Vortioxetine

Limits on what this shows

• Null/negative findings: No study found measuring mitochondrial complex activity in normal adult human tissue at standard clinical vortioxetine exposure; the only inhibitory findings required concentrations well above the paper's own stated clinical plasma range.
• At-risk subgroups: None established for standard adult dosing. The supratherapeutic inhibition findings would be most relevant to overdose scenarios, not routine treatment.

Regulatory status

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

Population evidence

Luptak M, Fisar Z, Hroudova J. Agomelatine, Ketamine and Vortioxetine Attenuate Energy Cell Metabolism, In Vitro Study. Int J Mol Sci. 2022;23(22):13824. PMID 36430306. In vitro, isolated pig brain (cortex) mitochondria, vortioxetine tested at 5 to 100 microM against a stated clinical plasma range of tenths to units of microM. Complex I activity fell to 5.5% +/- 1.8% of control at 100 microM (P<0.001); complex I-linked respiration was fully inhibited (IC50 10.5 +/- 2.3 microM); complex II+III activity fell to 43.9% +/- 1.2% at 100 microM (P<0.001); complex IV activity fell to 9.3% +/- 3.8% at 100 microM (P<0.001). The authors describe vortioxetine as the most potent inhibitor of all four complexes among the three drugs tested (agomelatine, ketamine, vortioxetine), at concentrations the paper itself frames as simulating overdose rather than therapeutic exposure. Chen F, Danladi J, Ardalan M, Elfving B, Muller HK, Wegener G, Sanchez C, Nyengaard JR. A Critical Role of Mitochondria in BDNF-Associated Synaptic Plasticity After One-Week Vortioxetine Treatment. Int J Neuropsychopharmacol. 2018;21(6):603-615. PMID 29514282. In vivo rat hippocampus, one week of dosing at pharmacologically relevant levels for vortioxetine and fluoxetine: vortioxetine significantly increased mitochondria and synapse counts in hippocampal CA1 by electron microscopy, while fluoxetine had no effect; BDNF levels were significantly higher in DG and CA1, with a significant positive correlation between BDNF and mitochondria/synapse numbers. Supporting Tier B context: a 2025 rat study of 3-nitropropionic-acid-induced Huntington's-disease-like pathology (Journal of Advanced Zoology, DOI 10.53555/jaz.v46i1.5097, a lesser-indexed journal, findings not independently replicated) reported that vortioxetine 5 and 10 mg/kg preserved striatal mitochondrial complex I, II, and IV expression against the toxin's damage.

Mechanism

Direct inhibition of electron transport chain complexes at high in vitro concentration (Luptak/Fisar/Hroudova); a separate, protective, biogenesis-linked mechanism at pharmacologically relevant exposure tied to BDNF signaling (Chen et al). Concentration- and context-dependent, not a single consistent direction.

Counter-evidence held on record

The inhibitory findings required concentrations well above typical clinical plasma levels and should not be read as evidence of mitochondrial harm at standard adult therapeutic dosing; the pharmacologically-relevant-dose findings point the opposite direction. This entry should not be read as a basis for CoQ10 or other mitochondrial-support supplementation, for which no dosing evidence exists in this drug's population. See Overlap map: the Luptak/Fisar/Hroudova source is shared with the ATP production entry, and the 3-NPA study is shared with the Oxidative stress entry.

Limits on what this shows

• Null/negative findings: Gpx1 rescue in the Caruso 2021 model held at the gene but not the protein level, a partial null worth preserving. No study found any oxidative-stress-increasing (pro-oxidant) direction for vortioxetine at pharmacologically relevant dosing in any model reviewed.
• At-risk subgroups: None established in humans; all direct evidence is animal or in vitro.

Regulatory status

Not addressed in FDA labeling.

