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Lecture 16

PHAR 301 Lecture Notes - Lecture 16: Arvid Carlsson, Atypical Antipsychotic, Positron Emission Tomography

Pharmacology and Therapeutics
Course Code
PHAR 301
Barbara Hales

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March 17, 2016
Phar 301
Lecture 16: Drugs for Psychosis
Drugs to know by name:
Chlorpromazine (PCZ) - the first typical antipsychotic
Haloperidol (Haldol) - a typical antipsychotic
Clozapine - an atypical antipsychotic
Phencyclidine (PCP)
Terms to know:
EPS (extrapyrimidal symptoms, i.e. Parkinson-like motor impairment)
APD = antipsychotic drug
Typical antipsychotic = first-generation = classical = traditional
Atypical antipsychotic = second-generation (i.e. little or no EPS, little or no increase in prolactin, little or no tardive dyskinesia)
Neuroleptic (an antipsychotic that produces EPS, especially catalepsy)
Depolarization block
Mesolimbic dopamine pathway
Nucleus accumbens (main terminal area for mesolimbic DA pathway)
Positron emission tomography (PET)
Brody Chapter 29 - Treatment of psychotic disorders
Ignore pharmacokinetics section and Table 29-1
Do not neglect the part about side-effects
Louis Waine
He was a well-known illustrator in the Victorian error
Got late-onset schizophrenia
Is not split personality
It's defined by symptoms
o Positive symptoms
Hallucinations (usually auditory)
Thought disorders
o Negative symptoms
Blunted emotions (i.e. flattened affect)
Emotional and social withdrawal
Poor rapport
Lack of spontaneity
o Cognitive
Poor memory
Poor abstract thinking
o There is a broad spectrum for this disorder; some people have only positive symptoms, others have both positive and
negative, etc.
o Is schizophrenia a single disorder or a number of discrete syndromes?
o Does schizophrenia progress from positive symptoms to negative symptoms?
o See Van Os and Kapur (2009)

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March 17, 2016
Phar 301
It's fundamentally a thought disorder which causes emotional withdrawal
What helps to cause schizophrenia?
Approximately a 0.5-1% prevalence
o Genetic
o Environmental
o Developmental disorder
o Virus
o Stress
o Structural changes in the brain
Thinning of the cortical mantle
Increase in the size of the ventricular space in the brain
But it's not a suitable biological test for schizophrenia because other disorders can show the same symptom
o Disordered (DA, neurotransmission)
Your lifetime risk of schizophrenia is much higher if a close relative has the disease
There is no biological test for schizophrenia; it is based on questionnaires and interviews
The discovery of antipsychotic drugs
Crude techniques were used to cure schizophrenia
Used a mixture of carbon dioxide and oxygen to put people into a coma; intended to shock people out of their illness
Henri Laborit (1914-1995)
o His success rates with surgeries was going down
o Thought that it was due to anxiety and the release of histamine
o Chlorpromazine, as an anti-histamine, was used on his patients
o He saw that chlorpromazine put his patients in a happy, calm state and suggested to psychiatrists to use it on
schizophrenic patients
o It didn't work at first
Delay and Deniker (1951)
o Found that chlorpromazine made patients less crazy
o Found that it calmed down the patients but it didn't sedate them as a barbiturate would
o They produced extrapyrimidal side-effects (EPS); Parkinson-like symptoms
o Was a "neuroleptic" (i.e. EPS-causing)
o It was not a "chemical straightjacket" - where they're more manageable but not actually happy
As long as the doses were in a moderate range, it was not a chemical straightjacket
Heinz Lehmann, 1954
o Was a McGill professor

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March 17, 2016
Phar 301
o Fluent in German, French, and English
o Was able to read European journals and quickly found out about Chlorpromazine
o Noticed that early psychotic drugs caused patients to have a shuffling gait, mask-like face, and didn't swing their arms
o Though patients improved a lot, they never became quite normal
It had a delayed response
There were adverse effects
Negative symptoms were unresponsive to the drugs
The neuroleptic revolution
o Enabled thousands of patients to leave and go back to their communities
o Mental hospitals were emptied out
Antipsychotic drugs
o Provide only symptomatic relief
o Need to be taken long-term
o Are often not taken
o Patients may believe that these drugs are what's making them ill (conspiracy theory)
o Drugs block dopamine in the brain which takes away some motivation to take the pills
What are antipsychotic drugs?
Older antipsychotics
o Classical
o Typical
o Traditional
o First-generation
o e.g. chlorpromazine
Newer antipsychotics
o Atypical
o Second-generation
o e.g. clozapine
How to antipsychotic drugs act?
Is DA just a precursor for NA?
o It was believed so in the 1950s
o Someone found that in the striatum, there was a lot of DA but no NA
o It was found that DA was a neurotransmitter
How do neuroleptics work?
o Chlorpromazine
Reduces craziness and reduces EPS
o Reserpine
Has an effect on depression
It was also found to reduce craziness and reduce EPS
Discussed further in depression lecture
o Wanted to find a common mechanism of action between chlorpromazine and reserpine
o By 1955, people have figured out ways to measure neurotransmitter in brain tissue of animals
o People noted PD-like symptoms in rats and that reserpine greatly reduced DA, NA, and 5HT
o Arvid Carlsson found that chlorpromazine injected in a rat caused no change in DA tissue content
People thought that DA must be irrelevant then
Carlsson then found a way to measure DA metabolite content in tissue
He found the CPZ increase DA metabolites in rat brain
He electrically stimulated DA pathways in the brain and found that when you make neurons more active by
stimulating them, you get more DA metabolite levels in the striatum
CPZ was probably increasing the firing rate of dopamine cells
He got the same result with other antipsychotics
Concluded that antipsychotics increase the activity of the DA neuron
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