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The Unwell Brain
Disturbance in the
 The first discovery in the mid 1950s was that
chronic usage of large daily doses of
Amphetamines could produce a psychosis that
was virtually indistinguishable from schizophrenia.
 The second discovery was that Chlorpromazine
could improve symptoms for schizophrenia.
 The effects of Amphetamines and
Chlorpromazine on the neurochemistry of the
brain were unknown.
Further Discoveries
 It was found that Amphetamine could enhance
neurotransmission of Dopamine, Norepinephrine
and (to a lesser extent) Serotonin Synapses.
 It was also discovered that Chlorpromazine could
prevent Dopamine from activating it’s D2
receptor subtype.
 The knowledge that Chlorpromazine improves
symptoms of schizophrenia while blocking D2
receptors for Dopamine has led to the
development of drugs that have similar
pharmacological properties to chlorpromazine.
Neuroleptics & Atypicals
 The Neuroleptics (older generation) are identified
in two categories: Phenothiazines &
 Chlorpromazine (Thorazine) is the original
phenothiazine anti-schizophrenic drug.
 Haloperidol (Haldol) is the most familiar and
widely used butyrophenone.
 What do these drugs have in common and what
are their effectiveness with treating schizophrenic
Positive symptoms
 The symptoms that are the most responsive to these
types of drugs came to be called the ‘positive
symptoms’ because they showed a positive
response to neuroleptic drug therapy.
 These positive symptoms included: delusions,
hallucinations, disorganised speech and bizarre
 The negative symptoms included: flattened
emotional response, impoverished speech,
diminished initiative and motivation, social
withdrawal, lack of feeling pleasure (anhedonia)
and intellectual impairment.
D2 receptors
 Phenothiazines & Butyrophenones also share the
ability to bind to D2 dopamine receptors and act as
antagonists, thereby preventing endogenous
(proceeding from within) dopamine from activating
those receptors.
 Different phenothiazines & butyrophenones drugs
bind to D2 receptors to varying degrees, and also
alter neurochemical processes other than
 There is a correlation between the potency of the
drug and the ability to improve symptoms of
schizophrenia in a clinical setting.
“Problem Schizophrenics”
 Newer generation antipsychotics (Atypicals) can
be effective in these normally unresponsive
schizophrenics. They also lack some of the
debilitating side effects of the older neuroleptics.
 These newer generation antipsychotics appear
to block multiple subtypes of dopamine
receptors (including D1 D2 D3 D4 D5); they are
also reported to alter serotonin neurotransmission
and to effect several other neurotransmitters,
including, acetylcholine, norepinephrine, and
Clozapine (Clozaril)
 Clozapine is effective in some schizophrenics
whose symptoms do not improve on haloperidol.
A patient maintained on clozapine is less likely to
show side effects related to involuntary
movements (tardive dyskinesia). It tends not to
block the receptors for dopamine in the striatum
(could explain it’s lack of motor side effects).
 Haloperidol tends to block D2 receptors in the
caudate and putamen areas of the brain
whereas clozapine blocks D1, D2, D3, D4 and D5
receptors as well as multiple subtypes of
serotonin receptors.
Brain processes &
 Neuroimaging studies show that excessive D2
receptors have been found in the striatum and
frontal cortex.
 Dopamine D1 receptors are deficient in number
in the prefrontal cortex of schizophrenics. This
deficiency is correlated with some of the
negative symptoms of schizophrenia.
Dopamine Neurons
 Dopamine neuron cell bodies originate in the
Ventral Tegmental Area (VTA) and Substantia Nigra
 D2 abnormality appears to be localised in
mesolimbic and mesocortical dopamine neurons,
which connect the prefrontal cortex with
subcorticol areas, including the striatum, caudate,
putmen and hippocampus.
 The prefrontal cortical and limbic (hippocampus)
link may represent the key vulnerability for
development of schizophrenia, which has long
been considered to be a disorder of cognitive
(cortical) and emotional (limbic) interactions.
Clinical Effectiveness
 Older generation neuroleptics that block D2
receptors in the caudate/putamen regions is
presumed to have secondary effects on the basal
ganglia, thalamus, hippocampus, and cortex.
 The newer generation Atypicals, Risperidone
(Risperdal) can cause greater effects upon
dopamine neurotransmission in the frontal cortex
and the striatum. It’s ability to improve both positive
and negative symptoms may be due to it’s
simultaneous alteration of dopamine
neurotransmission and blockade of serotonin 5HT2A receptors in the cortex.