negative symptoms

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Announcement
The following material related to the visual system will not be
tested on the December exam:
Lecture slides: Lecture 28, slides 15-24 (on- and off-center
cells, simple cortical cells, complex cortical cells).
Textbook: Bottom half of p. 294; bottom half of p. 300; figure
10.15; bottom half of p. 302 and top half of p. 303;
the spatial-frequency filter model, presented on p. 303-305 of
the textbook.
Guest Lecturer:
Naghmeh Shafiei
Biopsychology of
Psychiatric Disorders
Schizophrenia,
Affective disorders,
& Anxiety disorders
Psychiatric disorders
• What are Psychiatric disorders
(Symptoms)?
• What are some causal contributors?
• What are some hypothesis about why &
how they develop?
• What are some treatment options?
Outline
• Schizophrenia
• Symptoms
• Epidemiology
• Causes
• Heredity
• Cognitive deficiencies
• Neural abnormalities
•
•
•
•
•
•
•
Cognitive abnormalities in schizophrenia
The dopamine hypothesis
Problems with typical antipsychotics
Problems with the dopamine hypothesis
The Glutamate hypothesis
Neural Circuitry Implicated in
Schizophrenia
A new hypothesis
Schizophrenia
• Schizophrenia
• Paranoid Schizophrenic
• Disorganized schizophrenic
• Catatonic schizophrenic
• There are also:
• Schizoaffective disorder
• Schizophreniform disorder
Symptoms
• Schizophrenia as defined by DSM IV
• Delusions
• Incoherence
Catatonic
• Negative symptom
Hallucinations
Disorganized or
• 6 months duration, psychotic for 1 month
• Course:
• Continuous
• Episodic, with or without
residuals
• Single episode, partial or full
remission
Schizophrenia
Symptoms
• Negative Symptoms: Behavioral deficits
•
•
•
•
•
Social withdrawal
Flat affect, Apathy
Anhedonia, lack of pleasure
Reduced focus and motivation
Catatonia
Schizophrenia
Epidemiology
• Onset
• Late teenage years-early adulthood
• Earlier onset in males (20-28) than in
females (26-32)
• Rare onset in childhood and late
adulthood
• Lifetime prevalence of ∼1%.
Causes
Causes
causes
• Heredity
• Twin studies
• Family studies
• Adoption Studies
Causes
causes
• These findings indicate
• There is a strong genetic component to
schizophrenia, but
• Altered genes are NOT the only cause of the
disease
• Genetic component not linked to just one gene,
there may be dozens that are altered.
• So why some and not others?
• Birth complications, Early infections,
Autoimmune reactions, Toxins, Traumatic
injuries, Stress
CausesCausescauses
• Alterations throughout development
• In utero influence includes
Poor nutrition during pregnancy,
Premature birth/low birth weight
Physical and immune stressors during pregnancy
65
Average number of
schizophrenic births
•
•
•
60
55
50
1
2
3
4
5
6
7
8
9
Months after start of
flu epidemic
10
Cognitive deficiencies
• Cognitive functioning is the #1 predictor of
long term outcome (better function= better
prognosis)
• Seven primary domains of cognition that are
affected:
• Speed of Processing
• Working Memory
• Visual Learning/Memory
• Social Cognition
Attention/Vigilance
Verbal Learning/Memory
Reasoning/Problem Solving
Neural abnormalities
• Enlarged Ventricles
• Hippocampus: brain region in temporal lobe
critical for memory formation.
• Some schizophrenics have enlarged lateral
ventricles, due to smaller hippocampus and
other temporal lobe regions
Neural abnormalities
• Closer inspection reveals organization of
hippocampal neurons is altered in the
schizophrenic brain (neural organization occurs
during development)
Neural
abnormalities
Neural abnormalities
Neural abnormalities
Normal
Individual
Patient with
Schizophrenia
• Not brain damage per se: changes in the neural
organization can disrupt the way brain regions process
information
Neural
abnormalities
• Prefrontal Cortex (PFC): frontal lobe region critical for
higher order cognition (short term memory, planning,
behavioural flexibility, abstract thinking)
• Neurons in the PFC of schizophrenics have reduced number
of dendrites, which in turn reduces processing power of
these cells.
Neural abnormalities
• Cortical gray matter loss in
adolescence in the case of
early onset Schizophrenia
• No major structural
abnormalities in the frontal
lobes.
Cognitive Abnormalities in
Schizophrenia
Sort by
number
Sort by
shape
Sort by
colour
Wisconsin Card Sorting
Task: A classic PFC task
Test behavioural flexibility
(ability to change strategies)
Cognitive Abnormalities in
Schizophrenia
• Subjects initially sort cards by one dimension (e.g.,
number)
• Then task switches, subjects must ignore old
strategy and switch to new one (e.g., shape)
• Damage to PFC impairs switching strategies,
patients keep sorting cards by first dimension (keep
sorting by number)
• Schizophrenics also impaired on this task
Cognitive Abnormalities in
Schizophrenia
• Brain activation studies: schizophrenics
and discordant identical twin controls
performed Wisconsin Card Sort
• Schizophrenics had
activation of the PFC at rest;
showed no increase when performing task, unlike
controls
• Other brain regions were activated similarly in both
groups
• Schizophrenics show a dramatic decrease in PFC
function, but not other cortical regions
Cognitive Abnormalities in
Schizophrenia
At Rest
During card
sorting task
Normal
Schiz
• Hypofrontality (reduced PFC function) is
a characteristic negative symptom of
schizophrenia
Treatments
• Most of the dopamine in the brain is produced in small
nuclei in the midbrain
• 1950s: Chlorpromazine found to be antipsychotic; causes
Parkinson’s symptoms in healthy subjects
• Brains of Parkinson’s patients found to be depleted of
dopamine
• 1960s: Drugs that increase dopamine release (e.g.;
amphetamine) could
induce
psychotic symptoms
• Chlorpromazine
and other
antipsychotics
found to block
dopamine receptors (Typical antipsychotics)
• 1970s: Dopamine receptor subtypes discovered; antipsychotic
potency of a drug correlated with binding to D2 receptors (not D1)
• THUS, The dopamine hypothesis was born:
• Schizophrenia is caused by an abnormal increase in
dopamine transmission, leading to overstimulation of D2
receptors
The Dopamine
hypothesisTreatments
How are D2 receptors being overstimulated?
