Skip to main content
SpringerLink
Log in

Schizophrenia: A Complex Mental Illness

  • Chapter
  • First Online:
Psychiatry and Neuroscience Update

Abstract

Schizophrenia is a complex mental illness that affects 1% of the world population without differences of gender, race, or social status that requires effective antipsychotic treatments producing minimal adverse effects. Schizophrenia is thought as a disconnection disorder of functional brain networks that produces three essential types of clinical manifestations: psychotic symptoms, negative symptoms, and cognitive impairment. The former include loss of contact with reality, including delusions and hallucinations. Negative symptoms are states of deficit in which the basic behavior is diminished or absent. Cognitive impairment includes disturbance in attention, concentration, learning and memory, and operational functions. Schizophrenia is a neurodevelopmental disorder which is the result of multiple factor interactions such as viral illnesses during pregnancy, environmental agents, immunological dysfunction, or obstetric complications. Like other major psychiatric disorders, schizophrenia is also associated with abnormalities in multiple epigenetic mechanisms, resulting in altered gene expression during development and adulthood.

Several lines of evidence have studied anatomical and functional modifications and altered neurotransmission systems involved in the schizophrenia. This knowledge has been used to achieve better understanding of the disease and the possibility of developing new drugs; many of them have recently been approved for the routine clinical use.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Novella E, Huertas R. El síndrome de Kraepelin-Bleuler-Schneider. Clín Salud. 2010;3:205–19.

    Google Scholar 

  2. Langfeldt G. Schizophrenia: diagnosis and prognosis. Syst Res Behav Sci. 1969;14:173–82.

    Article  CAS  Google Scholar 

  3. Strakowski SM. Diagnostic validity of schizophreniform disorder. Am Psychiatry. 1994;151(6):815–24.

    Article  CAS  Google Scholar 

  4. Crow TJ. The two-syndrome concept: origins and current status. Schizophr Bull. 1985;11:471–88.

    Article  CAS  PubMed  Google Scholar 

  5. Liddle P, Friston K, Frith C, Frackowiak R. Cerebral blood flow and mental processes in schizophrenia. J R Soc Med. 1992;85:224–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Van den Heuvel M, Sporns O, Collin G, Scheewe T, Mandl R, Cahn W, Goñi J, Hulshoff PH, Kahn R. Abnormal rich club organization and functional brain dynamics in schizophrenia. JAMA Psychiat. 2013;70:783–92.

    Article  Google Scholar 

  7. Stephan KE, Friston KJ, Frith CD. Disconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull. 2009;35(3):509–27.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363:2063–72.

    Article  PubMed  Google Scholar 

  9. Addinton J, Cornblatt BA, Cadenhead KS, Cannon TD, McGlashan T, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, Woods SW, Heinssen R. At clinical high risk for psychosis: outcome for nonconverters. Am J Psychiatry. 2011;168(8):800–5.

    Article  Google Scholar 

  10. Schlosser DA, Jacobson S, Chen Q, Sugar CA, Niendam TA, Li G, Bearden CE, Cannon TD. Recovery from an at-risk state: clinical and functional outcomes of putatively prodromal youth who do not develop psychosis? Schizophr Bull. 2012;38(6):1225–33.

    Article  PubMed  Google Scholar 

  11. Gargiulo PA, Landa de Gargiulo AI. Glutamate and modeling of schizophrenia symptoms: review of our findings: 1990–2014. Pharmacol Rep. 2014;66:343–52.

    Article  CAS  PubMed  Google Scholar 

  12. López Mato A, Vazquez G. Esquizofrenias. In: López Mato A, editor. Psiconeuroinmunoendocrinlogía II. Buenos Aires: Editorial Polemos; 2002.

    Google Scholar 

  13. Lieberman JA, Sheitman BB, Kinon BJ. Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology. 1997;17(4):205–29.

    Article  CAS  PubMed  Google Scholar 

  14. Cantor-Graae E. The contribution of social factors to the development of schizophrenia: a review of recent findings. Can J Psychiatr. 2007;52(5):277–86.

    Article  Google Scholar 

  15. Van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull. 2008;34(6):1095–105.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10(1):40–68.

    Article  CAS  PubMed  Google Scholar 

  17. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III – the final common pathway. Schizophr Bull. 2009;35(3):549–62.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001;98(12):6917–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang H, Xu J, Lazarovici P, Zheng W. Dysbindin-1 involvement in the etiology of schizophrenia. Int J Mol Sci. 2017;22:18.

