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MyDeficiencies

Paliperidone

atypical (second-generation) antipsychotic

Also sold as Invega, Invega Sustenna, Invega Trinza, Invega Hafyera.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Paliperidone is chemically 9-hydroxyrisperidone, risperidone's own major active metabolite, marketed as a separate product. That relationship makes its pharmacokinetics a study in contrasts with risperidone rather than a repeat of them. Its label documents four minor metabolic pathways (dealkylation, hydroxylation, dehydrogenation, benzisoxazole scission), none accounting for more than 10 percent of the dose, and states plainly that although CYP2D6 and CYP3A4 were implicated in vitro, "in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone." Consistent with that, 59 percent of a single oral dose is excreted unchanged in urine, and roughly 80 percent of total radioactivity is recovered in urine against only 11 percent in feces, so paliperidone is overwhelmingly cleared by the kidney rather than the liver. Paliperidone itself is not described as a clinically meaningful inducer or inhibitor of CYP450 enzymes, and it does not inhibit P-glycoprotein at therapeutic concentrations. This is a materially lower-metabolism, more renally-dependent profile than risperidone's, which relies on CYP2D6-mediated hydroxylation for most of its clearance. The practical consequence is a pharmacokinetic profile with essentially no hepatic-enzyme-induction machinery for classical nutrient depletion, but a pronounced renal-accumulation risk: clearance falls by roughly 32, 64, and 71 percent in mild, moderate, and severe renal impairment, with exposure (AUC) rising 1.5-fold, 2.6-fold, and 4.8-fold respectively, a much steeper renal dependency than risperidone shows. Food also behaves oppositely to risperidone: a high-fat meal raises paliperidone's Cmax by 60 percent and AUC by 54 percent, rather than leaving absorption unaffected.

atypical (second-generation) antipsychotic · ATC N05AX13 · also sold as Invega and Invega Sustenna and Invega Trinza and Invega Hafyera · reviewed 2026-09-30. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Paliperidone in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Sodium, SIADH-mediated hyponatremia, dilutional not dietary

Yellow — Low

See study details

Paliperidone, including its long-acting injectable formulations, is associated with case reports of severe hyponatremia consistent with syndrome of inappropriate antidiuretic hormone secretion (SIADH); this is a hormonal, dilutional disturbance, not evidence of dietary sodium deficiency, and repletion strategy differs accordingly.

Full detail, limits and 3 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

  • Null/negative findings: A 2018 systematic review of case reports of antipsychotic-associated hyponatremia (Ali and Bazzano, Ochsner J ) found no paliperidone cases among aripiprazole, risperidone, ziprasidone, olanzapine, and clozapine reports, and noted baseline hyponatremia prevalence of about 4 percent in unmedicated schizophrenia versus about 10 percent in antipsychotic-treated chronic schizophrenia, a reminder that psychogenic polydipsia and the underlying illness are recognized confounders independent of any specific drug (Hard Rule 6).
  • At-risk subgroups: Not statistically defined from case-report-level evidence; the identified cases include both oral and once-monthly long-acting injectable use, and one case involved concurrent neuroleptic malignant syndrome, suggesting acute illness severity or polypharmacy may be relevant, though this cannot be established from case reports alone.

Regulatory status

Hyponatremia and SIADH are not listed as labeled adverse reactions for paliperidone in the sections reviewed; this is a post-marketing case-report and pharmacovigilance-database finding, not a labeled effect.

Population evidence

Kaur et al., Case Reports in Critical Care 2016 (PMID 27721999, human, drug-specific): a 35-year-old man given a 234 mg intramuscular paliperidone palmitate injection developed sodium of 113 mg/dL on admission, falling to 108 mg/dL with seizure onset by day 2, before normalizing over two weeks with dantrolene, bromocriptine, and lorazepam; the case also involved concurrent neuroleptic malignant syndrome and rhabdomyolysis. Isaacs et al., Ann Pharmacother 2017 (DOI 10.1177/1060028017708324, human, drug-specific case report): "Hyponatremia Associated With Once-Monthly Paliperidone Palmitate Use"; full text was behind a closed-access paywall during this review, so only the title and journal-level detail are available. Mazhar et al., J Clin Psychopharmacol 2020 (DOI 10.1097/jcp.0000000000001180, human, drug-specific): "Paliperidone-Associated Hyponatremia: Report of a Fatal Case With Analysis of Cases Reported in the Literature and to the US FDA Adverse Event Reporting System"; this combines a fatal case report with a broader literature and FAERS pharmacovigilance analysis, but the full abstract was behind a closed-access paywall (HTTP 402) during this review, so the underlying case count and statistics could not be independently confirmed beyond the title.

Mechanism

The case-report literature proposes long-term dopamine D2 receptor supersensitivity driving antidiuretic hormone release, and serotonergic 5-HT2/5-HT1c receptor stimulation of ADH secretion, mechanisms generic to antipsychotics rather than unique to paliperidone; no paliperidone-specific renal tubular sodium-wasting mechanism is described.

