Transcript How antipsychotics become anti-”psychotic” –from dopamine to

How antipsychotics become anti”psychotic” –from dopamine to
salience to psychosis
Kristoffer Lien
Abstract
• The relationship between dopamine, psychosis and
antipsychotic drugs has been challenged by the
suggestion that there is a delay of weeks between
the receptor blockade and the improvement in
psychosis.
• New data: There is no delay. Dopamine is part of
reward system  link to psychosis
• Psychosis is the result of disordered dopamine
transmission
Antipsychotic drugs
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Work by blocking the dopamine pathway
1st drug, Chlorpromazine
New generations, also dopamine block
The blockade of D2 receptors starts
immediatly, but the antipsychotic effect is
delayed for several weeks This has been a
paradox for many years
Not delayed
• New data suggest that the response in fact is not
delayed
• Within 24 hours, a response previously believed to
be a sedative side effect, has now proved to be the
first manifestations of an antipsychotic effect
•  Strengthens the position of dopamine
transmission dysregulation as the major factor
leading to psychosis
Why dopamine?
• Dopamine has a central role in the ”reward and
reinforcement” system.
• Influence how we respond to new experiences in
the environment
• On a longer time scale, this then becomes the basis
of motivational drive
• Motivational drive: reward associated stimulus
becomes the centre of goal directed behaviour
Why dopamine?
• Dopamine has a major role in reward to
new stimuli, motivation towards these,
and goal-directed behaviour.
Psychosis
• Hypothesis: Genetic and environmental
predispositions result in dysregulated
dopamine system
•  In psychosis, dopamine is released
independent of cue and context
Psychosis
• Under normal conditions this system is a
mediator of context-driven understanding
and elevation. In a psychotic state it
becomes the creator of an abnormal ideation
and the false feeling of importance attached
to it.
Manifestations
• The patient starts to feel different about a
person or an object, described as “ having
sharper senses” or as a “strange fascination
of simple, familiar things” by the patient
• There is a gradually increasing sense of
confusion caused by these new feelings,
until everything finally condenses into a
delusion.
Explanation
• A delusion can be seen as the creation of some
kind of “new reality, or new insight”, where all the
strange feelings and perceptions suddenly “make
perfect sense” to the patient
• When the world around the patient doesnt fit his
or her perception of it  the creation of a ”new
world” becomes the only solution
• All delusions are created by the patient, and are
therefore influenced by this. One may for example
find delusions typical for certain cultural
backgrounds.
The need of medication
• Sooner or later delusions and hallucinations
will cause a change in behaviour, and this is
when the patient is brought to care and
administration of antipsychotics is usually
given.
Problems associated with
treatment
• Antipsychotics create a state of psychic
indifference and emotional restriction
• By blocking the dopamine transmission,
antipsychotics dampen the motivational drive, and
thus also attenuate the emotional dimension
• This means that antipsychotics do not “treat” the
delusions, but they dampen the emotional and
motivational drive to form new abnormal beliefs,
and the patient will also loose interest in the
already established saliences
Problems associated with
treatment
• Antipsychotic therapy will dampen
dopamine mediation of all levels of
emotional and motivational drive, including
normal processes. This leads to an
unpleasant, dysphoric state, and as a result
non-compliance with these medications
continues to be high.
Problems associated with
treatment
• When antipsychotic treatment is stopped,
the endogenous-dopaminergic-system is reactivated
• The psychotic symptoms reappear, and the
same ideas, schemes and percepts become
reinvested
• Two different episodes in one patient are
very similar
Conclusion
• Some patients do not respond to even complete D2
blockade. This emphasizes that not everything can
be explained by the dopamine pathway, but
indicate that there must be other factors involved
as well
• This may explain differences in effect in different
antipsychotics
• According to this study, any drug with an impact
on reward and salience should have an influence
on psychosis. This may be used as an approach in
future experiments
Conclusion
• This study is based on incomplete
knowledge related to schizophrenia and
dopamine system. Future studies may reveal
whether this text is a useful approach in
bridging clinical data with scientific reports
or just a strange ideation harboured by the
author.
Resources
• Based on the article ”How antipsychotics
become anti-”psychotic” – from
dopamine to salience to psychosis” by
Shitij Kapur