Psychotropic Polypharmacy Common in Alzheimer's Despite Risks

Batya Swift Yasgur, MA, LSW

October 16, 2018

Close to half of people with Alzheimer's disease (AD) take a psychotropic drug, and one fifth use two or more psychotropic drugs concomitantly, new research shows.

Investigators analyzed data from a nationwide Finnish study that included more than 70,500 individuals with AD and found a threefold increase in the use of two or more psychotropic drugs, including antipsychotics, antidepressants, and benzodiazepines and related drugs (BZDR), from 5 years before a diagnosis of AD to 4 years after.

Patients aged 75 years and younger, women, and those with a history of psychiatric disease were more likely to receive psychotropic polypharmacy (PPP).

The use of acetylcholinesterase inhibitors (AChEIs) was associated with a decreased risk for PPP, whereas use of memantine (multiple brands) was associated with an increased risk.

"Use of psychotropic drugs is very common, as up to half of people with AD use a psychotropic drug, and 1 in 5 use two or more concomitantly," lead author Sirpa Hartikainen, MD, PhD, professor of geriatric pharmacotherapy, School of Pharmacy, University of Eastern Finland, told Medscape Medical News.

"Clinicians should avoid psychotropic pharmacology and assess on a regular basis the need for any psychotropic drug use in persons with cognitive disorder," she said.

The study was published online August 25 in European Neuropsychopharmacology.

Vulnerable Population

Behavioral and psychological symptoms of dementia (BPSD) are common in people with dementia, and psychotropic drugs are frequently used to treat BPSD, although "the evidence for benefits of their use is limited," the authors write.

PPP is also not generally recommended for older adults with dementia because it is associated with an increased risk for injurious falls, hospitalization, and mortality.

"We were motivated to conduct this study because persons with AD are among the most vulnerable persons, and our research aim, as well as my aim as a geriatrician, is to promote and improve treatment of this population," Hartikainen said.

"It is well known that all psychotropic drugs increase risk of several adverse effects and events, like falling," she added.

Previous observational studies have found that the prevalence of PPP ranges from 14% to 50% in people with dementia, but no previous research has focused on assessing prevalence and predictors of PPP both before and after AD diagnosis.

The researchers used data from the Finnish Nationwide Medication Use and Alzheimer's Disease (MEDALZ) study that included all community-dwelling individuals who received their first AD diagnosis from 2005 to 2011 (n = 70,719).

Each person with AD was matched with a non-AD control person by age, sex, and region of residence. Non-AD control persons who developed AD during the follow-up period were defined as AD cases and were matched to another control person.

PPP was defined as concomitant use of ≥2 psychotropic drugs. Use of PPP was assessed from 5 years prior to index date until 4 years afterward. Point prevalence was defined every 6 months.

Individuals who entered long-term care facilities were censored, and those who died were excluded from time points after death.

The final study sample contained approximately 141,438 individuals, but the number varied at any given time point, owing to censoring and exclusion.

AChEI vs Memantine

The mean follow-up times for the AD cohort after diagnosis and for the matched cohort after index date were 3.4 years (SD, 1.05) and 3.6 years (SD, 0.91), respectively.

During the follow-up, 27.1% of persons died (34.3% in the AD cohort and 19.9% in the matched cohort).

A history of any psychiatric disorder was present in 4.5% of persons with AD vs 3.8% without AD (unadjusted odds ratio [OR] = 1.20; 95% confidence interval [CI], 1.14 - 1.26).

Persons with AD were more likely to have diabetes, epilepsy, any cardiovascular disease, and history of hip fracture and stroke compared to matched control persons.

During the 9-year study period, the prevalence of use of any psychotropic drug was higher in the AD cohort than in the matched cohort — a difference that was highest 4 years after AD diagnosis (49.9% vs 25.9%, respectively; OR = 2.85; 95% CI, 2.78 - 2.93).

During the study period, the prevalence of antipsychotic and antidepressant drug use was higher in the AD cohort than in the matched cohort in the 5 years prior to the index date (2.2% vs 2.0% for antipsychotics; OR = 1.12; 95% CI, = 1.04 - 1.21).

Four years after the index date, the prevalence of antipsychotic drug use had increased to 23.5% in persons with AD vs 3.8% in persons without AD (OR,7.90; 95% CI, 7.52 - 8.30).

