Hostname: page-component-cd9895bd7-gbm5v Total loading time: 0 Render date: 2024-12-23T02:52:47.110Z Has data issue: false hasContentIssue false
  • English
  • Français

Beyond the facts in schizophrenia: closing the gaps in diagnosis, pathophysiology, and treatment

Part of: Special Articles

Published online by Cambridge University Press:  14 September 2011

H. Nasrallah ,
R. Tandon  and
M. Keshavan
H. Nasrallah*
Affiliation:
University of Cincinnati – College of Medicine, Cincinnati, OH, USA
R. Tandon
Affiliation:
University of Florida College of Medicine, Gainesville, FL, USA
M. Keshavan
Affiliation:
Harvard Medical School, Boston, MA, USA
*
*Address for correspondence: Dr H. A. Nasrallah, Department of Psychiatry, University of Cincinnati, 260 Stetson Street, Suite 3200, Cincinnati, OH 45244, USA. (Email: henry.nasrallah@uc.edu)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background.

Although schizophrenia has been considered a distinct disease entity for the past century, its precise definition and etio-pathophysiology remain obscure and its treatment remains unsatisfactory. In this review, we summarize our state of knowledge about the etiology, pathophysiology, clinical features, and treatment of schizophrenia.

Methodological Issues.

The inadequacy of the major conceptual models of schizophrenia is a major roadblock in providing a coherent explanation for the known facts of this illness, despite these limitations and its changing definitions, the construct of schizophrenia does convey useful information: (i) patients diagnosed as having schizophrenia do have a real disease – they experience both suffering and disability; (ii) a diagnosis of schizophrenia does suggest a distinctive clinical profile – a characteristic long-term course; an admixture of positive, negative, and cognitive symptoms; (iii) a diagnosis of schizophrenia has clear treatment and prognostic implications – likelihood of benefit from antipsychotic treatment and likelihood of incomplete recovery; and (iv) schizophrenia satisfies criteria for a valid diagnostic entity better than almost any other psychiatric diagnosis.

Discussion.

On the other hand, the concept of schizophrenia has serious shortcomings. First, it is not a single disease entity – it has multiple etiological factors and pathophysiological mechanisms but common phenotypic features. Second, its clinical manifestations are so diverse that its extreme variability has been considered by some to be a core feature. Third, its boundaries remain ill defined and not clearly demarcated from other clinical entities.

Conclusions.

A necessary next step is to deconstruct schizophrenia as an entity into component dimensions –endophenotypes linked to unique etiological and pathophysiological processes that may yield unique treatment targets. Innovative approaches are needed to elucidate the biological substrates of these entities because such clarity is vital for replicable research. We conclude by identifying the critical gaps in our knowledge, and unmet needs in our approaches to care, and outline steps that can move the field forward.

