Recent research published in JAMA reveals a disturbing reality: approximately 25% of Medicare beneficiaries with dementia are prescribed potentially dangerous brain-altering medications despite years of clinical guidelines warning against this practice. These medications, including antipsychotics, benzodiazepines, anticholinergics, and barbiturates, carry serious risks of increased mortality, falls, cognitive decline, and stroke in elderly patients with dementia.

This comprehensive analysis examines the scientific evidence behind these risks, identifies specific medications of concern, explores the mechanisms of harm, and provides evidence-based alternatives for managing behavioral symptoms in dementia patients. Understanding these risks is crucial for patients, families, and healthcare providers working together to ensure safe, effective care.

The Scope of the Problem

A 2026 study analyzing Medicare claims data for 4,842 people over age 65 found disturbing prescribing patterns. Researchers categorized participants by cognitive status (normal, mild impairment, or dementia) and tracked prescriptions for potentially inappropriate medications over the period from 2013 to 2021.

The findings revealed that these brain-altering drugs were prescribed at dramatically different rates based on cognitive status. Cognitively healthy patients received these medications 17% of the time, those with cognitive impairment without dementia received them nearly 22% of the time, and dementia patients received them 25% of the time.

Perhaps most concerning, the study found that prescriptions without documented clinical indications were nearly double those with clear medical justification. This suggests that many patients are receiving these risky medications for behavioral symptoms that might be better managed through non-pharmacological approaches.

Understanding the Beers Criteria

The American Geriatrics Society Beers Criteria, most recently updated in 2023, represents the gold standard for identifying potentially inappropriate medications for older adults. This comprehensive reference tool, used by clinicians, educators, and healthcare administrators worldwide, details which medications older people should avoid or use with extreme caution.

According to the National Center for Health Statistics, more than 88% of older adults use at least one prescription medication, and more than 66% use three or more in any given month. This high rate of polypharmacy increases the risk of drug-drug interactions and adverse effects, making the Beers Criteria an essential clinical tool.

The 2023 update strengthened warnings about several medication classes particularly dangerous for dementia patients, with new language emphasizing the increased risks associated with antipsychotics in patients with dementia or delirium and encouraging attempts at non-pharmacological management and deprescribing.

Antipsychotic Medications: The Highest Risk Category

Specific Medications and Mortality Risks

Antipsychotic medications represent the most dangerous category of drugs commonly prescribed to dementia patients. These include both first-generation (typical) and second-generation (atypical) antipsychotics, with dramatically different risk profiles.

First-Generation (Typical) Antipsychotics:

Haloperidol (Haldol) consistently shows the highest mortality risk across multiple studies. A 2015 Veterans Affairs study of 90,786 dementia patients found haloperidol users had a 12.3% increased absolute mortality risk compared to antidepressant users, with a Number Needed to Harm of just 8. This means that for every 8 dementia patients prescribed haloperidol, one additional death occurred within 180 days. The relative risk was 1.54 times higher than risperidone, which itself carries significant risks. Multiple studies have called for a complete ban on haloperidol use in dementia patients due to its potent neurotoxic effects.

Other first-generation antipsychotics showing elevated risks include chlorpromazine, fluphenazine, perphenazine, and thioridazine. These medications work primarily as dopamine D2 receptor antagonists, causing severe side effects including extrapyramidal symptoms, emotional numbing, and hyperprolactinemia.

Second-Generation (Atypical) Antipsychotics:

Risperidone (Risperdal) is the most commonly prescribed antipsychotic for dementia patients (approximately 40% in registry studies) and is licensed in Europe, Canada, New Zealand, and Australia for managing agitation in dementia. However, it carries an FDA black box warning and shows a 3.2% to 4.9% increased mortality risk. Studies have also identified a 4.53-fold increased risk of stroke in risperidone-treated dementia patients.

Olanzapine (Zyprexa) shows similar mortality rates to risperidone (relative risk 0.99 compared to risperidone as reference), with a 1.5% increased dose-adjusted mortality risk and a 6.93-fold increased risk of stroke.

Quetiapine (Seroquel) demonstrates the lowest mortality risk among antipsychotics studied, with a relative risk of 0.73 compared to risperidone and a 3.2% increased absolute mortality risk (NNH of 31). However, this is still a significant increase in death risk that must be carefully weighed against potential benefits.

Aripiprazole (Abilify) and other newer atypicals have been less extensively studied in dementia populations but carry similar black box warnings.

