Abstract
Background
Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms often accompanied by depression and cognitive deficits. Positive symptoms, like delusions and hallucinations are caused by an excess of dopamine (DA) signaling and are treated with the second generation antipsychotic drugs. Negative symptoms of schizophrenia are represented by social withdrawal, apathy and blunted emotional response. It was demonstrated that co-administration of risperidone and selective serotonin reuptake inhibitors alleviated depressive symptoms and cognitive dysfunction in animal models of schizophrenia. Moreover, combination of fluoxetine or mirtazapine with risperidone increased DA and 5-hydroxytryptamine (5-HT) release in the rat frontal cortex more potently than either drug given separately. The present study aimed to investigate whether combination of risperidone and escitalopram is effective in increasing DA and 5-HT release.
Methods
The extracellular level of neurotransmitters in the rat frontal cortex and nucleus accumbens was examined using microdialysis in freely moving animals. The dialysate concentration of DA and 5-HT was assayed by HPLC.
Results
It was found that risperidone (0.2 and 1 mg/kg) and escitalopram (5 and 10 mg/kg) given together significantly increased cortical DA and 5-HT levels and were more efficient in enhancing neurotransmitter concentrations than any single-drug treatment. A similar effect on DA and 5-HT release was observed in the nucleus accumbens after administration of risperidone (1 mg/kg) and escitalopram (5 mg/kg).
Conclusions
The present study demonstrates that co-administration of risperidone and escitalopram may be used to treat positive and negative symptoms of schizophrenia and will allow to minimize the drugs’ side effects.
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References
Iancu I, Tschernikowsky E, Bodner E, Piconne AS, Lowengrub K. Escitalopram in the treatment of negative symptoms in patients with chronic schizophrenia: a randomized double-blind placebo-controlled trial. Psychiatry Res 2010;179:19–23.
Mao YM, Zhang MD. Augmentation with antidepressants in schizophrenia treatment: benefit or risk. Neuropsychiatr Dis Treat 2015;11:701–13.
Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negatie symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry 2010;197:174–9.
Meltzer HY, Huang M. In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. In: Di Giovannin G, Di Matteo V, Esposito E, editors. Prog Brain Res. BV: Elsevier; 2008. p. 177–97.
Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 1996;124:57–73.
Aghajanian GK, Marek GJ. Serotonin Model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev 2000;31:302–12.
Fiorella D, Helsley S, Rabin RA, Winter JC. The interactions of typical and atypical antipsychotics with the (-)2,5-dimethoxy-4-methamphetamine (DOM) discriminative stimulus. Neuropharmacology 1995;34:1297–303.
Marek GJ, Carpenter LL, McDougle C, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 2003;28:402–12.
Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825–35.
Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(suppl. (2)):106S–15S.
Rogóż Z, Kamińska K. The effect of combined treatment with escitalopram and risperidone on the MK-801-induced changes in the object recognition test in mice. Pharmacol Rep 2016;68:116–20.
Marcus MM, Jardemark K, Malmerfelt A, Gertow J, Konradsson-Geuken Å, Svensson TH. Augmentation by escitalopram, but not citalopram or R-citalopram, of the effects of low-dose risperidone: behavioral, biochemical, and electrophysiological evidence. Synapse 2012;66:277–90.
Kamińska K, Rogóż Z. The effect of combined treatment with risperidone and antidepressants on the MK-801-induced deficits in the social interaction test in rats. Pharmacol Rep 2015;67:1183–7.
Huang M, Ichiwaka J, Li Z, Dai J, Meltzer HY. Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex. Psychopharmacology (Berl) 2006;185:274–81.
Kalivas PW, Duffy P, Barrow J. Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes. J Pharmacol Exp Ther 1989;251:378–87.
Kamińska K, Gołembiowska K, Rogóż Z. Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex. Pharmacol Rep 2013;65:1144–51.
Koch S, Perry KW, Bymaster FP. Brain region and dose effects of an olanzapine/ fluoxetine combination on extracellular monoamine concentrations in the rat. Neuropharmacology 2004;46:232–42.
Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press; 1998.
Meltzer HY. Mechanism of action of atypical antipsychotic drugs. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropharmacology: The Fifth Generation of Progress, vol. 58. Am Coll Neuropharmacol; 2002. p. 819–31.
Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY. 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001;76:1521–31.
Cartmell J, Perry KW, Salhoff CR, Monn JA, Schoepp DD. Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade. Neuropharmacology 2001;40:847–55.
Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68:29–39.
De Deurwaerdere P, Navailles S, Berg KA, Clarke WP, Spampinato U. Constitutive activity of the serotonergic2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. Neuroscience 2004;24:3235–41.
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E. SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system. Neuropharmacology 1999;38:1195–205.
Del Arco A, Mora F. Prefrontal cortex-nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex. Pharmacol Biochem Behav 2008;90:226–35.
Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expression of serotonin2a receptors in pyramidal and gabaergic neurons of the rat prefrontal cortex. Cereb Cortex 2004;14:1100–9.
Wadenberg M-LG, Soliman A, VanderSpek SC, Kapur S. Dopamine d(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology 2001;25:633–41.
Hertel P, Nomikos GG, Schilström B, Arborelius L, Svensson TH. Risperidone dose-dependently increases extracellular concentrations of serotonin in the rat frontal cortx: role of α2-adrenoceptor antagonism. Neuropsychopharmacology 1997;17:44–55.
Schilström B, Konradsson-Geuken A, Ivanov V, Gertow J, Feltmann K, Marcus MM, et al. Effects of S-citalopram, citalopram and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, NMDA receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat. Synapse 2011;65:357–73.
Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L, et al. Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology (Berl) 2002;160:353–61.
Tanda G, Carboni E, Frau R, Di Chiara G. Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacology (Berl) 1994;115:288.
Sakaue M, Somboonthum P, Nishihara B, Koyama Y, Hashimoto H, Baba A, et al. Postsynaptic 5-hydroxytryptamine1A receptor activation increases in vivo dopamine release in rat prefrontal cortex. Br J Pharmacol 2000;129:1028–34.
Wędzony K, Maćkowiak M, Fijał K, Gołembiowska K. Ipsapirone enhances the dopamine outflow via 5-HT1A receptors in the rat prefrontal cortex. Eur J Pharmacol 1996;305:73–8.
Pehek E, Nocjar C, Roth B, Byrd T, Mabrouk O. Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 2006;31:265–77.
Kamińska K, Gołembiowska K, Rogóż Z. The effect of risperidone on mirtazapine-induced changes in extracellular monoamines in the rat frontal cortex. Pharmacol Rep 2014;66:984–90.
Rogóż Z. Effect of co-treatment with mirtazapine and risperidone in animal models of the positive symptoms of schizophrenia in mice. Pharmacol Rep 2012;64:1567–72.
Rogóż Z. Effect of combined treatment with mirtazapine and risperidone on the MK-801-induced changes in the object recognition test in mice. Pharmacol Rep 2013;65:1401–6.
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Kamińska, K., Noworyta-Sokołowska, K., Jurczak, A. et al. Risperidone and escitalopram co-administration: A potential treatment of schizophrenia symptoms with less side effects. Pharmacol. Rep 69, 13–21 (2017). https://doi.org/10.1016/j.pharep.2016.09.010
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DOI: https://doi.org/10.1016/j.pharep.2016.09.010