A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia
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BACKGROUND: There are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period. METHODS: In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B. RESULTS: Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable. CONCLUSIONS: Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range. TRIAL REGISTRATION NO: ClinicalTrials.gov: NCT01150448.
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Steady state of PP1M is achieved 8-9 months after the initial injection (with the 234 mg dose).
“Steady state is achieved 8–9 months after the initial injection (with the 234 mg dose) [78, 80].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [80]
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Cites
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“is consistent with that shown in previous short-term studies that included this dose [22,23] as well as with studies across the dose range [10,21,24,25] and no new safety signals emerged.”
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“is consistent with that shown in previous short-term studies that included this dose [22,23] as well as with studies across the dose range [10,21,24,25] and no new safety signals emerged.”
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ResultSelf-citationD2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate
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“, externally validated) if the median PE% and the median |PE|% were ≤ |15|% and 30%, respectively [11,13-15].”
BackgroundSafety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia
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“Generally, the incidence of discontinuations in this long-term study (47%) is consistent with rates observed in previous short duration PP studies [23-25] and also with rates reported in other drug studies in schizophrenia [26,27].”
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“…the majority of patients had plasma concentrations above 7.5 ng/mL (Figure 3), the minimum required plasma paliperidone concentration associated with a central D2-receptor occupancy of approximately 60% (Karlsson et al., 2006) that is generally considered the threshold for antipsychotic efficacy.”
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“The safety and tolerability profiles of PP3M and PP1M were comparable over the 48-week DB phase and consistent with that observed in other trials with PP1M (Hough et al., 2009; Gopal et al., 2010, 2011; Kramer et al., 2010; Nasrallah et al., 2010; Pandina et al., 2010; Coppola et al., 2012).”
ResultSelf-citationSchoretsanitis, G., Spina, E., Hiemke, C., & de León, J. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1345623 · Cited by 94 · see citing works
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“Currently available long-acting injectable (LAI) formulations of antipsychotic medications provide sustained therapeutic plasma concentrations for several weeks, minimizing the risk of nonadherence and providing long-term clinical benefits.(1,2,5) Paliperidone palmitate (PP [Invega 1 ; Sustenna 1 ; Xeplion 1 ]), a onc…”
BackgroundSelf-citationA review of paliperidone palmitate
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Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotic Drugs.
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“Coppola and associates [49] claimed that median PP1M concentrations over 7.”
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“Recently, a 1-year prospective study evaluated safety and tolerability of 234 mg of PP, the highest marketed dose of PP (150 mg equivalents of paliperidone) in clinically stable patients with schizophrenia.(54) Akathisia and tremor were the most common EPS.”
BackgroundInfluentialIs paliperidone palmitate more effective than other long-acting injectable antipsychotics?
Patel, R., Chesney, E., Taylor, M. J., Taylor, D. M., & McGuire, P. K. (2017) · Psychological Medicine · doi:10.1017/s0033291717003051 · Cited by 30 · see citing works
“In comparison with placebo, paliperidone is effective at reducing psychotic symptoms(Kramer et al. 2010; Alphs et al. 2011) and the risk of relapse and hospitalization (Hough et al. 2010; Kozma et al. 2011; Berwaerts et al. 2015), and is generally well tolerated (Coppola et al. 2012).”
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Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics
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“According to this, another study estimates that time to reach steady ‐ state differs by 4 weeks between deltoid (38w) and gluteal (42w) injection [81].”
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“[71], orthostatic hypotension, asthenia, and sluggishness were experienced, although not in clinically significant percentages.”
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“injection-sites, which was in agreement with the results from other studies.(16,27) For the gluteal muscle, the increase in the mean predose plasma concentration of paliperidone after day 8 suggested that steady-state was not completely achieved after two injections of PP in the gluteal muscle.”
