Schizophrenia and the Affective Disorders

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Chapter 16

• Schizophrenia and the Affective Disorders

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Schizophrenia

• 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
• Thought disorders disorganized, irrational
  thinking (most important symptom)
• Delusions a belief that is clearly in
  contradiction to reality
• Persecution false beliefs that others are
  plotting against oneself
• Grandeur false beliefs in ones own power
• Control belief that one is being controlled by
  others
• Hallucinations perception of a nonexistent
  object or event

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Schizophrenia

• Negative symptoms characterized by the absence
  of behaviors that are normally present
• Flattened emotional response
• Poverty of speech
• Lack of initiative and persistence
• Inability to experience pleasure
• Social withdrawal
• Heritability
• 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 envtal event
• Study shows that higher paternal age is
  positively correlated with diagnosis of
  schizophrenia

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Pharmacology of Schizophrenia

• Dopamine hypothesis suggest that schizophrenia
  is caused by overactivity of DA synapses,
  probably those in the mesolimbic pathway
• Effects of DA agonists and antagonist
• 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

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Pharmacology of Schizophrenia

• Effects of DA agonists and antagonist
• 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
• Amygdala is involved with conditioned emotional
  responses for aversive events
• DA transmission abnormalities
• DA neurons may release more DA
• 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

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Pharmacology of Schizophrenia

• Long-term drug treatment
• The symptoms of up to 1/3 of all schizophrenic
  patients are not substantially reduced by
  antipsychotic drugs
• Many drugs produce serious side effects
• Until recently, all drugs caused at least some
  symptoms resembling those of Parkinsons disease
  slow movement, lack of facial expression, general
  weakness
• Tardive dyskinesia a movement disorder that can
  occur after prolonged treatment with
  antipsychotic medication, characterized by
  involuntary movements of the face and neck
• Caused by overstimulation of DA receptors
• Why would antagonists cause overstimulation of DA
  receptors?
• 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)

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Schizophrenia as a neurological disorder

• 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
• 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
• Relative size of lateral ventricles was more than
  twice the size of control subjects

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Schizophrenia as a neurological disorder

• Possible causes of brain abnormalities
• Why do less than ½ the children of schizophrenic
  patients become schizophrenic?
• 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 envt
• People born during late winter and early spring
  are more likely to develop schizophrenia
  seasonality effect
• Possibly caused by higher likelihood of mother
  contracting viral illness
• Also more likely to occur in cities rather than
  countryside

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Schizophrenia as a neurological disorder

• Possible causes of brain abnormalities
• People born far from the equator are more likely
  to develop schizophrenia latitude effect
• 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
• Red blood cells of Rh-positive person contain Rh
  factor
• If fetus is Rh incompatible with mother, then
  increased likelihood of schizophrenia in offspring

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Schizophrenia as a neurological disorder

• Evidence for abnormal brain development
• Prenatal brain development of children who become
  schizophrenic is not normal
• 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
• Does not involve death of neurons, but a loss of
  neuropil,the network of dendrites and axons in
  the brain

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Schizophrenia as a neurological disorder

• Positive and negative symptoms Prefrontal cortex
• 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
• May be caused by decrease in release of DA in
  prefrontal cortex, mediated mostly by D1
  receptors
• Chronic abuse of PCP (indirect glutamate
  antagonist) causes a decrease of metabolic
  activity in frontal lobes
• 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)
• Clozapine causes an increase in DA release in
  prefrontal cortex, and decrease of DA release in
  nucleus accumbens

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Major Affective Disorders

• 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

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Major Affective Disorders

• Heritability
• The tendency to develop a major affective
  disorder is heritable
• A single dominant gene is responsible for
  susceptibility to developing bipolar disorder
• Physiological treatments
• MAO inhibitors
• 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
• Tricyclic antidepressants
• 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)
• Inhibit reuptake of 5-HT
• Widely prescribed for depression and for symptoms
  of OCD and social phobia

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Major Affective Disorders

• Physiological treatments
• Electroconvulsive therapy (ECT)
• 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
• 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

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Major Affective Disorders

• Role of monoamines
• 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
• e.g. reserpine
• Suicidal depression is related to decreased CSF
  levels of 5-HIAA, 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
• Suggests that 5-HT metabolism or release is
  genetically controlled and is linked to depression

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Major Affective Disorders

• Role of monoamines
• Tryptophan depletion procedure
• 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
• This has no effect on healthy, non-depressed
  subjects, but does lower the mood of people with
  a family history of affective disorders

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Major Affective Disorders

• A role for Substance P?
• 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

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Major Affective Disorders

• Evidence for brain abnormalities
• 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
• 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

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Major Affective Disorders

• Evidence for brain abnormalities
• Silent cerebral infarctions
• 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)

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Major Affective Disorders

• Role of circadian rhythms
• 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
• The effect occurs slowly like that of drugs
• Other treatments for depression suppress REM
  sleep, suggesting that REM sleep and mood may be
  correlated
• Successful ECT treatments suppress REM sleep in
  depressed patients
• Total sleep deprivation produces immediate
  effects
• 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

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Major Affective Disorders

• Role of Zeitgebers
• 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
• 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