FDA Black Box Warnings

The FDA issued black box warnings for all antipsychotics used in elderly patients with dementia-related psychosis. Analysis of 17 placebo-controlled trials found that 15 showed approximately 1.7-fold increased mortality with atypical antipsychotics. Deaths were primarily cardiac-related or due to infections. The warning was later extended to conventional antipsychotics after studies showed they carried similar or higher risks.

Additional Risks Beyond Mortality

Antipsychotic use in dementia patients is associated with numerous other serious adverse effects including pneumonia (increased risk through sedation, aspiration, and immune suppression), cerebrovascular events and stroke, parkinsonian symptoms and movement disorders, increased venous thromboembolism, seizures (up to 3-fold increase), accelerated cognitive decline, and a twofold increased risk of long-term care dependency and nursing home admission.

The Dementia Antipsychotic Withdrawal Trial (DART-AD)

This landmark study randomly assigned dementia patients to either continue antipsychotics (majority taking risperidone 67% or haloperidol 26%) or discontinue and switch to placebo. Results showed significantly higher mortality rates for patients continuing antipsychotics, with increased risk lasting over 12 months. This provides strong evidence that periodic discontinuation attempts should be made whenever these medications are prescribed.

Benzodiazepines: Fall Risk and Cognitive Decline

Common Benzodiazepines and Their Risks

Benzodiazepines are widely prescribed for anxiety, agitation, and insomnia in elderly patients, with usage rates of 15% in the community increasing to over 30% in long-term care facilities. Despite their popularity, these medications carry substantial risks for older adults, particularly those with cognitive impairment.

Short-Acting Benzodiazepines (half-life under 12 hours): Midazolam, triazolam. These medications clear the system relatively quickly but can cause rebound anxiety and insomnia.

Intermediate-Acting Benzodiazepines (half-life 12-24 hours): Alprazolam (Xanax), lorazepam (Ativan), oxazepam (Serax), temazepam (Restoril), clonazepam (Klonopin). These are most commonly prescribed but accumulate with repeated dosing.

Long-Acting Benzodiazepines (half-life over 24 hours): Diazepam (Valium), chlordiazepoxide (Librium), flurazepam (Dalmane). These medications accumulate significantly in older adults due to slower metabolism and can cause prolonged sedation.

Dementia Risk

Multiple meta-analyses have examined the relationship between benzodiazepine use and dementia risk. A 2018 meta-analysis of 10 studies found that benzodiazepine use increased dementia risk by 51% (pooled rate ratio 1.51, 95% CI 1.17-1.95). Another meta-analysis found a 78% increased odds of developing dementia among benzodiazepine users.

The risk increases with cumulative dose and duration. Taking benzodiazepines for 3-6 months raised Alzheimer’s risk by 32%, while use for more than 6 months increased risk by 84%. For every additional 20 defined daily doses per year, dementia risk increased by 22%. Long-acting benzodiazepines (half-life over 20 hours) and use exceeding 3 years showed particularly strong associations with dementia development.

However, one 2022 USC study found no increased dementia risk after carefully accounting for confounding factors, suggesting the association may reflect prescribing for prodromal dementia symptoms rather than causation. Despite this, the medication class remains on the Beers Criteria due to other serious risks.

Fall and Fracture Risk

Benzodiazepines significantly increase fall and fracture risk through multiple mechanisms including increased reaction time, disrupted balance and gait, sedation, and impaired vision. The risk appears dose-dependent, starting at approximately 20% of an average prescribed daily dose (0.3 mg/day of lorazepam or 3 mg/day of diazepam). Studies estimate that benzodiazepine exposure increases fall risk by 40-50% and hip fracture risk substantially.

The combination of benzodiazepines with other psychotropic medications (antipsychotics, antidepressants, opioids) shows dose-dependent increases in fall risk, creating a dangerous synergistic effect.

Additional Risks

Benzodiazepine use in dementia patients is associated with increased pneumonia risk (22% increased hazard ratio in first 30 days of use), particularly through mechanisms of sedation leading to hypoventilation, reduced lower esophageal sphincter pressure causing reflux and aspiration, and immune function suppression. All-cause mortality increases by 1.2 to 3.7-fold per year compared to unexposed individuals, though causality remains unclear. Delirium risk increases significantly, particularly with diphenhydramine combination.

Anticholinergic Medications: The Hidden Danger

What Are Anticholinergics?

Anticholinergic medications block the action of acetylcholine, a neurotransmitter crucial for learning, memory, and cognitive function. These drugs are found across multiple medication classes, many available over-the-counter, making them a particularly insidious threat to cognitive health.

