Transcript Schizophrenia and Other Disorders

Schizophrenia and Other
Disorders
A talk given by Elaine M. Hull at
the Lawton Chiles High School,
Tallahassee, FL, February 2007
A bit of history
• Hideyo Noguchi, 1911: Syphilis (delusions,
grandiosity, impulsivity, altered thought structure)
is due to bacterium.
• Emil Kraeplin, 1919: dementia praecox
(paranoia, grandiose delusions, auditory
hallucinations, abnormal emotional reg., bizarre
thoughts)—partly genetic
• Eugen Bleuler, 1911: key is dissociative thinking;
also delusions, hallucinations, affective
disturbance, autism.
Genes
• Genes scattered across all but 8
chromosomes have been implicated
• Most important:
– Neuregulin 1: NMDA, GABA, & Ach receptors
– Dysbindin: synaptic plasticity
– Catechol-O-methyl transferase: DA metabol.
– G72: regulates glutamatergic activity
– Others: myelination, glial function
• Paternal age: more cell divisions in sperm
Twin studies
• Why does one twin become schizophrenic
and the other does not?
– Lower birth weight
– More physiological distress
– More submissive, tearful, sensitive
– Impaired motor coordination
Structural changes in brain
• Hippocampus, amygdala, parahippocamp.
– Smaller in affected twin (static trait)
– Disordered hippocampal pyramidal cells
• Correlation between cell disorder and severity
• May be due to maternal influenza in 2nd trimester
– Also in entorhinal, cingulate, parahippocampal
cortex
Structural changes in brain
• Larger ventricles
– Subgroup: inverse correlation between
ventricle size and response to drugs
Structural changes in brain
• Increased loss of gray matter in
adolescence
Structural changes in brain
• Shrinkage of cerebellar vermis
• Thicker corpus callosum
• Frontal lobes
– Abnormal neuronal migration in one study
– Dendrites have fewer spines
– But no major structural abnormalities
– Measures of frontal function impaired
Functional changes in brain
• Hypofrontality hypothesis
– Discordant twins: low frontal blood flow only in
affected twin
– Wisconsin card sorting task
• Schizophrenics can’t shift attn. to other criterion
• Functional imaging: frontal lobe activity lower at
rest, esp. in right hemisphere, does not increase
during task.
• Drug treatment increased activation of frontal lobes
Neurochemical changes
• LSD, mescaline  confusion, delirium,
disorientation, visual hallucinations.
• But schizophrenic hallucinations are
mostly auditory
• Schizophrenics given LSD say it’s different
from their symptoms
Dopamine hypothesis
• Amphetamine (very high doses) 
paranoia, delusions, auditory hallucination
• Also exacerbates symptoms of schiz.
• Effects blocked by DA antagonist
chlorpromazine
• Phenothiazines (incl. chlorprom.) & all
other typical neuroleptics block D2
receptors and alleviate (+) symptoms.
Atypical neuroleptics
• Clozapine blocks 5-HT2A receptors > D2
• As effective as typical neuroleptics on (+)
symptoms, more effective on (-) symptoms
• Fewer motor side effects (tardive
dyskinesia)
• Actually increase DA release in frontal
cortex
– L-DOPA can even be beneficial
Glutamate hypothesis
• Problem with DA hypothesis: time course
• Phencyclidine (PCP): dissociative
anesthetic 
– Auditory hallucinations
– Depersonalization
– Delusions
– Noncompetitive NMDA antagonist (blocks
Ca2+ channel)
Glutamate hypothesis
• 2 weeks PCP in monkeys  schiz.-like
symptoms
– Including poor performance on frontal lobesensitive task
• Dose- & time-sensitive
• Ketamine (NMDA antag) similar effects
• So, why not give glutamate agonists to
treat schizophrenia?????
Glutamate hypothesis
• Seizures!! (also excitotoxicity)
• Try mGluR agonists: 8 subtypes of mGluR
– Some modulate glutamate release
– Others modulate dopamine systems
Reconciliation
• Maybe hypofrontality results in hyperdopaminergic state in NAc
• Carr & Sesack, 2000, JNs:
– PFC sends Glu axons to VTA DA cells that  PFC
• Result: positive feedback to PFC
– PFC sends Glu axons to VTA GABA cells that  NAc
• Result: PFC inhibits NAc (probably amygdala, too)
Carr & Sesack, 2000, JNs:
Laruelle et al., 2003, NYAS
Schizophrenia Summary
• PFC and hippocampus cell density and activity
are lower in schizophrenics; neither works well.
– Hippocampal neurons are also disorganized.
• There is normally a positive feedback between
PFC and VTA DA neurons that  PFC
– Less PFC activity decreases that (+) feedback.
