What alternative treatments are available for a patient with depression and anxiety currently taking Vyvanse (lisdexamfetamine), venlafaxine (Effexor) ER, mirtazapine, and gabapentin?

Treatment Options for Depression with Increasing Anxiety in This Patient

Given the patient's increasing anxiety (evidenced by escalating gabapentin use) while on venlafaxine 37.5 mg, mirtazapine 30 mg, and Vyvanse, the most appropriate next step is to optimize the current regimen by increasing venlafaxine to therapeutic doses (75-225 mg) or switching to bupropion augmentation, as the current venlafaxine dose is subtherapeutic. 1

Current Medication Assessment

The patient is on a subtherapeutic dose of venlafaxine (37.5 mg is a starting dose, not a therapeutic dose for depression or anxiety). 2 This likely explains the lack of perceived benefit and potentially the worsening anxiety. The patient is already on mirtazapine 30 mg, which provides some antidepressant coverage but may not be sufficient alone. 2

Primary Treatment Options

Option 1: Optimize Venlafaxine Dosing

• Increase venlafaxine ER to 75-225 mg daily, as the current 37.5 mg dose is inadequate for treating either depression or anxiety. 2
• Venlafaxine has demonstrated superior efficacy compared to fluoxetine specifically for treating anxiety symptoms in patients with comorbid depression and anxiety. 2, 1
• An adequate antidepressant trial requires minimum licensed dosage for at least 4 weeks before determining treatment failure. 1

Option 2: Switch to Bupropion Augmentation

• Add bupropion to the existing mirtazapine (discontinue venlafaxine if not effective at higher doses). 1
• Bupropion augmentation decreases depression severity more than buspirone augmentation, with lower discontinuation rates due to adverse events. 1
• The combination of bupropion + SSRI or mirtazapine + venlafaxine represents evidence-based combination strategies. 3
• Critical caveat: Bupropion may increase anxiety in some patients and lowers seizure threshold, which requires monitoring given the patient is on Vyvanse (stimulant). 3

Option 3: Switch Antidepressant Classes

• Switch from venlafaxine to sertraline or another SSRI at therapeutic doses (sertraline 50-200 mg). 2
• The STAR*D trial showed that switching to sustained-release bupropion, sertraline, or extended-release venlafaxine resulted in 1 in 4 patients becoming symptom-free, with no difference among the three drugs. 2
• SSRIs show similar efficacy to SNRIs for treating depression with accompanying anxiety symptoms. 2

Augmentation Strategies if Optimization Fails

Atypical Antipsychotic Augmentation

• Add aripiprazole (2-15 mg) or quetiapine (50-300 mg) to the current antidepressant regimen. 1, 4
• The National Institute of Mental Health recommends augmentation with atypical antipsychotics such as aripiprazole or quetiapine for partial responders. 1
• Aripiprazole is FDA-approved for augmentation in treatment-resistant depression. 4
• These agents may also help with anxiety symptoms. 5

Lithium Augmentation

• Add lithium 300-900 mg daily (targeting blood levels 0.6-1.0 mEq/L). 1, 4
• Lithium augmentation is one of the best-documented treatments for treatment-resistant depression. 1
• Requires careful monitoring of blood levels, thyroid function, and renal function. 1

Addressing the Anxiety Component

Gabapentin Considerations

• The increasing gabapentin use suggests inadequate anxiety control. 5
• Pregabalin has stronger evidence for generalized anxiety disorder than gabapentin and could be considered as a switch. 5
• However, addressing the underlying depression with adequate antidepressant dosing should be the priority. 2

Alternative Anxiolytic Options

• Hydroxyzine 25-100 mg as needed has double-blind, placebo-controlled evidence for GAD and may be preferable to gabapentin. 5
• Pregabalin 150-600 mg daily has robust evidence for anxiety disorders. 5

Treatment Algorithm

1. First step: Increase venlafaxine ER to 150 mg daily (therapeutic dose) and reassess after 4-6 weeks. 2, 1

2. If inadequate response: Either switch to bupropion augmentation (add bupropion SR 150-300 mg to mirtazapine) OR switch to an SSRI like sertraline 100-200 mg. 2, 1

3. If still inadequate after 4-6 weeks: Add aripiprazole 5-10 mg or quetiapine 50-150 mg for augmentation. 1, 4

4. For persistent anxiety: Consider switching gabapentin to pregabalin 150-300 mg daily or adding hydroxyzine 25-50 mg as needed. 5

Critical Pitfalls to Avoid

• Do not continue subtherapeutic venlafaxine dosing (37.5 mg is insufficient). 2
• Monitor for serotonin syndrome when combining multiple serotonergic agents (venlafaxine + mirtazapine). 3
• Watch for increased anxiety or agitation if adding bupropion, especially with concurrent Vyvanse use. 3
• Ensure adequate trial duration (minimum 4 weeks at therapeutic dose) before declaring treatment failure. 1
• Consider that Vyvanse itself may be contributing to anxiety and may need dose adjustment or timing modification. 3