Serotonin

證據等級: L5

預測適應症: 10 個

Serotonin: From Endogenous Neurotransmitter to Insomnia

One-Sentence Summary

Serotonin (5-hydroxytryptamine) is an endogenous neurotransmitter with no approved drug indication of its own — it is not currently marketed in the jurisdiction covered by this evidence pack. TxGNN predicts a strong association with Insomnia (score 99.90%), but the 50 clinical trials and 18 publications identified all study downstream serotonergic drugs (trazodone, mirtazapine, SSRIs, pimavanserin) or non-pharmacological interventions — none administer serotonin itself, and the underlying pharmacology raises serious feasibility concerns for direct use.

Quick Overview

Item	Content
Original Indication	None on record — serotonin has no approved therapeutic indication (endogenous neurotransmitter; 0 licenses in dataset)
Predicted New Indication	Insomnia (disease)
TxGNN Prediction Score	99.90%
Evidence Level	L4 (mechanistic/preclinical; no interventional trial of serotonin itself)
US Market Status	Not Marketed (未上市)
Number of NDAs	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Detailed mechanism-of-action data for serotonin as a drug product is not available in DrugBank for this candidate. Based on known pharmacology, serotonin (5-HT) is an endogenous monoamine synthesized from tryptophan that signals through the 5-HT1–7 receptor family distributed across the central and peripheral nervous system, gut, and vasculature. It has never been developed as a standalone therapeutic — a fact consistent with its extremely short plasma half-life (~2 minutes), inability to cross the blood-brain barrier, and pronounced peripheral vasoactive and gastrointestinal effects when given exogenously.

The mechanistic link to insomnia is real: 5-HT1A/2A/2C receptor signaling helps regulate the sleep-wake cycle, and this is well documented in the literature. However, every one of the 50 clinical trials returned for this indication investigates a downstream serotonergic drug — trazodone, mirtazapine, pimavanserin, SSRIs/SNRIs — or a non-pharmacological intervention (acupuncture, probiotics, magnetotherapy). None administer serotonin itself. This is not a coincidence: drugs like SSRIs and trazodone were specifically developed as indirect modulators of the serotonin system precisely because direct serotonin administration is not clinically viable (poor CNS penetration, systemic side effects, risk of serotonin syndrome). TxGNN’s high score therefore reflects strong network-level association between “serotonin” and “insomnia” concepts, not evidence that serotonin itself is an actionable drug candidate for this indication.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT04532749	Phase 3	Terminated	212	Seltorexant (orexin antagonist) as adjunctive therapy to antidepressants in MDD with insomnia symptoms (MDDIS) inadequately responsive to SSRI/SNRI — not a serotonin agent
NCT06559306	Phase 3	Recruiting	752	Ongoing follow-up Seltorexant trial in MDDIS patients; evaluates efficacy/safety and maintenance of effect vs placebo
NCT06056258	NA	Completed	48	Placebo-controlled trial of nutraceutical VL-NL-02 for sleep quality, restorative sleep, and mood
NCT00765752	N/A	Completed	23	MRS study of cortical GABA levels in primary insomnia and in MDD patients with SSRI-residual insomnia — mechanistic, not interventional
NCT07229976	NA	Not yet recruiting	198	Thumbtack-needle acupuncture for chronic insomnia in perimenopausal/menopausal women
NCT05705830	NA	Unknown	400	Pulse magnetotherapy combined with medication for anxiety and insomnia
NCT03947216	Phase 2	Completed	117	Pimavanserin (5-HT2A inverse agonist) for impulse control disorders in Parkinson’s disease — graded C relevance, not insomnia-specific
NCT00025740	Phase 4	Completed	78	Clonazepam + paroxetine (SSRI) combination for rapid PTSD treatment — graded C, indirect serotonin-pathway support only
NCT03321526	Phase 2	Completed	107	JNJ-42847922 vs quetiapine XR as adjunctive therapy in MDD inadequately responsive to SSRI — graded C
NCT03977441	Phase 4	Unknown	240	Agomelatine for sleep disorders and depression in Parkinson’s disease; notes SSRI/clonazepam adverse effects including serotonin syndrome

Literature Evidence

PMID	Year	Type	Journal	Key Findings
40135470	2025	RCT	Age and Ageing	MIRAGE study: mirtazapine (blocks serotonin/histamine receptors) for chronic insomnia in older adults
34994734	2021	Review	Psychiatria Polska	Compares trazodone vs hypnotics for insomnia; summarizes evidence for serotonergic sedative antidepressants
24685396	2014	Review	Sleep Medicine Reviews	Insomnia pathophysiology framework (predisposing, precipitating, perpetuating factors)
26744739	2015	Review	Drugs of Today	Pharmacology review of pimavanserin (5-HT2A inverse agonist)
41123484	2025	Review	Annals of Medicine	Circadian clock gene dysregulation as a core mechanism in insomnia
21537726	2011	Review	Rev Bras Psiquiatr	Serotonergic transmission linking sleep and depression via sedative antidepressants
37834999	2023	Observational	J Clin Med	Serum 5-HT and SERT expression correlate with depressive/insomnia symptoms in inflammatory bowel disease
41392764	2026	Preclinical	Food & Function	Probiotic strain ameliorates insomnia in a mouse model by restoring GABA and serotonin signaling
39519543	2024	Preclinical	Nutrients	Lactobacillus plantarum reduces stress-induced insomnia/depression-like behavior in mice
39183410	2024	Observational	Medicine	Moxibustion + ear acupuncture + alprazolam improves neurotransmitter levels in coronary heart disease patients with insomnia

US Market Information

No marketing authorizations were found. Serotonin is not currently registered as an approved drug product in the reviewed dataset (0 licenses; market status: Not Marketed / 未上市). Serotonin is used clinically only as an endogenous biomarker/reference compound, not as a formulated therapeutic.

Safety Considerations

Please refer to the package insert for safety information. No formal drug-safety data (warnings, contraindications, or DDI records) is currently available for this candidate.

Important caveat surfaced in mechanistic review: exogenous serotonin has an extremely short plasma half-life, does not cross the blood-brain barrier, and is associated with peripheral vasoactive and gastrointestinal effects — properties that historically made direct serotonin administration clinically impractical and drove development of indirect serotonergic agents (SSRIs, trazodone, triptans) instead.

Conclusion and Next Steps

Decision: Hold

Rationale: The mechanistic link between serotonin signaling and insomnia is well established, but no clinical evidence tests serotonin itself as a therapeutic agent — all identified trials and most literature concern downstream serotonergic drugs. Combined with the missing TFDA label data (blocking safety gap) and missing MOA confirmation, this candidate cannot yet proceed to a safety-guardrail decision.

To proceed, the following is needed:

TFDA label warnings/contraindications (blocking gap — required before any S1 safety evaluation)
Confirmed mechanism-of-action data via DrugBank API query
Clarification of drug identity/strategy: whether “serotonin” here represents a literal exogenous-serotonin candidate, or should instead be reinterpreted as a class-level signal pointing to serotonergic precursors (e.g., 5-HTP) or receptor-selective agents
Pharmacokinetic/route-of-administration feasibility assessment given known BBB-penetration and half-life limitations
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.