• There is normally a negative feedback between
PFC and NAc. (May inhibit impulses, thoughts)
– Less PFC activity decreases that (-) feedback.
Schizophrenia Summary
• The reason D2 antagonists help (+) symptoms: inhibits
mostly NAc & other limbic structures.
– Few D2 receptors in PFC.
• The reason PCP  schizophrenic symptoms: mimics the
PFC hypofunction, releases NAc.
• There may also be anomalies in intracellular
messengers.
• No good biochemical/anatomical explanation for (-)
symptoms.
– Worse in those with greatest physical damage.
– But atypical antipsychotics do help (-) symptoms. (How???)
Schizophrenia Summary
• Possible treatments:
– Metabotropic glutamate (mGluR1) agonists
• Increase glutamate or DA release
– Glycine or cycloserine
• Bind to glycine site on NMDA receptor & enable
glutamate’s effects
– Neither would  seizures
– Not yet tested in humans
Unipolar Depression
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Sad & helpless every day for weeks
Loss of interests, energy, appetite
Feel worthless
Contemplate suicide
Difficulty in concentrating
Restless agitation
Little or no pleasure from eating or sex
Unipolar Depression
• 2 X as often in women as in men
• ~ 5% of adults in US have “clinically
significant” depression
• A genetic component
– 60% concordance for monozygotic twins
– 20% for dizygotic twins
– Especially for early-onset & among female
relatives
– Not a single-gene defect
Increased blood flow to frontal
lobes and amygdala
Increased blood flow also in:
• Parietal cortex (somatosensory/attention)
• Posterior temporal cortex (language)
• Anterior cingulate (emotional processing)
Cortisol is often increased in
depressed people.
Effects of high cortisol levels
• Increase cell death in hippocampus
– Probably due to apoptosis
– Brief cortisol exposure increases hippocampal
activity  helps remember acute stressor.
– Hipp  negative feedback on cortisol levels
– Lengthy high levels increase cell death, also
decrease neurogenesis
– As a result  vicious circle: High cortisol 
hipp. neurotoxicity  less (-) feedback  high
cortisol.
Effects of high cortisol levels
• Depressed people often have bad memories
and difficulty reasoning.
• SSRIs  increased survival of new neurons in
hipp., increased memory and reasoning.
• Hypothesis:
– 5-HT &/or NE  cAMP  CREB  BDNF
– 5-HT4, -6, -7 & β are coupled to Gs
• BDNF in rats also increases cell survival in
hippocampus and decreases behavioral
measures of animal “depression.”
Normal sleep pattern
Sleep pattern in depression
Early entry into REM
Altering sleep patterns sometimes
helps depression
• Most depressed people are phaseadvanced in their sleep cycles.
• Some are helped temporarily by total
sleep deprivation for 1 night.
• Others are helped by going to bed from
5pm to midnight for a week & gradually
going back to normal.
Electroconvulsive therapy
• Can help those who don’t respond to drug
therapy or are suicidal.
• Unclear why it works.
– Increases D1 & D2 receptors in NAc
– Decreases postsynaptic β NE receptors
Regulation of CREB phosphorylation
by antidepressant drugs
Summary of Depression
• Symptoms
– Sad & helpless; feel worthless
– Loss of interests, energy, appetite
– Agitated; Contemplate suicide
– Can’t concentrate
– Little or no pleasure from eating or sex
• High cortisol  damage hippocampus
– Decrease neg feedback; damage memory
Summary of Depression
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Diurnal rhythms phase advanced
Genetic predisposition (not just one gene)
Women > men (decreased allopregnanolone?)
Treatments
– SSRIs, MAOIs, tricyclics
• SSRIs  BDNF  new neuron survival
– ECT
– Don’t sleep for 1 night; Go to bed earlier
– GC antagonist
Seasonal Affective Disorder
• More prevalent in winter.
• Not necessarily more prevalent in far north
or south.
• Treated successfully with bright light AM &
PM.
– Dose response curve for both time & intensity
– Suppresses melatonin (probably not critical)
– 5-HT seasonal rhythm (low in winter)
• SSRIs can treat SAD
Light treatment for SAD
Bipolar Disorder
• Manic phase
– Overactivity & wakefulness
– Talkativeness
– Grandiosity
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Depressed phase: ~ unipolar depression
Men & women: similar incidence
Earlier onset than unipolar
Genes on chromosomes 4, 11, 12, 16, 21, X
– Including gene for BDNF
Brain activity in manic vs.
depressive episode
Bipolar Disorder
• Bipolar I: full-blown episodes of mania
• Bipolar II: episodes of hypomania
• Cycles can be a couple of days to a
couple of years.
• ~1% of people have at least a mild case in
their lifetime
• Enlarged ventricles: decreased brain vol.