Counter-evidence held on record

All paliperidone-specific evidence is case-report level (Tier B); no Tier A cohort or interventional study quantifying paliperidone-specific hyponatremia incidence was located. The Ochsner systematic review's baseline-prevalence data argue that a meaningful share of hyponatremia in treated schizophrenia reflects the illness itself (polydipsia) rather than any single drug. This is a dilutional, hormonally mediated disturbance, not a dietary sodium deficiency. Do not treat unexplained hyponatremia in a paliperidone-treated patient with salt supplementation; the documented treatment approach in the case reports was fluid management and, in one case, dantrolene and bromocriptine under acute medical care. Any sodium abnormality in a patient on paliperidone warrants prompt clinical evaluation, not self-directed electrolyte supplementation.

  • Kaur J, Kumar D, Alfishawy M, et al. Paliperidone Inducing Concomitantly Syndrome of Inappropriate Antidiuretic Hormone, Neuroleptic Malignant Syndrome, and Rhabdomyolysis. Case Rep Crit Care. 2016. — PMID 27721999. Human, case report, drug-specific. Full text retrieved via PMC.
  • Isaacs AN, Eaves SM, Ott CA. Hyponatremia Associated With Once-Monthly Paliperidone Palmitate Use. Ann Pharmacother. 2017. — DOI 10.1177/1060028017708324. Human, case report, drug-specific.Full text behind closed access (Unpaywall confirmed no OA location); title and journal-level detail only.
  • Mazhar F, Carnovale C, Haider N, Ahmed R, Taha M. Paliperidone-Associated Hyponatremia: Report of a Fatal Case With Analysis of Cases Reported in the Literature and to the US FDA Adverse Event Reporting System. J Clin Psychopharmacol. 2020. — DOI 10.1097/jcp.0000000000001180. Human, case report plus literature/FAERS pharmacovigilance analysis, drug-specific.Publisher page returned HTTP 402 (payment required) during this review; title and journal-level detail only, underlying case counts not independently confirmed.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden, animal injury-model data show a protective, not damaging, effect

Yellow — Low

See study details

The only direct paliperidone mitochondrial data located come from a rat neurotoxicity model in which paliperidone attenuated, rather than caused, mitochondrial dysfunction; no human or baseline (non-injury) mitochondrial marker study in paliperidone-treated subjects was located.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

  • Null/negative findings: No study measuring paliperidone's effect on mitochondrial function in the absence of an induced toxic injury (that is, baseline healthy-tissue mitochondrial function) was located, human or animal. No in vitro human cell mitochondrial toxicology study of paliperidone, comparable to risperidone's monocyte ATP study, was found.
  • At-risk subgroups: Not established; this is a disease-model (Huntington's-like neurotoxicity) finding, not evidence about ordinary paliperidone-treated patients without that specific injury.

Regulatory status

Not addressed in the FDA label.

Population evidence

Mishra and Kumar, Neurotoxicity Research 2014 (DOI 10.1007/s12640-014-9469-9, rat, drug-specific): using a bilateral intrastriatal quinolinic acid injection model of Huntington's-disease-like neurodegeneration, oral paliperidone at 0.5, 1, or 2 mg/kg for 21 days "significantly attenuated" quinolinic-acid-induced behavioral, neurochemical, antioxidant-enzyme, and mitochondrial-function impairment, along with striatal neurodegeneration, versus untreated quinolinic-acid controls.

Mechanism

The study frames this as modulation of the dopaminergic pathway protecting against toxin-induced mitochondrial and neurochemical injury; it did not report specific electron-transport-chain complex activities or direct ATP-synthesis measurements, only broader "mitochondrial function" and downstream antioxidant-enzyme and neurodegeneration endpoints, so the finding should be read as suggestive rather than a precise bioenergetic characterization.

Counter-evidence held on record

This is a protective-direction finding in an induced-injury animal model, the opposite of a burden finding, and it cannot be generalized to baseline mitochondrial safety in ordinary clinical use because no baseline (non-injury) study exists. This entry shares its underlying source with the ATP production category below, which remains ungraded because the same study did not directly assay ATP synthesis; see Overlap map. Do not interpret this entry as support for mitochondrial-support supplementation such as coenzyme Q10 in patients on paliperidone; no clinical trial evidence supports this, and the underlying study was conducted in a disease model unrelated to ordinary treatment.

  • Mishra J, Kumar A. Improvement of Mitochondrial Function by Paliperidone Attenuates Quinolinic Acid-Induced Behavioural and Neurochemical Alterations in Rats: Implications in Huntington's Disease. Neurotoxicity Research. 2014;26:363-381. — DOI 10.1007/s12640-014-9469-9. Rat, drug-specific, injury-model, protective direction.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress, human and animal data trend protective

Yellow — Low

See study details

In a paliperidone-inclusive human cohort, higher prolactin correlated with lower oxidative stress markers, and animal studies of paliperidone show it upregulating endogenous antioxidant pathways under stress; a reverse-direction finding relative to the general "antipsychotics cause oxidative damage" narrative, not established at a level bounded enough for orange.

