Quiz 8: Pharmacotherapy (Vouk+Bishop)

Why is depression in older adults clinically important?

it is common and worsens quality of life, function, cognition, and mortality (especially suicide risk in older males)

What are key risk factors for depression in older adults?

prior depression, female sex, chronic illness, sleep disturbance, medications (BBs, steroids, benzos), alcohol use, stress, and social isolation

What are DSM-5 criteria for MDD?

depressed mood or loss of interest plus ≥4 symptoms for ≥2 weeks causing impairment, not due to substances or medical conditions

How is depression screened in older adults?

- PHQ-9 (focuses on physical symptoms over 2 weeks)

- GDS (focuses on feelings, yes/no over 1 week)

How does depression present differently in older adults?

more somatic complaints, cognitive slowing, withdrawal, low motivation, and possible pseudodementia

What is pseudodementia?

cognitive impairment caused by depression that improves with treatment

What are non pharmacological treatments for MDD in older adults?

psychotherapy (alon or adjunctive), exercise, light therapy, family support, acitivty engagement

What are first-line treatments?

SSRIs, SNRIs, bupropion, mirtazapine, plus psychotherapy

What is the dosing principle in older adults?

start low (≈ half dose) and titrate slowly due to decreased metabolism and clearance

How long until antidepressant response in older adults?

partial response ~4 weeks, full response may take 10-12 weeks

When may treatment be switched/adjusted after initiation?

in 4-8 weeks if no improvement or at max tolerated dose

How long should treatment continue after remission?

at least 1-2 years (sometimes lifelong if severe/recurrent)

What is serotonin syndrome?

excess serotonin causing diaphoresis, rigidity, confusion, BP changes, seizures, diarrhea

What are general SSRI risks in older adults?

increased risk of hyponatremia/SIADH, GI bleeding, falls, and serotonin syndrome (Beers Criteria says to caution)

What is a key risk with citalopram?

QT prolongation → limit dose (≤20 mg in older adults); watch with escitalopram

Why avoid paroxetine in older adults?

strong anticholinergic effects, cognitive impairment risk, weight gain, withdrawal issues

Why is fluoxetine not prefereed in older adults?

due to long half-life and DDIs (same with fluvoxamine)

KD is an 80-year-old female with hx of depression taking citalopram 20 mg daily for 12 weeks with no improvement in mood. She previously tried sertraline but discontinued due to GI effects. What do you recommend?

B and C

3 multiple choice options

What are key characteristics of SNRIs?

generally activating, may increase BP, less sexual dysfunction than SSRIs, and useful for comorbid neuropathy

What are key risks of SNRIs?

falls (Beers), hypertension, anxiety, insomnia, and withdrawal symptoms (especially venlafaxine)

When are SNRIs preferred?

depression + neuropathy or fatigue (more activating)

What is unique about venlafaxine?

significant withdrawal symptoms if abruptly discontinued

What are key alternatives to SSRIs/SNRIs?

bupropion, mirtazapine, vortioxetine, vilazodone

When should bupropion be avoided?

seizure disorders or patients with anxiety, insomnia, or weight loss

When is mirtazapine useful?

depression with insomnia or weight loss (sedating + increases appetite)

When should vortioxetine and vilazodone be avoided?

caution in seizure history

Why avoid TCAs in older adults?

strong anticholinergic effects → confusion, falls, cognitive decline

When is buspirone used for MDD in older adults?

can be used as augmentation therapy

MO is a 70-year-old female with osteoporosis and osteoarthritis. She reports weight loss, insomnia, and decreased interest in activities. What is the best initial antidepressant?

mirtazapine

3 multiple choice options

What adjunctive options exist for depression?

methylphenidate (fatigue/apathy), antipsychotics (caution), lithium, liothyronine

Why is antipsychotic use cautioned?

increased mortality risk in dementia + akathisia/restlessness

Why is lithium use cautioned?

can worsen osteoporosis due to bone density loss

How common is anxiety in older adults?

common but less prevalent than in younger adults; often underdiagnosed

How does anxiety present?

often somatic; pain, GI symptoms, fatigue, sleep disturbance, poor concentration.

What happens when anxiety and depression coexist?

worse functioning, increased healthcare use, higher suicide risk

What increases anxiety risk?

female sex, comorbidities, stress, low health, medications (steroids, stimulants, beta-agonists)

What defines GAD?

excessive anxiety ≥6 months + ≥3 symptoms causing impairment

What are treatment goals for anxiety in older adults?

reduce anxiety severity, improve function, achieve remission

What are first-line non-drug options for anxiety in older adults?

CBT and applied relaxation

What pharmacological treatments are used acutely for anxiety ?

benzodiazepines (lorazepam, oxazepam) or hydroxyzine PRN

What is first-line long-term therapy?

