Heterocyclic antidepressants toxicity

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

Fluoxetine was the first SSRI to reach general clinical use. Paroxetine and sertraline differ mainly in having shorter half-lives and different potencies as inhibitors of specific P450 isoenzymes. While the SSRIs have not been shown to be more effective overall than prior drugs, they lack many of the toxicities of the tricyclic and heterocyclic antidepressants. Thus, patient acceptance has been high despite adverse effects such as nausea, decreased libido, and even decreased sexual function. 

Fluoxetine at a dose of 20-60 mg/day, may cause a 2-4-fold increase in plasma concentration of tricyclic antidepressants (TCAs), possibly associated with signs of toxicity, including decreased energy, psychomotor retardation, sedation, dry mouth, and memory loss. The mechanism of this interaction may be attributed to the potent inhibitory effect of fluoxetine and norfluoxetine on the CYP2D6-mediated hydroxylation of TCAs. When given in combination with the heterocyclic antidepressant trazodone, fluoxetine was found to produce a significant elevation in plasma levels of both trazodone and its metabolite m-cbloropbenylpiperazine (mCPP)... 

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