Update on Oxytocin, Phosphodiesterase, Neurokinin, Glycine as a Therapeutic Approach in the Treatment of Schizophrenia

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Abstract

Background: Schizophrenia is a chronic psychiatric disorder characterized by disrupted thoughts, perception, mood, and behavior. It has a heterogeneous genetic and neurobiological background and affects about 0.5-1% of the adult population worldwide. Herein, we review the current approaches and advances in schizophrenia. The potential therapeutic compounds for the treatment of schizophrenia act on the oxytocin receptor, phosphodiesterase system, neurokinin receptor, and glycine transport 1 receptor. Therefore, this article provides an update on the pharmacology of different receptors in addition to the dopaminergic system. These findings would guide the readers on novel targets for schizophrenia with the potential to be therapeutic agents in the future.

Objective: To provide the researchers an update on the emerging role of oxytocin, phosphodiesterase, neurokinin, and glycine which can be explored as potential pharmacotherapeutic targets in the treatment of schizophrenia.

Methods: An extensive literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: schizophrenia, novel receptors, oxytocin, phosphodiesterase, neurokinin, and glycine. Furthermore, to provide insights into newer drug treatments for Schizophrenia, Furthermore, Clinicaltrials.gov website was searched for newer receptor-based drugs.

Results: Current literature supported by preclinical and clinical provides substantial evidence that oxytocin, phosphodiesterase, neurokinin, and glycine play a crucial role in Schizophrenia.

Conclusion: Our findings indicate that though multiple antipsychotic drugs are prescribed to treat schizophrenia, novel approaches and/or mechanisms are plausible. Moreover, sensitive and specific diagnostic tools and safe and effective interventions, including novel therapeutic agents, are required to yield substantially improved future outcomes.

Keywords: Schizophrenia, novel receptors, oxytocin, phosphodiesterase, neurokinin, glycine.

Graphical Abstract

[1]
Morris BJ, Pratt JA. Novel treatment strategies for schizophrenia from improved understanding of genetic risk. Clin Genet 2014; 86(5): 401-11.
[http://dx.doi.org/10.1111/cge.12485] [PMID: 25142969]
[2]
Chopra K, Baveja A, Kuhad A. MMPs: A novel drug target for schizophrenia. Expert Opin Ther Targets 2015; 19(1): 77-85.
[http://dx.doi.org/10.1517/14728222.2014.957672] [PMID: 25214056]
[3]
Nicola R. P NSR, Understanding AJ. Learning Zone. Schizophrenia 2008; 22(28): 49-56.
[4]
Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers 2015; 1: 15067.
[http://dx.doi.org/10.1038/nrdp.2015.67] [PMID: 27189524]
[5]
Ved HS, Doshi GM. A review on emerging drug targets in treatment of schizophrenia. Curr Drug Targets 2020; 21(15): 1593-605.
[http://dx.doi.org/10.2174/1389450121666200615150429] [PMID: 32538726]
[6]
Nimgaonkar VL, Prasad KM, Chowdari KV, Severance EG, Yolken RH. The complement system: A gateway to gene-environment interactions in schizophrenia pathogenesis. Mol Psychiatry 2017; 22(11): 1554-61.
[http://dx.doi.org/10.1038/mp.2017.151] [PMID: 28761078]
[7]
Demjaha A, MacCabe JH, Murray RM. How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophr Bull 2012; 38(2): 209-14.
[http://dx.doi.org/10.1093/schbul/sbr100] [PMID: 21857009]
[8]
Kavanagh DH, Tansey KE, O’Donovan MC, Owen MJ. Schizophrenia genetics: Emerging themes for a complex disorder. Mol Psychiatry 2015; 20(1): 72-6.
[http://dx.doi.org/10.1038/mp.2014.148] [PMID: 25385368]
[9]
Mubarik A, Tohid H. Frontal lobe alterations in schizophrenia: A review. Trends Psychiatry Psychother 2016; 38(4): 198-206.
[http://dx.doi.org/10.1590/2237-6089-2015-0088] [PMID: 28076640]
[10]
Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: A review. Br Med Bull 2015; 114(1): 169-79.
[http://dx.doi.org/10.1093/bmb/ldv017] [PMID: 25957394]
[11]
Maric NP, Jovicic MJ, Mihaljevic M, Miljevic C. Improving current treatments for schizophrenia. Drug Dev Res 2016; 77(7): 357-67.
[http://dx.doi.org/10.1002/ddr.21337] [PMID: 27633376]
[12]
Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: A systematic review and meta-analysis. Int J Neuropsychopharmacol 2013; 16(6): 1205-18.
[http://dx.doi.org/10.1017/S1461145712001277] [PMID: 23199972]
[13]
Stępnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia. Molecules 2018; 23(8): E2087.
[http://dx.doi.org/10.3390/molecules23082087] [PMID: 30127324]
[14]
Rhodes CH, Morrell JI, Pfaff DW. Immunohistochemical analysis of magnocellular elements in rat hypothalamus: Distribution and numbers of cells containing neurophysin, oxytocin, and vasopressin. J Comp Neurol 1981; 198(1): 45-64.
