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Selective Serotonin Reuptake Inhibitors (SSRI)

4.16 Important drug interactions

SSRIs inhibit the activity of cytochrome P450 isoenzymes but the inhibitory effect on different isoforms varies between individual members of the class. Important interactions of SSRIs involve enhancement of serotonergic1 activity, which, in rare cases, could result in the serotonin syndrome.

Consult summaries of product characteristics and other sources for information on the interactions of individual SSRIs.

Interacting drug

Effect of interaction

Risk-reduction measures

Other antidepressants—including duloxetine; MAOIs2 (including moclobemide [specific for MAO-A] and older mixed MAO-A/B inhibitors such as phenelzine); St John’s wort; agomelatine; tricyclic antidepressants; tryptophan

Increased serotonergic3 effect

Avoid concomitant use (except under specialist supervision)—allow sufficient time for one drug to clear before starting another

Anticoagulants (including warfarin)

Increased anticoagulant effect

If SSRI needs to be continued, monitor INR closely during initiation of SSRI treatment and with any SSRI dose adjustment

Antiepileptics

Convulsive threshold lowered

Antimigraine drugs - 5HT1 receptor agonists (‘triptans4’)

Increased risk of serotonergic effects

Avoid concomitant use

Antiplatelet5 drugs (including aspirin, clopidogrel, dipyridamole, ticlopidine)

Increased risk of gastrointestinal bleeding

If possible, avoid concomitant use; otherwise, also prescribe a gastroprotective medicine (such as a proton pump inhibitor6 or a histamine H27 antagonist

Linezolid

Increased serotonergic effect

Avoid concomitant use (except under specialist supervision) - allow sufficient time for one drug to clear before starting another

Lithium

Increased risk of lithium toxicity

Monoamine oxidase B inhibitors8 (rasagiline, selegiline)

Increased risk of serotonergic effects

Avoid concomitant use—allow sufficient time for one drug to clear before starting another

NSAIDs

Increased risk of gastrointestinal bleeding

If possible, avoid concomitant use; otherwise, also prescribe a gastroprotective medicine (such as a proton pump inhibitor or a histamine H2 antagonist

Pimozide

Increased risk of ventricular arrhythmias

Avoid concomitant use

Tamoxifen

Inhibition of isoenzyme CYP2D6 by fluoxetine or paroxetine can reduce conversion of tamoxifen to active metabolites, thereby reducing anti-oestrogenic effect in breast cancer

Avoid concomitant use of either fluoxetine or paroxetine with tamoxifen

Tramadol

Increased risk of CNS toxicity (convulsions, serotonin syndrome9)

2 3 4 5 6 7 8 9


  1. A chemical agent (or synapse) that produces its effects via the serotonin transmitter system.
  2. Monoamine oxidase inhibitors act within nerve cells to block the enzyme that promotes breakdown of the monoamine neurotransmitters, noradrenaline and serotonin. Therefore, nerve endings can release more neurotransmitter at the synapse. Examples of MAOI antidepressants include isocarboxazid, phenelzine, and tranylcypromine. The antidepressant, moclobemide, is a reversible inhibitor of monoamine oxidase type A (RIMA).
  3. A chemical agent (or synapse) that produces its effects via the serotonin transmitter system.
  4. Drugs that bind to serotonin (5HT1) receptors in cranial blood vessels. They are used in the treatment of migraine headaches. Examples include sumatriptan and zolmitriptan.
  5. Antiplatelet medicines are used to prevent heart attacks and strokes. They prevent platelets from clumping together, which, in turn, helps to prevent the formation of clots. Antiplatelet medicines include aspirin, clopidogrel, dipyridamole, and prasugrel.
  6. Proton pump inhibitors reduce the secretion of acid in the stomach; they are used to prevent and heal duodenal and gastric ulcers and to manage other conditions aggravated by stomach acid. Examples of this class of medicine include esomeprazole, lansoprazole, and omeprazole.
  7. Histamine H2 antagonists reduce the secretion of acid in the stomach. They are used to prevent and heal duodenal and gastric ulcers and to manage other conditions aggravated by stomach acid. Examples of this class of medicine include cimetidine and ranitidine.
  8. Monoamine oxidase (MAO) is an enzyme involved in the breakdown of monoamine neurotransmitters, such as serotonin, dopamine and noradrenaline. MAO-B inhibitors (eg rasagiline and selegiline) are used in the treatment of Parkinson’s disease whereas MAO-A inhibitors are used as antidepressants (see Antidepressants, MAOI).
  9. A potentially life-threatening medical emergency, characterised by excessive serotonin stimulation. This is usually the result of an overdose of a single serotonergic substance or the mixture and additive effect of several serotonergic substances. A variety of symptoms are produced, which range from the relatively unnoticeable to extreme and fatal.