Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale

Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HT_Ext). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HT_Ext beyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HT_Ext beyond the SERT inhibitor effect in humans; however, 5-HTP cannot be a clinically viable drug because of its poor pharmacokinetics. A slow-release (SR) delivery mode would be predicted to overcome the pharmacokinetic limitations of 5-HTP, substantially enhancing the pharmacological action and transforming 5-HTP into a clinically viable drug. Animal studies bear out this prediction. Thus, adjunct 5-HTP SR could be an important new treatment for TRD. Here, we review the clinical and preclinical evidence for this treatment.