Vilazodone

Limits on what this shows

• Null/negative findings: None identified; no study of any kind measuring mitochondrial parameters with vilazodone specifically, positive or negative, was located.
• At-risk subgroups: None established for vilazodone.

Regulatory status

Not addressed in FDA labeling; no mitochondrial-toxicity warning for vilazodone.

Population evidence

A direct PubMed search for "vilazodone mitochondria" returned zero results, explicitly confirmed by PubMed's own "retrieved no results" message; the incidental hits shown were unrelated. Shen Y, Brown CE, Li X, et al. "Selective serotonin reuptake inhibitors induce cardiac toxicity through dysfunction of mitochondria and sarcomeres," Commun Biol, 2025 (PMID 40355528): human iPSC-derived cardiomyocyte 2D and 3D organoid models tested fluoxetine, paroxetine, and sertraline only, confirmed independently via OpenAlex; vilazodone was not among the drugs tested. That study found SSRI exposure "inhibited ATP production, disrupted mitochondrial respiration and homeostasis, and disrupted sarcomere structure" in differentiating cardiomyocytes.

Mechanism

Not established for vilazodone. The class-level mechanism proposed for the tested SSRIs is impairment of mitochondrial oxidative phosphorylation machinery at supratherapeutic concentration; vilazodone's distinct 5-HT1A partial agonism and different molecular scaffold mean this cannot be assumed to transfer without direct testing.

Counter-evidence held on record

This is Tier C class extrapolation: vilazodone itself was not in the studied cohort, and the supporting study used concentrations well above typical clinical plasma levels in cardiomyocytes, not adult tissue generally. This should not be read as established mitochondrial harm at standard vilazodone dosing, and does not support CoQ10 or other mitochondrial-support supplementation, for which no dosing evidence exists in this drug's population. See Overlap map: this source is shared with the ATP production entry.

Limits on what this shows

• Null/negative findings: None identified for vilazodone specifically; no study reports a null oxidative-stress result for this drug because no dedicated study exists.
• At-risk subgroups: None established for vilazodone.

Regulatory status

Not addressed in FDA labeling.

Population evidence

A PubMed search for "vilazodone oxidative stress" returned two results. One (Kalariya et al. 2015, PMID 25459935) concerns forced chemical degradation ("stress testing" in the ICH pharmaceutical-stability sense) of the vilazodone molecule itself, not biological oxidative stress, and is not relevant. The other, Arasmou-Idrovo et al., "Unexpected mechanisms of repurposed drugs in the pathogenic pathways of neurodegenerative diseases," Neuropharmacology, 2026 (PMID 42061810), appeared in the PubMed listing snippet discussing "calcium overload, neuroinflammation, and oxidative stress" in cellular models of repurposed drugs; however, the article is closed access, no abstract was retrievable via OpenAlex (abstract field null), and vilazodone does not appear in any of the metadata, keywords, or MeSH terms returned by OpenAlex for this record. Whether vilazodone is actually one of the repurposed drugs discussed, and if so what was found, could not be confirmed this session, so this source is disclosed but not used to support this grade. Chung YC, Kim SR, Jin BK. "Paroxetine prevents loss of nigrostriatal dopaminergic neurons by inhibiting brain inflammation and oxidative stress in an experimental model of Parkinson's disease," J Immunol, 2010 (PMID 20566832), confirmed independently via OpenAlex: paroxetine (not vilazodone) reduced oxidative DNA damage and suppressed reactive-oxygen-species production from NADPH oxidase and astroglial myeloperoxidase in an MPTP mouse model.

Mechanism

Not established for vilazodone. The Chung 2010 mechanism (suppression of microglial NADPH oxidase and proinflammatory cytokine-driven oxidative stress) is specific to paroxetine in a neurodegeneration model and has not been tested for vilazodone or its distinct 5-HT1A-agonist pharmacology.

Counter-evidence held on record

This is Tier C class extrapolation from a single other SSRI (paroxetine) in an animal disease model, in the protective rather than harmful direction. It does not establish that vilazodone increases or reduces oxidative stress in humans, and should not be used to justify antioxidant supplementation, for which no dosing evidence exists in this drug's population. The 2026 Arasmou-Idrovo paper is listed in Sources as access-limited and unconfirmed; a later revision should re-check whether vilazodone is actually discussed in its full text.

Limits on what this shows

• Null/negative findings: None found.
• At-risk subgroups: None established.

