Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs
- John Lauriello, MD
John Lauriello, MD
- Professor of Psychiatry
- University of Missouri
- Austin R Campbell, PharmD, BCPP
Austin R Campbell, PharmD, BCPP
- Adjunct Clinical Assistant Professor of Psychiatry
- University of Missouri School of Medicine and University of Missouri - Kansas City School of Pharmacy
The unpleasant adverse effects of antipsychotic drugs combined with patients’ disbelief of having an illness, which is common among individuals with schizophrenia, result in high rates of nonadherence to antipsychotics in the treatment of schizophrenia.
Long-acting injectable (LAI) antipsychotics are a pharmacologic strategy for treating patients with schizophrenia who relapse due to nonadherence to antipsychotic medication. Rather than the daily pill-taking required with oral antipsychotics, LAI antipsychotics are administered by injection at two to four week intervals.
This topic addresses the use of LAI antipsychotics in the treatment of schizophrenia. The pharmacology, administration, comparative side effects and treatment of schizophrenia with standard (non-LAI) antipsychotics are discussed separately as is the management of antipsychotic side effects. The epidemiology, clinical manifestations, and diagnosis of schizophrenia are discussed separately. (See "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Pharmacotherapy for schizophrenia: Side effect management" and "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Schizophrenia in adults: Epidemiology and pathogenesis".)
LONG-ACTING INJECTABLE ANTIPSYCHOTICS
Six antipsychotic medications are currently available in the United States (US) as long-acting injections. Naming conventions vary among agents. As listed below, this topic uses the format: medication name followed by “LAI.”
●Aripiprazole extended release (aripiprazole-LAI)
- Davis JM. Maintenance therapy and the natural course of schizophrenia. J Clin Psychiatry 1985; 46:18.
- Valenstein M, Blow FC, Copeland LA, et al. Poor antipsychotic adherence among patients with schizophrenia: medication and patient factors. Schizophr Bull 2004; 30:255.
- Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 1998; 49:196.
- Fluphenazine Decanoate [package insert]. Schaumberg, IL: APP Pharmaceuticals, LLC; 2010.
- Haloperidol Decanoate [package insert]. Titusville, NJ: Janssen, division of Ortho-McNeil-Janssen Pharmaceuticals Inc; 2011.
- Ravenstijn P, Remmerie B, Savitz A, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: A phase-1, single-dose, randomized, open-label study. J Clin Pharmacol 2016; 56:330.
- Aristada [package insert]. Waltham, MA: Alkermes Inc; 2017.
- Turncliff R, Hard M, Du Y, et al. Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia. Schizophr Res 2014; 159:404.
- Belanger MC, Chouinard G. Technique for injecting long-acting neuroleptics. Br J Psychiatry 1982; 141:316.
- Schooler NR, Levine J. The initiation of long-term pharmacotherapy in schizophrenia: dosage and side effect comparisons between oral and depot fluphenazine. Pharmakopsychiatr Neuropsychopharmakol 1976; 9:159.
- Ereshefsky L, Saklad SR, Jann MW, et al. Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches. J Clin Psychiatry 1984; 45:50.
- Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet 1985; 10:315.
- Abilify Maintena (aripiprazole) US Prescribing Information http://www.otsuka-us.com/Products/Documents/Abilify.M.PI.pdf (Accessed on January 15, 2016).
- Hard ML, Mills RJ, Sadler BM, et al. Pharmacokinetic Profile of a 2-Month Dose Regimen of Aripiprazole Lauroxil: A Phase I Study and a Population Pharmacokinetic Model. CNS Drugs 2017; 31:617.
- Zyprexa Relprevv [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.
- Paliperidone palmitate. FDA approved product information. US National Library of Medicine. (Available online at www.dailymed.nlm.nih.gov, accessed February 14, 2013)
- Invega Sustenna [package insert]. Titusville, NJ: Janssen, division of Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2015.
- Invega Trinza [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2015.
- Risperdal Consta [package insert]. Titusville, NJ: Janssen, division of Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2014.
- David A, Adams CE, Eisenbruch M, et al. Depot fluphenazine decanoate and enanthate for schizophrenia. Cochrane Database Syst Rev 2005; :CD000307.
