Drugs and the Brain:The Challenge of Schizophrenia

David A. Lewis, MDTranslational Neuroscience Program

Department of PsychiatryCenter for the Neuroscience of Mental Disorders

University of Pittsburgh

Leading Causes of Disability: Market Economies, 1990

Total (millions)*

% Total

All Causes 46.81 Major Depression 6.7 14.32 Alcohol use 4.5 9.63 Osteoarthritis 2.7 5.84 Dementia 2.4 5.15 Schizophrenia 2.2 4.76 Bipolar disorder 1.7 3.67 Cerebrovascular 1.6 3.38 Diabetes 1.5 3.29 OCD 1.5 3.110 Drug use 1.4 3.0*Years lived with a disability Murray and Lopez, The Global Burden of Disease, 1996

The Burden of Schizophrenia

• Common: ~1% of population• Chronic: Affected individuals typically ill

from adolescence or early adulthood• Co-morbidity: Depression, substance

abuse, suicide (10%)

Suicide• ~40,000 deaths by suicide in US annually.• 95% of people who commit suicide are suffering

from a diagnosable psychiatric illness.• Common diagnoses in suicide: major depression,

alcoholism, schizophrenia.• 2/3 communicate their intent and 50% have

consulted a physician within the month prior to death.

Schizophrenia:Historical Perspectives 1

• 1893 Kraepelin distinguished “dementia praecox” from manic-depressive psychosis

• Emphasized course and prognosis– Early onset– Deteriorating course– Dementia as the end state

• An “organic” brain disorder

Schizophrenia:Historical Perspectives 2

• 1911 Bleuler coins “schizophrenia” in reference to the splitting of mental functions

• Emphasized psychological mechanisms • Four fundamental features (“the 4 A’s”)

– Loosening of Associations– Autistic behavior and thought– Disturbance in Affect– Ambivalence

• Psychosis = Accessory Symptoms

Schizophrenia:Historical Perspectives 3

• 1939 Schneider emphasized diagnostic reliability

• Described “first rank symptoms” – Audible thoughts– Voices arguing or commenting– Thought insertion, withdrawal or broadcasting– Made impulses, feelings or will

• Very common in schizophrenia but not specific to this diagnosis

Video Interview• Auditory hallucinations• Paranoid delusions• Thought disorder

– Tangential associations– Blocking– Perseveration– Echolalia– Clanging

• Alogia – Poverty of speech– Poverty of speech content

• Avolition-apathy

• Affective flattening – Poor eye contact– Paucity of expressive

gestures– Inappropriate affect

• Motor disturbances– Posturing– Akathisia (drug-induced

restlessness)• Depressed

mood/suicidal ideation• Lack of insight

Schizophrenia as a Genetic Disorder

• The morbid risk of schizophrenia increases in relation to the percentage of genes shared with an affected individual.

Schizophrenia and Genetic Risk

relationship % shared genes relative risk

Gen population NA 1%

3rd degree 12.5% 2%

2nd degree 25% 2-6%

1st degree 50% 6-17%

Both parents 100% 46%

Identical twin 100% 48%

The familial nature of schizophrenia is NOT due simply to a shared environment

• The risk of schizophrenia is ~17% for fraternal twins and ~48% for identical twins.

• The risk for adopted-away biological children of individuals with schizophrenia… – is elevated as expected for first-degree relatives.– higher than rates of schizophrenia present in their

adoptive families.– higher than rates of schizophrenia in the adopted-

away offspring of unaffected parents.

Inheritance is not sufficient for the development of schizophrenia

• Conordance for schizophrenia in monozygotic twins is only ~ 50%.

• ~ 60% of individuals with schizophrenia have neither a 1st nor 2nd degree relative with the disorder.

• Patterns of inheritance do not fit single gene, Mendelian models, but suggest the influence of multiple susceptibility genes, each of small effect.

Schizophrenia as an Environmental Disorder

• A variety of “environmental” events appear to increase the risk for schizophrenia:

– Pregnancy and labor/delivery complications – Late winter/early spring births– Urban place of birth and rearing– Advanced paternal age

• However, the predictive value of all of these risk factors is low.

Schizophrenia as a Neurodevelopmental Disorder

• During childhood and adolescence, individuals who subsequently manifest schizophrenia may exhibit…– Motor abnormalities– Social abnormalities– Impairments in IQ and school

performance

Schizophrenia as a Neurodevelopmental Disorder

• Early model: Brain lesion from early in life remains clinically silent until normal developmental processes during adolescence bring the structures affected by the lesion “on line.”

• Late model: Brain dysfunction arises as a result of altered brain development (e.g., synaptic pruning) during adolescence.

The Disease Process of Schizophrenia

Pathogenesis

Etiology PathologicalEntity

ClinicalSyndrome

Adapted from Paul R. McHugh, M.D.

Pathophysiology

The Neurobiological Challenges of Schizophrenia

• The apparent absence of neuropathological abnormalities.

• The complexity of the brain systems that are dysfunctional.

Neuropathological Markers: A Tale of Two Disorders

• Alzheimer’s Disease• 1906 clinical description• 1906 neuritic plaques (NP)

and neurofibrillary tangles• 1984 amyloid protein in NP• 1987 gene for beta-amyloid

protein (BAP)• 1990’s molecular

mechanisms underlying BAP deposition

• 1990’s genes for rare familial forms and susceptibility genes for common forms

• Schizophrenia• 1895 clinical description• 1979 enlarged ventricles• 2000 alterations in

thalamo-cortical-striatal circuitry

• 2002 first compelling risk genes identified

Biological Complexity of the Clinical Features of Schizophrenia

• Disturbances in Vision –Visual field defects vs. visual

hallucinations

Sensory-Motor vs. Cognitive Circuits• The activities of encoding sensory

information and commanding movements occupy only about 20% of the volume of the cerebral cortex.

