Lurasidone

Limits on what this shows

• Null/negative findings: No clinical, in vivo, human mitochondrial-function marker study in lurasidone-treated patients was located. A separate rat behavioral-stress study (see Oxidative stress entry) found lurasidone protective on redox and antioxidant-enzyme markers at a lower, more clinically comparable dose, though it measured redox markers rather than mitochondrial respiration directly.
• At-risk subgroups: Not established; theoretical only, and dependent on an exposure level not reached with standard clinical dosing.

Regulatory status

Not addressed in the FDA label.

Population evidence

Ľupták M, Fišar Z, Hroudová J. Effect of Novel Antipsychotics on Energy Metabolism: In Vitro Study in Pig Brain Mitochondria. Mol Neurobiol. 2021;58(11):5548-5563 (PMID 34365585). Lurasidone was one of four novel antipsychotics tested (with brexpiprazole, cariprazine, loxapine) at 10 and 100 micromolar in isolated pig brain mitochondria. All four drugs, including lurasidone, dose-dependently inhibited complex I- and complex II-linked respiration and decreased electron-transport-chain complex activities (except complex IV, which increased with brexpiprazole and loxapine, not lurasidone), and all significantly decreased mitochondrial ATP production at the higher concentration.

Mechanism

Direct in vitro disruption of electron-transport-chain complex activity and downstream ATP synthesis at high concentrations; the study does not establish whether this occurs at clinically relevant lurasidone exposure. Typical clinical plasma concentrations of lurasidone are in the low tens of nanomolar range, well below the 10 micromolar lower test concentration used here.

Counter-evidence held on record

The tested concentrations are roughly two to three orders of magnitude above typical clinical plasma exposure. This entry shares its primary source with ATP production and, for the hydrogen-peroxide finding, with Oxidative stress below; see Overlap map, not counted as independent confirmation across entries. Do not interpret this entry as support for mitochondrial-support supplementation such as coenzyme Q10 in patients on standard therapeutic lurasidone dosing; no clinical trial evidence supports this, and the underlying data come from a toxicological exposure range, not therapeutic dosing.

Limits on what this shows

• Null/negative findings: No human clinical oxidative-stress biomarker study in lurasidone-treated patients was located; searches of PubMed and Europe PMC for lurasidone combined with oxidative stress in human cohorts were attempted but partially blocked by session-level rate limiting during this review (see access note).
• At-risk subgroups: Not established in humans.

Regulatory status

Not addressed in the FDA label.

Population evidence

Rossetti AC, Paladini MS, Colombo M, et al. Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone. Int J Neuropsychopharmacol. 2018;21(9):883-893 (PMID 29788232). Adult male Wistar rats (n=10/group), 7-week chronic mild stress protocol, lurasidone 3 mg/kg/day by oral gavage for 5 weeks starting after 2 weeks of stress. Chronic stress increased NOX2 (a pro-oxidant enzyme) by 33 percent (mRNA) and 98 percent (protein) and decreased NRF2 (an antioxidant-pathway regulator) protein by 40 percent; lurasidone attenuated the NOX2 increase, partially restored NRF2, reduced KEAP1 (NRF2's negative regulator) by 48 to 55 percent regardless of stress status, and selectively upregulated the downstream antioxidant enzymes NQO1 (+23 percent) and catalase (+21 percent) in stressed animals. Contrasting direction: Ľupták, Fišar, Hroudová, Mol Neurobiol 2021 (PMID 34365585, same source as Mitochondrial burden above): hydrogen peroxide production was significantly increased in isolated pig brain mitochondria at 10 micromolar lurasidone, a pro-oxidant direction, though at a concentration far above clinical plasma exposure.

Mechanism

The Rossetti dose (3 mg/kg/day in rats) is substantially closer to human-equivalent clinical dosing than the 10 to 100 micromolar in vitro concentrations in the Ľupták study, so the two findings are not directly comparable in exposure terms; taken together they suggest a possible concentration-dependent or model-dependent divergence (in vivo, sub-toxic dosing appears protective on redox-pathway markers; isolated-mitochondria exposure at very high concentration appears pro-oxidant on a single ROS marker) rather than a single consistent human-relevant direction.

