The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below).
B. Selective Serotonin-Norepinephrine Reuptake Inhibitors and Tricyclic Antidepressants
The SNRIs have relatively fewer CYP450 interactions than the SSRIs. Venlafaxine is a substrate but not an inhibitor of CYP2D6 or other isoenzymes, whereas desvenlafaxine is a minor substrate for CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6 and so may elevate TCA and levels of other CYP2D6 substrates. Since milnacipran is neither a substrate nor potent inducer of CYP450 isoenzymes, is not tightly protein bound, and is largely excreted unchanged in the urine, it is unlikely to have clinically significant pharmacokinetic drug interactions. On the other hand, levomilnacipran is reported to be a substrate of CYP3A4, and the dosage of the drug should be lowered when combined with potent inhibitors of CYP3A4 such as ketoconazole. Like all serotonergic antidepressants, SNRIs are contraindicated in combination with MAOIs.
Elevated TCA levels may occur when these drugs are combined with CYP2D6 inhibitors or from constitutional factors. About 7% of the Caucasian population in the USA has a CYP2D6 polymorphism that is associated with slow metabolism of TCAs and other 2D6 substrates. Combination of a known CYP2D6 inhibitor and a TCA in a patient who is a slow metabolizer may result in markedly increased effects. Such an interaction has been implicated, though rarely, in cases of TCA toxicity. There may also be additive anticholinergic or antihistamine effects when TCAs are combined with other agents that share these properties such as benztropine or diphenhydramine. Similarly, antihypertensive drugs may exacerbate the orthostatic hypotension induced by TCAs.
C. 5-HT Receptor Modulators
Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it can raise the level and thus exacerbate adverse effects of many 3A4-dependent drugs. For example, triazolam levels are increased
TABLE 30–4 Some antidepressant–CYP450 drug interactions.