• The remaining association cortices are concerned with attending to and recognizing complex stimuli, and to storing (both short and long term) such information in order to plan appropriate responses. Such abilities are termed cognitive processes.

Neuroscience, Purves et al

Fig 12.8 Neuroscience, Purves. P260.

Fig 2 Cerebral Cortex, VanEssen. 1991.

Fig 4 Cerebral Cortex, Van Essen. 1991.

The Disease Process of Schizophrenia

Pathogenesis

Etiology PathologicalEntity

ClinicalSyndrome

Adapted from Paul R. McHugh, M.D.

Pathophysiology

Schizophrenia affects multiple complex brain systems as evidenced by the range of

clinical features• Positive symptoms: Delusions, hallucinations,

thought disorder• Negative symptoms: Decreased motivation,

diminished emotional expression• Cognitive deficits: Impairments in attention,

executive function, certain types of memory• Sensory abnormalities: “Gating” disturbances • Sensorimotor abnormalities: Eye tracking

disturbances• Motor abnormalities: Posturing, impaired

coordination

Cognitive Deficits in Schizophrenia: Core Features of the Illness

• Present in individuals at high risk• Premorbid and prodromal phase marker• Persistent (progressive?) during illness• Predictor of long-term outcome

Cognitive Deficits in Schizophrenia

• Include impaired working memory, the ability to keep in mind briefly a bit of information in order to guide subsequent behavior.

• Working memory deficits are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC).

DLPFC Activation as a Function of Working Memory Load in Schizophrenia

R DLPFC (BA46)

+28 mm0-back 1-back 2-back

0

.10

.20

.30

WM Load

Controls

Patients

% fM

RI S

igna

l Cha

nge

Courtesy of Dr. Cameron Carter

n = 16 per group

Cognitive Deficits in Schizophrenia

• Working memory requires an intact dopamine innervation of the dorsolateral prefrontal cortex.

• Dopamine-containing axons project from the ventral mesencephalon (VTA) to the cerebral cortex.

Catechol-O-methyltransferase (COMT)• Enzyme involved in the metabolic degradation of

dopamine.• COMT appears to be the major contributor to the

termination of dopamine action in the prefrontal cortex due to low levels of the dopamine transporter.

• Single guanine to adenine transition (common) changes val to met at codon 108.

• Val-COMT has 4-fold greater activity than met-COMT, leading to decreased prefrontal dopamine levels.

• Schizophrenic individuals with val/val COMT show greater impairments on working memory tasks.

Deficits in Prefrontal Cortical Dopamine Neurotransmission in Schizophrenia

• Normal function of the DLPFC depends upon appropriate stimulation of dopamine D1 receptors

• Individuals with schizophrenia may have• Decreased dopamine axons in the DLPFC• Increased levels of D1 receptors in the DLPFC• Improvement in DLPFC function with

dopamine agonists

But, Schizophrenia Also Appears to be Associated with an Excess of Dopamine

Neurotransmission• Amphetamines can induce psychotic

symptoms.• All antipsychotic drugs share antagonism

of the dopamine D2 receptor.• Subjects with schizophrenia show excess

release of dopamine in the striatum.

Dopamine Neurotransmission in Schizophrenia

• The cognitive symptoms of schizophrenia may be associated with a functional deficit of dopamine at D1 receptors in the prefrontal cortex.

• The psychotic features of schizophrenia may be associated with a functional excess of dopamine at D2 receptors in the striatum (caudate/putamen).

Structural Brain Abnormalities in Schizophrenia

• ~40% increase in 3rd and lateral ventricular volumes – Associated with more neuropsychological

impairments and negative symptoms– More prominent in males

• 3-4% decrease in whole brain volume

Structural Brain Abnormalities in Schizophrenia

• Hippocampus and Association Cortices– Decreased gray matter volume– No cell loss– Reductions in pre- and post-synaptic

markers

Basic Neurochemistry, 1994

Structural Brain Abnormalities in Schizophrenia

• Mediodorsal thalamic nucleus– Decreased volume– ~30% Decrease in neuronal number

Structural Brain Abnormalities in Schizophrenia

• Convergent lines of evidence indicate that schizophrenia is associated with – A reduction in synaptic connections in the

hippocampus and cerebral cortex.– Fewer neurons in the mediodorsal thalamus.

• Which neurotransmitter systems are involved in these abnormalities?

Altered Glutamate Neurotransmission - 1

• Phencyclidine (PCP) and ketamine, non-competitive antagonists of the NMDA subtype of glutamate receptors…– Exacerbate clinical features of

schizophrenia.– May induce transiently some positive,

negative and cognitive symptoms resembling those of schizophrenia in normal adults.

– Rarely cause such symptoms in children.

Altered Glutamate Neurotransmission - 2

• The symptoms of schizophrenia, especially cognitive deficits, have been reported to be improved by…– Glycine, which facilitates NMDA receptor

function by binding to a modulatory site on the receptor.

– D-cycloserine, a selective partial agonist at the glycine modulatory site of the NMDA receptor.

Current Treatment of Schizophrenia

• Classical APD• High affinity D2

antagonists• Reduces positive sx• Limited against

negative/cognitive• High rates of EPS

and TD

• Atypical APD• Low affinity D2, high

affinity 5HT2A antagonists

• Broader efficacy• Blood dyscrasias,

weight gain, glucose intolerance, $$$