ANTIPSYCHOTIC DRUGS

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PSYCHOSIS

• A syndrome of chronic disordered thinking and
  disturbed behavior (schizophrenia, mania,
  depression)
• Deficits in integrating thought and perception
  with emotion (some refer to a loss of cognitive
  control)
• ?paranoid delusions/thought insertion/ideas of
  reference
• ?hallucinations (generally auditory, but can be
  visual)
• ?loss of affect/poverty of speech/social
  withdrawal
• ?impaired ability to function with others
• ?idiopathic or organic etiology
• Prevalence of schizophrenia 1 of population
  worldwide

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MENTAL ILLNESSES

• Environmental factors
• Maturational factors
• Neuronal connectivity
• Neurotransmitters
• Receptors/drug targets

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Schizophrenia

• Environmental Factors
• Exposure to infections Toxic/Traumatic
  ( in utero) Insults
• ALTERATIONS IN NEURODEVELOPMENT
• Autoimmunity Stress during gestation or
  early in childhood/adolescence

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Maturational Processes

• Apoptosis Synaptic Pruning Myelination
  (prenatal to adolescence)

Unmasking Genetic Vulnerability
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Neuronal Plasticity

• Structural changes during development and in
  response to environmental factors
• Changes in neurotransmitter activity in response
  to environmental factors
• Neurotrophic factors and changes in gene
  transcription
• (eg. neuroregulin-1 which regulates neuronal
  migration)
• Continues throughout life of the organism
• Underlies learning and memory

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NEURONAL CONNECTIVITY

• Functional activity in neocortex of schizophrenic
  patients may be decreased
• Myelination
• Synaptic pruning
• Hormonal effects of puberty
• Exposure to stressors
• Defective connections in midbrain, nucleus
  accumbens, thalamus, temporo-limbic and
  prefrontal cortex

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STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA

• Schizophrenics show deficits in tasks involving
  prefrontal cortex or those requiring working
  memory
• Prefrontal cortical thickness is reduced 5-10,
  neuron size is down, but no change in neuron
  number
• Synaptic connectivity is reduced
• Medial dorsal thalamus shows 30 reduction in
  neuron number
• Prefrontal cortex receives fewer projections from
  the thalamus
• Hippocampus shows altered cytoarchitecture

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The Dopamine Hypothesis

• Schizophrenia results from excess activity of
  dopamine neurotransmission
  because
• ALL antipsychotic drugs block dopamine
  receptors.
• Stimulant drugs which act through dopamine can
  produce schizophrenic-like
  behaviors (eg.amphetamines).
• Levodopa, a dopamine precursor, can exacerbate
  schizophrenic symptoms, or occasionally elicit
  them in non-schizophrenic patients.
• Higher levels of dopamine receptors measured in
  brains of schizophrenics.
• Brain DA increases during psychotic episodes
  but not during remissions.

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A HYPOTHESIS IN TRANSITION

• All antipsychotic drugs which block dopamine
  receptors do not reverse all symptoms
• positives are more responsive
• negatives may even be exacerbated
• Antipsychotics blocking DA and 5-HT receptors
  seem better for both positive and negative
  symptoms
• NMDA glutamate--based on effects of PCP in humans
• DA metabolites in CSF plasma not significantly
  elevated in schizophrenics
• Antipsychotic drugs block DA receptors
  immediately but antipsychotic benefits take
  several days to weeks to occur

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New Findings
Polymorphism of COMT gene with increased activity
and more efficient metabolism of DA leading
to lower than normal prefrontal cortex DA
releasehypofrontality Polymorphism of ?-7
nAChR on chromosome 15 as cause of disturbance in
sensory gatingnormalized by nicotine Partial
D-2 agonist and 5-HT-2/5-HT-1a antagonist
effective for positive/negative symptomatology
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DOPAMINE RECEPTORS THE HOLY GRAIL FOR
ANTIPSYCHOTIC MEDS?

• Dopamine recognized as a neurotransmitter in the
  1950s
• Five dopamine receptor subtypes D-1,-2,-3,-4,-5
• Drug naive schizophrenics show elevated D2
  receptor number
• Cortex has much higher amounts of D1 than D2
  receptors
• chronic antipsychotic drugs downregulate D1s in
  the cortex and striatum

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THE HOLY GRAIL FOR MEDS, CONTD

• Striatum has high concentrations of D1 D2
  receptors
• All effective antipsychotics possess some
  threshold level of D2 receptor blockade
• striatal D2s may be the site for antipsychotic
  drug-induced movement disorders
• clozapine upregulates cortical D2s at doses that
  do not affect striatal D2s
• Limbic structures contain high concentrations of
  D4s
• clozapine has high affinity for D4s, but
  selective D4 antagonists fail to show
  antipsychotic efficacy
• Serotonin inhibits dopamine neurotransmission
• atypicals show serotonin binding ability

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DRUG TARGETS,CONTD

• The newer atypicals have the ability to block
  the behavioral effects of phencyclidine (PCP)
• PCP elicits behavioral/ cognitive symptoms
  indistinguishable from schizophrenia
• PCP is an uncompetitive blocker of NMDA-glutamate
  ion channel function

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NEUROTRANSMITTERS

• Overactivity of dopamine in limbic regions
  (positive symptoms?)
• Abnormalities in dopamine storage, vesicular
  transport, release or reuptake
• NMDA-glutamate hypofunction (negative symptoms?)

