Alzheimer's disease (AD) patients who receive antipsychotics have more morbidity, as indicated by a greater number of days spent in the hospital, compared with their counterparts who were not prescribed these agents, new research shows.

During a 2-year period, AD patients taking antipsychotics had greater than 50% more accumulated hospital days than those not taking antipsychotics, with the strongest association observed during the first 6 months.

Reasons for hospitalization included psychiatric and behavioral disorders, as well as genitourinary, respiratory, and circulatory disorders, infections, and parasitic diseases.

"In this study, we found that community dwellers with Alzheimer's disease who initiated antipsychotic use accumulated more hospital days than noninitiators, which may partially reflect adverse effects and events of antipsychotic use," study investigator Marjaana Koponen, PhD, a postdoctoral researcher at the Kuopio Research Centre of Geriatric Care, School of Pharmacy, University of Eastern Finland in Kuopio, told Medscape Medical News.

"On the other hand, antipsychotic users accumulated more hospital days due to dementia, mental and behavioral disorders, and their caregivers' days off, thus another reason for a higher accumulation of hospital days is care burden and the difficulties in treating the most severe behavioral and psychological symptoms of dementia," she said.

The study was published online August 26 in the Journal of the American Medical Directors Organization.

Serious Adverse Event Risk

"Based on previous research, we know that antipsychotic use increases the risk of serious adverse events among person's with Alzheimer's disease, therefore we wanted to investigate whether antipsychotic use results in higher accumulation of hospital days in this vulnerable population," said Koponen.

"We anticipated that this study has public health importance, as the number of people with Alzheimer's disease is increasing worldwide and higher use of hospital care further increases the costs for society," she added.

To investigate the question, the researchers drew on data from the nationwide register-based Medication use and Alzheimer's disease (MEDALZ) cohort of all residents in Finland newly diagnosed with AD between 2005 and 2011, of whom 25,788 initiated antipsychotic use between AD diagnosis and December 31, 2013.

Subjects were required to be community dwelling at the time of AD diagnosis and data regarding patients' prescriptions were extracted from the Finnish Prescription Register.

The primary study outcome was the accumulated number of hospital days during the follow-up period (2 years), with hospital days classified based on primary discharge diagnosis.

In addition, the researchers compared the accumulation of hospital days of patients prescribed the two most commonly used antipsychotics — risperidone and quetiapine.

Each patient with AD who initiated treatment with an antipsychotic and met inclusion criteria was matched on the date of initiation with a person with AD who did not initiate antipsychotic treatment, with age, sex, and time since AD diagnosis as the criteria for the match (n = 19,909 in each group).

Of the patients, 67% were female, and the mean (SD) age was 81.5 (6.7) years.

Residual Confounding?

Those who initiated treatment with antipsychotics had more accumulated hospital days during the 2-year follow-up compared with their counterparts who were not taking antipsychotics (52.5 [SD, 97.7; median, 15; interquartile range (IQR), 1 - 57] and 34.7 [SD, 72.4; median, 7; IQR, 0 - 36]), respectively.

These increases were most prevalent during the first 6 months following treatment initiation.

Both groups contained patients who had not been hospitalized during the 2-year follow-up period, with a larger proportion of nonhospitalized patients among noninitiators than among initiators (23.8% vs 34.1%, respectively).

After adjusting for a variety of factors (eg, age, sex, time since AD diagnosis, medical comorbidities, and use of benzodiazepines, antidepressants, and opioids) the researchers found that initiators had 53% more hospital days (adjusted incidence rate ratio, 1.53 [95% confidence interval, 1.47 - 1.59]), compared with noninitiators.

In both groups, dementia was the most common reason for hospital days, followed by diseases of the circulatory and respiratory systems.

The percentages of antipsychotic initiators vs noninitiators with the most common diagnoses are listed in Table 1.

Table 1. Most Common Hospital Stay Diagnoses, Initiators vs Noninitiators

Diagnosis Antipsychotic Initiators Antipsychotic Noninitiators Dementia 39.0% 21.6% Mental/Behavioral Disorders 4.2% 1.8% Circulatory Disorders 18.7% 18.4% Respiratory Disorders 16.0% 12.0% Injuries and Poisoning 13.6% 13.3% Genitourinary Disorders 13.2% 10.4% Infectious and Parasitic Disorders 7.4% 6.5% Symptoms Not Elsewhere Classified 13.9% 12.4%

Caregivers' time off accounted for nearly 70% of hospital days, with a greater impact in initiators vs noninitiators of antipsychotics.

The most frequently initiated antipsychotics were risperidone and quetiapine (62.4% and 29.7%, respectively).

Patients treated with risperidone had more accumulated hospital days, compared with those treated with quetiapine (53.0 [SD, 100.1; median, 15; IQR, 1 - 57] vs 50.5 [SD, 92.2; median, 16; IQR, 1 - 56], respectively).

On the other hand, quetiapine initiators had fewer accumulated hospital days in general healthcare but more hospital days in specialized healthcare than risperidone initiators.

"There may be several reasons for the associations between antipsychotics and higher accumulation of hospital days due to nonpsychiatric disorders, such as genitourinary conditions and infections," said Koponen.

"Health-related problems such as urinary infection could trigger behavioral and psychological symptoms of dementia [BPSD], and if the actual underlying reason being behavioral and psychological symptoms remains unnoticed and untreated, this may lead to unnecessary use of antipsychotics and increase the risk of hospitalization," she noted.

"On the other hand, antipsychotics have been associated with an increased risk of several serious adverse events such as pneumonia, stroke, myocardial infarction, acute kidney injury, and hip fracture, which can also explain higher accumulation of hospital days due to nonpsychiatric disorders," she added.

The authors note that the register-based data did not provide information about the indication for antipsychotic drug use or BPSD severity, so "residual confounding by indication may exist."

Compassionate Care

Commenting on the study for Medscape Medical News, Charles F. Reynolds III, MD, distinguished professor of psychiatry emeritus, University of Pittsburgh School of Medicine, Pennsylvania, said that the findings "are useful and important, but need to be placed in the context of compassionate care for older adults with AD who have severe behavioral disturbances."

Antipsychotic treatment "has an important place in the therapeutic armamentarium of care and is an important tool to help family caregivers who bear a great deal of the burden of caring for such patients," said Reynolds, who was not involved with the study.

He himself "actively engages caregivers in dosing to achieve maximum benefit" and "discusses the potential risks of using antipsychotics such as risperidone and quetiapine."

However, "on balance, I think that the benefits and the important use of antipsychotics as part of compassionate care outweigh the risks," he said.

Koponen noted that it is important to assess and treat the underlying health problems triggering behavioral and psychological symptoms of dementia before initiating antipsychotic use.

If initiation of an antipsychotic is necessary, "careful and regular monitoring is needed to assess the efficacy and possible emergence of adverse effects," she said.

The study was conducted at the University of Eastern Finland and funded by the Academy of Finland. Koponen and Reynolds have disclosed no relevant financial relationships.

JAMDA. Published online August 26, 2019. Abstract

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