The concept of drug-drug interactions in psychiatry surfaced surprisingly recently. In 1988, a small letter was published in the American Journal of Psychiatry by Dr. D. A. Vaughan, a psychiatrist in practice in Wichita, Kansas. Dr. Vaughan described two women he had been treating for depression with tricyclics. The first had been on nortriptyline (NT) up to 175 mg/day, with no response. After decreasing the dose of NT to 100 mg/day, Dr. Vaughan added a newly approved antidepressant called “Prozac.” Hoping for a robust response to this augmentation strategy, he was disappointed when in fact his patient worsened, with decreased energy, sedation, and psychomotor retardation. On a whim, he decided to recheck her NT level-it was 162 ng/ml, double the pre-Prozac level of 88. He discontinued the NT immediately, continued the Prozac, and four weeks later the patient felt fully recovered from her depression. His second case was similar, except that the tricyclic in question was desipramine. In making sense of these events, Dr. Vaughan first wondered if Prozac mimicked tricyclics on chromotography methods used in his lab, but he ruled this out by analyzing a blood sample of a patient on Prozac alone, and no tricyclic appeared. He then presciently hypothesized that "one possible explanation for these incidents is a pharmacokinetic interaction." Over the ensuing years, the precise nature of this interaction became fully worked out, and it has become one of the best recognized of all drug-drug interactions in psychiatry.

Vaughan DA, Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 1988, 145:1478 (letter).