fluoxetine

Overview

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) used primarily as a psychiatric therapy, especially in the treatment of depressive and related disorders. Its core pharmacologic action is inhibition of serotonin reuptake, which increases serotonergic signaling in the central nervous system. Because of this mechanism, fluoxetine is widely used as a reference antidepressant in both clinical and preclinical research.

Beyond its established therapeutic role, fluoxetine is frequently studied as a biologically active probe in neuroscience, sleep medicine, pharmacology, and drug-repositioning research. Recent work has examined its associations with seizure risk, parasomnia management, antidepressant mechanism, drug–drug interaction risk, and experimental anticancer effects. It also serves as a comparator in studies of related agents such as vortioxetine, clomipramine, and non-benzodiazepine receptor agonists, and in mechanistic studies involving pathways such as Akt1, interleukin-6, SQSTM1, and VEGFR2-related signaling.

Focus of Latest Publications

Recent publications have used fluoxetine in several distinct research contexts, reflecting both its clinical use and its value as an experimental reference compound.

One study evaluated fluoxetine-associated adverse event reporting signals in the US Food and Drug Administration Adverse Event Reporting System (FAERS), with a specific focus on seizure. That work combined pharmacovigilance analysis with network pharmacology and molecular docking to explore whether the observed reporting signals had biological plausibility. The study was designed to connect real-world safety data with mechanistic hypotheses, rather than to establish causality directly.

In sleep medicine, fluoxetine was used therapeutically in a case of sexsomnia in a young man with a non-REM parasomnia. Initial therapy with fluoxetine at 20 mg/day, melatonin at 3 mg nightly, and clomipramine at 25 mg nightly was unsuccessful. The report noted that self-administered valerian root supplementation later achieved a marked symptom reduction, attributed to GABAergic effects. In this context, fluoxetine was part of an attempted pharmacologic regimen for a difficult parasomnia presentation, alongside clomipramine and melatonin.

Fluoxetine also appeared in a multi-omics comparison with St. John’s wort extract, where it was described as a common treatment for depression. That study compared convergent and divergent antidepressant mechanisms using transcriptomic and metabolomic analyses, proteomic networks, and related systems-level approaches. The inclusion of fluoxetine provided a standard SSRI benchmark against which the herbal remedy’s molecular effects could be interpreted.

In oncology-oriented experimental work, fluoxetine was incorporated into a study of Janus dendrimers and anticancer activity. Investigators evaluated the in vitro effects of free fluoxetine and fluoxetine coupled to synthesized dendrons and dendrimers on proliferation and apoptosis in breast cancer cells, including MCF-7, SK-LU-1, and COS-7 as a control normal cell line. The study assessed whether formulation with nanostructured carriers altered fluoxetine’s anticancer-related cellular effects.

Fluoxetine was also used as a comparator in a rat model of chronic unpredictable mild stress (CUMS) examining electroacupuncture-mediated antidepressant effects. In that study, rats were assigned to control, CUMS, electroacupuncture, electroacupuncture plus VEGFR2 inhibitor SU5416, electroacupuncture plus 3-methyladenine, and fluoxetine groups. Fluoxetine served as a reference antidepressant while the study investigated whether electroacupuncture improved depressive-like behaviors through autophagy, hippocampal neuroinflammation, and the VEGF/Akt1/ERK pathway, with interleukin-6 and Akt1 among the relevant mechanistic context.

A pharmacovigilance study also examined the risk of opioid overdose during concurrent oxycodone and SSRI use, specifically highlighting fluoxetine and paroxetine as strong cytochrome P450 family 2 subfamily D member 6 (CYP2D6)-inhibiting SSRIs. The reported association emphasized the importance of drug–drug interaction risk when fluoxetine is combined with oxycodone, given the potential for altered opioid metabolism and overdose risk.