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ANTIPSYCHOTIC DRUGS

• no compound can target a given symptom
• therapeutic effects correlated to potency at D-2
  dopamine receptors
• all have effects on other non-dopamine receptors
  (side-effects, or therapeutic effects)
• can also be used for Tourettes, control of acute
  mania, intractable hiccups, choreas and ballisms

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DRUG TARGETS

• Dopamine receptors D1, D2, D3, D4, D5
• Serotonin receptors 5-HT-1A, 2A, 3, 6, 7
• Norepinephrine ?-1 ?-2
• Muscarinic acetylcholine mACh-1 4
• Histamine H-1 2
• Dopamine, norepinephrine serotonin transporters
• NMDA-glutamate receptor

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Dopamine Receptors
Occupancytherapeutic vs. side effects At
therapeutic doses the classical antipsychotics
occupy gt75 of dopamine D-2 receptors. 85
occupancy needed to get extrapyramidal side
effects. Clozapine, the atypical, blocks only
35 D-2 receptors at therapeutic doses.
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DRUG CLASSES

• Phenothiazines eg. chlorpromazine
• Thioxanthenes
• Butyrophenones eg. haloperidol
• Diphenylbutylpiperidine
• Dihydroindolone
• Dibenzoxazepines eg. clozapine
• Benzisoxazol eg. risperidone

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PHARMACOLOGICAL PROPERTIES

• Neuroleptic syndrome
• suppression of spontaneous behavior
• loss of initiative and interest (anhedonia)
• loss of affect and emotional content
• slowness of movement
• Parkinson-like extrapyramidal effects
• Unpleasant when given to non-psychotic individual

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TYPE MANIFESTATIONS MECHANISM
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Spectrum of Adverse Effects Caused by
Antipsychotic Drugs

• Low Potency
• Fewer extrapyramidal reactions (especially
  thioridazine)
• More sedation, more postural hypotension
• Greater effect on the seizure threshold,
  electrocardiogram (especially thioridazine)
• More likely skin pigmentation and
  photosensitivity
• Occasional cases of cholestatic jaundice
• Rare cases of agranulocytosis

• High Potency
• More frequent extrapyramidal reactions
• Less sedation, less postural hypotension
• Less effect on the seizure threshold, less
  cardiovascular toxicity
• Fewer anticholinergic effects
• Occasional cases of neuroleptic malignant
  syndrome

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SIDE EFFECTS, contd.

• Parkinsonian syndrome
• neuroleptic malignant syndrome
• akathisia
• acute dystonic reactions
• tardivie dyskinesia

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Comparison of Tardive Dystonia and
Tardive Dyskinesia

• Tardive dystonia
• Strikes younger
• Strikes sooner in the course of neuroleptic
  treatment
• Poor prognosis
• More males
• Patients with mood disorders may be more
  susceptible
• Anticholinergics may improve condition

• Tardive dyskinesia
• Strikes older
• Strikes later in the course of neuroleptic
  treatment
• Variable prognosis
• More females (?)
• Patients with mood disorders may be more
  susceptible
• Anticholinergics usually worsen condition

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TABLE 6. Comparison of Tardive Dystonia and
Tardive Dyskinesia

• Tardive dystonia
• Strikes younger
• Strikes sooner in the course of neuroleptic
  treatment
• Poor prognosis
• More males
• Patients with mood disorders may be more
  susceptible
• Anticholinergics may improve condition

• Tardive dyskinesia
• Strikes older
• Strikes later in the course of neuroleptic
  treatment
• Variable prognosis
• More females (?)
• Patients with mood disorders may be more
  susceptible
• Anticholinergics usually worsen condition

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SIDE EFFECTS

• Autonomics--related to blockade of alpha-
  adrenergic and muscarinic receptors
• Endocrine effects, primarily prolactin increases
• Disruption of thermoregulatory control
• Hypersensitivity reactions eg. agranulocytosis
  with clozapine browning of vision with
  thioridizine

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Stress Schizophrenia

• Schizophrenic patients have altered sensitivity
  to stress
• They display abnormalities in autonomic nervous
  system and hypothalmic-pituitary adrenal function
  in response to stress
• Coping abilities seem best preserved in
  schizophrenics who suffer the least negative
  symptoms
• Cognitive deficits in schizophrenics may cause
  them to be less well adapted to their environment
• Schizophrenics have difficulty filtering incoming
  sensory stimuli

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Indications for Antipsychotic Drugs
Schizophrenia Schizoaffective disorders Acute
control of mania Tourettes syndrome Huntington
s chorea and ballism Intractable hiccups