Lecture 9:

Schizophrenia

Shuzo Sakata
shuzo.sakata@strath.ac.uk
HW423
Learning Outcomes

• Understand what is schizophrenia with respect to its

major symptoms and the current status of
treatments
• Understand the underlying genetic factors
• Understand the intermediate phenotypes, including
abnormalities in the brain structure and functions
• Understand how drugs work and don’t work
including the major hypotheses
Outline: what can we learn?
• Overview
• Genetics
• Brain abnormalities
• Drug
Schizophrenia: quick overview
• Lifelong disability
• 5.0M people in Europe
• 29B euros
• Of Schizophrenic patients …
• 5% … suicide
• Many more … homeless
• The vast majority … unable to function successfully in school or in the workplace.
• Symptoms
• Similar in all countries and cultures
• Prevalence … 0.5-1 %
• Male:Female=1.4:1
• Diagnosis
• Late adolescence or early adulthood
Overview: Symptoms
• Three clusters
• Each may reflect different aspects of the pathophysiology (mechanisms)
• Each responds differently to the medications
• Positive or Psychotic symptoms
• Hallucinations
• Delusions
• Negative symptoms
• Blunted emotional responses
• Withdrawal from social interactions
• A lack of motivation
• Cognitive symptoms
• Disorganized life  long-term disability
• Working memory
• Executive functions
• No treatment
• Can be found to some degree before the positive symptoms appeared
Overview: Psychotic episodes (positive symptoms)
• Hallucinations
• Percepts that occur in the absence of appropriate sensory stimuli
• Auditory hallucinations
• Voices
• A dialog
• Commands
• Noises or music
• Delusions
• Firm beliefs that are not realistic and not explained by the patient’s culture

• A film “A Beautiful Mind”

• A story of John Nash (Nobel prize winner)
 Overview: Early symptoms to full manifestation
• Negative symptoms
• Behave eccentrically
• Become socially isolated
• Exhibit blunted affect, poverty of speech, a poor attention span, and lack of motivation
• Periods of florid psychosis
• Accompanied by markedly disordered thinking and abnormalities in the regulation of
emotion
• Interspersed with periods of residual symptoms
• After the first few episodes
• The patient rarely returns to full normal functioning
Overview: Treatment

• Antipsychotic drugs
• Most effective at diminishing the positive symptoms
• None of the medications reliably benefits the cognitive symptoms
Outline: what can we learn?
• Overview
• Genetics
• Brain abnormalities
• Drug
Etiology: Genetic Factors

• SZ runs in families.
• Franz Josef Kallmann (1897-1965)
• German-born American psychiatrist
• Pioneer in the study of genetic basis of mental illness
• Developed the use of twin studies (1930s)
 Etiology: Genetic Factors

• Gottesman 1991
• More genes shared, more risk of
developing SZ
• But not 100%
• Huntington disease … 100%
• Suggesting other risk factors
• New mutations (de novo mutation:
mutations not from parents)
• Epigenetic modification of DNA
• Environmental factors
• Stochastic factors

(http://www.schizophrenia.com/research/hereditygen.htm)
Etiology: Genetic Factors
• Genetically heterogeneous
• No single gene proving necessary or sufficient
• Two forms of genetic variation
• Variations in single nucleotide bases
• Large chromosomal deletions, duplications, or translocations
• 22q11.2
• Scientific viewpoints
• When are the genes expressed in the brain?
• Abnormal development processes in the brain
Etiology: Disc-1
• A large Scottish Family
• Chromosomal translocation
• Chromosomes 1 & 11
• Inactivates (truncates) a gene, called Disrupted in Schizophrenia-1
• Disc-1
• Important for brain development
• Some family members exhibit serious mental illness, but not necessarily SZ.
• Bipolar disorder, major depression
• Disc-1 must interact with other genes and non-genetic factors to determine
the final phenotype
Etiology: Environmental factors?

• Some environmental factors may be just correlations

• Low socioeconomic status
• SZ  impairs occupational and social success  downward socioeconomic drift

Intermediate phenotypes  the next topic

Intermediate phenotypes

Intermediate phenotypes
Background: Anatomical divisions of CNS & brain
• Spinal cord
• Brain stem
• Medulla
• Pons
• Midbrain
• Cerebellum
• Diencephalon
• Thalamus
• Basal ganglia
• Hypothalamus
• Cerebral Cortex
• Frontal, Parietal, Temporal, Occipital lobes
MRI: Magnetic Resonance Imaging
• Structural Imaging
• Functional Imaging
Anatomy of Neuron: Essential structures

Cell body
Dendrite
Axon
Synapse
(Spine) axon

synapse
spine
Neurotransmitters: chemical languages of neurons
• Amino acids
• Glutamate
• GABA (γ-aminobutyric acid)
• Biogenic amines
• Histamine
• Serotonin
• Catecholamine (noradrenaline, adrenaline, dopamine)
• Acetylcholine
• Neuropeptide (e.g., orexin, oxytocin)
Outline: what can we learn?
• Overview
• Genetics
• Brain abnormalities
• Drug
Intermediate phenotypes

