french antipsychotic 4-14-10 presentation
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PSYCHOSIS#A syndrome of chronic disordered thinking and disturbed
behavior (schizophrenia, mania, depression)
Deficits in integrating thought and perception withemotion (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 populationworldwide
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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 responseto 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 inneocortex ofschizophrenic patientsmay be decreased
Myelination Synaptic pruning
Hormonal effects ofpuberty
Exposure to stressors
Defective connections inmidbrain, nucleusaccumbens, thalamus,temporo-limbic andprefrontal cortex
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STRUCTURAL BRAIN
CHANGES IN SCHIZOPHRENIA Schizophrenics show deficits
in tasks involving prefrontalcortex or those requiringworking memory
Prefrontal cortical thicknessis reduced 5-10%, neuron
size is down, but no changein neuron number
Synaptic connectivity isreduced
Medial dorsal thalamusshows 30% reduction inneuron number
Prefrontal cortex receivesfewer projections from thethalamus
Hippocampus shows altered
cytoarchitecture
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The Dopamine HypothesisSchizophrenia results from excess activity of
dopamine neurotransmission because:
ALL antipsychotic drugs block dopamine
receptors.
Stimulant drugs which act through dopamine canproduce 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 allsymptoms
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 butantipsychotic 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
release=hypofrontality
Polymorphism of-7 nAChR on chromosome 15 as cause of
disturbance in sensory gating=normalized 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
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DOPAMINE RECEPTORS: THE
HOLY GRAIL FOR
ANTIPSYCHOTIC MEDS?
Dopamine recognized as aneurotransmitter in the
1950s Five dopamine receptor
subtypes: D-1,-2,-3,-4,-5
Drug naive schizophrenicsshow elevated D2 receptornumber
Cortex has much higheramounts of D1 than D2receptors
chronic antipsychotic drugsdownregulate D1s in the
cortex and striatum
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THE HOLY GRAIL FOR MEDS,CONTD
Striatum has high concentrations of D1 & D2receptors
All effective antipsychotics possess some threshold
level of D2 receptor blockade striatal D2s may be the site for antipsychotic drug-inducedmovement disorders
clozapine upregulates cortical D2s at doses that do notaffect 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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DopamineReceptors
Occupancytherapeutic vs. sideeffects
At therapeutic doses the classical
antipsychotics occupy >75% of dopamineD-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
Autonomic nervous
system
Dry mouth, loss of
accommodation; difficultyurinating, constipation
Muscarinic blockade
Orthostatic hypotension,
impotence, failure to ejaculate
Alpha adrenergic
blockade
Central nervoussystem
Parkinsons syndrome; akathisia,dystonia
Dopamine receptorblockade
Tardive dyskinesia Dopamine receptor
supersensitivity
Toxic confusional state Muscarinic blockade
Endocrine system Galactorrhea; amenorrhea;
infertility, impotence
Hyperprolactinemia
secondary to dopamine
receptor blockade
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Spectrum of Adverse Effects Caused by
Antipsychotic Drugs
Low PotencyFewer extrapyramidal reactions
(especially thioridazine)
More sedation, more postural
hypotensionGreater effect on the seizure
threshold, electrocardiogram(especially thioridazine)
More likely skin pigmentation andphotosensitivity
Occasional cases of cholestaticjaundice
Rare cases of agranulocytosis
High PotencyMore 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 susceptibleAnticholinergics 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 susceptibleAnticholinergics 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 susceptibleAnticholinergics 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 susceptibleAnticholinergics 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 alteredsensitivity to stressThey display abnormalities in autonomic nervous
system and hypothalmic-pituitary adrenal function inresponse to stress
Coping abilities seem best preserved inschizophrenics who suffer the least negativesymptoms
Cognitive deficits in schizophrenics may cause themto be less well adapted to their environment
Schizophrenics have difficulty filtering incomingsensory stimuli
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Indications for Antipsychotic Drugs
Schizophrenia
Schizoaffective disorders
Acute control of mania
Tourettes syndrome
Huntingtons chorea and ballism
Intractable hiccups
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