[http://dx.doi.org/10.1002/cne.901980106] [PMID: 7014660]
[15]
Gimpl G, Fahrenholz F. The oxytocin receptor system: Structure, function, and regulation. Physiol Rev 2001; 81(2): 629-83.
[http://dx.doi.org/10.1152/physrev.2001.81.2.629] [PMID: 11274341]
[16]
Viero C, Shibuya I, Kitamura N, et al. REVIEW: Oxytocin: Crossing the bridge between basic science and pharmacotherapy. CNS Neurosci Ther 2010; 16(5): e138-56.
[http://dx.doi.org/10.1111/j.1755-5949.2010.00185.x] [PMID: 20626426]
[17]
Lee HJ, Macbeth AH, Pagani JH, Young WS III. Oxytocin: The great facilitator of life. Prog Neurobiol 2009; 88(2): 127-51.
[PMID: 19482229]
[18]
Caldwell HK. Neurobiology of sociability. Adv Exp Med Biol 2012; 739: 187-205.
[http://dx.doi.org/10.1007/978-1-4614-1704-0_12] [PMID: 22399403]
[19]
Souza RP, de Luca V, Meltzer HY, Lieberman JA, Kennedy JL. Schizophrenia severity and clozapine treatment outcome association with oxytocinergic genes. Int J Neuropsychopharmacol 2010; 13(6): 793-8.
[http://dx.doi.org/10.1017/S1461145710000167] [PMID: 20196918]
[20]
Goldman M, Marlow-O’Connor M, Torres I, Carter CS. Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits. Schizophr Res 2008; 98(1-3): 247-55.
[http://dx.doi.org/10.1016/j.schres.2007.09.019] [PMID: 17961988]
[21]
Rosenfeld AJ, Lieberman JA, Jarskog LF. Oxytocin, dopamine, and the amygdala: A neurofunctional model of social cognitive deficits in schizophrenia. Schizophr Bull 2011; 37(5): 1077-87.
[http://dx.doi.org/10.1093/schbul/sbq015] [PMID: 20308198]
[22]
Beckmann H, Lang RE, Gattaz WF. Vasopressin--oxytocin in cerebrospinal fluid of schizophrenic patients and normal controls. Psychoneuroendocrinology 1985; 10(2): 187-91.
[http://dx.doi.org/10.1016/0306-4530(85)90056-3] [PMID: 4034849]
[23]
Yoshida M, Takayanagi Y, Inoue K, et al. Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J Neurosci 2009; 29(7): 2259-71.
[http://dx.doi.org/10.1523/JNEUROSCI.5593-08.2009] [PMID: 19228979]
[24]
Jørgensen H, Riis M, Knigge U, Kjaer A, Warberg J. Serotonin receptors involved in vasopressin and oxytocin secretion. J Neuroendocrinol 2003; 15(3): 242-9.
[http://dx.doi.org/10.1046/j.1365-2826.2003.00978.x] [PMID: 12588512]
[25]
Teltsh O, Kanyas-Sarner K, Rigbi A, Greenbaum L, Lerer B, Kohn Y. Oxytocin and vasopressin genes are significantly associated with schizophrenia in a large Arab-Israeli pedigree. Int J Neuropsychopharmacol 2012; 15(3): 309-19.
[http://dx.doi.org/10.1017/S1461145711001374] [PMID: 21899794]
[26]
Glovinsky D, Kalogeras KT, Kirch DG, Suddath R, Wyatt RJ. Cerebrospinal fluid oxytocin concentration in schizophrenic patients does not differ from control subjects and is not changed by neuroleptic medication. Schizophr Res 1994; 11(3): 273-6.
[http://dx.doi.org/10.1016/0920-9964(94)90021-3] [PMID: 7910756]
[27]
Linkowski P, Geenen V, Kerkhofs M, Mendlewicz J, Legros JJ. Cerebrospinal fluid neurophysins in affective illness and in schizophrenia. Eur Arch Psychiatry Neurol Sci 1984; 234(3): 162-5.
[http://dx.doi.org/10.1007/BF00461555] [PMID: 6489403]
[28]
Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, “just the facts” what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 2008; 102(1-3): 1-18.
[http://dx.doi.org/10.1016/j.schres.2008.04.011] [PMID: 18514488]
[29]
Holt-Lunstad J, Birmingham W, Light KC. The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention. Psychoneuroendocrinology 2011; 36(8): 1249-56.
[http://dx.doi.org/10.1016/j.psyneuen.2011.03.007] [PMID: 21507578]
[30]
Rubin LH, Carter CS, Drogos L, Pournajafi-Nazarloo H, Sweeney JA, Maki PM. Peripheral oxytocin is associated with reduced symptom severity in schizophrenia. Schizophr Res 2010; 124(1-3): 13-21.
