What medication can be added to an elderly female patient's current regimen of mirtazapine, lamotrigine, bupropion, and trazodone for treatment-resistant depression, characterized by a lack of happiness or smiling?

Treatment-Resistant Depression in an Elderly Female: Medication Augmentation Strategy

For this elderly female patient with treatment-resistant depression on mirtazapine, lamotrigine, bupropion, and trazodone who lacks happiness or smiling (anhedonia), consider adding venlafaxine or switching to venlafaxine as the next step, as it has demonstrated superior response rates in treatment-resistant depression and may have faster onset than some SSRIs. 1

Understanding the Clinical Context

This patient presents with anhedonia (lack of happiness or smiling), which is a core feature of major depressive disorder and suggests inadequate response to her current four-medication regimen 1. The current regimen includes:

• Mirtazapine: Noradrenergic and specific serotonergic antidepressant (NaSSA) 2
• Bupropion: Norepinephrine-dopamine reuptake inhibitor 1
• Lamotrigine: Mood stabilizer (anticycling agent) 1
• Trazodone: Primarily used for sleep 3

Evidence-Based Medication Addition Strategy

First-Line Addition: Venlafaxine (SNRI)

Add venlafaxine (extended-release) starting at 37.5-75 mg daily, titrating to 150-225 mg daily over 2-4 weeks 1. The evidence supporting this approach includes:

• In the landmark STAR*D trial, venlafaxine showed equivalent efficacy to bupropion and sertraline when switching medications in treatment-resistant depression, with 1 in 4 patients achieving symptom-free status 1
• Two smaller studies demonstrated greater response rates with venlafaxine compared to other second-generation antidepressants in treatment-resistant cases 1
• Venlafaxine showed statistically significantly better response and remission rates than fluoxetine in patients with depression and anxiety symptoms 1

Alternative Consideration: Duloxetine (SSNRI)

If venlafaxine is not tolerated or contraindicated, duloxetine 30-60 mg daily represents a safer SNRI option, particularly for elderly patients 1. Duloxetine is:

• Well-tolerated in older adults with dementia 1
• Effective for depression with comorbid pain 1
• Associated with fewer drug interactions than some alternatives 1

Why NOT Add Certain Medications

Avoid adding SSRIs (fluoxetine, paroxetine, sertraline, citalopram) because:

• The patient already has serotonergic coverage through mirtazapine 2
• No evidence suggests SSRIs differ significantly in efficacy from current regimen components 1
• Fluoxetine specifically should be avoided in elderly patients due to its long half-life and increased side effects 1

Avoid tricyclic antidepressants (amitriptyline, imipramine) because:

• They have significant anticholinergic burden that should be avoided in elderly patients, especially those with frailty 1
• Higher risk of cardiotoxicity, orthostatic hypotension, and falls in older adults 4

Critical Monitoring Requirements

Assess patient status within 1-2 weeks of initiating or modifying therapy 1. Specifically monitor for:

• Suicidality: SSRIs and SNRIs carry increased risk for suicide attempts, particularly in the first 1-2 months of treatment 1
• Agitation or irritability: May indicate worsening depression 1
• Response to treatment: If no adequate response within 6-8 weeks, modify treatment again 1
• Drug interactions: Venlafaxine can interact with other serotonergic agents, increasing serotonin syndrome risk 1

Special Considerations for Elderly Patients

Dosing Adjustments

• Start low, go slow: Begin with lowest available dose and increase by small increments at weekly intervals 1
• Elderly patients are more prone to adverse effects due to slowed drug clearance 4

Safety Concerns

• Orthostatic hypotension: Check sitting and standing blood pressures before and during treatment 4
• Falls risk: SNRIs can cause dizziness, particularly during dose titration 1
• Cognitive effects: Monitor for confusion or worsening memory 4

Alternative Strategy: Lithium Augmentation

If adding an antidepressant is unsuccessful, consider lithium augmentation at 150-300 mg daily, targeting blood levels of 0.2-0.6 mEq/L 1. However:

• Elderly patients are at high risk of neurotoxicity with lithium 1
• Requires careful monitoring of renal function, thyroid function, and drug levels 1
• Should only be used when benefits clearly outweigh risks 1

Non-Pharmacological Interventions

While adding medication, simultaneously implement:

• Exercise programs: 50-60 minutes daily of combined aerobic, resistance, and balance training can improve both depression and frailty 1
• Psychotherapy: Combined pharmacotherapy and psychotherapy may be optimal for elderly depressives 4
• Social engagement: Address loneliness and social isolation through community programs 1

When to Consider ECT

Electroconvulsive therapy should be considered if the patient:

• Remains treatment-resistant after adequate trials of medication combinations 1
• Develops severe psychotic features 1
• Is at imminent risk of self-harm or starvation 1

Note that elderly patients, particularly those 75 or older, have higher rates of cardiovascular complications with ECT 4.

Timeline for Expected Response

• Week 1-2: Initial assessment for tolerability and emerging side effects 1
• Week 3-4: Some patients may show early improvement, particularly with venlafaxine 1
• Week 6-8: Full therapeutic assessment; if inadequate response, modify treatment 1
• Week 12+: Continue monitoring for sustained remission and relapse prevention 1