What medications can be added to a selective serotonin reuptake inhibitor (SSRI) for treatment-resistant depression?

Add-On Medications to SSRIs for Treatment-Resistant Depression

For patients with major depressive disorder who fail to respond adequately to SSRI monotherapy after 6-8 weeks, bupropion augmentation is the most practical first-line add-on strategy, followed by aripiprazole or other atypical antipsychotics if bupropion fails or is contraindicated. 1

When to Consider Augmentation

• Modify treatment if inadequate response occurs after 6-8 weeks of SSRI therapy at adequate doses 1
• Begin monitoring response within 1-2 weeks of initiating any treatment change 1
• Treatment resistance is defined as failure of adequate SSRI trial (maximum tolerated dose for 8-12 weeks) 2

First-Line Augmentation: Bupropion

Bupropion added to an SSRI is highly effective and well-tolerated for SSRI-resistant depression. 3

• Combination of escitalopram plus bupropion-SR achieved 62% response and 50% remission rates in patients with chronic/recurrent depression 3
• Start bupropion-SR at 150 mg/day, titrate to 300-400 mg/day as tolerated 3
• Only 6% of patients discontinued due to side effects in combination therapy 3
• Bupropion can be used as either augmentation or as a switch strategy, with response rates of 60-70% when switching from SSRIs 4

Important Drug Interactions with Bupropion

• Bupropion inhibits CYP2D6, which can increase levels of SSRIs (particularly paroxetine, fluoxetine, sertraline) 5
• May need to reduce SSRI dose when adding bupropion, especially for drugs with narrow therapeutic index 5
• Use extreme caution with drugs that lower seizure threshold 5
• Contraindicated with MAOIs (14-day washout required) 5

Second-Line Augmentation: Atypical Antipsychotics

If bupropion augmentation fails or is not tolerated, aripiprazole is the next best-supported option. 2, 6

• Aripiprazole and risperidone have the strongest evidence for SSRI-resistant depression 2
• Approximately one-third of SSRI-resistant patients show clinically meaningful response to antipsychotic augmentation 2
• Start aripiprazole at low doses (2.5-10 mg/day) for rapid improvement in depressive symptoms 6
• Aripiprazole can also be effective when added to bupropion in bupropion-resistant cases 6

Long-Term Safety Considerations with Antipsychotics

• Monitor for metabolic side effects including weight gain (mean +2.4 to +3.1 kg at 52 weeks) 7
• Check fasting glucose and lipid profiles regularly (abnormalities occurred in 8-17% for glucose, 25-35% for cholesterol) 7
• Common adverse events include fatigue (24-26%), akathisia (24%), and somnolence (22%) 7
• Sexual functioning may modestly improve despite antipsychotic addition 7

Alternative Augmentation: Buspirone

Buspirone augmentation (20-30 mg/day) can produce marked improvement in 59-63% of SSRI-resistant patients. 8

• Add buspirone for 4-5 weeks to existing SSRI regimen 8
• Clinical Global Impressions scores improved by 64% in responders 8
• Well-tolerated with no serious side effects reported 8
• 79% of initial responders remained symptom-free at 4-month follow-up 8

Treatment Duration After Response

• Continue treatment for 4-9 months after satisfactory response for first episode of major depression 1
• For patients with 2 or more episodes, longer duration of therapy is beneficial 1
• For OCD-spectrum conditions, maintain treatment for 12-24 months after remission due to high relapse rates 2

Common Pitfalls to Avoid

• Don't combine SSRIs with MAOIs due to risk of serotonin syndrome 1
• Monitor carefully when combining multiple serotonergic agents (SSRIs, SNRIs, tramadol, dextromethorphan) for serotonin syndrome symptoms 1
• Don't assume higher SSRI doses are better - optimize current dose before adding augmentation 1
• Watch for drug-drug interactions when adding bupropion to SSRIs metabolized by CYP2D6 5