[http://dx.doi.org/10.1016/j.schres.2010.09.014] [PMID: 20947304]
[31]
Patisaul HB, Scordalakes EM, Young LJ, Rissman EF. Oxytocin, but not oxytocin receptor, is rRegulated by oestrogen receptor beta in the female mouse hypothalamus. J Neuroendocrinol 2003; 15(8): 787-93.
[http://dx.doi.org/10.1046/j.1365-2826.2003.01061.x] [PMID: 12834440]
[32]
Bergemann N, Parzer P, Runnebaum B, Resch F, Mundt C. Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia. Psychol Med 2007; 37(10): 1427-36.
[http://dx.doi.org/10.1017/S0033291707000578] [PMID: 17451629]
[33]
Lapiz MD, Fulford A, Muchimapura S, Mason R, Parker T, Marsden CA. Influence of postweaning social isolation in the rat on brain development, conditioned behavior, and neurotransmission. Neurosci Behav Physiol 2003; 33(1): 13-29.
[http://dx.doi.org/10.1023/A:1021171129766] [PMID: 12617300]
[34]
Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharmacol 2011; 164(4): 1162-94.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01386.x] [PMID: 21449915]
[35]
Feifel D, Shilling PD, MacDonald K. A review of oxytocin’s effects on the positive, negative, and cognitive domains of schizophrenia. Biol Psychiatry 2016; 79(3): 222-33.
[http://dx.doi.org/10.1016/j.biopsych.2015.07.025] [PMID: 26410353]
[36]
Bartholomeusz CF, Ganella EP, Labuschagne I, Bousman C, Pantelis C. Effects of oxytocin and genetic variants on brain and behaviour: Implications for treatment in schizophrenia. Schizophr Res 2015; 168(3): 614-27.
[http://dx.doi.org/10.1016/j.schres.2015.06.007] [PMID: 26123171]
[37]
Bujanow W. Hormones in the treatment of psychoses. BMJ 1972; 4(5835): 298.
[http://dx.doi.org/10.1136/bmj.4.5835.298-c] [PMID: 5083904]
[38]
Bakharev VD, Tikhomirov SM, Lozhkina TK. Psychotropic properties of oxytocin. Neurosci Behav Physiol 1986; 16(2): 160-4.
[http://dx.doi.org/10.1007/BF01186517] [PMID: 3748373]
[39]
Björk A, Olsson NG, Christensson E, Martinsson K, Olsson O. Effects of amperozide on biting behavior and performance in restricted-fed pigs following regrouping. J Anim Sci 1988; 66(3): 669-75.
[http://dx.doi.org/10.2527/jas1988.663669x] [PMID: 3378924]
[40]
Kiss A, Bundzikova J, Pirnik Z, Mikkelsen JD. Different antipsychotics elicit different effects on magnocellular oxytocinergic and vasopressinergic neurons as revealed by Fos immunohistochemistry. J Neurosci Res 2010; 88(3): 677-85.
[PMID: 19774673]
[41]
Souza RP, Ismail P, Meltzer HY, Kennedy JL. Variants in the oxytocin gene and risk for schizophrenia. Schizophr Res 2010; 121(1-3): 279-80.
[http://dx.doi.org/10.1016/j.schres.2010.04.019] [PMID: 20547038]
[42]
Ditzen B, Schaer M, Gabriel B, Bodenmann G, Ehlert U, Heinrichs M. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol Psychiatry 2009; 65(9): 728-31.
[http://dx.doi.org/10.1016/j.biopsych.2008.10.011] [PMID: 19027101]
[43]
Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003; 54(12): 1389-98.
[http://dx.doi.org/10.1016/S0006-3223(03)00465-7] [PMID: 14675803]
[44]
Heringa SM, Begemann MJ, Goverde AJ, Sommer IE. Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review. Schizophr Res 2015; 168(3): 603-13.
[http://dx.doi.org/10.1016/j.schres.2015.04.002] [PMID: 25914107]
[45]
Zheng W, Zhu XM, Zhang QE, et al. Adjunctive intranasal oxytocin for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. Schizophr Res 2019; 206: 13-20.
[http://dx.doi.org/10.1016/j.schres.2018.12.007] [PMID: 30573406]
[46]
Ishak WW, Kahloon M, Fakhry H. Oxytocin role in enhancing well-being: A literature review. J Affect Disord 2011; 130(1-2): 1-9.
[http://dx.doi.org/10.1016/j.jad.2010.06.001] [PMID: 20584551]
[47]
Maejima Y, Rita RS, Santoso P, et al. Nasal oxytocin administration reduces food intake without affecting locomotor activity and glycemia with c-Fos induction in limited brain areas. Neuroendocrinology 2015; 101(1): 35-44.
[http://dx.doi.org/10.1159/000371636] [PMID: 25573626]
[48]
Zhang H, Wu C, Chen Q, et al. Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models. PLoS One 2013; 8(5): e61477.
[http://dx.doi.org/10.1371/journal.pone.0061477] [PMID: 23700406]
[49]
Ota M, Yoshida S, Nakata M, Yada T, Kunugi H. The effects of adjunctive intranasal oxytocin in patients with schizophrenia. Postgrad Med 2018; 130(1): 122-8.
