Dementia
Clinical Snapshot
Dementia is a syndrome of acquired, progressive cognitive impairment that interferes with a person's ability to function independently — not a single disease, but a clinical picture with several distinct underlying causes. Alzheimer disease (AD) is the most common cause, followed by vascular dementia (VD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and mixed pathology (most often combined AD and VD); dementia is also a recognized complication of Parkinson disease (Parkinson disease dementia, PDD).[1] The formal DSM-5-TR term is "major neurocognitive disorder," but "dementia" remains the term used throughout clinical practice and this chapter.
Dementia must be distinguished from delirium — an acute, fluctuating disturbance of attention and consciousness with an identifiable and often reversible medical or medication-related precipitant (see Delirium for the full diagnostic approach). The two conditions frequently coexist in the same patient, and a delirium that persists or only partly resolves can be genuinely difficult to distinguish from dementia — this overlap is especially relevant to Lewy body dementia, where fluctuating consciousness is itself a core diagnostic feature rather than automatically a sign of superimposed delirium.
Recognize the Condition
How dementia actually presents
Presentation depends heavily on the underlying subtype, but common threads include a decline in memory, language, visuospatial ability, or executive function severe enough to interfere with instrumental activities of daily living — driving, managing medications and finances, cooking, shopping, using a telephone or other devices, housekeeping — before progressing to impair basic self-care (bathing, grooming, dressing, toileting, feeding).[1]
The 4 common dementia subtypes
Alzheimer disease (AD)
Accumulation of beta-amyloid plaques and tau neurofibrillary tangles causes neuronal degeneration. Gradual onset with progressive loss of memory and cognition, difficulty recalling recent events, sleep disturbance, apathy, and apraxia.
Vascular dementia (VD)
Cerebrovascular disease — single or multiple infarcts, cortical and/or subcortical, ischemic, hemorrhagic, or hypoperfusion mechanisms. A stepwise decline after cerebrovascular events, with deficits in memory, executive function, language, and attention.
Lewy body dementia (LBD) / Parkinson disease dementia (PDD)
Aggregates of alpha-synuclein (Lewy bodies) in the brainstem, limbic, and/or neocortical regions; amyloid plaques and neurofibrillary tangles may coexist. Early visual hallucinations, daytime drowsiness and napping, fluctuating consciousness, disorganized speech, parkinsonian motor symptoms, REM sleep behaviour disorder, and — critically for pharmacists — marked antipsychotic sensitivity.
Frontotemporal dementia (FTD)
Selective neurodegeneration of the frontal and temporal lobes from abnormal intracellular protein deposits, including tau. Disinhibition, socially inappropriate behaviour, compulsive behaviours, apathy, loss of empathy, and changes in habits or beliefs; some subtypes present with prominent language deficits.
Functional stages of dementia
Mild
Impaired instrumental activities of daily living — driving, medication management, finances, cooking, shopping, using a telephone or electronic device, housekeeping.
Moderate
Instrumental activities remain impaired, and some personal activities of daily living — bathing, grooming, dressing, toileting, feeding — now require assistance or prompting.
Severe
Personal activities of daily living cannot be performed independently even with prompting.
Terminal
The patient must be fed and becomes immobile and non-verbal.
Some jurisdictions use the Functional Assessment Staging Tool (FAST) to adjudicate reimbursement for dementia medications — mild corresponds to FAST 4, moderate to FAST 5, severe to FAST 6, and terminal to FAST 7.[1]
Risk Factors
- Older age — the single strongest risk factor for dementia overall.
- Family history of dementia, and known genetic risk factors (e.g., ApoE epsilon-4 carriage for Alzheimer disease).
- Down syndrome (markedly increased lifetime Alzheimer disease risk).
- Parkinson disease (risk of Parkinson disease dementia).
- Less education (to age 11-12).
- Social isolation and reduced social engagement.
- Untreated hearing impairment.
- Late-life depression.
- Mid-life obesity.
- Physical inactivity.
- Diabetes.
- Mid-life hypertension.
- Smoking.
- Excessive alcohol consumption.
- Traumatic brain injury.
- Air pollution exposure.
- Untreated or unmanaged sleep apnea, and severe sleep deprivation.
Drawn from the Lancet Commission's synthesis of modifiable dementia risk across the life course, alongside established non-modifiable factors.[2]
Red Flags & Refer
Escalate or refer urgently for any of the following:
- A severe or atypical antipsychotic sensitivity reaction in a patient with suspected or known Lewy body dementia — new or worsened rigidity, further impaired consciousness, or autonomic instability (temperature, blood pressure, or heart rate swings) after any antipsychotic exposure is a medical emergency requiring the antipsychotic to be stopped and urgent medical assessment, not just a dose adjustment.[3]
- Rapid or atypical cognitive decline — onset under 2 years, progression over 1-2 months, or an unexpected/unexplained decline in a patient with previously stable dementia — which suggests a reversible or different (non-degenerative) cause requiring urgent workup rather than routine dementia management.
