Anticholinergic burden in psychiatric prescribing

What anticholinergic burden means

Anticholinergic drugs block muscarinic acetylcholine (M1 to M5) receptors. Peripheral effects include dry mouth, blurred vision, constipation, urinary retention, and tachycardia. Central effects (from drugs that cross the blood-brain barrier) include sedation, cognitive slowing, memory impairment, and (at high burden or in vulnerable patients) delirium.

The clinical problem is that anticholinergic drugs are used across many indications (allergy, sleep, urinary incontinence, GI motility, EPS management, mood, psychosis) and the individual drugs are often mild. But burden accumulates. A patient on olanzapine plus benztropine plus diphenhydramine for sleep plus oxybutynin for urinary urgency has substantial cumulative burden even though no single drug looks alarming.

Two scoring systems are widely used:

• Anticholinergic Cognitive Burden (ACB) Scale: 0 (no effect), 1 (mild), 2 (moderate), 3 (severe). Total scores above 3 are considered clinically meaningful.
• Anticholinergic Risk Scale (ARS): similar 0 to 3 scoring per drug, with total scores predicting adverse outcomes.

Free calculators are available online. Building the total burden into the medication review is the practical intervention.

Psychiatric drugs contributing anticholinergic burden

High burden (ACB 3 or ARS 3):

• Amitriptyline (Elavil)
• Nortriptyline (Pamelor)
• Doxepin (Silenor)
• Clomipramine (Anafranil)
• Chlorpromazine (Thorazine)
• Thioridazine (Mellaril)
• Clozapine (Clozaril)
• Olanzapine (Zyprexa), moderate to high
• Benztropine (Cogentin)
• Trihexyphenidyl (Artane)
• Diphenhydramine (Benadryl)
• Doxylamine (Unisom)
• Hydroxyzine (Vistaril, Atarax)

Moderate burden (ACB 2):

• Paroxetine (Paxil), the only SSRI with meaningful anticholinergic activity
• Quetiapine (Seroquel), moderate

Low or minimal:

• Most SSRIs (sertraline, escitalopram, citalopram, fluoxetine)
• SNRIs (venlafaxine, duloxetine)
• Aripiprazole, brexpiprazole, cariprazine
• Lurasidone, ziprasidone, lumateperone
• Bupropion, mirtazapine

Non-psychiatric drugs that commonly add burden in psychiatric patients:

• Oxybutynin, tolterodine, solifenacin (overactive bladder)
• Dicyclomine, hyoscyamine (GI antispasmodics)
• Antihistamines (diphenhydramine, chlorpheniramine, hydroxyzine)
• Some antiemetics (promethazine, prochlorperazine)
• Cyclobenzaprine (muscle relaxant)
• Meclizine (dizziness)

Cognitive risk and dementia

Multiple studies have linked high cumulative anticholinergic burden to increased dementia risk. The Coupland et al. BMJ 2019 case-control study of 58,000+ dementia cases found substantially elevated dementia risk in patients with prolonged high anticholinergic exposure, particularly for antidepressants (paroxetine, amitriptyline), bladder drugs (oxybutynin), antipsychotics, and antiepileptics.

The association is dose- and duration-dependent. Short-term high-burden regimens carry less risk than years of moderate burden. Reducing exposure earlier is better than later.

In patients with existing dementia, anticholinergic burden accelerates cognitive decline and increases delirium risk. This is why Beers Criteria specifically flag anticholinergics for avoidance in older adults.

Clinical consequences

Beyond cognitive effects, high anticholinergic burden causes:

• Falls: from orthostatic hypotension, sedation, and impaired proprioception. Meta-analyses show 30 to 50 percent increased fall risk with high burden.
• Delirium: particularly in hospitalized older adults, post-surgical patients, and those with existing cognitive impairment.
• Urinary retention and UTI: particularly in older men with BPH.
• Constipation and rare bowel obstruction: additive with opioid burden.
• Dry mouth and dental disease: often overlooked but affects quality of life and dental health.
• Blurred vision: particularly for reading.
• Heat intolerance and hyperthermia risk: reduced sweating, dangerous in heat waves.

