Can a Selective Serotonin Reuptake Inhibitor (SSRI) and a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) be used together and what are the potential side effects?

Concurrent Use of SSRIs and SNRIs: Safety Concerns and Side Effects

Combining SSRIs and SNRIs is generally not recommended due to the significant risk of serotonin syndrome, which can be potentially life-threatening. 1

Risks of Combined SSRI and SNRI Therapy

• The concurrent use of SSRIs and SNRIs significantly increases the risk of serotonin syndrome, a potentially fatal condition characterized by mental status changes, neuromuscular hyperactivity, and autonomic instability 1
• Advanced symptoms of serotonin syndrome can include fever, seizures, arrhythmias, unconsciousness, and potentially fatal outcomes 1
• Both medication classes have similar mechanisms affecting serotonin reuptake, leading to excessive serotonergic activity when combined 2
• The risk persists for several days or even weeks after SSRI withdrawal due to their long elimination half-lives, particularly with fluoxetine 3

Clinical Presentation of Serotonin Syndrome

• Typically presents with a triad of symptoms including mental status changes, neuromuscular hyperactivity, and autonomic instability 1
• Symptoms usually develop within 24-48 hours after combining serotonergic medications 1
• Common symptoms include:
  • Mental status changes: confusion, agitation, anxiety, restlessness 1
  • Neuromuscular symptoms: tremor, rigidity, myoclonus, hyperreflexia 1
  • Autonomic symptoms: hyperthermia, tachycardia, diaphoresis, hypertension 1

Other Side Effects of SSRIs and SNRIs

• Both medication classes share common side effects including:

  • Gastrointestinal effects: nausea, vomiting, diarrhea, abdominal discomfort 2, 4
  • Neuropsychiatric effects: headache, dizziness, insomnia, somnolence 2, 4
  • Sexual dysfunction 2
  • Risk of suicidal thinking and behavior (through age 24 years) 2

• SNRIs have additional side effects:

  • Increased blood pressure and pulse 2
  • Diaphoresis and dry mouth 2
  • Fatigue/somnolence (more common than with SSRIs) 2
  • Potential for hepatic issues with duloxetine 2

Management Recommendations

• If treatment with both serotonergic agents is absolutely necessary:

  • Start with low doses of the second serotonergic drug when adding to an existing regimen 1
  • Increase doses slowly and monitor closely for symptoms of serotonin syndrome 1
  • Avoid additional serotonergic agents that could further increase risk 1

• If serotonin syndrome is suspected:

  • Immediately discontinue all serotonergic agents 1
  • Seek emergency medical attention for hospital-based supportive care 1
  • In severe cases, intensive care may be necessary, including the use of serotonin antagonists such as cyproheptadine 1

Alternative Approaches

• Consider monotherapy with either an SSRI or SNRI before attempting combination therapy 2
• Both medication classes have demonstrated efficacy across a broad range of psychiatric conditions including depression, anxiety disorders, and other conditions 5
• Novel antidepressants have shown better efficacy and tolerability than SSRIs and SNRIs in recent research, making them potential alternatives for patients who don't respond well to conventional treatments 6

High-Risk Combinations to Avoid

• Combining either SSRIs or SNRIs with MAOIs is absolutely contraindicated due to extremely high risk of serotonin syndrome 2, 1
• Other high-risk combinations include:
  • Opioids (particularly tramadol, meperidine, methadone, fentanyl) 1
  • St. John's Wort and other serotonergic supplements 1
  • Dextromethorphan-containing over-the-counter medications 1
  • Stimulants and illicit drugs with serotonergic properties 1