Live webcast, with multiple discussion rooms, of a workshop at the International Congress on Schizophrenia Research

“Body of Knowledge: The Purposes, Approaches and Outcome of Appraising What We Know about Schizophrenia”

Moderators: Angus MacDonald III, University of Minnesota; Rajiv Tandon, University of Florida
Panel: Matcheri Keshavan, Harvard University; Henry Nasrallah, University of Cincinnatti; S. Charles Schulz, University of Minnesota
References: Tandon et al., 2008; MacDonald and Schulz, 2009


SRF is grateful the support and collaboration of the following organizations:

  • FACT from Minnesota Consensus Group
  • Impact in Odds Ratio or Effect Size
  • FACT from Schizophrenia Research
  • Schizophrenia Research Rating (Reproducibiity; Primary; Durability)

  • 1. Schizophrenia has a heterogeneous presentation, with disorganized, positive, and negative symptoms having different levels of prominence across time and across individuals.  
  • The nosological boundaries between schizophrenia and other psychiatric disorders are indistinct.
  • HIGH; LOW; MEDIUM
  • Although characteristic symptoms (eg., avolition, “first-rank symptoms”, formal thought disorder, deteriorating course) are described, none is pathognomonic and diagnosis is based on a profile of symptoms and course.
  • HIGH; MEDIUM; HIGH
  • There is significant heterogeneity in neurobiology, clinical manifestations, course, and treatment response across patients.
  • HIGH; LOW; MEDIUM
  • Schizophrenia is a chronic and relapsing disorder with generally incomplete remissions.
  • MEDIUM; MEDUIM; HIGH
  • Schizophrenia is characterized by an admixture of positive, negative, cognitive, and mood symptoms.
  • HIGH; MEDUIM; HIGH
  •  
  • The severity of different symptoms varies across patients and through the course of the illness.
  • HIGH; MEDUIM; HIGH
  •  -
  • There are significant premorbid impairments in a substantial proportion of patients.
  • HIGH; MEDUIM; HIGH
  •  -
  • Descriptions have been fairly consistent over past century
  • MEDUIM; MEDUIM; MEDUIM
  • FACT from Minnesota Consensus Group
  • Impact in Odds Ratio or Effect Size
  • FACT from Schizophrenia Research
  • Schizophrenia Research Rating (Reproducibiity; Primary; Durability)

  • 2. Schizophrenia is relatively common, affecting approximately 0.7% of the world's population (CI 95% 0.3-2.7%) 
  • Lifetime risk=approximately 0.7%
  • MEDIUM; MEDIUM; MEDIUM
  •  
  • Point Prevalence = 2-10/1,000 with pockets of high and low prevalence.
  • HIGH; LOW; HIGH
  •  -
  • Annual Incidence = 8-40/100,000/year with relatively similar incidence across continents.
  • HIGH; MEDIUM; HIGH
  • 3. Prevalence is greater in men throughout most of adulthood, but is equal by the end of the risk period
  • OR = 1.4 (male)
    [PMID:12796219]
  • Greater lifetime risk in males
  • MEDIUM; MEDIUM; MEDIUM
  • 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.
  • Onset of psychotic symptoms is usually during adolescence or early adulthood.
  • HIGH; MEDIUM; HIGH
  • Age of onset is earlier in males.
  • HIGH; MEDUIM; HIGH
  • FACT from Minnesota Consensus Group
  • Impact in Odds Ratio or Effect Size
  • FACT from Schizophrenia Research
  • Schizophrenia Research Rating (Reproducibiity; Primary; Durability)