[http://dx.doi.org/10.1080/00325481.2018.1398592] [PMID: 29105546]
[50]
Oya K, Matsuda Y, Matsunaga S, Kishi T, Iwata N. Efficacy and safety of oxytocin augmentation therapy for schizophrenia: An updated systematic review and meta-analysis of randomized, placebo-controlled trials. Eur Arch Psychiatry Clin Neurosci 2016; 266(5): 439-50.
[http://dx.doi.org/10.1007/s00406-015-0634-9] [PMID: 26303414]
[51]
Feifel D, Macdonald K, Nguyen A, et al. Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. Biol Psychiatry 2010; 68(7): 678-80.
[http://dx.doi.org/10.1016/j.biopsych.2010.04.039] [PMID: 20615494]
[52]
Pedersen CA, Gibson CM, Rau SW, et al. Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia. Schizophr Res 2011; 132(1): 50-3.
[http://dx.doi.org/10.1016/j.schres.2011.07.027] [PMID: 21840177]
[53]
Gibson CM, Penn DL, Smedley KL, Leserman J, Elliott T, Pedersen CA. A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia. Schizophr Res 2014; 156(2-3): 261-5.
[http://dx.doi.org/10.1016/j.schres.2014.04.009] [PMID: 24799299]
[54]
Cacciotti-Saija C, Langdon R, Ward PB, et al. A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis. Schizophr Bull 2015; 41(2): 483-93.
[http://dx.doi.org/10.1093/schbul/sbu094] [PMID: 24962607]
[55]
Davis MC, Green MF, Lee J, et al. Oxytocin-augmented social cognitive skills training in schizophrenia. Neuropsychopharmacology 2014; 39(9): 2070-7.
[http://dx.doi.org/10.1038/npp.2014.68] [PMID: 24637803]
[56]
Averbeck BB, Bobin T, Evans S, Shergill SS. Emotion recognition and oxytocin in patients with schizophrenia. Psychol Med 2012; 42(2): 259-66.
[http://dx.doi.org/10.1017/S0033291711001413] [PMID: 21835090]
[57]
Goldman MB, Gomes AM, Carter CS, Lee R. Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia. Psychopharmacology (Berl) 2011; 216(1): 101-10.
[http://dx.doi.org/10.1007/s00213-011-2193-8] [PMID: 21301811]
[58]
Feifel D, Macdonald K, Cobb P, Minassian A. Adjunctive intranasal oxytocin improves verbal memory in people with schizophrenia. Schizophr Res 2012; 139(1-3): 207-10.
[http://dx.doi.org/10.1016/j.schres.2012.05.018] [PMID: 22682705]
[59]
Fischer-Shofty M, Brüne M, Ebert A, Shefet D, Levkovitz Y, Shamay-Tsoory SG. Improving social perception in schizophrenia: The role of oxytocin. Schizophr Res 2013; 146(1-3): 357-62.
[http://dx.doi.org/10.1016/j.schres.2013.01.006] [PMID: 23433504]
[60]
Michalopoulou PG, Averbeck BB, Kalpakidou AK, et al. The effects of a single dose of oxytocin on working memory in schizophrenia. Schizophr Res 2015; 162(1-3): 62-3.
[http://dx.doi.org/10.1016/j.schres.2014.12.029] [PMID: 25579054]
[61]
Shin NY, Park HY, Jung WH, et al. Effects of oxytocin on neural response to facial expressions in patients with schizophrenia. Neuropsychopharmacology 2015; 40(8): 1919-27.
[http://dx.doi.org/10.1038/npp.2015.41] [PMID: 25666311]
[62]
Goh KK, Chen CH, Lane HY. Oxytocin in schizophrenia: Pathophysiology and implications for future treatment. Int J Mol Sci 2021; 22(4): 1-26.
[http://dx.doi.org/10.3390/ijms22042146] [PMID: 33670047]
[63]
Ganjiwale AD, Rao GS, Cowsik SM. Molecular modeling of neurokinin B and tachykinin NK₃ receptor complex. J Chem Inf Model 2011; 51(11): 2932-8.
[http://dx.doi.org/10.1021/ci2000264] [PMID: 21913652]
[64]
Misono K, Lessard A. Apomorphine-evoked redistribution of neurokinin-3 receptors in dopaminergic dendrites and neuronal nuclei of the rat ventral tegmental area. Neuroscience 2012; 203: 27-38.
[http://dx.doi.org/10.1016/j.neuroscience.2011.12.018] [PMID: 22200547]
[65]
Hether S, Misono K, Lessard A. The neurokinin-3 receptor (NK3R) antagonist SB222200 prevents the apomorphine-evoked surface but not nuclear NK3R redistribution in dopaminergic neurons of the rat ventral tegmental area. Neuroscience 2013; 247: 12-24.
