Is it safe to combine tricyclic antidepressants (TCAs) with selective serotonin reuptake inhibitors (SSRIs)?

From the Guidelines

Combining tricyclic antidepressants (TCAs) with selective serotonin reuptake inhibitors (SSRIs) is not recommended due to the significant risk of serotonin syndrome, a potentially life-threatening condition, as highlighted in the 2020 clinical practice guideline for the assessment and treatment of children and adolescents with anxiety disorders 1.

Safety Concerns

The combination of TCAs and SSRIs increases the risk of serotonin syndrome, characterized by symptoms such as mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity, which can lead to fatalities if not treated promptly 1.

• The symptoms of serotonin syndrome can arise within 24 to 48 hours after combining medications and include confusion, agitation, anxiety, tremors, clonus, hyperreflexia, muscle rigidity, hypertension, tachycardia, arrhythmias, tachypnea, diaphoresis, shivering, vomiting, and diarrhea.
• Advanced symptoms of serotonin syndrome can include fever, seizures, arrhythmias, and unconsciousness.

Mechanism of Interaction

Both TCAs and SSRIs increase serotonin levels in the brain, but through different mechanisms, which can lead to elevated brain serotonin levels and trigger serotonin syndrome 1.

• SSRIs block serotonin reuptake, while TCAs affect multiple neurotransmitters, including serotonin.
• Some SSRIs, such as fluoxetine, paroxetine, and fluvoxamine, can also inhibit liver enzymes that metabolize TCAs, potentially leading to high TCA blood levels and increased risk of cardiac arrhythmias, seizures, and anticholinergic effects.

Clinical Considerations

If a clinician determines that the combination of TCAs and SSRIs is necessary, they should start with low doses, monitor closely for adverse effects, and educate patients about the warning signs of serotonin syndrome requiring immediate medical attention 1.

• Close monitoring for suicidality is also recommended, especially in the first months of treatment and following dosage adjustments, as SSRIs have a boxed warning for suicidal thinking and behavior through age 24 years 1.

From the FDA Drug Label

Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered.

Combining TCAs and SSRIs is not recommended without caution due to the potential for drug interactions, particularly those involving the CYP2D6 enzyme system.

• Key considerations:
  • TCAs have a narrow therapeutic index, making them a concern when coadministered with SSRIs like fluoxetine.
  • The risk of increased plasma levels of TCAs and potentially serious ventricular arrhythmias or sudden death may occur.
  • Patients should be closely monitored, and the dose of the original medication may need to be decreased when adding fluoxetine to the treatment regimen.
  • Caution is advised when combining these medications, and alternative treatment options should be considered when possible 2.

From the Research

Safety Considerations

• The safety and tolerability of combining tricyclic antidepressants (TCAs) with selective serotonin reuptake inhibitors (SSRIs) is a concern due to potential adverse interactions 3, 4.
• SSRIs have a more favorable side-effect profile compared to TCAs, with fewer treatment discontinuations and lower toxicity in overdose situations 3.
• TCAs can cause anticholinergic, hypotensive, and sedating reactions, which are not typically associated with SSRIs 3.

Efficacy and Tolerability

• A meta-analysis found no overall difference in efficacy between SSRIs and TCAs, but SSRIs were better tolerated with significantly lower rates of treatment discontinuations 4.
• Individual SSRIs, such as fluoxetine and sertraline, have a similar advantage in terms of tolerability compared to TCAs, except for fluvoxamine which does not differ from TCAs 4.
• The evidence suggests that SSRIs have a modest advantage in terms of tolerability against most TCAs, but the overall efficacy between the two classes is comparable 4.

Pharmacological Interactions

• SSRIs and TCAs can interact with each other, and therapeutic drug monitoring is important to minimize potential adverse effects 5.
• The pharmacodynamic and pharmacokinetic properties of SSRIs and TCAs should be considered when combining these medications, including side effects, chemical-clinical correlations, and interactions with other drugs 5.

Treatment of Chronic Depression

• Both SSRIs and TCAs are efficacious in the treatment of chronic depression, with no statistically significant differences in response rates between the two types of antidepressants 6.
• SSRIs showed better acceptability in terms of dropout rates compared to TCAs, but more evidence is needed to assess the efficacy of SSRIs and TCAs in patients suffering from chronic forms of depression other than dysthymia 6.