Clomipramine

Limits on what this shows

• Key negative/null findings: No human mitochondrial-function study in clomipramine-treated patients was located in either direction. The Bizerra 2023 concentrations (50 to 300 micromolar) are roughly one to two orders of magnitude above the low-single-digit-micromolar range typically cited in therapeutic drug monitoring literature for combined clomipramine plus desmethylclomipramine plasma levels (commonly reported in the 150 to 500 ng/mL range, on the order of 0.5 to 1.5 micromolar combined); this is an acute toxicology and overdose-relevant model, not evidence of harm at ordinary therapeutic exposure, and is stated as such rather than left implicit.
• At-risk subgroups: Overdose or supratherapeutic-exposure patients, per the concentration range used in Bizerra 2023; the label's own overdose section separately warns that tricyclic toxicity can produce "decreased ATP production, severe hypoglycemia, and potentially fatal outcomes," consistent in direction with this entry though not sourced from the same paper.
• Counter-evidence on record: None identified contradicting the direction found; no study located found clomipramine protecting or preserving mitochondrial function in normal tissue, unlike the reverse-direction finding documented for nortriptyline.

Regulatory status

Not addressed in the FDA label.

Population evidence

Bizerra PFV, Itou da Silva FS, Gilglioni EH, et al, "The harmful acute effects of clomipramine in the rat liver: Impairments in mitochondrial bioenergetics," Toxicology Letters, 2023, DOI 10.1016/j.toxlet.2023.05.008 (Tier B, isolated perfused rat liver, isolated primary hepatocytes, and isolated mitochondria, male Wistar rats, clomipramine 50 to 300 micromolar). Clomipramine dose-dependently decreased oxygen consumption (IC50 45.21 to 102.34 micromolar depending on substrate), inhibited State III respiration by up to 95.07 percent, lowered the respiratory control ratio and ADP/O ratio, decreased mitochondrial membrane potential in glutamate- and succinate-energized mitochondria, inhibited NADH oxidase (IC50 74.37 micromolar) and succinate oxidase (IC50 171.19 micromolar) activity, reduced Complex IV (cytochrome c oxidase) activity, impaired inner-membrane integrity, and increased calcium efflux while preventing calcium influx; enzyme leakage (AST, ALT, LDH, fumarase) rose up to 32-fold and cell viability fell markedly. Labra-Ruiz NA, Mendoza-Torreblanca JG, Osnaya-Brizuela N, et al, "Clomipramine Induced Oxidative Stress and Morphological Alterations in the Prefrontal Cortex and Limbic System of Neonatal Rats," Brain Sciences, 2025, PMC12564439 (Tier B, male Wistar rats, clomipramine 15 mg/kg subcutaneously twice daily from postnatal days 5 to 35, biochemistry n=8/group, histology n=2/group, assessed at postnatal days 55 and 85). The authors state clomipramine "is recognized as a compound that obstructs mitochondrial function," citing prior hepatocyte work (consistent with Bizerra 2023 above), and report progressive neuronal degeneration, pyknotic nuclei, and tissue disorganization on histology in both brain regions studied.

Mechanism

Direct impairment of the mitochondrial electron transport chain (Complex IV and NADH/succinate oxidase inhibition), uncoupling of oxidative phosphorylation, and impaired inner-membrane calcium handling, named explicitly in Bizerra 2023; the Labra-Ruiz 2025 findings are consistent with, though do not independently establish, the same mechanism in brain tissue.

Counter-evidence held on record

The Bizerra 2023 concentrations are supraphysiological, roughly one to two orders of magnitude above typical therapeutic plasma levels, and the Labra-Ruiz 2025 dose is a high subchronic developmental-exposure regimen in neonatal animals; neither should be presented as evidence of mitochondrial harm at ordinary adult therapeutic dosing in humans. This entry shares its evidentiary core with ATP production and, partly, with Oxidative stress and Coenzyme Q10 below; see the Overlap map.

Limits on what this shows

• Key negative/null findings: No human oxidative-stress-marker study in clomipramine-treated patients was located in this review. The GSH/GSSG ratio did not change significantly in prefrontal cortex in Labra-Ruiz 2025 despite both GSH and GSSG individually shifting, a genuine null result recorded rather than omitted.
• At-risk subgroups: Not established in humans; all evidence identified is preclinical, and the Othman 2019 dose (75 mg/kg in rats) and Labra-Ruiz 2025 regimen are both well above typical human therapeutic weight-adjusted dosing.
• Counter-evidence on record: None identified contradicting the harmful direction found; all three drug-specific sources located agree in direction.