Population evidence

Caruso G, Grasso M, Fidilio A, Torrisi SA, Musso N, Geraci F, Tropea MR, Privitera A, Tascedda F, Puzzo D, Salomone S, Drago F, Leggio GM, Caraci F. Antioxidant Activity of Fluoxetine and Vortioxetine in a Non-Transgenic Animal Model of Alzheimer's Disease. Front Pharmacol. 2021;12:809541. PMID 35002742. In vivo, C57BL/6 mice given intracerebroventricular amyloid-beta oligomers, vortioxetine 5 and 10 mg/kg/day intraperitoneally for 24 days starting 7 days before amyloid-beta injection. Amyloid-beta significantly increased iNOS and Nox2 (pro-oxidant) expression; vortioxetine at 5 to 10 mg/kg completely counteracted this over-expression (P<0.001). Amyloid-beta decreased Gpx1 (antioxidant enzyme) mRNA (P<0.05); vortioxetine rescued gene-level but not protein-level expression. In cultured neurons, vortioxetine 1 microM prevented amyloid-beta toxicity comparably to fluoxetine. 3-NPA Huntington's-disease rat model (Journal of Advanced Zoology, 2025, DOI 10.53555/jaz.v46i1.5097, lesser-indexed journal): vortioxetine 5 and 10 mg/kg reduced oxidative and nitrosative stress markers alongside preserving mitochondrial complex expression (shared source with Mitochondrial burden, see Overlap map). Magnesium-potentiation exercise-stress study (Medicina, 2022, PMID 36295524, DOI 10.3390/medicina58101363): vortioxetine 20 mg/kg alone (without added magnesium) reduced malondialdehyde and increased SOD and GPx activity in Wistar rats relative to control, alongside a significant glycemia decrease (P<0.05) and BDNF increase (P<0.01); combining vortioxetine with magnesium chloride produced a larger effect, but the study tested magnesium as a potentiating co-treatment, not as a nutrient depleted by vortioxetine, so it does not support a magnesium classical-nutrient entry in this dossier.

Mechanism

Not established at the systemic or human level. Proposed mechanism across the animal literature is suppression of pro-oxidant enzyme induction (iNOS, Nox2) combined with support of endogenous antioxidant enzymes (Gpx1, SOD), consistent across three unrelated toxicity/stress models.

Counter-evidence held on record

All evidence is animal or in vitro; no human oxidative-stress marker data exist for vortioxetine. Consistent protective direction across models is notable but does not establish a clinical antioxidant benefit, and this entry does not support antioxidant supplementation, for which no dosing evidence exists in this drug's population. See Overlap map for sources shared with Mitochondrial burden.

Limits on what this shows

• Null/negative findings: Brain copper (hippocampus and cerebellum) was unaffected by either citalopram or imipramine in the source study, a partial null worth preserving alongside the serum finding. The only vortioxetine-specific copper-adjacent source found anywhere in this review, a 2026 paper using the cuprizone copper-chelation toxin model to study vortioxetine's anti-inflammatory effect on demyelination (PMID 42126609), does not measure vortioxetine's own effect on copper status: it uses copper chelation as a disease-modeling tool, not as an endpoint. Re-verified in this revision via OpenAlex and Unpaywall, this paper remains fully closed-access with no repository or green-OA copy anywhere, so its full text still could not be checked for any secondary copper-status data; it is treated as neither supporting nor contradicting evidence.
• At-risk subgroups: None established. The source population is adult rats; no vortioxetine human or animal copper data of any kind exist to define an at-risk human subgroup.

Regulatory status

Not addressed in FDA labeling; no copper interaction or monitoring language in the label.

Population evidence

Schlegel-Zawadzka M, Nowak G. Alterations in Serum and Brain Trace Element Levels After Antidepressant Treatment. Part II. Copper. Biol Trace Elem Res. 2000;73(1):37-46. DOI 10.1385/BTER:73:1:37. In vivo rat study, the copper installment of a three-part trace-element series from the same laboratory (Part I, 1999, zinc; Part III, 2000, magnesium, published separately in Human Psychopharmacology). Chronic citalopram and chronic imipramine were each compared against untreated controls and against electroconvulsive shock (ECS). Citalopram and imipramine (but not ECS) significantly decreased serum copper by approximately 14 percent; neither drug altered brain copper in hippocampus or cerebellum. ECS produced the opposite pattern, no serum copper change but a significant brain copper increase (36 percent hippocampus, 16 percent cerebellum), which the authors read as evidence that copper's involvement in ECS's action differs mechanistically from its involvement in the two drugs' action. Vortioxetine was approved in 2013, thirteen years after this study, and could not have been in the cohort; this is Tier C class-level evidence, not drug-specific data, and is extrapolated here only because citalopram shares vortioxetine's core serotonin-reuptake-inhibition mechanism, per this project's allowance for a defensible, clearly-labeled multimodal-antidepressant-class extrapolation.