- New focal neurologic signs, seizure, or a significantly depressed level of consciousness.
- Severe agitation or aggression posing an immediate safety risk to the patient or others.
- Early urinary incontinence with a gait disorder, particularly with a rapid course — suggests normal pressure hydrocephalus, a potentially treatable cause.
- Recent significant head trauma, anticoagulant use with new cognitive change, or a history of cancer with brain metastasis risk.
- New headache, worsening confusion, visual disturbance, nausea, or seizure in a patient receiving lecanemab or donanemab — possible amyloid-related imaging abnormalities (ARIA); hold therapy and obtain urgent MRI.
Assessment & Diagnosis
History
A careful history — including collateral history from a caregiver or family member, since insight is often impaired — should establish the cognitive domains affected (memory, language, orientation, visuospatial ability, executive function), the speed of onset and progression, mood and behaviour changes (the NPI-Q and PHQ are useful structured tools), noncognitive symptoms (incontinence, gait disorder, dysphagia, constipation, parkinsonism), functional impact on instrumental and personal activities of daily living, and safety concerns such as wandering or leaving appliances on.
Distinguishing dementia from delirium and other reversible causes
New or acutely worsened confusion should always prompt consideration of delirium first — an acute, fluctuating disturbance of attention with an identifiable precipitant (see Delirium) — before attributing the change to progression of an existing or new dementia. A structured medication review and the laboratory workup below are aimed specifically at identifying reversible or contributing causes before a dementia diagnosis is finalized.
Medication review
Anticholinergic medication burden can itself cause or worsen cognitive impairment, and is more likely when a patient has multiple prescribers.[1] Use an explicit tool — the Beers Criteria, STOPP/START criteria, or the Anticholinergic Cognitive Burden Scale and calculator — or an implicit tool such as the Medication Appropriateness Index to systematically identify contributing medications.
| Drug class (examples) | Relevance to cognitive impairment |
|---|---|
| Antidepressants with strong anticholinergic properties — amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, paroxetine | May increase dementia risk; other SSRIs/SNRIs without significant anticholinergic activity do not appear to. |
| Antiemetics/antivertigo agents — dimenhydrinate, promethazine, scopolamine | Not an established dementia risk factor, but can precipitate acute cognitive impairment or delirium. |
| Antihistamines — diphenhydramine, hydroxyzine | Not an established dementia risk factor, but can precipitate acute cognitive impairment or delirium. |
| Antimuscarinics for overactive bladder — darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine | Strong anticholinergic activity — associated with increased dementia risk and can precipitate acute cognitive impairment or delirium. |
| Antipsychotics — chlorpromazine, clozapine, olanzapine, and others | Not an established dementia risk factor, but can cause delirium or worsen existing cognitive impairment; all carry increased cerebrovascular and mortality risk in older patients with dementia (see Red Flags and Common Errors to Avoid). |
| Hypnotics — benzodiazepines, zolpidem, zopiclone | Benzodiazepines may increase dementia risk; all sedative-hypnotics can precipitate acute cognitive impairment or delirium. |
Physical examination
A full examination including a neurological exam helps identify contributing findings such as parkinsonism or apraxia, and should specifically screen for potentially reversible contributors such as findings suggesting hypothyroidism.
Laboratory tests
CBC, fasting glucose, electrolytes, calcium, renal function, TSH, and vitamin B12 in every patient being newly assessed for cognitive impairment. Atypical presentations warrant additional specialized investigation guided by a dementia specialist (e.g., FDG-PET, SPECT, or CSF studies). CSF or plasma amyloid/tau biomarkers to assess for prodromal Alzheimer disease are not recommended outside of a research setting for routine diagnostic workup — their role today is limited to confirming amyloid pathology as an eligibility requirement before anti-amyloid disease-modifying therapy (see Choose Initial Treatment).
Neuroimaging
Consider CT or MRI (MRI preferred where feasible) broadly for most older adults newly presenting with cognitive impairment. When imaging resources are limited, prioritize patients with any of the following: age under 60; new onset (under 2 years of symptoms); rapid progression (1-2 months); unexpected or unexplained decline in a patient with known dementia; recent significant head trauma or repeated mild head trauma; anticoagulant use or a bleeding disorder; unexplained neurologic symptoms, focal or lateralizing signs, or gait disturbance; early urinary incontinence with gait disorder; significant vascular risk factors; a history of cancer, particularly with brain metastasis risk; or atypical cognitive symptoms.
