The Dirt on Drugs

Several months ago, in writing about Katy Butler’s generally admirable new book, The Art of Dying Well,I questioned her uncritical acceptance of claims that certain drugs, the anticholinergics, caused dementia. That drugs such as antihistamines and some antidepressants cause delirium, or acute confusion, is well-established. But dementia? A large, well-conceived study just published in JAMA Internal Medicine provides additional evidence that they may well result in dementia. Previous studies were tainted because they tended to be small, observational studies that lumped many different anticholinergic drugs together, some of which are known to be far more potent than others. So how does the new study fare by comparison?

The recent analysis is still an observational study—it is impossible to randomize patients into those who receive anticholinergics and those who do not and then follow them for years—but it is very large, it analyzes different classes of anticholinergics separately, and it focuses on the cumulative anticholinergic exposure over a period of many years. While not perfect, it is probably the best we are going to get and it provides strong, although not definitive, evidence that anticholinergics are a risk factor for dementia.

This “nested case control study” allowed the authors to identify just under 59,000 people over age 55 with dementia from a British data base of 30 million. For each case, they found 5 controls matched along four discrete dimensions. The main variable of interest was the total, cumulative anticholinergic exposure which they calculated according to a well-established protocol that allows standardization across drugs with different dosage regimens. The authors also decided in advance to study the association between the total standardized daily dose (TSDD) for each type of anticholinergic: antihistamines, antidepressants, antipsychotics, antiparkinsonian drugs were considered both separately and collectively. Finally, the study repeated the analysis for patients diagnosed with Alzheimer’s disease, those diagnosed with vascular dementia, and those with some other form of dementia. So what did they find?

The main finding was that the adjusted odds ratio associated with low anticholinergic exposure was 1.06, while the ratio associated with the highest degree of anticholinergic exposure was 1.49, a highly significant difference. Also interesting was the observation that only certain groups of anticholinergics increased the risk of developing dementia. In particular, antidepressants, antipsychotics, antiepileptics, and drugs used to treat Parkinson’s and incontinence were the main offenders (and antihistamines, which geriatric physicians inveigh against as potential causes of delirium, had no effect). Curiously, the effects were more dramatic in patients with vascular dementia than in those with Alzheimer’s disease, a novel finding. Finally, the strongest association was found in people diagnosed before age 80.

As the authors are quick to point out, associations do not demonstrate causality. They can’t. Researchers simply cannot exclude the possibility that some of the drug use in fact reflected early, preclinical effects of as yet undiagnosed dementia. For example, many people with dementia are depressed; it is entirely possible that the depression manifests itself before a formal diagnosis is made, at a time when patients are beginning to detect subtle but disturbing changes in their memory and problem-solving ability. But if anticholinergics are causative, then they may well be responsible for as much as 10 percent of all dementia. The evidence is sufficiently suggestive and the magnitude of the danger sufficiently great that it’s time to be very wary of these drugs, especially in people under age 80. 

Persistent Confusion About Confusion

The modern concept of delirium or an acute confusional state has been around for decades, but physicians are still confused about it. A recent review article in the New England Journal of Medicine summarizes what we know about delirium: what it is, how to treat it, and how to try to prevent it. “Delirium in Hospitalized Older Adults,” as the title says, does not address delirium outside the hospital, i.e. in the skilled nursing facility, where it is even less well-recognized, but despite this limitation it is a welcome update of an important topic.

            Older patients—most of the studies define “older” in this context as at least 70—are at high risk of developing the acute onset of confusion after they are admitted to the hospital. Lumping all older people together, regardless of age or reason for admission, roughly one-third will become delirious. Among people who have certain operations such as hip fracture repair or cardiac surgery, the rate is more like 50 percent, and among older patients in the ICU on a ventilator, it rises to 75 percent. What’s particularly striking is that once delirium strikes, it’s hard to get rid of. At the time they are discharged, nearly half of all patients who got delirium in the hospital still have it, and a month later one-third still meet the criteria for delirium. It’s not always “hyperactive delirium,” the agitation we usually think of when we hear the word delirium; in fact, nearly 75 percent of the time it’s the opposite, or “hypoactive delirium,” a more insidious, quieter form of the disorder.