Keywords

Clinical featuresepidemiologypathophysiologyrisk factorsschizophreniatreatmentunmet needs
Type
Special Article
Information
Epidemiology and Psychiatric Sciences , Volume 20 , Issue 4 , December 2011 , pp. 317 - 327
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aleman, A, Kahn, RS, Selten, J-P (2003). Sex differences in the risk of schizophrenia: evidence from meta-analysis. Archives of General Psychiatry 60, 565–571.CrossRefGoogle ScholarPubMed
American Psychiatric Association (1952). Diagnostic and Statistical Manual of Mental Disorders, 1st edn.American Psychiatric Association: Washington, DC.Google Scholar
American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR), 4th edn.American Psychiatric Association: Washington, DC.Google Scholar
Andreasen, NC (1982). Negative symptoms in schizophrenia: Definition and reliability. Archives of General Psychiatry 39, 784–788.CrossRefGoogle ScholarPubMed
Bassett, AS, Scherer, SW, Brzustowicz, LM (2010). Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. American Journal of Psychiatry 167, 899–914.CrossRefGoogle ScholarPubMed
Beneyto, M, Lewis, DA (2011). Insights into the neurodevelopmental origin of schizophrenia from postmortem studies of prefrontal cortical circuitry. International Journal of Developmental Neuroscience 29, 295–304.CrossRefGoogle ScholarPubMed
Bleuler, E (1911). Dementia Praecox or the Group of Schizophrenias. Translated by Zinkin, J.. International University Press: New York NY.Google Scholar
Braff, DL, Freedman, R, Schork, NJ, Guttesman, II. (2007). Deconstructing schizophrenia: An overview of the use of endophenotypes in order to understand a complex disorder. Schizophrenia Bulletin 33, 21–32.CrossRefGoogle ScholarPubMed
Braga, RJ, Petrides, G, Fifueira, I (2004). Anxiety disorders in schizophrenia. Comprehensive Psychiatry 45, 460–468.CrossRefGoogle ScholarPubMed
Brown, S, Inskip, H, Barraclough, B (2000). Causes of the excess mortality of schizophrenia. British Journal of Psychiatry 177, 212–217.CrossRefGoogle ScholarPubMed
Bruijnzeel, D, Tandon, R (2011). The concept of schizophrenia: from the 1850s to the DSM-5. Psychiatric Annals 41, 289–295.CrossRefGoogle Scholar
Cantor-Graae, E (2007). The contribution of social causes to schizophrenia: a review of recent findings. Canadian Journal of Psychiatry 52, 277–286.CrossRefGoogle ScholarPubMed
Cantor-Graae, E, Selten, J-P (2005). Schizophrenia and migration: a meta-analysis and review. American Journal of Psychiatry 162, 12–24.CrossRefGoogle ScholarPubMed
Carpenter, WT, Koenig, JI (2008). The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 33, 2061–2079.CrossRefGoogle ScholarPubMed
Done, DJ, Crow, TJ, Johnstone, EC, Sacker, A (1994). Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. British Medical Journal 309, 699–703.CrossRefGoogle ScholarPubMed
Eack, SM, Hogarty, GE, Cho, RY, Prasad, KM, Greenwald, DP, Hogarty, SS, Keshavan, MS (2010). Neuroprotective effects of cognitive enhancement therapy against gray matter loss in early schizophrenia: results from a 2-year randomized controlled trial. Archives of General Psychiatry 67, 674–682.CrossRefGoogle ScholarPubMed
Fish, B (1957). The detection of schizophrenia in infancy: a preliminary report. Journal of Nervous and Mental Disease 12, 1–24.CrossRefGoogle Scholar
Fish, B. (1968). A classification of schizophrenic children under age five years. American Journal of Psychiatry 124, 1415–1523.CrossRefGoogle Scholar
Gejman, PV, Sanders, AR, Kendler, KS (2011). Genetics of schizophrenia: new findings and challenges. Annual Review of Genomics and Human Genetics 12, 1–24.CrossRefGoogle Scholar
Gonzalez-Burgos, G, Lewis, DA (2008). GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophrenia Bulletin 34, 944–961.CrossRefGoogle ScholarPubMed
Gottesman, II, Gould, TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636–645.CrossRefGoogle ScholarPubMed
Gottesman, II, McGuffin, P, Farmer, AE (1987). Clinical genetics as clues to the ‘real’ genetics of schizophrenia. Schizophrenia Bulletin 13, 23–47.CrossRefGoogle Scholar
Green, MF (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry 153, 321–330.Google ScholarPubMed
