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Elderly patients with memory problems who suddenly have visual hallucinations may need to stop taking ACE inhibitors, researchers suggested.

In four case studies, the hallucinations experienced by patients with various memory deficits disappeared after they discontinued lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, reported John Doane, MD, and Barry Stults, MD, from the University of Utah Health Sciences Center in Salt Lake City.

Although hallucinations are "a generally unrecognized side effect" of ACE inhibitors, this is the first published account showing an association between lisinopril and hallucinations, they wrote online in the Journal of Clinical Hypertension.

"Commonly reported adverse effects of ACE inhibitors include cough, rash, angioedema, hypotension, hyperkalemia, and renal insufficiency," researchers noted. "Visual hallucinations as an adverse effect of ACE inhibitors are not listed in recent reviews of this drug class but have been reported, primarily in elderly persons."

Patients in these four cases ranged in age from 92 to 101, were being treated with lisinopril for hypertension or heart failure, and had some form of memory impairment: mild cognitive impairment (two), Alzheimer's disease (one), and dementia (one).

In these four cases, stopping lisinopril resulted in the cessation of hallucinations within 48 hours for two patients, and within 7 and 30 days for the third and fourth patients.

The onset of symptoms after starting the drug and cessation of hallucinations following drug stoppage varied:

• 5 months until hallucinations occurred and 7 days after medication discontinuation until they stopped
• 2 months and 2 days
• 1 year and 2 days
• 6 years and 30 days

One patient who stopped taking hydrochlorothiazide first and then lisinopril experienced recurrent hypertension 12 weeks post-ACE inhibitor discontinuation. She was again given lisinopril, but the hallucinations came back within a week, after which the lisinopril was stopped.

Researchers noted the "contrasting reports from observational and small randomized clinical trials" trying to determine whether or not ACE inhibitors protect patients from cognitive decline.

Doane and Stults also conducted a search of the literature and found seven previously published case reports of visual hallucinations associated with other ACE inhibitors: cilazapril, enalapril, captopril, and quinapril.

The age range in these cases spanned 49 to 92, and the dates of publication ranged from 1988 to 2001.

The investigators reported that two patients went back on the ACE inhibitor and again had hallucinations, which resolved when they stopped the medication.

Doane and Stults also searched the database of the Medicines and Healthcare Products Regulatory Agency (MHRA), a government entity in the U.K, for cases of adverse drug reactions. These unpublished reports have a number of limitations, however, including the lack of a necessity for causal evidence related to the drug and the adverse reaction.

Nevertheless, researchers found another 14 cases of ACE inhibitor-related hallucinations when they searched through MHRA category II data, which is more comprehensive than category I. Four of these cases involved lisinopril. Other ACE inhibitors involved were ramipril, enalapril, captopril, and perindopril.

When they examined category I data, they found another 35 cases of hallucinations related to ACE inhibitors. Symptoms resolved for 25 of these patients after stopping the drug, continued in two, and no further data were available for the remaining eight cases.

This evidence doesn't prove causality but its strength is that when some patients were rechallenged with lisinopril, the symptoms returned, and when they were taken off the drug, the symptoms ceased, the investigators noted.

As far as a mechanism of action for hallucinations to be associated with ACE inhibitors, researchers suggested it could related to the observation that these drugs raise the level of opioid peptides.

It's important to recognize this complication associated with ACE inhibitors, particularly as the aging population increases, the researchers said.

The study was limited because it had only four cases and there was missing information in the database search.

From the American Heart Association:

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