Full detail, limits and 3 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

  • Null/negative findings: None identified among the paliperidone-inclusive sources retrieved; all trend protective or antioxidant. No human study isolating paliperidone from risperidone within the Radmanovic cohort was located, so the magnitude specific to paliperidone alone cannot be separated from the combined-regimen analysis.
  • At-risk subgroups: None established; direction of effect appears consistent across the paliperidone- and risperidone-treated groups in the human data reviewed.

Regulatory status

Not addressed in the FDA label.

Population evidence

Radmanovic et al., Biomedicines 2024 (PMID 39061992, human, drug-specific): 155 patients with psychotic disorder on oral risperidone, two-week depot risperidone, or monthly/quarterly depot paliperidone; paliperidone patients were explicitly present in the cohort (the LAI-Pm and LAI-Pq groups) though results were reported by treatment regimen rather than stratified separately by molecule. TBARS (r = -0.630, p less than 0.001), superoxide (r = -0.368, p less than 0.001), and SOD (r = -0.184, p = 0.022) all correlated negatively with prolactin level, titled "protective effect of hyperprolactinemia on oxidative stress." MacDowell et al., Neurotherapeutics 2016 (DOI 10.1007/s13311-016-0438-2, rat, drug-specific): oral paliperidone 1 mg/kg given before acute (6-hour) or chronic (21-day) restraint stress increased NRF2 levels and upregulated antioxidant enzymes (SOD, GPx, CAT, HO1) and anti-inflammatory cytokines (IL-4, IL-10, TGF-beta) relative to stressed, untreated controls, with statistically significant interaction effects (for example chronic catalase activity F(1,22) = 4.09, p = 0.02). A second rat study, cited by title only after a 403 access block prevented full-text retrieval (PMID 25545018, "Paliperidone regulates intracellular redox system in rat brain: Role of purine mechanism"), is consistent in direction with these findings based on its title but could not be independently verified in full during this review.

Mechanism

Proposed mechanisms center on paliperidone's effect on NRF2-mediated antioxidant gene transcription and on downstream anti-inflammatory microglial polarization in the animal data; a specific mechanism linking the human prolactin-oxidative-stress correlation to a causal pathway is not established, only an association.

Counter-evidence held on record

The human cohort did not stratify results by paliperidone versus risperidone, so this finding cannot be certified as independently confirmed for paliperidone alone at full Tier A strength; it is treated as supportive drug-inclusive evidence. This entry shares its hyperprolactinemia axis with the headline finding and the bone-density fails-verification entry; see Overlap map. This is a reverse-direction, context finding, not evidence that paliperidone should be chosen or avoided for oxidative-stress reasons, and it does not support withholding antioxidant-rich foods or adding antioxidant supplementation.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Iron, extrapolated from risperidone's pediatric iron-depletion literature

Yellow — Low

See study details

Long-term pediatric risperidone use is associated with iron depletion in Tier A drug-specific studies; because paliperidone is risperidone's own active circulating metabolite, this is carried forward here as a plausible, mechanism-consistent extrapolation, not as independently confirmed paliperidone-specific evidence, since no study administering paliperidone itself measured iron status.

Full detail, limits and 3 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

  • Null/negative findings: None identified in the risperidone-specific literature; no paliperidone-specific iron study, positive or negative, exists to confirm or refute the extrapolation.
  • At-risk subgroups: If the extrapolation holds, children and adolescents on long-term paliperidone with substantial treatment-associated weight gain would be the plausible at-risk group, by analogy with the risperidone cohorts; this has not been independently tested.

Regulatory status

Not addressed in either the paliperidone or risperidone FDA label; this is a post-marketing research finding from independent pediatric psychiatry cohorts, not a labeled effect for either drug.

Population evidence (extrapolation basis)

Calarge et al., J Child Adolesc Psychopharmacol 2013 (PMID 23480322): children and adolescents on long-term risperidone (mean duration about 2.4 years) showed 45 percent iron depletion and 14 percent frank iron deficiency, inversely associated with treatment-related weight gain. Calarge et al., J Child Adolesc Psychopharmacol 2016 (PMID 26894929): mean serum ferritin 37.3 microgram/L in risperidone-treated youth, with 21 percent below 20 microgram/L "despite appropriate daily dietary iron intake." Calarge et al., J Clin Psychiatry 2015 (PMID 26301448): longitudinal iron homeostasis tracked against weight change with risperidone initiation or discontinuation. In every one of these studies the drug administered was risperidone, not paliperidone; no study identified in this review administered Invega, Invega Sustenna, Invega Trinza, or Invega Hafyera and then measured ferritin or iron status. A targeted search for "paliperidone iron" and "paliperidone ferritin" returned zero results on PubMed and zero relevant results via the Crossref API.

