Schizophrenia is considered to involve a range of cognitive, behavioral, and emotional dysfunction that can be broadly classified into several domains, including positive, negative, and cognitive symptoms. Positive symptoms include delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior.1 Disorganized speech can lead to frequent derailment and incoherence. Negative symptoms include flat affect, with lack of pleasure and difficulty in sustaining activities.1 Cognitive symptoms include poor executive functioning and problems with working memory.1

The lifetime prevalence of schizophrenia is estimated to be 0.3% to 0.7%.1 The peak age for onset of the first psychotic episode is in the early to mid-20s for men and in the late 20s for women.1 It is a chronic disorder that results in functional impairment and imposes an economic burden on the health care system with estimated direct medical costs ranging from $43 to $58 billion annually.2 The pathogenesis of schizophrenia is complex and is based on the dopamine hypothesis.3 Recent advances show the dysfunction of other neuronal pathways including glutamatergic, serotonergic, cholinergic, and gamma aminobutyric acid pathways.3

Treatment of schizophrenia can be challenging and difficult. Current guidelines suggest long-term treatment with antipsychotic medications, along with psychosocial intervention, both for the first psychotic break and for acute exacerbation of psychotic symptoms in patients with chronic schizophrenia.3 Barriers to treatment include nonadherence, negative and cognitive symptoms, and side effects of medications. The risk of relapse is 77% in the first year and up to 90% in the following 2 years for both the first and subsequent psychotic episodes due to nonadherence.4 Several factors contribute to nonadherence: negative symptoms, involvement with the criminal justice system, comorbid substance abuse disorder, unemployment, and a poor family or social support system.2,4

Dopamine-modulating drugs are the mainstay of treatment for schizophrenia. The medications are mostly effective for positive symptoms, leaving the negative and cognitive symptoms mostly unaddressed, resulting in functional impairment with a poor quality of life.4 No medication has been approved by the US Food and Drug Administration for negative and cognitive symptoms. So far, augmentation strategies that are in use are mostly disappointing.3 Most of the medications have an effect on dopamine D2 receptors, resulting in extrapyramidal effects and hyperprolactinemia.3 The effects of these medications on off-target receptors result in other side effects, including weight gain, sedation, metabolic abnormalities, and cardiovascular risk factors.3 These side effects compromise medication adherence resulting in nonadherence, which can lead to decompensation. New treatment modalities are required that can effectively target negative and cognitive symptoms with less side effects to encourage treatment adherence.

What Is Paliperidone?

 The chemical name for paliperidone is 9-hydroxy-risperidone, which is an active metabolite of risperidone. This subtle change in structure is caused by adding the hydroxyl group, which results in significant difference in functioning.5 Compared with risperidone, paliperidone is a weak antagonist at the 5-HT2A receptor, which results in a lower 5-HT2A/D2 affinity ratio.5 Bioavailability of oral paliperidone is <30%  compared with 100% for risperidone.5 Plasma protein binding of paliperidone is 74% vs 90% in risperidone.5 Risperidone is mainly metabolized in the liver via cytochrome P450 2D6, whereas paliperidone has less hepatic metabolism and 60% of the drug is excreted by the kidneys unchanged.5  Therefore, metabolism of paliperidone is not significantly affected by drugs that affect the cytochrome P450 enzyme system.

Paliperidone in the form of a long-acting injectable (LAI) agent is dispensed as a water solution of nanocrystals of the ester.5 Hydrolysis is relatively rapid at the injection site,5 which results in an effect within the first few days of treatment. Clinically significant levels of paliperidone are present after the first injection, and maximum drug level is achieved on the 12th postinjection day.5 Administration in the deltoid muscle results in a 30% increase in serum level as compared with gluteal injection.5

Treatment nonadherence with LAI agents was identified as an issue of concern soon after the discovery of oral antipsychotics in the 1950s.6 This led to development of the first LAI antipsychotic agent, fluphenazine, in the 1960s, followed by haloperidol approximately 20 years later.6 Although oral second-generation antipsychotics were anticipated to be associated with less severe effects, rates of adherence did not improve with the use of these agents.6

