What medication should be added to a Selective Serotonin Reuptake Inhibitor (SSRI) for treatment-resistant depression?

Medication Augmentation Strategies for SSRI-Resistant Depression

For patients with treatment-resistant depression who have not responded adequately to an SSRI, the addition of an atypical antipsychotic, particularly aripiprazole, is the most evidence-based augmentation strategy.

First-Line Augmentation Options

Atypical Antipsychotics

• Aripiprazole: 2.5-10 mg/day is the preferred first-line augmentation agent

  • FDA-approved specifically for adjunctive treatment in unipolar, non-psychotic depression 1
  • Produces rapid improvement in depressive symptoms, often within weeks 1-5 2
  • Use lower doses than those recommended for schizophrenia or bipolar disorder 1
  • Monitor for akathisia, which can be managed by lowering the dose 3

• Other Atypical Antipsychotics:

  • Brexpiprazole and cariprazine are also FDA-approved for depression augmentation 4
  • Olanzapine-fluoxetine combination and quetiapine extended-release are additional options 4
  • Risperidone has several controlled clinical trials supporting its efficacy at low doses 1

Second-Line Augmentation Options

Bupropion

• Can be added to SSRIs for patients who don't respond to atypical antipsychotics
• Caution: Bupropion inhibits CYP2D6 and can increase concentrations of SSRIs including:
  • Venlafaxine, paroxetine, fluoxetine, sertraline 5
  • Consider dose reduction of the SSRI when adding bupropion 5

Other Augmentation Strategies

• Traditional augmentation agents include:
  • Buspirone
  • Lithium
  • Triiodothyronine (T3) 1

Important Safety Considerations

Drug Interactions

• Avoid MAOIs: Increased risk of hypertensive reactions when combined with other antidepressants 5
• Serotonin Syndrome Risk: Exercise caution when combining two or more serotonergic drugs 6
  • Monitor for mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity
  • Symptoms can arise within 24-48 hours after combining medications 6
  • Treatment requires hospital-based care with discontinuation of serotonergic agents 6

Monitoring Requirements

• Assess response to augmentation therapy within 6-8 weeks 6
• For atypical antipsychotics, monitor for:
  • Weight gain
  • Metabolic parameters (glucose, lipids)
  • Extrapyramidal symptoms
  • Tardive dyskinesia 4

Treatment Duration

• Continue treatment for 4-9 months after satisfactory response for first episode of depression
• For patients with 2 or more episodes, longer duration of therapy is beneficial 6

Clinical Pitfalls to Avoid

1. Inadequate dosing or duration of the initial SSRI before augmentation
2. Failure to monitor for drug-drug interactions when adding augmentation agents
3. Not addressing potential side effects of combination therapy
4. Overlooking the need for regular assessment of treatment response
5. Discontinuing treatment too early after symptom improvement

Remember that approximately one-third of patients with major depressive disorder will develop treatment-resistant depression 4, making augmentation strategies an essential part of comprehensive depression management.