Common Anticholinergic Medications

First-Generation Antihistamines: Diphenhydramine (Benadryl, ZzzQuil, Tylenol PM, Unisom, Simply Sleep), promethazine (Phenergan), meclizine (for vertigo), hydroxyzine.

Tricyclic Antidepressants: Amitriptyline (Elavil), imipramine (Tofranil), doxepin (Sinequan), nortriptyline.

Overactive Bladder Medications: Oxybutynin, tolterodine (Detrol), solifenacin, darifenacin. These show particularly strong anticholinergic effects.

Other Medications with Anticholinergic Properties: Some antipsychotics (particularly olanzapine), muscle relaxants, antiemetics, and some sleep aids.

The Anticholinergic Cognitive Burden Scale

The Anticholinergic Cognitive Burden (ACB) Scale, developed by geriatrician Malaz Boustani in 2008, ranks medications by severity of cognitive effects. Medications with ACB scores of 3 (highest burden) should be avoided in older adults whenever possible.

Dementia Risk from Anticholinergics

A landmark 2015 JAMA Internal Medicine study tracked nearly 3,500 adults aged 65 and older for over 10 years. The study found that cumulative anticholinergic use was strongly associated with dementia risk. Taking an anticholinergic medication daily for the equivalent of three years or more was associated with a 54% higher dementia risk compared to taking the same dose for three months or less.

The study calculated Total Standardized Daily Doses (TSDD) and found dose-response relationships. The risk was particularly pronounced for specific medication classes, with antidepressants, bladder antimuscarinics, antipsychotics, and antiepileptic drugs showing the strongest associations in a 2019 study of adults 55 and older.

A 2021 Cochrane systematic review analyzing 25 studies concluded there is likely a link between anticholinergic medications and dementia, though they recommended further research due to some study limitations and inconsistencies.

Acute Cognitive Effects

Even short-term anticholinergic use causes measurable cognitive impairment. Multiple high-quality trials show that diphenhydramine significantly impairs alertness, attention, memory (both working and episodic), executive function, reaction time, and vigilance. These drugs also increase fatigue and sleepiness while decreasing motivation.

A study of 426 older hospitalized patients found diphenhydramine treatment associated with significantly increased delirium risk (relative risk 1.7), including inattention (RR 3.0), disorganized speech (RR 5.5), and altered consciousness (RR 3.1).

Nursing Home Population

In a large study of 141,740 elderly nursing home residents with depression, anticholinergic medication use was associated with a 26% increased dementia risk. Commonly prescribed anticholinergics in this population included oxybutynin, tolterodine, promethazine, olanzapine, meclizine, and amitriptyline.

The Diphenhydramine Problem

Diphenhydramine (Benadryl) deserves special attention as it is widely available over-the-counter and present in numerous sleep aids, cold medications, and allergy products. Many users don’t realize that Tylenol PM, ZzzQuil, Unisom SleepTabs, Simply Sleep, and many store-brand sleep aids all contain the same problematic ingredient.

One study found diphenhydramine use associated with higher education levels (possibly reflecting greater over-the-counter medication use) but paradoxically also associated with lower cognitive test scores despite the protective effect education typically provides.

Why Are These Medications Still Prescribed?

Data Limitations

Medicare claims data often fail to capture the full clinical picture. Behavioral symptoms of dementia, such as severe agitation, combativeness, and psychosis, are frequently underreported in billing codes. The limited diagnosis codes used in claims data often don’t reflect all the reasons doctors prescribed these medications.

As Dr. Anupam Jena, professor of health care policy at Harvard Medical School notes, “We always have to be a little bit cautious” of studies suggesting “large numbers of patients are on drugs that are harmful to them. That sort of presumes that the doctors don’t know that these drugs have risks” as opposed to understanding the risk-benefit trade-off.

Lack of Effective Alternatives

One reason pharmacological intervention remains widely used is the current lack of other immediately accessible, proven effective treatments. Non-pharmacological interventions, while effective, require significant resources including trained staff, time, and supportive environments that many care settings lack.

Crisis Situations

In some cases, severe agitation poses immediate safety risks to the patient or others. Healthcare providers may feel they have no choice but to use medications to manage acute crises, even while recognizing the long-term risks.

Systemic Issues

Understaffed nursing homes and overstretched healthcare systems often lack the resources to implement comprehensive non-pharmacological approaches. Medications become a default option when person-centered care is not feasible due to time and staffing constraints.

