Is it common to be prescribed two antidepressants, such as a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine reuptake inhibitor (SNRI), simultaneously?

Combination Antidepressant Therapy in Clinical Practice

While it is not uncommon for patients to be taking two antidepressants simultaneously, this practice should only be implemented with a clear rationale and under close supervision, as there is limited evidence supporting the use of two antidepressants as an initial treatment approach or specific endpoint for treatment. 1

Prevalence and Clinical Scenarios

• Combination antidepressant therapy is relatively common in treatment-resistant depression (TRD), with approximately 60% of patients receiving augmentation and/or combination strategies in some clinical settings 2
• The most common scenarios for antidepressant combinations include:
  • During transition periods when switching from one antidepressant to another 1
  • For treatment-resistant depression when monotherapy has failed 1, 3
  • For treating multiple concurrent disorders (e.g., depression with anxiety) 1
  • For augmentation to address specific symptom profiles 1

Evidence Base for Combination Therapy

• Current guidelines indicate limited empirical support for combining medications from the same class (e.g., two SSRIs or two SNRIs) 1
• For treatment-resistant OCD, evidence supports augmentation strategies including:
  • Adding an antipsychotic to an SSRI 1
  • Combining an SSRI with clomipramine (a tricyclic antidepressant) 1
• For treatment-resistant depression, some evidence supports combinations such as:
  • SSRI plus bupropion (which has a different mechanism of action) 4
  • SSRI plus mirtazapine 5

Safety Considerations and Risks

• The most serious risk of combining serotonergic antidepressants is serotonin syndrome, which can be life-threatening 1
• Particular caution is required when combining:
  • Any antidepressant with MAOIs (generally contraindicated) 1, 6, 7
  • Two or more serotonergic drugs (SSRIs, SNRIs, tricyclics) 1
  • Antidepressants with other medications that affect serotonin (triptans, tramadol, St. John's wort) 6, 7
• Drug-drug interactions may occur through:
  • Pharmacokinetic interactions (one drug affecting the metabolism of another) 1, 7
  • Pharmacodynamic interactions (additive or synergistic effects) 1, 7

Clinical Decision-Making Algorithm

1. First-line approach: Start with antidepressant monotherapy 1

   • Allow adequate trial (8-12 weeks) at therapeutic doses 1
   • Monitor for response and side effects 1

2. If inadequate response to first antidepressant:

   • Consider switching to a different antidepressant 1
   • Consider higher doses within the therapeutic range 1
   • Consider augmentation with psychotherapy (particularly CBT) 1

3. For treatment-resistant cases (failed 2+ adequate trials):

   • Consider evidence-based augmentation strategies with medications having different mechanisms:
     • SSRI + bupropion 5, 4
     • SSRI + mirtazapine 5
     • SSRI + antipsychotic (for certain conditions) 1
   • Avoid combining two medications from the same class (e.g., two SSRIs) 1

4. When implementing combination therapy:

   • Develop a clear treatment and monitoring plan 1
   • Educate patient about potential risks and benefits 1
   • Start the second agent at a low dose and titrate slowly 1
   • Monitor closely for adverse effects, particularly in the first 24-48 hours after dosage changes 1

Common Pitfalls to Avoid

• Combining antidepressants without a clear rationale or evidence base 1
• Using combinations based solely on theoretical neurotransmitter effects without clinical evidence 1
• Failing to monitor for drug-drug interactions 1, 7
• Not having a plan for discontinuation if the combination proves ineffective or causes adverse effects 1
• Combining MAOIs with other antidepressants without extreme caution and expertise 1, 3

In conclusion, while combination antidepressant therapy is not uncommon in clinical practice, particularly for treatment-resistant cases, it should be approached with caution, clear rationale, and close monitoring due to the increased risk of adverse effects and limited supporting evidence compared to monotherapy approaches.