Abstract
Antipsychotics are the mainstay of the long-term treatment of patients with schizophrenia. In this context, the evidence also supports the effectiveness of long-acting injections (LAIs) or depots of antipsychotics regarding their relapse-preventing properties. When a LAI formulation of risperidone was launched as the first second-generation depot, there was a renaissance of interest in these formulations. In the meantime, olanzapine, paliperidone, and aripiprazole have been approved by regulatory authorities as LAIs in various countries. All studies using the new-generation depots have shown a clear advantage over placebo regarding relapse prevention and symptom reduction. Safety profiles of the long-acting compounds are comparable to their oral formulations with the exception of olanzapine pamoate injections, which can sometimes lead to a post-injection delirium. Despite the fact that many treatment guidelines recommend LAI antipsychotics as an important treatment option for the long-term management of schizophrenia, they are still most frequently used in chronically ill patients with considerable compliance problems. It is imperative to overcome this indication bias in order to be able to utilize all available treatment options in the long-term management of schizophrenia. There is little evidence on comparisons between LAIs and their oral mother compounds, and even less concerning effectiveness comparisons between different depots. The purpose of this manuscript is to review the recent clinical evidence on new-generation depot antipsychotics.
Similar content being viewed by others
References
Goff DC, Hill M, Freudenreich O. Strategies for improving treatment adherence in schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2010;71(Suppl 2):20–6.
Patel MX, Nikolaou V, David AS. Psychiatrists’ attitudes to maintenance medication for patients with schizophrenia. Psychol Med. 2003;33(1):83–9.
Heres S, Hamann J, Kissling W, et al. Attitudes of psychiatrists toward antipsychotic depot medication. J Clin Psychiatry. 2006;67(12):1948–53.
Harrison TS, Goa KL. Long-acting risperidone: a review of its use in schizophrenia. CNS Drugs. 2004;18(2):113–32.
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(6):1125–32.
Chue P, Eerdekens M, Augustyns I, et al. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharm. 2005;15(1):111–7.
Turner M, Eerdekens E, Jacko M, et al. Long-acting injectable risperidone: safety and efficacy in stable patients switched from conventional depot antipsychotics. Int Clin Psychopharmacol. 2004;19(4):241–9.
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(10):1250–7.
Fleischhacker WW. Second-generation antipsychotic long-acting injections: systematic review. Br J Psychiatr Suppl. 2009;52:S29–36.
Fleischhacker WW, Gopal S, Lane R, et al. A Randomized Trial of Paliperidone Palmitate and Risperidone Long-Acting Injectable in Schizophrenia. Int J Neuropsychopharmacol. p. 1–12. [Epub 2011 Jul 22].
Pandina G, Lane R, Gopal S, et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Progress Neuro-Psychopharm. 2011;35(1):218–26.
Macfadden W, Ma YW, Thomas Haskins J, et al. A prospective study comparing the long-term effectiveness of injectable risperidone long-acting therapy and oral aripiprazole in patients with schizophrenia. Psychiatry. 2010;7(11):23–31.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76.
Andreasen NC, Carpenter WT Jr, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162(3):441–9.
Gaebel W, Schreiner A, Bergmans P, et al. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology. 2010;35(12):2367–77.
Csernansky JG, Mahmoud R, Brenner R. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. New Engl J Med. 2002;346(1):16–22.
Rosenheck RA, Krystal JH, Lew R, et al. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. New Engl J Med. 2011;364(9):842–51.
Morosini PL, Magliano L, Brambilla L, et al. Development, reliability and acceptability of a new version of the DSM-IV social and occupational functioning assessment scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101(4):323–9.
Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med. 1983;13(1):177–83.
Quiroz JA, Rusch S, Thyssen A, et al. Deltoid Injections of risperidone long-acting injectable in patients with schizophrenia. Innov Clin Neurosci. 2011;8(6):20–8.
Olivares JM, Rodriguez-Morales A, Diels J, et al. Long-term outcomes in patients with schizophrenia treated with risperidone long-acting injection or oral antipsychotics in Spain: results from the electronic schizophrenia treatment adherence registry (e-STAR). Eur Psychiatry. 2009;24(5):287–96.
Guy W. Ecdeu assessment manual for psychopharmacology. Revised ed. Rockville, MD: National Institute of Mental Health; 1976. p. 218–22.