[http://dx.doi.org/10.1016/j.neuroscience.2013.05.006] [PMID: 23673279]
[66]
Saito S, Takahashi N, Maeno N, et al. An association study of tachykinin receptor 3 gene with schizophrenia in the Japanese population. Neuroreport 2008; 19(4): 471-3.
[http://dx.doi.org/10.1097/WNR.0b013e3282f600b4] [PMID: 18287949]
[67]
Primi MC, Magalha JG, Rangel-yagui CO, Henrique G, Trossini G. Convergent QSAR studies on a series of NK 3 receptor antagonists for schizophrenia treatment 2015; 6366: 1-12.
[68]
Nordquist RE, Delenclos M, Ballard TM, et al. Cognitive performance in neurokinin 3 receptor knockout mice. Psychopharmacology (Berl) 2008; 198(2): 211-20.
[http://dx.doi.org/10.1007/s00213-008-1119-6] [PMID: 18351324]
[69]
Dawson LA, Smith PW. Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia. Curr Pharm Des 2010; 16(3): 344-57.
[http://dx.doi.org/10.2174/138161210790170067] [PMID: 20109143]
[70]
Geldenhuys WJ, Kuzenko SR, Simmons MA. Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor. J Med Chem 2010; 53(22): 8080-8.
[http://dx.doi.org/10.1021/jm1010012] [PMID: 21047106]
[71]
Griebel G, Beeské S. Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases? Pharmacol Ther 2012; 133(1): 116-23.
[http://dx.doi.org/10.1016/j.pharmthera.2011.09.007] [PMID: 21963368]
[72]
Dawson LA, Porter RA. Progress in the development of neurokinin 3 modulators for the treatment of schizophrenia: Molecule development and clinical progress. Future Med Chem 2013; 5(13): 1525-46.
[http://dx.doi.org/10.4155/fmc.13.122] [PMID: 24024945]
[73]
Dawson LA, Cato KJ, Scott C, et al. In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): Potential therapeutic utility in the treatment of schizophrenia. Neuropsychopharmacology 2008; 33(7): 1642-52.
[http://dx.doi.org/10.1038/sj.npp.1301549] [PMID: 17728699]
[74]
Hanessian S, Babonneau V, Boyer N, Mannoury la Cour C, Millan MJ, De Nanteuil G. Design and synthesis of potential dual NK(1)/NK(3) receptor antagonists. Bioorg Med Chem Lett 2014; 24(2): 510-4.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.033] [PMID: 24374277]
[75]
Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA. Pharmacological treatment of schizophrenia: A critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 2012; 17: 1206-27.
[76]
Catalani MP, Alvaro G, Bernasconi G, et al. Identification of novel NK1/NK3 dual antagonists for the potential treatment of schizophrenia. Bioorg Med Chem Lett 2011; 21(22): 6899-904.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.116] [PMID: 21974957]
[77]
Lessard A, Savard M, Gobeil F Jr, Pierce JP, Pickel VM. The neurokinin-3 (NK3) and the neurokinin-1 (NK1) receptors are differentially targeted to mesocortical and mesolimbic projection neurons and to neuronal nuclei in the rat ventral tegmental area. Synapse 2009; 63(6): 484-501.
[http://dx.doi.org/10.1002/syn.20627] [PMID: 19224600]
[78]
Nordquist RE, Savignac H, Pauly-Evers M, et al. Characterization of behavioral response to amphetamine, tyrosine hydroxylase levels, and dopamine receptor levels in neurokinin 3 receptor knockout mice. Behav Pharmacol 2008; 19(5-6): 518-29.
[http://dx.doi.org/10.1097/FBP.0b013e32830cd7f5] [PMID: 18690106]
[79]
Kumar A, Yadav M, Parle M, Dhingra S, Dhull DK. Potential drug targets and treatment of schizophrenia. Inflammopharmacology 2017; 25(3): 277-92.
[http://dx.doi.org/10.1007/s10787-017-0340-5] [PMID: 28353125]
[80]
Malherbe P, Bissantz C, Marcuz A, et al. Me-talnetant and osanetant interact within overlapping but not identical binding pockets in the human tachykinin neurokinin 3 receptor transmembrane domains. Mol Pharmacol 2008; 73(6): 1736-50.
[http://dx.doi.org/10.1124/mol.107.042754] [PMID: 18308898]
[81]
Xiong H, Kang J, Woods JM, et al. Synthesis and SAR of sulfoxide substituted carboxyquinolines as NK3 receptor antagonists. Bioorg Med Chem Lett 2011; 21(6): 1896-9.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.003] [PMID: 21320776]
[82]
Geldenhuys WJ, Simmons MA. 3D-Quantitative structure-activity relationship and docking studies of the tachykinin NK3 receptor. Bioorg Med Chem Lett 2011; 21(24): 7405-11.
