- Objectives: Rapid reduction of up to 80% in plasma tryptophan level can be accomplished by administering an oral tryptophan-free amino acid solution, which induces hepatic protein synthesis and thereby depletes available plasma tryptophan. Rapid tryptophan depletion (RTD) has been shown to induce transient depressive symptoms in patients with remitted major depression. The effect of RTD in acutely manic patients has not been studied. Methods: We carried out a double-blind, placebo-controlled pilot study of RTD in acutely manic patients. Patients were randomized to the treatment groups. Sodium valproate treatment was started at a dose of 1000 mg/day and continued throughout the 7-day study. On days 1-7, patients received a daily tryptophan-free amino acid drink or a placebo drink. The tryptophan-free amino acid drink contained a mix of amino acids without tryptophan. The placebo drink contained the additives and constituents of the real mixture to provide identical flavor and texture without the amino acids. Ratings were administered at baseline and then repeated on days 3, 5, and 7. All ratings were carried out by an experienced rater who was blind to the group assignment of patients. Results: A total of 23 patients entered the study and 17 completed the 7-day treatment protocol. The patients who received the amino acid drink showed greater improvement in mania ratings. The differences in Young Mania Rating Scale (YMRS) and Clinical Global Impression (GCI) scores were significant. However, the intolerance rate was high (23%) and the findings in this pilot study are based only on results from those patients who were able to tolerate the drink. Conclusions: Rapid tryptophan depletion may have an antimanic effect.