What are the newest adjunct medications to support Selective Serotonin Reuptake Inhibitor (SSRI) therapy?

Newest Adjunct Medications to Support SSRI Therapy

Aripiprazole is the most strongly recommended adjunct medication for SSRI-resistant depression, with FDA approval since 2007 and the most robust evidence base demonstrating clinically meaningful efficacy at 2 mg/day. 1, 2

Primary Adjunct: Aripiprazole

Aripiprazole should be initiated at 2 mg/day (starting dose 5 mg/day with adjustments between 2-20 mg/day) after patients demonstrate inadequate response to at least one adequate SSRI trial. 1

Evidence Base

• Three large-scale, 6-week, randomized, double-blind, placebo-controlled trials demonstrated clinically meaningful efficacy, with response rates of 32.4% versus 17.4% for placebo (NNT = 12) 1, 2
• Remission rates were significantly higher at 25.4% versus 15.2% for placebo 1
• The mechanism involves partial agonism at dopamine D2/D3 and serotonin 5-HT1A receptors, with antagonism at 5-HT2A receptors 2

Tolerability Profile

• Akathisia is the most common adverse event, occurring in 25.9% of patients versus 4.2% with placebo (NNH = 15), though most cases are mild to moderate 1
• Discontinuation rates due to adverse events remain low at 3.7% versus 1.1% for placebo 1
• Weight gain is minimal over 6-week treatment periods 2
• Monitor for metabolic effects including weight, blood glucose, and lipid profiles 3

Emerging Adjunct: Brexpiprazole

Brexpiprazole represents a newer alternative at 2 mg/day for patients who cannot tolerate aripiprazole, though it has a less favorable NNT of 12 compared to aripiprazole's pooled data. 4

Key Characteristics

• FDA-approved for adjunctive treatment of major depressive disorder 4
• Response rates of 23.2% versus 14.5% for placebo when pooling 1,2, and 3 mg doses 4
• Akathisia occurs in 8.6% of MDD patients, with NNH of 15 4
• Discontinuation due to adverse events occurs in only 3% versus 1% for placebo (NNH = 53) 4

Alternative Adjuncts for Specific Contexts

For OCD-Related Depression or SSRI-Resistant OCD

Risperidone and aripiprazole have the strongest evidence, with approximately one-third of SSRI-resistant patients showing clinically meaningful response. 5, 3

Glutamatergic Agents for Treatment-Resistant Cases

• N-acetylcysteine has the largest evidence base among glutamatergic agents, with three out of five randomized controlled trials demonstrating superiority to placebo. 5
• Memantine can be considered based on several trials demonstrating efficacy in SSRI augmentation for treatment-resistant cases. 5

Critical Implementation Algorithm

Step 1: Verify Adequate SSRI Trial

• Ensure at least 8-12 weeks at therapeutic doses before considering augmentation 1

Step 2: Initiate Aripiprazole

• Start at 5 mg/day, target 2 mg/day for depression (adjustable 2-20 mg/day based on response) 1
• Mean endpoint dose in trials was 11.0 mg/day 1

Step 3: Monitor Response

• Assess for early treatment effect within 1-2 weeks 2
• Continue for minimum 6 weeks to evaluate full response 1

Step 4: Manage Akathisia if Present

• Reduce aripiprazole dose first 6
• Consider switching to brexpiprazole if akathisia persists 4
• Adjunctive propranolol (10-30 mg two to three times daily) is an alternative option 5

Common Pitfalls to Avoid

Do not combine clomipramine with SSRIs due to severe risk of serotonin syndrome, seizures, and cardiac arrhythmias. 5, 7

Do not use antipsychotic augmentation as first-line before ensuring adequate SSRI dose and duration. 5

Do not ignore metabolic monitoring—obtain baseline BMI, waist circumference, blood pressure, HbA1c, glucose, and lipids before initiating antipsychotic augmentation, then recheck at 4 weeks and 3 months. 5

For patients with undiagnosed bipolar disorder, aripiprazole has established FDA approval for bipolar mania, making it potentially safer than other augmentation strategies. 3