What is the recommended assessment and first‑line treatment, including medication choice, dosing, monitoring, psychotherapy, and follow‑up, for a patient aged 65 years or older with a major depressive episode and medical comorbidities?

Late-Life Depression: Assessment and First-Line Treatment

Initial Screening and Assessment

Screen all patients ≥65 years with the two-question screen or Geriatric Depression Scale (GDS) during the initial evaluation period (first 3 months) and whenever unexplained clinical decline occurs. 1, 2

• Use the PHQ-9 to guide treatment intensity: scores 1-7 indicate minimal symptoms, 8-14 moderate symptoms, and 15-27 moderate-to-severe symptoms requiring more aggressive intervention 2
• Screen specifically for bipolar disorder by obtaining detailed personal and family history of mania, hypomania, or bipolar disorder before initiating any antidepressant, as treating unrecognized bipolar depression with antidepressants alone may precipitate manic episodes 3, 4
• Assess for suicidal ideation at every visit, as antidepressants paradoxically reduce suicide risk in adults ≥65 years (odds ratio 0.06) compared to younger adults where risk increases 5

Critical Baseline Assessments Before Treatment

• Calculate creatinine clearance using Cockcroft-Gault equation to guide dosing 5
• Obtain baseline sodium level (hyponatremia occurs in 0.5-12% of elderly on SSRIs, typically within first month) 5
• Measure blood pressure supine and standing to assess orthostatic hypotension risk 5, 4
• Obtain ECG if cardiac risk factors present, particularly before using citalopram or escitalopram due to QT prolongation risk 5
• Document all current medications including over-the-counter drugs, vitamins, and herbal supplements to identify drug-drug interactions 1
• Assess for concurrent medical comorbidities: cardiovascular disease, diabetes, renal/hepatic impairment, and bleeding risk factors 5, 6, 7

First-Line Pharmacotherapy

Initiate treatment with sertraline 25-50 mg daily, citalopram 10 mg daily, escitalopram 5-10 mg daily, venlafaxine (extended-release), or bupropion—starting at approximately 50% of standard adult doses. 5, 2

Preferred First-Line Agents (in order of preference)

1. Sertraline or Citalopram: Highest ratings for both efficacy and tolerability in older adults 5

   • Sertraline: Start 25-50 mg daily, target 50-100 mg daily 5
   • Citalopram: Start 10 mg daily, maximum 20 mg daily (never exceed due to QT prolongation) 5, 3
   • Both have minimal drug interactions and favorable cardiac safety profiles 5

2. Escitalopram: Preferred when minimal drug interactions are critical 5

   • Start 5-10 mg daily, maximum 10 mg daily in patients >60 years (FDA limit due to QT prolongation) 5, 3
   • No dose adjustment needed for age alone, though lower starting dose recommended 5
   • Lowest potential for cytochrome P450 interactions 5

3. Venlafaxine (SNRI): Particularly valuable when cognitive symptoms are prominent 5

   • Showed no association with cardiac arrest in registry studies, unlike SSRIs and TCAs 5
   • Requires blood pressure monitoring as it can worsen hypertension 5

4. Bupropion: Optimal when cognitive symptoms dominate or sexual dysfunction is a concern 5

   • Dopaminergic/noradrenergic effects with lower rates of cognitive side effects 5
   • Lower sexual dysfunction rates compared to SSRIs 5
   • Start at 50% usual adult dose, adjust for renal/hepatic impairment 5

Agents to Absolutely Avoid

• Paroxetine: Do NOT use as first-line—highest anticholinergic burden, highest sexual dysfunction rates, potent CYP2D6 inhibition 5
• Fluoxetine: Avoid due to greater agitation risk, long half-life, and drug interaction potential 5
• Tertiary-amine TCAs (amitriptyline, imipramine): Potentially inappropriate per Beers Criteria—severe anticholinergic effects, cardiac toxicity, increased cardiac arrest risk (OR 1.69) 5

Dosing Strategy and Titration

Always start at 50% of standard adult doses due to slower metabolism and increased sensitivity to adverse effects. 5, 2

• Assess treatment response at week 4 and week 8 using standardized scales (PHQ-9, GDS) 5, 2
• If inadequate response by 6-8 weeks, increase dose (e.g., citalopram to 20 mg, escitalopram to 10 mg, sertraline to 100 mg) or switch agents 5
• For escitalopram: if increasing to 20 mg in adults <60 years, wait minimum 3 weeks; for citalopram, wait minimum 1 week before increasing 3

Critical Safety Monitoring

First Month (Weeks 1-4)

• Weekly contact (telephone acceptable) during dose titration to assess response and emerging problems 8
• Monitor for suicidal ideation, agitation, or unusual behavioral changes during first 1-2 weeks 5, 4
• Check sodium level within first month to detect hyponatremia (occurs in 0.5-12% of elderly on SSRIs) 5
• Assess for bleeding risk, especially if taking NSAIDs, aspirin, or anticoagulants (SSRI + NSAID increases GI bleeding risk 15-fold, adjusted OR 15.6) 5

