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.
B.
C.
D.
E.
0.01%.
0.1%.
1%.
5%.
10%
According to data from the NIMH Epidemiological Catchment Area study, the
lifetime prevalence of schizophrenia is:
•
•
•
•
A.
B.
C.
D.
E.
0.01%.
0.1%.
1%.
5%.
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 with
schizophrenia 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 with
schizophrenia 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.
b.
c.
d.
e.
Positive symptoms
Married
Early age onset
Precipitating factors
Family history of bipolar disorder
Which of the following features is associated with a poor prognosis in patients
with schizophrenia?
•
•
•
•
•
a.
b.
c.
d.
e.
Positive symptoms
Married
Early age onset
Precipitating factors
Family history of bipolar disorder
Which of the following is NOT a likely characteristic of childhood-onset
schizophrenia?
•
•
•
•
•
a.
b.
c.
d.
e.
Chronic course
Unfavorable prognosis
Acute onset
Hallucinations
Delusions
Which of the following is NOT a likely characteristic of childhood-onset
schizophrenia?
•
•
•
•
•
a.
b.
c.
d.
e.
Chronic course
Unfavorable prognosis
Acute onset
Hallucinations
Delusions
Clinical Components of Schizophrenia:
Symptom Types
• Positive
Delusions
Halucinations
Thought Disorder
• Negative
Flat Affect
Poverty of Thought
Loss of Motivation
Social Withdrawal
• Cognitive
Distractability
Impaired Working Memory
Disruption of Executive Function
Early-Onset Schizophrenia:
Positive Symptoms:
• Hallucinations
• Delusions
• Disorganized Speech
• Disorganized or catatonic behavior
Negative Symptoms:
• Flattened affect
• Anergia (lack of energy)
• Alogia (complete lack of speech)
• Avolition (lack of motivation)
• Social withdrawal
Cognitive 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.
b.
c.
d.
e.
the addition of paroxetine.
the addition of diazepam.
a crossover to depot haloperidol.
the addition of carbamazepine.
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.
b.
c.
d.
e.
the addition of paroxetine.
the addition of diazepam.
a crossover to depot haloperidol.
the addition of carbamazepine.
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
Cognitive Deficits, Delusional
Thinking, Impaired Executive
Function
Sensory-Motor Gating,
Hallucinations
Salience Detection, Distractability
Memory Deficit, False
Memories
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