What are the next best options for managing ongoing depressive symptoms in a patient with treatment-resistant depression and anxiety on fluoxetine, buspirone, hydroxyzine, and bupropion?

Treatment Options for Ongoing Depression in Treatment-Resistant Depression

Your best next step is to augment the current regimen with an atypical antipsychotic (aripiprazole 2-15 mg or quetiapine 50-300 mg), as this strategy has the strongest evidence for reducing depressive symptoms in treatment-resistant depression, though you must counsel the patient about higher dropout rates due to side effects. 1, 2, 3

Primary Recommendation: Atypical Antipsychotic Augmentation

• Augmentation with quetiapine or aripiprazole demonstrates high-quality evidence for reducing depression severity (SMD -0.32 for quetiapine, MD -1.50 on MADRS for cariprazine) compared to continuing antidepressant monotherapy alone. 3

• The National Institute of Mental Health specifically recommends augmentation with atypical antipsychotics such as aripiprazole or quetiapine for partial responders in treatment-resistant depression. 1

• Critical caveat: Dropout rates are significantly higher with antipsychotic augmentation (RR 1.57-1.68) due to side effects, ranging from 10-39% versus 12-23% in control groups. 3 Monitor closely for metabolic side effects, extrapyramidal symptoms, and sedation.

• Olanzapine augmentation is also effective (MD -7.9 on HAM-D, MD -12.4 on MADRS) but carries substantial metabolic risks that may limit its use. 2, 3

Alternative Strategy: Optimize Current Bupropion Dose

• Before adding new agents, ensure the bupropion SR dose is optimized to 300-400 mg daily (current dose of 250 mg may be subtherapeutic). 4

• The American Medical Association requires a minimum of 4 weeks at therapeutic dosage before declaring treatment failure. 1, 5

• Bupropion augmentation specifically decreases depression severity more than buspirone augmentation, with moderate-quality evidence showing lower discontinuation rates due to adverse events. 6, 1

Secondary Augmentation Options

Lithium Augmentation

• Lithium augmentation is one of the best-documented treatments for treatment-resistant depression with decades of evidence supporting its efficacy. 1, 2

• Requires careful monitoring: serum lithium levels (target 0.6-1.0 mEq/L), thyroid function (TSH every 6-12 months), and renal function (creatinine, eGFR every 6-12 months). 1

• Start at 300 mg daily and titrate to therapeutic levels over 1-2 weeks. 2

Mirtazapine Consideration

• The American College of Physicians recommends mirtazapine for rapid symptom relief in treatment-resistant depression, with statistically significantly faster onset compared to SSRIs. 1

• However, high-quality evidence shows that augmenting with mirtazapine produces minimal clinical benefit (MD on BDI-II -1.7, not clinically significant). 3

• Mirtazapine is particularly beneficial for comorbid anxiety and insomnia due to sedating properties, which may be relevant given this patient's concurrent anxiety and PRN hydroxyzine use. 1

Switch to Venlafaxine

• Venlafaxine demonstrates superior efficacy compared to fluoxetine specifically for treating anxiety symptoms in patients with comorbid depression and anxiety. 1, 5

• Consider switching from fluoxetine 40 mg to venlafaxine XR 150-225 mg daily, as this addresses both depression and anxiety more effectively. 5

• The STAR*D trial showed that switching to bupropion, sertraline, or venlafaxine resulted in 1 in 4 patients becoming symptom-free, with no difference among the three drugs. 5

Treatment Algorithm

Step 1: Optimize bupropion SR to 300-400 mg daily (split dosing: 200 mg AM + 150-200 mg midday) and reassess after 4-6 weeks. 1, 5, 4

Step 2: If inadequate response after optimization, add aripiprazole 2-5 mg daily (can titrate to 15 mg) or quetiapine 50 mg at bedtime (can titrate to 300 mg). 1, 2, 3

Step 3: If antipsychotic augmentation is refused or not tolerated, add lithium 300 mg daily and titrate to therapeutic levels (0.6-1.0 mEq/L). 1, 2

Step 4: If multiple augmentation strategies fail, consider switching fluoxetine to venlafaxine XR 150-225 mg daily to better address comorbid anxiety, or refer for non-pharmacological interventions including cognitive behavioral therapy or electroconvulsive therapy. 1, 5

Additional Considerations

• Buspirone at 5 mg BID is likely subtherapeutic; therapeutic dosing is typically 15-60 mg daily in divided doses. However, evidence shows buspirone augmentation provides no benefit for depression severity (MD on MADRS -0.30). 3

• Consider increasing buspirone to 10-15 mg TID if targeting anxiety specifically, but recognize this will not significantly impact depressive symptoms. 3

• Ketamine or esketamine can be used for treatment-resistant depression and may help reduce suicidal ideation, though this requires specialized administration and monitoring. 4, 2

• Ensure adequate trial duration of at least 4 weeks at therapeutic doses before declaring treatment failure with any intervention. 1, 5