Dopamine hypothesis of schizophrenia

Dopamine hypothesis of schizophrenia

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.

Contents

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 (PCP, Angel Dust)[1], 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.[2] 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

Amphetamine, cocaine and similar drugs increase levels of dopamine in 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.[3][4]

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.[5]

A group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, has been found to antagonize dopamine binding (particularly at receptors known as D2 dopamine receptors) and reduce positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenones including haloperidol. The 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.[6][7]

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.[8]

Tobacco use is strongly associated with schizophrenia, likely through dopamine modulation by nicotinic acetylcholine receptors.

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.[9]

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.[10] 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.[11]

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.[12]

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

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. ^ Carlsson, M. and Carlsson, A. (1990). Schizophrenia: A Sub cortical Neurotransmitter Imbalance Syndrome? Schizophrenia Bulletin, 16, (3). P. 425 – 430.
  2. ^ a b Seeman, P.; Weinshenker, D.; Quirion, R.; Srivastava, K.; Bhardwaj, K.; Grandy, K.; Premont, T.; Sotnikova, D. et al. (Mar 2005). "Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis" (Free full text). Proceedings of the National Academy of Sciences of the United States of America 102 (9): 3513–3518. Bibcode 2005PNAS..102.3513S. doi:10.1073/pnas.0409766102. ISSN 0027-8424. PMC 548961. PMID 15716360. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15716360.  edit
  3. ^ Lieberman, J. A.; Kane, J. M.; Alvir, J. (1987). "Provocative tests with psychostimulant drugs in schizophrenia". Psychopharmacology 91 (4): 415–433. doi:10.1007/BF00216006. PMID 2884687.  edit
  4. ^ Curran, C.; Byrappa, N.; Mcbride, A. (Sep 2004). "Stimulant psychosis: systematic review" (Free full text). The British journal of psychiatry : the journal of mental science 185 (3): 196–204. doi:10.1192/bjp.185.3.196. ISSN 0007-1250. PMID 15339823. http://bjp.rcpsych.org/cgi/pmidlookup?view=long&pmid=15339823.  edit
  5. ^ Jacobs, D; Silverstone, T (May 1986). "Dextroamphetamine-induced arousal in human subjects as a model for mania". Psychological medicine 16 (2): 323–9. doi:10.1017/S0033291700009132. ISSN 0033-2917. PMID 3726006.  edit
  6. ^ Creese I, Burt DR, Snyder SH (April 1976). "Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs". Science 192 (4238): 481–3. doi:10.1126/science.3854. PMID 3854. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=3854. 
  7. ^ Seeman, P.; Lee, T.; Chau-wong, M.; Wong, K. (1976). "Antipsychotic drug doses and neuroleptic/dopamine receptors". Nature 261 (5562): 717–719. Bibcode 1976Natur.261..717S. doi:10.1038/261717a0. PMID 945467.  edit
  8. ^ Arguello, A.; Gogos, A. (Jun 2008). "A signaling pathway AKTing up in schizophrenia" (Free full text). The Journal of clinical investigation 118 (6): 2018–2021. doi:10.1172/JCI35931. ISSN 0021-9738. PMC 2391280. PMID 18497888. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2391280.  edit
  9. ^ R. Thompson, The Brain, ISBN 0716714620
  10. ^ Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.
  11. ^ Richtand, M.; Welge, A.; Logue, D.; Keck Pe, R.; Strakowski, M.; Mcnamara, K. (Aug 2007). "Dopamine and serotonin receptor binding and antipsychotic efficacy" (Free full text). Neuropsychopharmacology 32 (8): 1715–1726. doi:10.1038/sj.npp.1301305. ISSN 0893-133X. PMID 17251913.  edit
  12. ^ "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.

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