What add-on medication could be used for a patient with depression and anxiety already on venlafaxine (Effexor), mirtazapine (Remeron), and clonazepam (Klonopin) who remains depressed?

Add-On Medication for Treatment-Resistant Depression with Anxiety

Immediate Recommendation

The most evidence-based add-on strategy is augmentation with an atypical antipsychotic (aripiprazole 2-15 mg or quetiapine 50-300 mg), given that the patient is already on both venlafaxine and mirtazapine—a combination that represents dual-mechanism coverage. 1

Critical Assessment of Current Regimen

Before adding another medication, the current regimen requires optimization:

• The venlafaxine dose must be increased to therapeutic levels (75-225 mg daily) if currently subtherapeutic, as doses below 75 mg are inadequate for treating either depression or anxiety and may paradoxically worsen anxiety symptoms. 1

• The venlafaxine-mirtazapine combination itself is evidence-based for treatment-resistant depression, with response rates of 44% at 4 weeks, 50% at 8 weeks, and 56% at 6 months when both agents are used at moderate to high doses. 2

• This combination demonstrates synergistic effects through complementary mechanisms: venlafaxine blocks serotonin and norepinephrine reuptake while mirtazapine antagonizes presynaptic alpha-2 receptors and postsynaptic 5-HT2/5-HT3 receptors, enhancing noradrenergic and serotonergic neurotransmission. 2, 3

Primary Augmentation Options

First-Line: Atypical Antipsychotics

Aripiprazole (2-15 mg) or quetiapine (50-300 mg) added to the current antidepressant regimen represents the strongest augmentation strategy for treatment-resistant depression. 1

• These agents have moderate-strength evidence specifically for augmentation in depression that has not responded to adequate antidepressant trials. 1

• This approach is appropriate when the patient has already failed optimization of dual-mechanism antidepressants. 1

Second-Line: Lithium Augmentation

Lithium augmentation is one of the best-documented treatments for treatment-resistant depression, though it requires careful monitoring of blood levels (target 0.6-1.0 mEq/L), thyroid function, and renal function. 1

• Lithium should be considered if atypical antipsychotics are not tolerated or contraindicated. 1

Alternative: Bupropion Augmentation

Adding bupropion (150-300 mg SR) to the existing regimen can be considered, particularly if the patient has prominent symptoms of low energy, poor concentration, or psychomotor retardation. 1

• Bupropion augmentation decreases depression severity more than buspirone augmentation and has lower discontinuation rates due to adverse events. 1

• However, bupropion is ineffective for PTSD and may not adequately address anxiety symptoms. 4

• Critical caveat: Bupropion lowers seizure threshold, and combining it with clonazepam (which the patient is already taking) requires careful consideration of the risk-benefit ratio. 1

Addressing the Benzodiazepine Issue

The continued use of clonazepam in this patient warrants reassessment:

• Long-term benzodiazepine use can paradoxically worsen depression and anxiety, create tolerance, and complicate treatment response assessment. 5

• Once adequate antidepressant augmentation achieves response, a gradual taper of clonazepam should be considered. 5

Treatment Algorithm

Step 1: Verify venlafaxine is at therapeutic dose (≥75 mg, optimally 150-225 mg) and mirtazapine is at adequate dose (typically 30-45 mg). Reassess after 4-6 weeks at optimized doses. 1, 2

Step 2: If inadequate response persists despite optimized dual antidepressant therapy, add aripiprazole 2-5 mg initially, titrating to 10-15 mg based on response and tolerability. 1

Step 3: If aripiprazole is not tolerated or ineffective after 4-6 weeks, switch to quetiapine 50 mg at bedtime, titrating to 150-300 mg. 1

Step 4: If atypical antipsychotics fail or are contraindicated, consider lithium augmentation with appropriate monitoring. 1

Step 5: Alternative strategy: Add bupropion SR 150 mg, increasing to 300 mg if tolerated, while monitoring for increased anxiety or activation. 1

Critical Monitoring Points

• Serotonin syndrome risk: The combination of venlafaxine and mirtazapine carries theoretical risk, though clinical studies show good tolerability. Monitor for agitation, confusion, tremor, hyperthermia, and autonomic instability. 2, 3

• Metabolic effects: Both mirtazapine and atypical antipsychotics (especially quetiapine) can cause weight gain and metabolic syndrome. Monitor weight, glucose, and lipids. 6, 2

• Cardiovascular effects: Venlafaxine can modestly increase blood pressure at higher doses. Monitor blood pressure regularly. 7

• Treatment duration: An adequate trial requires minimum 4 weeks at therapeutic doses before declaring treatment failure. 1

Common Pitfalls to Avoid

• Do not add multiple agents simultaneously—this prevents identification of which intervention is effective or causing adverse effects. 1

• Do not declare treatment failure prematurely—ensure each medication is at therapeutic dose for adequate duration (4-6 weeks minimum). 1

• Do not continue ineffective augmentation indefinitely—if no response after 6-8 weeks of adequate dosing, move to next strategy rather than continuing to add medications. 1

• Do not neglect non-pharmacological interventions—cognitive behavioral therapy shows efficacy comparable to pharmacotherapy in severe depression and may enhance medication response. 5