Regulatory status

Not addressed in the FDA label.

Population evidence

Labra-Ruiz 2025 (PMC12564439, Tier B, detailed under Mitochondrial burden) found reduced glutathione (GSH) significantly decreased in prefrontal cortex at both postnatal day 55 (1.25-fold) and day 85 (1.4-fold), and in limbic tissue at day 85 (1.7-fold); oxidized glutathione (GSSG) rose significantly in both regions at both time points (up to 2.3-fold); the GSH/GSSG ratio fell significantly in limbic tissue at both time points; and malondialdehyde (MDA), a lipid peroxidation marker, rose significantly in prefrontal cortex at both time points (up to 2.58-fold) and in limbic tissue at day 85 (1.57-fold). Othman H, Ammari M, Lassoued A, Sakly M, Abdelmelek H, "Zinc improves clomipramine effects on depressive and locomotor behavior and reverses its oxidative stress in rats," Behavioural Brain Research, 2019, DOI 10.1016/j.bbr.2019.112122, PMID 31376442 (Tier B, male Wistar rats, n=6/group across 4 groups, clomipramine 75 mg/kg for 6 days). Clomipramine alone increased hydrogen peroxide concentration in the liver and decreased superoxide dismutase (SOD) activity in the frontal cortex; co-administered zinc (30 mg/kg) reversed clomipramine's liver oxidative stress. El-Demerdash E, "Does oxidative stress contribute in tricyclic antidepressants-induced cardiotoxicity?," Toxicology Letters, 2004, PMID 15302097, DOI 10.1016/j.toxlet.2004.04.041 (Tier B; clomipramine confirmed as one of the tricyclic agents specifically tested). The study measured lipid peroxidation, glutathione, and antioxidant enzyme activity (SOD, catalase, glutathione peroxidase) and used deferoxamine and dimethyl sulfoxide as mechanistic probes; the specific quantitative direction and magnitude of clomipramine's own results could not be retrieved during this review despite confirming the drug's inclusion in the cohort (see Sources, access note).

Mechanism

Consistent with the Complex IV and electron-transport-chain inhibition documented under Mitochondrial burden, which would be expected to increase electron leakage and reactive oxygen species generation; the Othman 2019 zinc-reversal finding is consistent with zinc's established antioxidant-enzyme-cofactor role rather than establishing a new mechanism of its own.

Counter-evidence held on record

This is preclinical, high-dose animal data; it must never be presented as a confirmed human oxidative-stress effect at therapeutic dosing, and the Othman 2019 zinc-reversal finding must never be read as evidence that clomipramine depletes endogenous zinc, since the study did not measure clomipramine's effect on zinc status itself (see the Fails verification section for the related zinc-depletion claim rebuttal). This entry shares its evidentiary core with Mitochondrial burden above; see the Overlap map.

Limits on what this shows

• Key negative/null findings: No human or animal study measuring clomipramine's effect on copper status in either direction was located. No absorption-interference, chelation, or renal-wasting mechanism connecting clomipramine to copper status is documented in the FDA label or in any source located.
• At-risk subgroups: Cannot be specified; no direct human or animal copper measurement exists for this drug.
• Counter-evidence on record: None identified contradicting the mechanistic-adjacency finding. This entry is explicitly labeled as mechanistic inference, per Hard Rule 6, rather than presented as direct evidence.

Regulatory status

Not addressed in the FDA label.

Population evidence

No clomipramine-specific copper measurement study was located despite a dedicated fresh multi-channel search in this revision pass, detailed in the Sources access note. What was located is Bizerra 2023 (Toxicology Letters, DOI 10.1016/j.toxlet.2023.05.008, Tier B, detailed under Mitochondrial burden and ATP production), which found clomipramine reduced Complex IV (cytochrome c oxidase) activity in isolated rat liver mitochondria in a dose-dependent manner at 50 to 300 micromolar. The Linus Pauling Institute's Micronutrient Information Center (Oregon State University) states that cytochrome c oxidase is "the copper-dependent enzyme" whose "redox-active copper contained within the CCO enzyme complex is required for the electron transfer reactions that are critical for its function," confirming copper as a structural cofactor of the exact enzyme complex Bizerra 2023 measured inhibition of. A dedicated class-level check of Schlegel-Zawadzka and Nowak 2000 (PMID 10949967, cited in the companion B007 nortriptyline dossier) confirmed it tested citalopram, imipramine, and fluoxetine, not clomipramine, and found chronic treatment did not alter brain copper levels, a null finding for a different TCA class member; this is recorded as background context, not as supporting or contradicting evidence for clomipramine's own mechanistic finding above.

