Skip to main content

Advertisement

SpringerLink
Log in

Potential drug targets and treatment of schizophrenia

  • Review
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Schizophrenia is one of the most prevalent chronic psychiatric disorders that affect 1% of the world’s population. Despite its societal burden, pathophysiology of schizophrenia remains poorly understood. Currently available drugs predominantly control positive symptoms, and often have no or poor control on negative and related cognitive symptoms, which strongly affect functional outcome in schizophrenia. The present article is an attempt to provide a critical review of recent hypothesis to understand pathophysiology of schizophrenia and to highlight exploitable molecular drug targets other than dopaminergic systems to treat and manage schizophrenia effectively.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Akyol O, Zoroglu SS, Armutcu F, Sahin S, Gurel A (2004) Nitric oxide as a physiopathological factor in neuropsychiatric disorders. In Vivo 18:377–390

    CAS  PubMed  Google Scholar 

  • Allan ER, Alpert M, Sison CE, Citrome L, Laury G, Berman I (1996) Adjunctive nadolol in the treatment of acutely aggressive schizophrenic patients. J Clin Psychiatry 57:455–459

    Article  CAS  PubMed  Google Scholar 

  • Altamura AC, Mauri MC, Mantero M, Brunetti M (1987) Clonazepam/haloperidol combination therapy in schizophrenia: a double blind study. Acta Psychiatr Scand 76:702–706

    Article  CAS  PubMed  Google Scholar 

  • Asevedo E, Gadelha A, Noto C, Mansur RB, Zugman A, Belangero SI, Berberian AA, Scarpato BS, Leclerc E, Teixeira AL, Gama CS, Bressan RA, Brietzke E (2013) Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia. J Psychiatr Res 47:1376–1382

    Article  PubMed  Google Scholar 

  • Ban TA (2007) Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat 3(4):495–500

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bardgett ME, Griffith MS, Foltz RF, Hopkins JA, Massie CM, O’Connell SM (2006) The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage. Neurobiol Learn Memory 85(1):86–94

    Article  CAS  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  CAS  PubMed  Google Scholar 

  • Bartoli F, Dell’Osso B, Crocamo C, Fiorillo A, Ketter TA, Suppes T, Clerici M, Carrà G (2017) Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: a meta-analysis. J Psychiatr Res 88:38–46

    Article  PubMed  Google Scholar 

  • Berman I, Sapers BL, Chang HH, Losonczy MF, Schmildler J, Green AI (1995) Treatment of obsessive-compulsive symptoms in schizophrenic patients with clomipramine. J Clin Psychopharmacol 15(3):206–210

    Article  CAS  PubMed  Google Scholar 

  • Bernstein HG, Bogerts B, Keilhoff G (2005) The many faces of nitric oxide in schizophrenia. A review. Schizophr Res 78:69–86

    Article  PubMed  Google Scholar 

  • Binder EB, Kinkead B, Owens MJ, Nemeroff CB (2001) The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs. Biol Psychiatry 50:856–872

    Article  CAS  PubMed  Google Scholar 

  • Bodkin JA, Cohen BM, Salomon MS, Cannon SE, Zornberg GL, Cole JO (1996) Treatment of negative symptoms in schizophrenia and schizoaffective disorder by selegiline augmentation of antipsychotic medication. A pilot study examining the role of dopamine. J Nerv Ment Dis 184:295–301

    Article  CAS  PubMed  Google Scholar 

  • Boskovic M, Vovk T, Kores Plesnicar B, Grabnar I (2011) Oxidative stress in schizophrenia. Curr Neuropharmacol 9(2):301–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bredt DS (1999) Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res. 31(6):577–596

    Article  CAS  PubMed  Google Scholar 

  • Bredt DS, Snyder SH (1992) Nitric oxide, a novel neuronal messenger. Neuron 8(1):3–11

    Article  CAS  PubMed  Google Scholar 

  • Brisch R, Bernstein HG, Krell D, Dobrowolny H, Bielau H, Steiner J, Gos T, Funke S, Stauch R, Knüppel S, Bogerts B (2009) Dopamine-glutamate abnormalities in the frontal cortex associated with the catechol-O-methyltransferase (COMT) in schizophrenia. Brain Res 1269:166–175

    Article  CAS  PubMed  Google Scholar 

  • Buchanan RW, Summerfelt A, Tek C, Gold J (2003) An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia. Schizophr Res 59:29–33

    Article  PubMed  Google Scholar 

  • Caceda R, Kinkead B, Nemeroff CB (2006) Neurotensin: role in psychiatric and neurological diseases. Peptides 27:2385–2404

    Article  CAS  PubMed  Google Scholar 

  • Carlsson A (1988) The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacol 1:179–186