Cognitive screening tools
The Montreal Cognitive Assessment (MoCA) is most useful for screening mild cognitive impairment or early dementia. The Mini-Mental State Exam (MMSE), alone or combined with a clock-drawing test, is sensitive and specific for distinguishing moderate-stage dementia from normal cognition. The Ascertain Dementia-8 (AD-8) is completed by a caregiver. The Depistage Cognitif de Quebec (DCQ) includes a behavioural domain and is validated for atypical dementias. All brief screening tools carry test-specific biases and an increased risk of false-positive results and misclassification in patients of advanced age, those in a nursing home, those with lower educational attainment, and racialized populations — interpret results through an individualized lens rather than as a stand-alone diagnostic threshold, and use a culturally adapted translated version where available.[1]
Routine screening for cognitive impairment in asymptomatic older adults — even those with vascular risk factors or a family history — is not recommended; screening is for patients with a specific cognitive or functional concern, not a population-wide test.[1]
Treatment Targets
- Optimize function and slow the trajectory of cognitive and functional decline to the extent the specific dementia subtype and stage allow.
- Define specific, individualized target symptoms with the patient and caregiver at the outset, and reassess against those same specific targets — "reduction in repetitive questioning" is a more useful target than "improved cognition."
- Manage behavioural and psychological symptoms of dementia (BPSD) with the least restrictive, lowest-risk effective approach.
- Minimize the risk of harm to the patient and to others.
- Minimize medication-related harm — anticholinergic burden, sedative burden, and antipsychotic adverse effects in particular.
- Support caregiver capacity and reduce caregiver burden as an explicit part of the treatment plan, not an afterthought.
Choose Initial Treatment
Cognitive and functional pharmacotherapy
1st line - mild-moderate Alzheimer disease, mixed AD/VD, or Lewy body/Parkinson disease dementia start a cholinesterase inhibitor - donepezil, rivastigmine, or galantamine - selecting the agent by individual tolerability, drug interactions, and half-life rather than by a proven efficacy difference between the 3 agents.[1]
Vascular dementia without a mixed AD/LBD/PDD component a cholinesterase inhibitor trial is reasonable given how often a mixed component exists in practice, but the evidence for benefit in "pure" vascular dementia is weak - base continuation on an individual trial with clearly defined target-symptom monitoring rather than routine, indefinite use.
Frontotemporal dementia, or isolated mild cognitive impairment that has not progressed to dementia do not start a cholinesterase inhibitor or memantine - neither is effective in FTD or MCI, and cholinesterase inhibitors may worsen agitation in FTD.
Progression to moderate-severe Alzheimer disease, mixed AD/VD, or LBD while already on a cholinesterase inhibitor add memantine rather than switching - continuing the cholinesterase inhibitor and adding memantine is supported by randomized trial evidence, while simply switching to memantine alone is not.[4]
Moderate Alzheimer disease with cholinesterase-inhibitor intolerance or contraindication memantine monotherapy is the evidence-based alternative in this specific situation only.
Anti-amyloid disease-modifying therapy (specialist-directed)
Mild cognitive impairment or mild (early-stage) Alzheimer dementia, confirmed amyloid pathology, and an ApoE epsilon-4 non-carrier or heterozygote genotype lecanemab or donanemab are Health Canada-approved, specialist-initiated options shown to modestly slow - not reverse, halt, or cure - cognitive and functional decline in this specific population.[5][6] Both require confirmed amyloid pathology and ApoE genotyping before initiation, and a scheduled MRI monitoring program for amyloid-related imaging abnormalities (ARIA) throughout treatment.[7] Initiation and monitoring are specialist-directed, not a community-pharmacy-level decision, but pharmacists are positioned to counsel on the realistic, modest magnitude of benefit, the ARIA-monitoring schedule, and anticoagulant-interaction caution.
ApoE epsilon-4 homozygote, significant cerebral microhemorrhage or amyloid angiopathy burden, moderate-severe dementia, or anticoagulant use anti-amyloid therapy carries substantially higher ARIA risk and/or falls outside the studied and approved population - this is a specialist eligibility decision, not a routine option.
BPSD (responsive behaviours) pharmacologic escalation
Any BPSD, always the first step nonpharmacologic strategies plus identification and treatment of any precipitant (pain, infection, constipation, a new or changed medication, delirium - see Delirium). This is first-line therapy in its own right, not a formality to complete before "real" treatment, and is often sufficient alone.[8]
Agitation with prominent mood or anxiety features, nonpharmacologic measures inadequate a trial of citalopram (capped at 20 mg/day in patients aged 65 and older per Health Canada QTc guidance) or sertraline is a reasonable next step before an antipsychotic.
