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Introduction

These tables contain information on some of the important drug interactions with the SSRIs and other antidepressants. It is not fully comprehensive or inclusive and it is especially important to check out the possibility of an interaction occurring with drug combinations that you are not familiar with. Individual susceptibility and response to a drug interaction can be quite variable and the clinical significance is often approached on a case by case basis. The notes on importance and management give some advice but specialised texts such as Stockley’s should be consulted for detailed information on clinical significance and management.

Fluoxetine, paroxetine and citalopram are metabolised by the cytochrome P-450 system in the liver but are substrates for different isoenzymes and vary in their potential to inhibit the metabolism of other drugs. In general, citalopram is less likely to cause drug interactions due to enzyme inhibition than fluoxetine or paroxetine. Drug interactions due to enzyme inhibition or induction are pharmacokinetic drug interactions. SSRIs (and other antidepressants) can also cause pharmacodynamic drug interactions where there is no change in the drug concentration of the interacting drug but the effects are additive or antagonistic due to the drug’s pharmacological properties. Examples include additive sedation with CNS depressants and serotonin syndrome with other serotonergic drugs.

In Table 1 “All” refers to the three SSRIs available in New Zealand; paroxetine, fluoxetine and citalopram. Table 2 refers to TCAs in general although individual drugs have different properties which can increase the risk of an interaction; for example amitriptyline is one of the most sedative TCAs and clomipramine has marked serotonergic properties which increase the risk of serotonin syndrome if given with SSRIs.

Table 1: Some important drug interactions with Antidepressants
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SSRI Interacting Drug Possible Effect(s) Importance and Management
All Alcohol Increased CNS sedation Advise vigilance in early stages of treatment
All Benzodiazepines Increased sedation possible.
Fluoxetine and paroxetine may reduce metabolism of some benzodiazepines		 Warn that increased sedation is possible
All Warfarin Increased INR and increased bleeding risk due to antiplatelet effect Monitor INR and advise patients to report signs of bleeding
Fluoxetine & paroxetine Metoprolol and propranolol Increased beta-blocking effects, bradycardia Monitor heart rate. Interaction not reported with citalopram
All Buspirone Serotonin syndrome and lowering of seizure threshold theoretically possible Monitor concurrent use
All Antiepileptics SSRIs may lower the seizure threshold Unlikely to be a problem if epilepsy well controlled.
Observe seizure frequency
Fluoxetine Antiepileptics, carbamazepine and phenytoin Increased plasma concentrations of carbamazepine and phenytoin with fluoxetine Monitor plasma concentrations of carbamazepine and phenytoin. Adjust dose if necessary. No similar reports with paroxetine and an interaction appears unlikely with citalopram.
Paroxetine Antiepileptics, carbamazepine and phenytoin Reported to decrease plasma concentration of paroxetine Clinical significance not clear. Monitor clinical response
All NSAIDs including aspirin Increased risk of GI bleeding Concurrent use not contraindicated but be aware of increased risk of bleeding especially in those with additional risk factors
All Monoamaine oxidase inhibitors (MAOIs), including moclobemide Hypertensive crisis Avoid concurrent use. Washout periods essential when switching. Refer to product prescribing information and reference texts
Fluoxetine & paroxetine (possibly citalopram) Clozapine, haloperidol and risperidone Increased plasma concentrations of antipsychotics Monitor for dose related adverse effects and reduce dose of antipsychotic if necessary
All Tramadol Both tramadol and SSRIs lower seizure threshold.
Serotonin syndrome reported with concurrent use		 Use the combination of tramadol and an SSRI very cautiously especially at high doses. Alternative analgesic may be preferable
All Tricyclic antidepressants Increased plasma concentrations of TCA and increased adverse effects.
Risk of serotonin syndrome especially with clomipramine
Increases are variable but can be in the order of 3–4 times and more.		 Increases usually less significant or negligible with citalopram. If the combination is judged necessary, start with the lowest dose of TCA and monitor for dose related adverse effects, e.g sedation, or anticholinergic symptoms
All Sibutramine Increased risk of CNS toxicity Avoid
All (especially fluoxetine & paroxetine) Perhexilene, flecainide and other antiarrhythmic drugs Plasma concentrations can be increased leading to toxicity. Refer to individual product prescribing information and reference texts
Fluoxetine & paroxetine Protease inhibitors (ritonavir) Fluoxetine increases ritonavir concentrations and ritonavir may increase fluoxetine and paroxetine concentrations.
Cases of serotonin syndrome with fluoxetine reported		 Monitor for symptoms of serotonin syndrome.
Reduce dose if necessary
All Lithium Neurotoxic symptoms and serotonin like syndrome occasionally reported Addition of lithium to an SSRI can be beneficial and is usually uneventful. Observe for adverse effects
All Selegiline Hypertension, CNS excitation, serotonin syndrome Avoid this combination as serious interactions have been reported.
Manufacturers advise to avoid.
N.B. apparent safe use of this combination has also been reported in the literature
All St John’s Wort Serotonin syndrome Avoid this combination
All Sumatriptan A few cases of dyskinesias with fluoxetine. Occasional reports of serotonin syndrome Concurrent use of sumatriptan and SSRIs not usually a problem but monitor for any adverse effects when the combination is started

Table 2: Some important drug interactions with tricyclic antidepressants (TCAs)

Interacting drugs(s) Possible effect(s) Importance and management
SSRIs Increased plasma concentrations of TCA causing increased adverse effects.
Serotonin syndrome possible, especially with clomipramine		 Increases are variable but can be in the order of 3 – 4 times and more. Increases usually less significant or negligible with citalopram.
If the combination is judged necessary, start with the lowest dose of TCA and monitor for dose related adverse effects, e.g. sedation, or anticholinergic symptoms
Alcohol Increased CNS depression, sedation Warn patient about increased drowsiness. Limit alcohol intake
Antiarrhythmic drugs, e.g. amiodarone, flecainide, quinidine Increased risk of ventricular arrhythmias Avoid concurrent use. Refer to specialised texts.
CNS depressants e.g.
Benzodiazepines Antihistamines Antipsychotics		 Increased CNS depression, sedation Warn patient about increased drowsiness
Clonidine Antihypertensive effects of clonidine are reduced or abolished Avoid concurrent use
Warfarin Occasional reports of changes in INR Evidence for an interaction is poor and inconclusive.
Monitor INR as normal
Lithium Neurotoxic symptoms and serotonin-like syndrome occasionally reported Concurrent use can be beneficial and is usually uneventful. Observe for adverse effects
Antipsychotics Increased sedation, additive anticholinergic effects
Plasma concentrations of phenothiazines and/or the TCA may be increased		 Often used together in clinical practice but be aware of the possibility of additive pharmacological and adverse effects
Selegiline CNS excitation, serotonin syndrome Interaction appears less likely than with an SSRI
Caution and awareness of possible symptoms advised
Ritonavir Plasma concentrations of TCAs may be increased. Monitor for increased dose related adverse effects. Reduce dose of TCA if necessary.
Tramadol Increased risk of seizures. Possibility of serotonin syndrome especially with clomipramine Adverse effects unlikely but be aware of symptoms