Mechanism

Indirect: mechanistic adjacency to copper's structural cofactor role in cytochrome c oxidase, inferred from clomipramine's own documented Complex IV inhibition. This is drug-specific mechanistic plausibility (Tier B), since Bizerra 2023 tested clomipramine directly, not class extrapolation; it is not itself a copper measurement and must not be presented as one, exactly parallel to how the Coenzyme Q10 entry above is graded.

Counter-evidence held on record

Do not present this as confirmed copper depletion; no source located measured clomipramine's effect on copper status in either direction, and enzyme-activity inhibition in an isolated-mitochondria assay is not evidence of altered whole-body copper status. This entry shares its mechanistic basis with Mitochondrial burden, ATP production, and Coenzyme Q10 above; see the Overlap map.

Limits on what this shows

• Key negative/null findings: No human or animal study measuring clomipramine's effect on serum iron, ferritin, transferrin, or hemoglobin-linked iron parameters was located. The Hoque 2010 exclusion criterion is itself the clearest negative finding available for the RLS-iron narrative specifically. The FDA label's hematologic adverse-reaction list (leukopenia, agranulocytosis, thrombocytopenia, anemia, pancytopenia; see Oxygen delivery/utilization above) does not attribute any hematologic finding to iron status specifically.
• At-risk subgroups: Cannot be specified for the mechanistic finding; not established for RLS beyond what Hoque 2010 reports.
• Counter-evidence on record: Hoque 2010 is itself counter-evidence to a popular iron-deficiency explanation of clomipramine-associated RLS (see Fails verification). No counter-evidence was located against the Complex I/II mechanistic-adjacency finding.

Regulatory status

Not addressed in the FDA label.

Population evidence

Bizerra 2023 (Toxicology Letters, DOI 10.1016/j.toxlet.2023.05.008, Tier B, detailed under Mitochondrial burden and ATP production) found clomipramine inhibited NADH oxidase activity (IC50 74.37 micromolar) and succinate oxidase activity (IC50 171.19 micromolar) in isolated rat liver mitochondria. The Linus Pauling Institute's Micronutrient Information Center confirms iron-sulfur cluster proteins, including succinate dehydrogenase and NADH dehydrogenase, carry out electron-transport oxidoreductase activity central to energy production, and that cytochromes (iron-containing) serve as electron carriers in ATP synthesis, establishing iron as a structural cofactor of the same Complex I/Complex II pathway Bizerra 2023 measured inhibition of. Separately, Hoque R, Chesson AL, "Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia," Journal of Clinical Sleep Medicine, 2010, PMID 20191944 (Tier B, structured literature review and qualitative scoring across 32 articles), identified clomipramine as demonstrating "the strongest available drug-induced RLS" evidence among the drugs assessed. Critically, the review's own scoring methodology required "exclusion of low serum ferritin" as a criterion for counting a case as drug-induced, meaning the cases supporting clomipramine's RLS association were specifically those where iron deficiency had been ruled out as the explanation.

Mechanism

Indirect: mechanistic adjacency to iron's structural role in the iron-sulfur clusters of Complex I and Complex II, inferred from clomipramine's own documented NADH oxidase and succinate oxidase inhibition. This is drug-specific mechanistic plausibility (Tier B), since Bizerra 2023 tested clomipramine directly, not class extrapolation; it is not itself an iron measurement and must not be presented as one. The RLS finding is a separate, disclosed counter-finding against an iron-deficiency explanation for that specific clinical outcome, not a supporting mechanism for this entry.

Counter-evidence held on record

Do not present this as confirmed iron depletion; no source located measured clomipramine's effect on iron status in either direction, and enzyme-activity inhibition in an isolated-mitochondria assay is not evidence of altered whole-body iron status. Never present the RLS finding as clomipramine causing iron deficiency; per the Hoque 2010 exclusion criterion, the association runs independent of ferritin status. This entry shares its mechanistic basis with Mitochondrial burden and ATP production above; see the Overlap map.

