Is it safe to take duloxetine and fluoxetine (selective serotonin reuptake inhibitors, SSRIs) concurrently?

From the Guidelines

Duloxetine and fluoxetine should not be taken together due to the increased risk of serotonin syndrome and other adverse effects. These medications are both antidepressants that work in similar ways - duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) while fluoxetine is a selective serotonin reuptake inhibitor (SSRI). Taking them simultaneously increases the risk of developing serotonin syndrome, a potentially serious condition caused by excessive serotonin levels in the body, as noted in the clinical practice guideline for the assessment and treatment of children and adolescents with anxiety disorders 1. Symptoms of serotonin syndrome include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremor, and in severe cases, seizures or loss of consciousness.

Some key points to consider when prescribing these medications include:

• The potential for drug-drug interactions, particularly with monoamine oxidase inhibitors (MAOIs), which can increase the risk of serotonin syndrome 1
• The importance of monitoring for symptoms of serotonin syndrome, especially in the first 24 to 48 hours after combining medications 1
• The need for a gradual transition plan when switching between medications, including tapering off one medication before starting the other, with appropriate waiting periods between them due to their half-lives (especially fluoxetine, which has a long half-life of 4-6 days) 1
• The potential for overlapping side effects, such as nausea, headache, insomnia, and sexual dysfunction, which may be intensified when taken together 1

It is essential to work with a healthcare provider to develop a safe and effective treatment plan, taking into account the potential risks and benefits of combining these medications, as well as the individual patient's medical history and needs 1.

From the FDA Drug Label

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including duloxetine delayed-release capsules, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Duloxetine and fluoxetine should not be taken together due to the increased risk of serotonin syndrome, a potentially life-threatening condition.

• Key points:
  • Concomitant use of duloxetine and other serotonergic drugs, including SSRIs like fluoxetine, may increase the risk of serotonin syndrome.
  • Patients should be monitored for the emergence of serotonin syndrome symptoms, such as mental status changes, autonomic instability, and neuromuscular symptoms.
  • Treatment with duloxetine and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs 2.

From the Research

Duloxetine and Fluoxetine Combination

• There is no direct evidence in the provided studies that specifically addresses the combination of duloxetine and fluoxetine.
• However, a study 3 investigated the combination of antidepressant medications from treatment initiation for major depressive disorder, which included fluoxetine in combination with other medications, but not duloxetine.
• Another study 4 discussed the pharmacokinetics and drug interactions of duloxetine, mentioning that CYP1A2 inhibition, such as by fluvoxamine, significantly increases duloxetine exposure, but it does not specifically address the combination of duloxetine and fluoxetine.

Pharmacokinetics and Interactions

• Duloxetine achieves a maximum plasma concentration approximately 6 hours after dosing, with an elimination half-life of approximately 10-12 hours 4.
• The study also found that patient demographic characteristics, such as hepatic function and renal function, can influence the pharmacokinetics of duloxetine, but it does not provide information on the interaction between duloxetine and fluoxetine.
• A review of duloxetine's efficacy, safety, and tolerability 5 confirmed its suitability for the treatment of various clinical conditions, but it does not address the specific combination of duloxetine and fluoxetine.

Safety and Efficacy

• A study on selective serotonin reuptake inhibitors (SSRIs) 6 discussed the adverse effects of SSRIs, including fluoxetine, but it does not provide information on the combination of duloxetine and fluoxetine.
• The study on duloxetine 7 reviewed its pharmacology, pharmacokinetics, efficacy, safety, and place in therapy, but it does not address the combination with fluoxetine.
• In general, the provided studies suggest that duloxetine and fluoxetine are effective and relatively safe when used individually, but there is limited information on their combined use.