14.5 Delirium & the Pharmacotherapy of Cognitive Disorders

Pharmacotherapy of Alzheimer Disease & Anti-Amyloid Monoclonal Antibodies

1. Acetylcholinesterase Inhibitors (AChEIs)

• Agents: Donepezil (5-10 mg PO daily; up to 23 mg daily), Rivastigmine (1.5-6 mg PO BID or 4.6-13.3 mg/24h transdermal patch), Galantamine (8-24 mg PO daily extended-release).
• Mechanism: Reversibly inhibits acetylcholinesterase, increasing synaptic acetylcholine concentration in the central nervous system.
• Adverse Effects (Cholinergic Excess): Gastrointestinal (nausea, vomiting, diarrhea, anorexia, weight loss), central (vivid dreams, insomnia), and cardiovascular (bradycardia, sick sinus syndrome, AV block, and syncope). Baseline ECG should be checked prior to initiation in patients with suspected conduction disease.

2. NMDA Receptor Antagonists

• Agent: Memantine (5-20 mg PO daily; titrate weekly by 5 mg).
• Mechanism: Uncompetitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist. Blocks pathological tonic glutamate excitotoxicity without interfering with physiological neurotransmission.
• Indication: Moderate-to-severe AD (MMSE <20) either as monotherapy or combined with Donepezil (demonstrates additive functional and cognitive benefits).
• Adverse Effects: Dizziness, headache, confusion, and constipation.

3. Amyloid-Beta Directed Monoclonal Antibodies (Lecanemab & Donanemab)

• Lecanemab (Leqembi - approved 2023): Humanized IgG1 mAb targeting soluble amyloid-beta protofibrils (10 mg/kg IV every 2 weeks).
• Donanemab (Kisunla - approved 2024): Humanized IgG1 mAb targeting insoluble, N-terminally truncated pyroglutamate amyloid-beta plaques (administered IV every 4 weeks).
• Clinical Indications: Indicated strictly for Early Symptomatic AD (patients with Mild Cognitive Impairment due to AD or Mild AD Dementia) with objective, laboratory-confirmed brain amyloid pathology (via Amyloid Positron Emission Tomography [PET] or CSF biomarker ratios [$A\beta_{42}/A\beta_{40}$ and phosphorylated tau $p-tau_{181}$]).
• Mandatory Pre-Treatment Genotyping: Baseline Apolipoprotein E (ApoE) genotyping is mandatory. Homozygous ApoE $\varepsilon4/\varepsilon4$ carriers have the highest risk of developing severe, life-threatening amyloid-related adverse events.
• Amyloid-Related Imaging Abnormalities (ARIA) & MRI Surveillance:
  • ARIA-E (Vasogenic Edema): Sulcal effusion and parenchymal vasogenic edema on FLAIR sequences. Occurs in 12-25% of patients (highest in ApoE4 homozygotes). Often asymptomatic, but can manifest as headache, confusion, visual disturbances, dizziness, or seizures. Requires temporary drug suspension until edema fully resolves on follow-up MRI.
  • ARIA-H (Microhemorrhages & Superficial Siderosis): Intracerebral petechial microbleeds and leptomeningeal hemosiderin deposition on gradient-echo (GRE) or susceptibility-weighted imaging (SWI) MRI. If >4 new microhemorrhages or superficial siderosis develop, therapy must be held or discontinued permanently.
  • Surveillance Protocol: Baseline brain MRI within 12 months, followed by routine surveillance MRIs prior to the 5th, 7th, and 14th infusions (for Lecanemab) or weeks 12, 24, and 52 (for Donanemab).

1. Delirium: Diagnosis, Etiologies & Management

Delirium is an acute, fluctuating disturbance in attention, awareness, and baseline cognition. It occurs in up to 30-50% of hospitalized older adults and carries a 1-year mortality of 35-40%.

Clinical Subtypes

• Hyperactive Delirium (25%): Agitation, psychomotor restlessness, delusions, vivid hallucinations, paranoia, and combative behavior. Readily recognized.
• Hypoactive Delirium (50%): Lethargy, psychomotor slowing, apathy, decreased verbal output, and stupor. Most common subtype and frequently missed (often misdiagnosed as depression or worsening dementia; carries worse clinical outcomes).
• Mixed Delirium (25%): Fluctuates between hyperactive and hypoactive states.