Endicott J, Spitzer RL, Fleiss JL, et al. The global assessment scale: a procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry. 1976;33(6):766–71.
Macfadden W, DeSouza C, Crivera C, et al. Assessment of effectiveness measures in patients with schizophrenia initiated on risperidone long-acting therapy: the source study results. BMC Psychiatry. 2011;11:167.
Strauss JS, Carpenter WT. Prediction of outcome in schizophrenia: III. Five-year outcome and its predictors. Arch Gen Psychiatry. 1977;34(2):159–63.
Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care. 1992;30(6):473–83.
Lambert T, Olivares JM, Peuskens J, et al. Effectiveness of injectable risperidone long-acting therapy for schizophrenia: data from the US, Spain, Australia, and Belgium. Ann Gen Psychiatry. 2011;10:10.
Covell NH, McEvoy JP, Schooler NR, et al. Effectiveness of switching from long-acting injectable fluphenazine or haloperidol decanoate to long-acting injectable risperidone microspheres: an open-label, randomized controlled trial. J Clin Psychiatry. 2012;73(5):669–75. [Epub 2012 March 6].
Weiden PJ, Schooler NR, Weedon JC, et al. A randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J Clin Psychiatry. 2009;70(10):1397–406.
Weiden P, Rapkin B, Mott T, et al. Rating of medication influences (ROMI) scale in schizophrenia. Schizophr Bull. 1994;20(2):297–310.
Emsley R, Oosthuizen P, Koen L, et al. Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection. Int Clin Psychopharmacol. 2008;23(6):325–31.
Grimaldi-Bensouda L, Rouillon F, Astruc B, et al. Does long-acting injectable risperidone make a difference to the real-life treatment of schizophrenia? Results of the cohort for the general study of schizophrenia (CGS). Schizophr Res. 2012;134(2–3):187–94.
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl. 20:22–33;quiz 4-57.
Wiffen BD, Rabinowitz J, Fleischhacker WW, et al. Insight: demographic differences and associations with one-year outcome in schizophrenia and schizoaffective disorder. Clin Schizophr Relat Psychoses. 2010;4(3):169–75.
Mintz AR, Addington J, Addington D. Insight in early psychosis: a 1-year follow-up. Schizophr Res. 2004;67(2–3):213–7.
Lysaker PH, Bell MD, Bryson G, et al. Personality as a predictor of the variability of insight in schizophrenia. J Nerv Ment Dis. 1999;187(2):119–22.
Parellada E, Kouniakis F, Siurkute A, et al. Safety and efficacy of long-acting injectable risperidone in daily practice: an open-label, noninterventional, prospective study in schizophrenia and related disorders. Int Clin Psychopharmacol. 2010;25(3):149–54.
Rossi A, Bagala A, Del Curatolo V, et al. Remission in schizophrenia: one-year italian prospective study of risperidone long-acting injectable (RLAI) in patients with schizophrenia or schizoaffective disorder. Hum Psychopharmacol. 2009;24(7):574–83.
Emsley R, Oosthuizen PP, Koen L, et al. Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-year open-label clinical study. J Clin Psychiatry. 2012;73(4):e541–7.
Lloyd K, Latif MA, Simpson S, et al. Switching stable patients with schizophrenia from depot and oral antipsychotics to long-acting injectable risperidone: efficacy, quality of life and functional outcome. Hum Psychopharmacol. 2010;25(3):243–52.
Schmauss M, Diekamp B, Gerwe M, et al. Does oral antipsychotic pre-treatment influence outcome of a switch to long-acting injectable risperidone in patients with schizophrenia? Pharmacopsychiatry. 2010;43(2):73–80.
Lindenmayer JP, Eerdekens E, Berry SA, et al. Safety and efficacy of long-acting risperidone in schizophrenia: a 12-week, multicenter, open-label study in stable patients switched from typical and atypical oral antipsychotics. J Clin Psychiatry. 2004;65(8):1084–9.
Moller HJ, Llorca PM, Sacchetti E, et al. Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies. Int Clin Psychopharmacol. 2005;20(3):121–30.
Llorca PM, Sacchetti E, Lloyd K, et al. Long-term remission in schizophrenia and related psychoses with long-acting risperidone: results obtained in an open-label study with an observation period of 18 months. Int J Clin Pharmacol Ther. 2008;46(1):14–22.