Severe agitation or psychosis causing significant distress or posing a genuine safety risk to self or others, refractory to the above a second-generation antipsychotic - risperidone preferred, the only Health Canada-indicated agent for this specific use - at the lowest effective dose and for the shortest effective duration, with explicit counselling to the caregiver or substitute decision-maker about the boxed-warning-level increased risk of stroke and death.[9][10]
Suspected or confirmed Lewy body dementia avoid antipsychotics whenever possible (see Red Flags). If truly unavoidable for safety, quetiapine at the lowest possible dose under close specialist supervision is the better-tolerated option, and first-generation agents such as haloperidol should not be used routinely.[3]
Deprescribing
Any point in the treatment course actively reassess the ongoing need for a cholinesterase inhibitor, memantine, or antipsychotic - deprescribing is an ongoing treatment decision from the outset, not something considered only once all other options fail (see Treatment Failure and Next Steps, and Monitoring and Follow-up, for specific triggers and taper approach).
Non-Pharmacologic Treatment
- Ongoing physical exercise, cognitive stimulation, and social engagement benefit most older adults with dementia, across subtypes and stages.
- Group cognitive stimulation therapy is beneficial for mild-moderate dementia.[1]
- Frontotemporal dementia management is primarily nonpharmacologic, with emphasis on family/caregiver support; subtypes with prominent language deficits benefit from early speech-language pathology involvement.
- Address advance care planning early - advance health-care directives (a living will) and durable power of attorney - before disease progression affects decision-making capacity.
- Offer psychosocial and psychoeducational interventions to caregivers, and refer to the local Alzheimer Society as a starting point for resources, which vary by province.
- Counsel against driving once the patient has progressed beyond the earliest stages, particularly with prominent visuospatial or executive deficits, or with hallucinations or delusions - many provinces have mandatory reporting requirements at this stage.
- For BPSD specifically, apply nonpharmacologic strategies first and always: multidisciplinary care (recreation therapy, exercise, outdoor activity), sensory stimulation (music, therapeutic touch, massage), environmental modification (safe spaces to wander, removal of hazards), person-centred communication with the patient, and caregiver/staff education on distraction, redirection, avoiding confrontation, reassurance, and providing structure. Supervised skills training for care staff (person-centred care, communication, dementia care mapping) is effective; light therapy, aromatherapy, and caregiver training in formal behavioural-management therapy have insufficient evidence to expect benefit.[8]
- Identify and manage sleep apnea, and avoid severe sleep deprivation (under 5 hours/night) - both may improve cognition.
- A Mediterranean-pattern diet - high in mono- and polyunsaturated fats, low in saturated fat, high in fruits and vegetables - is a reasonable, low-risk recommendation for cognitive health.
- When pharmacologic therapy for BPSD is genuinely necessary, continue nonpharmacologic strategies alongside it - this often allows a lower effective medication dose.
Special Populations
Breastfeeding: the same limited-data caveat applies; individualize with specialist input given how uncommon this clinical scenario is.
Renal and hepatic impairment
Memantine is renally cleared - reduce the target dose in significant renal impairment (e.g., target 5 mg PO BID rather than 10 mg BID with moderate-severe impairment). Galantamine should be avoided in severe hepatic or severe renal impairment. Donepezil is hepatically metabolized via CYP2D6/3A4 - use caution with significant hepatic impairment or strong CYP2D6/3A4 inhibitors. Rivastigmine is not hepatically metabolized and has no established interactions through the cytochrome P450 system, which can make it a useful choice when interactions are a specific concern.
Cardiac disease
All cholinesterase inhibitors carry a small risk of QT-interval prolongation and bradycardia. Consider a baseline ECG before starting one in a patient who is already bradycardic, on multiple other rate-limiting drugs (beta-blockers, calcium channel blockers, amiodarone), or has a history of unexplained syncope or presyncope - and discuss with a specialist first in that situation.
Lewy body dementia
Patients with LBD have markedly increased sensitivity to antipsychotic-induced dopamine blockade given the disease's core dopaminergic deficit - this can precipitate a severe, potentially irreversible neuroleptic sensitivity reaction with worsened parkinsonism, further impaired consciousness, and autonomic instability. Reserve an antipsychotic for LBD only when cholinesterase-inhibitor therapy has failed and responsive behaviours are causing severe distress or a safety risk; when unavoidable, quetiapine at the lowest possible dose under close supervision is better tolerated than risperidone, olanzapine, or any first-generation agent.[3]
Parkinson disease dementia
Cholinesterase inhibitors (rivastigmine has the most trial evidence in this specific population) are generally well tolerated and do not meaningfully worsen motor symptoms beyond a possible mild increase in tremor. Minimize anticholinergic-burden medications, which worsen both motor and cognitive symptoms in this population. If an antipsychotic is required, the same LBD-level caution applies given the shared dopaminergic vulnerability.