Mechanism

The proposed mechanism (increased iron utilization or hepcidin-mediated sequestration linked to treatment-associated weight gain and low-grade inflammation, rather than reduced dietary intake or absorption) is a property of the shared active moiety and the shared weight-gain/metabolic-syndrome liability both drugs carry, which is why the extrapolation is considered plausible rather than merely a generic class link. It remains an extrapolation, not direct evidence, because systemic drug exposure, dosing, and patient population differ between the risperidone cohorts studied and paliperidone as clinically prescribed.

Counter-evidence held on record

No study has tested whether paliperidone, dosed as such, reproduces the risperidone pediatric iron findings. The extrapolation logic (shared active moiety) is pharmacologically reasonable but unverified; the cohort test that this protocol applies to every citation is failed for paliperidone specifically, which is exactly why this entry is graded yellow rather than orange. Do not supplement iron in a child or adolescent on paliperidone 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 (40 mg/day for ages 1 to 13, 45 mg/day for ages 14 and up). This dossier makes no standing dosing recommendation.

  • Calarge CA et al. Iron deficiency in pediatric patients in long-term risperidone treatment. J Child Adolesc Psychopharmacol. 2013. — PMID 23480322. Human, pediatric, risperidone-specific (not paliperidone). Extrapolation basis for the Iron entry; cohort excluded paliperidone as administered drug.Cohort administered risperidone, not paliperidone; Tier A for risperidone, extrapolation basis only for paliperidone.
  • Calarge CA et al. Serum ferritin, weight gain, disruptive behavior, and extrapyramidal symptoms in risperidone-treated youth. J Child Adolesc Psychopharmacol. 2016. — PMID 26894929. Human, pediatric, risperidone-specific.Cohort administered risperidone, not paliperidone; extrapolation basis only.
  • Calarge CA et al. Iron homeostasis during risperidone treatment in children and adolescents. J Clin Psychiatry. 2015. — PMID 26301448. Human, pediatric, risperidone-specific, longitudinal.Cohort administered risperidone, not paliperidone; extrapolation basis only.

Copper

Not graded — disclosed evidence gap

See study details

No paliperidone-specific evidence was located at any tier, and no circulating consumer claim naming paliperidone and copper specifically was located to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

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 paliperidone specifically, and no circulating claim was located naming paliperidone and copper together for this review to rebut as white. This mirrors the same gap risperidone's dossier disclosed for copper, and it remains a gap for paliperidone independently; it was not assumed from the risperidone result.

Channels tried

PubMed search-listing pages for "paliperidone copper" (zero results, confirmed with automatic term-mapping message); Crossref API queries for "paliperidone copper trace element" (returned only unrelated copper-mining, copper-toxicology, and unrelated trace-element literature, no paliperidone hits); Europe PMC REST API (blocked outright by session-level proxy policy, connect_rejected/403, on every attempt this session); Semantic Scholar Graph API and OpenAlex API (both returned repeated HTTP 429 rate-limit responses across multiple attempts and could not be completed); individual PubMed article pages and most PubMed search-listing pages later in the session returned Google reCAPTCHA bot-verification challenges rather than results.

Outcome

No paliperidone-copper pairing was found in any accessible channel. Risperidone's own copper entry found only illness-associated (schizophrenia, not drug-specific) copper literature that argued against, not for, an antipsychotic-attributable copper effect; nothing in this review's searches surfaced anything different for paliperidone.

Genuine gap vs tooling limited

Assessed as substantially a genuine evidence gap, consistent with the same conclusion reached independently for risperidone, but compounded by a real tooling limitation: Europe PMC was blocked by policy for the entire session, Semantic Scholar and OpenAlex were rate-limited on every attempt, and PubMed itself became bot-blocked partway through this review. A future revision should re-attempt the blocked channels, particularly Europe PMC and Semantic Scholar, before treating this gap as fully closed.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk, extrapolated from risperidone's pediatric and mouse microbiome literature

Yellow — Low

See study details

Risperidone use, especially in children, is associated with gut microbiota shifts that mouse studies tie causally to the drug's weight-gain and metabolic effects; carried forward here for paliperidone as a labeled, mechanism-based extrapolation only, since no identified study dosed paliperidone itself and measured microbiome composition.

Full detail, limits and 2 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

  • Null/negative findings: None identified in the risperidone-specific literature; no paliperidone-specific microbiome study, positive or negative, was located.
  • At-risk subgroups: By analogy with the risperidone data, children and adolescents with substantial paliperidone-associated weight gain would be the plausible at-risk group; this is unverified for paliperidone specifically.