    Article  CAS  Google Scholar 

  • Carlsson ML, Carlsson A, Nilsson M (2004) Schizophrenia: from dopamine to glutamate and back. Curr Med Chem 11:267–277

    Article  CAS  PubMed  Google Scholar 

  • Carpenter WT Jr, Heinrichs DW, Wagman AM (1988) Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry 145:578–583

    Article  PubMed  Google Scholar 

  • Carpenter LL, McDougle CJ, Epperson CN, Price LH (1996) A risk-benefit assessment of drugs used in the management of obsessive-compulsive disorder. Drug Saf 15(2):116–134

    Article  CAS  PubMed  Google Scholar 

  • Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M (2001) Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study. Int Clin Psychopharmacol 16:111–115

    Article  CAS  PubMed  Google Scholar 

  • Chopra K, Baveja A, Kuhad A (2015) MMPs: a novel drug target for schizophrenia. Expert Opin Ther Targets 19(1):77–85

    Article  CAS  PubMed  Google Scholar 

  • Ciobica A, Padurariu M, Dobrin I, Stefanescu C, Dobrin R (2011) Oxidative stress in schizophrenia—focusing on the main markers. Psychiatr Danub 23:237–245

    CAS  PubMed  Google Scholar 

  • Cioffi CL (2013) Modulation of NMDA receptor function as a treatment for schizophrenia. Bioorg Med Chem Lett 23:5034–5044

    Article  CAS  PubMed  Google Scholar 

  • Colquhoun LM, Patrick JW (1997) Pharmacology of neuronal nicotinic acetylcholine receptor subtypes. Adv Pharmacol 39:191–220

    Article  CAS  PubMed  Google Scholar 

  • Coskran TM, Morton DG, Menniti FS, Adamowicz WO, Kleiman RJ, Ryan AM, Strick CA, Schmidt CJ, Stephenson DT (2006) Immunohistochemical localization of phosphodiesterase 10A, PDE10A, in multiple mammalian species. J Histochem Cytochem 54:1205–1213

    Article  CAS  PubMed  Google Scholar 

  • Coyle J (1997) The nagging question of the function of N acetylaspartylglutamate. Neurobiol Dis 4:231–238

    Article  CAS  PubMed  Google Scholar 

  • Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B (2000) Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry 48:381–388

    Article  CAS  PubMed  Google Scholar 

  • Culotta E, Koshland DE (1992) NO news is good news. Science 258:1862–1865

    Article  CAS  PubMed  Google Scholar 

  • Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust NZ J Psychiatry 48:512–529

    Article  Google Scholar 

  • Dawson LA, Smith PW (2010) Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia. Curr Pharm Des 16:344–357

    Article  CAS  PubMed  Google Scholar 

  • De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V (2003) Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis 2:5

    Article  PubMed  PubMed Central  Google Scholar 

  • Dean B, Sundram S, Bradbury R, Scarr E, Copolov D (2001) Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid 1 receptors associated with schizophrenia and cannabis use. Neuroscience 103:9–15

    Article  CAS  PubMed  Google Scholar 

  • Di Giovanni G, Di Matteo V, Di Mascio M, Esposito E (2000) Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study. Synapse 35(1):53–61

    Article  PubMed  Google Scholar 

  • Dietrich-Muszalska A (2015) Oxidative stress in schizophrenia. Studies on psychiatric disorders. Springer, New York, pp 43–72

    Google Scholar 

  • Dose M, Hellweg R, Yassouridis A, Theison M, Emrich HM (1998) Combined treatment of schizophrenic psychoses with haloperidol and valproate. Pharmacopsychiatry 31:122–125

    Article  CAS  PubMed  Google Scholar 

  • Ebstein RP, Biederman J, Rimon R, Zohar J, Belmaker RJ (1976) Cyclic GMP in the CSF of patients with schizophrenia before and after neuroleptic treatment. Psychopharmacology 51(1):71–74

    Article  CAS  PubMed  Google Scholar 

  • Emrich HM, Leweke FM, Schneider U (1997) Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol Biochem Behav 56:803–807

    Article  CAS  PubMed  Google Scholar 

  • Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC (2000) Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 157:826–828

    Article  CAS  PubMed  Google Scholar 

  • Feifel D, Reza TL, Wustrow DJ, Davis MD (1999) Novel antipsychotic-like effects on prepulse inhibition of startle produced by a neurotensin agonist. J Pharmacol Exp Ther 288:710–713

    CAS  PubMed  Google Scholar 

  • Fell MJ, McKinzie DL, Monn JA, Svensson KA (2012) Group II metabotropic glutamate receptor agonists and positive allosteric modulators as novel treatments for schizophrenia. Neuropharmacology 62:1473–1483