Vascular dementia
Aggressive management of the underlying cardiovascular risk factors - blood pressure, lipids, diabetes, smoking cessation, and antiplatelet/anticoagulant therapy as indicated for the underlying vascular disease - is an essential parallel treatment track, not just prevention. Cholinesterase-inhibitor benefit is modest and of uncertain clinical significance in "pure" vascular dementia without a mixed AD component.
Older adults generally
Start low and titrate slowly for every drug class in this chapter. Minimize overall anticholinergic and sedative burden, and weigh fall risk carefully with any sedating or antipsychotic medication.
Monitoring & Follow-Up
- Reassess target symptoms 2-4 weeks after starting or increasing the dose of a cholinesterase inhibitor or memantine, then periodically thereafter.
- In an untreated patient with mild-moderate dementia, MMSE typically declines by 2-4 points per year; an annual decline of under 2 points while on cholinesterase-inhibitor therapy is generally interpreted as a beneficial treatment effect, even though MMSE is a poor tool for judging response in an individual patient day-to-day.[1]
- Monitor for cholinesterase-inhibitor adverse effects - GI symptoms, weight loss, bradycardia - and consider baseline/follow-up ECG in patients with the cardiac risk factors noted in Special Populations.
- Reassess renal function periodically to confirm memantine dosing remains appropriate.
- For anti-amyloid antibody therapy, follow the scheduled MRI monitoring program - baseline, before specific early infusions, and again at 1 year, with closer monitoring in ApoE epsilon-4 carriers or after any prior ARIA event - and ask specifically about new headache, confusion, visual change, nausea, or seizure between scheduled scans.[7]
- For any antipsychotic started for BPSD, reassess the ongoing need every 3-6 months with a specific goal of tapering or discontinuing once symptoms have been stable - most patients do not need indefinite therapy.
- Review the full medication list at every visit for anticholinergic burden and other deprescribing candidates (see the medication-review table in Assessment and Diagnosis).
- Ask about caregiver wellbeing and burden at every visit - this is a monitoring parameter in its own right, not a courtesy question.
Common Errors to Avoid
- Starting or continuing an antipsychotic in a patient with suspected or known Lewy body dementia without recognizing the severe neuroleptic sensitivity risk.[3]
- Reaching for an antipsychotic as first-line or routine management of agitation without an adequate nonpharmacologic trial first, and without explicit boxed-warning-level mortality-risk counselling to the caregiver or substitute decision-maker.[9]
- Treating antipsychotic-induced akathisia as inadequate drug effect and escalating the dose rather than recognizing it as an adverse effect.
- Stopping a cholinesterase inhibitor based on a single low MMSE score alone rather than the full clinical picture, including caregiver-reported function and behaviour.
- Adding a new medication to treat a cholinesterase inhibitor's side effect (e.g., an anticholinergic bladder agent for urinary frequency) instead of reducing the dose or switching agents.
- Using a cholinesterase inhibitor or memantine in frontotemporal dementia - not effective, and may worsen agitation.
- Missing an anticholinergic-burden medication - an over-the-counter first-generation antihistamine sleep aid, a bladder antimuscarinic, an older tricyclic antidepressant - as a reversible contributor to cognitive impairment.
- Treating a positive cognitive screening test (MMSE or MoCA) alone as diagnostic, without the supporting history, exam, and laboratory workup.
- Assuming eligibility for lecanemab or donanemab without confirmed amyloid pathology and ApoE genotyping - both are required prerequisites, not optional add-ons.
- Overlooking caregiver burden and support needs as part of the treatment plan.
Clinical Decision Algorithm
Drug Tables
How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.
