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Chapter 16
Schizophrenia and the Affective
Disorders
Schizophrenia
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A serious mental disorder characterized by disordered
thoughts, delusions, hallucinations, and often bizarre
behaviors
Afflicts ~1% of population
Probably the most misused psychological term – literally
means “split mind”, so often confused with multiple
personality disorder
Positive symptoms – symptoms evident by their presence
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Thought disorders – disorganized, irrational thinking (most
important symptom)
Delusions – a belief that is clearly in contradiction to reality
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Persecution – false beliefs that others are plotting against oneself
Grandeur – false beliefs in one’s own power
Control – belief that one is being controlled by others
Hallucinations – perception of a nonexistent object or event
Schizophrenia
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Negative symptoms – characterized by the absence of
behaviors that are normally present
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Flattened emotional response
Poverty of speech
Lack of initiative and persistence
Inability to experience pleasure
Social withdrawal
Heritability
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Both adoption and twin studies indicate that schizophrenia is a
heritable trait
If there is a “schizophrenia gene”, then it must be triggered by
some type of env’tal event
Study shows that higher paternal age is positively correlated
with diagnosis of schizophrenia
Pharmacology of Schizophrenia
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Dopamine hypothesis – suggest that schizophrenia is
caused by overactivity of DA synapses, probably those in
the mesolimbic pathway
Effects of DA agonists and antagonist
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A drug used to prevent surgical shock, chlorpromazine, was
dramatically effective in reducing symptoms of schizophrenia
Since this discovery, many other drugs have been developed
that relieve the positive symptoms of schizophrenia; All of
these drugs block DA receptors
DA agonists act to produce positive symptoms of schizophrenia
(e.g amphetamine, cocaine and L-DOPA)
The mesolimbic pathway is most likely involved in
schizophrenia; could be caused by reinforcing effects of this
pathway for any of the behaviors found with positive
symptoms
Pharmacology of Schizophrenia
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Effects of DA agonists and antagonist
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Schizophrenics often report feelings of elation and euphoria at
the beginning of a schizophrenic episode, suggesting that this
is caused by hyperactivity of DA neurons involved in
reinforcement
Paranoid delusions may be caused by increased activity of the
DA input to the amygdala
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Amygdala is involved with conditioned emotional responses for
aversive events
DA transmission abnormalities
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DA neurons may release more DA
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Amphetamine administration caused the release of more DA in the
striatum of schizophrenic patients; patients with greater amounts
of DA showed greater increases in positive symptoms
There may be moderate increases in the numbers of D2 receptors,
but it is unlikely that that is the cause of the disorder
Clozapine – an atypical antipsychotic drug; blocks D4 receptors in
the nucleus accumbens
Pharmacology of Schizophrenia
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Long-term drug treatment
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The symptoms of up to 1/3 of all schizophrenic patients are
not substantially reduced by antipsychotic drugs
Many drugs produce serious side effects
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Tardive dyskinesia – a movement disorder that can occur after
prolonged treatment with antipsychotic medication,
characterized by involuntary movements of the face and neck
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Caused by overstimulation of DA receptors
Why would antagonists cause overstimulation of DA receptors?
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Until recently, all drugs caused at least some symptoms
resembling those of Parkinson’s disease: slow movement, lack of
facial expression, general weakness
Supersensitivity – the increased sensitivity of NT receptors; caused
by damage to the afferent axons or long-term blockage of NT
release
However, new drugs have been developed that do not produce
these long-term side effects – atypical antipsychotic drugs
(Clozapine)
Schizophrenia as a neurological
disorder
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Whereas the positive symptoms are unique to
schizophrenia, the negative symptoms are similar to those
produced by brain damage caused by several different
means
Brain abnormalities in schizophrenia
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Patients with schizophrenia exhibit neurological symptoms
that suggest brain damage (e.g. poor control of eye
movements, unusual facial expressions)
This suggests that schizophrenia may be associated with brain
damage of some kind
MRI and CT studies have found loss of brain tissue in patients
with schizophrenia
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Relative size of lateral ventricles was more than twice the size of
control subjects
Schizophrenia as a neurological
disorder
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Possible causes of brain abnormalities
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Why do less than ½ the children of schizophrenic patients
become schizophrenic?
