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

Trends Pharmacol Sci. 2016 Nov;37(11):933-944. doi: 10.1016/ Epub 2016 Sep 28.


Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HTExt). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HTExt beyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HTExt 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.

Keywords: 5-hydroxytryptophan; Antidepressant; depression; treatment-resistant depression.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • 5-Hydroxytryptophan / administration & dosage*
  • 5-Hydroxytryptophan / pharmacokinetics
  • 5-Hydroxytryptophan / pharmacology
  • Animals
  • Antidepressive Agents, Second-Generation / administration & dosage*
  • Antidepressive Agents, Second-Generation / pharmacokinetics
  • Antidepressive Agents, Second-Generation / pharmacology
  • Delayed-Action Preparations
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / physiopathology
  • Humans
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism


  • Antidepressive Agents, Second-Generation
  • Delayed-Action Preparations
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Serotonin
  • 5-Hydroxytryptophan