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