ResultSelf-citationCatalán, R., González-Rodríguez, A., Penadés, R., García‐Rizo, C., Bioque, M., Parellada, E., & Bernardo, M. (2015) · Patient Preference and Adherence · doi:10.2147/ppa.s63948 · Cited by 26 · see citing works
“30 In this study, all patients did not receive injectable antipsychotic formulations previously, and the authors concluded that safety results of this PP dosing were consistent with previous results recently published.”
Gopal, S., Xu, H., Bossie, C. A., Burón, J. A., Fu, D., Savitz, A. J., Nuamah, I. F., & Hough, D. W. (2014) · International Journal of Clinical Practice · doi:10.1111/ijcp.12493 · Cited by 25 · see citing works
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“The study included stable patients with SCZ spectrum disorders followed for a 1-year period.(60) The overall discontinuation rate was higher than 50%.”
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“) [30].”
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“21 With increased concentrations of PP3M expected in patients from Asia, it becomes imperative to assess the clinical outcomes of schizophrenia associated with PP3M administration in this population.”
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“Assuming a dropout rate of 15% based on experiences from 2 previous clinical studies of PP1M, 353 patients were expected to be enrolled in this study.”
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Placental Transfer of Paliperidone During Treatment With a Depot Formulation
Binns, R., O’Halloran, S., Teoh, S. W. K., Doherty, K., & Joyce, D. A. (2017) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000714 · Cited by 13 · see citing works
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Critical appraisal of 3-monthly paliperidone depot injections in the treatment of schizophrenia
Carpiniello, B., & Pinna, F. (2016) · Drug Design Development and Therapy · doi:10.2147/dddt.s86301 · Cited by 12 · see citing works
Paliperidone Palmitate-induced Urinary Incontinence: A Case Report
Karslıoğlu, E. H., Özalp, E., & Çayköylü, A. (2016) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2016.14.1.96 · Cited by 10 · see citing works
How Loading Dose Strategies for Depot Paliperidone Can Go Wrong
Preskorn, S. (2022) · Journal of Psychiatric Practice · doi:10.1097/pra.0000000000000615 · Cited by 9 · see citing works
Helland, A., Syrstad, V. E. G., & Spigset, O. (2014) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000240 · Cited by 9 · see citing works
“In comparison, a prospective study of the pharmacokinetics of intramuscular paliperidone 150 mg monthly showed mean plasma concentrations of 35 and 40 ng/mL after the second and eighth injections, respectively.(4) He also showed a considerably longer elimination time after cessation of therapy than expected from the k…”
BackgroundRemmerie, B. M. M., Meulder, M. D., Ariyawansa, J., & Savitz, A. J. (2016) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.291 · Cited by 8 · see citing works
Self-citationKarslıoğlu, E. H., Kolcu, Z., Karslioğlu, N. İ., & Çayköylü, A. (2021) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.2827 · Cited by 8 · see citing works
“The prevalence of hyperprolactinemia we found is consistent with the values reported in the literature for high‐dose paliperidone palmitate use (Coppola et al., 2012).”
BackgroundResultInfluentialSavitz, A. J., Xu, H., Gopal, S., Nuamah, I. F., Mathews, M., & Soares, B. G. (2019) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2018-0153 · Cited by 8 · see citing works
Self-citationShimizu, H., Neyens, M., Meulder, M. D., Gopal, S., Tsukamoto, Y., Samtani, M. N., & Remmerie, B. M. M. (2019) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.737 · Cited by 8 · see citing works
Self-citationThe Switch From Paliperidone Long-Acting Injectable 1- to 3-Monthly
Mauri, M., Franco, G., Minutillo, A., Paletta, S., Pace, C. D., Reggiori, A., Baldelli, S., & Cattaneo, D. (2021) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001484 · Cited by 8 · see citing works
“com Regarding the metabolic profile, in our study, as in other previous ones, no significant changes were observed in laboratory tests (glycemia, total CHO, Try, GGT).(14,15,20,44) Regarding dyskinesia, the incidencewould probably cease to be relevant on a larger sample of patients, but it should be noted with concern…”
ResultSavitz, A. J., Xu, H., Gopal, S., Nuamah, I. F., Ravenstijn, P. G. M., Hough, D. W., & Hargarter, L. (2019) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s189668 · Cited by 7 · see citing works
Self-citationOhnishi, T., Wakamatsu, A., & Kobayashi, H. (2021) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s294503 · Cited by 5 · see citing works
“Pharmacokinetic studies demonstrated that PP1M achieves therapeutic, steady-state plasma levels rapidly on initiation without oral antipsychotics supplementation.(42,43) Such pharmacokinetics may explain early symptomatic improvement observed with PP1M therapy.”
