What treatment options are available for a patient with irritability and sad moods who has failed treatment with antidepressants and Abilify (aripiprazole)?

Treatment Options for Treatment-Resistant Depression with Irritability and Sad Mood

Primary Recommendation

Switch to an SNRI (venlafaxine or duloxetine) or augment the current antidepressant with a different atypical antipsychotic such as quetiapine, brexpiprazole, or cariprazine, as aripiprazole has already failed. 1

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Treatment Algorithm

Step 1: Verify Treatment Adequacy

Before changing treatment, confirm that previous trials were truly adequate:

• Antidepressant dose and duration: At least 6-8 weeks at maximum FDA-approved doses (e.g., escitalopram 20mg, sertraline 200mg) 2
• Aripiprazole dose and duration: Adequate trial typically means 5-15mg daily for at least 6-8 weeks 3
• Medication adherence: Document adherence through pharmacy records, pill counts, or plasma level monitoring when possible, as up to 50% of patients with depression are non-adherent 2
• Rule out pseudo-resistance: Exclude substance use, thyroid dysfunction, unrecognized bipolar disorder, or ongoing psychosocial stressors that may mimic treatment resistance 2

Step 2: Choose Next-Line Strategy

You have three evidence-based options with similar efficacy:

Option A: Switch to SNRI (Preferred for irritability)

• Venlafaxine extended-release 37.5-225mg daily or duloxetine 40-120mg daily 4
• SNRIs demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression, with dual action on serotonin and norepinephrine potentially addressing both depressive and irritability symptoms 4
• The STAR*D trial showed approximately 25% of patients become symptom-free after switching medication classes 2
• Caution: SNRIs have higher rates of nausea, vomiting, and discontinuation compared to SSRIs 4

Option B: Augment with Different Atypical Antipsychotic

Since aripiprazole failed, consider FDA-approved alternatives:

• Quetiapine extended-release: FDA-approved for depression augmentation 1
• Brexpiprazole: FDA-approved for depression augmentation 1
• Cariprazine: FDA-approved for depression augmentation 1
• Olanzapine-fluoxetine combination: FDA-approved but carries significant weight gain risk 1

Rationale: Atypical antipsychotics are the most widely studied augmentation agents in treatment-resistant depression, with multiple agents showing efficacy in controlled trials 5, 1

Critical safety consideration: Weigh benefits against adverse events including weight gain, metabolic abnormalities, akathisia, and tardive dyskinesia risk 1

Option C: Switch to Different Antidepressant Class

• Bupropion SR 150-400mg daily: Different mechanism (dopamine/norepinephrine reuptake inhibition), may be particularly helpful for irritability and low energy 4
• The STAR*D trial showed no significant difference between bupropion, sertraline, and venlafaxine when switching from initial SSRI failure 2

Step 3: Add Psychotherapy if Not Already Implemented

• Cognitive behavioral therapy (CBT) combined with medication shows superior efficacy to medication alone, with similar response rates to antidepressants when used as monotherapy 2, 4
• CBT addresses both neurobiological and psychological components of depression 4
• This combination is particularly important for patients with psychosocial stressors contributing to irritability 2

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Monitoring Protocol

• Assess response every 2-4 weeks using standardized depression rating scales (PHQ-9 or HAM-D) 4
• Monitor specifically for suicidality during the first 1-2 months after medication changes, as suicide risk is greatest during this period 4
• Watch for behavioral activation/agitation, particularly with irritability as a presenting symptom 2, 4
• Allow 6-8 weeks at therapeutic dose before declaring treatment failure 2, 4

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Common Pitfalls to Avoid

• Premature switching: Changing medications before allowing adequate trial duration (6-8 weeks at therapeutic dose) leads to missed opportunities for response 4
• Inadequate dose trials: Using subtherapeutic doses increases risk of multiple medication switches or unnecessary polypharmacy 2
• Ignoring adherence: Many cases of apparent treatment-resistant depression represent partial or full non-adherence rather than true biological resistance 2
• Misattributing psychosocial stress as biological illness: Irritability may represent reaction to life stressors rather than medication-responsive symptoms, requiring psychosocial interventions instead of medication escalation 2
• Continuing ineffective treatment beyond 8 weeks: This delays recovery and worsens outcomes 4

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Duration of Continuation Therapy

• First episode: Continue treatment for 4-9 months after achieving remission 4
• Recurrent depression (2+ episodes): Consider years to lifelong maintenance therapy 4

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Alternative Augmentation Strategies (If Above Options Fail)

Traditional augmentation agents with evidence but less robust data than atypical antipsychotics:

• Lithium augmentation: Established efficacy but requires monitoring of levels, thyroid, and renal function 6
• Buspirone augmentation: STAR*D trial showed similar efficacy to bupropion but higher discontinuation rates (20.6% vs 12.5%) 4
• Thyroid hormone (T3): Off-label option with some evidence 6
• Stimulants: Off-label option for augmentation 6