Regulatory status

Not addressed in either label; investigational mechanistic literature only.

Population evidence (extrapolation basis)

Bahr et al., Transl Psychiatry 2015 (PMID 26440540, human, pediatric): risperidone treatment and secondary weight gain were associated with altered gut microbiota composition. Bahr et al., EBioMedicine 2015 (PMID 26870798, mouse, mechanistic, causal companion study): risperidone-induced weight gain was mediated through gut microbiome shifts suppressing host energy expenditure. As with the iron entry above, every one of these studies administered risperidone, not paliperidone; a targeted search for "paliperidone microbiome," "paliperidone microbiota," and "paliperidone gut" returned no drug-specific results on PubMed or via the Crossref API during this review, only unrelated general-microbiome and general-antipsychotic-class literature.

Mechanism

The proposed mechanism (microbiome-mediated suppression of host energy expenditure contributing to the drug's own weight-gain liability) is tied to shared pharmacology between risperidone and its active metabolite, making extrapolation more plausible than a typical unrelated-class extrapolation, but it remains untested for paliperidone as administered.

Counter-evidence held on record

Causal confirmation exists only in mice dosed with risperidone, not paliperidone, and only in a single human pediatric risperidone cohort; no paliperidone arm has been studied. This entry shares its underlying evidence base with the Iron entry above; see Overlap map. No probiotic strain or dose has clinical trial support for reversing this effect in paliperidone-treated patients. Do not substitute probiotic supplementation for standard metabolic monitoring (weight, glucose, lipids).

  • Bahr SM et al. Use of the second-generation antipsychotic risperidone and secondary weight gain are associated with an altered gut microbiota in children. Transl Psychiatry. 2015. — PMID 26440540. Human, pediatric, risperidone-specific.Cohort administered risperidone, not paliperidone; extrapolation basis only.
  • Bahr SM et al. Risperidone-induced weight gain is mediated through shifts in the gut microbiome. EBioMedicine. 2015. — PMID 26870798. Mouse, mechanistic, causal, risperidone-specific.Animal model dosed with risperidone, not paliperidone; extrapolation basis only.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization

Not graded — disclosed evidence gap

See study details

No paliperidone-specific evidence on hemoglobin, hematocrit, or oxygen-carrying capacity was located, and the one related-drug data point (a single risperidone case report of anemia) was judged too weak on its own to support even a yellow extrapolation.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Both conditions for ungraded status are met: no paliperidone-specific Tier B or C evidence exists, and no circulating consumer claim linking paliperidone to anemia or oxygen delivery was located to rebut as white. Unlike the Iron and Gut microbiome entries above, where risperidone's extrapolation basis rests on multiple real Tier A cohort studies, the only related-drug signal here is a single, uncorroborated risperidone case report, itself flagged in risperidone's own dossier as insufficient to establish causation; extending an already-weak single case report across drugs was judged to fall short of the "real Tier B/C evidence for a class member" bar this protocol sets for a yellow extrapolation.

Channels tried

PubMed search-listing pages for "paliperidone anemia" (zero results) and "paliperidone hemoglobin" (three results, all incidental: a forensic toxicology paper, a cardiometabolic-monitoring cross-sectional study, and a psychoeducation study, none measuring hemoglobin as an outcome of paliperidone treatment); Crossref API queries for related terms; Europe PMC (blocked by proxy policy all session); Semantic Scholar and OpenAlex (rate-limited on every attempt).

Outcome

Paliperidone's hematologic case-report literature that was located concerns white-cell effects, not red-cell ones: Wakuda et al., Aust N Z J Psychiatry 2019 (PMID 30636434), reports acute agranulocytosis when switching from risperidone to paliperidone. This is an idiosyncratic immune-mediated white-cell adverse reaction, not an oxygen-delivery or nutrient finding, and is not filed under this category, consistent with how risperidone's own white-cell case reports were treated in that dossier.

Genuine gap vs tooling limited

Assessed as substantially a genuine evidence gap: even a good-faith, multi-channel search found no paliperidone-specific red-cell or oxygen-delivery signal, and the related-drug basis for extrapolation is itself too thin to responsibly upgrade to yellow. Compounded by the same tooling limitations disclosed under Copper above (Europe PMC blocked, Semantic Scholar/OpenAlex rate-limited, PubMed intermittently bot-blocked).

  • Wakuda T, Suzuki A, Hasegawa M, Ichikawa D, Yamasue H. Acute agranulocytosis when switching from risperidone to paliperidone. Aust N Z J Psychiatry. 2019. — PMID 30636434. Human, case report, white-cell effect, cited for context only (not an oxygen-delivery finding).