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Perhaps what is inherited is a susceptibility to environmental
factors that may lead to some type of brain damage
Development of disorder is most likely caused by interaction b/t
genes and environment
However, people can develop schizophrenia without and family
history
Epidemiology – study of distribution and causes of diseases in
populations; try to correlate disease frequencies with factors
that are present in the env’t
People born during late winter and early spring are more likely
to develop schizophrenia – seasonality effect
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Possibly caused by higher likelihood of mother contracting viral
illness
Also more likely to occur in cities rather than countryside
Schizophrenia as a neurological
disorder
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Possible causes of brain abnormalities
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People born far from the equator are more likely to develop
schizophrenia – latitude effect
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Decreased winter temp may magnify seasonality effects
Famine (especially thiamine deficiency) during pregnancy may
cause schizophrenia in offspring
Underweight women are more likely to give birth to babies
who later develop schizophrenia; low birth-weight babies have
higher incidence of schizophrenia
Vitamin D deficiency
Rh incompatibility
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Red blood cells of Rh-positive person contain Rh factor
If fetus is Rh incompatible with mother, then increased likelihood
of schizophrenia in offspring
Schizophrenia as a neurological
disorder
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Evidence for abnormal brain development
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Prenatal brain development of children who become
schizophrenic is not normal
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Reports of both behavioral and anatomical abnormalities
Children who later became schizophrenic displayed more negative
affect in their facial expressions and were more likely to show
abnormal movements
Some monozygotic twins are discordant (i.e. one develops it, the
other does not) for schizophrenia: difference in brain structure
(one has larger ventricles, degeneration in specific regions of
cerebral cortex)
Monochorionic (share one placenta) vs. dichorionic (separate
placentas) in monozygotic twins: concordance rate for
schizophrenia was lower in dichorionic vs. monochorionic
Schizophrenia not caused by degeneration, but by a rapid loss
of brain volume during young adulthood
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Does not involve death of neurons, but a loss of neuropil,the
network of dendrites and axons in the brain
Schizophrenia as a neurological
disorder
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Positive and negative symptoms: Prefrontal cortex
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Is there a relationship b/t the 2 categories of symptoms?
Negative symptoms caused by hypofrontality (decreased
activity of the frontal lobes), primarily in the dorsolateral
prefrontal cortex
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Chronic abuse of PCP (indirect glutamate antagonist) causes a
decrease of metabolic activity in frontal lobes
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May be caused by decrease in release of DA in prefrontal cortex,
mediated mostly by D1 receptors
Chronic PCP treatment reduces DA activity in the prefrontal cortex,
which in turn produces hypofrontality that appears to be
responsible for the negative symptoms of schizophrenia
Prefrontal hypoactivity (neg. symptoms) causes mesolimbic DA
hyperactivity (pos. symptoms)
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Clozapine causes an increase in DA release in prefrontal cortex,
and decrease of DA release in nucleus accumbens
Major Affective Disorders
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Affect – refers to feelings or emotions
Major affective disorders – a serious mood disorder;
includes unipolar and bipolar disorder
Bipolar disorder – characterized by cyclical periods of mania
(extreme elation) and depression (extreme despair);
episodes of mania generally shorter than episodes of
depression
Unipolar depression – consists of unremitting depression or
periods of depression that do not alternate with periods of
mania
Depression causes very little energy, crying, inability to
experience pleasure, disturbed sleep, depressed bodily
functions
Mania involves sense of euphoria, nonstop speech and
motor activity, easily angered, go without sleep
Major Affective Disorders
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Heritability
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The tendency to develop a major affective disorder is heritable
A single dominant gene is responsible for susceptibility to
developing bipolar disorder
Physiological treatments
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MAO inhibitors
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Tricyclic antidepressants
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Drugs (e.g. Iproniazid) that inhibit the activity of MAO, the enzyme
that destroys excess monoamine transmitter substance within
terminal buttons, increase the release of DA, NE and 5-HT
Have serious side effects, e.g. cheese effect with pressor amines
Inhibit the reuptake of 5-HT and NE by terminal buttons
This keeps the NT in contact with the postsynaptic receptor, thus
prolonging the postsynaptic potentials
Specific serotonin reuptake inhibitors (SSRI)
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Inhibit reuptake of 5-HT
Widely prescribed for depression and for symptoms of OCD and
social phobia
Major Affective Disorders
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Physiological treatments
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Electroconvulsive therapy (ECT)
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Electrodes placed on patients scalp deliver a jolt of electricity to
trigger a seizure
Most effective with mania and depression