BackgroundPharmacokinetic Correlates of Once-Monthly Paliperidone Palmitate-Related Adverse Drug Reactions
Schoretsanitis, G., Haen, E., Piacentino, D., Conca, A., Endres, K., Carpi, F., Hiemke, C., Gründer, G., & Paulzen, M. (2021) · Clinical Pharmacokinetics · doi:10.1007/s40262-021-01044-8 · Cited by 5 · see citing works
Snoeck, E., Luyckx, N., Lindauer, A., D., L. O., Anta, L., Martínez, J., & Gutierro, I. (2025) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2025.2594496 · Cited by 4 · see citing works
“…that the steady-state after once-monthly IM injections of PP1M was only achieved after a long period of treatment (about 8–9 months), as reported in a one-year prospective study [38], it remains unclear to what extent both treatments would achieve a similar D2RO during longer periods of treatment.”
Glaser, N., Reuser, M., Feistkorn, E., & Begemann, K. (2024) · Clinical Toxicology · doi:10.1080/15563650.2024.2333651 · Cited by 4 · see citing works
Richarz, U., Han, J. S., Bai, Y., Chen, E. Y. H., Chung, Y., Jhanwar, V. G., Kim, S., Sulaiman, A. H., Knight, K., & Gopal, S. (2023) · Medicine · doi:10.1097/md.0000000000034623 · Cited by 4 · see citing works
Self-citationQuitian, H., Arciniegas, J. A., Peñaranda, A. P. B., & Gómez–Restrepo, C. (2015) · Revista Colombiana de Psiquiatría · doi:10.1016/j.rcp.2015.05.013 · Cited by 4 · see citing works
“Adherencia 57,00% (19) [55,40%] – [58,90%] 47,30% (37) [5,60%] – [65,80%] 52,90% (32) [39,68%] – [66,30%) 40,30% (29) [20%] – [60%] 41,43% (13) [31,07%] – [51,79%) Parkinsonismo 27,42% (20) [20,25%] – [37%] 6% (37) [2%] – [32,40%] 0,90% (33) [0,68%] – [1,13%] 6,19% (14) [1,70%] – [28%] 17,02% (14) [12,77%] – [21,28%]…”
Boels, D., Mahé, J., Olry, A., Citterio‐Quentin, A., Moragny, J., & Jolliet, P. (2021) · Clinical Toxicology · doi:10.1080/15563650.2021.1878206 · Cited by 4 · see citing works
Schoretsanitis, G., Haen, E., Piacentino, D., Conca, A., Endres, K., Hiemke, C., Gründer, G., & Paulzen, M. (2021) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2022.2020641 · Cited by 4 · see citing works
Expansion of guidance for the day 8 initiation dose of paliperidone palmitate to avoid a missed dose
Samtani, M. N., Nuamah, I. F., Gopal, S., Remmerie, Sliwa, & Alphs, L. D. (2013) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s40836 · Cited by 4 · see citing works
“In order to evaluate the potential safety issues, we needed to determine whether this initial higher exposure would still be lower than the exposure observed with the previously tested highest initiation regimen of PP (150 mg eq on both days 1 and 8).(5,8) On the other hand, the”
InfluentialSelf-citationA case of recurrent acute pancreatitis due to paliperidone palmitate long-acting injectables (LAI)
Al-Ibrahim, A., & Francis, K. (2023) · Psychiatry Research Case Reports · doi:10.1016/j.psycr.2023.100203 · Cited by 2 · see citing works
Perlstein, I., Meyer, J. M., Yue, Z., Ivaturi, V. D., Franzenburg, K. R., Suett, M., Hansen, R., Wagner, A. M., Phatak, A., & Singh, R. (2025) · Advances in Therapy · doi:10.1007/s12325-025-03329-x · Cited by 1 · see citing works
“To accurately simulate the PK of PP1m and match it to the published PK profile from Coppola (2012) [28], ethnicity was randomly assigned to virtual subjects based on percentages listed in the demographics table.”