Kissling W, Glue P, Medori R, et al. Long-term safety and efficacy of long-acting risperidone in elderly psychotic patients. Hum Psychopharmacol. 2007;22(8):505–13.
Taylor D, Fischetti C, Sparshatt A, et al. Risperidone long-acting injection: a 6-year mirror-image study of healthcare resource use. Acta Psychiatr Scand. 2009;120(2):97–101.
Carswell C, Wheeler A, Vanderpyl J, et al. Comparative effectiveness of long-acting risperidone in New Zealand: a report of resource utilization and costs in a 12-month mirror-image analysis. Clin Drug Investig. 2010;30(11):777–87.
De la Gandara J, San Molina L, Rubio G, et al. Experience with injectable long-acting risperidone in long-term therapy after an acute episode of schizophrenia: the sphere study. Expert Rev Neurother. 2009;9(10):1463–74.
Tiihonen J, Haukka J, Taylor M, et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011;168(6):603–9.
Thyssen A, Rusch S, Herben V, et al. Risperidone long-acting injection: pharmacokinetics following administration in deltoid versus gluteal muscle in schizophrenic patients. J Clin Pharmacol. 2010;50(9):1011–21.
Bartzokis G, Lu PH, Amar CP, et al. Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory. Schizophr Res. 2011;132(1):35–41.
Surguladze SA, Chu EM, Marshall N, et al. Emotion processing in schizophrenia: fMRI study of patients treated with risperidone long-acting injections or conventional depot medication. J Psychopharmacol. 2011;25(6):722–33.
Morris JS, Frith CD, Perrett DI, et al. A differential neural response in the human amygdala to fearful and happy facial expressions. Nature. 1996;383(6603):812–5.
Phillips ML, Young AW, Senior C, et al. A specific neural substrate for perceiving facial expressions of disgust. Nature. 1997;389(6650):495–8.
Doknic M, Maric NP, Britvic D, et al. Bone remodeling, bone mass and weight gain in patients with stabilized schizophrenia in real-life conditions treated with long-acting injectable risperidone. Neuroendocrinology. 2011;94(3):246–54.
Rabinowitz J, Napryeyenko O, Burba B, et al. Premorbid functioning and treatment response in recent-onset schizophrenia: prospective study with risperidone long-acting injectable. J Clin Psychopharmacol. 2011;31(1):75–81.
Cannon-Spoor HE, Potkin SG, Wyatt RJ. Measurement of premorbid adjustment in chronic schizophrenia. Schizophr Bull. 1982;8(3):470–84.
Marder SR, Kramer M, Ford L, et al. Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry. 2007;62(12):1363–70.
Davidson M, Emsley R, Kramer M, et al. Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res. 2007;93(1–3):117–30.
Kramer M, Simpson G, Maciulis V, et al. Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2007;27(1):6–14.
Kane J, Canas F, Kramer M, et al. Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res. 2007;90(1–3):147–61.
Citrome L. Paliperidone palmitate: review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication. Int J Clin Pract. 2010;64(2):216–39.
Kramer M, Litman R, Hough D, et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia: results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol. 2010;13(5):635–47.
Gopal S, Hough DW, Xu H, et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. Int Clin Psychopharmacol. 2010;25(5):247–56.
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(2–3):107–17.
Gopal S, Vijapurkar U, Lim P, et al. A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia. J Psychopharmacol. 2011;25(5):685–97.
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(10):2072–82.
Pandina GJ, Lindenmayer JP, Lull J, et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol. 2010;30(3):235–44.
Li H, Rui Q, Ning X, et al. A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1002–8.
Hough D, Lindenmayer JP, Gopal S, et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(6):1022–31.
Alphs L, Bossie CA, Sliwa JK, et al. Onset of efficacy with acute long-acting injectable paliperidone palmitate treatment in markedly to severely ill patients with schizophrenia: post hoc analysis of a randomized, double-blind clinical trial. Ann Gen Psychiatry. 2011;10(1):12.
Bossie CA, Sliwa JK, Ma YW, et al. Onset of efficacy and tolerability following the initiation dosing of long-acting paliperidone palmitate: post-hoc analyses of a randomized, double-blind clinical trial. BMC Psychiatry. 2011;11:79.
Sliwa JK, Bossie CA, Ma YW, et al. Effects of acute paliperidone palmitate treatment in subjects with schizophrenia recently treated with oral risperidone. Schizophr Res. 2011;132(1):28–34.