Mechanism

Not established for vortioxetine, and not directly tested even in the source paper. Ceruloplasmin, the major serum copper-carrying protein and an acute-phase reactant, is one plausible pathway for a serotonergic-drug-associated serum copper change, but the source study did not measure it. The extrapolation to vortioxetine rests solely on the serotonin-transporter-inhibition mechanism it shares with citalopram; vortioxetine's additional receptor-level activity (5-HT1A, 5-HT1B, 5-HT3, 5-HT7, 5-HT1D antagonism/agonism) has no counterpart in citalopram and is not covered by this extrapolation.

Counter-evidence held on record

This is a Tier C class-level extrapolation from citalopram and imipramine in rats, not a vortioxetine-specific finding; vortioxetine itself has never been studied for its effect on copper status in any species. A roughly 14 percent serum copper reduction in rats does not establish a clinical copper-deficiency risk in humans taking vortioxetine, and no copper dosing recommendation follows from this entry, for which no dosing evidence exists in this drug's population regardless.

Limits on what this shows

• Why no grade: Both conditions for ungraded are met, now on stronger evidence than the prior review: no Tier B or Tier C evidence was found, across five independently phrased completed queries and a check of the one relevant existing research series, to support even a yellow grade, and no circulating consumer claim specific to vortioxetine and iron/hemoglobin/ferritin was found on the sources checked. The mechanism screen (Step 1/2) also found no chelation, gastric-pH, or renal-wasting pathway by which vortioxetine would plausibly alter iron status. This is disclosed as a genuine literature gap, with the PubMed/Europe PMC/Semantic Scholar channels specifically disclosed as blocked by network policy rather than as completed negatives.

Channels tried

This revision re-ran the full channel list with a dedicated research budget. Crossref bibliographic API, four separate completed queries with varied phrasing: "vortioxetine iron deficiency" (5 results, none vortioxetine-related), "vortioxetine anemia hemoglobin hematocrit" (10 results, none vortioxetine-related), "SSRI antidepressant serum iron ferritin rat" (10 results, none about antidepressants and iron at all), and "citalopram fluoxetine serum iron level rat" (8 results, none measuring iron in relation to any SSRI). A fifth query, targeting a possible companion paper to the drug/copper study below, confirmed the known Schlegel-Zawadzka/Nowak three-part antidepressant trace-element series covers only zinc (Part I, 1999), copper (Part II, 2000), and magnesium (Part III, 2000); no iron installment exists in that series. OpenAlex per-record lookups (single-DOI/PMID) succeeded when tried, but the OpenAlex search endpoint itself returned repeated HTTP 503 errors and could not be used for a fresh iron query. PubMed search-listing pages, PubMed's own eutils API, and the Europe PMC REST API were all confirmed blocked at the network-proxy level with an explicit "organization policy" CONNECT rejection (verified directly via command-line diagnostics against the proxy, not merely a slow or bot-gated response), consistent with an organization-level access policy rather than a transient rate limit. The Semantic Scholar Graph API returned HTTP 429/403 on every attempt. Google Scholar, Bing, and DuckDuckGo's HTML search endpoints were all disallowed by robots.txt for automated fetching, and the general WebSearch tool had exhausted its session budget before this category's research began. DailyMed/FDA label: no iron-related language anywhere in the vortioxetine label (already established in Step 1). Consumer sources re-checked: Drugs.com, RxList, the Blackmores Institute guide, and a "drug mugging"-style consumer source; none mention vortioxetine and iron.