Hafner, H, an der Heiden, W (1999). The course of schizophrenia in the light of modern follow-up studies: the ABC and WHO studies. European Archives of Psychiatry and Clinical Neuroscience 249(Suppl. 4), 14.CrossRefGoogle ScholarPubMed
Heckers, S, Konradi, C (2010). Hippocampal pathology in schizophrenia. Current Topics in Behavioral Neuroscience 4, 529–553.CrossRefGoogle ScholarPubMed
Heinrichs, DW, Buchanan, RW (1988). Significance and meaning of neurological signs in schizophrenia. American Journal of Psychiatry 145, 11–18.Google ScholarPubMed
Ho, BC, Andreasen, NC, Ziebill, S, Pierson, R, Magnotta, V (2011). Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry 68, 128–137.CrossRefGoogle ScholarPubMed
Honer, WG, Kopala, LC, Rabinowitz, J (2005). Extrapyramidal symptoms and signs in first-episode, antipsychotic exposed and non-exposed patients with schizophrenia or related psychotic illness. Journal of Psychopharmacology 19, 277–285.CrossRefGoogle ScholarPubMed
Horrobin, D. (1980 Mar 29). Prostaglandins and schizophrenia. Lancet 1 (8170), 706–7.CrossRefGoogle ScholarPubMed
Howes, OD, Kapur, S (2009). The dopamine hypothesis of schizophrenia: version III – the final common pathway. Schizophrenia Bulletin 35, 549–562.CrossRefGoogle ScholarPubMed
Jones, PB, Barnes, TR, Davies, L, Dunn, G, Lloyd, H, Hayhurst, KP, Murray, RM, Markwick, A, Lewis, SW (2006). Randomized controlled trial of the effect on quality of life of second- vs. first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Archives of General Psychiatry 63, 1079–1087.CrossRefGoogle Scholar
Kahn, RS, Fleischhacker, WW, Boter, H, Davidson, M, Vergouwe, Y, Keet, IP, Gheorghe, MD, Rybakowski, JK, Galderisi, S, Libiger, J, Hummer, M, Dollfus, S, López-Ibor, JJ, Hranov, LG, Gaebel, W, Peuskens, J, Lindefors, N, Riecher-Rössler, A, Grobbee, DE, EUFEST Study, Group (2008). Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomized clinical trial. Lancet 371, 1085–1097.CrossRefGoogle Scholar
Kantrowitz, JT, Javitt, DC (2010). Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models. Clinical Schizophrenia and Related Psychoses 4, 189–200.CrossRefGoogle ScholarPubMed
Keefe, RS, Eesley, CE, Poe, MP. (2005). Defining a cognitive function decrement in schizophrenia. Biological Psychiatry 57, 688–691.CrossRefGoogle ScholarPubMed
Keshavan, Ms, Tandon, R, Boutrus, NN, Nasrallah, HA (2008). Schizophrenia: “Just the facts”: What we know in 2008 Part 3: Neurology. Schizophrenia Research 106, 89–107.CrossRefGoogle Scholar
Keshavan, M, Nasrallah, HA, Tandon, R (2011). ‘Just the facts’ 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse. Schizophrenia Research 127, 3–13.CrossRefGoogle ScholarPubMed
Kim, Y, Zerwas, S, Trace, SE, Sullivan, PF (2011). Schizophrenia genetics: where next? Schizophrenia Bulletin 37, 456–463.CrossRefGoogle ScholarPubMed
Kirkbride, JB, Fearon, P, Morgan, C, Dazzan, P, Morgan, K, Tarrant, J, Lloyd, T, Holloway, J, Hutchinson, G, Leff, JP, Mallett, RM, Harrison, GL, Murray, RM, Jones, PB (2006). Heterogeneity in incidence rates in schizophrenia and other psychotic syndromes: findings from the 3-center Aetiology and Ethnicity in Schizophrenia and Related Psychoses (AeSOP) study. Archives of General Psychiatry 63, 250–258.CrossRefGoogle Scholar
Kraepelin, E (1971). Dementia Praecox and Paraphrenia, 1919 (ed. Robertson, GM). Krieger: New York.Google Scholar
Large, HH, Nielssen, O (2011). Violence in first-episode psychosis: a systemic review and meta-analysis. Schizophrenia Research 125, 209–220.CrossRefGoogle Scholar
Lin, A, Hudson, CJ (1996). The niacin challenge test in schizophrenia: past, present and future. Prostaglandins, Leukotrienes and Essential Fatty Acids 55, 17–19.CrossRefGoogle ScholarPubMed
Lubman, DI, King, JA, Castle, DJ (2010). Treating comorbid substance use disorders in schizophrenia. International Review of Psychiatry 22, 191–201.CrossRefGoogle ScholarPubMed
Malaspina, D, Harlap, S, Fennig, S, Heiman, D, Nahon, D, Feldman, D, Susser, ES (2001). Advancing paternal age and the risk of schizophrenia. Archives of General Psychiatry 58, 361–367.CrossRefGoogle ScholarPubMed
McEvoy, JP, Meyer, JM, Goff, DC, Nasrallah, HA, Davis, SM, Sullivan, L, Stroup, S, Lieberman, JA (2005). Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the CATIE and comparison with national estimates from the NHANES III. Schizophrenia Research 80, 9–18.CrossRefGoogle ScholarPubMed
