Current status of antidepressants: clinical pharmacology and therapy

Effective antidepressants, including imipramine and monoamine oxidase (MAO) inhibitors, were discovered serendipitously in the 1950s. Many additional agents have been introduced since then, but most are chemically or pharmacologically similar to those known for nearly four decades. Some recently introduced antidepressants offer either lesser or dissimilar side effects, but none exceeds older treatments in efficacy. Selective serotoninpotentiating agents and short-acting MAO-A inhibitors promise efficacy with greater safety. Progress is made difficult because atypical or treatment-resistant patients are more often available for study than typical patients, and because most studies must rely heavily on potentially misleading "standard drug versus new drug" comparisons. Rational development of novel or better agents is slow, in part, due to limited understanding of the biological basis of major affective disorders and some circularity in relating actions of known drugs to pathophysiologic hypotheses. Action mechanisms of antidepressants are subtle and complex: adaptive changes occur in brain monoaminergic neurotransmission following repeated administration of agents of the tricyclic antidepressant (TCA) type that may lead to net facilitation of alpha 1-adrenergic transmission. Important advances have been made in using plasma TCA levels to guide individualization of dosing, in exploring higher doses of antidepressants when ordinary doses prove ineffective, and in recognizing a broadening spectrum of possible indications for antidepressants in adults and children. These indications include panic disorder, obsessive compulsive disorder, attention deficit disorder, and bulimia. Evidence for the prophylactic effects of antidepressants after the first months following recovery from an index episode of major depression is weak, and the treatment of common recurrent or chronic depression remains unsatisfactory. Gains have been made in increasing clinicians' and the general public's awareness of the common occurrence and appropriate treatment of major depression, even when the depression is associated with other medical or psychiatric disorders.