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
MENTAL ILLNESSES
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Environmental factors
Maturational factors
Neuronal connectivity
Neurotransmitters
Receptors/drug targets
Schizophrenia
Environmental Factors
Exposure to infections
( in utero)
Toxic/Traumatic
Insults
ALTERATIONS IN NEURODEVELOPMENT
Autoimmunity
Stress during gestation or
early in childhood/adolescence
Maturational Processes
Apoptosis
Synaptic Pruning Myelination (prenatal
to adolescence)
Unmasking Genetic Vulnerability
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
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
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
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.
A HYPOTHESIS IN TRANSITION
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All antipsychotic drugs which block dopamine receptors do not reverse all
symptoms
 positives are more responsive
 negatives may even be exacerbated
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Antipsychotics blocking DA and 5-HT receptors seem better for both
positive and negative symptoms
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NMDA glutamate--based on effects of PCP in humans
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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
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
DOPAMINE RECEPTORS: THE
HOLY GRAIL FOR
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
THE HOLY GRAIL FOR MEDS,
CONT’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
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 NMDAglutamate ion channel
function
NEUROTRANSMITTERS
Overactivity of dopamine in limbic regions
(positive symptoms?)
Abnormalities in dopamine storage, vesicular
transport, release or reuptake
NMDA-glutamate hypofunction (negative
symptoms?)
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 (sideeffects, or therapeutic effects)
• can also be used for Tourette’s, control of acute mania,
intractable hiccups, choreas and ballisms
DRUG TARGETS
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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
Dopamine Receptors
Occupancy—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.
DRUG CLASSES
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Phenothiazines: eg. chlorpromazine
Thioxanthenes
Butyrophenones: eg. haloperidol
Diphenylbutylpiperidine
Dihydroindolone
Dibenzoxazepines: eg. clozapine
Benzisoxazol: eg. risperidone
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
TYPE
MANIFESTATIONS
MECHANISM
Autonomic nervous
system
Dry mouth, loss of
accommodation; difficulty
urinating, constipation
Muscarinic blockade
Orthostatic hypotension,
impotence, failure to ejaculate
Alpha adrenergic
blockade
Parkinson’s syndrome; akathisia,
dystonia
Dopamine receptor
blockade
Tardive dyskinesia
Dopamine receptor
supersensitivity
Toxic confusional state
Muscarinic blockade
Galactorrhea; amenorrhea;
infertility, impotence
Hyperprolactinemia
secondary to dopamine
receptor blockade
Central nervous
system
Endocrine system
Spectrum of Adverse Effects Caused by
Antipsychotic Drugs
Low Potency
High 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
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
SIDE EFFECTS, cont’d.
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Parkinsonian syndrome
neuroleptic malignant syndrome
akathisia
acute dystonic reactions
tardivie dyskinesia
Comparison of Tardive Dystonia and
Tardive Dyskinesia
Tardive dystonia
Tardive dyskinesia
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
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
TABLE 6. Comparison of Tardive Dystonia and
Tardive Dyskinesia
Tardive dystonia
Tardive dyskinesia
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
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
SIDE EFFECTS
• Autonomics--related to blockade of alphaadrenergic and muscarinic receptors
• Endocrine effects, primarily prolactin
increases
• Disruption of thermoregulatory control
• Hypersensitivity reactions; eg.
agranulocytosis with clozapine; browning
of vision with thioridizine
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
Indications for Antipsychotic Drugs
Schizophrenia
Schizoaffective disorders
Acute control of mania
Tourette’s syndrome
Huntington’s chorea and ballism
Intractable hiccups