Counter-evidence held on record

The two studies directly conflict in direction and neither was replicated by an independent group; the protective study did not measure glutathione or lipid peroxidation directly, and the pro-oxidant study measured only hydrogen peroxide in isolated mitochondria, not a validated in vivo or human redox marker. This entry shares its pro-oxidant-direction source with Mitochondrial burden and ATP production above; see Overlap map. This mixed, model-dependent finding does not support antioxidant supplementation in patients on standard therapeutic lurasidone dosing, and should not be read as either reassurance or alarm.

Limits on what this shows

• Null/negative findings: No cohort study measuring ferritin or serum iron in lurasidone-treated patients was located. PubMed and Europe PMC searches for "lurasidone AND iron" returned no dedicated cohort studies beyond this case report during this review.
• At-risk subgroups: Not established beyond the single reported case; a middle-aged adult male on long-term, higher-range dosing with a concurrent antipsychotic (blonanserin).

Regulatory status

Not addressed in the FDA label; iron status is not a labeled monitoring parameter for lurasidone.

Population evidence

Kirpekar VC et al., Indian J Pharmacol 2019 (PMID 31571715), Case 2: 50-year-old male on lurasidone 40 to 80 mg daily for about 10 months, ferritin 5.10 ng/mL (low) and serum iron 14 microgram/dL (low) measured at the time of severe anemia (hemoglobin 6.6 g/dL). Case 1 in the same report did not have iron studies reported in the retrieved text, only a raised MCV.

Mechanism

Not established as a specific biochemical pathway for lurasidone. The authors note antipsychotics may alter iron metabolism generally; no absorption-interference, chelation, or renal-wasting mechanism is described in lurasidone's own pharmacokinetic profile that would independently predict iron depletion (see PK basis above), so a utilization or inflammation-linked mechanism, as documented for other antipsychotics in pediatric cohorts, is the more plausible but unconfirmed explanation.

Counter-evidence held on record

A single case cannot establish causation or population prevalence, and the concurrent antipsychotic (blonanserin) in this case is a confound the source itself cannot exclude. This entry shares its underlying source with Oxygen delivery/utilization above; see Overlap map, not counted as independent confirmation. Do not supplement iron in a lurasidone-treated patient without a lab-confirmed low ferritin or iron panel. Iron overload carries its own toxicity risk; any repletion dose should be prescriber-directed and kept under the NIH Office of Dietary Supplements tolerable upper intake level for elemental iron (45 mg/day for adults, higher doses not advised without medical supervision). This dossier makes no standing dosing recommendation.

Limits on what this shows

• Why no grade: Both conditions for ungraded status are met: no Tier B or Tier C evidence supports even a yellow grade for lurasidone specifically, and no circulating claim was located naming lurasidone and copper together for this review to rebut as white. The Tier D consumer nutrient-depletion page identified for this drug (revivelifeclinic.com) lists lurasidone under calcium/vitamin D, B1, B2, B6, folate/B12, vitamin A, vitamin C, vitamin K, biotin, and CoQ10 claims, but does not name copper.

Channels tried

PubMed search-listing pages for "lurasidone copper" and "lurasidone AND copper" (zero results, both attempts, not a bot-check page); Europe PMC REST API for lurasidone-related microbiome and homocysteine queries succeeded on other terms during this review but returned 429 rate-limit responses specifically when a copper query was attempted; Semantic Scholar Graph API returned a 429 rate-limit response when queried for lurasidone-related terms generally during this review.

Outcome

Direct "lurasidone copper" and "lurasidone AND copper" queries on PubMed both returned a clean, explicit zero-results page (not a blocked or captcha page), which is a genuine negative result rather than a tooling failure for that specific channel. A broader class-level literature on antipsychotics and serum copper exists (documented in this project's risperidone dossier, itself found to be illness-associated with schizophrenia generally rather than attributable to any specific drug), but under Hard Rule 6, confounding by indication is presumed until excluded, and that illness-associated, non-drug-specific literature does not by itself establish even a class-level yellow claim for lurasidone, which was not itself in any of those studied cohorts as confirmed during this review.

