SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept.

Journal Article (Journal Article)

Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HTExt beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HTExt elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HTExt elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HTExt beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HTExt spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HTExt beyond the SSRI effect and represent a novel treatment for TRD.

Full Text

Duke Authors

Cited Authors

  • Jacobsen, JP; Rudder, ML; Roberts, W; Royer, EL; Robinson, TJ; Oh, A; Spasojevic, I; Sachs, BD; Caron, MG

Published Date

  • August 2016

Published In

Volume / Issue

  • 41 / 9

Start / End Page

  • 2324 - 2334

PubMed ID

  • 26932820

Pubmed Central ID

  • PMC4946063

Electronic International Standard Serial Number (EISSN)

  • 1740-634X

Digital Object Identifier (DOI)

  • 10.1038/npp.2016.35


  • eng

Conference Location

  • England