McGlashan, TH, Fenton, WS (1993). Sub-type progression and pathophysiologic deterioration in early schizophrenia. Schizophrenia Research 19, 71–84.Google Scholar
McGorry, PD, Hickie, IB, Yung, AR, Pantelis, C, Jackson, HJ (2006). Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions. Australian and New Zealand Journal of Psychiatry 40, 616–622.CrossRefGoogle ScholarPubMed
McGrath, J, Saha, S, Welham, J, El Saadi, O, MacCauley, C, Chant, D (2004). A systematic review of the incidence of schizophrenia. BMC Medicine 2, 13.CrossRefGoogle ScholarPubMed
Minzenberg, MJ, Laird, AR, Thelen, S, Carter, CS, Glahn, DC (2009). Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Archives of General Psychiatry 66, 811–822.CrossRefGoogle ScholarPubMed
Morrens, M, Hulstijn, W, Sabbe, B (2007). Psychomotor slowing in schizophrenia. Schizophrenia Research 33, 1038–1053.Google ScholarPubMed
Nasrallah, HA, Smeltzer, DJ (2011). Contemporary Diagnosis and Management of Schizophrenia. Handbook in Healthcare Inc.: Newtown, PA.Google Scholar
Nasrallah, HA, Tippin, J, McCalley-Whitters, M, Kuperman, S. (1982). Neurological differences between paranoid and nonparanoid schizophrenia III. Neurological soft signs. Journal of Clinical Psychiatry 43, 310–312.Google ScholarPubMed
Nasrallah, HA, Meyer, JM, Goff, DC, McEvoy, JP, Davis, SM, Stroup, TS, Lieberman, JA (2006). Low rates of treatment for hypertension, dyslipidemia, and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophrenia Research 86, 15–22.CrossRefGoogle ScholarPubMed
Newcomer, J, Haupt, D (2006). The metabolic effects of antipsychotic medications. Canadian Journal of Psychiatry 51, 480–491.CrossRefGoogle ScholarPubMed
Nieratschker, V, Nöthen, MM, Rietschel, M (2010). New genetic findings in schizophrenia: is there still room for the dopamine hypothesis of schizophrenia? Frontiers in Behavioral Neuroscience 4, 23.Google ScholarPubMed
Pedersen, CB, Mortensen, PB (2001). Evidence of a dose–response relationship between urbanicity during upbringing and schizophrenia risk. Archives of General Psychiatry 58, 1039–1046.CrossRefGoogle ScholarPubMed
Penner, JD, Brown, AS (2007). Prenatal infectious and nutritional factors and risk of schizophrenia. Expert Reviews of Neurotherapeutics 7, 797–805.CrossRefGoogle Scholar
Pompili, M, Lester, D, Innamorati, M, Tatarelli, R, Girardi, P (2008). Assessment and treatment of suicide risk in schizophrenia. Expert Reviews of Neurotherapeutics 8, 51–74.CrossRefGoogle ScholarPubMed
Prasad, KM, Keshavan, MS (2008). Structural cerebral variations as useful endophenotypes in schizophrenia: do they help construct ‘extended endophenotypes’? Schizophrenia Bulletin 34, 774–790.CrossRefGoogle ScholarPubMed
Psychiatric GWAS Consortium (2009). Genome-wide association studies: history, rationale, and prospects for psychiatric disorders. American Journal of Psychiatry 166, 540–546.CrossRefGoogle Scholar
Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752.Google ScholarPubMed
Raballo, A, Saebye, D, Parnas, J (2011). Looking at the schizophrenia spectrum through the prism of self-disorders: an empirical study. Schizophrenia Bulletin 37, 344–351.CrossRefGoogle ScholarPubMed
Read, J, van Os, J, Morrison, AP, Ross, CA. (2005). Childhood trauma, psychosis, and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatrica Scandinavica 112, 330–350.CrossRefGoogle ScholarPubMed
Saha, S, Chant, D, Welham, J, McGrath, J (2005). A systematic review of the prevalence of schizophrenia. PLoS Medicine 2, 413–433.CrossRefGoogle ScholarPubMed
Saykin, AJ, Gur, RC, Gur, RE, Mozley, PD, Mozley, LH, Resnick, SM, Kester, DB, Stafiniak, P (1991). Neuropsychological function in schizophrenia: selective impairment in memory and learning. Archives of General Psychiatry 48, 618–624.CrossRefGoogle ScholarPubMed
Schneider, K (1959). Clinical Psychopathology. Translated by Hamilton, MW. Grune and Stratton: New York, NY.Google Scholar
Shenton, ME, Whitford, TJ, Kubicki, M (2010). Structural neuroimaging in schizophrenia: from methods to insights to treatments. Dialogues in Clinical Neuroscience 12, 317–32.CrossRefGoogle ScholarPubMed