    Article  CAS  PubMed  Google Scholar 

  • Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M (2001) A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 158:2071–2074

    Article  CAS  PubMed  Google Scholar 

  • Ferraro L, Tomasini MC, Fuxe K, Agnati LF, Mazza R, Tanganelli S, Antonelli T (2007) Mesolimbic dopamine and cortico-accumbens glutamate afferents as major targets for the regulation of the ventral striato-pallidal GABA pathways by neurotensin peptides. Brain Res Rev 55:144–154

    Article  CAS  PubMed  Google Scholar 

  • Finberg JP, Youdim MB (2002) Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours. Neuropharmacology 43:1110–1118

    Article  CAS  PubMed  Google Scholar 

  • Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M, Keck PE Jr, Marangell LB, Richardson AJ, Lake J, Stoll AL (2006) Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 67:1954–1967

    Article  CAS  PubMed  Google Scholar 

  • Friedman JI, Adler DN, Howanitz E, Harvey PD, Brenner G, Temporini H, White L, Parrella M, Davis KL (2002) A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry 51:349–357

    Article  CAS  PubMed  Google Scholar 

  • Ganzinelli S, Borda E, Sterin-Borda L (2010) Autoantibodies from schizophrenia patients induce cerebral cox-1/iNOS mRNA expression with NO/PGE2/MMP-3 production. Int J Neuropsychopharmacol 13:293–303

    Article  CAS  PubMed  Google Scholar 

  • Gattaz WF, Carmer H, Beckmann H (1983) Low CSF concentrations of cyclic GMP in schizophrenia. Br J Psychiatry 142:288–291

    Article  CAS  PubMed  Google Scholar 

  • Godar SC, Bortolato M (2014) Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission. Front Behav Neurosci 8:71

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377

    Article  CAS  PubMed  Google Scholar 

  • Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden DL, McCarley R, Coyle JT (1999) A placebo-controlled trial of d-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 56:21–27

    Article  CAS  PubMed  Google Scholar 

  • Gray JA, Roth BL (2007) The pipeline and future of drug development in schizophrenia. Mol Psychiatry 12(10):904–922

    Article  CAS  PubMed  Google Scholar 

  • Griebel G, Beeske S (2011) Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases? Pharmacol Ther 133:116–123

    Article  PubMed  CAS  Google Scholar 

  • Gupta VK, Sharma SK (2006) Plants as natural antioxidants. Nat Prod Radiance. 5(4):326–334

    Google Scholar 

  • Gupta S, Droney T, Kyser A, Keller P (1999) Selegiline augmentation of antipsychotics for the treatment of negative symptoms in schizophrenia. Compr Psychiatry 40:148–150

    Article  CAS  PubMed  Google Scholar 

  • Gutteridge JMC (1995) Free radicals in disease processes: a compilation of cause and consequence. Free Radic Res Commun 19:141

    Article  Google Scholar 

  • Harvey PD, Keefe RSE (2001) Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 158:176–184

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Su TP (2004) Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18(5):269–284

    Article  CAS  PubMed  Google Scholar 

  • He J, Yang Y, Xu H, Zhang X, Li XM (2005) Olanzapine attenuates the okadaic acid-induced spatial memory impairment and hippocampal cell death in rats. Neuropsychopharmacology 30(8):1511–1520

    Article  CAS  PubMed  Google Scholar 

  • Hemish J, Nakaya N, Mittal V, Enikolopov G (2003) Nitric oxide activates diverse signaling pathways to regulate gene expression. J Biol Chem 278:42321–42329

    Article  CAS  PubMed  Google Scholar 

  • Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D (1996) Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry 169:610–617

    Article  CAS  PubMed  Google Scholar 

  • Hesslinger B, Normann C, Langosch JM, Klose P, Berger M, Walden J (1999) Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. J Clin Psychopharmacol 19:310–315

    Article  CAS  PubMed  Google Scholar 

  • Hippius H (1989) The history of clozapine. Psychopharmacology 99(Suppl):S3–S5

    Article  PubMed  Google Scholar 

  • Hobbs AJ, Ignarro LJ (1996) Nitric oxide-cyclic GMP signal transduction system. Methods Enzymol 269:134–148

    Article  CAS  PubMed  Google Scholar 

  • Hoffer A (1960) Adrenaline metabolites and schizophrenia. Dis Nerv Syst 21:79

    PubMed  Google Scholar 

  • Hoffer A, Prousky J (2008) Successful treatment of schizophrenia requires optimal daily doses of vitamin B3. Altern Med Rev 13(4):287–291

    PubMed  Google Scholar 

  • Hosak L, Libiger J (2002) Antiepileptic drugs in schizophrenia: a review. European psychiatry 17(7):371–378

