The pharmacology of three serotonin-selective drugs

With the introduction of clomipramine, the clinician now has three drugs available in the United States that are selective for blockade of serotonin uptake at the synapse. Selectivity for serotonin is based upon in vitro studies and does not take into account metabolism of a drug into compounds that may block uptake of other neurotransmitters, such as norepinephrine. Clomipramine is a classical tricyclic antidepressant. It is also the most potent, but least selective, of the three drugs for blockade of serotonin uptake over norepinephrine uptake. Its receptor binding profile is similar to that for some other tricyclic antidepressants. The side effect profile of clomipramine, predicted from its in vitro pharmacology, is also similar to that for some other tricyclic antidepressants. Thus, blockade of muscarinic, histamine H₁, and α₁-adrenergic receptors can be expected to occur in patients given this drug. Also, like other tricyclic drugs, clomipramine can lower the seizure threshold. The experience of CIBA-Geigy, the developer of the drug, with over 3500 patients at doses up to 300 mg/day gives a seizure incidence of 0.7%. The company recommends that the drug should not be given at dosages greater than 250 mg/day and that it be given cautiously in patients with a history of seizure disorders. Fluoxetine is unique since it is weak at blocking known neurotransmitter receptors, while it is potent at blocking uptake of serotonin. Thus, none of its receptor blocking effects determined in vitro are potent enough to cause clinical effects in patients. Unusual in the clinical pharmacology of this drug is its very long elimination half-life, and even longer elimination half-life for an active metabolite. The clinician needs to be aware of this long elimination time when starting the medication, adjusting dosages, and discontinuing the medication. Finally, trazodone is a drug that has a pharmacological profile unlike any other antidepressant. Although most selective at blocking uptake of serotonin, it is by far the weakest at doing so. In addition, because of potent effects at blocking serotonin receptors, it is likely that this drug has no direct effect at enhancing serotonergic function. However, its metabolite, m-chlorophenylpiperazine, is an agonist at one serotonin subtype (5-HT(1c)). Trazodone was the first non-monoamine oxidase inhibitor antidepressant marketed in the United States to be completely devoid of any muscarinic receptor blocking effects. However, its blocking effects on other receptors lead to some effects seen with other antidepressants. In addition, priapism, a side effect unique to trazodone among the antidepressants but not the neuroleptics, may result from blockade of adrenergic receptors in the absence of muscarinic cholinergic blockade.