Genuine gap vs tooling limited

Assessed as substantially a genuine evidence gap for lurasidone specifically: the core PubMed query for this exact pairing returned a clean zero-result page on a working channel, not a blocked one. This is nonetheless compounded by a real, partial tooling limitation: Europe PMC and Semantic Scholar access were intermittently rate-limited during this specific review session (see access note), so a small residual possibility remains that a class-level or mechanistic source exists on one of those platforms that a fully unblocked search would have surfaced. A future revision should re-attempt the blocked channels before treating this gap as fully closed.

Limits on what this shows

• Null/negative findings: No human cohort study measuring gut microbiome composition in lurasidone-treated patients was located. Both underlying studies are single-cohort rat experiments from the same research group; independent replication was not found.
• At-risk subgroups: Not established in humans. The bioavailability-reversal finding, if it translates to humans, would be most relevant to patients on concurrent broad-spectrum antibiotics or major dietary/prebiotic changes during lurasidone treatment; this is speculative extrapolation from a single rat PK study and is not a clinical recommendation.

Regulatory status

Not addressed in the FDA label; this is investigational animal pharmacology, not a labeled effect.

Population evidence

Kamath et al., "The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine," bioRxiv 2024.02.28.582623 (preprint; later published as Kamath et al., Br J Pharmacol 2024, DOI 10.1111/bph.16507, PMID/pagination not independently confirmed due to session-level access limits, see access note): 8-week-old Sprague-Dawley rats (n=8/group), 21 days of lurasidone 7.5 mg/kg, olanzapine 7.5 mg/kg, or vehicle by oral gavage. Lurasidone increased Shannon diversity index by about 0.5 and operational taxonomic units by about 50, with no significant change in Firmicutes:Bacteroidetes ratio, and produced no significant change in body weight, blood glucose, triglycerides, or TNF-alpha versus control. Olanzapine in the same protocol decreased Shannon diversity by about 1.0, reduced OTUs by about 75, increased the Firmicutes:Bacteroidetes ratio roughly 5-fold (strongly correlated with weight gain, R-squared 0.76), and produced significant increases in body weight (about 30 percent), glucose (about 3-fold), triglycerides (about 2-fold), and TNF-alpha (about 2-fold).

Mechanism

Proposed as a receptor-binding and metabolic-liability difference between the two drugs rather than a lurasidone-specific microbiome-protective mechanism narrowly defined; the authors frame lurasidone's result as "gut neutrality." Separately, a companion rat pharmacokinetic study (Prebiotic/antibiotic manipulation, bioRxiv 2024.07.17.604016) found gut-microbiome-driven shifts in short-chain fatty acid production altered intestinal luminal pH (about 6.25 with an enriched microbiome versus about 7.50 with a depleted one), which changed lurasidone's aqueous solubility (lurasidone's piperazine ring protonates and becomes more soluble below its pKa of 7.6) and bioavailability: an enriched microbiome (inulin) produced a 4.3-fold increase in lurasidone AUC and 3.3-fold increase in Cmax versus control in a single-dose 20 mg/kg oral-gavage pharmacokinetic study (n=5/group); an antibiotic-depleted microbiome showed no significant bioavailability change versus control in the same study. This is the reverse direction under Hard Rule 4 (microbiome affecting the drug, not the drug affecting the microbiome) and is disclosed here as PK context, not as an independent depletion or protective grade.

Counter-evidence held on record

Both studies come from the same laboratory and the diversity/metabolic comparison to olanzapine has not been independently replicated by another group; a companion bioRxiv preprint is not yet confirmed as peer-reviewed (see access note). The bioavailability finding was published in a rat single-dose model at 20 mg/kg, a supratherapeutic exposure relative to typical clinical mg/kg dosing, and has not been tested in humans. This entry's metabolic-neutrality data (weight, glucose, triglycerides, TNF-alpha) overlaps with the headline finding's discussion of lurasidone's comparatively low metabolic-syndrome liability; see Overlap map. This is a reverse-direction, protective/neutral context finding in animals, not human clinical evidence, and does not support probiotic or prebiotic supplementation as a way to boost lurasidone levels or effectiveness. Do not adjust lurasidone dosing based on diet or supplement use without a prescriber's guidance.