    Article  CAS  PubMed  Google Scholar 

  • Hunter R (2014) Developing tomorrow’s antipsychotics: the need for a more personalised approach. Adv Psychiatr Treat 20(1):3–12

    Article  Google Scholar 

  • Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva IP (1977) Agranulocytosis during treatment with chlozapine. Eur J Clin Pharmacol 11(3):193–198

    Article  PubMed  Google Scholar 

  • Insel TR (2010) Rethinking schizophrenia. Nature 468:187e93

  • Jakubík J, El-Fakahany EE (2010) Allosteric modulation of muscarinic acetylcholine receptors. Pharmaceuticals 3:2838–2860

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Javitt DC, Zukin SR (1991) Recent advances in the phenciclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    Article  CAS  PubMed  Google Scholar 

  • Javitt DC, Silipo G, Cienfuegos A, Shelley AM, Bark N, Park M, Lindenmayer JP, Suckow R, Zukin SR (2001) Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol 4:385–391

    Article  CAS  PubMed  Google Scholar 

  • Jones CK, Byun N, Bubser M (2012) Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology 37(1):16–42

    Article  CAS  PubMed  Google Scholar 

  • Kapur S, Seeman P (2000) Antipsychotic agents differ in how fast they come off the dopamine D2 receptors: implications for atypical antipsychotic action. J Psychiatry Neurosci 25:161–166

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kasckow J, Nemeroff CB (1991) The neurobiology of neurotensin: focus on neurotensin–dopamine interactions. Regul Pept 36:153–164

    Article  CAS  PubMed  Google Scholar 

  • Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13(2):261–276

    Article  CAS  PubMed  Google Scholar 

  • Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA, CATIE Investigators, Neurocognitive Working Group (2007) Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 64(6):633–647

    Article  CAS  PubMed  Google Scholar 

  • Kerner B (2009) Glutamate neurotransmission in psychotic disorders and substance abuse. Open Psychiatr J. 3:1–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (2004) 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation—an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47(2):195–204

    Article  CAS  PubMed  Google Scholar 

  • Kirli S, Caliskan M (1998) A comparative study of sertraline versus imipramine in postpsychotic depressive disorder of schizophrenia. Schizophr Res 33:103–111

    Article  CAS  PubMed  Google Scholar 

  • Klein DF, Davis JM (1969) Diagnosis and drug treatment of psychiatric disorders. Krieger, Huntington

    Google Scholar 

  • Kontis D, Theochari E, Fryssira H, Kleisas S, Sofocleous C, Andreopoulou A, Kalogerakou S, Gazi A, Boniatsi L, Chaidemenos A, Tsaltas E (2013) COMT and polymorphisms interaction on cognition in schizophrenia: an exploratory study. Neurosci Lett 537:17–22

    Article  CAS  PubMed  Google Scholar 

  • Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28:519–526

    Article  CAS  PubMed  Google Scholar 

  • Kroken RA, Loberg EM, Dronen T, Gruner R, Hugdahl K, Kompus K, Skrede S, Johnsen E (2014) A critical review of pro-cognitive drug targets in psychosis: convergence on myelination and inflammation. Front Psychiatry 5:11

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuperberg G, Kerwin R, Murray R (2002) Developments in the pharmacological treatment of schizophrenia. Expert Opin Investig Drugs 11(10):1335–1341

    Article  CAS  PubMed  Google Scholar 

  • Lambert P, Perrin J, Revol L et al (1959) Essai de classification des neuroleptiques d’après leurs activités psychopharmacologiques et cliniques. In: Bradley PB, Deniker P, Radouco-Thomas C (eds) Neuropsychopharmacology. Elsevier, Amsterdam, pp 619–624

    Google Scholar 

  • Large CH, Webster EL, Goff DC (2005) The potential role of lamotrigine in schizophrenia. Psychopharmacology 181(3):415–436

    Article  CAS  PubMed  Google Scholar 

  • Laruelle M, Kegeles LS, Abi-Dargham A (2003) Glutamate, dopamine, and schizophrenia from pathophysiology to treatment. Ann NY Acad Sci 1003:138–158

    Article  CAS  PubMed  Google Scholar 

  • Lepeta K, Kaczmarek L (2015) Matrix metalloproteinase-9 as a novel player in synaptic plasticity and schizophrenia. Schizophr Bull 41(5):1003–1009

    Article  PubMed  PubMed Central  Google Scholar 

  • Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR (1991) Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci 11:3218–3226

    CAS  PubMed  Google Scholar 

  • Liljequist R, Haapalinna A, Ahlander M, Li YH, Mannisto PT (1997) Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behav Brain Res 82:195–202

    Article  CAS  PubMed  Google Scholar 

  • Lin A, Kenis G, Bignotti S, Tura GJ, De Jong R, Bosmans E, Pioli R, Altamura C, Scharpe S, Maes M (1998) The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res 32:9–15