[http://dx.doi.org/10.1016/j.bmcl.2011.10.014] [PMID: 22056747]
[83]
Malherbe P, Knoflach F, Hernandez MC, et al. Characterization of RO4583298 as a novel potent, dual antagonist with in vivo activity at tachykinin NK₁ and NK₃ receptors. Br J Pharmacol 2011; 162(4): 929-46.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01096.x] [PMID: 21039418]
[84]
Tian G, Wilkins D, Scott CW. Neurokinin-3 receptor-specific antagonists talnetant and osanetant show distinct mode of action in cellular Ca2+ mobilization but display similar binding kinetics and identical mechanism of binding in ligand cross-competition. Mol Pharmacol 2007; 71(3): 902-11.
[http://dx.doi.org/10.1124/mol.106.029868] [PMID: 17172464]
[85]
Malherbe P, Kratzeisen C, Marcuz A, et al. Identification of a critical residue in the transmembrane domain 2 of tachykinin neurokinin 3 receptor affecting the dissociation kinetics and antagonism mode of osanetant (SR 142801) and piperidine-based structures. J Med Chem 2009; 52(22): 7103-12.
[http://dx.doi.org/10.1021/jm900948q] [PMID: 19817444]
[86]
Kronenberg G, Berger P, Tauber RF, Bandelow B, Henkel V, Heuser I. Randomized, double-blind study of SR142801 (Osanetant). A novel neurokinin-3 (NK3) receptor antagonist in panic disorder with pre- and posttreatment cholecystokinin tetrapeptide (CCK-4) challenges. Pharmacopsychiatry 2005; 38(1): 24-9.
[http://dx.doi.org/10.1055/s-2005-837768] [PMID: 15706463]
[87]
Meltzer HY, Arvanitis L, Bauer D, Rein W. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 2004; 161(6): 975-84.
[http://dx.doi.org/10.1176/appi.ajp.161.6.975] [PMID: 15169685]
[88]
Sanofi, a global leader in healthcare. Sanofi. 2004.
[89]
Werkman TR, McCreary AC, Kruse CG, Wadman WJ. NK3 receptors mediate an increase in firing rate of midbrain dopamine neurons of the rat and the guinea pig. Synapse 2011; 65(8): 814-26.
[http://dx.doi.org/10.1002/syn.20908] [PMID: 21218451]
[90]
Malherbe P, Ballard TM, Ratni H. Tachykinin neurokinin 3 receptor antagonists: A patent review (2005 - 2010). Expert Opin Ther Pat 2011; 21(5): 637-55.
[http://dx.doi.org/10.1517/13543776.2011.568482] [PMID: 21417773]
[91]
Liem-Moolenaar M, Gray FA, de Visser SJ, et al. Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol. J Psychopharmacol 2010; 24(1): 73-82.
[http://dx.doi.org/10.1177/0269881108094524] [PMID: 18755817]
[92]
Study of talnetant versus placebo and risperidone in schizophrenia- Full text view. ClinicalTrialsgov Available from: https://clinicaltrials.gov/ct2/show/NCT00103727 [Accessed on: 2022 May 12].
[93]
Malherbe P, Knoflach F, Marcuz A, et al. Mapping the binding pocket of a novel, high-affinity, slow dissociating tachykinin NK3 receptor antagonist: Biochemical and electrophysiological characterization. Neuropharmacology 2014; 86: 259-72.
[http://dx.doi.org/10.1016/j.neuropharm.2014.07.017] [PMID: 25107588]
[94]
Spooren W, Riemer C, Meltzer H. Opinion: NK3 receptor antagonists: The next generation of antipsychotics? Nat Rev Drug Discov 2005; 4(12): 967-75.
[http://dx.doi.org/10.1038/nrd1905] [PMID: 16341062]
[95]
Nordquist RE, Durkin S, Jacquet A, Spooren W. The tachykinin NK3 receptor agonist senktide induces locomotor activity in male Mongolian gerbils. Eur J Pharmacol 2008; 600(1-3): 87-92.
[http://dx.doi.org/10.1016/j.ejphar.2008.10.011] [PMID: 18930726]
[96]
de la Flor R, Dawson LA. Augmentation of antipsychotic-induced neurochemical changes by the NK3 receptor antagonist talnetant (SB-223412). Neuropharmacology 2009; 56(2): 342-9.
[http://dx.doi.org/10.1016/j.neuropharm.2008.09.003] [PMID: 18822303]
[97]
Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacol Rev 2006; 58(3): 488-520.
[http://dx.doi.org/10.1124/pr.58.3.5] [PMID: 16968949]
[98]
Lin CS, Xin ZC, Lin G, Lue TF. Phosphodiesterases as therapeutic targets. Urology 2003; 61(4): 685-91.
[http://dx.doi.org/10.1016/S0090-4295(02)02439-1] [PMID: 12670544]
[99]
Kehler J, Nielsen J. PDE10A inhibitors: Novel therapeutic drugs for schizophrenia. Curr Pharm Des 2011; 17(2): 137-50.
[http://dx.doi.org/10.2174/138161211795049624] [PMID: 21355834]
[100]
Czopek A, Partyka A, Bucki A, et al. Impact of N-alkylamino substituents on serotonin receptor (5-HTR) affinity and phosphodiesterase 10A (PDE10A) inhibition of isoindole-1,3-dione derivatives. Molecules 2020; 25(17): E3868.