            The article goes through the major triggers of delirium, with medications (especially sedatives, opioid pain medications and other mind-altering substances) at the head of the list. Out-of-whack blood chemistries (technically known as electrolyte disturbances) and infection are two other leading offenders, but the bottom line is that almost anything can result in delirium, from a heart attack to severe constipation. Treatment consists primarily of removing or curing the underlying precipitant—for example, getting rid of the implicated medicine, limiting the heart attack damage, or getting the bowels moving. The author is at pains to tell us that among twelve randomized controlled trials of antipsychotic medications in the treatment of delirium, none of them resulted in decreasing the severity or duration of delirium, none of them lowered mortality rates or length of stay in the hospital. Nonetheless, he indicates that antipsychotic drugs may be prescribed if needed to control particular symptoms.

            Most interesting are the reminders about what works best to prevent delirium. The gold standard is still the 1999 HELP study (Hospital Elder Life Program) that used trained volunteers to make sure older patients wear their glasses and their hearing aids and that they get a back rub rather than a sleeping pill if they have trouble sleeping at night. Another approach that also makes a difference is a proactive geriatric consultation. Especially when initiated on a surgical service, this can assure that older patients are not prescribed sedating medications, that they receive round-the-clock acetaminophen whenever possible instead of as needed opioids, and that they get out of bed and moving as soon as possible. A related approach that the author doesn’t mention is use of the ACE unit (Acute Care for the Elderly), a specially designed inpatient unit that builds anti-delirium measures into its mode of operation.

            But what’s important to emphasize is that even the best delirium prevention strategies are only moderately successful. Delirium is a nasty disorder: it is extremely unpleasant, it’s dangerous, and it lingers. Some people never recover fully, some die. For older people who have some degree of cognitive impairment, those who have significant trouble carrying out daily activities, and those with multiple problems on many medications, the best approach may be to avoid the hospital altogether.

Antipsychotics: Use as Directed

Antipsychotic medication is effective for people who are psychotic—period. It’s been used for other conditions, such as the behavioral symptoms of dementia, and it turned out not to work. It’s been used for delirium, a type of confusion that often arises in older people or people nearing the end of life, especially in the hospital, and many doctors swear it’s the only medication that helps this distressing and dangerous disorder. But a new study from Australia suggests that antipsychotic medication doesn’t work for delirium either. 

The specific situation the Australian doctors looked at was delirium in the setting of patients with advanced illness, either patients on an inpatient palliative care service or patients enrolled in a hospice facility. Out of well over 1000 patients with delirium, they were able to identify 247 who were both eligible and willing to enter the study. This group, with a mean age of 75, were randomized to risperidone (a commonly used antipsychotic), haloperidol (another commonly used antipsychotic), or placebo. Patients were also given unspecified non-medicinal treatment, presumably things like a sitter (someone to stay with them) or relaxation techniques such as massage. They were also given subcutaneous midazolam, a very short acting anti-anxiety medication under the skin, for extreme agitation. The results? Patients receiving either risperidone or haloperidol had more severe symptoms of delirium than those treated with placebo. They also, not surprisingly, had more Parkinsonian symptoms, the main side effect of these antipsychotic medications, and were more likely to die.

This is a disturbing result. Not only did antipsychotics fail to help, but they also seemed to make matters worse. Now maybe there’s something different about Australians, or maybe the specific environment they were in—a palliative care service or hospice, though neither is clearly described—makes generalization to the American general hospital impossible. Or maybe people with delirium and advanced illness are somehow different from people with delirium who don’t have an advanced illness. And conceivably, other antipsychotics such as quetiapine or olanzapine are different. More likely, antipsychotics are simply a bad choice in the treatment of delirium.

Antipsychotic medications are remarkable medications—for the treatment of psychosis in psychiatric conditions such as schizophrenia and bipolar disorder. But maybe we should stop using them for anything other than these indications.