    Article  CAS  PubMed  Google Scholar 

  • Litman RE, Su TP, Potter WZ, Hong WW, Pickar D (1996) Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. Br J Psychiatry 168:571–579

    Article  CAS  PubMed  Google Scholar 

  • Madras BK (2013) History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia. J Hist Neurosci 22:62–78

    Article  PubMed  Google Scholar 

  • Manatt M, Chandra SB (2011) The effects of mitochondrial dysfunction in schizophrenia. J Med Genet Genomics 3(5):84–94

    CAS  Google Scholar 

  • Marazziti D, Baroni S, Picchetti M, Landi P, Silvestri S, Vatteroni E, Catena Dell’Osso M (2011) Mitochondrial alterations and neuropsychiatric disorders. Curr Med Chem 18:4715–4721

    Article  CAS  PubMed  Google Scholar 

  • Martin LF, Kem WR, Freedman R (2004) Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology 174:54–64

    Article  CAS  PubMed  Google Scholar 

  • Maurer I, Zierz S, Möller H (2001) Evidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia. Schizophren Res 48:125–136

    Article  CAS  Google Scholar 

  • Mayer B, Hemmens B (1997) Biosynthesis and action of nitric oxide in mammalian cells. Trends Biochem Sci 22:477–481

    Article  CAS  PubMed  Google Scholar 

  • Meiri KF, Saffell JL, Walsh FS, Doherty P (1998) Neurite outgrowth stimulated by neural cell adhesion molecules requires growth-associated protein-43 (GAP-43) function and is associated with GAP-43 phosphorylation in growth cones. J Neurosci 18:10429–10437

    CAS  PubMed  Google Scholar 

  • Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine—the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology 99:S18–S27

    Article  PubMed  Google Scholar 

  • Meltzer D (1999) Perspective and the measurement of costs and benefits for cost effectiveness analysis in schizophrenia. J Clin Psychiatry 60(Suppl 3):32–35 (discussion 36–7)

    PubMed  Google Scholar 

  • Millan MJ, Schreiber R, Dekeyne A, Rivet JM, Bervoets K, Mavridis M, Sebban C, Maurel-Remy S, Newman-Tancredi A, Spedding M, Muller O, Lavielle G, Brocco M (1998) S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: II. Functional profile in comparison to clozapine and haloperidol. J Pharmacol Exp Ther 286(3):1356–1373

    CAS  PubMed  Google Scholar 

  • Monji A, Kato T, Kanba S (2009) Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 63(3):257–265

    Article  CAS  PubMed  Google Scholar 

  • Morris HM, Hashimoto T, Lewis DA (2008) Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder. Cereb Cortex 18:1575–1587

    Article  PubMed  PubMed Central  Google Scholar 

  • Muller N, Schwarz MJ (2008) COX-2 inhibition in schizophrenia and major depression. Current pharmaceutical design 14(14):1452–1465

    Article  PubMed  Google Scholar 

  • Müller N, Weidinger E, Leitner B, Schwarz MJ (2015) The role of inflammation in schizophrenia. Front Neurosci 9:372

    Article  PubMed  PubMed Central  Google Scholar 

  • Negre-Aminou P, Pfenninger KH (1993) Arachidonic acid turnover and phospholipase A2 activity in neuronal growth cones. J Neurochem 60:1126–1136

    Article  CAS  PubMed  Google Scholar 

  • Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11:851–876

    Article  CAS  PubMed  Google Scholar 

  • Nissinen L, Kahari VM (2014) Matrix metalloproteinases in inflammation. Biochim Biophys Acta 1840:2571–2580

    Article  CAS  PubMed  Google Scholar 

  • Oliveira JP, Zuardi AW, Hallak JE (2008) Role of nitric oxide in patients with schizophrenia—a systematic review of the literature. Curr Psychiatry Rev 4:219–227

    Article  CAS  Google Scholar 

  • Osmond H, Smythies J (1952) Schizophrenia: a new approach. J Ment Sci 98(411):309–315

    CAS  PubMed  Google Scholar 

  • Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58(3):389–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parle M, Kadian R (2013a) Behavioral models of psychosis. Int Res J Pharm 7:26–30

    Article  Google Scholar 

  • Parle M, Kadian R (2013b) Non behavioral models of psychosis. Int Res J Pharm 4(8):89–95

    Article  Google Scholar 

  • Parle M, Sharma K (2013) Biomarker and causative factor of schizophrenia. Int Res J Pharm 4:78–85

    Article  Google Scholar 

  • Peet M, Brind J, Ramchand CN, Shah S, Vankar GK (2001) Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 49:243–251