The LAI formulation of second-generation antipsychotic agents is useful for the early treatment of schizophrenia.5  These agents are convenient to use with less-frequent dosing and have been found to improve treatment adherence (relapse rate with risperidone LAI was <5% vs 33% with oral administration).5 LAIs bypass first-pass metabolism in the liver, which results in consistent bioavailability and establishes a strong correlation between dose and plasma levels, thereby minimizing adverse effects.6 LAI administration helps with reducing the risk of unintentional or deliberate overdose, thus enhancing patient safety from self-harm. A structured interview of 24 patients who were treated with LAI antipsychotics showed that patients expressed satisfaction with their current mental and physical wellbeing.7 Apart from the benefits of LAIs, there are some limitations of their use that include slow dose titration, longer time for relief in case of side effects, pain at the injection site, and perception of stigma.6 Educating patients and their families about the chronic disease course and the importance of treatment adherence can help in overcoming the perception of stigma associated with the use of LAI antipsychotic agents.

Paliperidone is available both as an oral agent and in an LAI. Paliperidone LAI is available as 2 formulations of paliperidone palmitate: monthly injectable (PP1M) and a 3-month formulation (PP3M). PP1M was approved by the FDA in 2009 for clinical use, whereas PP3M was approved by the FDA in 2015 and by the European Medicines Agency in 2016.8 PP1M has been found to be effective and safe in the acute and maintenance phases of schizophrenia,9 and both PP1M and PP3M have established efficacy in relieving the positive symptoms and associated depressive and anxiety symptoms.8  When initiating treatment with PP3M, PP1M is recommended for the initial 4 months with the equivalent PP3M dose that is a 3.5-fold dose multiplier of the stable PP1M dosage.8

In an open-label, randomized, controlled trial (Prevention of Relapse With Oral Antipsychotics vs Injectable Paliperidone Palmitate [PROSIPAL]; Identifier: NCT01081769), patients diagnosed with schizophrenia within 1 to 5 years were randomly assigned to either paliperidone or an oral antipsychotic medication.10 Paliperidone was administered as 150 mg on day 1, 100 mg on day 8, and 75 mg on day 38, followed by a monthly flexible dose that ranged from 25 mg to 150 mg for 24 months. Time to relapse was longer in the PP1M group compared with those who were treated with oral antipsychotics (85% of patients in the PP1M group were relapse-free by 469 days vs 249 days in patients who were treated with oral antipsychotic medications [P =.019]). Relapse criteria were met by 14.8% of patients in the PP1M group vs 20.9% in the oral antipsychotic group, representing a 29.4% relative risk reduction with the use of PP1M.10

Similarly, the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE; Identifier: NCT01157351) is another multicenter trial that was conducted at 50 sites in the United States to establish efficacy in a real-world population to increase the generalizability of results.2 This study enrolled 444 patients with schizophrenia and a history of incarceration. In this randomized, open-label, parallel-arm trial, patients were randomly assigned to either paliperidone or an oral antipsychotic medication for 15 months. Paliperidone was given as an intramuscular injection in the deltoid at 234 mg on day 1 and 156 mg on day 8, followed by a monthly flexible dose ranging from 74 mg to 234 mg starting from day 38. The primary study end point was treatment failure, which was defined by criteria including by not limited to arrest or incarceration, decompensation to the point of psychiatric hospitalization, suicide attempt, or discontinuation of antipsychotic treatment because of a lack of efficacy. Treatment failure was experienced by 39.8% in the paliperidone group vs 53.7% in the oral antipsychotic groups, demonstrating statistically significant superiority of paliperidone (P =.011).2

A retrospective study comparing the efficacy of LAIs paliperidone, haloperidol, and aripiprazole showed  equal efficacy among all 3 agents after 6 to 12 months of treatment.4 The safety profiles of LAI second-generation antipsychotics including aripiprazole, risperidone, paliperidone, and olanzapine have been found to be similar to their oral counterparts, with the exception of post-injection delirium and sedation syndrome seen with olanzapine LAI.8

Research has shown that paliperidone is well tolerated, and the incidence of extrapyramidal symptoms and weight gain is low.5 In a meta-analysis, paliperidone LAI was found to have a higher number needed to harm compared with haloperidol LAI with regard to movement disorders such as akathisia, tremors, and tardive dyskinesia.11

