Murray_subbed.qxp 6/8/09 10:41 Page 23
Dopamine Dysfunction and Delusions, Hallucinations and Anhedonia
conditioning paradigm. They noted abnormal activation in the ventral dorsolateral system could be more related to positive symptoms, and
striatum in schizophrenia patients, together with difficulty in this could be overactive. There is preliminary evidence to suggest that
discriminating between motivational salient and neutral stimuli. positive psychotic symptoms are linked specifically to abnormalities
Specifically, patients activated the ventral striatum more towards in the ‘associative’ striatum (i.e. the head of the caudate nucleus).
neutral (motivationally irrelevant) stimuli than healthy controls. These Another possibility is that dopaminergic systems could be
results are consistent with a recent fMRI study of reward learning dysregulated; the dopamine neurons could be overactive
than my colleagues and I conducted in first-episode psychosis patients inappropriately, resulting in aberrant assignment of motivational
with active psychotic symptoms at the time of the experiment.
We salience to irrelevant phenomena, or they could be underactive
showed that brain responses correlating with reward prediction error inappropriately, failing to fire to rewards or cues predictive of rewards.
in the dopaminergic midbrain and associated dopamine neuron
striatal and limbic target regions – in addition to cortical regions such In this article I have outlined theoretical arguments and empirical
as the temporal and dorsolateral prefrontal cortex – were abnormal in data relating abnormalities in reward processing to particular
patients. Although some patients in the study were taking dopamine psychiatric symptoms. The imaging and behavioural studies that I
receptor antagonist medication, some were not, and the results also have reviewed show that patients with schizophrenia and other
held in the unmedicated patients, showing that the results could not psychoses show behavioural and physiological abnormalities when
solely be explained by medication effects. The results were consistent learning about or anticipating rewards or other important events.
with a companion study employing a complementary learning Patients also show impaired ability to modulate behaviour in
paradigms. Using a largely overlapping sample of patients in a study response to incentives. There are plausible theoretical arguments to
led by Phil Corlett, we examined causal learning as opposed to reward directly link these abnormalities to the manifestation of positive and
learning in early psychosis and, again, found abnormal activation in a negative psychotic symptoms, but, as yet, these links remain
network of midbrain, striatal and frontal regions.
Interestingly, the unproven. The key issues to investigate further will be the specificity
severity of the dysfunction of activation in the lateral prefrontal cortex of reward learning and motivational abnormalities to particular
correlated with the severity of delusions. symptom expression, and the degree to which such abnormalities
can be normalised by treatment. ■
Could it be that the same neural (dopaminergic) system could be
Graham Murray is a Senior Clinical Research Associate
responsible for both positive and negative symptoms in psychosis? At
at the University of Cambridge, where he works in the
first glance it would appear not. Hyperdopaminergic activity in the Brain Mapping Unit, Department of Psychiatry and
striatum has been linked to positive symptoms;
Behavioural and Clinical Neuroscience Institute. He also
works at the Cambridgeshire Early Psychosis Clinical
hedonic theories of dopamine’s role would predict that
Service (CAMEO). He has been awarded research prizes
hypodopaminergic activity would be related to negative symptoms. by a number of bodies, including the Royal College of
Thus, at first consideration, these possibilities seem inconsistent. Two
Psychiatrists (RCP) and the European Psychiatric
Association (EPA). He studied physics and philosophy at
possible solutions could be advanced. First, there could be
Oxford University before going on to read medicine at King’s College, London, where
subsystems that display different pathologies in psychotic illness: for he graduated with distinction. He received training in post-graduate psychiatry in
example, a more ventro-medial system could be more implicated in
Cambridge and at the University of Oulu in Finland.
negative symptoms, and this could be underactive, while a more
1. Breier A, Su TP, Saunders R, et al., Proc Natl Acad Sci U S A, 22. Miller R, Psychol Med, 1984;14:779–89. 2006;442:1042–5.
1997;94:2569–74. 23. Miller R, Psychopharmacology, 1987;92:405–15. 41. Murray GK, Clark L, Corlett PR, et al., BMC Psychiatry,
2. Abi-Dargham A, Rodenhiser J, Printz D, et al., Proc Natl Acad 24. Miller R, Int Rev Neurobiol, 1993;35:161–278. 2008;8:34.
Sci U S A, 2000;97:8104–9. 25. Garmezy N, J Pers, 1952;20:253–76. 42. Horan WP, Kring AM, Blanchard JJ, Schizophr Bull,
3. Laruelle M, Abi-Dargham A, van Dyck CH, et al., Proc Natl 26. Lindsley OR, Psychiatr Res Rep Am Psychiatr Assoc, 2006;32:259–73.
