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What We Know ... What We Don't Know About Schizophrenia  
By the Minnesota Consensus Group: Angus MacDonald, S. Charles Schulz, S. Hossein Fatemi, Irving I. Gottesman, William Iacono, Daniel Hanson, Kelvin O. Lim, Peter Milev, Steve Olson, Scott Sponheim, John Vuchetich, and Tonya White.

We invite your comments and suggested edits to these facts about schizophrenia. At the bottom of the table, you can also submit suggestions to the Minnesota Consensus Group for additional facts.

* Measures of Impact: "OR" (Odds Ratio) is the odds of a condition (such as schizophrenia) occurring in the first group compared to the odds of it occurring in the second group (with OR = 1.00 meaning no difference); "d" (effect size measured in standard deviations) is the extent to which one group (patients with schizophrenia) scores higher on a quantitative variable relative to another (controls, with d = 0.00 meaning no difference).

Item What We Know What We Don't Know Impact* Relevant Link Please Comment
BASIC FACTS
 1 Schizophrenia has a heterogeneous presentation, with disorganized, positive, and negative symptoms having different levels of prominence across time and across individuals. What causes some symptoms to be more expressed in one patient, and a different subset in another? Are other factors (e.g. mania, depression, cognitive function) also independent components of schizophrenia?   Peralta and Cuesta, 2001 Submit Comment View Comments
 2 Schizophrenia is relatively common, affecting approximately 0.7% of the world's population (CI 95% 0.3-2.7%) What are the sources of variation in prevalence across the world? Why do some groups have higher rates (such as migrants)?   Saha et al., 2005 Submit Comment View Comments
 3 Prevalence is greater in men throughout most of adulthood, but is equal by the end of the risk period Is estrogen protective, or is testosterone a risk factor? Why are MZ twin concordance rates similar for men and women (see Fact #7)? OR = 1.4 (Male:female during younger adulthood) Gottesman, I. I., & Shields, J. (1982). Schizophrenia: The epigenetic puzzle. New York: Cambridge University Press.

Aleman et al., 2003
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 4 Schizophrenia has a peak of onset in young adulthood and is rare before adolescence. Onset also interacts with sex, such that men are likely to become ill earlier in life than women. Is psychosis that appears early (before age 14) or particularly late (after age 40) similar to cases in adolescents and younger adults? How should diagnostic criteria adapt to differences in symptoms with age?   Howard et al., 2000 Submit Comment
 5 Liability to schizophrenia is highly heritable (about .81), and concordance between identical twins is almost 50%, suggesting a role for environmental or stochastic influences as well. Do the same genes account for the disorder in different populations? What are the relevant environmental factors, and are they shared or unshared?   Gottesman and Gould, 2003

Sullivan et al., 2003
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 6 All drugs with established anti-psychotic effects decrease dopamine neurotransmission, but anti-psychotic drugs are not effective for all schizophrenia symptoms. Among available agents, the atypical antipsychotic clozapine is the most effective for most patients, however it carries unique risks for some. Why aren't the most effective dopamine antagonists also the most effective for reducing symptoms? What is the most cost effective way to treat schizophrenia?   Kapur and Remington, 2001

Lieberman et al., 2005
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ETIOLOGICAL FACTS
 7 Linkage studies (which identify regions of the genome where schizophrenia genes might be found) suggests a number of regions that show genome-wide significance (1q, 6p, 6q, 13q, 17p), with several other regions found across multiple studies. Should we expect different populations to have schizophrenia genes in the same locations?   Owen et al., 2005 Submit Comment
 8 Association studies (which identify which form of a particular gene or part of a gene is associated with risk) suggest alleles in a number of promising genes confer risk, including RGS4, DISC1, DTNBP1, NRG1, DAOA and COMT How many genes should we expect? In the absence of any genes that are sufficient or necessary to cause schizophrenia, how do these (and others yet undiscovered) contribute to liability? How should research proceed in the face of large numbers of potential interactions? OR = 1.4 (C:G polymorphisms of Ser311Cys allele of DRD2, largest as of July 2007), OR close to 1.0 for most alleles Owen et al., 2005

SchizophreniaGene Database
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 9 Non-hereditary genetic risk factors, such as paternal age increase risk. What proportion of cases can be attributed to risk factors such as these that exist between hereditary and environmental modes of action? OR = 3.8 (older fathers: younger fathers) Zammit et al., 2003 Submit Comment
10 A number of early neurological insults and later life stressors confer additional risk for schizophrenia and other neurological disorders. While many such factors have been studied, obstetrical complications and migrant status illustrate two of the largest effects known at this time. Are there any risk factors that are diagnostically specific to schizophrenia? OR=1.79 (obstetrical complications); OR= 4.6 (migrant status) Heinrichs, R. W. (2001). In search of madness: Schizophrenia and neuroscience. New York, NY: Oxford University Press.