  • 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. 
  • OR = 99 (identical twin of patient) [PMID:14662555]
  • Schizophrenia is highly heritable and genetic factors contribute to approximately 80% of the liability for the illness.
  • HIGH; MEDUIM; HIGH
  • 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). 
  • There is genetic heterogeneity, with multiple chromosomal regions and variations in several genes of small effect across the genome linked to illness liability.
  • HIGH; LOW; LOW
  • 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 or spring birth. 
  • OR=4.6 (migrant status) [PMID:16938013]; OR = 3.8 (older fathers) [PMID:15846819]; OR = 2.73 (T gondii antibodies) [PMID:12963669]; OR=2.3 (prenatal famine) [PMID:16077049]; OR=2.1 (lifetime cannabis use) [PMID: 15976013]; OR=1.79 (obstetrical complications) Link Here; OR = 1.72 (urban) [PMID:12714172]; OR 1.07 (winter/spring birth) [PMID: 14609251]
  • Higher incidence associated with urbanicity.
  • MEDIUM; MEDIUM; MEDIUM
  • Higher incidence associated with migration.
  • MEDIUM; MEDIUM; MEDIUM
  • Several environmental factors of small effect (eg., cannabis abuse, winter/spring birth, prenatal infection and famine, obstetric and perinatal complications, social stress, older paternal age, etc.) are associated with an increased risk of developing schizophrenia.
  • HIGH; MEDIUM; MEDIUM
  • Higher prevalence among lower socio-economic classes.
  • HIGH; LOW; HIGH
  • FACT from Minnesota Consensus Group
  • Impact in Odds Ratio or Effect Size
  • FACT from Schizophrenia Research
  • Schizophrenia Research Rating (Reproducibiity; Primary; Durability)

  • 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. 
  • Dopamine agonists exacerbate and dopamine-2 antagonists alleviate schizophrenic symptoms.
  • HIGH; LOW; HIGH
  • 12. A single exposure to phencycline (PCP) and other NMDA receptor antagonists (such as ketamine) can result in schizophrenia-like symptoms in some individuals 
  • Phenylcyclidine (PCP) and other NMDA antagonists induces symptoms highly similar to schizophrenia.
  • HIGH; HIGH; HIGH
  • 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. 
  • There are abnormalities in central GABA neurotransmission.
  • MEDIUM; LOW; MEDIUM
  • -
  • There are abnormalities in several other neurotransmitter systems (eg., cholinergic and serotonergic).
  • MEDIUM; LOW; MEDIUM
  • -
  • There is hypercortisolemia and features of hypothalamo-pituitary-adrenal axis dysregulation.
  • MEDIUM; LOW; MEDIUM
  • 16. In post-mortem 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
  • prefrontal cell abnormalities d=.87-1.12 [PMID:15329307]; hippocampal cell abnormalities d=.36-.90 [PMID:7654125]
  • Post-mortem brain findings include absence of gliosis, and reductions in neuropil, and altered placement of a variety of neuronal elements in a range of cortical and limbic structures.
  • MEDIUM; LOW; MEDUIM
  • -
  • There are reductions in N-Acetyl Aspartate (NAA) in the frontal and temporal cortex.
  • MEDUIM; LOW; MEDUIM
-
  •  
  • There are reductions in phosphomonoesters (PME) in prefrontal cortex.
  • LOW; LOW; MEDUIM
  • 18. Even in first-episode patients, the lateral and third ventricles are somewhat larger whereas total brain volume is slightly smaller
  • d=.24 (about 2.7%, total brain volume decrease); d=.32 (lateral ventricle increase); d=.59 (third ventricle increase) [PMID:17962231]
  • Total brain volume is reduced, and lateral and third ventricular spaces are larger.
  • HIGH; MEDIUM; HIGH
  •  
  • Structural brain abnormalities are present at illness onset
  • MEDUIM; MEDUIM; MEDUIM
  • 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
  • d=.55 (hippocampus reduction in patients) [PMID:18291627]; d=.40 (superior temporal gyri) [PMID:18291627]; d=.39-.41 (prefrontal cortex) [PMID:18291627]; d=.30 (thalamus) [PMID:18519821]
  • There is reduced grey matter volume in specific brain regions such as medial and superior temporal lobe structures, prefrontal cortex, and thalamus.
  • MEDIUM; MEDIUM; MEDIUM
  •  -
  • There are structural alterations in cortico-cortical white matter tracts.
  • LOW; LOW; LOW
  •  -
  • There is reduction or reversal of cerebral asymmetry.
  • LOW; LOW; MEDUIM
  •  -
  • There are enlargements of the caudate nucleus and other basal ganglia in response to treatment.
  • MEDIUM; HIGH; MEDUIM
  •  -
  • Structural brain abnormalities may progress in subgroup of patients during course of illness.
  • LOW; LOW; MEDUIM
  • 8, cont. Overall grey matter and hippocampal volume are slightly smaller in the relatives of patients with schizophrenia
  • total grey matter decrease in relatives d=.18 [PMID:10359468]; hippocampus reduction in relatives d=.31 [PMID:10359468]
  • Some structural brain abnormalities of milder degree are present among unaffected family members.
  • MEDUIM; LOW; LOW
  • FACT from Minnesota Consensus Group
  • Impact in Odds Ratio or Effect Size
  • FACT from Schizophrenia Research
  • Schizophrenia Research Rating (Reproducibiity; Primary; Durability)

