Can Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) be given together?

Combining SSRIs and SNRIs Is Not Recommended Due to Risk of Serotonin Syndrome

SSRIs and SNRIs should not be administered together due to the significant risk of developing potentially life-threatening serotonin syndrome. 1

Mechanism and Risks

The primary concern with combining SSRIs and SNRIs is the development of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonergic activity in the central nervous system. Both medication classes increase serotonin levels through different but complementary mechanisms:

• SSRIs selectively inhibit serotonin reuptake
• SNRIs inhibit both serotonin and norepinephrine reuptake

When combined, these medications can cause dangerously high levels of serotonin, leading to serotonin syndrome characterized by:

• Mental status changes (confusion, agitation, anxiety)
• Neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity)
• Autonomic hyperactivity (hypertension, tachycardia, arrhythmias, tachypnea, diaphoresis)
• Advanced symptoms: fever, seizures, arrhythmias, unconsciousness 1

Evidence Against Combination

The American Academy of Child and Adolescent Psychiatry explicitly warns that monoamine oxidase inhibitors (MAOIs) combined with other serotonergic drugs pose the highest risk for serotonin syndrome, but also cautions about combining two or more non-MAOI serotonergic drugs, including SSRIs and SNRIs 1.

FDA labeling for venlafaxine (an SNRI) specifically warns about the risk of serotonin syndrome when combining SNRIs with other serotonergic drugs, including SSRIs 2.

Alternative Approaches

Instead of combining these medication classes, guidelines recommend the following approaches:

For Anxiety Disorders:

1. First-line options (choose one):

   • SSRI monotherapy (sertraline, escitalopram, fluoxetine)
   • SNRI monotherapy (venlafaxine)
   • CBT (cognitive behavioral therapy) 1, 3

2. For inadequate response:

   • Switch to a different SSRI
   • Switch from SSRI to SNRI (or vice versa)
   • Add CBT to medication therapy 1

For Depression:

Similar stepped approach is recommended, with either an SSRI or SNRI as first-line pharmacotherapy, but not both simultaneously.

Special Considerations

If transitioning between an SSRI and SNRI is necessary:

• Implement a cross-titration schedule
• Gradually taper the first medication while slowly introducing the second
• Monitor closely for signs of serotonin syndrome during the transition period

Common Pitfalls to Avoid

1. Abrupt switching: Never abruptly discontinue one agent and immediately start another, as this can cause both discontinuation syndrome and increased risk of serotonin syndrome.

2. Overlooking drug interactions: Both SSRIs and SNRIs can interact with other medications through cytochrome P450 pathways, particularly CYP2D6 4.

3. Ignoring discontinuation symptoms: Both medication classes require gradual tapering to avoid discontinuation syndrome, characterized by dizziness, fatigue, sensory disturbances, and anxiety 3.

4. Failure to monitor: Close monitoring is essential when starting any serotonergic medication, especially during the first months of treatment and following dosage adjustments 1, 3.

By adhering to these guidelines and using either an SSRI or SNRI (not both), clinicians can effectively treat anxiety and depressive disorders while minimizing the risk of dangerous adverse effects.