Indicators of treatment of schizophrenia in different stages of psychiatric care
Sofronov, A. G., Spikina, A., & Парфенов, Ю. А. (2014) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro201411411222-26 · Cited by 1 · see citing works
Jann, M. W., & Kennedy, W. K. (2016) · Springer eBooks · doi:10.1007/978-3-319-27883-4_7 · Cited by 1 · see citing works
Erdoğan, E. (2020) · Dusunen Adam The Journal of Psychiatry and Neurological Sciences · doi:10.14744/dajpns.2019.00065 · Cited by 1 · see citing works
“Longacting injectable (LAI) formulations of antipsychotic agents have been reported to provide advantages in the treatment of acute and maintenance of schizophrenia patients having difficulty in oral medication with relapse risk (2,3).”
BackgroundKim, E., Gopal, S., O’Donnell, A., Ramcharran, D., Mathews, M., & Singh, A. (2017) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2017.08.012 · Cited by 1 · see citing works
Self-citationSchizophrenia and Related Psychoses
(2025) · Wiley eBooks · doi:10.1002/9781119870203.mpg001.pub2 · Cited by 1 · see citing works
Audit of inpatient and outpatient paliperidone palmitate injection prescribing practices
Adewumi, A. D. (2016) · Journal of Pharmacy Practice and Research · doi:10.1002/jppr.1180
Solmi, M., Corbeil, O., Miguelez, M., Procyshyn, R. M., Blier, P., Barakat, M., & Correll, C. U. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15166393
“Comparative profile of selected LAI medications for psychosis for the treatment of schizophrenia with injection intervals up to every month [2,23,24].”
- Authors
- Coppola, D., Liu, Y., Gopal, S., Remmerie, B., Samtani, M. N., Hough, D. W., Nuamah, I., Sulaiman, A., & Pandina, G.
- Affiliations
- Janssen Research & Development (United States) (US)
- Janssen (Belgium) (BE)
- University of Malaya (MY)
- Corresponding author
- Coppola, Danielle
- Venue
- BMC Psychiatry
- Published
- 2012-03-28
- Volume
- 12
- Issue
- 1
- Pages
- 26-26
- ISSN
- 1471-244X (ISSN-L)
- PMC
- PMC3384238
- OpenAlex
- W2096393984
- Cited by
- 61
- References
- 34
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 8 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 8 · 2016: 7 · 2015: 5 · 2014: 7 · 2013: 3 · 2012: 3
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The University of Malaya Research Repository (University of Malaya) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- paliperidone palmitate, schizophrenia, long-acting injectable antipsychotics, pharmacokinetics, safety and tolerability, deltoid injection, gluteal injection, treatment-emergent adverse events, akathisia, antipsychotic dose reduction, dose titration, antipsychotic switching
- MeSH terms
- Paliperidone Palmitate, Adolescent, Adult, Aged, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Injections, Intramuscular, Isoxazoles, Male, Middle Aged, Palmitates, Prospective Studies, Psychiatric Status Rating Scales, Schizophrenia, Schizophrenic Psychology, Antipsychotic Agents, Treatment Failure
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