Management

Baseline burden assessment: for every complex polypharmacy patient, particularly older adults, calculate total ACB or ARS score. A single view of the medication list often reveals opportunities.

Substitute where possible: swap high-burden drugs for lower-burden alternatives with similar indication.

• Amitriptyline for depression → SSRI or SNRI or bupropion or mirtazapine
• Doxepin for sleep → trazodone or melatonin
• Benztropine for antipsychotic EPS → dose-reduce the antipsychotic or switch to a lower-EPS drug
• Diphenhydramine for sleep or allergies → cetirizine or loratadine (less sedating antihistamines); melatonin for sleep
• Oxybutynin for bladder → mirabegron (beta-3 agonist, low anticholinergic)
• Paroxetine → sertraline or escitalopram
• Olanzapine → aripiprazole or lumateperone

Non-pharmacologic alternatives where possible: behavioral therapy for insomnia (CBT-I), pelvic floor therapy for urinary urgency, cognitive rehabilitation for cognitive symptoms.

Timing considerations: anticholinergic burden matters most in older adults, patients with existing cognitive impairment, and patients on many drugs simultaneously. Young adults on a single moderate-burden drug carry less risk.

Deprescribing during hospital admission: hospital admission is often the opportunity to trim burden. Many polypharmacy medications were started years ago and never reviewed.

Common questions

Which SSRI has the most anticholinergic activity? Paroxetine (Paxil). It has moderate M1 receptor affinity, which contributes to its sedation, weight gain, constipation, and cognitive slowing profile. Other SSRIs are essentially non-anticholinergic. In older adults or patients on other anticholinergic drugs, paroxetine is usually a poor choice.

Is diphenhydramine safe for sleep? For occasional use in young healthy adults, low risk. For regular use in older adults, no. Diphenhydramine (Benadryl, ZzzQuil, Tylenol PM) is one of the most anticholinergic drugs available OTC, and it contributes substantially to cumulative burden. Standard geriatric guidance is to avoid it for sleep. Better options: melatonin, CBT-I, ramelteon.

Does clozapine really cause that much anticholinergic burden? Yes. Clozapine has strong M1, M2, and M3 antagonism, which contributes to its side effect profile (sialorrhea via M4 partial agonism is a separate issue) and its cognitive slowing. Clozapine plus benztropine plus another anticholinergic is a high-burden combination that shows up frequently in real practice.

What is the safest antipsychotic for anticholinergic burden? Aripiprazole, brexpiprazole, cariprazine, lurasidone, ziprasidone, and lumateperone all have minimal anticholinergic activity. For patients where cognitive function or delirium risk is a top priority, these are first choices among antipsychotics. See the atypical antipsychotics class page.

How much does anticholinergic burden increase dementia risk? The Coupland et al. BMJ 2019 study estimated 50 percent increased dementia risk in patients with prolonged high anticholinergic exposure compared to non-users. The magnitude varies by drug class; antidepressants (paroxetine, amitriptyline) and bladder drugs showed the largest signals. Effect appears dose- and duration-dependent.

Can anticholinergic effects be reversed? Peripheral effects (dry mouth, constipation, blurred vision) usually resolve within days to weeks of stopping the offending drug. Cognitive effects also improve, sometimes over weeks to months. Chronic damage in patients with prolonged high exposure may not fully reverse.

How do I calculate my total burden? Free calculators are available online (search "ACB calculator" or "anticholinergic risk scale"). Or bring your medication list to a pharmacist and ask for an anticholinergic burden review. Many outpatient clinics and community pharmacies now do this routinely.

Sources

• Boustani M, Campbell N, Munger S, Maidment I, Fox C. Impact of anticholinergics on the aging brain: a review and practical application. Aging Health. 2008;4(3):311-320. (ACB Scale)
• Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008;168(5):508-513. (ARS)
• Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. BMJ. 2019;367:l6754.
• Fox C, Richardson K, Maidment ID, et al. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc. 2011;59(8):1477-1483.
• American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 Updated AGS Beers Criteria. J Am Geriatr Soc. 2023;71(7):2052-2081.