  • 20. Functional abnormalities occur in a number of brain systems, including prefrontal and temporal cortices and subcortical structures 
  • d=.99 (reduction in MMN) [PMID:16764608]; d=.87 (reduction in P300) [PMID:15803162]; d=.20 (decrease in DLPFC activity with performance as a significant moderator) [PMID:15796677]
  • There is decreased activity of the prefrontal cortex (“hypofrontality”) both in resting state and during cognitive challenge studies
  • MEDUIM; LOW; HIGH
  •  
  • There are abnormal activation patterns in several brain regions during performance of various cognitive tasks in functional imaging studies.
  • MEDIUM; LOW; LOW
  •  
  • There are abnormalities in latencies and/or amplitudes of several event related potentials such as P-50, P-300, N-100, and mismatch negativity.
  • MEDIUM; MEDIUM; MEDIUM
  • -
  • There are smooth pursuit eye movement abnormalities in patients and, to a lesser extent, in unaffected relatives.
  • MEDIUM; LOW; HIGH
  • -
  • There is an increased prevalence of neurological abnormalities, including movement disorders and “soft” neurological signs.
  • MEDUIM; LOW; MEDIUM
  • 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.
  • d=.90 (overall cognitive performance); d=1.4 (verbal memory) [PMID:3947210]; d=1.4 (performance IQ) [PMID:7654125]; d=1.57 (coding) [PMID:6984643]
  • There is a generalized intellectual impairment.
  • HIGH; LOW; MEDIUM
  • There is specific impairment in a range of cognitive functions (such as executive functions, memory, psychomotor speed, attention, and social cognition).
  • MEDUIM; LOW; MEDUIM
  •  -
  • Cognitive impairments are present prior to onset of psychosis and persist during the course of the illness.
  • MEDUIM; LOW; MEDUIM
  • 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' non-psychotic relatives, have been measured on executive functioning... 
  • continuous performance tasks in relatives d=.56-.66 [PMID:12418933]; trail-making tests .43-50 [PMID: 12418933]
  • Less extensive cognitive impairments are present in unaffected relatives.
  • MEDUIM; LOW; MEDUIM
  •  -
  • There are alterations in sleep architecture such as delta sleep deficits and shortening of REM sleep latency.
  • MEDUIM; LOW; MEDUIM
  • FACT from Minnesota Consensus Group
  • Impact in Odds Ratio or Effect Size
  • FACT from Schizophrenia Research
  • Schizophrenia Research Rating (Reproducibiity; Primary; Durability)

