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

Augmentation Strategies for SSRI-Resistant Depression

For treatment-resistant depression, adding an atypical antipsychotic like aripiprazole or risperidone is the most evidence-based strategy for augmenting an SSRI, with approximately one-third of patients showing clinically meaningful improvement. 1

First-Line Augmentation Options

Atypical Antipsychotics

• Aripiprazole: Strong evidence for efficacy as SSRI augmentation

  • Starting dose: 2.5-10 mg/day
  • Monitor for akathisia, which can be managed by dose reduction 2
  • Requires ongoing monitoring for metabolic side effects (weight gain, lipid abnormalities)

• Risperidone: Meta-analysis shows efficacy comparable to aripiprazole

  • Lower doses typically used for augmentation than for primary psychotic disorders
  • One-third of patients with SSRI-resistant depression show clinically meaningful response 1

Bupropion

• Mechanism complements SSRIs (dopaminergic + noradrenergic vs. serotonergic)
• Dosage: 150-300 mg/day (sustained release)
• Approximately 54% response rate when added to SSRIs 3
• Advantages:
  • May improve SSRI-associated sexual dysfunction 4
  • Minimal weight gain 5
  • Different mechanism of action from SSRIs 1

Second-Line Augmentation Options

Glutamatergic Agents

• N-acetylcysteine: Strongest evidence among glutamatergic agents

  • Three of five randomized controlled trials showed superiority to placebo 1

• Memantine: Several trials demonstrate efficacy as SSRI augmentation 1

Tricyclic Antidepressants

• Clomipramine: Can be effective when added to fluoxetine
  • In a head-to-head trial, fluoxetine+clomipramine was superior to fluoxetine+quetiapine 1
  • CAUTION: Increased risk of serotonin syndrome, seizures, and cardiac arrhythmias due to drug interactions and increased blood levels 1

Third-Line Options

SNRI Combination

• Venlafaxine + Bupropion: Case reports show efficacy in treatment-resistant depression 6
• Consider when multiple other strategies have failed

Algorithm for Augmentation Selection

1. Confirm true treatment resistance:

   • Verify patient has had adequate trials of at least two antidepressants of different mechanisms of action at adequate doses for at least 4 weeks each 1
   • Ensure current SSRI is at optimal dose for at least 8-12 weeks 1

2. Select augmentation based on symptom profile:

   • For depression with prominent fatigue/low energy: Consider bupropion (activating)
   • For depression with anxiety/insomnia: Consider atypical antipsychotic (may be sedating)
   • For depression with sexual dysfunction: Bupropion may help reverse these side effects 4

3. Consider medical comorbidities:

   • Metabolic concerns (diabetes, obesity): Avoid agents with high metabolic risk
   • Seizure history: Use caution with bupropion
   • Cardiac issues: Avoid clomipramine augmentation

Monitoring and Follow-up

• Assess response after 4-6 weeks of augmentation therapy
• Monitor for specific side effects:
  • Atypical antipsychotics: Weight gain, metabolic parameters, extrapyramidal symptoms
  • Bupropion: Seizure risk (dose-dependent), insomnia
  • Clomipramine: ECG changes, anticholinergic effects, serotonin syndrome

Important Caveats

• Augmentation strategies have smaller effect sizes than the initial antidepressant treatment 1
• Time on the primary antidepressant remains an important factor in eventual response 1
• Consider switching to a different antidepressant class if multiple augmentation strategies fail
• For severe, highly refractory depression, consider neuromodulation approaches (rTMS, ECT) 1

Remember that approximately half of patients with depression fail to fully respond to first-line treatment 1, making augmentation strategies an essential part of depression management.