Schizophrenia
What causes schizophrenia? Neuropathology
– Structural and functional changes – Neurochemical alterations
Treatments
Schizophrenia
Emil Kraepelin ―Dementia Praecox‘ (1896) Blueler ―Schizophrenia‖ Onset: adolescence or young adulthood DSM-IV review:
– Positive symptoms (delusions, hallucinations, disorganized speech or behavior) – Negative symptoms (catatonia, affective flattening, withdrawal, or avolition) – Social-occupational disturbance – 6+ months
Associated Features
Cognitive Disturbances
– Memory – Sensory filtering – Attention – Emotion recognition – Eye-tracking
Interpersonal Dysfunction
Subtypes
Catatonic Paranoid Disorganized Unlikely to be a related to a single physiopathology
Neuropathology
Neurodevelopmental hypothesis Neurodegenerative hypothesis Dopamine hypothessis Glutamatergic hypothesis
**These are not exclusive
What causes schizophrenia?
Heritable (Shastry, 2002)
Environmental factors
– Epidemiological studies
Birth complications Maternal stress Seasonality effect Viral epidemics Latitude effect Rh incompatibility
Neuropathology Structural alterations
Behavioral symptoms indicative of brain damage (unusual rates of blinking, poor control of eye movements, unusual facial expressions) Enlarged ventricles (Weinberger & Wyatt, 1982;
Andreason)
Ventricular enlargement in monozygotic twin with schizophrenia
Barondes, 1993
Hippocampal volume loss and enlarged ventricles
Van Heron et al., 2005
Neuropathology Structural alterations (cont)
Alterations in numerous areas, including frontal lobes, medial temporal lobes, lateral temporal lobes, parietal lobe, basal ganglia, corpus callosum, thalamus and even the cerebellum White matter deficits Evidence of disorganized neurons and failures of migration
– Altered density and disorganization of neurons found in the white matter below layer VI in the cortex – Disorganized pyramidal cells in the hippocampus
Altered development of hippocampal pyramidal neurons
Neurodevelopmental Hypothesis
Home movies from families with schizophrenic child displayed abnormal behavior (Walker et al, 1994;
1996)
Children who later become schizophrenic exhibit poor social adjustment and school performance Developmental delays Premorbid psychopathology (anxiety, depression, conduct disorders, ADHD) (Kim-Cohen
et al, 2003)
Physical abnormalities (Schiffman, et al. 2002) Rates of concordance are higher in monochorionic twins compared dichorionic twins (60% vs. 11%) (Davis, et al, 1995)
But why are symptoms not observed until adolescence?
Something must trigger the degenerative process at the period of adolescence Loss and disorganization of neurons become ‗unmasked‘ with pruning and synaptic reorganization
Rapid loss of brain volume during adolescence in schizophrenics
Thompson et al, 2001
Thompson et al, 2001
Twin study—loss of dlPFC and temporal cortical tissue
Cannon et al 2002
Hypofrontality
Reduced activation of the dorsolateral prefrontal cortex contributes to negative symptoms and cognitive deficits
– Functional imaging studies report reduced activation – Evidence of executive functioning deficits
Reduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first episode/drug naïve schizophrenics
MacDonald et al., 2005
dysfunction
death
toxic or genetic insult
poor neuronal migration
inadequate synapse selection
poorly innervated
Could altered development be related to glutamatergic dysfunction?
-Underactivation of systems alters migration, synaptic organization and cell survival -Overactivation of systems can lead to altered synaptic connectivity and cell death
Neurodegenerative Hypothesis
SPECTRUM OF EXCITATION BY GLUTAMATE
Normal
Excess excitation - Mania - Panic
Excitotoxicity - Damage to neurons Excitotoxicity
- Slow neurodegeneration Excitotoxicity
- Catastrophic neurodegeneration
excitation
Could the psychotic symptoms themselves be producing additional excitotoxicity?
Neurochemical Alterations
Dopamine Hypothesis
Original Formulation
– Overactivity of subcortical D2 receptors contributes to positive symptoms
Classical antipsychotics were DA D2 antagonists DA agonists induce psychotogenic effects
DOPAMINE PATHWAYS
Basal Nucleus Ganglia accumbens Substantia nigra
a
b
c
hypothalamus
d
Tegmentum
mesolimbic pathway
mesolimbic overactivity = positive symptoms of psychosis
pure D2 blocker
11-2
Stahl S M, Essential Psychopharmacology (2000)
Re-formulation of dopamine hypothesis
Imaging studies indicate loss of tissue in the frontal lobes as well as reduced activation Deficit in activation of D1 receptors in the prefrontal cortex contributes to negative symptoms and cognitive deficits
meso-cortical pathway
Amphetamine-induced dopamine release is enhanced in schizophrenics
Laruelle et al 2003
Amphetamine-induced dopamine release produces positive symptoms
Laruelle et al, 1996
Increased dopamine release in medication-naïve schizophrenic patients
Hietala, et al. 1995
D2 receptors?
Mixed data Some find no differences Others find moderate increases (Kestler et al., 2001) What about D3 and D4 receptors?
What about the mesocortical DA system?