Cholinesterase inhibitors
Block acetylcholinesterase, increasing synaptic acetylcholine - the mainstay of cognitive/functional therapy for Alzheimer disease, mixed AD/VD, Lewy body dementia, and Parkinson disease dementia. Not effective in frontotemporal dementia. Start at the lowest dose and titrate slowly - starting at a high dose without gradual titration is associated with more serious adverse events.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Donepezil | Initial: 5 mg PO once daily Target: 10 mg PO once daily, after at least 4 weeks | Nausea, diarrhea, GI upset (most common); vivid dreams, muscle cramps, fatigue, anorexia, syncope; bradycardia and prolonged QT interval (uncommon) | CYP2D6/3A4 inhibitors (paroxetine, erythromycin, ketoconazole, grapefruit juice) increase levels; CYP2D6/3A4 inducers (carbamazepine, phenytoin, rifampin) reduce effectiveness; additive bradycardia with other rate-limiting drugs | Once-daily dosing - longest half-life of the class (about 70 hours), useful when adherence is a concern but slower to wash out if not tolerated. Doses above 10 mg/day show no added benefit. |
| Rivastigmine, oral | Initial: 1.5 mg PO BID with food Titration: increase by 1.5 mg BID every 4 weeks as tolerated Target: 3-6 mg PO BID (6-12 mg/day) | Nausea, vomiting, diarrhea, anorexia, dizziness, headache (more common than with the patch) | Not hepatically metabolized - no cytochrome P450 interactions reported | Take with breakfast and dinner to reduce GI upset. Consider the patch if oral GI tolerability is a problem. |
| Rivastigmine, transdermal patch | Initial: 4.6 mg/24h patch, applied once daily Titration: increase to 9.5 mg/24h after at least 4 weeks if tolerated (usual maintenance dose) Maximum: 13.3 mg/24h - reserve for inadequate response at 9.5 mg/24h; no added benefit above this dose | GI upset (less than oral), dizziness, application-site skin reactions | Not hepatically metabolized - no cytochrome P450 interactions reported | Change the patch daily and remove the previous one first - Health Canada has warned of accidental overdose from failing to do so. Rotate application sites. |
| Galantamine, extended-release | Initial: 8 mg PO once daily Titration: increase to 16 mg once daily after at least 4 weeks Target: 16-24 mg PO once daily | Nausea, vomiting, diarrhea, weight loss, abdominal pain, bradycardia, dizziness | CYP2D6/3A4 inhibitors increase levels; CYP2D6/3A4 inducers reduce effectiveness | Take in the morning with food. In Lewy body/Parkinson disease dementia, reserve for donepezil/rivastigmine intolerance - weaker evidence base in this subtype. |
NMDA receptor antagonist
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Memantine | Initial: 5 mg PO once daily Titration: increase by 5 mg/day at weekly intervals Target (week 4 onward): 10 mg PO BID | Dizziness, headache, confusion, constipation - generally well tolerated | No cytochrome P450 interactions; theoretically, urinary alkalizers (e.g., carbonic anhydrase inhibitors) may reduce clearance | NMDA-receptor antagonist - a different mechanism from cholinesterase inhibitors, added on rather than substituted. Reduce the target dose to 5 mg PO BID in significant renal impairment. Combining memantine with an existing cholinesterase inhibitor is supported by randomized trial evidence in moderate-severe disease.[4] |
Anti-amyloid disease-modifying monoclonal antibodies (specialist-initiated only)
Health Canada-approved for mild cognitive impairment or mild Alzheimer dementia with confirmed amyloid pathology and a permitted ApoE genotype; access is currently limited pending public drug plan reimbursement decisions, which are evolving rapidly.[11][12]
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Lecanemab | Dosing: 10 mg/kg IV infusion every 2 weeks | Amyloid-related imaging abnormalities (ARIA-E edema, ARIA-H microhemorrhage - usually asymptomatic, detected by scheduled MRI; occasionally headache, confusion, visual change, nausea, or seizure), infusion reactions | Higher ARIA risk with concurrent anticoagulation | Specialist-initiated only. Requires confirmed amyloid pathology and ApoE epsilon-4 genotyping before starting, plus a scheduled MRI monitoring program throughout treatment (baseline, before specific early infusions, and at 1 year).[5][7] |
| Donanemab | Dosing: IV infusion every 4 weeks, titrated over the first several doses per current product labeling | ARIA (as above), infusion reactions | Higher ARIA risk with concurrent anticoagulation | Specialist-initiated only, same eligibility requirements as lecanemab. Fixed-duration course - typically stopped once amyloid clearance is confirmed on PET imaging (usually 12-18 months), unlike lecanemab's continued dosing.[6] |
Antipsychotics for BPSD - reserve for severe, dangerous, or significantly distressing symptoms after nonpharmacologic measures fail
The chance of symptomatic benefit from a second-generation antipsychotic in dementia-related agitation is roughly matched by the chance of an adverse effect such as extrapyramidal symptoms, sedation, or worsened confusion - this is genuine equipoise, not a reason to avoid treatment when symptoms are severe and safety is at risk, but it is the basis for explicit informed counselling every time.[13][10]
