How antipsychotics become antipsychotic from dopamine to salience

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 • • Work by blocking the dopamine pathway 1 st drug, Chlorpromazine New generations, also dopamine block The blockade of D 2 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 D 2 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