ATP production

Not graded — disclosed evidence gap

See study details

No study directly measuring ATP synthesis or cellular energy output in paliperidone-exposed tissue, human or animal, was located, and no circulating consumer claim specifically naming paliperidone and ATP or energy production was found to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Both conditions for ungraded status are met. The Mitochondrial burden entry above rests on a study (Mishra and Kumar 2014) that reports broader "mitochondrial function" and antioxidant-enzyme outcomes in an induced-injury rat model, but the retrieved detail on that study does not include a direct ATP-synthesis assay, electron-transport-chain complex activity, or any other specific energy-output measurement; using it to support an ATP-specific grade would risk exactly the kind of over-reading this protocol's Hard Rule 7 (Copper/Iron and Oxygen delivery/ATP kept independent) and Hard Rule 9 (overlap disclosure) are designed to prevent. It is disclosed in the Overlap map rather than double-counted here.

Channels tried

Crossref API queries for "paliperidone ATP production energy metabolism" and "paliperidone mitochondrial ATP oxidative phosphorylation" (both returned only unrelated general bioenergetics literature, no paliperidone hits); PubMed search-listing pages for "paliperidone mitochondrial" (attempted but returned a rate-limit response before results could be captured, and a repeat attempt later in the session hit the PubMed bot-verification block described above); Europe PMC (blocked by proxy policy); Semantic Scholar and OpenAlex (rate-limited).

Outcome

No direct ATP-production evidence for paliperidone was found in any accessible channel. Risperidone's own ATP-production entry rested on a human monocyte study at a supratherapeutic concentration; no comparable in vitro human study exists for paliperidone in the sources located during this review.

Genuine gap vs tooling limited

Assessed as a genuine evidence gap, compounded by the same tooling limitations disclosed above (Europe PMC blocked all session, Semantic Scholar/OpenAlex rate-limited on every attempt, PubMed intermittently bot-blocked). A future revision should re-attempt the blocked channels, particularly a direct PubMed search for "paliperidone" combined with "oxidative phosphorylation" or "electron transport chain," which could not be completed cleanly this session.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • Calcium and vitamin D supplementation corrects paliperidone-associated bone density loss

    Where it comes from: Extension, by drug-class association, of risperidone's well-documented hyperprolactinemia-bone-density literature, combined with the general "low bone density means take calcium and vitamin D" framing common in consumer nutrition content.

    Why it fails: The largest available paliperidone-inclusive cohort study (Somrak et al. 2026, Pharmacoepidemiology ) found no statistically significant association between serum prolactin and bone mineral density Z-scores at the lumbar spine (adjusted beta = 0.196, 95% CI -0.212 to 0.605, p = 0.340), femoral neck (beta = 0.157, p = 0.298), or total hip (beta = -0.224, p = 0.221), with physical activity and BMI showing stronger associations than prolactin. Paliperidone contributed only 2 of 68 subjects and was not analyzed separately. This is weaker, not stronger, support than existed for risperidone's own (still ultimately Hard-Rule-2-excluded) bone finding, and gives no evidence-based basis for a calcium/vitamin D fix.

  • Paliperidone (or antipsychotics generally) depletes folate/B12, raising homocysteine

    Where it comes from: A common general claim in psychiatric-drug nutrient-depletion content, applied broadly across antipsychotics and other CNS-active drugs as a class, and specifically demonstrated for risperidone (where treatment was associated with a homocysteine decrease, not increase) in this series' companion dossier.

    Why it fails: A direct search for "paliperidone" combined with "vitamin D" and separately with "homocysteine" returned zero relevant results via the Crossref API (only unrelated figure captions and pharmacopeial monograph entries from an unrelated study). No Tier B or Tier C evidence of any kind linking paliperidone to folate, B12, or homocysteine status was located in any channel searched.

  • Paliperidone depletes coenzyme Q10

    Where it comes from: Circulates in general antipsychotic drug-nutrient depletion handbook-style content (Tier D, no drug-specific citation), part of a broader genre applying mitochondrial-support nutrient claims across psychiatric medications, and previously found to fail verification for risperidone in this series.

    Why it fails: No paliperidone-specific or class-level antipsychotic coenzyme Q10 study was located in the Crossref, PubMed, or FDA-label channels searched during this review. No Tier B or Tier C evidence exists to support even a yellow grade, and this drug-nutrient pairing could not be traced to any primary source, the same outcome reached independently for risperidone.