•More D2 receptors?
–Unlikely: Some post mortem studies report
D2 receptors in
schizophrenic brains, others failed to find this effect
–Changes may be due to chronic antipsychotic medication
•More dopamine being produced?
–Probably not: Schizophrenics do not show differences in dopamine
metabolites in CSF
•More dopamine being released?
–Study: imaging allows for non-invasive measure of dopamine release in human
brain
–Give amphetamine to schizophrenics or controls
–Greater dopamine release in the Nucleus Accumbens (NAcc) of
schizophrenics
–More dopamine release = more positive symptoms
Problems with typical
antipsychotics
• Dopamine is heavily involved in motor functions.
– Long term treatment with antipsychotics (dopamine
blockers) can cause movement (a.k.a extrapyramidal) side
effects
• Tardive dyskinesia occurs in about one third of patients
treated with classical antipsychotics
– grimacing, tongue protrusion, lip smacking, rapid limb/trunk
movements; symptoms continue after discontinuing
medication.
– Drugs that are more selective for dopamine vs other
receptors usually cause the worst side effects
• Antipsychotic drugs treat psychosis (delusions,
Problems with the DA
hypothesis
1.Antipsychotics block dopamine receptors right away, yet
drug treatment takes ~2 weeks to reach full effect
If schizophrenia is merely an increase in dopamine, drugs
should work right away
2.Not all schizophrenic patients respond to drugs that block
dopamine receptors
If schizophrenia is merely an increase in dopamine, drugs
should work for all patients
3.Dopamine blockers can alleviate psychosis, but do not treat
negative symptoms.
If cognitive deficits are due to an increase in dopamine,
these drugs should alleviate the symptoms
Problems with the Dopamine
Hypothesis
• 4) Some drugs that reduce symptoms do
not block D2 receptors very well
• Example: Clozapine (atypical
antipsychotic)
• Not as effective at blocking D2 receptors as
classical antipsychotics
• Less likely to produce motor side effects
• Has a much higher affinity to other
receptors, like serotonin (5 HT)
• Can improve negative symptoms
(possibly via 5 HT blockade)
– If positive and negative symptoms are merely due to overstimulation of D2
receptors, atypical antipsychotics shouldn’t work very well
• Problems: some patients have an adverse blood reaction to clozapine; not all
patients can take it safely
10
9
Controls
Schizophrenics
8
7
Errors
• 5) Drugs that increase dopamine release
can improve performance on cognitive
tasks
• Study: Schizophrenics and controls tested on
a working memory task (dependent on PFC
function)
• Given either placebo or low dose of
amphetamine (dose dopamine release, but
not psychotic symptoms)
• Under placebo, schizophrenics performed
worse than controls
• Amphetamine, improved performance in
schizophrenics, up to control levels
6
5
4
3
2
1
0
Placebo Amphetamine
• If schizophrenia is just an increase in dopamine, then why should
a drug that increases dopamine release;
– 1) not affect psychosis (even at low doses)
– 2) improve cognitive functions?
The Glutamate hypothesis
• Abuse of phencyclidine (PCP, angeldust) or
ketamine (Special K) can cause psychotic
symptoms and cognitive deficits
resembling schizophrenia
– Long lasting effects; can persist after drug use has
stopped
– Can also cause degeneration of PFC neurons
• These drugs block NMDA subtype of
glutamate receptors
– Block the ion channel: glutamate cannot activate
receptor
• Glutamate hypothesis: Schizophrenia is caused by decreased
glutamate transmission
– Neurons in PFC/hippocampus use glutamate as a transmitter
– Degeneration of these neurons in schizophrenia disrupts their function, less
glutamate released in these areas
The Glutamate hypothesis
Dopamine
levels
Working memory
performance
• Rat/primate studies show that
repeated PCP:
• 1) decreases dopamine release in
PFC
• 2) causes cognitive deficits on PFCdependent tasks
• These effects persist weeks after
drug treatment has stopped
• Schizophrenics show decrease dopamine activity in PFC
• This model encompasses both positive and negative symptoms of the disorder
• Recent finding: these drugs are also potent D2 receptor agonists (stimulate
the receptors)
– Negative symptoms = decreased glutamate/dopamine transmission in PFC
– Positive symptoms = increased D2 receptor stimulation in NAcc
Neural Circuitry Implicated in
Schizophrenia
PFC projects
back to VTA
Prefrontal
cortex
Cognitive functions
impaired in
schizophrenia
(decreased glutamate,
dopamine?)
Dopamine
(VTA)
VTA sends dopamine
input to PFC and
accumbens
Nucleus
Accumbens
Increased dopamine release in
schizophrenia; related to
psychotic symptoms
• This connectivity suggests that prefrontal cortex can modulate
dopamine release in the NAcc
A New Hypothesis
2
PFC
1
Dopamine
(VTA)
3
Nucleus
Accumbens
1) Decreased PFC dopamine/glutamate reduces activity,
(negative symptoms)
2) Decreased PFC activation reduces inhibition of dopamine
system
3) Release from this inhibition leads to increased dopamine
transmission in NAcc (positive symptoms)
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