Regulatory status

Not addressed in FDA labeling.

Population evidence

A direct PubMed search for "vilazodone copper" returned zero results, explicitly confirmed by PubMed's own "retrieved no results" message. Gong A, Wan D, Liang HW, et al. "Joint replenishment of zinc and folic acid enhances the anti-depressive effect of paroxetine via increasing serum calcium and copper and decreasing serum arsenic," Neurosci Lett, 2020 (PMID 32777348), confirmed independently via OpenAlex (title, authors, journal, year, and Sprague-Dawley rat model confirmed; full abstract and quantitative data not retrievable, closed access): paroxetine, not vilazodone, was the drug tested, and the zinc/folic-acid co-administration design cannot isolate paroxetine's own effect on copper, let alone establish anything about vilazodone.

Mechanism

Not established for vilazodone or, independently, even for paroxetine given the confounded design. The mechanism screen (Step 1/2) found no chelation, gastric-pH, or renal-wasting pathway by which vilazodone would plausibly alter copper status on its own.

Counter-evidence held on record

This is a doubly indirect extrapolation: a confounded study of a different drug (paroxetine), not vilazodone. It does not establish that vilazodone alone changes copper status, and no copper dosing recommendation follows from it.

Limits on what this shows

• Why no grade: Both conditions for ungraded are met: no Tier B or Tier C evidence was found to support even a yellow grade for vilazodone or any close class analog, and no circulating consumer claim specific to vilazodone and iron was found on the sources checked. This is treated as a genuine evidence gap. Some of the search friction in this review (see access note in Sources) was tooling-related rather than literature-related, but the PubMed searches that did complete for this category returned clean, explicit negative results, so the gap itself is assessed as genuine rather than purely a tooling artifact.

Channels tried

PubMed search-listing pages, two separately phrased queries: (1) "vilazodone iron"; (2) the same term re-checked as part of the broader "vilazodone AND (vitamin OR folate OR zinc OR B12)" sweep, which also returned nothing usable. Also reviewed: FDA label Clinical Pharmacology, Warnings and Precautions, and Adverse Reactions sections (Step 1) for any hematologic or iron-related signal; consumer sources (Drugs.com, a representative drug-nutrient-depletion consumer site) for any circulating iron/energy claim.

Outcome

Clean zero on the direct PubMed search: PubMed's own interface explicitly reported "retrieved no results" for "vilazodone iron," and the incidental hits shown (unrelated genetics and immunology papers matching "vil" as a text fragment) had no connection to the drug. No class-level Tier B or C source was located either; unlike the copper and gut-microbiome categories, no other SSRI-class iron study was found during this review to extrapolate from (the one iron-adjacent finding located for a related drug in a companion B007 dossier, an unrelated in vitro amyloid-precursor-protein screen, predates vilazodone's 2011 approval and was not re-verified or re-used here because it was not located independently in this session's own searches).

Limits on what this shows

• Null/negative findings: None identified for vilazodone; the Dethloff study of paroxetine found no significant beta-diversity difference at 7 or 14 days despite the alpha-diversity signal, a partial null worth preserving alongside the positive finding, though it does not speak to vilazodone directly.
• At-risk subgroups: None established in humans or specifically for vilazodone; all class-level evidence is murine.

Regulatory status

Not addressed in FDA labeling.

Population evidence

A direct PubMed search for "vilazodone gut microbiome" returned zero results, explicitly confirmed by PubMed's "retrieved no results" message (the displayed hits were Villin-Cre mouse model studies, unrelated). Dethloff F, Vargas F, Elijah EO, et al. "Paroxetine Administration Affects Microbiota and Bile Acid Levels in Mice," Front Psychiatry, 2020 (PMID 32581888), confirmed independently via OpenAlex: male DBA/2J mice treated with paroxetine for 14 days showed reduced fecal microbial alpha diversity and altered bacterial composition, and significantly changed primary and secondary bile acid levels. The abstract itself states "several antidepressants, particularly selective serotonin reuptake inhibitors, demonstrate antimicrobial activity," a class-level statement, though vilazodone (an SSRI plus 5-HT1A partial agonist, not a pure SSRI) was not tested in this or any other microbiome study located.

Mechanism

Not established for vilazodone specifically. Serotonin signaling has documented roles in gut motility, mucosal immune function, and bacterial gene expression, offering general biological plausibility for a serotonergic antidepressant to affect gut microbiota, but this has not been tested for vilazodone's dual reuptake-inhibitor/partial-agonist pharmacology.

