Over the last half of the 20th century, there have been a series of psychopharmacologic strategies for treatment of depression. As we approach the next century, new therapies in varying stages of American release are being developed. This review will focus on information available for the following proposed antidepressants: 1) reboxetine, a norepinephrine selective reuptake inhibitor; 2) milnacipran, a combined serotonin/norepinephrine reuptake inhibitor; 3) a new enantiomer of fluoxetine, a selective serotonin reuptake inhibitor; 4) duloxetine, another combined serotonin/norepinephrine reuptake inhibitor; 5) sunepitron, a combined 5-HT1A agonist and α2 antagonist; and, 6) MK-869, a substance P inhibitor. Finally, other possible developing directions will be reviewed, including corticotropin-releasing factor.

The end of the millennium provides an opportunity to review some of the common practices that were present in psychopharmacology during the 20th century. The author focuses on two approaches that have dominated research and guided the clinical application of psychopharmacologic therapeutics: the unitary clinically-based and single-lesion perspectives. The author expands upon these older formulations of neuropsychiatric disease pathogenesis and describes how the approach to psychopharmacologic research and therapeutics has changed in light of advances in the basic neurosciences. Relevant recent advances in the basic neurosciences that shed light on the pathophysiology of neuropsychiatric disease states and that guide psychopharmacologic practices are described. The use of atypical antipsychotic agents to treat schizophrenia is given as one example of the clinical applications of the approach to psychopharmacology in the next century.

New knowledge about the specific brain regions involved in depression is rapidly evolving due to advances in functional neuroimaging techniques. Several new regionally specific somatic interventions build on this modern neuroanatomic information. These latest methods promise to revolutionize the understanding and treatment of depression. This article reviews the past and current use of these techniques, with an eye toward where they are heading in the next century.

This article reviews recent studies of psychotherapy for treatment of depression. There is evidence that cognitive behavioral and interpersonal therapies are useful treatments for depressed outpatients, roughly comparable to antidepressant pharmacotherapy. Pharmacotherapy and psychotherapy do not, however, necessarily treat the same patients and there is emerging evidence of a neurobiological “boundary” that may delimit therapy response. Psychotherapy plus pharmacotherapy combinations appear particularly useful for outpatients with more severe, recurrent depressions. Depression-focused psychotherapy may also provide an important alternative to an indefinite course of maintenance pharmacotherapy for patients at high risk for recurrence.