What is a suitable adjunctive medication for persistent anxiety and depression in a patient currently taking Lexapro (escitalopram) 20 mg, Caplyta (lumateperone) 21 mg, and gabapentin, with a previous unsuccessful trial of Remeron (mirtazapine)?

Adjunctive Treatment for Persistent Anxiety and Depression

Add bupropion sustained-release (150-400 mg daily) as augmentation to your current Lexapro regimen, as this combination addresses both persistent depressive and anxiety symptoms without overlapping serotonergic mechanisms that could increase side effect burden. 1

Rationale for Bupropion Augmentation

Your current regimen includes:

• Lexapro (escitalopram) 20 mg - SSRI at maximum dose
• Caplyta (lumateperone) 21 mg - atypical antipsychotic
• Gabapentin - for anxiety symptoms
• Failed mirtazapine trial - eliminates this as an option

Why Bupropion is the Optimal Choice

Bupropion works through norepinephrine-dopamine reuptake inhibition rather than serotonin, providing complementary mechanisms to your existing SSRI without increasing serotonergic side effects or risk of serotonin syndrome. 1 The STAR*D trial, the largest and highest-quality study of treatment-resistant depression, demonstrated that switching to bupropion SR, sertraline, or venlafaxine XR resulted in 25% of patients achieving remission, with no significant differences among these agents. 1

For patients with depression and accompanying anxiety symptoms, second-generation antidepressants show similar efficacy, though evidence suggests bupropion can be effective when combined with SSRIs for treatment-resistant cases. 1

Dosing Strategy

• Start bupropion SR 150 mg once daily in the morning for 3-4 days
• Increase to 150 mg twice daily (total 300 mg) after the first week
• Maximum dose is 400 mg daily (200 mg twice daily) if needed after 4 weeks 1
• Monitor for initial activation or insomnia, which typically resolves within 1-2 weeks

Alternative Considerations

Venlafaxine XR as Second Option

If bupropion is not tolerated or ineffective after 6-8 weeks, consider switching to or augmenting with venlafaxine XR (75-225 mg daily). 1 Evidence shows venlafaxine may have superior efficacy specifically for anxiety symptoms in depression compared to fluoxetine, though this comes with higher rates of nausea and vomiting. 1

Why NOT Other Options

Avoid adding another SSRI - You're already on maximum-dose escitalopram; adding another serotonergic agent increases risk without clear benefit. 1

Mirtazapine is off the table - Your previous unsuccessful trial eliminates this option. 1

Buspirone carries significant risks - While traditionally used for anxiety augmentation, buspirone poses hazards when combined with serotonergic agents, including potential serotonin syndrome, and should not be used with SSRIs without extreme caution. 2

Atypical antipsychotic augmentation - You're already on Caplyta (lumateperone). Adding aripiprazole could be considered if bupropion and venlafaxine fail, as evidence supports aripiprazole augmentation for treatment-resistant depression and anxiety, though this would mean managing two antipsychotics. 3, 4

Critical Monitoring Points

Watch for Serotonin Syndrome

With your current SSRI plus gabapentin regimen, adding any serotonergic agent requires vigilance for:

• Mental status changes (agitation, confusion)
• Autonomic instability (tachycardia, blood pressure changes, sweating)
• Neuromuscular changes (tremor, rigidity, hyperreflexia)
• GI symptoms (nausea, vomiting, diarrhea) 2

Timeline Expectations

38% of patients don't respond to initial antidepressant therapy within 6-12 weeks, and 54% don't achieve remission. 1 After augmentation or switching:

• Assess response at 4 weeks for early improvement
• Full evaluation at 8-12 weeks before declaring treatment failure
• Continue successful treatment for at least 4-12 months after first episode remission 1

Common Pitfalls to Avoid

Don't discontinue Lexapro prematurely - Augmentation maintains your existing partial response while adding complementary mechanisms. 1, 5

Don't add multiple agents simultaneously - This makes it impossible to determine which intervention is effective or causing side effects. 5

Don't undertreated anxiety symptoms - Somatic anxiety is present in up to 86% of depressed patients and failure to address it diminishes functional recovery. 6

If This Approach Fails

After adequate trials of bupropion augmentation (8-12 weeks) and venlafaxine (either as switch or augmentation), consider:

• Aripiprazole augmentation (2-15 mg daily) for treatment-resistant depression 3
• Duloxetine switch (40-120 mg daily) for depression with prominent anxiety and pain symptoms 1
• Formal psychiatric consultation for consideration of other augmentation strategies or psychotherapy integration 5