The difference in BZDR use, however, was higher in the AD cohort only until 2.5 years after AD diagnosis, after which there was no difference between the groups, a trend that had continued 4 years later (P=.13).

On the index date, 37.1% of the persons with AD used ≥1 psychotropic drug compared to 25.5% in the non-AD cohort (OR, 1.73; 95% CI, 1.69 - 1.77). Four years later, the use of any antipsychotic drug had increased in the AD cohort to 49.9%.

In those with AD, antidepressant and antipsychotic use steadily increased, from 19.2% and 8.7%, respectively, at the index date to 27.5% and 23.5%, respectively, 4 years after the index date. However, the use of BZDRs decreased after AD diagnosis to 18.1% 4 years after the index date.

Use of psychotropic drugs among those with AD was associated with female sex, asthma/chronic obstructive pulmonary disease, hip fracture, stroke, history of psychiatric disorder, and cardiovascular disease.

Individuals aged 85 years or older were more likely to use psychotropic drugs 3 years before AD diagnosis; but 3 years after the index date, those younger than 65 years were more likely to use them.

Notably, the use of AChEIs was inversely associated with psychotropic drug use, whereas the use of memantine or the combination of an AChEI and memantine was associated with the use of psychotropic drugs.

"In Finland, the main indication for memantine is BPSD in persons with Alzheimer's disease, so one explanation [for increased PPP in patients taking memantine] is that use of memantine reflects more severe BPSD, compared to use of AChEI, so memantine users are more frequently using psychotropics as well," Hartikainen suggested.

Younger Age, Female Sex

Among persons with AD, PPP increased from 5.9% 5 years before AD diagnosis to 18.3% 4 years after. By contrast, in those without AD, it rose from 4.7% to only 6.7%.

The most common combination of psychotropic drugs until 2.5 years after AD diagnosis was the combination of BZDRs and antidepressants. The prevalence of this combination increased from 3.6% 5 years before AD diagnosis to 7.7% 2.5 years after.

Three years after AD diagnosis, the most frequently used combination was that of an antipsychotic and an antidepressant. The use of medications in the same class increased as well, from 0.3% to 1.3% in those taking ≥2 antipsychotics and from 0.6% to 2.0% in those taking ≥2 antidepressants.

By contrast, 6 months after AD diagnosis, the prevalence of the concomitant use of ≥2 BZDRs decreased from 2.5% to 1.7% 4 years after the index date.

When the researchers conducted multivariate analyses that included all variables, factors associated with PPP (vs psychotropic monotherapy) were found to be younger age, female sex, and a history of psychiatric disorder, both 3 years before and 3 years after AD diagnosis.

Having diabetes or using an AChEI or the combination of an AChEI and memantine was inversely associated with PPP.

"The association between polypharmacy and younger age may be attributed to the fact that younger persons with AD are more fit and might have more severe symptoms than older persons with AD; thus, symptoms like agitation or aggression may cause more distress for caregivers," Hartikainen commented.

Additionally, "previous studies have reported that women, compared to men, commonly have more behavioral symptoms, like depressive and anxiety symptoms, as well as delusions, which might explain the difference between men and women," she suggested.

Look for Opportunities to Deprescribe

Commenting on the study for Medscape Medical News, Emily H. Trittschuh, PhD, of the Geriatric Research Education and Clinical Center, VA Puget Sound Healthcare Center, and associate professor of psychiatry and behavioral sciences, University of Washington School of Medicine, Seattle, who was not involved with the study, called it "excellent" and "important because of the way they [the investigators] have analyzed the data for change over time, rather than just taking a cross-sectional approach."

The study has important clinical applications, she added. "Anyone working with older adults needs to be forever on their guard to combat polypharmacy and to be on the lookout for opportunities to deprescribe," she said.

She emphasized that use of medications to treat behavioral disturbance "should be a last resort."

She recommended making "little tweaks in the environment or how caretakers interact with a person with dementia," since it has been shown that environmental influences are "the root cause of behavior challenges."

The results are "a good reminder to clinicians to think about their prescribing practices and watch out for gender bias or other subtle trends in how they prescribe certain medications."

The study received no funding. Dr Hartikainen has disclosed no relevant financial relationships. The other authors' disclosures are listed in the original article. Dr Trittschuh has disclosed no relevant financial relationships.

Eur Psychoneuropharmacol. Published online August 25, 2018. Abstract

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