Confusion Assessment Method (CAM) Diagnostic Algorithm

Diagnosis of delirium requires the presence of Feature 1 AND Feature 2 PLUS EITHER Feature 3 OR Feature 4:

1. Feature 1: Acute Onset and Fluctuating Course (Evidence of acute change in mental status from baseline; behavior waxes and wanes over the course of a day).
2. Feature 2: Inattention (Difficulty focusing, sustaining, or shifting attention; assessed by asking patient to spell "WORLD" backwards, recite months of the year backwards from December, or perform serial 7 subtractions).
3. Feature 3: Disorganized Thinking (Rambling, irrelevant, or incoherent conversation; illogical flow of ideas; unpredictable switching between subjects).
4. Feature 4: Altered Level of Consciousness (Any state other than "alert", including hyperalert/vigilant, lethargic, stuporous, or unarousable).

Etiologies: The DELIRIUMS Mnemonic

• D — Drugs: Anticholinergics, sedative-hypnotics, opioids, corticosteroids, polypharmacy, drug intoxication.
• E — Electrolyte Disturbances / Endocrine: Hyponatremia, hypercalcemia, hypoglycemia, thyroid storm/myxedema, acute adrenal insufficiency.
• L — Lack of Drugs (Withdrawal): Alcohol withdrawal (delirium tremens), benzodiazepine withdrawal, SSRI discontinuation.
• I — Infection: Urinary tract infection (UTI), pneumonia, sepsis, bacteremia, meningitis, encephalitis, COVID-19, C. diff colitis.
• R — Reduced Sensory Input: Uncorrected visual or hearing impairment, sleep deprivation, social isolation.
• I — Intracranial Disorders: Acute ischemic stroke, intracranial hemorrhage, subdural hematoma, non-convulsive status epilepticus, traumatic brain injury.
• U — Urinary Retention & Fecal Impaction: Bladder outlet obstruction, severe constipation/obstipation (extremely common occult triggers).
• M — Myocardial / Metabolic / Hypoxia: Acute coronary syndrome, acute decompensated heart failure, pulmonary embolism, hypoxemia, hypercapnia, hepatic encephalopathy, uremic encephalopathy.
• S — Surgery / Severe Pain / Sleep Deprivation: Postoperative state, general anesthesia, uncontrolled acute pain.

Evidence-Based Management of Delirium

1. First-Line: Environmental & Non-Pharmacologic Interventions (The HELP Protocol):

   • Frequent Reorientation: Clocks, calendars, clear communication, whiteboards with nurse/date names, familiar personal photos.
   • Sensory Optimization: Ensure patient is wearing functioning eyeglasses and hearing aids.
   • Circadian Sleep-Wake Cycle: Bright natural sunlight during daytime; quiet, dim environment at night; eliminate non-essential nighttime vitals, medication passes, and phlebotomy between 22:00 and 06:00.
   • Early Mobilization: Ambulate out of bed >=3 times daily; physical and occupational therapy.
   • Remove Tethering Devices: Prompt removal of urinary Foley catheters, sequential compression devices when ambulating, and unnecessary IV lines.
   • AVOID Physical Restraints: Physical restraints drastically increase agitation, delirium duration, falls, strangulation, and mortality. They are strictly contraindicated.

2. Pharmacologic Management: Highly Restricted Indications:

   • ABIM Board Rule: Antipsychotics are NOT recommended for the prevention of delirium, nor for the treatment of hypoactive delirium or mild agitation.
   • Emergency Rescue Pharmacotherapy: Reserved ONLY for patients with severe, intractable agitation or perceptual disturbances that pose an immediate, life-threatening danger to patient/staff safety or interrupt critical medical therapies (e.g., pulling out endotracheal tubes, central venous lines).
   • Medication Regimens: Low-dose Haloperidol (0.5 to 1.0 mg PO/IV) or atypical antipsychotics (Quetiapine 12.5-25 mg PO, Olanzapine 2.5-5 mg PO). Monitor QTc interval on ECG. Discontinue within 24-48 hours as soon as severe agitation resolves.
   • CRITICAL CONTRAINDICATION: Benzodiazepines (Lorazepam) are CONTRAINDICATED in delirium (they worsen and prolong delirium, increase paradoxical agitation, and cause respiratory depression). EXCEPTION: Benzodiazepines are first-line ONLY when delirium is caused by alcohol or sedative-hypnotic withdrawal.