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Risperidone | Initial: 0.25 mg PO once daily Usual target: 1 mg PO once daily Maximum: 2 mg/day | Extrapyramidal symptoms, sedation, hyperglycemia, increased risk of stroke and death (boxed warning) | CYP2D6/3A4 inhibitors (erythromycin, paroxetine, grapefruit juice) increase levels; CYP2D6/3A4 inducers (carbamazepine, phenytoin, rifampin) reduce effectiveness | The only Health Canada-indicated antipsychotic for dementia - short-term use in severe Alzheimer dementia with aggression/psychosis and safety risk, unresponsive to nonpharmacologic measures. Avoid in Lewy body dementia.[9][3] |
| Olanzapine | Initial: 2.5 mg PO once daily Usual: 5-10 mg PO once daily Maximum: 10 mg/day | Sedation, constipation, weight gain, metabolic dysregulation, increased risk of stroke and death (boxed warning, class effect) | CYP1A2 inhibitors (ciprofloxacin, fluvoxamine) increase levels; CYP1A2 inducers (carbamazepine, smoking) reduce effectiveness | Off-label for BPSD in Canada; strong evidence base for reducing aggression alongside risperidone. |
| Quetiapine | Initial: 12.5 mg PO once daily Usual: 25-50 mg PO once daily Maximum: 200 mg/day | Sedation, orthostatic hypotension, metabolic dysregulation, increased risk of stroke and death (boxed warning, class effect) | CYP3A4 inhibitors (clarithromycin, ketoconazole, grapefruit juice) increase levels; CYP3A4 inducers reduce effectiveness | Off-label for BPSD. Lower extrapyramidal-symptom risk than risperidone/olanzapine - preferred when EPS-sensitivity or Lewy body/Parkinson disease dementia makes those agents unsuitable.[3] |
| Aripiprazole | Dosing: Individualized, low starting dose with slow titration - specialist-directed | Akathisia, insomnia, increased risk of stroke and death (boxed warning, class effect) | CYP2D6/3A4 inhibitors increase levels | Off-label for BPSD, with weaker evidence than risperidone/olanzapine. An option when metabolic or sedation concerns make other second-generation agents unsuitable. |
| Haloperidol | Acute crisis only, combined with lorazepam: 0.5-1.5 mg IM, combined with lorazepam 0.5-1 mg IM in the same syringe, every 8 hours for a maximum of 3 days, per institutional protocol | Extrapyramidal symptoms (highest risk of the class), tardive dyskinesia, increased risk of stroke and death (boxed warning) | Additive QT prolongation with other QT-prolonging drugs | First-generation antipsychotic - not recommended for routine BPSD management given the highest extrapyramidal and tardive-dyskinesia risk of the class. Reserve for acute crisis combination use only. |
Antidepressants - depression, and BPSD with mood/anxiety features
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Citalopram | Initial: 10 mg PO once daily Target (age 65 or older): 20 mg PO once daily, do not exceed | Nausea, hyponatremia/SIADH, QT prolongation | Additive hyponatremia risk with thiazide diuretics; additive QT prolongation with other QT-prolonging drugs | Randomized trial evidence supports use for agitation with mood/anxiety features. Maximum 20 mg/day in patients 65 and older per Health Canada guidance, even though some agitation-trial dosing was higher. |
| Sertraline | Initial: 25 mg PO once daily Usual target: 50-100 mg PO once daily Maximum: 200 mg/day | GI upset, hyponatremia/SIADH | Fewer QT/CYP interactions than citalopram | A reasonable alternative to citalopram for agitation with mood/anxiety features. |
| Escitalopram | Initial: 5-10 mg PO once daily Usual target: 10 mg PO once daily | Nausea, hyponatremia/SIADH, QT prolongation | Additive QT prolongation with other QT-prolonging drugs | An alternative to citalopram with a similar QTc caution; less dementia-specific agitation-trial evidence than citalopram. |
| Trazodone | Initial (sleep/sundowning): 25-50 mg PO at bedtime Usual (sleep/sundowning): 50 mg PO at bedtime Other responsive behaviours: 100-200 mg/day in divided doses | Sedation, orthostatic hypotension, rare priapism | CYP3A4 inhibitors increase levels | Useful specifically for sundowning and disrupted sleep/wake cycles; randomized trial evidence supports low-dose use for sleep. |
| Mirtazapine | Not recommended for agitation in dementia: - | Sedation, increased appetite/weight gain | None significant | Randomized trial evidence found no efficacy for agitation in dementia, with a possible trend toward increased mortality - not recommended for this indication despite being commonly considered. |
Benzodiazepines - severe acute agitation only, not for routine or chronic use
Data on efficacy for BPSD are conflicting, and use carries a real risk of oversedation, falls, and worsening cognition; reserve for acute severe agitation when other measures fail.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Lorazepam | Severe acute agitation: 0.5-1 mg PO/SL/IM, may repeat | Sedation, falls, worsening cognition, paradoxical agitation | Additive sedation with other CNS depressants | Short-acting, no active metabolites - the preferred agent of this class when a benzodiazepine is genuinely needed. |
