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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? Are there valid subtypes, such as a deficit syndrome or 22qDS, that can establish more homogeneous groupings?   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? Across populations, what is the rate of remission and relapse?   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. Are the relevant differences between men and women cultural, behavioral, biological, or an ascertainment bias? Is schizophrenia equally prevalent in both sexes by age 50 or 60, and if so why? Why are identical twin concordance rates similar for men and women? OR = 1.4 (male) 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 or after middle age. 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? OR = 99 (identical twin of patient) Gottesman and Gould, 2003

Sullivan et al., 2003
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 6 All drugs with established anti-psychotic effects block dopamine D2–like receptors, but antipsychotic drugs are not effective for all schizophrenia symptoms. Among available agents, the atypical antipsychotic Clozaril is the most effective; however, it carries unique risks for some. Why are not the most effective dopamine antagonists also the most effective for reducing symptoms? What is the most cost-effective way to treat schizophrenia? How do effects at other receptors (eg, 5HT2c, mGlu) and pharmacologically induced changes in gene expression influence efficacy?   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) suggest a number of regions that show genome-wide significance (8p and 22q), with several other regions also receiving strong support (1q, 2q, 3p, 5q, 6p, 11q, 13q, 14p, 20q). Should we expect different populations to have schizophrenia genes in the same locations? How many genes should we expect? Will studies that identify particular genes, known as association studies, show reliable effects? How should research proceed in the face of large numbers of potential interactions?   Owen et al., 2005 Submit Comment
 8 The unexpressed genetic liability to schizophrenia affects cognitive and brain functioning and brain structure. The most prominent impairments in individuals with heightened genetic liability, such as patients’ nonpsychotic relatives, have been measured on executive functioning. Overall gray matter and hippocampal volume are also slightly smaller in the relatives of patients with schizophrenia. Will these "endophenotypes" that reflect the unexpressed genetic liability to schizophrenia help to identify risk genes? Can such behavioral data inform efforts to understand variability in patients? Continuous performance tasks in relatives d = 0.56–0.6611; trail-making tests 0.43–0.5011; total grey matter decrease in relatives d = 0.1812; hippocampus reduction in relatives d = 0.31 Owen et al., 2005

SchizophreniaGene Database
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 9 Several early neurological insults, later life stressors, and nonhereditary genetic risk factors confer additional risk. These include (in order of impact): migrant status, older fathers, Toxoplasmosis gondii antibodies, prenatal famine, lifetime cannabis use, obstetrical complications, urban rearing, and winter or spring birth. Are these independent or related risk factors? How do they interact with genetic risk, and to what degree are they specific to schizophrenia? In other words, what is the causal path between each factor and the illness outcome? OR = 4.6 (migrant status)13; OR = 3.8 (older fathers)14; OR = 2.73 (T. gondii antibodies)15; OR = 2.3 (prenatal famine)115; OR = 2.1 (lifetime cannabis use)16; OR = 1.79 (obstetrical complications)27; OR = 1.72 (urban)17; OR 1.07 (winter/spring birth) Zammit et al., 2003 Submit Comment
10 While antipsychotics can lead to immediate improvement for some individuals, the time course of medication effects varies widely with some patients showing responses to medication more than a month after beginning treatment. Is receptor occupancy only one of several ways in which antipsychotics produce therapeutic effects? 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 Exposure to amphetamine, a dopamine agonist, can result in schizophrenia-like symptoms in some individuals. This effect may interact with liability, such that a single dose can trigger relapse in patients, but more chronic use is usually needed to induce psychosis in low risk populations. Why is this effect observed in chronic, but not acute, amphetamine use?   Agid et al., 2003

Emsley et al., 2006
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12 A single exposure to phencyclidine 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?   Lieberman et al., 1990

Segal and Kuczenski, 1997
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13 A number of psychosocial treatments, including social skills training, family interventions, cognitive behavioral therapy, and cognitive training have been found to be effective for a number of psychotic symptoms. To what extent do these treatments have specific effects? How can positive outcomes be sustained over time? How can barriers to implementing these treatments in the field be addressed? d = 0.23–0.77 (social skills training); d = 0.22–0.71 (family interventions); d = 0.20–0.49 (cognitive training); d = 0.39–0.47 (cognitive behavioral therapy) Javitt and Zukin, 1991 Submit Comment View Comments
PATHOLOGICAL FACTS
14 Longer duration of untreated psychosis is associated with a poorer treatment response. Can prodromal and early intervention programs alter long-term outcomes on a widespread basis? d = 0.50 (increased symptoms in untreated patients) Lewis et al., 2003 Submit Comment View Comments
15 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?   Steen et al., 2006
Vita et al., 2006
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16 In postmortem studies, pyramidal neurons in input layers of prefrontal cortex have a reduced dendritic spine density; whereas hippocampal neurons appear to abnormally oriented with signs of arrested migration. Are reduced arborization and migration causal or epiphenomenal in the schizophrenia disease process? Prefrontal cell abnormalities d = 0.87–1.12; hippocampal cell abnormalities d = 0.36–0.90 Davidson and Heinrichs, 2003 Submit Comment
17 GAD67, that converts glutamate to GABA, is reduced in schizophrenia patients. Reelin, an important factor involved in synaptic plasticity which colocalizes to GABergic interneurons, is also reduced. What is the role of GABAergic interneurons in the symptoms of schizophrenia? Are they amenable targets for new anti-psychotic agents?   Boos et al., 2007 Submit Comment
18 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 = 0.24 (about 2.7%, total brain volume decrease); d = 0.32 (lateral ventricle increase); d = 0.59 (third ventricle increase) Van Snellenberg et al., 2006

Glahn et al., 2005
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BEHAVIORAL FACTS
19 Medial temporal lobe structures such as the hippocampus, 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 = 0.55 (hippocampus reduction in patients)33; d = 0.40 (superior temporal gyri)33; d = 0.39–0.41 (prefrontal cortex)33; d = 0.30 (thalamus) Heinrichs, 2005

Dickinson et al., 2007

MacDonald and Carter, 2002

Heinrichs and zakzanis, 1998
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TREATMENT FACTS
20 Functional abnormalities occur in a number of brain systems, including prefrontal and temporal cortices and subcortical structures. Is this a general feature of patients’ brain or are functional abnormalities in certain regions more closely linked to symptom expression? d = 0.99 (reduction in MMN)35; d = 0.87 (reduction in P300)36; d = 0.20 (decrease in dorsolateral prefrontal cortex activity with performance as a significant moderator) Perkins et al., 2005 Submit Comment
21 Cognitive tests are challenging for many, but not all, patients even during remission. 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 (ie, concentrated in a particular function)? For example are executive control functions and early perceptual functions more compromised than other functions? d = 0.90 (overall cognitive performance); d = 1.4 (verbal memory)28; d = 1.4 (performance IQ)39; d = 1.57 (coding) Palmer et al., 2001 Submit Comment
SUGGEST OTHER FACTS
22 The extent of patients’ cognitive deficits generally predicts functioning in work, social interactions, and independent living perhaps even more than symptom expression. What treatment modalities are best suited to improve cognitive functioning and everyday living? Are there some treatments that work for some patients but not as well for others? d >0.50 (performance predicting outcome) Submit Comment View Comments
23 Submit facts, with appropriate citations, to consider. What questions do these facts raise?   Citations, please. Submit Comment
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