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Dopamine hypothesis of schizophrenia

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The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing symptoms of schizophrenia (like psychoses) to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia.

Introduction

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

Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine, or phencyclidine (Angel Dust)[citation needed], or excess steroids[citation needed], or by removing various genes (COMT, DBH, GPRK6, RGS9, RIIbeta), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D2 receptors in the high-affinity state for dopamine.[1] This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical.

Discussion

Evidence for the dopamine hypothesis

Some of the most obvious evidence for this theory is from the effects of drugs such as amphetamine and cocaine. Tobacco use is also strongly associated with schizophrenia. These drugs (and others like them) alter levels of dopamine in certain parts of the brain and can cause symptoms which resemble those present in 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 the positive symptoms associated with schizophrenia. Similarly, those treated with dopamine enhancing levodopa for Parkinson's disease can experience psychotic side effects mimicking the symptoms of schizophrenia. Up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of methylphenidate or amphetamine or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.[2][3] 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. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia.[4]

Another important development was the serendipitous discovery that a group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, antagonized dopamine binding (particularly at receptors known as D2 dopamine receptors) and reduced positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenones including haloperidol. This link was strengthened by experiments in 1970s which suggested that the binding affinity of antipsychotic drugs for D2 dopamine receptors seemed to be inversely proportional to their therapeutic dose. This correlation, suggesting that receptor binding is causally related to therapeutic potency, was reported by two laboratories in 1976.[5][6]

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 include COMT, DRD4, and AKT1.[7]

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. This primarily occurs in patients who have had the psychosis for ten to thirty years. At least 90-95% of first-episode patients, however, respond to antipsychotics at low doses and do so with D2 occupancy of 60-70%. The antipsychotic aripiprazole occupies over 90% of D2 receptors, but this drug is both an agonist and an antagonist at D2 receptors.

Furthermore, although dopamine-inhibiting medications modify dopamine levels within minutes, the associated improvement in patient symptoms is usually not visible for at least several days, suggesting that dopamine may be indirectly responsible for the illness.[8]

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, particularly the negative symptoms, despite the fact that they have lower affinity for dopamine receptors than for various other neurotransmitter receptors.[9] More recent work, however, has shown that atypical antipsychotic drugs such as clozapine and quetiapine bind and unbind rapidly and repeatedly to the dopamine D2 receptor.[10]

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, but may also involve other neurotransmitters.[11]

Similarly, there is now 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.[12] It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions.

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. Such socio-economic-cultural factors can become highly stressful to certain individuals, such as immigrants, markedly altering their brain chemistry, including dopamine, and can be associated with increased risk to psychotic episodes.

Psychiatrist David Healy has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as a deliberate and calculated simplification for the benefit of drug marketing.

See also

References

  1. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15716360, please use {{cite journal}} with |pmid=15716360 instead.
  2. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1007/BF00216006, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1007/BF00216006 instead.
  3. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15339823, please use {{cite journal}} with |pmid=15339823 instead.
  4. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 3726006, please use {{cite journal}} with |pmid=3726006 instead.
  5. ^ Creese I, Burt DR, Snyder SH (1976). "Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs". Science (journal). 192 (4238): 481–3. PMID 3854. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/261717a0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/261717a0 instead.
  7. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18497888, please use {{cite journal}} with |pmid=18497888 instead.
  8. ^ R. Thompson, The Brain, ISBN 0716714620
  9. ^ Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.
  10. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/sj.npp.1301305, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/sj.npp.1301305 instead.
  11. ^ "Daring to Think Differently about Schizophrenia". New York Times, February 24, 2008. http://www.nytimes.com/2008/02/24/business/24drug.html?_r=1&ei=5087&em=&en=6a0e8fe7296833ff&ex=1204002000&pagewanted=all&oref=slogin.
  12. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15716360, please use {{cite journal}} with |pmid=15716360 instead.
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