    Article  CAS  PubMed  Google Scholar 

  • Perenyi A, Goswami U, Frecska E, Arato M, Bela A (1992) l-Deprenyl in treating negative symptoms of schizophrenia. Psychiatry Res 42:189–191

    Article  CAS  PubMed  Google Scholar 

  • Pieczenik SR, Neustadt J (2007) Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 83(1):84–92

    Article  CAS  PubMed  Google Scholar 

  • Piletz JE, Chikkala DN, Ernsberger P (1995) Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and alpha 2-adrenergic receptors. J Pharmacol Exp Ther 272:581–587

    CAS  PubMed  Google Scholar 

  • Piomelli D, Pilon C, Giros B, Sokoloff P, Martres MP, Schwartz JC (1991) Dopamine activation of the arachidonic acid cascade as a basis for D1/D2 receptor synergism. Nature 353:164–167

    Article  CAS  PubMed  Google Scholar 

  • Poulin B, Butcher A, McWilliams P, Bourgognon JM, Pawlak R, Kong KC, Bottrill A, Mistry S, Wess J, Rosethorne EM, Charlton SJ, Tobin AB (2010) The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner. Proc Natl Acad Sci USA 107:9440–9445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JTJ, Griffin JL, Wayland M, Freeman T, Dudbridge F, Lilley KS, Karp NA, Hester S, Tkachev D, Mimmack ML, Yolken RH, Webster MJ, Torrey EF, Bahn S (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9(684–97):643

    Article  Google Scholar 

  • Puzzo D, Sapienza S, Arancio O, Palmeri A (2008) Role of phosphodiesterase 5 in synaptic plasticity and memory. Neuropsychiatr Dis Treat. 4(2):371–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raiteri M, Leardi R, Marchi M (1984) Heterogeneity of presynaptic muscarinic receptors regulating neurotransmitter release in the rat brain. J Pharmacol Exp Ther 228:209–214

    CAS  PubMed  Google Scholar 

  • Raiteri M, Marchi M, Paudice P, Pittaluga A (1990) Muscarinic receptors mediating inhibition of g-aminobutyric acid release in rat corpus striatum and their pharmacological characterization. J Pharmacol Exp Ther 254:496–501

    CAS  PubMed  Google Scholar 

  • Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M (2015) Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. Neurosci Biobehav Rev 48:10–21

    Article  CAS  PubMed  Google Scholar 

  • Rao NP, Remington G (2013) Investigational drugs for schizophrenia targeting the dopamine receptor: phase II trials. Expert Opin Investig Drugs 22(7):881–894

    Article  CAS  PubMed  Google Scholar 

  • Reznik I, Sirota P (2000) An open study of fluvoxamine augmentation of neuroleptics in schizophrenia with obsessive and compulsive symptoms. Clin Neuropharmacol 23(3):157–160

    Article  CAS  PubMed  Google Scholar 

  • Richardson AJ (2006) Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int Rev Psychiatry 18:155–172

    Article  PubMed  Google Scholar 

  • Riecher-Rossler A, Hafner H (2000) Gender aspects in schizophrenia: bridging the border between social and biological psychiatry. Acta Psychiatr Scand Suppl 102:58–62

    Article  Google Scholar 

  • Risch SC, McGurk S, Horner MD, Nahas Z, Owens SD, Molloy M, Gilliard C, Christie S, Markowitz JS, DeVane CL, Mintzer J, George MS (2001) A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: functional MRI correlates. Neurocase 7:105–110

    Article  CAS  PubMed  Google Scholar 

  • Rogers DC, Hagan JJ (2001) 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology 158(2):114–119

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg GA (2009) Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 8:205–216

    Article  CAS  PubMed  Google Scholar 

  • Roth BL, Hanizavareh SM, Blum AE (2004) Serotonin receptors represent highly favourable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology 174:17–24

    Article  CAS  PubMed  Google Scholar 

  • Rouse ST, Edmunds SM, Yi H, Gilmor ML, Levey AI (2000) Localization of M(2) muscarinic acetylcholine receptor protein in cholinergic and non-cholinergic terminals in rat hippocampus. Neurosci Lett 284:182–186

    Article  CAS  PubMed  Google Scholar 

  • Rubeša G, Gudelj L, Kubinska N (2011) Etiology of schizophrenia and therapeutic options. Psychiatr Danub. 23(3):308–315

    PubMed  Google Scholar 

  • Rukmini MS, D’Souza B, D’Souza V (2004) Superoxide dismutase and catalase activities and their correlation with malondialdehyde in schizophrenic patients. Indian J Clin Biochem 19(2):114–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samochocki M, Höffle A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira EF, Lübbert H, Albuquerque EX, Maelicke A (2003) Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 305(3):1024–1036