    Google Scholar 

  20. Martinez Cué C, Flórez J. Fármacos antipsicóticos neurolépticos. In: Flórez J, editor. Farmacología Humana. Madrid: Elsevier-Mason Ed; 2014. p. 519–32.

    Google Scholar 

  21. Shorter KR, Miller BH. Epigenetic mechanisms in schizophrenia. Prog Biophys Mol Biol. 2015;118(1–2):1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Korkmaz A, Oter S, Seyrek M, Topal T. Molecular, genetic and epigenetic pathways of peroxynitrite-induced cellular toxicity. Interdiscip Toxicol. 2009;2(4):219–28.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tremolizzo L, Doueiri S, Dong E, Grayson DR, Davis J, Pinna G, Tueting P, Rodriguez-Menendez V, Costa E, Guidotti A. Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biol Psychiatry. 2005;57:500–9.

    Article  CAS  PubMed  Google Scholar 

  24. Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, Szyf M. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci. 2005;25:11045–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry. 2010;15(12):1176–89.

    Article  CAS  PubMed  Google Scholar 

  26. Lodge DJ, Grace AA. Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharmacol Sci. 2011;32(9):507–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Goldman-Rakic PS. Regional and cellular fractionation of working memory. Proc Natl Acad Sci U S A. 1996;93:13473–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Weinberger DR, Gallhofer B. Cognitive function in schizophrenia. Int Clin Psychopharmacol. 1997;12(Suppl 4):S29–36.

    Article  PubMed  Google Scholar 

  29. Ingvar DH, Franzén G. Distribution of cerebral activity in chronic schizophrenia. Lancet. 1974;2(7895):1484–6.

    Article  CAS  PubMed  Google Scholar 

  30. Tamminga CA. The neurobiology of cognition in schizophrenia. J Clin Psychiatry. 2006;67(Suppl 9):9–13.

    CAS  PubMed  Google Scholar 

  31. Husted JA, Greenwood C, Bassett AS. Re: familial aggregation of clinical and neurocognitive features in sibling pairs with and without schizophrenia. Schizophr Res. 2010;116(2–3):289–90.

    Article  PubMed  Google Scholar 

  32. Heckers S. Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus. 2001;11(5):520–8.

    Article  CAS  PubMed  Google Scholar 

  33. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, Cooper TB, Carlsson A, Laruelle M. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000;48(7):627–40.

    Article  CAS  PubMed  Google Scholar 

  34. Medoff DR, Holcomb HH, Lahti AC, Tamminga CA. Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus. 2001;11(5):543–50.

    Article  CAS  PubMed  Google Scholar 

  35. Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, Jones T, Frackowiak RSJ. A functional neuroanatomy of hallucinations in schizophrenia. Nature. 1995;378:176–9.

    Article  CAS  PubMed  Google Scholar 

  36. Ewing SG, Grace AA. Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia. Schizophr Res. 2013;143(2–3):377–83.

    Article  PubMed  Google Scholar 

  37. Heckers S, Konradi C. GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. Schizophr Res. 2015;167(0):4–11.

    Article  PubMed  Google Scholar 

  38. Perez-Costas E, Melendez-Ferro M, Roberts RC. Basal ganglia pathology in schizophrenia: dopamine connections and anomalies. J Neurochem. 2010;113(2):287–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Andreasen NC, Pierson R. The role of the cerebellum in schizophrenia. Biol Psychiatry. 2008;15:81–8.

    Article  Google Scholar 

  40. Carlsson M, Carlsson A. Interactions between glutamatergic and monoaminergic systems within the basal ganglia – implications for schizophrenia and Parkinson’s disease. Trends Neurosci. 1990;13(7):272–6.

    Article  CAS  PubMed  Google Scholar 

  41. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44(7):660–9.

    Article  CAS  PubMed  Google Scholar 

  42. Keshavan MS, Tandon R, Boutros NN, Nasrallah HA. Schizophrenia, “just the facts”: what we know in 2008 part 3: neurobiology. Schizophr Res. 2008;106(2–3):89–10.

    Article  PubMed  Google Scholar 

  43. Carlsson A, Lindqvit M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 1963;20:140–4.

    Article  CAS  Google Scholar 

  44. Matthysse S. Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Fed Proc. 1973;32(2):200–5.

    CAS  PubMed  Google Scholar 

  45. Snyder SH. The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Am J Psychiatry. 1976;133(2):197–202.

    Article  CAS  PubMed  Google Scholar 

  46. Ashcroft GW, Blackwood GW, Besson JA, Palomo T, Waring HL. Positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry. 1981;138:268–9.