McGrath et al., 2004
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PHARMACOLOGICAL FACTS
11 While antipsychotics lead to some immediate improvement for many individuals, the time course varies widely and a minority of patients do not show a medication response until a month after beginning treatment. Is receptor occupancy only one of several ways in which antipsychotics produce therapeutic effects?   Agid et al., 2003

Emsley et al., 2006
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12 Chronic exposure to amphetamine, a dopamine agonist, can result in schizophrenia-like symptoms in some individuals. Why is this effect observed in chronic, but not acute, amphetamine use?   Lieberman et al., 1990

Segal and Kuczenski, 1997
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13 A single exposure to phencycline (PCP) and other NMDA receptor antagonists (such as ketamine) can result in schizophrenia-like symptoms in some individuals. Are NMDA receptors a useful target for new antipsychotic agents?   Javitt and Zukin, 1991 Submit Comment View Comments
PATHOLOGICAL FACTS
14 In post-mortem studies, pyramidal neurons in input layers of prefrontal cortex have a reduced dendritic spine density; whereas hippocampal neurons appear to be abnormally oriented with signs of arrested migration. Are reduced arborization and migration causal or epiphenomenal in the schizophrenia disease process? d=.87-1.12 (prefrontal cell abnormalities); d=.36-.90 (hippocampal cell abnormalities) Lewis et al., 2003 Submit Comment View Comments
15 Even in first-episode patients, the lateral and third ventricles are somewhat larger, whereas total brain volume is slightly smaller. Given the great degree of variability in brain size in the general population, how is such a subtle change related to risk? d=.24 (about 2.7%, total brain volume decrease); d=.32 (lateral ventricle increase); d=.59 (third ventricle increase) Steen et al., 2006
Vita et al., 2006
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16 Medial temporal lobe structures such as the hippocampus, and superior, temporal, and prefrontal cortices, as well as the thalamus tend to be smaller in patients with schizophrenia. What is the relationship between volume reduction, function, and symptom expression? d=.55 ( hippocampus reduction in patients); d=.40 ( superior temporal gyri); d=.39-.41 (prefrontal cortex); d=.30 (thalamus) Davidson and Heinrichs, 2003 Submit Comment
17 Overall grey matter and hippocampal volumes are also slightly smaller in the healthy relatives of patients with schizophrenia. Do symptoms arise from many small brain changes, or just a few large ones? d=.18 (total grey matter decrease in relatives); d=.31 (hippocampus reduction in relatives) Boos et al., 2007 Submit Comment
18 Functional abnormalities occur in a number of brain systems, including prefrontal and temporal cortices and subcortical structures. Is this a general feature of the brain, or are some functional abnormalities likely to be more closely linked to symptom expression? d=.20 (decrease in DLPFC activity with performance as a significant moderator) Van Snellenberg et al., 2006

Glahn et al., 2005
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BEHAVIORAL FACTS
19 Cognitive tests are challenging for many, but not all, patients. The greatest deficits appear on tasks such as verbal memory, performance IQ, and coding tasks. To what extent are cognitive deficits general (that is, affecting all functions), or specific (that is, concentrated in a particular function)? For example, are executive control functions and early perceptual functions more compromised than other functions? d=.90 (overall cognitive performance); d=1.4 (verbal memory); d=1.4 (performance IQ); d=1.57 (coding) Heinrichs, 2005

Dickinson et al., 2007

MacDonald and Carter, 2002

Heinrichs and zakzanis, 1998
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TREATMENT FACTS
20 Longer duration of untreated psychosis is associated with a poorer treatment response. Can outreach programs diagnose and treat patients before they begin a downward course? d=.50 (increased symptoms in untreated patients) Perkins et al., 2005 Submit Comment
21 Patients have a 4.9% rate of suicide, which is far greater than the average risk in the United States. Can suicide-prevention interventions directed at patients early in their illness help to reduce this risk and save lives?   Palmer et al., 2001 Submit Comment
SUGGEST OTHER FACTS
22 Submit facts, with appropriate citations, for Minnesota Consensus Group to consider. What questions do these facts raise?   Citations, please. Submit Comment View Comments
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