agar and colleagues to reduce the use of antipsychotic medications for delirium in patients receiving palliative care should be immediately implemented into current practice. However, while the investigators offer alternatives to relieve distress in these patients, “such alternatives can be time-consuming and are not incentivized in the current reimbursement systems in the United States;” therefore, the change that is advocated in the findings of this study is unlikely, Maust and Kales argue.

“Choosing to not prescribe an antipsychotic should not mean not providing support and treatment,” they conclude. “Physicians need training and resources so that they are equipped to provide environmental or biopsychosocial interventions in place of a prescription. But to fully engage in such training and shift the treatment paradigm, physicians need to let go of the idea that dopamine receptor blockade is the answer to treating distress in these patients. Some distress cannot be medicated away.” – by Alaina Tedesco

Disclosure: Agar and colleagues report receiving study funding by the Australian Government’s Department of Health under the National Palliative Care Strategy, as well as the National Health and Medical Research Council in Australia. Maust and Kales do not report any relevant financial disclosures.