• Larger amygdala than normal
Treatments for Bipolar Disorder
• Lithium (for Bipolar I)
– Discovered by accident (JF Cade, uric acid)
– Not clear why it works (can be toxic)
– Usually given during manic phase  prevents
subsequent depression and mania
– Li+ alters Na+ transport & “inhibits recycling of
membranes involved in second-messenger
systems”  reduces responsiveness to
transmitters
Treatments for Bipolar Disorder
• Valproic acid (Depakote, Depakene) or
carbamazepine (anticonvulsants)
– Usually effective only in Bipolar II
– Increase GABA activity, block synthesis of
arachidonic acid (produced during brain
inflammation)
• Patients don’t like to lose the euphoria and
creativity of the manic phase.
Summary of Bipolar Disorder
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Genes on several chromosomes (incl. BDNF)
Bipolar I vs. Bipolar II
Men & women similar incidence
Enlarged ventricles, large amygdala
Treatments
– Bipolar I: lithium
– Bipolar II: Anticonvulsants  GABA activity,
decrease arachidonic acid
Anxiety Disorders
• Panic disorder
– Can be induced by lactate or CO2 in PD
sufferers (only occasionally in normal people)
– Increased activity in parahippocampal gyrus,
– Decreased activity in anterior temporal cortex
& amygdala (seems odd!)
– May have 3, rather than 2, repeats of a
section on chromosome 15
• Also have joint laxity (bend too far)
Anxiety Disorders
• Treatments for panic disorder
– Benzodiazepines (e.g., Valium)
• Increase frequency of Cl- channel openings in
response to GABA
• Have little or no effect alone: safer than
barbiturates
• Allopregnanolone = endogenous agonist at
benzodiazepine binding site.
– Buspirone (Buspar): 5-HT1a agonist (GI/O)
– SSRIs: fluoxetine (Prozac), paroxetine (Paxil)
Benzodiazepine receptors in brain
PTSD
PTSD
• Monozygotic > dizogotic concordance
– Genetics  1/3 of variance
• NMDA mechanisms in amygdala
– May mediate both the conditioning and the
extinction
• NMDA antagonists in amygdala prevent extinction
• Hippocampus and PFC also lose effectiveness in
extinction
PTSD
PTSD
• Not due to high levels of glucocorticoids:
– Usually PTSD sufferers have LOWER than normal
cortisol levels, despite high CRH
• Maybe it’s the high CRH that  symptoms
• Or maybe it’s increased responsiveness to CRH or cortisol
• Individual differences in responsiveness to
trauma
• Sometimes treated with β NE antagonists
(propranolol) or protein synthesis inhibitors soon
after the trauma or during recall of the trauma
OCD
OCD
• Increased metabolism in orbitofrontal
cortex, cingulate, and caudate nuclei.
• Decreased REM latency (~ to depression)
• At least 2 gene polymorphisms:
– For BDNF, 5-HT2A receptor
• Treatment: SSRIs
Cingulotomy to treat OCD
Tourette’s Syndrome
Tourette’s syndrome
• In many ways opposite Parkinson’s disease
• Treated with dopamine antagonists
• Monozygotic concordance: 53-77%; dizygotic
concordance: 8-23%
• Witty Ticcy Ray (by Oliver Sacks): “We
Touretters…are forced into levity by our
Tourette’s and forced into gravity when we take
Haldol….You have a natural balance: we must
make the best of an artificial balance.”
Summary of Mood Disorders
• Depression symptoms:
– Sad & helpless every day for weeks
– Loss of interests, energy, appetite
– Feel worthless
– Contemplate suicide
– Difficulty in concentrating
– Restless agitation
– Little or no pleasure from eating or sex
Summary of Mood Disorders
• Genetic component: 60 vs 20% concordance for
identical vs fraternal twins
• High activity in PFC and amygdala
– PFC inhibits NAc—and therefore pleasure and behavioral
activation
– Amygdala  anxiety
• High cortisol levels may contribute to depression
– Kills hippocampal cells, impairs memory
• Alteration of sleep cycles sometimes helps
• SSRIs for unipolar depression
– ECT for severe cases that don’t respond to SSRIs
• Lithium for bipolar disorder
– Or drugs that increase GABA effect for milder cases
Summary of Mood Disorders
• There is a genetic component for all.
• High cortisol levels may contribute to depression
– Kills hippocampal cells, impairs memory
• Alteration of sleep cycles sometimes helps
• SSRIs for unipolar depression
– ECT for severe cases that don’t respond to SSRIs
• Lithium for bipolar disorder
– Or drugs that increase GABA effect for milder cases
• Anxiety: benzodiazepines, buspirone, SSRIs