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A randomized, double-blind, phase 3 study compared PP3M and PP1M in European and non-European patients who were naive to treatment with paliperidone or risperidone.12 This study had 4 phases: 3 weeks of screening during which patients received paliperidone extended release 6 mg/d orally for 4 to 6 days; 17 weeks of open-label stabilization during which patients received PP1M 156 mg injected into the deltoid on day 1 and 100 mg on day 8 followed by flexible doses of 50 mg, 75 mg, 100 mg, or 150 mg on weeks 5 and 9 (the week 9 dose was continued to week 13); 48 weeks of double-blind phase; and 4 to 12 weeks of follow-up. The double-blind, 48-week parallel arm involved clinically stable patients (defined as <70 on the Positive and Negative Syndrome Scale) receiving either a fixed dose of paliperidone 175 mg, 263 mg, 350 mg, or 525 mg on weeks 17, 29, 41, and 53 (PP3M) or continuation of the week 13 dose on a monthly basis as a fixed dose throughout (PP1M). Similar efficacy was seen between PP1M and PP3M in both European and non-European populations in large sample sizes as noted by the number of patients being relapse-free (primary end point). The secondary end point, which included the Positive and Negative Syndrome Scale total score, also showed comparable improvement among the 2 groups.12

Research studies establishing the cost-effectiveness of paliperidone LAI have presented varying conclusions. A study conducted in Sweden compared the cost-effectiveness of paliperidone LAI 75 mg/mo vs risperidone LAI 37.5 mg every 2 weeks and olanzapine 300 mg/mo in a 5-year observational cohort. Treatment with paliperidone LAI was found to be cost-effective with better outcomes in the form of increased quality-adjusted life years (QALY).13 The cost reduction was due to less hospitalizations in the paliperidone LAI arm (40.1%) vs risperdal LAI (40.5%) and olanzapine LAI (48.6%). A  study conducted in the Czech Republic comparing paliperidone LAI, risperidone LAI, and olanzapine LAI showed similar results in terms of efficacy and cost-effectiveness.14 Improvement was shown in QALY with fewer emergency department visits and hospitalizations in patients who were treated with paliperidone compared with patients receiving the other 2 agents.14 A 5-year observational study conducted in Germany compared the cost-effectiveness of paliperidone LAI, risperidone LAI, and olanzapine LAI, among other agents.15 Although patients treated with paliperidone LAI showed few relapses and a greater number of QALY score, the overall cost with paliperidone LAI was slightly higher than with olanzapine.15 In the United States, the cost-effectiveness of paliperidone LAI was compared with aripiprazole LAI; aripiprazole LAI was shown to be cost-effective in this study vs paliperidone LAI in terms of fewer relapses and less hospitalizations.16 Another study assessing the cost-effectiveness of haloperidol decanoate vs paliperidone LAI revealed haloperidone to be cost-effective as compared with paliperidone LAI.17 Further research studies are therefore required to elaborate the cost-effectiveness of paliperidone in relation to other second-generation antipsychotic LAI agents.

Nonadherence is a persistent and challenging issue in the treatment of individuals with schizophrenia. Although several second-generation antipsychotic LAIs are available for treatment, some of them require an initial loading dose or concomitant oral medication. The intramuscular injection method has its own limitations, especially pain at the injection site. The FDA approval of aripiprazole lauroxil by injection came about as a result of the agent achieving faster efficacy with the first dose, thereby eliminating the need for oral supplementation.18 Similarly, the FDA approved RBP-7000 (risperidone) in July 2018 as the first LAI to be used subcutaneously.3 Comparison with the former risperidone LAI, RBP-7000 does not require initial oral medication and is dispensed as a once-monthly depot formulation. Similarly, risperidone extended release in subcutaneous formulation in variable doses (TV46000) is under investigation with results of the trials expected in 2023. A phase 3 trial for a paliperidone 6-month formulation is also currently underway.3

Research is ongoing to find ways to minimize side effects with antipsychotic medications. Tardive dyskinesia is a side effect that presents a barrier to the use of antipsychotic agents. The FDA has approved valbenazine and deutetrabenazine for the treatment of tardive dyskinesia associated with antipsychotic agents in the management of schizophrenia.3  To address another side effect of treatment for schizophrenia, the ALKS 3831 study ( Identifier: NCT02873208) is exploring ways to minimize weight gain with olanzapine by adding samidorphan, an opioid antagonist.3 Other innovative treatment options for schizophrenia that are the subject of future research include F17464 (a D3 antagonist/5HT1A partial agonist), lumateperone (which has an effect on NMDA GluN2B receptors), phosphodiesterase inhibitors that act on dopamine and glutamate receptors, and trace amine-associated receptor 1 agonists.3 These novel studies will help to explore future options targeting negative and cognitive symptoms that will contribute to treatment adherence.