Limits on what this shows

• Null/negative findings: No cohort or randomized-trial study directly measuring hemoglobin or hematocrit change as a primary endpoint in lurasidone-treated patients was located; the label's own adverse-reaction table frames anemia as infrequent rather than as a routine finding, which is itself evidence against a common, dose-proportional effect.
• At-risk subgroups: Not established beyond the two reported cases; both were adult males on standard-to-higher within-label doses for extended periods (2 and 10 months) before symptom onset.

Regulatory status

The current FDA label (accessdata.fda.gov, 200603s041lbl, section 6.1 Clinical Trials Experience) lists anemia among infrequent adverse reactions (occurring in 1/100 to 1/1000 patients) in the premarketing database. Leukopenia/neutropenia is separately flagged under Warnings and Precautions (5.8) as a class-level antipsychotic effect, a distinct white-cell phenomenon not filed here.

Population evidence

FDA label, section 6.1: anemia, infrequent, premarketing clinical trial database (regulatory Tier A). Kirpekar VC et al., Indian J Pharmacol 2019 (PMID 31571715): two-case series. Case 1, 29-year-old male, lurasidone 40 mg monotherapy about 2 months: hemoglobin fell from 13.4 g/dL at baseline to 6.5 g/dL at symptom onset (raised MCV), rising to 9.1 g/dL one month after discontinuation and 12 g/dL by 2.5 months post-discontinuation. Case 2, 50-year-old male, lurasidone 40 to 80 mg daily for about 10 months (with blonanserin 8 mg): hemoglobin fell from 15.5 g/dL at baseline to 6.6 g/dL at symptom onset, with reduced ferritin (5.10 ng/mL) and iron (14 microgram/dL); hemoglobin rose to 8.9 g/dL one month after dose reduction and 12.2 g/dL by 3 months post-discontinuation.

Mechanism

Not established as a single named biochemical pathway. The case-series authors raise drug-induced myelosuppression as one possibility, given normal other blood parameters in Case 1, and note antipsychotics may alter iron metabolism generally; Case 2's low ferritin and serum iron point toward an iron-utilization component specifically (see Iron entry), while Case 1's raised MCV without documented iron studies leaves the mechanism there unresolved.

Counter-evidence held on record

Both cases fully reversed on dose reduction or discontinuation, arguing for a reversible drug effect rather than an independent hematologic disease process, but a two-patient case series cannot establish population-level incidence or a definitive mechanism, and confounding by concurrent medication (blonanserin in Case 2) was not excludable. Do not attribute unexplained anemia in a lurasidone-treated patient to the drug without first excluding standard causes. A low hemoglobin result should prompt clinical evaluation, including iron studies, not reflexive iron supplementation; any repletion dose should be prescriber-directed and kept under the NIH Office of Dietary Supplements tolerable upper intake level for elemental iron (45 mg/day for adults). This dossier makes no standing dosing recommendation.

Limits on what this shows

• Null/negative findings: No in vivo or human clinical energy-metabolism study (fatigue, exercise capacity, lactate) was located for lurasidone specifically.
• At-risk subgroups: Not established; the finding comes from a toxicological exposure range roughly two to three orders of magnitude above typical clinical plasma levels, not chronic therapeutic dosing.

Regulatory status

Not addressed in the FDA label.

Population evidence

Ľupták M, Fišar Z, Hroudová J, Mol Neurobiol 2021 (PMID 34365585): lurasidone, along with brexpiprazole, cariprazine, and loxapine, significantly decreased mitochondrial ATP production in isolated pig brain mitochondria at the higher (100 micromolar) test concentration, following dose-dependent inhibition of complex I- and complex II-linked respiration at both 10 and 100 micromolar.

Mechanism

Proposed as a direct consequence of electron-transport-chain inhibition reducing the proton-motive force available for ATP synthase. This entry shares its underlying source with Mitochondrial burden above; see Overlap map, not counted as independent confirmation.

Counter-evidence held on record

No clinical correlate, such as fatigue, exercise capacity, or lactate, has been studied in lurasidone-treated patients specifically. All four antipsychotics tested in the source study showed a similar ATP-reduction direction at the highest concentration, suggesting a possible class/concentration effect of this chemical family in isolated mitochondria rather than a lurasidone-distinguishing finding. Does not support ATP-support supplementation, such as coenzyme Q10 or creatine, in patients on standard therapeutic lurasidone dosing.