Can patients be treated with a Selective Serotonin Reuptake Inhibitor (SSRI) and a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) concurrently?

From the Guidelines

Patients should not be treated with a Selective Serotonin Reuptake Inhibitor (SSRI) and a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) concurrently due to the risk of serotonin syndrome, a potentially life-threatening condition. The use of medication combinations, including SSRIs and SNRIs, requires a clear rationale and careful consideration of the potential risks and benefits 1. While there may be limited evidence to support the use of two antidepressants or two antipsychotics as an initial treatment approach or as a specific endpoint for treatment, combining medications from the same class is not generally recommended 1.

The mechanism of action of SSRIs and SNRIs, which both increase serotonin levels in the brain, can lead to excessive serotonin accumulation when combined, resulting in symptoms such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and in severe cases, seizures or loss of consciousness. The risk of serotonin syndrome is a significant concern when combining these medications, and healthcare providers should exercise caution when considering such combinations 1.

In general, if a patient is not responding adequately to either an SSRI or SNRI alone, healthcare providers typically recommend switching to a different medication within the same class or to the other class entirely, rather than combining them. In rare cases, specialists might carefully combine these medications at low doses with close monitoring, but this is not standard practice and carries significant risks. The potential benefits of combining SSRIs and SNRIs must be carefully weighed against the potential risks, and patients should be closely monitored for signs of serotonin syndrome or other adverse effects if such a combination is used 1.

Key considerations when evaluating the use of SSRIs and SNRIs include:

• The potential risk of serotonin syndrome and other adverse effects
• The limited evidence to support the use of medication combinations
• The importance of careful monitoring and close follow-up when combining medications
• The need for a clear rationale and treatment plan when using medication combinations 1.

From the FDA Drug Label

The concomitant use of venlafaxine HCl with MAOIs intended to treat psychiatric disorders is contraindicated. The development of a potentially life-threatening serotonin syndrome have been reported with SNRIs and SSRIs, including venlafaxine HCl, alone but particularly with concomitant use of serotonergic drugs Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non–selective MAOI), lithium, tramadol, or St John’s Wort The concomitant use of Prozac with other SSRIs, SNRIs or tryptophan is not recommended

Concurrent use of SSRI and SNRI is not recommended due to the potential risk of serotonin syndrome. Patients should be monitored for the emergence of serotonin syndrome when using these drugs. Caution is advised when coadministering these drugs, and the decision to use them together should be made with careful consideration of the potential risks and benefits. 2 3

From the Research

Concurrent Use of SSRI and SNRI

• The provided studies do not directly address the concurrent use of a Selective Serotonin Reuptake Inhibitor (SSRI) and a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) 4, 5, 6, 7, 8.
• However, studies have investigated the risks of serotonin syndrome when combining SSRIs or SNRIs with other medications, such as triptans 5, 6 and monoamine oxidase inhibitors (MAOIs) 7, 8.
• The FDA has issued alerts regarding the potential risk of serotonin syndrome with combined use of SSRIs or SNRIs and certain medications, but the evidence suggests that the risk may be low 5, 6, 7.
• Some studies suggest that combination therapy with SSRIs or SNRIs and other medications may be effective and safe when used under close supervision and with caution 8.

Risks and Considerations

• The risk of serotonin syndrome is a concern when combining SSRIs or SNRIs with other medications that affect serotonin levels 5, 6, 7.
• Close supervision and monitoring are necessary when using combination therapy to minimize the risk of adverse effects 8.
• The decision to use concurrent SSRI and SNRI therapy should be made on a case-by-case basis, taking into account the individual patient's medical history, current medications, and potential risks and benefits 8.