One postmortem study indicated a decrease in DA innervation of the dorsolateral prefrontal cortex (Akil, et al 1999) Two PET studies had mixed findings, but the ligands used for D1 receptors were not selective (Okubo et al 1997; Karlsson et al 2002) More recently, there is evidence of an upregulation of D1 receptors in the DLPFC
Increased D1 receptor availability in schizophrenics suggests underactivation
Abi-Dargham et al, J Neurosci, 2002
Increases in D1 receptor availability in the DLPFC are correlated with working memory deficits
Abi-Dargham et al, J Neurosci, 2002
Reduction in dendritic spines in dopaminergic neurons in the dorsolateral prefrontal cortex
Lewis et al, 2003
Glutamate Hypothesis
Deficiencies in glutamatergic neurotransmission Dysregulation of DA systems may be secondary to a deficit in the function of the glutamatergic NMDA receptor
Glutamate Hypothesis
Noncompetitve NMDA receptor antagonists (like PCP and ketamine) induce both positive and negative symptoms Unmedicated schizophrenic patients are more sensitive to the effects of NMDA receptor antagonists Adjunctive treatment with NMDA agonists might provide a modest improvement in symptoms
Evidence from human studies
Alterations in CSF glutamate levels, altered glutamate metabolism and altered NMDA receptor subunit gene expression
(Keshavan, 1999)
Direct evidence is still lacking and a coherent picture has not yet emerged Lack of adequate radioligands to visualize the GLU system in the living brain is a major impediment
Glutamate-Dopamine Interactions
Laruelle et al, 2003
Chronic PCP treatment reduces dorsolateral prefrontal cortex dopamine and leads to negative symptoms
Human studies Animal studies
Jentsch and Roth, 1999
Chronic PCP leads to behavioral deficits consistent with dorsolateral prefrontal cortex dysfunction
Jentsch et al, Science, 1997
Chronic PCP reduces cortical dopamine
Jentsch et al, Science, 1997
Effects are reversed with clozapine
Jentsch et al, Science, 1997
NMDA receptor antagonism enhances amphetamine-induced subcortical DA release
Kegelles et al 2000
Reduced prefrontal cortex activation in schizophrenics
Meyer et al., 2002
Reduced dlPFC activation was negatively correlated with striatal dopamine release
Meyer et al., 2002
Subcortical Dopamine-Glutamate Interactions
GABA alterations
Glutamate or GABA?
Put it all together
Neurodevelopmental brain damage, leads to dysfunction in areas like the prefrontal cortex, which leads to increased DA in the mesolimbic areas
What about the temporal lobe damage?
Hippocampus and amygdala control a gate that influences the effects of the prefrontal cortex on n. accumbens neuronal firing This gate modulates reactions of the n. accumbens given the context
Hippocampus may modulate prefrontal activation of n. accumbens
Grace, 2000
Grace, 2000
How does exaggerations of mesolimbic DA activity lead to positive symptoms?
Could altered dopamine in the nucleus accumbens alter the salience attributed to internal and external stimuli? Kapur reading
Treatments
Conventional neuroleptics
– Chlorpromazine – Haloperidol – Loxapine – Pimozide – Thieoridazine – thirothixene
pure D2 blocker
Typical antipsychotics are D2 receptor antagonists
Blockade of receptors in the nigrostriatal dopamine pathway causes them to upregulate
This up-regulation may lead to tardive dyskinesia
Conventional antipsychotics have other sites of action
Muscarinic cholinergic blockade
– Side effects of constipation and blurred vision – Reduce the likelihood of extrapyramidal symptoms
Problems with conventional antipsychotics
Because of side effects, many patients discontinue treatments, relapse, go back on treatment repeatedly Neuroleptic malignant syndrome
Atypical antipsychotic drugs
Serotonin-dopamine antagonists
– Clozapine – Risperidone – Olanzapine – Quetiapine – Ziprasidone
5HT-DA Interactions
brake
Substantia nigra
brake
raphe nucleus
dopamine neuron
dopamine
Substantia nigra
5HT2A receptor
serotonin
5HT2A receptor
serotonin neuron
Raphe
dopamine neuron
dopamine
Substantia nigra
5HT2A receptor
serotonin
5HT2A receptor
serotonin neuron
Raphe
11-19
Stahl S M, Essential Psychopharmacology (2000)
dopamine neuron
Substantia nigra
5HT2A receptor
serotonin neuron
Raphe
11-20
Stahl S M, Essential Psychopharmacology (2000)
Nigrostriatal pathway
dopamine
D2 receptor
DA neuron
postsynaptic neuron
5HT2A receptor
5HT neuron
Nigrostriatal pathway
no dopamine release
serotonin
11-22
Stahl S M, Essential Psychopharmacology (2000)
Nigrostriatal pathway
D2 receptor
SDA
11-23
Stahl S M, Essential Psychopharmacology (2000)
Nigrostriatal pathway
5HT2A receptor
11-24
Stahl S M, Essential Psychopharmacology (2000)
conventional antipsychotic
caudate nucleus
serotonin-dopamine antagonist
caudate nucleus
mesocortical pathway
primary dopamine deficiency
dopamine release
SDA
serotonin
secondary dopamine deficiency
11-27
Stahl S M, Essential Psychopharmacology (2000)
conventional antipsychotic
Cortex
11-28
Stahl S M, Essential Psychopharmacology (2000)
serotonin-dopamine antagonist
Cortex
11-29
Stahl S M, Essential Psychopharmacology (2000)
Fortunately, the serotonin 2A antagonists do not block dopamine antagonism in the mesolimbic system This suggests that combination drugs may enhance DA activity in the prefrontal cortex while reducing DA activity in the mesolimbic system
What about glutamate agonists?
Heresco-Levy, et al. 2004
Heresco-Levy et al., 2002
Summary
Schizophrenia is characterized by damage to brain areas, including the frontal cortices (particularly the DLPFC), temporal lobes, parietal cortex Glutamate dysfunction may lead to developmental disorganization and cell loss DA dysfunction and/or glutamate dysregulation in the prefrontal cortex and limbic system may contribute to symptoms of schizophrenia
Future directions
Neuroprotection