    Article  CAS  PubMed  Google Scholar 

  47. Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience. 1991;41(1):1–24.

    Article  CAS  PubMed  Google Scholar 

  48. Weinberger DR, Lipska BK. Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: a search for common ground. Schizophr Res. 1995;16(2):87–110.

    Article  CAS  PubMed  Google Scholar 

  49. Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci. 2002;25:409–32.

    Article  CAS  PubMed  Google Scholar 

  50. Chavez Noriega L, Marino M, Schaffhauser H, Campbell U, Conn P. Novel potential therapeutics for schizophrenia: focus on the modulation of metabotropic glutamate receptor function. Curr Neuropharmacol. 2005;3:9–34.

    Article  CAS  Google Scholar 

  51. Stefani MR, Groth K, Moghaddam B. Glutamate receptors in the rat medial prefrontal cortex regulates set-shifting ability. Behav Neurosci. 2003;117(4):728–37.

    Article  CAS  PubMed  Google Scholar 

  52. Wang H, Pickel VM. Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus. J Comp Neurol. 2002;442(4):392–404.

    Article  CAS  PubMed  Google Scholar 

  53. Langmead CJ, Watson J, Reavill C. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther. 2008;117(2):232–43.

    Article  CAS  PubMed  Google Scholar 

  54. D’Souza MS, Markou A. Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments. Addict Sci Clin Pract. 2011;6:4–16.

    PubMed  PubMed Central  Google Scholar 

  55. Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E. Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2002;7(10):1083–91.

    Article  CAS  PubMed  Google Scholar 

  56. Edelstein P, Schultz JR, Hirschowitz J, Kanter DR, Garver DL. Physostigmine and lithium response in the schizophrenias. Am J Psychiatry. 1981;138(8):1078–81.

    Article  CAS  PubMed  Google Scholar 

  57. Spalding TA, Trotter C, Skjaerbaek N, Messier TL, Currier EA, Burstein ES, Li D, Hacksell U, Brann MR. Discovery of an ectopic activation site on the M(1) muscarinic receptor. Mol Pharmacol. 2002;61(6):1297–302.

    Article  CAS  PubMed  Google Scholar 

  58. Sur C, Kinney G. Selective targeting of muscarinic receptor: novel therapeutic. Approaches for psychotic disorders. Curr Neuropharmacol. 2005;3:63–71.

    Article  CAS  Google Scholar 

  59. De Luca V, Wang H, Squassina A, Wong G, Yeomans J, Kennedy J. Linkage of M5 muscarinic, alpha 7 nicotinic receptor genes on 15q13 to schizophrenia. Neuropsychobiology. 2004;50:124–7.

    Article  PubMed  CAS  Google Scholar 

  60. Leonard S, Gault J, Adams C, Breese CR, Rollins Y, Adler LE, Olincy A, Freedman R. Nicotinic receptors, smoking and schizophrenia. Restor Neurol Neurosci. 1998;12(2–3):195–201.

    CAS  PubMed  Google Scholar 

  61. Martin-Ruiz CM, Haroutunian VH, Long P, Young AH, Davis KL, Perry EK, Court JA. Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia. Biol Psychiatry. 2003;54(11):1222–33.

    Article  CAS  PubMed  Google Scholar 

  62. Krenz I, Kalkan D, Wevers A, de Vos RA, Steur EN, Lindstrom J, Pilz K, Nowacki S, Schütz U, Moser N, Witter B, Schröder H. Parvalbumin-containing interneurons of the human cerebral cortex express nicotinic acetylcholine receptor proteins. J Chem Neuroanat. 2001;21(3):239–46.

    Article  CAS  PubMed  Google Scholar 

  63. La Crosse AL, Olive MF. Neuropeptide systems and schizophrenia. CNS Neurol Disorder Drug Targets. 2013;12(5):619–32.

    Article  Google Scholar 

  64. Boules MM, Fredrickson P, Muehlmann AM, Richelson E. Elucidating the role of neurotensin in the pathophysiology and management of major mental disorders. Behav Sci (Basel). 2014;4(2):125–53.

    Article  CAS  Google Scholar 

  65. López Ordieres MG, Rodríguez de Lores Arnaiz G. Neurotensin in central neurotransmission. In: Rodríguez de Lores Arnaiz G, editor. Function of neuropeptides at central nervous system. Trivandrum: Ed. Research Signpost; 2009. p. 1–30.

    Google Scholar 

  66. López Ordieres MG, Alvarez Juliá A, Kemmling A, Rodriguez de Lores Arnaiz G. Postnatal nitric oxide inhibition modifies neurotensin effect on ATPase activity. Neurochem Res. 2011;36(12):2278–86.