1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.

2. Alphs L, Benson C, Cheshire-Kinney K, et al. Real-world outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a randomized, open-label, review board-blinded 15-month study. J Clin Psychiatry. 2015;76(5):554-561.

3. Krogmann A, Peters L, von Hardenberg L, Bodeker K, Nöhles VB, Correll CU. Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. CNS Spectr. 2019;24(S1):38-69.

4. Di Lorenzo R, Ferri P, Cameli M, Rovesti S, Piemonte C. Effectiveness of 1-year treatment with long-acting formulation of aripiprazole, haloperidol, or paliperidone in patients with schizophrenia: retrospective study in a real-world clinical setting. Neuropsychiatric Dis Treat. 2019;15:183-198.

5. Jarema M, Bieńkowski P, Heitzman J, Parnowski T, Rybakowski J. Paliperidone palmitate: effectiveness, safety, and the use for treatment of schizophrenia. Psychiatr Pol. 2017;51(1):7-21.

6. Brissos S, Veguilla MR, Taylor D, Balanzá-Martinez V. The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Ther Adv Psychopharmacol. 2014;4(5):198-219.

7. Mollerhoj J, Os Stolan L, Erdner A, et al. “I live, I don’t work, but I live a very normal life” — a qualitative interview study of Scandinavian user experiences of schizophrenia, antipsychotic medication, and personal recovery processes [published online October 21, 2019]. Perspect Psychiatr Care. doi: 10.1111/ppc.12444

8. Mathews M, Gopal S, Nuamah I, et al. Clinical relevance of paliperidone palmitate 3-monthly in treating schizophrenia. Neuropsychiatr Dis Treat. 2019;15:1365-1379.

9. Brown B, Turkoz I, Mancevski B, Mathews M. Evaluation of paliperidone palmitate long-acting injectable antipsychotic therapy as an early treatment option in patients with schizophrenia [published online September 13, 2019]. Early Interv Psychiatry. doi: 10.1111/eip.12868

10. Schreiner A, Aadamsoo K, Altamura AC, et al. Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr Res. 2015;169(1-3):393-399.

11. Morris MT, Tarpada SP. Long-acting injectable paliperidone palmitate: a review of efficacy and safety. Psychopharmacol Bull. 2017;47(2):42-52.

12. Savitz AJ, Xu H, Gopal S, et al. Efficacy and safety of paliperidone palmitate 3-month versus 1-month formulation in patients with schizophrenia: comparison between European and non-European population. Neuropsychiatr Dis Treat. 2019;15:587-602.

13. Mehnert A, Nicholl D, Pudas H, Martin M, McGuire A. Cost effectiveness of paliperidone palmitate versus risperidone long-acting injectable and olanzapine pamoate for the treatment of patients with schizophrenia in Sweden. J Med Econ. 2012;15(5):844-861.

14. Einarson TR, Zilbershtein R, Skoupá J, Veselá Š, Garg M, Hemels ME. Economic and clinical comparison of atypical depot antipsychotic drugs for treatment of chronic schizophrenia in the Czech Republic. J Med Econ. 2013;16(9):1089-1095.

15. Zeidler J, Mahlich J, Greiner W, Heres S. Cost effectiveness of paliperidone palmitate for the treatment of schizophrenia in Germany. Appl Health Econ Health Policy. 2013;11(5):509-521.

16. Citrome L, Kamat SA, Sapin C, et al. Cost-effectiveness of aripiprazole once-monthly compared with paliperidone palmitate once-monthly injectable for the treatment of schizophrenia in the United States. J Med Econ. 2014;17(8):567-576.

17. Rosenheck RA, Leslie DL, Sint KJ, et al. Cost-effectiveness of long-acting injectable paliperidone palmitate versus haloperidol decanoate in maintenance treatment of schizophrenia. Psychiatr Serv. 2016;67(10):1124-1130.

18. Meltzer HY, Risinger R, Nasrallah HA, et al. A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. 2015;76(8):1085-1090.