Associations and interactions: tricyclic antidepressants and selective serotonin reuptake inhibitors

Following the commercialization of the SSRIs clinicians described cases of drug interactions with tricyclic antidepressants among their patients. When combining tricyclic antidepressants and SSRIs clinical side effects and elevated plasma levels of tricyclics appeared. A better knowledge of the cytochrome P450 system allows to understand the mechanism of such drug interactions. The cytochrome P450 is composed of a group of isoenzymes, which are classified, into families and subfamilies on the basis of amino acid sequence homology. A number of the cytochrome genes have a genetic polymorphism responsible for poor and extensive metabolisers. The clinical importance of genetic polymorphism is highly dependent upon the therapeutic index. Thus, poor metabolisers, will experience side effects and rapid metabolisers prone to therapeutic failure. Concerning pharmacological issues SSRIs have a great affinity for at least one of the isoenzymes which accounts for drug interactions. Due to the inhibitory potential of the SSRIs drug interactions occur with tricyclics that ha ve a narrow therapeutic index. The SSRIs do not exert the same inhibitory effect on the various isoenzymes. The inhibitory activity for an isoenzyme depends on the molecule of the SSRIs. In clinical practice, the associations between tricyclics and SSRIs should be practiced with caution. It is recommended to decrease the tricyclic dose before administering the SSRI, to start with low doses of the SSRI and to take into account the therapeutic index. Although the coadministration of tricyclics and SSRIs can produce adverse reactions it has also two main interests in clinical practice. First, the drug combination enhances clinical response to treatment. Secondly, it converts non-responders of pharmacological treatment to responders. Used with caution the association of tricyclics and SSRIs is well tolerated. However, it should be kept in mind that a single drug therapy should be tried first. These data show the complexity of drug interactions.