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What We Know … What We Don't Know About Schizophrenia



What We Know … What We Don't Know About Schizophrenia
We invite your comments and suggested edits to these generally accepted facts about schizophrenia.

* 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).

ID What We Know What We Don't Know Impact* Relevant Link
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
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
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). Leung and Chue, 2000
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
5 Schizophrenia is highly heritable (81%), and concordance between identical twins is almost 50%, suggesting a role for environmental or stochastic influences as well. Genetic risk for schizophrenia overlaps with schizoaffective disorder and bipolar disorder. What is the genetic architecture—the collective characteristics of risk (and protective) alleles—of schizophrenia? That is, how many alleles contribute to disease in the population, what are their frequencies and effect sizes, and how do they act together, additively or with interaction? OR = 99 (identical twin of patient); relative risk to siblings 8.6.

Sullivan et al., 2003

6 All drugs with established antipsychotic 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 (e.g., 5HT2c, mGlu) and pharmacologically induced changes in gene expression influence efficacy?   Kapur et al., 2001

Lieberman et al., 2005


What We Know

WHat We Don't Know

Impact* Relevant Link
7 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 in 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 identify risk genes? Can such behavioral data inform efforts to understand variability in patients? d = 0.56-0.6611 (continuous performance tasks in relatives); 0.43-0.5011 (trail-making tests); d = 0.1812 (total gray matter decrease in relatives); d = 0.31 (hippocampus reduction in relatives). Snitz et al., 2006

Boos et al., 2007

8 Studies of genome structure have identified about 10 loci at which copy number variants (CNVs: deletions or duplications) occur that confer large increments in risk. All are rare (occur in less than 1% of cases). Most also confer risk for other developmental disorders such as autism, intellectual disability, ADHD, and physical anomalies. In most instances, we don't know which genes within the CNVs are relevant. Why do some people with a given CNV exhibit autism, some schizophrenia, some intellectual disability, and some no disorder? Is this chance, environment, or combinations of other genetic risk factors? Are there any, or even many, rare single base mutations that confer similar effect sizes? Can these alleles of large effects be used in some families to predict risk? Can new mutations explain the association between advanced paternal age and schizophrenia? ORs range from 2 to 30. Kirov et al., 2011

Rees et al., 2014

9 Several early neurological insults, later life stressors, and non-hereditary 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/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); OR = 3.8 (older fathers); OR = 2.73 (T. gondii antibodies); OR = 2.3 (prenatal famine); OR = 2.1 (lifetime cannabis use); OR = 1.79 (obstetrical complications); OR = 1.72 (urban); OR = 1.07 (winter/spring birth). McGrath et al., 2004

Zammit et al., 2003

Torrey et al., 2007

Henquet et al., 2005

Krabbendam and van Os, 2005

Davies et al., 2003

Heinrichs RW. In Search of Madness: Schizophrenia and Neuroscience. Oxford: Oxford University Press; 2001.

St Clair et al., 2004

10 Genomewide association studies have identified over 100 independent genomic regions where common alleles are significantly associated with schizophrenia. Most of these are likely to be true associations, but the effect sizes are small. The lower boundary for the number of common alleles contributing to schizophrenia risk is in the high hundreds, accounting for at least 25% of genetic risk. What are the functional alleles underpinning the associations? How representative are common alleles in one major ethnic population of those in others? What proportion of risk comes from common alleles? How do they co-act with each other and with rare alleles? OR <1.2 (for individual SNPs); 23% (s.e. = 1%) of variation in liability to schizophrenia is captured by SNPs. Owen et al., 2005

PGC, 2014

Lee et al., 2012

ID What We Know What We Don't Know Impact* Relevant Link
11 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). Agid et al., 2003

Emsley et al., 2006

12 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?   Lieberman et al., 1990

Segal and Kuczenski, 1997

13 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?   Javitt and Zukin, 1991
14 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). Pfammatter et al., 2006
15 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). Perkins et al., 2005
16 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 reduce this risk and save lives?   Steen et al., 2006
Vita et al., 2006

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17 In postmortem 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 = 0.87–1.12 (prefrontal cell abnormalities); d = 0.36–0.90 (hippocampal cell abnormalities). Heinrichs RW. In Search of Madness: Schizophrenia and Neuroscience. Oxford: Oxford University Press; 2001.

Heinrichs, 2005

Lewis et al., 2003

18 GAD67, which converts glutamate to GABA, is reduced in schizophrenia patients. Reelin, an important factor involved in synaptic plasticity which co-localizes to GABergic interneurons, is also reduced. What is the role of GABAergic interneurons in the symptoms of schizophrenia? Are they amenable targets for new antipsychotic agents?   Akbarian and Huang, 2006
19 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). Davidson and Heinrichs, 2003

Konick and Friedman, 2001

20 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); d = 0.40 (superior temporal gyri); d = 0.39-0.41 (prefrontal cortex); d = 0.30 (thalamus). Vita et al., 2006

Steen et al., 2006

21 Functional abnormalities occur in a number of brain systems, including prefrontal and temporal cortices and subcortical structures. Is this a general feature of patients’ brains, or are functional abnormalities in certain regions more closely linked to symptom expression? d = 0.99 (reduction in MMN); d = 0.87 (reduction in P300); d = 0.20 (decrease in dorsolateral prefrontal cortex activity with performance as a significant moderator). Umbricht and Krljes, 2005

Bramon et al., 2004

Van Snellenberg et al., 2006

Glahn et al., 2005

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22 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 (i.e., affecting all functions) or specific (i.e., 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); d = 1.4 (performance IQ); d = 1.57 (coding). Heinrichs, 2005

Heinrichs and Zakzanis, 1998

Dickinson et al., 2007

23 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). Green et al., 2004

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