Antipsychotics Linked to Acute Kidney Injury

Deborah Brauser

August 19, 2014

(Updated Aug. 20, 2014) Atypical antipsychotic medications are linked to acute kidney injury (AKI) in elderly patients, new research suggests, causing investigators to call for their use in this population to be reevaluated.

Dr. Amit Garg

A population-based study examining medical records for nearly 200,000 adults older than 64 years showed that those who received a prescription for quetiapine (Seroquel, AstraZeneca Pharmaceuticals LP), risperidone (Risperdal, Janssen Pharmaceuticals, Inc), or olanzapine had an almost 2-fold increased risk for hospitalization for AKI within the next 90 days vs those who did not receive these prescriptions.

In addition, patients who received 1 of these oral atypical antipsychotics had increased risk for acute urinary retention, hypotension, and even death.

"This shows that use of these medications was associated with a higher risk of being hospitalized for kidney injury, as well as other adverse outcomes that might explain the reasons why people get kidney injuries," principal investigator Amit X. Garg, MD, PhD, kidney specialist at the London Health Sciences Center and from the London Kidney Clinical Research Unit in Ontario, Canada, told Medscape Medical News.

"We wanted to raise awareness around this issue and recommend that physicians should be cautious around the use of these medications in the elderly," said Dr. Garg.

"However, if a patient is on this medication and the physician is monitoring it very carefully, we don't want to be alarmists. But it's healthy to have these types of conversations."

The study was published in the August 19 issue of the Annals of Internal Medicine.

Off-Label Use

Millions of adults worldwide are prescribed atypical antipsychotics every year, the investigator note.

"These drugs are frequently used to manage behavioral symptoms of dementia, which is not an approved indication, and such use has raised safety concerns," they write.

These medications antagonize alpha-adrenergic, muscarinic, serotonin, and dopamine receptors. AKI, or a sudden loss of kidney function, has been linked to use of these drugs in several case reports.

However, no clinical or epidemiologic studies have quantified the risk for AKI, and information on outcomes of hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis is limited, the investigators report.

For the current study, they examined 5 databases for medical information on 97,777 adults aged 65 years or older (mean age, 80.7 years) who lived in Ontario, Canada, and who received a new outpatient prescription for the oral atypical antipsychotic quetiapine, risperidone, or olanzapine between June 2003 and December 2011. A total of 53.8% of these individuals had been diagnosed with dementia.

The researchers also examined records for the same number of relatively age-, sex-, and health-matched adults who did not receive prescriptions for these medications.

The primary outcome measure was hospitalization due to AKI within 3 months of receiving 1 of these prescriptions.

Results showed that risperidone was the most frequently prescribed of the atypical antipsychotics (45.7%), followed by quetiapine (35.3%) and olanzapine (19%).

Prescriber information was available for a total of 89.2% of the recipient patients. Of these patients, 89.2% received their prescriptions from family physicians, 6.8% received them from psychiatrists, and 4.7% received them from geriatricians.

Robust Findings

Patients prescribed an atypical antipsychotic had a significantly higher relative risk (RR) for hospitalization with AKI vs those without these types of prescriptions (RR, 1.73; 95% confidence interval [CI], 1.55 - 1.92).

In subpopulation analysis that evaluated serum creatinine levels, an association between the medications and AKI hospitalization was still significant (RR, 1.70; 95% CI, 1.22 - 2.38).

"I was actually surprised that this evidence was so robust. We did the study to determine what the association could be, and we clearly saw it," said Dr. Garg.

Use of these antipsychotics was also linked to hospitalization with acute urinary retention (RR, 1.98; 95% CI, 1.63 - 2.40), hypotension (RR, 1.91; 95% CI, 1.60 - 2.28), pneumonia (RR, 1.50; 95% CI, 1.39 - 1.62), ventricular arrhythmia (RR, 1.47; 95% CI, 1.18 - 1.82), and myocardial infarction (RR, 1.36; 95% CI, 1.20 - 1.53).

Their use was also significantly associated with a higher 90-day risk for all-cause mortality (RR, 2.39; 95% CI, 2.28 - 2.50; 6.8% of the recipients vs 3.1% of the nonrecipients).

Interestingly, neither antipsychotic drug type nor dosage influenced any of the examined associations.

The investigators note that the US Food and Drug Administration issued a black-box warning in 2005 on the basis of 17 randomized controlled trials showing that elderly patients with dementia who received an atypical antipsychotic had a 1.6 to 1.7 times' greater mortality risk than those who received placebo.

Because of this, Dr. Garg said he was surprised that so many patients were still receiving these prescriptions.

"We looked at almost 100,000 adults in the province of Ontario who received these medications. This shows how commonly they're used in just a single province, never mind worldwide," he said.

The researchers write that current evidence calls for a careful reevaluation of the prescribing of these medications in older adults.

"The drugs should be used only after other approaches have been exhausted; when prescribed, patients must be warned about potential adverse effects [and] proactive clinical monitoring shortly after initiation seems reasonable," they add.

Caution Needed

"I think this is a really good study," Dilip V. Jeste, MD, distinguished professor of psychiatry and neurosciences and associate dean for Healthy Aging and Senior Care at the University of California, San Diego, told Medscape Medical News.

Dr. Dilip Jeste

"It had a large sample size, and it was interesting how they selected people. They chose only those who were starting on the atypicals, which is appropriate. They also followed them for 90 days and did their best to have a similar control group."

Dr. Jeste, who was not involved with this research, is also past president of both the American Psychiatric Association and the American Association for Geriatric Psychiatry. He and his colleagues published a recent study in the Journal of Clinical Psychiatry that assessed 4 atypical antipsychotics ― the same 3 examined in the current study plus aripiprazole (Abilify, Otsuka Pharmaceutical Co, Ltd).

"The bottom line was that in people over 40, we found that these drugs were not that useful, and all of them had side effects. So this [current] study is logical," said Dr. Jeste.

However, he noted that it also had some limitations. These include the facts that the investigators used hospitalization as the marker for increased AKI risk; that different clinicians often use different ways of treating; and that because individuals who are treated often have more serious symptoms than their untreated counterparts, it is difficult to have an exact comparison group.

"You can't take care of that unless you do a randomized controlled trial. But you can't collect that kind of data in 98,000 people [as the investigators did in the current study]. Also, it would be unethical to do this type of randomized trial for 90 days," he said. "Still, they tried to control for what they could."

Still, "overall I felt that this was a good study. Its findings were important, and they should be taken into account in the treatment of older patients," Dr. Jeste said.

"The bottom line is not that people should stop using these medications in older people. However, they should be more cautious, especially in patients with low blood pressure or evidence of kidney injury in the past."

Ann Intern Med. 2014;161:242-248. Abstract

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