Effects are rapid, as compared to drugs
Lithium
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Most effective in treating the manic phase of bipolar disorder
Does not suppress normal feelings of emotion
Does not impair intellectual processes
Does have some side effects, including hand tremors, weight gain,
excessive urine production and thirst
Some patients with bipolar disorder have trouble continuing with
medication
Those who cannot tolerate side effects can take carbamazepine, an
anti-seizure medication
Major Affective Disorders
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Role of monoamines
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Monoamine hypothesis: hypothesis that states that depression
is caused by a low level of activity of one or more
monoaminergic synapses
Since the symptoms of depression do not respond to potent
DA agonists (e.g. amphetamine or cocaine), researchers have
focused on NE and 5-HT
Depression can be caused by monoamine antagonists
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e.g. reserpine
Suicidal depression is related to decreased CSF levels of 5HIAA, a metabolite of 5-HT that is produced when MAO breaks
it down
Families of subjects with low levels of 5-HIAA were more likely
to include people with depression
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Suggests that 5-HT metabolism or release is genetically controlled
and is linked to depression
Major Affective Disorders
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Role of monoamines
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Tryptophan depletion procedure
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Depressed patients currently taking medication
Gave low-tryptophan diet, follwed by an amino acid “cocktail”,
which would inhibit what little tryptophan was left from entering
the brain
Tryptophan depletion caused most of the patients to relapse back
into depression
 However, recovered after resuming normal diet
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This has no effect on healthy, non-depressed subjects, but does
lower the mood of people with a family history of affective
disorders
Major Affective Disorders
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A role for Substance P?
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A peptide secreted as a NT and neuromodulator in several
regions of the brain
May be involved in emotional behavior, the response to stress,
and the symptoms of depression
Long-term admin of antidepressants cause a reduction of
substance P levels in several regions of the brain
MK-869, a drug that blocks the receptor for substance P (NK1)
shows a reduction in depressive symptoms
Substance P antagonists appear to act independently of drugs
that reduce depression by blocking the reuptake of 5-HT and
NE
Major Affective Disorders
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Evidence for brain abnormalities
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Studies have found abnormalities in the prefrontal cortex,
basal ganglia, and cerebellum of patients with unipolar
depression, and abnormalities of the cerebellum in those with
bipolar disorder
Found in young patients, which suggests the presence of a
developmental abnormality or a degenerative process that
occurs early in life
Repeated episodes of depression and mania caused an
increase in the size of the lateral ventricles
The amygdala and several regions of the prefrontal cortex play
a role in the development of depression
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Activity of amygdala of depressed patients was correlated with the
severity of their depression
Orbitofrontal cortex generally more active in depressed patients
Subgenual prefrontal cortex shows a lower level of activation in
depressed patients; activity in this region is increased during
manic episodes
Major Affective Disorders
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Evidence for brain abnormalities
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Silent cerebral infarctions
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A small cerebrovascular accident (stroke) that causes minor brain
damage without producing obvious neurological symptoms
Appears to be a major cause of late-onset depression (first occurs
later in life)
Risk factors are similar for stroke (e.g. smoking, hypertension)
Major Affective Disorders
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Role of circadian rhythms
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One of the most prominent symptoms of depression is
disordered sleep
Sleep of depressed individuals is shallow, Stages 3 & 4 are
reduced, Stage 1 is increased
REM sleep occurs earlier
Selective deprivation of REM sleep alleviates depression
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Successful ECT treatments suppress REM sleep in depressed
patients
Total sleep deprivation produces immediate effects
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The effect occurs slowly like that of drugs
Other treatments for depression suppress REM sleep, suggesting
that REM sleep and mood may be correlated
Perhaps, during sleep a substance is produced that has a
depressogenic effect
Depressed patients whose moods fluctuate more often will
benefit from sleep deprivation more
Major Affective Disorders
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Role of Zeitgebers
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Seasonal affective disorder – a mood disorder characterized by
depression, lethargy, sleep disturbances, and craving for
carbohydrates during the winter season when days are short
Summer depression – a mood disorder characterized by
depression, sleep disturbances, and loss of appetite
Seasonal affective disorder appears to have a genetic basis
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Molecular genetic studies suggest that seasonal affective disorder
may be linked to genes involved in production of the 5-HT
transporter and the 5-HT2A receptor
SAD can be treated with phototherapy, treatment of exposing
people to bright light for several hours a day