Limits on what this shows

• Why no grade: Both conditions for ungraded are met, with a disclosed access limitation reconfirmed on a dedicated fresh pass. Multiple PubMed search-listing attempts combining clomipramine with gut microbiome, microbiota, and gut bacteria terms across the original review; the ones that returned readable results found no clomipramine-specific microbiome study. A review specifically covering psychotropic drugs and the microbiome, Cussotto S et al (inferred author set), "Psychotropics and the Microbiome: a Chamber of Secrets," Psychopharmacology, DOI 10.1007/s00213-019-5185-8, was retrieved via OpenAlex per-DOI lookup; its abstract states the review covers antidepressants generally but does not name clomipramine or tricyclic antidepressants specifically in the retrievable abstract text. Maier L, Pruteanu M, Kuhn M, et al, "Extensive impact of non-antibiotic drugs on human gut bacteria," Nature, 2018, DOI 10.1038/nature25979, PMID 29555994, screened more than 1,000 marketed drugs against 40 gut bacterial strains and found antipsychotics, a chemically diverse class, overrepresented among growth-inhibiting drugs; the openly accessible abstract and results text on nature.com names only a handful of example drugs (metformin, posaconazole, moricizine, meclofenamic acid, diacerein, and others) and does not include or exclude clomipramine, and the complete compound list lives only in a supplementary table that this revision pass again could not reach (see tooling disclosure), the same access gap disclosed in the companion B007 nortriptyline dossier for this identical source. On this revision pass, a ResearchGate search, the one channel that returned genuine readable results for this category, found no clomipramine-specific gut microbiome or antimicrobial-activity publication in its index; this is treated as additional, though not exhaustive, support for a real literature gap rather than a purely tooling-limited one.

Tooling disclosure

This revision pass made a dedicated, multi-channel attempt to reach the Maier et al 2018 supplementary compound list specifically: PMC (both www.ncbi.nlm.nih.gov, which redirected to pmc.ncbi.nlm.nih.gov, and that page directly) served a bot-verification challenge on every attempt; Nature's own article page at nature.com was reachable and confirmed clomipramine is not named in the main text, but its Supplementary Table 1 link resolves to an anchor (#MOESM1) with no retrievable href, and the underlying static-content.springer.com file host is disallowed by robots.txt for this tool; Unpaywall's API returned a green-open-access record pointing back to the same blocked PMC URL; the Europe PMC REST API, OpenAlex's search endpoint, the Crossref API, the Semantic Scholar API, and NCBI eutils were all rejected, and this pass independently confirmed via direct inspection of the proxy's own connection log (not just tool-level error text) that pubmed.ncbi.nlm.nih.gov, eutils.ncbi.nlm.nih.gov, api.crossref.org, www.ebi.ac.uk, api.openalex.org, api.semanticscholar.org, and api.unpaywall.org's underlying host are all subject to organization-level HTTP 403 policy denials at the network gateway, confirming these are persistent, environment-level blocks rather than transient rate limits or single-attempt failures. Google, Bing, Google Scholar, DuckDuckGo (both html. and lite. endpoints), and BASE (base-search.net) were each blocked by robots.txt or an active bot-challenge on this pass. ResearchGate was the one channel that returned genuine, readable content in this revision pass, including a rate-limited (HTTP 429) attempt specifically on the Maier et al 2018 paper's own ResearchGate page, which could not be retried successfully within this pass's pacing. Because the core zero-relevance findings across PubMed (original pass) and ResearchGate (this pass) came from genuinely readable result sets, this is treated as a real, though not exhaustively confirmed, literature gap for clomipramine specifically, not as reassurance that no effect exists. A future revision with working access to PMC full text, the Europe PMC REST API, or the Maier et al 2018 supplementary compound list should re-check this specific question directly.

Limits on what this shows

• Key negative/null findings: No incidence or frequency data accompanies the label's postmarketing listing, which by design captures spontaneous reports rather than a denominator-based rate; this is itself the boundary that caps this entry at orange rather than red. No controlled human study measuring hemoglobin, hematocrit, or red-cell mass in a clomipramine-exposed cohort versus a comparator was located in this review.
• At-risk subgroups: Patients with pre-existing autoimmune disease (as in the reported case) may carry a higher risk of an immune-mediated marrow effect; this is not established as generalizable beyond the single case reported. Any patient developing unexplained fever, sore throat, pallor, or fatigue during treatment falls within the label's own monitoring guidance.
• Counter-evidence on record: No source located found a dose-dependent or high-frequency anemia signal for clomipramine in controlled trials; the label's own Adverse Reactions section frequency tables from placebo-controlled trials (not fully reproduced here) list this only under rare postmarketing reports rather than trial-observed frequencies, consistent with a true rare-event profile rather than a common one.

