Can a tricyclic antidepressant (TCA) be safely used in combination with a selective serotonin reuptake inhibitor (SSRI)?

From the Guidelines

Combining a tricyclic antidepressant (TCA) with a selective serotonin reuptake inhibitor (SSRI) is generally not recommended due to the increased risk of serotonin syndrome, a potentially life-threatening condition. This combination should only be used under careful medical supervision in specific circumstances where the benefits clearly outweigh the risks 1. Common TCAs include amitriptyline, nortriptyline, and imipramine, while common SSRIs include fluoxetine, sertraline, and escitalopram. If this combination is deemed necessary, it typically requires lower doses of both medications, gradual titration, and close monitoring for symptoms of serotonin syndrome such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and hyperthermia.

The risk of serotonin syndrome is particularly high when combining TCAs with certain SSRIs like fluoxetine and paroxetine, which strongly inhibit the CYP2D6 enzyme that metabolizes many TCAs, potentially leading to dangerously high TCA blood levels 1. Patients should immediately report any unusual symptoms and avoid other serotonergic substances including St. John's Wort, certain pain medications, and some cough medicines. This combination works by affecting both serotonin and norepinephrine neurotransmission, which may provide additional benefit in treatment-resistant depression but carries significant risks.

Some studies have also highlighted the risk of arrhythmia induced by psychotropic medications, including TCAs and SSRIs 1. However, the most recent and highest quality study 1 prioritizes the risk of serotonin syndrome as the primary concern when combining TCAs and SSRIs. Key points to consider when combining these medications include:

• Close monitoring for symptoms of serotonin syndrome
• Gradual titration and lower doses of both medications
• Avoiding other serotonergic substances
• Educating patients on the risks and symptoms of serotonin syndrome
• Careful medical supervision to weigh the benefits and risks of this combination.

From the FDA Drug Label

While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other

• Caution is advised when using a tricyclic antidepressant (TCA) in combination with a selective serotonin reuptake inhibitor (SSRI) due to potential interactions and increased risk of side effects.
• The combination may require lower doses of either the TCA or the SSRI, and close monitoring of the patient's response is necessary.
• It is also important to note that sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary) 2.

From the Research

Combination Therapy

• The use of tricyclic antidepressants (TCAs) in combination with selective serotonin reuptake inhibitors (SSRIs) is a topic of interest in the treatment of depression 3.
• Studies have shown that SSRIs can increase TCA plasma levels when given concurrently, which may lead to adverse effects 3.
• The effect of sertraline on TCA serum levels may be less profound than that of fluoxetine, fluvoxamine, and paroxetine 3.
• Limited data suggest that citalopram may not affect TCA serum levels 3.

Safety and Tolerability

• SSRIs have a more favorable safety profile than TCAs, with fewer treatment discontinuations and lower toxicity 4, 5.
• TCAs are associated with anticholinergic, hypotensive, and sedating reactions, as well as impaired cognitive function, which are not seen with SSRIs 4.
• The most common side effects of SSRIs, such as nausea, vomiting, nervousness, insomnia, headache, and sexual dysfunction, are usually mild and typically disappear as treatment continues 4.

Efficacy

• There is no overall difference in efficacy between SSRIs and TCAs, although TCAs may be more effective in in-patients and amitriptyline may be more effective than SSRI comparators 6.
• SSRIs have a modest advantage in terms of tolerability compared to most TCAs 6.

Clinical Use

• The use of SSRIs in combination with TCAs is not well supported by literature evidence as a treatment for refractory depression 3.
• General practitioners should prescribe a therapeutic dose of antidepressant for a recognized therapeutic period to ensure that patients with depression receive the most effective treatment 7.