[http://dx.doi.org/10.3390/molecules25173868] [PMID: 32854402]
[101]
Tseng KY, Snyder-Keller A, O’Donnell P. Dopaminergic modulation of striatal plateau depolarizations in corticostriatal organotypic cocultures. Psychopharmacology (Berl) 2007; 191(3): 627-40.
[http://dx.doi.org/10.1007/s00213-006-0439-7] [PMID: 16758237]
[102]
Picconi B, Bagetta V, Ghiglieri V, et al. Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia. Brain 2011; 134(Pt 2): 375-87.
[http://dx.doi.org/10.1093/brain/awq342] [PMID: 21183486]
[103]
Padovan-Neto FE, Sammut S, Chakroborty S, et al. Facilitation of corticostriatal transmission following pharmacological inhibition of striatal phosphodiesterase 10A: Role of nitric oxide-soluble guanylyl cyclase-cGMP signaling pathways. J Neurosci 2015; 35(14): 5781-91.
[http://dx.doi.org/10.1523/JNEUROSCI.1238-14.2015] [PMID: 25855188]
[104]
Qi Z, Miller GW, Voit EO. The internal state of medium spiny neurons varies in response to different input signals. BMC Syst Biol 2010; 4: 26.
[http://dx.doi.org/10.1186/1752-0509-4-26] [PMID: 20236543]
[105]
Geerts H, Spiros A, Roberts P. Phosphodiesterase 10 inhibitors in clinical development for CNS disorders. Expert Rev Neurother 2017; 17(6): 553-60.
[http://dx.doi.org/10.1080/14737175.2017.1268531] [PMID: 27917685]
[106]
Peuskens J, Pani L, Detraux J, De Hert M. The effects of novel and newly approved antipsychotics on serum prolactin levels: A comprehensive review. CNS Drugs 2014; 28(5): 421-53.
[http://dx.doi.org/10.1007/s40263-014-0157-3] [PMID: 24677189]
[107]
Suzuki K, Kimura H. TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia. CNS Neurosci Ther 2018; 24(7): 604-14.
[http://dx.doi.org/10.1111/cns.12798] [PMID: 29318783]
[108]
Suzuki K, Harada A, Suzuki H, Miyamoto M, Kimura H. TAK-063, a PDE10A inhibitor with balanced activation of direct and indirect pathways, provides potent antipsychotic-like effects in multiple paradigms. Neuropsychopharmacology 2016; 41(9): 2252-62.
[http://dx.doi.org/10.1038/npp.2016.20] [PMID: 26849714]
[109]
A phase 2 efficacy and safety study of TAK-063 in participants with an acute exacerbation of schizophrenia - Full text view. ClinicalTrialsgov Available from: https://clinicaltrials.gov/ct2/show/NCT02477020 [Accessed on: 2022 May, 12
[110]
Takakuwa M, Watanabe Y, Tanaka K, et al. Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor T-251 in rodents. Pharmacol Biochem Behav 2019; 185: 172757.
[http://dx.doi.org/10.1016/j.pbb.2019.172757] [PMID: 31404565]
[111]
Efficacy of pimozide augmentation for clozapine partial response- Full text view. ClinicalTrialsgov Available from: https://clinicaltrials.gov/ct2/show/NCT00374244 [Accessed on: 2022 May, 12
[112]
Arakawa K, Maehara S, Yuge N, et al. Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 10A inhibitor, PDM-042 [(E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine] in rats: Potential for the treatment of schizophrenia. Pharmacol Res Perspect 2016; 4(4): e00241.
[http://dx.doi.org/10.1002/prp2.241] [PMID: 28116094]
[113]
Arakawa K, Nakao K, Maehara S. Dopamine D1 signaling involvement in the effects of the phosphodiesterase 10A inhibitor, PDM-042 on cognitive function and extrapyramidal side effect in rats. Behav Brain Res 2017; 317: 204-9.
[http://dx.doi.org/10.1016/j.bbr.2016.09.043] [PMID: 27659554]
[114]
Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: Essential regulators of neurotransmission. Trends Biochem Sci 2005; 30(6): 325-33.
[http://dx.doi.org/10.1016/j.tibs.2005.04.004] [PMID: 15950877]
[115]
Curtis DR, Hösli L, Johnston GAR. Inhibition of spinal neurons by glycine. Nature 1967; 215(5109): 1502-3.
[http://dx.doi.org/10.1038/2151502a0] [PMID: 4293850]
[116]
Aragón C, López-Corcuera B. Glycine transporters: Crucial roles of pharmacological interest revealed by gene deletion. Trends Pharmacol Sci 2005; 26(6): 283-6.
[http://dx.doi.org/10.1016/j.tips.2005.04.007] [PMID: 15925702]
[117]
Borowsky B, Mezey E, Hoffman BJ. Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene. Neuron 1993; 10(5): 851-63.