Counter-evidence held on record

All supporting evidence is in mice and concerns a different drug (paroxetine); no human or vilazodone-specific gut microbiome data exist. This should not be generalized as a uniform depletion or harm claim for vilazodone, whose added 5-HT1A partial agonism is a pharmacological difference from paroxetine that has not been tested for this endpoint.

Limits on what this shows

• Null/negative findings: None identified at therapeutic concentrations for either line of evidence; the Shen 2025 finding required concentrations well above typical clinical plasma levels, and the Lee 2020 IPMK finding is a distinct pharmacological phenomenon not designed to test, and therefore silent on, mitochondrial ATP production.
• At-risk subgroups: None established for vilazodone.

Regulatory status

Not addressed in FDA labeling.

Population evidence

Shen Y, et al., Commun Biol, 2025 (PMID 40355528), the same source as the Mitochondrial burden entry: fluoxetine, paroxetine, and sertraline (not vilazodone) "inhibited ATP production" alongside disrupted mitochondrial respiration in human iPSC-derived cardiomyocyte 2D and 3D organoid models. Separately, Lee B, Park SJ, Lee S, et al., "Identification of the Antidepressant Vilazodone as an Inhibitor of Inositol Polyphosphate Multikinase by Structure-Based Drug Repositioning," Mol Cells, 2020 (PMID 32209735), confirmed via OpenAlex abstract: structure-based virtual screening identified vilazodone as an inhibitor of inositol polyphosphate multikinase (IPMK), a cellular signaling kinase; docking simulations and in vitro assays confirmed vilazodone's affinity for IPMK's ATP-binding site, and treatment of fibroblasts and cancer cells with vilazodone reduced highly phosphorylated inositol phosphate levels and decreased Akt phosphorylation.

Mechanism

For the class-extrapolated finding: impaired mitochondrial oxidative phosphorylation at supratherapeutic concentration, the same underlying mechanism as Mitochondrial burden (see Overlap map). For the vilazodone-specific IPMK finding: vilazodone occupies the ATP-binding catalytic pocket of a signaling kinase unrelated to mitochondrial energy metabolism; this is an off-target pharmacological interaction affecting inositol-phosphate and Akt signaling, not a measurement of cellular or mitochondrial ATP levels, and it is not evidence that vilazodone reduces the body's capacity to produce ATP.

Counter-evidence held on record

The IPMK finding is included here for research completeness because it surfaced under an "ATP" search and involves vilazodone specifically, but it must not be read, marketed, or cited as evidence that vilazodone impairs cellular energy production; it describes an unrelated off-target kinase interaction. The class-extrapolated cardiomyocyte finding does not establish an ATP-production deficit at standard adult vilazodone dosing and does not support CoQ10 or other ATP-targeted supplementation, for which no dosing evidence exists in this drug's population. See Overlap map for the source shared with Mitochondrial burden.

Limits on what this shows

• Why no grade: Both conditions for ungraded are met: no Tier B or Tier C evidence was found to support even a yellow grade, and no circulating consumer claim specific to vilazodone and oxygen delivery/hemoglobin/hematocrit was found on the sources checked. This is treated as a genuine evidence gap rather than a purely tooling-limited one, since the searches that did complete returned clean, explicit negative results consistent with the equivalent finding for other SSRIs reviewed in this project's earlier batches.

Channels tried

PubMed search-listing pages, two separately phrased queries: (1) "vilazodone AND (hemoglobin OR hematocrit OR anemia)" combined with OR logic, which returned an over-broad, unusable result set; (2) "vilazodone hematologic," a cleaner single-concept phrasing, which PubMed's own interface explicitly reported as "not found" beyond unrelated viral-interleukin hematologic-malignancy papers matching a text fragment. Also reviewed: FDA label Warnings and Precautions and Adverse Reactions sections (Step 1) for any hematologic parameter or oxygenation signal; consumer sources (Drugs.com, a representative drug-nutrient-depletion consumer site) for any circulating oxygen/energy claim.

Outcome

No hematologic or oxygen-delivery adverse reaction is listed in the FDA label's most common adverse reactions (diarrhea, nausea, vomiting, insomnia) or elsewhere in the sections reviewed. Both completed PubMed searches returned genuine negative results with no relevant hits for vilazodone specifically or for the broader antidepressant class in this context.