How These Medications Cause Harm

Age-Related Pharmacological Changes

As people age, their ability to metabolize and eliminate drugs changes dramatically. The kidneys and liver clear drugs more slowly, causing blood levels to remain elevated for longer periods. Body composition changes, with increased fat and decreased muscle mass, alter how drugs are distributed and broken down in tissues. Older adults also tend to take multiple medications, increasing the risk of drug-drug interactions.

Mechanism-Specific Harm

Antipsychotics: These drugs work by blocking dopamine receptors in the brain. While this can reduce psychotic symptoms, it also causes widespread effects throughout the dopaminergic system including sedation and confusion, parkinsonian symptoms and movement disorders, metabolic changes affecting glucose and lipids, QT interval prolongation leading to cardiac arrhythmias, and suppression of immune function.

Benzodiazepines: These medications enhance the effect of GABA, the brain’s primary inhibitory neurotransmitter, leading to central nervous system depression and sedation, impaired balance and coordination, slowed reaction time and decreased alertness, respiratory depression, particularly dangerous when combined with opioids, and paradoxical agitation in some elderly patients.

Anticholinergics: By blocking acetylcholine, these drugs directly interfere with memory formation and cognitive processing, disrupt the blood-brain barrier in ways that may accelerate neurodegeneration, cause brain pathology changes similar to those seen in Alzheimer’s disease, impair multiple cognitive domains simultaneously, and potentially cause irreversible changes with cumulative exposure.

Evidence-Based Non-Pharmacological Interventions

Clinical guidelines emphasize that non-pharmacological approaches should be the first line of defense for managing behavioral symptoms in dementia. These interventions address the underlying causes of distress without the serious risks associated with medications.

Person-Centered Approaches

Understanding Unmet Needs: Agitation in dementia is often a form of communication about unmet needs. Similar to small children, people with dementia may become agitated due to hunger, thirst, pain, fear, boredom, overstimulation, need for toileting, uncomfortable temperature, or constipation. Systematically addressing these basic needs can dramatically reduce behavioral symptoms.

Tailored Activity Programs: Research shows that activities customized to individual capabilities, preferences, and past interests significantly reduce agitation. A home-based occupational therapy program based on personal capabilities showed greater agitation reduction than standard care. The Tailored Activities Program has been found cost-effective and should be considered part of clinical dementia management.

Music Therapy

Music therapy has emerged as one of the most effective non-pharmacological interventions for dementia. A meta-analysis of controlled studies found clinically and statistically robust effects of music intervention on agitation. Music therapy works through multiple mechanisms including providing sensory stimulation without overwhelming the person, accessing preserved long-term memories associated with familiar music, regulating emotional states, and creating opportunities for social connection.

Both active music therapy (singing, playing instruments) and passive music therapy (listening to preferred music) show benefits. Personalized music selections based on the individual’s preferences and history appear more effective than generic playlists. Music played during care situations (bathing, dressing) leads to higher compliance and reduced resistance.

Reminiscence Therapy

Introduced in the 1980s, reminiscence therapy is considered one of the most popular psychosocial interventions in dementia care. It can be conducted individually or in groups using free recall through conversation, specific stimuli like photographs or music, or life-review methods creating life-history books. Evidence supports positive effects on mood, depression, and agitation in the short term, typically using 30-60 minute sessions one to two times per week for 3-8 weeks.

Validation Therapy

Validation therapy accepts the reality and emotions of the person with dementia rather than trying to reorient them. Studies show significant reduction in physically aggressive behaviors and verbally aggressive behaviors with validation therapy compared to usual care.

One-on-One Social Contact

Research consistently shows that individualized social interaction is highly effective for reducing behavioral symptoms. One study comparing various interventions found that one-on-one social contact was the most effective intervention for reducing verbal agitation, more effective than videotapes of family members, music, or usual care.

Sensory Interventions

Aromatherapy: Evidence suggests aromatherapy can significantly improve agitation in people with dementia, though effects vary by individual.

Massage Therapy: Gentle massage and touch-based interventions have shown benefits for reducing agitation and improving mood.

Light Therapy: Exposure to bright light, particularly in the morning, can help regulate circadian rhythms and improve sleep disturbances.

Physical Activity and Exercise

Aerobic exercise and physical activity programs demonstrate effectiveness in treating behavioral and psychological symptoms of dementia. Regular movement promotes beneficial changes in brain chemistry, improves sleep quality, reduces anxiety and agitation, and provides structured daily activities.

Environmental Modifications

Creating dementia-friendly environments reduces behavioral symptoms by reducing noise and overstimulation, ensuring adequate lighting to prevent confusion and falls, maintaining comfortable temperature, providing clear visual cues and familiar objects, establishing predictable routines, and creating safe spaces for wandering.

