Is there any risk of interactions between sertraline and atomoxetine?/nBackground: A 10-year-old, m

Fråga: Is there any risk of interactions between sertraline and atomoxetine?

Background: A 10-year-old, mentally retarded boy, with an attention-deficit hyperactivity disorder diagnosis (ADHD), has been treated with Zoloft (sertraline) 25 mg daily for many months. Four weeks ago, treatment with Strattera (atomoxetine) was added against ADHD, current dosage 60 mg daily. No adverse effects have been noticed.

Sammanfattning: There is no data showing a significant interaction between atomoxetine and sertraline. However, given that several adverse drug reactions are in common for both drugs, there is indeed cause for careful monitoring of adverse effects in a patient with combined treatment. Furthermore, there is also a potential risk of pharmacokinetic interactions causing drug accumulation, and analysis of sertraline plasma levels is recommended together with careful dosage of atomoxetine.

Svar: Atomoxetine (or tomoxetine) is a selective noradrenaline uptake inhibitor (SNRI) with minimal affinity for other monoamine transporters or receptors (1, 2). It has been approved by the Food and Drug Administration in the USA for the treatment of ADHD (3), but to date, it may only be prescribed in Sweden after individual approval by the Medical Products Agency.

In theory, a pharmacodynamic interaction at the receptor level between an SNRI such as atomoxetine and an SSRI, such as sertraline, appears unlikely. However, commonly reported side effects for both drugs include gastrointestinal symptoms such as nausea and decreased appetite, dizziness, and insomnia, which suggests an increased risk of these symptoms during combined treatment.

There are potential pharmacokinetic interactions between the two drugs. Sertraline has been described as an inhibitor of CYP2D6 (5, 6), which is the major enzyme responsible for the metabolism of atomoxetine (6). However, in comparison with the other SSRIs like paroxetine and fluoxetine, the inhibitory effect on CYP2D6 by sertraline is more moderate and the clinical significance is not fully understood (4,5,6). Therefore, it is not clear whether or not the plasma level of atomoxetine will be affected by sertraline, and the dose of atomoxetine should be carefully titrated or kept low.

In theory, there is also a risk for a reverse interaction. Sertraline plasma levels might increase by atomoxetine, since the latter substance was found to inhibit CYP2D6 and CYP3A4 in vitro, i.e. two major enzymes involved in the metabolism of sertraline (2). However, the in vivo kinetics of midazolam, known to be specifically metabolised by CYP3A4, was unaffected by atomoxetine, even in individuals defined as poor metabolisers of CYP2D6-substrates, i.e. completely lacking expression of the CYP2D6 enzyme. This indicates that also the metabolism of sertraline by CYP3A4, is unaffected by atomoxetine.

In conclusion, even though there is no direct evidence for a pharmacokinetic interaction between the two substances, some patients may be at risk of accumulation of atomoxetine and/or sertraline. Analysis of sertraline plasma levels is recommended. Analysis of atomoxetine levels is not available in Sweden, and doses should be kept low together with an increased attention for adverse effects.