    Article  CAS  PubMed  Google Scholar 

  • Sarter M, Bruno JP (1997) Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 23:28–46

    Article  CAS  PubMed  Google Scholar 

  • Saudou F, Hen R (1994) 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates. Neurochem Int 25(6):503–532

    Article  CAS  PubMed  Google Scholar 

  • Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, Hoffman WE, Lebel LA, McCarthy SA, Nelson FR, Proulx-LaFrance C, Majchrzak MJ, Ramirez AD, Schmidt K, Seymour PA, Siuciak JA, Tingley FD 3rd, Williams RD, Verhoest PR, Menniti FS (2008) Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 325(2):681–690

    Article  CAS  PubMed  Google Scholar 

  • Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, Lanfear J, Ryan AM, Schmidt CJ, Strick CA, Varghese AH, Williams RD, Wylie PG, Menniti FS (2003) Immunohistochemical localization of PDE10A in the rat brain. Brain Res 985:113–126

    Article  CAS  PubMed  Google Scholar 

  • Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neutrons. Science 188:1217–1219

    Article  CAS  PubMed  Google Scholar 

  • Selvaraj S, Arnone D, Cappai A, Howes O (2014) Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci Biobehav Rev 45:233–245

    Article  CAS  PubMed  Google Scholar 

  • Shekhawat LS, Jiloha RC (2009) Recent advances in the treatment of schizophrenia. Delhi Psych J 12(2):176–187

    Google Scholar 

  • Shen WW (1999) A history of antipsychotic drug development. Compr Psychiatry 40(6):407–414

    Article  CAS  PubMed  Google Scholar 

  • Siris SG, Bermanzohn PC, Mason SE, Shuwall MA (1994) Maintenance imipramine therapy for secondary depression in schizophrenia: a controlled trial. Arch Gen Psychiatry 51:109–115

    Article  CAS  PubMed  Google Scholar 

  • Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, Schmidt CJ (2006) Inhibition of the striatum- enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 51:386–396

    Article  CAS  PubMed  Google Scholar 

  • Skosnika PD, Yao JK (2003) From membrane phospholipid defects to altered neurotransmission: is arachidonic acid a nexus in the pathophysiology of schizophrenia? Prostaglandins Leukot Essent Fatty Acids 69:367–384

    Article  CAS  Google Scholar 

  • Snyder SH, Banerjee SP, Yamamura HI, Greenberg D (1974) Drugs, neurotransmitters, and schizophrenia. Science 184:1243–1253

    Article  CAS  PubMed  Google Scholar 

  • Sorenson EM, Shiroyama T, Kitai ST (1998) Postsynaptic nicotinic receptors on dopaminergic neurons in the substantia nigra pars compacta of the rat. Neuroscience 87:659–673

    Article  CAS  PubMed  Google Scholar 

  • Spear N, Gadient RA, Wilkins DE, Do M, Smith JS, Zeller KL, Schroeder P, Zhang M, Arora J, Chhajlani V (2011) Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator. Eur J Pharmacol 659:146–154

    Article  CAS  PubMed  Google Scholar 

  • Spooren W, Riemer C, Meltzer H (2005) NK3 receptor antagonists: the next generation of antipsychotics? Nat Rev Drug Discov 4:967–975

    Article  CAS  PubMed  Google Scholar 

  • Steullet P, Cabungcal JH, Monin A, Dwir D, O’Donnell P, Cuenod M, Do KQ (2016) Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia pathophysiology? Schizophr Res 176(1):41–51

    Article  CAS  PubMed  Google Scholar 

  • St-Gelais F, Menard C, Congar P, Trudeau LE, Massicotte G (2004) Postsynaptic injection of calcium-independent phospholipase A2 inhibitors selectively increases AMPA receptor-mediated synaptic transmission. Hippocampus 14:319–325

    Article  CAS  PubMed  Google Scholar 

  • Tsai G, Coyle JT (2002) Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42:165–179

    Article  CAS  PubMed  Google Scholar 

  • Tzavara ET, Bymaster FP, Felder CC, Wade M, Gomeza J, Wess J, McKinzie DL, Nomikos GG (2003) Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice. Mol Psychiatry 8:673–679

    Article  CAS  PubMed  Google Scholar 

  • Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, Wess J, McKinzie DL, Felder C, Nomikos GG (2004) M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. FASEB J 18:1410–1412

    CAS  PubMed  Google Scholar 

  • Ungvari GS, Chiu HF, Chow LY, Lau BS, Tang WK (1999) Lorazepam for chronic catatonia: a randomized, double blind, placebo-controlled cross-over study. Psychopharmacology 142:393–398

