neurobiological factors in schizophrenia
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Neurobiological Factors in Schizophrenia. Overview. Definition of Schizophrenia: Clinical Features Component Symptoms Endophenotype testing Mechanisms Etiology of Schizophrenia: Current Evidence GABA control of network function Dopamine Hypothesis NMDA/Network Hypothesis - PowerPoint PPT PresentationTRANSCRIPT
Neurobiological Factors in Schizophrenia
Overview• Definition of Schizophrenia: Clinical Features
– Component Symptoms– Endophenotype testing
• Mechanisms • Etiology of Schizophrenia: Current Evidence
– GABA control of network function– Dopamine Hypothesis – NMDA/Network Hypothesis– Genetic and Environmental Factors
According to data from the NIMH Epidemiological Catchment Area study, the lifetime prevalence of schizophrenia is:
• A. 0.01%.• B. 0.1%.• C. 1%.• D. 5%.
E. 10%
According to data from the NIMH Epidemiological Catchment Area study, the lifetime prevalence of schizophrenia is:
• A. 0.01%.• B. 0.1%.• C. 1%.• D. 5%.
E. 10%
Which of the following specific populations has the highest prevalence of schizophrenia?
• a. Child with one schizophrenic parent• b. Non-twin sibling of a schizophrenic
patient• c. Monozygotic twin of a schizophrenic
patient• d. Child of two schizophrenic parents• e. Dizygotic twin of a schizophrenic patient
Which of the following specific populations has the highest prevalence of schizophrenia?
• a. Child with one schizophrenic parent• b. Non-twin sibling of a schizophrenic
patient• c. Monozygotic twin of a schizophrenic
patient• d. Child of two schizophrenic parents• e. Dizygotic twin of a schizophrenic patient
NIMH
Schizophrenia afflicts 1% of the general population
10% of people with an immediate family member with the disorder will also develop the disorder
Someone with an identical twin with the disorder has a 40-65% chance of developing the disorder
The most common eye-tracking movement abnormality in patients withschizophrenia is
• inaccurate saccades (hypermetric or hypometric).
• impaired initiation of saccades (ocular apraxia).
• inappropriate saccades (saccadic intrusions).• impersistence of gaze (large amplitude
saccadic intrusions).• abnormal saccadic velocity (slow saccades).
The most common eye-tracking movement abnormality in patients withschizophrenia is
• inaccurate saccades (hypermetric or hypometric).
• impaired initiation of saccades (ocular apraxia).
• inappropriate saccades (saccadic intrusions).• impersistence of gaze (large amplitude
saccadic intrusions).• abnormal saccadic velocity (slow saccades).
Which of the following features is associated with a poor prognosis in patients with schizophrenia?
• a. Positive symptoms• b. Married• c. Early age onset• d. Precipitating factors• e. Family history of bipolar disorder
Which of the following features is associated with a poor prognosis in patients with schizophrenia?
• a. Positive symptoms• b. Married• c. Early age onset• d. Precipitating factors• e. Family history of bipolar disorder
Which of the following is NOT a likely characteristic of childhood-onset schizophrenia?
• a. Chronic course• b. Unfavorable prognosis• c. Acute onset• d. Hallucinations• e. Delusions
Which of the following is NOT a likely characteristic of childhood-onset schizophrenia?
• a. Chronic course• b. Unfavorable prognosis• c. Acute onset• d. Hallucinations• e. Delusions
Clinical Components of Schizophrenia:Symptom Types
• Positive
• Negative
• Cognitive
DelusionsHalucinationsThought Disorder
Flat AffectPoverty of ThoughtLoss of MotivationSocial Withdrawal
Distractability Impaired Working MemoryDisruption of Executive Function
Early-Onset Schizophrenia:Positive Symptoms:• Hallucinations• Delusions• Disorganized Speech• Disorganized or catatonic behaviorNegative Symptoms:• Flattened affect• Anergia (lack of energy)• Alogia (complete lack of speech)• Avolition (lack of motivation)• Social withdrawalCognitive Symptoms:• Borderline mental retardation
Which of the following features characterizes patients with schizophrenia who smoke cigarettes?
• Lower incidence of positive symptoms• Less vulnerable to tardive dyskinesia• Require more antidepressant medication• Require more neuroleptic medication• Require more depot neuroleptic medication
Which of the following features characterizes patients with schizophrenia who smoke cigarettes?
• Lower incidence of positive symptoms• Less vulnerable to tardive dyskinesia• Require more antidepressant medication• Require more neuroleptic medication• Require more depot neuroleptic medication
A patient who is being treated for schizophrenia has improved and stabilized on haloperidol 10 mg per day. The patient develops acute extrapyramidal symptoms. Which of the following events is the most likely cause?
• a. Use of a hallucinogen• b. Cessation of smoking• c. Addition of phenobarbital• d. Addition of phenytoin• e. Discontinuation of paroxetine
A patient who is being treated for schizophrenia has improved and stabilized on haloperidol 10 mg per day. The patient develops acute extrapyramidal symptoms. Which of the following events is the most likely cause?