  • 6. All drugs with established anti-psychotic effects block dopamine D2-like receptors, but anti-psychotic 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. 
  • Dopamine-2 antagonists (“antipsychotics”) are the only effective therapeutic agents which are currently available.
  • HIGH; LOW; HIGH
  • Clozapine is more effective than other agents for neuroleptic-refractory positive symptoms and suicidality.
  • MEDIUM; LOW; MEDIUM
  •  
  • All other currently available antipsychotics are similarly efficacious across patients for positive symptoms.
  • MEDIUM; LOW; HIGH
  • Antipsychotics have limited efficacy on negative symptoms and cognitive deficits.
  • MEDIUM; MEDIUM; MEDIUM
  • 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
  • -
  • Extrapyramidal side-effects are not necessary for an antipsychotic effect and compromise benefit on cognitive, negative, and mood symptoms.
  • MEDIUM; HIGH; MEDIUM
  • -
  • Antipsychotics vary widely in their adverse effect profiles.
  • HIGH; HIGH; HIGH
  • 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.
  • d=.23-.77 (social skills training); d=.22-.71 (family interventions); d=.20-.49 (cognitive training); d=.39-.47 (cognitive behavioral therapy) [PMID:11381111]
  • Family and patient psycho-education reduce relapse rates.
  • MEDIUM; LOW; MEDUIM
  •  
  • Cognitive behavior therapy reduces psychotic symptoms.
  • MEDUIM; LOW; LOW
  •  
  • Social skills training improves outcomes.
  • MEDUIM; LOW; MEDUIM
  •  
  • Assertive community treatment reduces hospitalization rates.
  • MEDUIM; LOW; MEDUIM
  •  
  • Cognitive remediation reduces cognitive deficits.
  • LOW; LOW; HIGH
  •  -
  • Antidepressants are effective in treating depressive symptoms.
  • MEDUIM; HIGH; MEDIUM
  •  -
  • Electroconvulsive therapy may be effective.
  • LOW; LOW; HIGH
  •  -
  • Transcranial magnetic stimulation (rTMS) can be effective.
  • LOW; LOW; HIGH
  •  -
  • Early intervention in high-risk individuals with pharmacological and psychosocial treatments prevents development of schizophrenia.
  • LOW; LOW; HIGH
  • FACT from Minnesota Consensus Group
  • Impact in Odds Ratio or Effect Size
  • FACT from Schizophrenia Research
  • Schizophrenia Research Rating (Reproducibiity; Primary; Durability)

  • -
  • Outcome has modestly improved over the past century
  • LOW; LOW; MEDIUM
  • 14. Longer duration of untreated psychosis is associated with a poorer treatment response
  • d=.50 (increased symptoms in untreated patients) [PMID:9081563]
  • Poor outcome is predicted by male gender, early age of onset, prolonged period of untreated illness, and severity of cognitive and negative symptoms.
  • MEDIUM; LOW; MEDIUM
  •  
  • Early intervention during first episode of psychosis improves outcomes.
  • MEDIUM; LOW; MEDIUM
  • 22. The extent of patients' cognitive deficits generally predicts functioning in work, social interactions, and independent living perhaps even more than symptom expression.
  • d>.50 (performance predicting outcome) [15531406]
  • -
  • There is an approximate doubling of age-standardized mortality.
  • HIGH; LOW; MEDIUM
  • -
  • There is a higher occurrence of obesity and cardiovascular disease.
  • HIGH; LOW; MEDIUM
  • -
  • There is a reduced occurrence of rheumatoid arthritis.
  • MEDIUM; LOW; MEDIUM
  •  -
  • There is a reduced occurrence of cancer.
  • LOW; LOW; MEDUIM
  •  -
  • There is increased prevalence of cigarette smoking and other substance use disorders.
  • HIGH; LOW; MEDIUM
  • 15. Patients have a 4.9% rate of suicide, which is far greater than the average risk in the United States.
  • There is increased suicidality.
  • HIGH; LOW; HIGH
  •  -
  • There is some increase in violent behavior.
  • MEDIUM; LOW; MEDIUM


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