Ongoing Monitoring (Monthly until stable, then quarterly)

• Systematically assess specific side effects at each visit: insomnia, appetite changes, headaches, dizziness, dry mouth, fatigue, tremor, sweating, constipation, sexual dysfunction 8
• Weigh patient at each visit to objectively track weight changes 8
• Monitor blood pressure if on venlafaxine 5
• Continue sodium monitoring periodically, as hyponatremia can occur at any time 5
• Reassess for improvement in target symptoms at 6 weeks and 12 weeks 1, 2

Drug-Drug Interaction Precautions

• Never combine SSRIs with NSAIDs without gastroprotection (proton pump inhibitor or misoprostol) given 15-fold increased bleeding risk 5
• Monitor carefully if combining with anticoagulants or antiplatelet agents (aspirin, clopidogrel) 5
• Avoid combining with other serotonergic drugs due to serotonin syndrome risk 5
• Allow 14 days between discontinuing MAOI and starting SSRI/SNRI, and vice versa 3

Psychotherapy and Non-Pharmacologic Interventions

Cognitive Behavioral Therapy (CBT), including behavioral activation and problem-solving therapy, is equally effective as antidepressants, with treated older adults more than twice as likely to achieve remission (OR 2.47-2.63). 5, 2

• Psychotherapy is recommended for mild-to-moderate depression and can be combined with pharmacotherapy for moderate-to-severe depression 2, 9
• Structured aerobic exercise programs have moderate antidepressant effect (standardized mean difference -0.82) and should be incorporated 5, 2
• Address social isolation and loneliness through referral to local social assistance programs 5
• Optimize nutrition and encourage social engagement 5

Treatment Duration and Maintenance

Continue treatment for 4-12 months after achieving remission for first-episode major depression. 5, 2

• For patients with ≥3 prior episodes, consider indefinite maintenance at lowest effective dose (recurrence risk reaches ~90% after third episode) 5
• Continued treatment after remission protects against recurrence 5
• Periodically reassess need for maintenance treatment and attempt to use lowest effective dose 3

Discontinuation Protocol

Never abruptly discontinue—taper gradually over minimum 10-14 days to limit withdrawal symptoms. 8, 3

• If intolerable symptoms occur during taper, resume previous dose and decrease more gradually 3
• Monitor closely during discontinuation, as premature cessation increases relapse risk dramatically (>90% relapse in noncompliant patients versus 37.5% in compliant patients) 8

Special Populations and Comorbidities

Patients with Cardiovascular Disease

• Sertraline is specifically validated and safe in heart failure and post-MI patients (SADHART trial) 5
• Avoid TCAs due to hypotension, worsening heart failure, and arrhythmia risk 5
• Citalopram and escitalopram require strict dose limits (20 mg and 10 mg respectively) due to QT prolongation 5

Patients with Diabetes

• Depression is more common in diabetes and impedes self-management 1
• Treat or refer within 2 weeks of presentation 1
• Successful depression treatment improves diabetes outcomes 1

Patients with Dementia or Frailty

• Among SSRIs, avoid fluoxetine due to long half-life and side effects 5
• Venlafaxine, vortioxetine, and mirtazapine are safer regarding drug interactions 5
• High-quality evidence does not support pharmacologic treatment of depression in patients with established dementia 9
• Interventions targeting frailty (physical activity, nutrition, social engagement, cognitive stimulation) can reduce depressive symptoms 5

Nursing Home Residents

• SSRIs (specifically sertraline or citalopram) are most appropriate first-line agents 5
• Avoid tertiary TCAs and psychostimulants as first-line treatment 5
• Assess treatment response at 6 weeks and 12 weeks using validated instruments 5
• Continue full-dose treatment for at least 6 months after significant improvement for first or second episode 5

Common Pitfalls to Avoid

• Do not use standard adult starting doses—always reduce by approximately 50% 5, 2
• Do not prescribe paroxetine or fluoxetine as first-line agents 5
• Do not combine SSRIs with NSAIDs without gastroprotection 5
• Do not exceed citalopram 20 mg daily or escitalopram 10 mg daily in patients >60 years 5, 3
• Do not rely solely on patient self-report of side effects—systematically ask about specific adverse effects, as patients may not volunteer embarrassing symptoms like sexual dysfunction 8
• Do not assume stable patients no longer need monitoring—maintain at least quarterly follow-up even when patients feel well 8
• Do not overlook psychosocial interventions—medication alone is insufficient; combining with CBT or psychoeducation improves long-term outcomes 8

When to Refer or Escalate Treatment

• Refer within 2 weeks if patient is danger to self or others 1, 2
• Consider ECT for treatment-resistant depression (response rates 70-80%, remission rates 40-50% or higher, superior to pharmacotherapy) 1
• Older patients show amplified response rates to ECT and experience augmented quality of life 1
• Collaborative programs with mental health specialists are significantly more effective than typical primary care treatment alone 1