Newer and Older Antidepressants: A Comparative Review of Drug Interactions

Edoardo Spina, Emilio Perucca

Research output: Contribution to journalArticlepeer-review


A large number of drug interactions involving antidepressants have been described. Some of these are common to specific classes of antidepressant drugs, while others are related to peculiar properties of individual compounds and vary greatly from one compound to another within the same drug class. In general, the broader the range of receptors and enzymes affected by a given drug, the greater the potential for pharmacodynamic interactions. Older generation monoamine oxidase inhibitors (MAOIs) are particularly likely to cause interactions. These can occur with a wide range of compounds including tyra-mine-containing foods, alcohol (ethanol), opioids, sympathomimetic agents and other antidepressant drugs [e.g. tricyclic antidepressants (TCAs) and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs)]. The more recently developed reversible and selective inhibitors of monoamine oxidase-A, such as moclobemide, appear to carry a much lower risk of causing serious drug interactions. TCAs affect several neurotransmitter systems, but to differing degrees. This may result in many clinically significant pharmacodynamic interactions, including the reversal of the hypotensive action of some centrally active antihypertensive agents and the potentiation of the effects of anticholinergic agents and CNS depressants. Important pharmacokinetic interactions with TCAs include induction of their metabolism by anticonvulsants and impairment of their elimination by metabolic inhibitors such as fluoxetine, fluvoxamine, antipsychotics and quinidine. Appropriate dosage adjustments may be required to minimise the potentially adverse effects resulting from these interactions. Some second generation antidepressants do not differ greatly from TCAs in pharmacological profile and so may be involved in similar interactions. However, others have a more selective mechanism of action and a lower potential for drug interactions. This is especially true for the SSRIs, which cause fewer pharmacodynamic interactions than MAOIs and TCAs. Nevertheless, SSRIs may interact adversely with drugs that also affect serotonergic transmission (including lithium) and may inhibit selectively the hepatic enzymes involved in the metabolism of concurrently prescribed drugs such as TCAs, antipsychotics, carbamazepine, oral anticoagulants and β-adrenoceptor blocking agents. Fluoxetine and paroxetine, in particular, appear to be powerful inhibitors of CYP2D6, whereas fluvoxamine is a more potent inhibitor of CYP1A2. Avoidance of unnecessary polytherapy, knowledge of the interaction potential of individual agents and careful individualisation of dosage based on close evaluation of clinical response are essential to minimise potentially adverse drug interactions among patients receiving antidepressant therapy.

Original languageEnglish
Pages (from-to)479-497
Number of pages19
JournalCNS Drugs
Issue number6
Publication statusPublished - 1994

ASJC Scopus subject areas

  • Clinical Neurology
  • Pharmacology (medical)
  • Psychiatry and Mental health


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