Pharmacology of Antidepressants—Characteristics of the Ideal Drug

To describe the clinical and basic pharmacologic properties of antidepressants and thus define the pharmacologic criteria for the ideal antidepressant. A review of the pharmacologic characteristics of the newer second-generation antidepressants is presented in relationship to those of the older compounds. Clinical pharmacologic and in vitro data on the synaptic effects of antidepressants (inhibition of synaptosomal uptake and blockade of neurotransmitter receptors) were obtained for the older antidepressants and for the more recently marketed and approved drugs. The group of antidepressants includes six new antidepressants approved for marketing since 1988 and two additional drugs marketed outside the United States as antidepressants but approved for use in the United States for obsessive-compulsive disorder. Thus, 18 antidepressant drugs are discussed. All antidepressants seem to be equally efficacious in treating depression, and no drug seems to work more rapidly than another. Nonetheless, antidepressant drugs differ substantially in pharmacokinetic variables (elimination half-lives); in their effects on the metabolism of other drugs (by inhibiting the cytochrome P₄₅₀ system); in their potencies for blocking the reuptake of norepinephrine, serotonin, and dopamine; and in their affinities for blocking histamine H₁, muscarinic acetylcholine, α-adrenergic, and dopamine D₂ receptors. Most side effects of antidepressants can be explained by their effects on blocking uptake and on blocking neurotransmitter receptors. The newer second-generation antidepressants have distinct pharmacologic advantages in comparison with the tricyclic antidepressants and the older second-generation compounds. These advantages are clearly seen from their synaptic effects, in which most newer second-generation antidepressants are practically devoid of blocking effects at neurotransmitter receptors. Although the newer second-generation antidepressants are much closer to being the ideal antidepressant than are the older compounds, none completely fulfills the criteria for being the ideal drug.