Outcome

Every channel that returned a completed result this revision was a clean negative; no source, at any tier, connects vortioxetine, or any serotonergic antidepressant tested for comparison, to iron, ferritin, transferrin, hemoglobin, or hematocrit. This strengthens rather than weakens the prior finding: the completed Crossref channel alone returned a clean negative in the original review, and four independently phrased Crossref queries plus a targeted check of the one antidepressant-trace-element research series that does exist (which covers zinc, copper, and magnesium but never iron) now support the same conclusion from multiple angles. The channels that remain blocked (PubMed, Europe PMC, Semantic Scholar) are disclosed as a confirmed organization-level proxy policy denial in this revision, not merely unresolved rate limiting, so a future revision should not expect a different outcome from retrying those same hosts without a policy change.

Limits on what this shows

• Null/negative findings: Neither study found a significant overall diversity difference attributable to vortioxetine (Ye 2021: P>0.05 for diversity indices pre/post; Lin 2025: no significant diversity difference across the three groups), a partial null worth preserving alongside the compositional findings. The specific genera reported as altered do not overlap meaningfully between the two studies.
• At-risk subgroups: None established; both studies are in adults with major depressive disorder, so findings should not be generalized to other indications.

Regulatory status

Not addressed in FDA labeling.

Population evidence

Ye X, Wang D, Zhu H, Wang D, Li J, Tang Y, Wu J. Gut Microbiota Changes in Patients With Major Depressive Disorder Treated With Vortioxetine. Front Psychiatry. 2021;12:641491. PMID 34025474. Longitudinal observational cohort, 26 MDD patients (10 mg/day for 8 weeks) versus 28 healthy controls, fecal sampling at baseline, 4, and 8 weeks. MDD patients had higher baseline alpha diversity than controls (P<0.05); treatment did not significantly alter diversity indices (P>0.05). Post-treatment, Firmicutes increased and Bacteroidetes decreased; Firmicutes abundance correlated positively with clinical improvement. Lin SKK, Chen HC, Chen CH, Chung YCE, Chen IM, Lu ML, Hsu CD, Chiu YH, Wang TY, Liu CM, Huang MC, Wu SI, Kuo PH. Investigation of gut microbiota composition alterations in depressive patients prescribed with vortioxetine. Int J Neuropsychopharmacol. 2025;28(Suppl 1):i313 (conference abstract, CINP 2024), with a fuller manuscript at PMC11814665 (full text access-limited for this review, see Sources). Cross-sectional comparison, 211 depressive patients (fecal DNA analyzed from 271 total participants across a vortioxetine group, an SSRI group, and an untreated group) from northern Taiwan hospitals. Versus untreated patients, vortioxetine users showed decreased Ruminococcus, Turicibacter, Enterorhabdus, and Lachnospira, and increased Eggerthella, Gemella, Gordonibacter, and Eubacterium; versus SSRI users, three genera decreased and one (Gemella) increased. Eggerthella abundance correlated negatively with depression severity (r=-0.44, P=0.04). No significant between-group difference in overall microbial diversity.

Mechanism

Not fully characterized. Serotonin signaling has documented roles in gut motility, mucosal immune function, and bacterial gene expression, offering biological plausibility, but neither human study isolates a vortioxetine-specific mechanism from the effect of depression itself or from concurrent treatment response.

Counter-evidence held on record

Confounding by indication is presumed until excluded (Hard Rule 6): both studies compare treated depressed patients to controls or to a different drug class, not the same patients before and after treatment against a placebo arm, so the depression itself, illness severity, diet, or treatment response cannot be ruled out as the driver of these compositional differences. Do not read this as an established harm to the gut microbiome, and no probiotic or prebiotic dosing recommendation follows from either study.

Limits on what this shows

• Null/negative findings: N-back accuracy and reaction time did not differ between vortioxetine and placebo groups, which is itself evidence against a functional oxygen-delivery or performance deficit accompanying the BOLD reduction.
• At-risk subgroups: None established. The trial enrolled adults 20 to 53 years old; findings have not been replicated in older adults or in patients with pre-existing cerebrovascular disease.