Stefansson, H, Ophoff, RA, Steinberg, S, Andreassen, OA, Cichon, S, Rujescu, D, Werge, T, Pietiläinen, OP, Mors, O, Mortensen, PB, Sigurdsson, E, Gustafsson, O, Nyegaard, M, Tuulio-Henriksson, A, Ingason, A, Hansen, T, Suvisaari, J, Lonnqvist, J, Paunio, T, Børglum, AD, Hartmann, A, Fink-Jensen, A, Nordentoft, M, Hougaard, D, Norgaard-Pedersen, B, Böttcher, Y, Olesen, J, Breuer, R, Möller, HJ, Giegling, I, Rasmussen, HB, Timm, S, Mattheisen, M, Bitter, I, Réthelyi, JM, Magnusdottir, BB, Sigmundsson, T, Olason, P, Masson, G, Gulcher, JR, Haraldsson, M, Fossdal, R, Thorgeirsson, TE, Thorsteinsdottir, U, Ruggeri, M, Tosato, S, Franke, B, Strengman, E, Kiemeney, LA, Genetic Risk and Outcome in Psychosis (GROUP), Melle, I, Djurovic, S, Abramova, L, Kaleda, V, Sanjuan, J, de Frutos, R, Bramon, E, Vassos, E, Fraser, G, Ettinger, U, Picchioni, M, Walker, N, Toulopoulou, T, Need, AC, Ge, D, Yoon, JL, Shianna, KV, Freimer, NB, Cantor, RM, Murray, R, Kong, A, Golimbet, V, Carracedo, A, Arango, C, Costas, J, Jönsson, EG, Terenius, L, Agartz, I, Petursson, H, Nöthen, MM, Rietschel, M, Matthews, PM, Muglia, P, Peltonen, L, St Clair, D, Goldstein, DB, Stefansson, K, Collier, DA (2009). Common variants conferring risk of schizophrenia. Nature 460, 744–747.CrossRefGoogle ScholarPubMed
Sullivan, PF (2010). The psychiatric GWAS consortium: big science comes to psychiatry. Neuron 68, 182–186.CrossRefGoogle ScholarPubMed
Sullivan, PF, Kendler, KS, Neale, MC (2003). Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry 60, 1187–1192.CrossRefGoogle ScholarPubMed
Sweet, RA, Fish, KN, Lewis, DA (2010). Mapping synaptic pathology within cerebral cortical circuits in subjects with schizophrenia. Frontiers of Human Neuroscience 4, 44.Google ScholarPubMed
Tandon, R, Maj, M (2008). Nosological status and definition of schizophrenia: some considerations for DSM-V and ICD-11. Asian Journal of Psychiatry 1, 22–28.CrossRefGoogle ScholarPubMed
Tandon, R, Keshavan, MS, Nasrallah, HA (2008 a). Schizophrenia, ‘Just the facts’ what we know in 2008. 2. Epidemiology and etiology. Schizophrenia Research 102, 1–18.CrossRefGoogle ScholarPubMed
Tandon, R, Keshavan, MS, Nasrallah, HA (2008 b). Schizophrenia, ‘Just the facts’: what we know in 2008 part 1: overview. Schizophrenia Research 100, 4–19.CrossRefGoogle Scholar
Tandon, R, Belmaker, RH, Gattaz, WF (2008 c). World Psychiatry Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophrenia Research 100, 20–38.CrossRefGoogle ScholarPubMed
Tandon, R, Nasrallah, HA, Keshavan, MS (2009). Schizophrenia: ‘Just the facts’ 4. Clinical features and conceptualization. Schizophrenia Research 110, 1–23.CrossRefGoogle ScholarPubMed
Tandon, R, Nasrallah, HA, Keshevan, MS (2010). Schizophrenia: ‘Just the facts’ 5. Treatment and prevention, past, present, and future. Schizophrenia Research 122, 1–23.CrossRefGoogle ScholarPubMed
Thaker, GK (2008). Neurophysiological endophenotypes across bipolar and schizophrenia psychosis. Schizophrenia Bulletin 34, 760–773.CrossRefGoogle ScholarPubMed
Tsuang, MT, Woolson, RF, Fleming, JA (1979). Long term outcomes of major psychoses I: schizophrenia and affective disorders compared with psychiatrically symptom-free surgical conditions. Archives of General Psychiatry 36, 1295–1301.CrossRefGoogle ScholarPubMed
Uhlhaas, PJ, Singer, W (2010). Abnormal neural oscillations and synchrony in schizophrenia. Nature Reviews Neuroscience 11, 100–113.CrossRefGoogle ScholarPubMed
Valenstein, ES (1997). Great and Desperate Cures: The Rise and Decline of Psychosurgery and Other Radical Treatments for Mental Illness. Simon and Schuster: New York, NY.Google Scholar
Van Os, J (2008). Schizophrenia etiology: do gene–environment interactions hold the key? Schizophrenia Research 102, 22–26.Google Scholar
Van Os, J (2011). From schizophrenia meta-facts to non-schizophrenia facts. Schizophrenia Research 127, 16–17.CrossRefGoogle Scholar
Weiden, PJ, Buckley, PF, Grody, M (2007). Understanding and treating first-episode schizophrenia. Psychiatric Clinics of North America 30, 481–510.CrossRefGoogle ScholarPubMed
Yung, AR, McGorry, PD (1996). The prodromal phase of first-episode psychosis. Schizophrenia Bulletin 22, 353–370.CrossRefGoogle ScholarPubMed