Fluoxetine was additionally used as a reference antiviral compound in a study of leritrelvir repositioning for coxsackievirus B4 and common enterovirus infections. In that context, leritrelvir showed superior anti-CVB4 efficacy in vitro and in vivo compared with fluoxetine, indicating that fluoxetine served as the benchmark drug rather than the primary investigational agent.

Finally, fluoxetine was studied in a mouse model of psychedelic-induced behavior. Acute fluoxetine at 10 mg/kg did not affect DOI-induced head-twitch response, whereas chronic fluoxetine at 10 mg/kg for 14 days produced a downward shift in the DOI dose-response function. This suggests that fluoxetine’s effects on serotonergic signaling can depend strongly on treatment duration, which is relevant to translational interpretation in clinical trial design.

Key Publications

Jun Fluoxetine-associated adverse event signals with a focus on seizure: A study based on the FAERS database, network pharmacology, and molecular docking. (Progress in neuro-psychopharmacology & biological psychiatry, 2026, PMID 42264128): "To evaluate fluoxetine-associated adverse event reporting signals in the FDA Adverse Event Reporting System (FAERS), focusing on seizure, and to explore potential biological plausibility using network pharmacology and molecular docking."
Jun Sexsomnia in a Young Man: A Non-REM Parasomnia With Diagnostic and Therapeutic Challenges. (The American journal of case reports, 2026, PMID 42219748): "Initial therapy with fluoxetine (20 mg/day), melatonin (3 mg nightly), and clomipramine (25 mg nightly) was unsuccessful, but self-administered valerian root supplementation achieved a 90% reduction in symptoms due to its GABAergic effects."
May A multi-omics comparison unveils convergent and divergent antidepressant mechanisms of fluoxetine and St. John's wort extract. (Journal of proteomics, 2026, PMID 41796893): "Fluoxetine (Flx), a selective serotonin reuptake inhibitor, and St. John's Wort extract (SJW), a herbal remedy, are common treatments for depression."
May Anticancer activity of fluoxetine Janus dendrimer against cancer cells. (Artificial cells, nanomedicine, and biotechnology, 2026, PMID 42167254): "We evaluated the in vitro anticancer effects of sulindac, ketoprofen, celecoxib and the antidepressant fluoxetine, both free and coupled with synthesized dendrons and dendrimers, on the proliferation and apoptosis of human MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma) and as a control the normal monkey kidney (COS-7) cell line."
May Electroacupuncture Ameliorates Depressive-Like Behaviors by Enhancing Autophagy to Attenuate Hippocampal Neuroinflammation via the VEGF/AKT1/ERK Pathway in CUMS Rats. (Neurochemical research, 2026, PMID 42149321): "Rats were divided into control, CUMS, EA, EA + VEGFR2 inhibitor (SU5416) (EA+SU5416), EA + 3-methyladenine (3-MA), and FXL (fluoxetine) groups."
May Duration of Concurrent Oxycodone and Selective Serotonin Reuptake Inhibitors Use and the Risk of Opioid Overdose. (The Annals of pharmacotherapy, 2026, PMID 41063462): "Concurrent use of oxycodone and strong cytochrome P450 2D6 (CYP2D6)-inhibiting selective serotonin reuptake inhibitors (SSRIs), specifically paroxetine and fluoxetine, is associated with the risk of opioid overdose."
Apr The potential of leritrelvir repositioning for the treatment of coxsackievirus B4 and common enterovirus infections. (Antiviral research, 2026, PMID 41707713): "Leritrelvir exhibited superior anti-CVB4 efficacy both in vitro and in vivo compared with the reference drug fluoxetine."
Apr Differential Effects of Acute and Chronic Fluoxetine on Psychedelic-Induced Behavior in Mice: Implications for Clinical Trials. (ACS pharmacology & translational science, 2026, PMID 41852641): "In male mice, acute fluoxetine at 10 mg/kg had no effect on DOI-induced HTR, whereas chronic fluoxetine (10 mg/kg for 14 days) produced a downward shift in the DOI dose-response function."