How the body handles this medication

Metabolism
Minimally hepatically metabolized. Four minor in vivo pathways identified (dealkylation, hydroxylation, dehydrogenation, benzisoxazole scission), none exceeding 10 percent of the dose. Although CYP2D6 and CYP3A4 were implicated in vitro, in vivo data show these isozymes play only a limited role in paliperidone's overall elimination, a sharp contrast with risperidone's CYP2D6-dependent clearance.FDA label, INVEGA Extended-Release Tablets, Section 12.3 (accessdata.fda.gov 022043lbl.pdf)
CYP450 induction/inhibition
Paliperidone is not identified as a clinically significant inducer or inhibitor of CYP450 enzymes, and at therapeutic concentrations it does not inhibit P-glycoprotein. It is instead a substrate affected by other drugs: strong CYP3A4/P-glycoprotein inducers (carbamazepine, rifampin, St John's wort) increase its renal clearance (carbamazepine documented a 35 percent increase) and may require a dose increase, while divalproex sodium increases its Cmax and AUC by about 50 percent.FDA label, INVEGA SUSTENNA, Sections 7.2 and 12.3 (accessdata.fda.gov 022264s037lbl.pdf)
Elimination
Following a single oral immediate-release dose, 59 percent (range 51 to 67 percent) was excreted unchanged into urine; about 80 percent of total radioactivity was recovered in urine and 11 percent in feces, confirming predominantly renal, largely unmetabolized clearance. Terminal half-life is about 23 hours for the oral extended-release tablet and 25 to 49 days for the palmitate long-acting injectable, depending on dose.FDA label, INVEGA Extended-Release Tablets, Section 12.3
Absorption
Absolute oral bioavailability is 28 percent from the OROS extended-release tablet; Tmax is approximately 24 hours, reflecting the controlled-release design. A high-fat, high-calorie meal increases mean Cmax by 60 percent and AUC by 54 percent relative to fasting, the opposite direction from risperidone, where food does not affect absorption; the label nonetheless states INVEGA can be taken without regard to food because trials were conducted without meal standardization. Plasma protein binding is 74 percent.FDA label, INVEGA Extended-Release Tablets, Section 12.3
Renal and hepatic impairment
Renal impairment substantially raises exposure: clearance falls approximately 32, 64, and 71 percent in mild, moderate, and severe impairment, with AUC rising 1.5-fold, 2.6-fold, and 4.8-fold and half-life extending to 24, 40, and 51 hours respectively; dose reduction is required and the long-acting injectable is not recommended in moderate to severe impairment. Mild to moderate hepatic impairment requires no dose adjustment; free (unbound) paliperidone levels are similar to healthy subjects even though total exposure falls because of reduced protein binding.FDA label, INVEGA Extended-Release Tablets and INVEGA SUSTENNA, Section 12.3
Food, mineral, antacid interactions
No chelation, gastric-pH, or antacid interaction is described. The only food interaction identified is the meal-related increase in absorption above, a magnitude, not a mineral-specific, effect. A case report has separately proposed a P-glycoprotein-mediated interaction lowering paliperidone levels; this concerns the drug's own disposition, not a nutrient effect, and is noted here for completeness rather than as a drug-nutrient finding.FDA label, Section 7; Beilby et al., J Pharm Pract Res 2024 (P-glycoprotein case report, context only)
All references used above
  1. INVEGA (paliperidone) Extended-Release Tablets, prescribing information — FDA label via accessdata.fda.gov, initial approval 2006. Used for Clinical Pharmacology (12.3): absorption, metabolism, elimination, renal/hepatic impairment.
  2. INVEGA SUSTENNA (paliperidone palmitate) extended-release injectable suspension, prescribing information — FDA label via accessdata.fda.gov, 2024 revision. Used for drug interactions (7.1, 7.2), renal dosing, prolactin elevation percentages, QT prolongation data.
  3. DailyMed, INVEGA (paliperidone) tablet, extended release — Secondary confirmation of label content.
  4. DailyMed, INVEGA SUSTENNA (paliperidone palmitate) injection — Secondary confirmation of label content.
  5. Kaur J, Kumar D, Alfishawy M, et al. Paliperidone Inducing Concomitantly Syndrome of Inappropriate Antidiuretic Hormone, Neuroleptic Malignant Syndrome, and Rhabdomyolysis. Case Rep Crit Care. 2016. — PMID 27721999. Human, case report, drug-specific. Full text retrieved via PMC.
  6. Isaacs AN, Eaves SM, Ott CA. Hyponatremia Associated With Once-Monthly Paliperidone Palmitate Use. Ann Pharmacother. 2017. — DOI 10.1177/1060028017708324. Human, case report, drug-specific.Full text behind closed access (Unpaywall confirmed no OA location); title and journal-level detail only.
  7. Mazhar F, Carnovale C, Haider N, Ahmed R, Taha M. Paliperidone-Associated Hyponatremia: Report of a Fatal Case With Analysis of Cases Reported in the Literature and to the US FDA Adverse Event Reporting System. J Clin Psychopharmacol. 2020. — DOI 10.1097/jcp.0000000000001180. Human, case report plus literature/FAERS pharmacovigilance analysis, drug-specific.Publisher page returned HTTP 402 (payment required) during this review; title and journal-level detail only, underlying case counts not independently confirmed.
