Dopamine hypothesis of schizophrenia

The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a theory that argues that the unusual behaviour and experiences associated with schizophrenia (sometimes extended to psychosis in general) can be fully or largely explained by changes in dopamine function in the brain.

Some researchers have suggested that overactivity of dopamine systems in the mesolimbic pathway may contribute to the 'positive symptoms' of schizophrenia (such as delusions and hallucinations), whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such as avolition, flat emotional response and alogia.

This theory is now thought to be too simple to be a complete explanation for the development of psychosis and schizophrenia, although it has been instrumental in motivating experiments which have highlighted the role of dopamine in psychotic states.

Contents

Evidence for the dopamine hypothesis

Some of the most obvious evidence for this theory is from the effect of drugs such as amphetamine and cocaine. These drugs (and others like them) increase levels of dopamine in the brain and can cause psychosis, particularly after large doses or prolonged use. This is often referred to as 'amphetamine psychosis' or 'cocaine psychosis', but may produce experiences virtually indistinguishable from psychosis associated with schizophrenia.

Another important development was an accidental discovery that a group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine and haloperidol, blocked dopamine uptake (particularly at receptors known as D2 dopamine receptors) and reduced psychotic symptoms.

This link was strengthened by experiments in the 1980s which suggested that the affinity of antipsychotic drugs for the D2 dopamine receptor family seemed to be correlated with the reduction of psychotic symptoms.

More recent experimental studies have shown that amphetamine increases the level and intensity of psychotic symptoms in people who already have, or are liable to psychosis. Some functional neuroimaging studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals.

Genetic evidence has suggested that there may be genes, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Dopamine related genes linked to psychosis in this way included COMT and DRD4.

Evidence against the dopamine hypothesis

Further experiments, conducted as new methods were developed (particularly the ability to use PET scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D2 receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses, suggesting that dopamine overactivity was not a complete explanation.

Similarly, a new generation of antipsychotic drugs (called the atypical antipsychotics) were found to be just as effective as older typical antipsychotic drugs in controlling psychosis, but actually blocked less dopamine receptors. With the exception of amisulpride, the newer antipsychotic drugs have an additional effect on serotonin function, suggesting that other neurotransmitters are important.

The excitatory neurotransmitter glutamate is now also thought to be associated with schizophrenia. Phencyclidine (also known as PCP or 'Angel Dust') and ketamine, both of which block glutamate (NMDA) receptors, are known to cause psychosis closely resembling schizophrenia, further suggesting that psychosis and schizophrenia cannot fully be explained in terms of dopamine function.

Similarly, there is now a great deal of evidence to suggest there may be a number of functional and structural anomalies in the brains of some people diagnosed with schizophrenia, such as changes in grey matter density in the frontal and temporal lobes.

Psychiatrist David Healy has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as it makes for an easy explanation for doctors to understand and communicate to their patients, and implies that drugs which effect dopamine (i.e. antipsychotics) are a 'cure'. Healy argues that this is deliberate simplification of a complex disorder for the benefit of drug marketing.

Other evidence suggests that social and environmental factors are important in explaining how either schizophrenia, or specific episodes of psychosis, are triggered. This research has led people to argue that a purely biological explanation, without reference to social, cultural or environmental factors will never fully explain such phenomena.

See also

Further reading

  • Healy, D (2002) The Creation of Psychopharmacology. ISBN 0674006194
  • Jones, H. M., & Pilowsky, L. S. (2002) (http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12356650&dopt=Abstract) Dopamine and antipsychotic drug action revisited. British Journal of Psychiatry, 181, 271-275. Full text (http://bjp.rcpsych.org/cgi/content/full/181/4/271)
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