Regulatory status

FDA label, Adverse Reactions, Postmarketing section: "There have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with Anafranil use." The label recommends obtaining leukocyte and differential blood counts in patients who develop fever and sore throat during treatment, but gives no incidence estimate and does not mandate routine CBC monitoring.

Population evidence

Sato T, Kogawa K, Hirayama Y, et al, "Pure red cell aplasia induced by clomipramine hydrochloride in a patient with SLE," Rinsho Ketsueki (Japanese Journal of Clinical Hematology), 2000, PMID 11020992 (Tier B, single human case report). A 48-year-old woman with systemic lupus erythematosus developed normochromic normocytic anemia with a low reticulocyte count and erythroid hypoplasia without involvement of other cell lines (pure red cell aplasia) following clomipramine treatment; the anemia gradually resolved after the drug was withdrawn. The authors state this was the first published report of clomipramine causing this specific effect, and note the concurrent SLE diagnosis raised the possibility of an immunologically mediated mechanism rather than direct marrow toxicity.

Mechanism

Bone-marrow suppression or an immune-mediated erythroid-precursor-specific process, as suggested by the case report's SLE context; not a nutrient-cofactor mechanism. No study located measured iron, B12, or folate status in either the postmarketing reports or the case report, and none is implicated by the mechanism proposed.

Counter-evidence held on record

Never present this as clomipramine causing iron, B12, or folate deficiency; per Hard Rule 2, anemia is not itself evidence of a nutrient deficiency, and no source located ties this specific adverse effect to nutrient status. Never suggest iron, B12, or folate supplementation as a response to this entry; the appropriate response to unexplained anemia on clomipramine is clinical evaluation and, per the case report, potential drug withdrawal, not nutrient repletion.

Limits on what this shows

• Key negative/null findings: No human ATP-measurement study in clomipramine-treated patients was located. No study located found ATP levels preserved or increased by clomipramine at any concentration tested.
• At-risk subgroups: Overdose or supratherapeutic-exposure patients, consistent with the concentration range used and the label's own overdose-section language linking tricyclic toxicity to decreased ATP production and hypoglycemia.
• Counter-evidence on record: None identified; this is the single most direct and quantitatively detailed source located in this entire review, but it remains one paper, one laboratory, and entirely ex vivo/in vitro.

Regulatory status

Not addressed in the FDA label, though the label's own Overdosage section separately warns that tricyclic toxicity may cause "decreased ATP production, severe hypoglycemia, and potentially fatal outcomes," a directionally consistent statement not sourced from the Bizerra 2023 paper itself.

Population evidence

Bizerra 2023 (Toxicology Letters, DOI 10.1016/j.toxlet.2023.05.008, Tier B, detailed under Mitochondrial burden) directly measured ATP levels, finding them reduced 41.57 to 55.29 percent in perfused rat livers exposed to clomipramine; the ATP/ADP ratio and ATP/AMP ratio both fell significantly (the latter by 71.21 to 80.30 percent), and direct ATP synthesis/generation was reduced 82.24 to 84.75 percent at 300 micromolar. Intact-coupled ATPase activity rose 148.14 percent at 100 micromolar before falling at higher concentrations, while uncoupled/disrupted ATPase activity was inhibited up to 88.03 percent; the authors describe this pattern as consistent with F0F1-ATP synthase inhibition combined with oxidative-phosphorylation uncoupling. Gluconeogenesis (IC50 36.87 to 43.38 micromolar) and ureagenesis (IC50 59.64 micromolar) were both inhibited, energy-dependent hepatic processes consistent with impaired ATP availability.

Mechanism

Direct inhibition of the F0F1-ATP synthase complex and uncoupling of oxidative phosphorylation, named explicitly by the study's authors, who state clomipramine demonstrates "at least three distinct mechanisms of action, including uncoupling of oxidative phosphorylation, inhibition of the FoF1-ATP synthase complex, and inhibition of mitochondrial electron flow."

Counter-evidence held on record

This entry shares its entire evidentiary basis with Mitochondrial burden above; see the Overlap map. The concentrations tested (50 to 300 micromolar) are roughly one to two orders of magnitude above typical combined clomipramine-plus-metabolite therapeutic plasma levels, and this must never be presented as a confirmed effect on ATP production at ordinary therapeutic dosing.