- Deberdt R, Elens P, Berghmans W, et al. Intramuscular haloperidol decanoate for neuroleptic maintenance therapy. Efficacy, dosage schedule and plasma levels. An open multicenter study. Acta Psychiatr Scand 1980; 62:356.
- Kane JM, Davis JM, Schooler N, et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. Am J Psychiatry 2002; 159:554.
- Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2012; 73:617.
- Kane JM, Peters-Strickland T, Baker RA, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2014; 75:1254.
- 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; 76:1085.
- Chue P, Eerdekens M, Augustyns I, et al. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol 2005; 15:111.
- Kane JM, Eerdekens M, Lindenmayer JP, et al. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003; 160:1125.
- Fleischhacker WW, Eerdekens M, Karcher K, et al. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry 2003; 64:1250.
- Nasrallah HA, Gopal S, Gassmann-Mayer C, et al. A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology 2010; 35:2072.
- Nussbaum AM, Stroup TS. Paliperidone palmitate for schizophrenia. Cochrane Database Syst Rev 2012; :CD008296.
- Berwaerts J, Liu Y, Gopal S, et al. Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry 2015; 72:830.
- Hough D, Gopal S, Vijapurkar U, et al. Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 2010; 116:107.
- Lauriello J, Lambert T, Andersen S, et al. An 8-week, double-blind, randomized, placebo-controlled study of olanzapine long-acting injection in acutely ill patients with schizophrenia. J Clin Psychiatry 2008; 69:790.
- Adams CE, Fenton MK, Quraishi S, David AS. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry 2001; 179:290.
- Haddad PM, Taylor M, Niaz OS. First-generation antipsychotic long-acting injections v. oral antipsychotics in schizophrenia: systematic review of randomised controlled trials and observational studies. Br J Psychiatry Suppl 2009; 52:S20.
- Bai YM, Ting Chen T, Chen JY, et al. Equivalent switching dose from oral risperidone to risperidone long-acting injection: a 48-week randomized, prospective, single-blind pharmacokinetic study. J Clin Psychiatry 2007; 68:1218.
- Keks NA, Ingham M, Khan A, Karcher K. Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder. Randomised, controlled, open-label study. Br J Psychiatry 2007; 191:131.
- Tiihonen J, Mittendorfer-Rutz E, Majak M, et al. Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia. JAMA Psychiatry 2017; 74:686.
- Rosenheck RA, Krystal JH, Lew R, et al. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med 2011; 364:842.
- Buckley PF, Schooler NR, Goff DC, et al. Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study. Schizophr Bull 2015; 41:449.
- 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; 76:554.
- Schreiner A, Aadamsoo K, Altamura AC, et al. Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr Res 2015; 169:393.
- McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 311:1978.
- Naber D, Hansen K, Forray C, et al. Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia. Schizophr Res 2015; 168:498.
- McDonnell DP, Sorsaburu S, Brunner E, et.al. Injection-related adverse events observed with olanzapine long-acting injection. Poster presented at the Annual Meeting of the Collegium Internationale Neuro-Psychopharmacologicum. July 13-17, 2008. Munich, Germany
- Citrome L. Olanzapine pamoate: a stick in time? A review of the efficacy and safety profile of a new depot formulation of a second-generation antipsychotic. Int J Clin Pract 2009; 63:140.
- Gulliver A, McDonnell DP, Sorsaburu S, et.al. Injection-related adverse events observed with olanzapine long-acting injection [abstract]. Int J Neuropsychopharmacol 2008; 11:152
- Detke HC, McDonnell DP, Brunner E, et al. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases. BMC Psychiatry 2010; 10:43.
- Zyprexa Relprevv (Olanzapine Pamoate): Drug Safety Communication - FDA Investigating Two Deaths Following Injection http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm357601.htm (Accessed on June 21, 2013).
- FDA Drug Safety Communication: FDA is investigating two deaths following injection of long-acting antipsychotic Zyprexa Relprevv (olanzapine pamoate). http://www.fda.gov/Drugs/DrugSafety/ucm356971.htm (Accessed on July 01, 2013).
- LONG-ACTING INJECTABLE ANTIPSYCHOTICS
- ANTIPSYCHOTIC NONADHERENCE
- Aripiprazole lauroxil-LAI
- Paliperidone 12-week-LAI
- ADVERSE EVENTS
- Postinjection delirium sedation syndrome
- SUMMARY AND RECOMMENDATIONS