Regulatory status

Not addressed in FDA labeling.

Population evidence

Smith J, Browning M, Conen S, Smallman R, Buchbjerg J, Larsen KG, Olsen CK, Christensen SR, Dawson GR, Deakin JF, Hawkins P, Morris R, Goodwin G, Harmer CJ. Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls. Mol Psychiatry. 2018;23(5):1127-1133. DOI 10.1038/mp.2017.104. Randomized, double-blind, placebo-controlled, parallel-group trial, n=96 (48 remitted depressed patients, 48 healthy controls), vortioxetine 20 mg/day for 13-14 days versus placebo. Vortioxetine reduced task-related activation in the right dorsolateral prefrontal cortex, left hippocampus, right insula, fusiform gyrus, and lingual gyri (cluster-corrected P<0.05). N-back behavioral performance did not differ between groups; Trail Making Test-A completion time improved (P=0.01 across groups) and subjective cognitive complaints improved (Perceived Deficits Questionnaire, P=0.02). Supporting Tier B mechanistic context: a one-week rat hippocampal study found vortioxetine, unlike fluoxetine, significantly increased astrocyte and microglia counts and elevated VEGF protein in hippocampal subregions (title and journal confirmed; full author list not independently confirmed for this review, PMID 33199100, see Sources), a vascular-growth-factor signal consistent with a supportive rather than compromising effect on the brain's microvascular bed, though the study did not directly measure oxygen delivery or tissue oxygenation.

Mechanism

The BOLD signal is a proxy for local blood oxygenation coupled to neural activity, not a direct measure of oxygen-carrying capacity, hemoglobin, or tissue hypoxia. A reduction in task-evoked BOLD signal alongside preserved or improved task performance is the classic neuroimaging signature of reduced neural effort for the same cognitive output, which the trial's own authors name explicitly as their interpretation.

Counter-evidence held on record

Per Hard Rule 2, this entry must never be read as evidence that vortioxetine impairs oxygen delivery or causes tissue hypoxia. It reflects the drug's own intended pharmacodynamic effect on neural efficiency, directly comparable to a beta-blocker's intentional reduction in myocardial oxygen demand: a mechanism clarification, not a nutrient-style deficiency. No oxygen-support supplement or intervention follows from this entry.

Limits on what this shows

• Null/negative findings: No ATP change was reported at the lower concentrations tested (5 to 50 microM), all still above typical clinical plasma levels; no data exist at concentrations within the clinical range in either direction.
• At-risk subgroups: None established. As with Mitochondrial burden, the only positive findings occurred at concentrations more relevant to overdose than to routine dosing.

Regulatory status

Not addressed in FDA labeling.

Population evidence

Luptak M, Fisar Z, Hroudova J. Agomelatine, Ketamine and Vortioxetine Attenuate Energy Cell Metabolism, In Vitro Study. Int J Mol Sci. 2022;23(22):13824. PMID 36430306 (same source as Mitochondrial burden; see Overlap map). Isolated pig brain mitochondria, complex-I-linked ATP content increased to 119.0% +/- 10.6% of control at 100 microM vortioxetine (P=0.037), despite complex I activity itself falling to 5.5% of control at the same concentration. Hydrogen peroxide production, a marker of electron-transport-chain stress, increased at 50 microM but fell to 85.4% +/- 5.0% of control at 100 microM (P=0.037), a non-monotonic pattern the paper does not fully explain. All concentrations tested (5 to 100 microM) exceeded the paper's own stated clinical plasma range (tenths to units of microM).

Mechanism

Not established. The dissociation between falling complex I activity and rising ATP content at the same concentration is not mechanistically resolved in the source paper; possible compensatory flux through alternative pathways is not tested directly.

Counter-evidence held on record

This finding runs in the opposite direction from a depletion claim and was measured only at a supratherapeutic, overdose-relevant concentration. It does not establish an ATP-production deficit at standard adult dosing in either direction, and does not support CoQ10 or other ATP-targeted supplementation, for which no dosing evidence exists in this drug's population.