  8. Ali SN, Bazzano LA. Hyponatremia in Association With Second-Generation Antipsychotics: A Systematic Review of Case Reports. Ochsner J. 2018;18(3):230-235. — Systematic review of 9 case reports (aripiprazole, risperidone, ziprasidone, olanzapine, clozapine); baseline hyponatremia prevalence data used as illness-confounding context.Paliperidone not among the drugs covered in this review's cohort; used for baseline-prevalence context only, Tier C for paliperidone.
  9. Somrak K, Werawattanachai C, Sangngarm A, Silaket S, Boonlue T. Serum Prolactin and Bone Mineral Density in Women with Schizophrenia Receiving Prolactin-Raising Antipsychotics: A Cross-Sectional Study. Pharmacoepidemiology. 2026;5(3):31. — Human, cross-sectional, n=68 (risperidone 88.2%, paliperidone 2.9%, perphenazine 4.4%, other FGA 4.4%); paliperidone in cohort but not separately stratified. Key null-finding source for bone density claim.
  10. Radmanovic B, et al. Protective Effect of Hyperprolactinemia on Oxidative Stress in Patients with Psychotic Disorder on Atypical Antipsychotics Risperidone and Paliperidone: A Cross-Sectional Study. Biomedicines. 2024;12(7):1418. — PMID 39061992. Human, n=155, drug-specific (paliperidone LAI-monthly and LAI-quarterly groups included, not separately stratified from risperidone).
  11. MacDowell KS, Caso JR, Martin-Hernandez D, et al. The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress. Neurotherapeutics. 2016;13(4):833-843. — DOI 10.1007/s13311-016-0438-2. Rat, drug-specific, protective/antioxidant direction.
  12. Paliperidone regulates intracellular redox system in rat brain: Role of purine mechanism. Neurol Res. 2015. — PMID 25545018. Rat, drug-specific, title suggests protective direction consistent with other sources.Publisher page returned HTTP 403 during this review; title-level information only, full text and specific markers could not be independently verified.
  13. Mishra J, Kumar A. Improvement of Mitochondrial Function by Paliperidone Attenuates Quinolinic Acid-Induced Behavioural and Neurochemical Alterations in Rats: Implications in Huntington's Disease. Neurotoxicity Research. 2014;26:363-381. — DOI 10.1007/s12640-014-9469-9. Rat, drug-specific, injury-model, protective direction.
  14. Boyda HN, Procyshyn RM, Tse L, et al. A comparison of the metabolic side-effects of the second-generation antipsychotic drugs risperidone and paliperidone in animal models. PLoS ONE. 2021;16(1):e0246211. — Female rats, both drugs dosed head-to-head (0.1 to 6 mg/kg), glucose tolerance and hyperinsulinemic clamp outcomes; modest difference favoring paliperidone at lower doses.
  15. Wakuda T, Suzuki A, Hasegawa M, Ichikawa D, Yamasue H. Acute agranulocytosis when switching from risperidone to paliperidone. Aust N Z J Psychiatry. 2019. — PMID 30636434. Human, case report, white-cell effect, cited for context only (not an oxygen-delivery finding).
  16. Calarge CA et al. Iron deficiency in pediatric patients in long-term risperidone treatment. J Child Adolesc Psychopharmacol. 2013. — PMID 23480322. Human, pediatric, risperidone-specific (not paliperidone). Extrapolation basis for the Iron entry; cohort excluded paliperidone as administered drug.Cohort administered risperidone, not paliperidone; Tier A for risperidone, extrapolation basis only for paliperidone.
  17. Calarge CA et al. Serum ferritin, weight gain, disruptive behavior, and extrapyramidal symptoms in risperidone-treated youth. J Child Adolesc Psychopharmacol. 2016. — PMID 26894929. Human, pediatric, risperidone-specific.Cohort administered risperidone, not paliperidone; extrapolation basis only.
  18. Calarge CA et al. Iron homeostasis during risperidone treatment in children and adolescents. J Clin Psychiatry. 2015. — PMID 26301448. Human, pediatric, risperidone-specific, longitudinal.Cohort administered risperidone, not paliperidone; extrapolation basis only.
  19. Bahr SM et al. Use of the second-generation antipsychotic risperidone and secondary weight gain are associated with an altered gut microbiota in children. Transl Psychiatry. 2015. — PMID 26440540. Human, pediatric, risperidone-specific.Cohort administered risperidone, not paliperidone; extrapolation basis only.
  20. Bahr SM et al. Risperidone-induced weight gain is mediated through shifts in the gut microbiome. EBioMedicine. 2015. — PMID 26870798. Mouse, mechanistic, causal, risperidone-specific.Animal model dosed with risperidone, not paliperidone; extrapolation basis only.
  21. Beilby J, et al. A case of extrapyramidal side effects due to possible paliperidone: voriconazole interaction. J Pharm Pract Res. 2024. — Human, case report; discusses P-glycoprotein-related interaction affecting paliperidone's own disposition. Cited for PK context only, not a nutrient finding.
  22. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index, code N05AX13. — Confirms ATC code N05AX13 for paliperidone.