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PSYCHOSISPSYCHOSIS#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 referencehallucinations (generally auditory, but can be visual)loss of affect/poverty of speech/social withdrawalimpaired ability to function with othersidiopathic or organic etiology
Prevalence of schizophrenia: 1% of population worldwide
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MENTAL ILLNESSESMENTAL ILLNESSES
Environmental factors Maturational factors Neuronal connectivity Neurotransmitters Receptors/drug targets
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SchizophreniaSchizophrenia
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 ProcessesMaturational Processes
Apoptosis Synaptic Pruning Myelination (prenatal to adolescence)
Unmasking Genetic Vulnerability
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Neuronal PlasticityNeuronal 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 CONNECTIVITYNEURONAL 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 STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIACHANGES 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 HypothesisThe Dopamine HypothesisSchizophrenia 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 TRANSITIONA 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 FindingsNew 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 DOPAMINE RECEPTORS: THE HOLY GRAIL FOR HOLY GRAIL FOR
ANTIPSYCHOTIC MEDS?ANTIPSYCHOTIC MEDS?
Dopamine recognized as a neurotransmitter in the 1950’s
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 D1’s in the cortex and striatum
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THE HOLY GRAIL FOR MEDS, THE HOLY GRAIL FOR MEDS, CONT’DCONT’D
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,CONT’D
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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NEUROTRANSMITTERSNEUROTRANSMITTERS
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 DRUGSANTIPSYCHOTIC 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 Tourette’s, control of acute mania, intractable hiccups, choreas and ballisms
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DRUG TARGETSDRUG 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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DopamineDopamine ReceptorsReceptorsOccupancy—therapeutic vs. side effects
At therapeutic doses the “classical” antipsychotics occupy >75% 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 CLASSESDRUG CLASSES
• Phenothiazines: eg. chlorpromazine
• Thioxanthenes
• Butyrophenones: eg. haloperidol
• Diphenylbutylpiperidine
• Dihydroindolone
• Dibenzoxazepines: eg. clozapine
• Benzisoxazol: eg. risperidone
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PHARMACOLOGICAL PROPERTIESPHARMACOLOGICAL 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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TYPETYPE MANIFESTATIONS MANIFESTATIONS MECHANISM MECHANISM
Autonomic nervous system
Dry mouth, loss of accommodation; difficulty urinating, constipation
Muscarinic blockade
Orthostatic hypotension, impotence, failure to ejaculate
Alpha adrenergic blockade
Central nervous system
Parkinson’s syndrome; akathisia, dystonia
Dopamine receptor blockade
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 Spectrum of Adverse Effects Caused by Antipsychotic DrugsAntipsychotic Drugs
Low PotencyFewer extrapyramidal reactions
(especially thioridazine)More sedation, more postural
hypotensionGreater effect on the seizure
threshold, electrocardiogram (especially thioridazine)
More likely skin pigmentation and photosensitivity
Occasional cases of cholestatic jaundice
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, cont’d.SIDE EFFECTS, cont’d.
• Parkinsonian syndrome
• neuroleptic malignant syndrome
• akathisia
• acute dystonic reactions
• tardivie dyskinesia
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Comparison of Tardive Dystonia and Tardive Dyskinesia
Tardive dystoniaStrikes 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 dyskinesiaStrikes 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 dystoniaStrikes 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 dyskinesiaStrikes 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 EFFECTSSIDE 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 & SchizophreniaStress & Schizophrenia
Schizophrenic patients have altered sensitivity to stressThey 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 DrugsIndications for Antipsychotic Drugs
Schizophrenia
Schizoaffective disorders
Acute control of mania
Tourette’s syndrome
Huntington’s chorea and ballism
Intractable hiccups