[http://dx.doi.org/10.1016/0896-6273(93)90201-2] [PMID: 8494645]
[118]
Zafra F, Gomeza J, Olivares L, Aragón C, Giménez C. Regional distribution and developmental variation of the glycine transporters GLYT1 and GLYT2 in the rat CNS. Eur J Neurosci 1995; 7(6): 1342-52.
[http://dx.doi.org/10.1111/j.1460-9568.1995.tb01125.x] [PMID: 7582108]
[119]
Cubelos B, Giménez C, Zafra F. Localization of the GLYT1 glycine transporter at glutamatergic synapses in the rat brain. Cereb Cortex 2005; 15(4): 448-59.
[http://dx.doi.org/10.1093/cercor/bhh147] [PMID: 15749988]
[120]
Tsai G, Ralph-Williams RJ, Martina M, et al. Gene knockout of glycine transporter 1: Characterization of the behavioral phenotype. Proc Natl Acad Sci USA 2004; 101(22): 8485-90.
[http://dx.doi.org/10.1073/pnas.0402662101] [PMID: 15159536]
[121]
Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2004; 55(5): 452-6.
[http://dx.doi.org/10.1016/j.biopsych.2003.09.012] [PMID: 15023571]
[122]
Lane HY, Huang CL, Wu PL, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 2006; 60(6): 645-9.
[http://dx.doi.org/10.1016/j.biopsych.2006.04.005] [PMID: 16780811]
[123]
Lane HY, Liu YC, Huang CL, et al. Sarcosine (N-methylglycine) treatment for acute schizophrenia: A randomized, double-blind study. Biol Psychiatry 2008; 63(1): 9-12.
[http://dx.doi.org/10.1016/j.biopsych.2007.04.038] [PMID: 17659263]
[124]
Strzelecki D, Szyburska J. Rabe-Jabłońska J. Two grams of sarcosine in schizophrenia - is it too much? A potential role of glutamate-serotonin interaction. Neuropsychiatr Dis Treat 2014; 10: 263-6.
[http://dx.doi.org/10.2147/NDT.S54024] [PMID: 24523591]
[125]
Strzelecki D, Podgórski M, Kałużyńska O, et al. Supplementation of antipsychotic treatment with sarcosine - GlyT1 inhibitor - causes changes of glutamatergic (1)NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia. Neurosci Lett 2015; 606: 7-12.
[http://dx.doi.org/10.1016/j.neulet.2015.08.039] [PMID: 26306650]
[126]
Strzelecki D, Podgórski M, Kałużyńska O, et al. Adding sarcosine to antipsychotic treatment in patients with stable schizophrenia changes the concentrations of neuronal and glial metabolites in the left dorsolateral prefrontal cortex. Int J Mol Sci 2015; 16(10): 24475-89.
[http://dx.doi.org/10.3390/ijms161024475] [PMID: 26501260]
[127]
Clinical trial of BI 425809 effect on cognition and functional capacity in schizophrenia (CONNEX-3) - Full text view. Clinical- Trialsgov Available from: https://clinicaltrials.gov/ct2/show/NCT04860830 [Accessed on: 2022 May 12].
[128]
Fleischhacker WW, Podhorna J, Gröschl M, et al. Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: A double-blind, randomised, placebo-controlled phase 2 study. Lancet Psychiatry 2021; 8(3): 191-201.
[http://dx.doi.org/10.1016/S2215-0366(20)30513-7] [PMID: 33610228]
[129]
A study of PF-03463275 as add-on therapy in outpatients with persistent negative symptoms of schizophrenia-Full text view. ClinicalTrialsgov Available from: https://clinicaltrials.gov/ct2/show/NCT00977522 [Accessed on: 2022 May, 12
[130]
Agarwal SM, Shivakumar V, Bose A, et al. Transcranial direct current stimulation in schizophrenia. Clin Psychopharmacol Neurosci 2013; 11(3): 118-25.
[http://dx.doi.org/10.9758/cpn.2013.11.3.118] [PMID: 24465247]
[131]
Borgomaneri S, Battaglia S, Avenanti A, Pellegrino GD. Don’t hurt me no more: State-dependent transcranial magnetic stimulation for the treatment of specific phobia. J Affect Disord 2021; 286: 78-9.
[http://dx.doi.org/10.1016/j.jad.2021.02.076] [PMID: 33714173]
[132]
Borgomaneri S, Battaglia S, Sciamanna G, Tortora F, Laricchiuta D. Memories are not written in stone: Re-writing fear memories by means of non-invasive brain stimulation and optogenetic manipulations. Neurosci Biobehav Rev 2021; 127: 334-52.
[http://dx.doi.org/10.1016/j.neubiorev.2021.04.036] [PMID: 33964307]
[133]
Blay M, Adam O, Bation R, Galvao F, Brunelin J, Mondino M. Improvement of insight with non-invasive brain stimulation in patients with schizophrenia: A systematic review. J Clin Med 2022; 11(1): 40.