Gopal S, Pandina G, Lane R, et al. A post-hoc comparison of paliperidone palmitate to oral risperidone during initiation of long-acting risperidone injection in patients with acute schizophrenia. Innov Clin Neurosci. 2011;8(8):26–33.
Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009;48(9):585–600.
Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60(6):553–64.
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(1):140–50.
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(5):790–9.
Kane JM, Detke HC, Naber D, et al. Olanzapine long-acting injection: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry. 2010;167(2):181–9.
Ascher-Svanum H, Zhao F, Detke HC, et al. Early response predicts subsequent response to olanzapine long-acting injection in a randomized, double-blind clinical trial of treatment for schizophrenia. BMC Psychiatry. 2011;11:152.
Witte MM, Case MG, Schuh KJ, et al. Effects of olanzapine long-acting injection on levels of functioning among acutely ill patients with schizophrenia. Curr Med Res Opin. 2012;28(3):315–23.
McDonnell DP, Kryzhanovskaya LA, Zhao F, et al. Comparison of metabolic changes in patients with schizophrenia during randomized treatment with intramuscular olanzapine long-acting injection versus oral olanzapine. Hum Psychopharmacol. 2011;26(6):422–33.
Hill AL, Sun B, Karagianis JL, et al. Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with schizophrenia. BMC Psychiatry. 2011;11:28.
Detke HC, Zhao F, Garhyan P, et al. Dose correspondence between olanzapine long-acting injection and oral olanzapine: recommendations for switching. Int Clin Psychopharmacol. 2011;26(1):35–42.
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.
McDonnell DP, Detke HC, Bergstrom RF, et al. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection: II. Investigations of mechanism. BMC Psychiatry. 2010;10:45.
Ascher-Svanum H, Peng X, Montgomery W, et al. Assessing the infrequent oral supplementation of olanzapine long-acting injection in the treatment of schizophrenia. Eur Psychiatry. 2011;26(5):313–9.
Mamo D, Kapur S, Keshavan M, et al. D2 receptor occupancy of olanzapine pamoate depot using positron emission tomography: an open-label study in patients with schizophrenia. Neuropsychopharmacology. 2008;33(2):298–304.
Fleischhacker WW. Aripiprazole. Expert Opin Pharmacother. 2005;6(12):2091–101.
Sanford M, Scott LJ. Intramuscular aripiprazole: a review of its use in the management of agitation in schizophrenia and bipolar I disorder. CNS Drugs. 2008;22(4):335–52.
Fleischhacker W. Pharmacokinetic study of once-monthly aripiprazole intramuscular depot in adult patients with schizophrenia [poster]. In: 164th annual meeting of the American Psychiatric Association; 2011 May 14–18; Honolulu.
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(5):617–24.
Guy W. AIMS: ECDEU assessment manual for psychopharmacology. Washington, DC: Government Printing Office; 1976.
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–9.
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672–6.
Fleischhacker WW, Sanchez R, Perry PP, et al. Aripiprazole once-monthly for the treatment of schizophrenia: a double-blind, randomized, non-inferiority study vs. oral aripiprazole. Poster presented at the ACNP 2012 Annual Meeting, Dec 2012, Hollywood, FL.
Kwatra SG, Batson NE, Kramer SI. Long-acting risperidone and oral antipsychotics in schizophrenia. New Engl J Med. 2011;364(23):2264–5 author reply 265-6.
Suzuki T. Long-acting risperidone and oral antipsychotics in schizophrenia. N Engl J Med. 2011;364(23):2265 author reply 265-6.
Keks NA, Ingham M, Khan A, et al. Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder: randomised, controlled, open-label study. Br J Psychiatry. 2007;191:131–9.
Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia: a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res. 2011;127(1–3):83–92.
Heres S, Schmitz FS, Leucht S, et al. The attitude of patients towards antipsychotic depot treatment. Int Clin Psychopharmacol. 2007;22(5):275–82.
Acknowledgments
There was no direct or indirect funding for this manuscript. WF has received research grants from Janssen and Otsuka and consultancy and speaker honoraria from the same companies. AR has no potential conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rauch, AS., Fleischhacker, W.W. Long-Acting Injectable Formulations of New-Generation Antipsychotics: A Review from a Clinical Perspective. CNS Drugs 27, 637–652 (2013). https://doi.org/10.1007/s40263-013-0083-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40263-013-0083-9