    Article  CAS  PubMed  Google Scholar 

  • Uzbay IT, Kayir H, Göktalay G, Yildirim M (2008) Agmatine induces schizophrenia like-symptom in Wistar rats. Eur Neuropsychopharmacol 18(Suppl. 4):S399

    Article  Google Scholar 

  • Vilaro MT, Palacios JM, Mengod G (1990) Localization of m5 muscarinic receptor mRNA in rat brain examined by in situ hybridization histochemistry. Neurosci Lett 114:154–159

    Article  CAS  PubMed  Google Scholar 

  • Vizi ES, Kobayashi O, Töröcsik A, Kinjo M, Nagashima H, Manabe N, Goldiner PL, Potter PE, Foldes FF (1989) Heterogeneity of presynaptic muscarinic receptors involved in modulation of transmitter release. Neuroscience 31:259–267

    Article  CAS  PubMed  Google Scholar 

  • Vyas NS, Patel NH, Puri BK (2011) Neurobiology and phenotypic expression in early onset schizophrenia. Early Interv Psychiatry 5:3–14

    Article  PubMed  Google Scholar 

  • Wamsley JK, Zarbin MA, Kuhar MJ (1984) Distribution of muscarinic cholinergic high and low affinity agonist binding sites: a light microscopic autoradiographic study. Brain Res Bull 12:233–243

    Article  CAS  PubMed  Google Scholar 

  • Wei J, Hemmings GP (1999) The CCK-A receptor gene possibly associated with auditory hallucinations in schizophrenia. Eur Psychiatry 14:67–70

    Article  CAS  PubMed  Google Scholar 

  • Weiner DM, Levey AI, Brann MR (1990) Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia. Proc Natl Acad Sci USA 87:7050–7054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams HJ, Owen MJ, O'donovan MC (2007) Is COMT a susceptibility gene for schizophrenia. Schizophr Bull 33(3):635–641

    Article  PubMed  PubMed Central  Google Scholar 

  • Wils RS, Gotfredsen DR, Hjorthøj C, Austin SF, Albert N, Secher RG, Thorup AA, Mors O, Nordentoft M (2016) Antipsychotic medication and remission of psychotic symptoms 10 years after a first-episode psychosis. Schizophr Res (in press)

  • Wolkowitz OM, Pickar D (1991) Benzodiazepines in the treatment of schizophrenia: a review and reappraisal. Am J Psychiatry 148:714–726

    Article  CAS  PubMed  Google Scholar 

  • Xie Z, Adamowicz WO, Eldred WD, Jakowski AB, Kleiman RJ, Morton DG, Stephenson DT, Strick CA, Williams RD, Menniti FS (2006) Cellular and subcellular localization of PDE10A, a striatal-specific phosphodiesterase. Neuroscience 139:597–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yadav M, Parle M, Kadian M, Sharma K (2015) A review on psychosis and anti-psychotic plants. Asian J Pharm Clin Res 8(4):24–28

    Google Scholar 

  • Yoshida K, Higuchi H, Hishikawa Y (1998) Marked improvement of tardive dystonia after replacing haloperidol with risperidone in a schizophrenic patient. Clin Neuropharmacol 21(1):68–69

    CAS  PubMed  Google Scholar 

  • Zang Z, Creese I (1997) Differential regulation of expression of rat hippocampal muscarinic receptor subtypes following fimbria–fornix lesion. Biochem Pharmacol 53:1379–1382

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Basile AS, Gomeza J, Volpicelli LA, Levey AI, Wess J (2002) Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knockout mice. J Neurosci 22:1709–1717

    CAS  PubMed  Google Scholar 

  • Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY (2003) Elevated blood superoxide dismutase in neuroleptic-free schizophrenia: association with positive symptoms. J Psychiatr Res 117:85–88

    Article  CAS  Google Scholar 

  • Ziimmer R, Teelken AW, Cramer H, Ackenheil M, Zandler KJ, Fischer H (1980) Short- and long-term effects on GABA and dopamine neurons during treatment with sulpiride. Adv Biochem Psychopharmacol 24:537–539

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuropharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies (UGC-CAS), Panjab University, Chandigarh, 160014, India

    Anil Kumar & Dinesh K. Dhull

  2. Pharmacology Division, Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, 125001, India

    Monu Yadav & Milind Parle

  3. Faculty of Medical Sciences, School of Pharmacy, The University of the West Indies, St. Augustine, Trinidad and Tobago

    Sameer Dhingra

Authors
  1. Anil Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monu Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Milind Parle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sameer Dhingra
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dinesh K. Dhull
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anil Kumar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, A., Yadav, M., Parle, M. et al. Potential drug targets and treatment of schizophrenia. Inflammopharmacol 25, 277–292 (2017). https://doi.org/10.1007/s10787-017-0340-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-017-0340-5

Keywords

Search

Navigation