• a. Use of a hallucinogen• b. Cessation of smoking• c. Addition of phenobarbital• d. Addition of phenytoin• e. Discontinuation of paroxetine
A patient with schizophrenia has had a poor response to three adequate trials of antipsychotic medications. The next therapeutic strategy to use includes:
• a. the addition of paroxetine.• b. the addition of diazepam.• c. a crossover to depot haloperidol.• d. the addition of carbamazepine.• e. a crossover to clozapine.
A patient with schizophrenia has had a poor response to three adequate trials of antipsychotic medications. The next therapeutic strategy to use includes:
• a. the addition of paroxetine.• b. the addition of diazepam.• c. a crossover to depot haloperidol.• d. the addition of carbamazepine.• e. a crossover to clozapine.
A patient who is being treated for schizophrenia has improved and stabilized on haloperidol 10 mg per day. The patient develops a return of characteristic
psychotic symptoms following the addition of a medication for another condition. Which of the following medications is the most likely cause?
• a. Atenolol• b. Efavirenz• c. Doxycycline• d. Carbamazepine• e. Pravastatin
A patient who is being treated for schizophrenia has improved and stabilized on haloperidol 10 mg per day. The patient develops a return of characteristic
psychotic symptoms following the addition of a medication for another condition. Which of the following medications is the most likely cause?
• a. Atenolol• b. Efavirenz• c. Doxycycline• d. Carbamazepine• e. Pravastatin
Testing For Schizophrenia: Endophenotypes
Network dysfunction in schizophrenia
Fletcher and Frith. Nature Reviews Neuroscience, 2009
Brain Activity Changes in Schizophrenia: Importance of the Prefrontal Cortex
White Matter Tract Disruption in Schizophrenia
Cortical Connectivity Regional Connectivity
Abnormal Network Synchrony in Schizophrenic Patients
Esslinger et al. Science 2009
Fletcher and Frith. Nature Reviews Neuroscience, 2009
How might there be altered connectivity in schizophrenia?
Investigations of networks
Networks Disrupted in Schizophrenia
Sensory-Motor Gating,Hallucinations
Salience Detection, Distractability
Cognitive Deficits, DelusionalThinking, Impaired Executive Function
Memory Deficit, FalseMemories
Possible Mechanism of Network Disruption after Loss of Normal Function in Interneurons
Changes in markers of GABAergic Interneurons in Schizophrenia
Changes in marker of GABAergic Interneurons in Schizophrenia
Local Cortical Network Disruption in Schizophrenia
Dopamine Hypothesis of Schizophrenia: Methods of Treatment
Actions of Dopamine on PFC Function
Possible Mechanisms For the Involvement of Dopamine in Schizophrenia
The NMDA Hypothesis of Schizophrenia: Psychotomimetic Drugs
• PCP, a noncompetative NMDAR antagonist, produces symptoms similar to Schizophrenia
Structure of the NMDA receptor
Changes in Network Activity Associated with NMDA Receptor Antagonists
Chronic Application of NMDAR Antagonists Recapitulates Interneuronal Changes Seen in Schizophrenia
Cortical Parvalbumin Positive Structures
Schizophrenia is a developmental disorder
Early detection of mutations and modulation of dysfunctional circuits during
critical period may be the optimal treatment
Susceptibility Genes in Schizophrenia
Schizophrenia: Many Targets, Few Treatments
Abnormal Trafficking of NMDA Receptors In Schizophrenia
Mutations in Dysbindin Gene Are Linked to Increase in Incidence of Schizophrenia
Mutations in Dysbindin Gene Are Linked to Increase in Incidence of Schizophrenia
Weickert et al., Schizophrenia Research 2008
Mutations in Dysbindin Gene Are Linked to Increase in Incidence of Schizophrenia
Gray & Roth, Molecular Psychiatry 2007
Mutations in DISC1 Gene Are Linked to Increase in Incidence of Schizophrenia
Roles of DISC1 in development and Function
Polymorphisms in DISC1 Affect Hippocampal Activation During Working Memory Tasks
Mutations in DISC1 Gene Are Linked to Increase in Incidence of Schizophrenia
COMT is involved in regionally specific dopamine regulation
Origin of Schizophrenia: Other Factors
• Epidemiological Studies Have Identified Factors in Early Development Associated with Higher Rates of Schizophrenia:– Fetal Malnutrition– Infection Induced Inflamation During Fetal
Development– Increased Fetal Cytokine levels– Cannabinoid Activity?
Take home• Current pharmacological tools (antipsychotics) treat
positive symptoms only• There are many non-invasive ways to assess some hallmark
features of schizophrenia (ERP and PPI)• There are many identified genetic factors which may
predict disease onset• Early identification of disruptions in NMDAR function
(through PET imaging) and restoration of normal NMDAR function throughout development may be a way to prevent cognitive deficits and negative symptoms of schizophrenia