SSRIs or SNRIs

What are second-line options?

buspirone, mirtazapine, pregabalin, trazodone

Why should benzodiazepines be avoided long-term?

can cause sedation, falls, cognitive decline, respiratory depression

What are concerns with hydroxizine use?

anticholinergic effects → confusion, sedation

What is a key risk with trazodone use?

orthostatic hypotension → falls

What is a limitation of buspirone use in older adults for anxiety?

often less effective; may cause dizziness and falls

How long should anxiety be treated?

at least 1 year; longer for chronic/recurrent cases

Why are antidepressants often chosen by trial and error?

response rates are only ~40-60%, and there is high inter-individual variability in both efficacy and tolerability

What factors must be balanced when choosing antidepressants?

benefits (symptom + functional improvement) vs risks (side effects, cost, stigma, tolerability)

What is the relationship between dose and antidepressant efficacy?

minimal exposure is needed for response, but increasing dose does NOT strongly increase efficacy

What is the relationship between dose and side effects?

strong dose/concentration-dependent relationship → higher doses increase ADRs and dropout rates

What factors require antidepressant dose adjustments?

renal impairment, hepatic impairment, and drug-drug interactions (PK-based adjustments)

Is genetics the only factor affecting antidepressant response?

No, response is multifactorial (adherence, DDIs, age, sex, comorbidities, organ function, genetics)

What genetic domains influence treatment?

drug metabolism (PK), drug target (PD), and disease genetics

What are the CYP2C19 metabolizer phenotypes?

poor, intermediate, normal, rapid, ultra-rapid metabolizers

What is phenoconversion?

environmental/drug-induced change in phenotype (e.g., drug inhibition makes someone act like a poor metabolizer)

Which drugs can cause CYP2D6 phenoconversion?

paroxetine, fluoxetine, and bupropion (strong CYP2D6 inhibitors)

Why is phenoconversion important?

genotype alone is insufficient, must consider current medications and clinical context

What are the two major PGx gene categories?

pharmacokinetic (drug metabolism) and pharmacodynamic (drug targets)

Which enzymes are most relevant for antidepressants?

CYP2D6, CYP2C19, and CYP2B6

What are key PGx evidence resources?

CPIC, DPWG, and FDA PGx tables

What is the main MOA of TCAs?

serotonin and norepinephrine reuptake inhibition (SNRI-like)

Why are TCAs high-risk?

anticholinergic, antihistamine, and alpha blockade → CV and CNS toxicity

Why is TDM important for TCAs?

narrow therapeutic window; toxicity can be fatal at high levels

Which enzymes metabolize TCAs?

CYP2D6 and CYP2C19 (primary)

Metabolism difference between secondary vs tertiary amines?

Secondary (e.g., nortriptyline) → CYP2D6

Tertiary (e.g., amitriptyline) → CYP2C19 → CYP2D6

How does CYP2D6 copy number affect drug levels?

more copies → lower exposure; fewer copies → higher exposure

What happens in CYP2D6 poor metabolizers?

increased drug levels → higher side effect risk → reduce dose or avoid

What happens in CYP2D6 ultra-rapid metabolizers?

low drug levels → reduced efficacy → consider alternative

What is the key recommendation for poor metabolizers?

avoid or reduce dose (~50%) + consider TDM

When is CYP2C19 relevant for TCAs?

only for tertiary amines (e.g., amitriptyline)

What are TCAs most commonly used for currently and is PGx still relevant?

used for pain at lower doses; still relevant for poor/ultrarapid metabolizers

Why is PGx used if TDM exists?

PGx allows dose adjustment BEFORE steady state, preventing early toxicity or failure

How are SSRI guidelines different from TCAs?

drug-specific (not class-based like TCAs)

Which enzyme is most important for escitalopram metabolism?

CYP2C19 (primary driver of variability)

What happens in CYP2C19 poor metabolizers?

higher concentrations → increased side effects

What happens in ultra-rapid metabolizers?

low concentrations → reduced efficacy

What pattern is seen in discontinuation rates?

U-shaped; high in both poor (toxicity) and ultra-rapid (inefficacy) metabolizers

Which drugs require adjustment based on CYP2D6?

paroxetine, venlafaxine, vortioxetine (drug-specific)

What is key guidance for citalopram/escitalopram?

Poor metabolizers → reduce dose or switch

Ultra-rapid → consider alternative

Which drug is affected by CYP2B6?

sertraline → slower titration in intermediate metabolizers

What is the main PD target of SSRIs?

serotonin transporter (SLC6A4)

What polymorphism affects SLC6A4?

5-HTTLPR (short vs long allele affects expression)

Are SLC6A4 findings clinically actionable?

mixed evidence; no clear prescribing recommendations

What does HTR2A influence?

serotonin signaling affecting mood, cognition, and response to antidepressants

What is the key finding from the remission meta-analysis?

PGx-guided patients are ~1.46× more likely to achieve remission

What did the PRIME trial show?

faster remission (~2-3 months earlier) and fewer gene-drug interactions

What economic benefits are seen with PGx?

fewer ER visits, hospitalizations, and lower overall costs

What is a limitation of commercial PGx tests?

different algorithms → inconsistent recommendations

What are the steps to integrate PGx into care?

assess patient → determine need → choose drug → review PGx → adjust dose/therapy