title: SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept.
abstract: 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.
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.
authors.forename: Jacob Pr
authors.initials: JP
authors.lastname: Jacobsen
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Rudder
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Royer
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Robinson
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.
authors.forename: Adrianna
authors.initials: A
authors.lastname: Oh
authors.affiliation: Department of Medicine, Duke University, Durham, NC, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sachs
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC, USA.|Department of Medicine, Duke University, Durham, NC, USA.|Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D006916:5-Hydroxytryptophan; D005473:Fluoxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors