SSRIs are predominantly metabolized by the hepatic cytochrome P450 system and may inhibit their own metabolism or that of other drugs (Table 6). Among SSRIs, sertraline, citalopram, and escitalopram possess minimal interactions within the P450 system; this quality makes them the antidepressants of choice in medically ill patients requiring coadministration of other medications.
The inhibitory action of SSRIs may give rise to multiple drug-drug interactions with other medications; these interactions when the drugs are coadministered may lead to no effect, intoxication, or even improving a drug's therapeutic response via a rise in its plasma concentration. Generally, SSRIs that inhibit the CYP 450 systems will impair metabolism of other medications (P450 enzyme substrates), thus prolonging their elimination half-life and increasing their blood level. For example, the SSRI inhibition of cytochrome P450 activity may lead to elevated levels of concurrently administered TCAs which are metabolized by CYP 2D6 and 3A4 isoenzymes (62). This may lead to side effects, but it may also permit clinicians to use a low-dose TCA to augment or potentiate the SSRI. Citalopram does not alter TCA levels (62). On the other hand, fluvoxamine inhibits the CYP 1A2 isoenzyme and can produce toxic levels of medications that are usually metabolized by this isoenzyme, namely tacrine, warfarin, theophylline, propranolol, and many others.
Since SSRIs are also substrates for the hepatic cytochrome system, medications such as carbamazepine, rifampin, dexamethasone, which induce CYP 450 isoenzymes, accelerate SSRI metabolism if coadministered. Medications such as quini-dine, cimetidine, and diltiazem inhibit CYP 450; they will delay SSRI clearance and may produce toxic levels of SSRI (34, 63, 64). Comprehensive lists of drug interactions with SSRI antidepressants can be accessed at http://www.drugfactsand-comparisons.com, The Medical Letter: Adverse Drug Interactions Program, or other computer databases (35, 63-67).
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