Caregiver Training and Support

Training family caregivers in non-pharmacological techniques has been shown to reduce behavioral symptoms and delay nursing home placement. Programs like the Tailored Activities Program teach caregivers to identify triggers for agitation, implement personalized activity plans, and use communication strategies that reduce distress.

Safer Medication Alternatives When Necessary

When non-pharmacological approaches are insufficient and medication becomes necessary, safer alternatives should be considered.

For Agitation and Behavioral Symptoms

SSRIs (Selective Serotonin Reuptake Inhibitors): Citalopram (Celexa) and sertraline (Zoloft) may help with agitation and depression in dementia with fewer anticholinergic effects than tricyclic antidepressants. However, citalopram requires cardiac monitoring due to QT prolongation risk.

Dextromethorphan-Quinidine (Nuedexta): FDA-approved for pseudobulbar affect, this combination has shown some promise for agitation in dementia in clinical trials, though more research is needed.

For Sleep Disturbances

Melatonin: Natural sleep hormone with minimal side effects, though evidence for efficacy in dementia is mixed.

Trazodone: Low doses may help with sleep and has less anticholinergic activity than many alternatives.

Non-pharmacological approaches should be prioritized: Sleep hygiene, light therapy, and activity programs often prove more effective than medications.

For Allergy Symptoms

Second and Third-Generation Antihistamines: Loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) have minimal anticholinergic effects and don’t cross the blood-brain barrier as readily as first-generation antihistamines. Studies show these cause no more side effects than placebo while maintaining effectiveness for allergy symptoms.

For Depression

SSRIs: Escitalopram (Lexapro), sertraline (Zoloft), and citalopram (Celexa) are preferred over tricyclic antidepressants due to lower anticholinergic burden.

For Overactive Bladder

Pelvic floor exercises (Kegel exercises) and behavioral training can reduce urinary incontinence without medication.

If medication is necessary, newer agents like mirabegron (Myrbetriq) work through a different mechanism than traditional anticholinergics and may have fewer cognitive effects.

Important Principles for Any Medication Use

Start with the lowest effective dose, regularly assess continued need and consider discontinuation, monitor closely for adverse effects especially in the first 30-120 days, avoid polypharmacy whenever possible, and conduct comprehensive medication reviews at least annually.

Action Plan for Patients and Families

Immediate Steps

1. Conduct a Medication Review: Gather all prescription and over-the-counter medications, including sleep aids, allergy medicines, and pain relievers. Bring them to the next appointment with the primary care physician. Specifically ask about medications on the Beers Criteria and their necessity.

2. Identify Triggers for Behavioral Symptoms: Keep a detailed log noting when agitation or other behavioral symptoms occur, what was happening before the symptom appeared, what environmental factors were present (noise, lighting, number of people), whether basic needs (hunger, thirst, toileting, pain) had been met, and what interventions helped or didn’t help.

3. Request Non-Pharmacological Interventions First: Ask the healthcare team about music therapy programs, activity therapy and occupational therapy, validation therapy training for caregivers, environmental modification recommendations, and referral to dementia care specialists.

Questions to Ask Healthcare Providers

Is this medication on the Beers Criteria for potentially inappropriate medications? What specific symptom is this medication intended to treat? Have we tried non-pharmacological approaches first? What are the specific risks of this medication for someone with dementia? How will we monitor for side effects? What is the plan for reassessing whether this medication is still needed? Are there safer alternatives we could try?

For Medications Currently Being Taken

Never stop medications abruptly without medical supervision. Many of these medications require gradual tapering to avoid withdrawal symptoms. Work with healthcare providers to develop a tapering plan if discontinuation is appropriate. Be aware that behavioral symptoms may temporarily worsen during medication withdrawal as the body adjusts.

Creating a Supportive Care Environment

Establish consistent daily routines, ensure adequate nutrition and hydration, manage pain proactively, provide opportunities for meaningful activities, minimize environmental stressors, maintain social connections, and ensure caregivers have adequate support and respite.

Advance Care Planning

Document preferences for medication use in advance directives. Discuss with family and healthcare providers what level of risk is acceptable for behavioral symptom management. Designate a healthcare proxy who understands these preferences.

Advocating for Better Care

If a loved one in a care facility is prescribed these medications, ask detailed questions about the justification, request care plan meetings to discuss alternatives, and consider involving a geriatric psychiatrist or neurologist who specializes in dementia care. Document concerns and advocate persistently for person-centered, non-pharmacological approaches.