| Oxazepam | Severe acute agitation: 5-10 mg PO | Sedation, falls, worsening cognition | Additive sedation with other CNS depressants | Short-acting, no active metabolites. |
| Temazepam | Sleep, short-term only: 15 mg PO at bedtime | Sedation, falls, worsening cognition | Additive sedation with other CNS depressants | For short-term sleep disturbance only when nonpharmacologic measures and trazodone have failed. |
Agents with weak (case-report-level) evidence only - not routine therapy
These agents seem to work best when the target behaviour resembles the psychiatric syndrome the drug is otherwise used for (e.g., lithium for manic-spectrum features), or after agents with a stronger evidence base have failed under specialist direction.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Buspirone | Dosing: Individualized, low starting dose - specialist-directed | Dizziness, headache | Avoid with MAOIs | Case-report-level evidence for anxiety-predominant BPSD only. |
| Methylphenidate | Dosing: Individualized, low starting dose - specialist-directed | Insomnia, anxiety, appetite suppression, cardiovascular stimulation | Avoid with MAOIs | Emerging but not yet high-quality evidence for apathy specifically in Alzheimer disease; not established for agitation. |
| Gabapentin | Dosing: Individualized, renally adjusted - specialist-directed | Sedation, dizziness, ataxia | Additive sedation with other CNS depressants | Case-report-level evidence only. |
| Pregabalin | Dosing: Individualized, renally adjusted - specialist-directed | Sedation, dizziness, peripheral edema | Additive sedation with other CNS depressants | Case-report-level evidence only. |
| Carbamazepine | Dosing: Individualized - specialist-directed | Sedation, ataxia, hyponatremia | Numerous - strong CYP3A4 inducer affecting many concurrent drugs | Case-report-level evidence only; requires level monitoring. |
| Divalproex sodium | Dosing: Individualized - specialist-directed | Sedation, thrombocytopenia, hepatotoxicity | Numerous - CYP interactions and protein-binding displacement | Case-report-level evidence only; not established for routine BPSD use. |
| Lithium carbonate | Dosing: Individualized, requires level monitoring - specialist-directed | Narrow therapeutic index - tremor, GI upset, renal and thyroid effects with chronic use | NSAIDs, ACE inhibitors, and thiazides increase lithium levels | Case-report-level evidence only; best considered when the target behaviour resembles a manic-spectrum presentation. |
| Pindolol | Dosing: Individualized - specialist-directed | Bradycardia, hypotension, bronchospasm | Additive bradycardia with other rate-limiting drugs | Case-report-level evidence only, for aggression specifically. |
Evidence note: drug selection, dosing, adverse effects, and comments in this table reflect current Canadian practice, cross-checked against the 5th Canadian Consensus Conference on the diagnosis and treatment of dementia.[1]
References
- Recommendations of the 5th Canadian Consensus Conference on the diagnosis and treatment of dementia — Alzheimer's & Dementia (Ismail Z, Black SE, Camicioli R, et al.). Alzheimers Dement 2020;16(8):1182-1195
- Dementia prevention, intervention, and care: 2020 report of the Lancet Commission — The Lancet (Livingston G, Huntley J, Sommerlad A, et al.). Lancet 2020;396(10248):413-446
- Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium — Neurology (McKeith IG, Boeve BF, Dickson DW, et al.). Neurology 2017;89(1):88-100
- Donepezil and memantine for moderate-to-severe Alzheimer's disease — New England Journal of Medicine (Howard R, McShane R, Lindesay J, et al.). N Engl J Med 2012;366(10):893-903
- Lecanemab in early Alzheimer's disease — New England Journal of Medicine (van Dyck CH, Swanson CJ, Aisen P, et al.). N Engl J Med 2023;388(1):9-21
- Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial — JAMA (Sims JR, Zimmer JA, Evans CD, et al.). JAMA 2023;330(6):512-527
- Lecanemab: appropriate use recommendations — Journal of Prevention of Alzheimer's Disease (Cummings J, Apostolova L, Rabinovici GD, et al.). J Prev Alzheimers Dis 2023;10(3):362-377
- Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012 — Alzheimer's Research & Therapy (Herrmann N, Lanctot KL, Hogan DB). Alzheimers Res Ther 2013;5(Suppl 1):S5
- Risperidone - restriction of the dementia indication — Health Canada. Recalls and Safety Alerts, February 2015
- The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia — American Journal of Psychiatry (Reus VI, Fochtmann LJ, Eyler AE, et al.). Am J Psychiatry 2016;173(5):543-546
- Regulatory Decision Summary - Leqembi (lecanemab) — Health Canada. Drug and Health Products Portal, October 2025
- Regulatory Decision Summary - Kisunla (donanemab) — Health Canada. Drug and Health Products Portal, May 2026
- Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease — New England Journal of Medicine (Schneider LS, Tariot PN, Dagerman KS, et al.). N Engl J Med 2006;355(15):1525-1538
Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.