Intermediate phenotypes
Structural Abnormalities
• Thinning of specific areas of the prefrontal, temporal and parietal cerebral
cortex.
• Prefrontal cortex
• The most pronounced area … dorsolateral prefrontal cortex (working memory, cognitive functions)
• Temporal lobe
• Loss of gray matter in
• the superior temporal gyrus
• Temporal pole
• Amygdala (may be limited to males)
• Hippocampus
Structural and functional abnormalities
• Structural abnormalities have been correlated with functional abnormalities.
• Prefrontal abnormalities are well-documented
• Working memory and PFC activity
Intermediate phenotypes

Intermediate phenotypes
Cellular & Synaptic level
• Loss of gray matter in the cerebral cortex
• Not the result of cell death
• A reduction in dendritic, axonal, and synaptic processes
• Smaller thalamus
• May be loss of cell bodies in the mediodorsal nucleus of the thalamus
• Loss of axonal terminals in the DLPFC
• Contribute to the reduction of cortical dendrites and the dendritic spines
DLPFC

MD
thalamus
When the abnormalities are observed?
• SZ occurs in late teenage years or in the early twenties.
• Early adulthood is an important period of brain development
• Synaptic pruning
• May be particularly important in the PFC
• Pruning coincides with major changes in dopaminergic neurotransmission during late
adolescence
• Cortical abnormalities and ventricular enlargement are generally observed at
the time of first diagnosis
• Severity of gray matter deficits in PFC correlates with severity of symptoms
• In SZ adolescents the loss of gray matter is more pronounced in broad
regions of temporal cortex
Outline: what can we learn?
• Brain abnormalities
• Structural & Functional abnormalities
• Cellular & Synaptic level
• Time course
• Drug
Outline: what can we learn?
• Brain abnormalities
• Structural & Functional abnormalities
• Cellular & Synaptic level
• Time course
• Drug
 Drug: Antipsychotic drugs
• Antipsychotic drugs: 1st generation
• All act on the dopaminergic pathways
• Chlorpromazine
• Originally developed for anti-histamic and sedating effects, not for its psychiatric effects
• Mid 1960s … specifically reducing the positive symptoms of SZ, such as hallucinations and
delusions.
• Less impact on the negative symptoms and little or no impact on cognitive deficits
• Produced Parkinson-like side effects
• Antipsychotic drugs block dopamine receptors.
• Arvid Carlsson … Dopamine hypothesis
• Nobel Prize Winner in 2000
• Parkinsonian side effects
 Dopamine receptors
• Two families of dopamine receptors
• D1 (D1 and D5)
• coupled to stimulatory G proteins that activate adenylyl cyclase
• Striatum, cerebral cortex and hippocampus
• D2 (D2, D3 and D4)
• Coupled to inhibitory G protein that inhibits AC
• Striatum, cerebral cortex, amygdala and hippocampus
• The main target of antipsychotic drugs on positive symptoms
Drug: 2nd generation

• Inspiration of Clozapine … less likelihood of casing Parkinsonian side effects

• Lower affinity for D2 receptors
• Some also block the serotonin 5HT2A receptors
• None of the newer drugs is equal to clozapine in efficacy
More antipychotic drugs
• Clozapine
• Atypical drug
• affinity: D1 > D2
• Chlorpromazine
• ‘dirty’ drug
• acting on many receptors
• Haloperidol
• Typical drug
• high affinity for D2 receptors
• Olanzapine
• Atypical drug
• affinity: 5-HT2A receptors > D2 receptors
• Risperidone
• Qualitatively atypical drug
• More pronounced serotonin antagonism than dopamine antagonism
• See more
• https://en.wikipedia.org/wiki/Antipsychotic
Theory of Schizophrenia

•Dopamine Hypothesis
•Glutamate Hypothesis
Dopamine Hypothesis
• Some drugs that block D2 receptors reduce psychotic symptoms
• Other drugs that increase dopamine at synapses (such as amphetamine and
cocaine) can produce psychotic symptoms, especially paranoid symptoms
• Carlsson … dopaminergic systems are hyperactive in SZ
• 1990s … Amphetamine-produced increases in dopamine release were
greater in SZ patients than in healthy subjects
• Abnormalities in amphetamine-sensitive processes (such as DA storage, vesicular
transport, DA release or DA reuptake by presynaptic neurons) might lead to
hyperactivity in the subcortical dopaminergic systems
• Dopamine activity might decrease in cortical regions and this might
contribute to the cognitive symptoms
• The number of D1 receptors in PFC is thought to be reduced in SZ
• D1 receptors play a role in working memory and executive functions
Glutamate Hypothesis
• Implicated in SZ
• Phencyclidine and ketamine
• Block the NMDA-type glutamate receptor
• Produce psychotic symptoms
• In healthy subjects ketamine also produces cognitive dysfunction
• Decreased function of NMDA-type glutamate receptors might play a role in
producing some of the positive and cognitive symptoms of SZ
• Positive and Cognitive symptoms … probably the result of abnormalities in several
transmitter systems that act either in parallel or in combination with dopamine
Summary
• Overview
• Genetics
• Brain abnormalities
• Drug

To learn more, access

http://www.nature.com/news/specials/schizophrenia/index.html
Lecture 10. Pharmaceutical development and
pharmacokinetic profile of treatments associated
with affective & psychotic disorders