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

Abstract

Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HT Ext ) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HT Ext 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-HT Ext 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-HT Ext 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-HT Ext 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-HT Ext beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HT Ext 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-HT Ext beyond the SSRI effect and represent a novel treatment for TRD.

Antidepressive Mechanisms of Probiotics and Their Therapeutic Potential

“…In contrast, 5-HTP readily crosses the BBB and can be converted into 5-HT. Therapeutic 5-HTP has also been shown to treat clinical depression with a potency equivalent to or better than SSRIs (Birdsall, 1998;Jangid et al, 2013;Jacobsen et al, 2016). Furthermore, B. infantis intake increased plasma TRP levels in healthy rats (Desbonnet et al, 2008), but another study with chronic-stressed rats reported otherwise (Desbonnet et al, 2010).…”

Serotonin concentration enhancers at clinically relevant doses reduce [11C]AZ10419369 binding to the 5-HT1B receptors in the nonhuman primate brain

“…The dose of 5-HTP (5 mg/kg) in the present study was comparable with the clinical dose range of 200 to 300 mg/day, typically administered per os or intravenous 24 . Furthermore, a slow-release (SR) formulation of 5-HTP has been shown to provide more stable increases in 5-HT concentration, with less adverse effects, than the immediate-release form in rodent studies 58 . Therefore, PET measurement with [ 11 C]AZ10419369 and pretreatment with oral administration of 5-HTP SR is a promising paradigm to investigate 5-HT release in the human brain.…”

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

“…Directed by the clinical data reviewed above we carried out an adjunctive 5-HTP SR proof-of-concept study in mice [83]. We modeled 5-HTP SR using subcutaneous minipumps, which produces constant (zero-order) SR delivery.…”

“…Such slower metabolism could account for the observed longer human T 1/2 of 5-HTP (2h) vs. L-DOPA (1h) [94]. In mice, in a study discussed in the main text, we determined the T 1/2 to be about 12 min [83], 10 times faster than in humans, in accordance with the typical mouse:human metabolism and dose-extrapolation scaling factor of about 10 [95]. …”