    Article  PubMed  CAS  Google Scholar 

  67. Maggio R, Aloise G, Silvano E, Rossi M, Millan MJ. Heterodimerization of dopamine receptors: new insights into functional and therapeutic significance. Parkinsonism Relat Disord. 2009;15(Suppl 4):S2–7.

    Article  PubMed  Google Scholar 

  68. Fuxe K, Tarakanov A, Romero Fernandez A, Ferraro L, Tanganelli S, Filip. Diversity and bias through receptor–receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization. Front Endocrinol. et al., 2014;71:1–11.

    Google Scholar 

  69. Fuxe K, Marcellino D, Woods AS, Giuseppina L, Antonelli T, Ferraro L, et al. Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of the forebrain: relevance for schizophrenia. J Neural Transm. 2009;116:923–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jufé G. Psicofarmacología Práctica. Buenos Aires: Ed. Polifemos; 2012. p. 1–633.

    Google Scholar 

  71. Caraci F, Leggio GM, Salomone S, Drago F. New drugs in psychiatry: focus on new pharmacological targets. F1000Res. 2017;6:39.

    Article  CAS  Google Scholar 

  72. Arif SA, Mitchel MM. Iloperidone: a new drug for the treatment of schizophrenia. Am J Health Syst Pharm. 2011;68(4):301–8.

    Article  CAS  PubMed  Google Scholar 

  73. Loebel A, Citrome L. Lurasidone: a novel antipsychotic agent for the treatment of schizophrenia and bipolar depression. Br J Psych Bull. 2015;39(5):237–41.

    Google Scholar 

  74. Scarff JR. Brexpiprazole: a new treatment option for schizophrenia. Innov Clin Neurosci. 2016;13(7–8):26–9.

    PubMed  PubMed Central  Google Scholar 

  75. Kim S, Solari H, Weiden PJ, Bishop JR. Paliperidone palmitate injection for the acute and maintenance treatment of schizophrenia in adults. Patient Prefer Adherence. 2012;6:533–45.

    PubMed  PubMed Central  Google Scholar 

  76. Balaraman R, Ghandi H. Asenapine, a new sublingual atypical antipsychotic. J Pharmacol Pharmacother. 2010;1(1):60–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Davidson M, Saoud J, Staner C, Noel N, Luthringer E, Werner S, Reilly J, Schaffhauser JY, Rabinowitz J, Weiser M, Luthringer R. Efficacy and safety of MIN-101: a 12-week randomized, double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia. Am J Psychiatry. 2017;174(12):1195–20.

    Article  PubMed  Google Scholar 

  78. Walker AG, Wenthur CJ, Xiang Z, Rook JM, Emmitte KA, Niswender CM, Lindsley CW, Conn PJ. Metabotropic glutamate receptor 3activation is required for long-term depression in medial prefrontal cortex and fear extinction. Proc Natl Acad Sci U S A. 2015;112(4):1196–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Griebel G, Pichat P, Boulay D, Naimoli V, Potestio L, Featherstone R, Sahni S, Defex H, Desvignes C, Slowinski F, Vigé X, Bergis OE, Sher R, Kosley R, Kongsamut S, Black MD, Varty GB. The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia. Sci Rep. 2016;6:35320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

Financial support was provided by CONICET and Universidad de Buenos Aires, Argentina.

Conflict of Interest

There is no known conflict of interest associated with this publication.

Author information

Authors and Affiliations

  1. Faculty of Exact and Natural Sciences, University of Belgrano, Buenos Aires, Argentina

    María Graciela López Ordieres

  2. Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

    María Graciela López Ordieres

Authors
  1. María Graciela López Ordieres
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María Graciela López Ordieres .

Editor information

Editors and Affiliations

  1. Cathedra of Psychopathology, Catholic University of Argentina, Mendoza, Argentina

    Pascual Ángel Gargiulo

  2. Laboratory of Neurosciences and Experimental Psychology, Area of Pharmacology, Department of Pathology, National University of Cuyo, Council of Scientific and Technological Research (CONICET), Mendoza, Argentina

    Humberto Luis Mesones Arroyo

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ordieres, M.G.L. (2019). Schizophrenia: A Complex Mental Illness. In: Gargiulo, P., Mesones Arroyo, H. (eds) Psychiatry and Neuroscience Update . Springer, Cham. https://doi.org/10.1007/978-3-319-95360-1_33

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-95360-1_33

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-95359-5

  • Online ISBN: 978-3-319-95360-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation