Abstract
Rationale
Atypical antipsychotics are commonly prescribed to clinically referred youngsters for treatment of heightened aggressive behavior associated with various psychiatric disorders. Previously, we demonstrated risperidone’s anti-aggressive effects using a well-validated animal model of offensive aggression. Paliperidone, the main active metabolite of risperidone, is a potent serotonin-2A and dopamine-2 receptor antagonist with slightly different pharmacodynamic properties compared to risperidone. Given that much of risperidone’s therapeutic efficacy is due to its active metabolite, paliperidone may effectively suppress aggression with fewer adverse side effects.
Objectives
Investigate whether paliperidone administration would reduce heightened aggressive behavior induced by low-dose cocaine exposure in a developmentally sensitive model of offensive aggression.
Materials and methods
Male Syrian hamsters (n = 12/group) were administered an acute dose of paliperidone (0.05, 0.1, 0.2, and 0.3 mg/kg) and then tested for aggressive behavior using the resident–intruder paradigm. To investigate the effects of chronic paliperidone administration, a separate set of animals (n = 12/group) was exposed to repeated paliperidone administration (0.1 mg kg−1 day−1) during different developmental periods and varying lengths of time (1–4 weeks).
Results
Experiment 1 results revealed a dose-dependent decrease in bite and attack behaviors with an effective dose observed at 0.1 mg/kg. In Experiment 2, the maximal reduction in aggressive behavior in response to chronic paliperidone treatment was observed in animals treated during the third week of adolescence, and this reduction occurred without concomitant alterations in non-aggressive behaviors.
Conclusions
These results support the specific aggression-suppressing properties of paliperidone and the potential use of this compound in the treatment of maladaptive aggression in clinical settings.
Similar content being viewed by others
References
Aguirre N, Barrionuevo M, Lasheras B, Del Rio J (1998) The role of dopaminergic systems in the perinatal sensitivity to 3, 4-methylenedioxymethamphetamine-induced neurotoxicity in rats. J Pharmacol Exp Ther 286:1159–1165
Aman MG, Binder C, Turgay A (2004) Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ. J Child Adolesc Psychopharmacol 14:243–254
Arregui A, Azpiroz A, Brain PF, Simon V (1993) Effects of two selective dopaminergic antagonists on ethologically-assessed encounters in male mice. Gen Pharmacol 24:353–356
Balant-Gorgia AE, Balant LP (1995) Therapeutic drug monitoring in psychiatry: relevance during the drug treatment of psychiatric disorders. CNS Drugs 4:432–453
Balsara JJ, Jadhav JH, Chandorkar AG (1979) Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy. Psychopharmacology 62:67–69
Biederman J, Mick E, Hammerness P, Harpold T, Aleardi M, Dougherty M, Wozniak J (2005) Open-label, 8-week trial of olanzapine and risperidone for the treatment of bipolar disorder in preschool-age children. Biol Psychiatry 58:589–594
Blanchard DC, Blanchard RJ (1999) Cocaine potentiates defensive behaviors related to fear and anxiety. Neurosci Biobehav Rev 23:981–991
Broening HW, Bacon L, Slikker W Jr (1994) Age modulates the long-term but not the acute effects of the serotonergic neurotoxicant 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 271:285–293
Buitelaar JK (2000) Open-label treatment with risperidone of 26 psychiatrically-hospitalized children and adolescents with mixed diagnoses and aggressive behavior. J Child Adolesc Psychopharmacol 10:19–26
Citrome L (2007) Paliperidone: quo vadis? Int J Clin Pract 61:653–662
Connor DF, McLaughlin TJ (2006) Aggression and diagnosis in psychiatrically referred children. Child Psychiatry Hum Dev 37:1–14
Connor DF, Glatt SJ, Lopez ID, Jackson D, Melloni RH Jr (2002) Psychopharmacology and aggression. I: A meta-analysis of stimulant effects on overt/covert aggression-related behaviors in ADHD. J Am Acad Child Adolesc Psychiatry 41:253–261
Connor DF, Steingard RJ, Cunningham JA, Anderson JJ, Melloni RH Jr (2004) Proactive and reactive aggression in referred children and adolescents. Am J Orthopsychiatry 74:129–136
Croonenberghs J, Fegert JM, Findling RL, De Smedt G, Van Dongen S (2005) Risperidone in children with disruptive behavior disorders and subaverage intelligence: a 1-year, open-label study of 504 patients. J Am Acad Child Adolesc Psychiatry 44:64–72
Curtis LH, Masselink LE, Ostbye T, Hutchison S, Dans PE, Wright A, Krishnan RR, Schulman KA (2005) Prevalence of atypical antipsychotic drug use among commercially insured youths in the United States. Arch Pediatr Adolesc Med 159:362–366
DelBello MP, Kowatch RA, Adler CM, Stanford KE, Welge JA, Barzman DH, Nelson E, Strakowski SM (2006) A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. J Am Acad Child Adolesc Psychiatry 45:305–313
DeLeon KR, Grimes JM, Connor DF, Melloni RH Jr (2002) Adolescent cocaine exposure and offensive aggression: involvement of serotonin neural signaling and innervation in male Syrian hamsters. Behav Brain Res 133:211–220
Dolder C, Nelson M, Deyo Z (2008) Paliperidone for schizophrenia. Am J Health Syst Pharm 65:403–413
Findling RL, Steiner H, Weller EB (2005) Use of antipsychotics in children and adolescents. J Clin Psychiatry 66(Suppl 7):29–40
Floody OR, Pfaff DW (1977) Aggressive behavior in female hamsters: the hormonal basis for fluctuations in female aggressiveness correlated with estrous state. J Comp Physiol Psychol 91:443–464
Gray JA, Roth BL (2001) Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists. Brain Res Bull 56(5):441–451
Grimes JM, Melloni RH Jr (2006) Prolonged alterations in the serotonin neural system following the cessation of adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus). Behav Neurosci 120:1242–1251
Grimes JM, Ricci LA, Melloni RH Jr (2007) Alterations in anterior hypothalamic vasopressin, but not serotonin, correlate with the temporal onset of aggressive behavior during adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus). Behav Neurosci 121:941–948
Harrison RJ, Connor DF, Nowak C, Melloni RH Jr (2000a) Chronic low-dose cocaine treatment during adolescence facilitates aggression in hamsters. Physiol Behav 69:555–562
Harrison RJ, Connor DF, Nowak C, Nash K, Melloni RH Jr (2000b) Chronic anabolic-androgenic steroid treatment during adolescence increases anterior hypothalamic vasopressin and aggression in intact hamsters. Psychoneuroendocrinology 25:317–338
Izenwasser S (2005) Differential effects of psychoactive drugs in adolescents and adults. Crit Rev Neurobiol 17:51–67
Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF (1988) Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244:685–693
Jensen PS, Buitelaar J, Pandina GJ, Binder C, Haas M (2007) Management of psychiatric disorders in children and adolescents with atypical antipsychotics: a systematic review of published clinical trials. Eur Child Adolesc Psychiatry 16:104–120
Karlsson P, Dencker E, Nyberg S, Mannaert E, Boom S, Talluri K, Rossenu S, Eriksson B, Eerdekens M, Farde L (2005) Pharmacokinetics, dopamine D2 and serotonin 5-HT2A receptor occupancy and safety profile of paliperidone ER in healthy subjects [poster]. 18th Annual Meeting of the European College of Neuropsychopharmacology. October 22–26, Amsterdam, The Netherlands
Knyshevski I, Ricci LA, McCann TE, Melloni RH Jr (2005a) Serotonin type-1A receptors modulate adolescent, cocaine-induced offensive aggression in hamsters. Physiol Behav 85:167–176
Knyshevski I, Connor DF, Harrison RJ, Ricci LA, Melloni RH Jr (2005b) Persistent activation of select forebrain regions in aggressive, adolescent cocaine-treated hamsters. Behav Brain Res 159:277–286
Lerwill CJ, Makings P (1971) The agonistic behavior of golden hamster. Anim Behav 19:714–721
Maj J, Mogilnicka E, Przewlocka B (1975) Antagonistic effect of cyproheptadine on neuroleptic-induced catalepsy. Pharmacol Biochem Behav 3:25–27
Malone RP, Maislin G, Choudhury MS, Gifford C, Delaney MA (2002) Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness. J Am Acad Child Adolesc Psychiatry 41:140–147
Mannens G, Huang ML, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J (1993) Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos 21:1134–1141
McCracken JT et al (2002) Risperidone in children with autism and serious behavioral problems. N Engl J Med 347:314–321
Melloni RH Jr, Connor DF, Hang PT, Harrison RJ, Ferris CF (1997) Anabolic-androgenic steroid exposure during adolescence and aggressive behavior in golden hamsters. Physiol Behav 61:359–364
Melloni RH Jr, Connor DF, Todtenkopf MS, DeLeon KR, Sanyal P, Harrison RJ (2001) Repeated cocaine treatment activates flank marking in adolescent female hamsters. Physiol Behav 73:561–570
Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246
Moechars D, Gilis M, Kuiperi C, Laenen I, Van Leuven F (1998) Aggressive behaviour in transgenic mice expressing APP is alleviated by serotonergic drugs. Neuroreport 9:3561–3564
Moyer KE (1977) A model of aggression with implications for research [proceedings]. Psychopharmacol Bull 13:14–15
Navarro JF, Manzaneque JM (1997) Acute and subchronic effects of tiapride on isolation-induced aggression in male mice. Pharmacol Biochem Behav 58:255–259
Olsen OV, Licht RW, Thomsen E, Bruun T, Viftrup JE, Linnet K (1998) Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit 20:380–384
Pappadopulos E, Woolston S, Chait A, Perkins M, Connor DF, Jensen PS (2006) Pharmacotherapy of aggression in children and adolescents: efficacy and effect size. J Can Acad Child Adolesc Psychiatry 15:27–39
Ricci LA, Grimes JM, Melloni RH Jr (2004) Serotonin type 3 receptors modulate the aggression-stimulating effects of adolescent cocaine exposure in Syrian hamsters (Mesocricetus auratus). Behav Neurosci 118:1097–1110
Ricci LA, Grimes JM, Knyshevski I, Melloni RH (2005) Repeated cocaine exposure during adolescence alters glutamic acid decarboxylase-65 (GAD65) immunoreactivity in hamster brain: correlation with offensive aggression. Brain Res 1035:131–138
Ricci LA, Connor DF, Morrison R, Melloni RH Jr (2007) Risperidone exerts potent anti-aggressive effects in a developmentally immature animal model of escalated aggression. Biol Psychiatry 62:218–225
Rodriguez-Arias M, Minarro J, Aguilar MA, Pinazo J, Simon VM (1998) Effects of risperidone and SCH 23390 on isolation-induced aggression in male mice. Eur Neuropsychopharmacol 8:95–103
Sakaue M, Ago Y, Sowa C, Sakamoto Y, Nishihara B, Koyama Y, Baba A, Matsuda T (2002) Modulation by 5-hT2A receptors of aggressive behavior in isolated mice. Jpn J Pharmacol 89:89–92
Saller CF, Czupryna MJ, Salama AI (1990) 5-HT2 receptor blockade by ICI 169,369 and other 5-HT2 antagonists modulates the effects of D-2 dopamine receptor blockade. J Pharmacol Exp Ther 253:1162–1170
Sanchez C, Arnt J, Hyttel J, Moltzen EK (1993) The role of serotonergic mechanisms in inhibition of isolation-induced aggression in male mice. Psychopharmacology 110:53–59
Schenk S, Partridge B (1997) Sensitization to cocaine and tolerance in psychostimulant self-administration. Pharmacol Biochem Behav 57:543–550
Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124:57–73
Schur SB, Sikich L, Findling RL, Malone RP, Crismon ML, Derivan A, Macintyre Ii JC, Pappadopulos E, Greenhill L, Schooler N, Van Orden K, Jensen PS (2003) Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part I: a review. J Am Acad Child Adolesc Psychiatry 42:132–144
Schwartzer J, Connor D, Morrison R, Ricci L, Melloni R (2008) Repeated risperidone administration during puberty prevents the generation of the aggressive phenotype in a developmentally immature animal model of escalated aggression. Physiol Behav 95:176–181
Scott LJ, Dhillon S (2007) Risperidone: a review of its use in the treatment of irritability associated with autistic disorder in children and adolescents. Paediatr Drugs 9:343–354
Shih JC, Ridd MJ, Chen K, Meehan WP, Kung MP, Seif I, De Maeyer E (1999) Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A. Brain Res 835:104–112
Skrebuhhova-Malmros T, Pruus K, Rudissaar R, Allikmets L, Matto V (2000) The serotonin 5-HT(2A) receptor subtype does not mediate apomorphine-induced aggressive behaviour in male Wistar rats. Pharmacol Biochem Behav 67:339–343
Soderstrom H, Rastam M, Gillberg C (2002) A clinical case series of six extremely aggressive youths treated with olanzapine. Eur Child Adolesc Psychiatry 11:138–141
Stewart JT, Myers WC, Burket RC, Lyles WB (1990) A review of the pharmacotherapy of aggression in children and adolescents. J Am Acad Child Adolesc Psychiatry 29:269–277
Troost PW, Lahuis BE, Steenhuis MP, Ketelaars CE, Buitelaar JK, van Engeland H, Scahill L, Minderaa RB, Hoekstra PJ (2005) Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study. J Am Acad Child Adolesc Psychiatry 44:1137–1144
Ugedo L, Grenhoff J, Svensson TH (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology 98:45–50
Vitiello B, Stoff DM (1997) Subtypes of aggression and their relevance to child psychiatry. J Am Acad Child Adolesc Psychiatry 36:307–315
Werry JS (1997) Severe conduct disorder–some key issues. Can J Psychiatry 42:577–583
Wommack JC, Salinas A, Melloni RH Jr, Delville Y (2004) Behavioral and neuroendocrine adaptations to repeated stress during puberty in male golden hamsters. J Neuroendocrinol 16:767–775
Yildiz A, Sachs GS, Turgay A (2003) Pharmacological management of agitation in emergency settings. Emerg Med J 20:339–346
Acknowledgments
The authors extend special thanks to M. Carrillo for critical insight and editorial comments incorporated in the construction of this manuscript and to S. Marsh for technical support in the completion of the experimental procedures. This work was supported by Research Grant R076477-NAP-0012 from Janssen Pharmaceutica.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schwartzer, J.J., Morrison, R.L., Ricci, L.A. et al. Paliperidone suppresses the development of the aggressive phenotype in a developmentally sensitive animal model of escalated aggression. Psychopharmacology 203, 653–663 (2009). https://doi.org/10.1007/s00213-008-1412-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-008-1412-4