Acad Sci U S A, 1996;93:9235–40. 1956;5:118–39. 43. Kring AM, Neale JM, J Abnorm Psychol, 1996;105:
4. Howes OD, Montgomery AJ, Asselin MC, et al., Arch Gen 27. Lindsley OR, Skinner BF, Am Psychol, 1954;9:419–20. 249–57.
Psychiatry, 2009;66:13–20. 28. Rosenbaum G, Mackavey WR, Grisell JL, J Abnorm Psychol, 44. Gard DE, Gard MG, Kring AM, et al., J Res Per, 2006;40:
5. Nestler EJ, Carlezon WA Jr, Biol Psychiatry, 2006;59:1151–9. 1957;54:364–8. 1086–1102.
6. Frith CD, The cognitive neuropsychology of schizophrenia, Hove: 29. Topping GG, O’Connor N, Br J Med Psychol, 1960;33: 45. Barch DM, Schizophr Bull, 2005;31:875–81.
Taylor and Francis, 1992. 211–14. 46. Juckel G, Schlagenhauf F, Koslowski M, et al., Neuroimage,
7. David AS, Cortex, 2006;42:921–5. 30. Gray JA, Feldon J, Rawlins JNP, et al., Behavior Brain Sci, 2006;29:409–16.
8. Schultz W, Dickinson A, Annu Rev Neurosci, 2000;23:473–500. 1991;14:1–19. 47. Schlagenhauf F, Juckel G, Koslowski M, et al.,
9. Berridge KC, Psychopharmacology, 2007;191:391–431. 31. Roiser JP, Stephan KE, Ouden HE, et al., Psychol Med, Psychopharmacology, 2008;196:673–84.
10. Robbins TW, Everitt BJ, Psychopharmacology, 2007;191:433–7. 2008:1–11. 48. Juckel G, Schlagenhauf F, Koslowski M, et al.,
11. Crow TJ, Psychol Med, 1973;3:66–73. 32. Waltz JA, Gold JM, Schizophr Res, 2007;93:296–303. Psychopharmacology, 2006;187:222–8.
12. Bleuler E, Dementia Praecox or the group of schizophrenias, 33. Gold JM, Waltz JA, Prentice KJ, et al., Schizophr Bull, 2008;34: 49. Abler B, Greenhouse I, Ongur D, et al.,
New York: International University Press, 1911/1950. 835–47. Neuropsychopharmacology, 2008;33:2217–27.
13. Stein L, Wise CD, Science, 1971;171:1032–6. 34. Elliott R, McKenna PJ, Robbins TW, et al., Psychol Med, 50. Mizrahi R, Kiang M, Mamo DC, et al., Schizophr Res,
14. Miller R, Med Hypotheses, 1976;2:203–11. 1995;25:619–30. 2006;88:111–18.
15. McKenna PJ, Br J Psychiatry, 1987;151:288–301. 35. Pantelis C, Barnes TR, Nelson HE, et al., Brain, 1997;120: 51. Agid O, Kapur S, Arenovich T, et al., Arch Gen Psychiatry,
16. Beninger RJ. In: Simon P, Soubrie P, Widlocher D (eds), 1823–43. 2003;60:1228–35.
Selected Models of Anxiety, Depression and Psychosis, Basel: 36. Murray GK, Cheng F, Clark L, et al., Schizophr Bull, 2008;34: 52. Jensen J, Willeit M, Zipursky RB, et al.,
Karger, 1988;36–51. 848–55. Neuropsychopharmacology, 2008;33:473–9.
17. Kapur S, Am J Psychiatry, 2003;160:13–23. 37. Heerey EA, Bell-Warren KR, Gold JM, Biol Psychiatry, 53. Murray GK, Corlett PR, Clark L, et al., Mol Psychiatry,
18. Robbins T, Nature, 1976;264:57–9. 2008;64:62–9. 2008;13:239:67–76.
19. Heinz A, Schmidt LG, Reischies FM, Pharmacopsychiatry, 38. Heerey EA, Gold JM, J Abnorm Psychol, 2007;116:268–78. 54. Corlett PR, Murray GK, Honey GD, et al., Brain, 2007;130:
1994;27(Suppl. 1):7–10. 39. Abler B, Erk S, Walter H, Psychopharmacology, 2007;191: 2387–2400.
20. Spitzer M, Compr Psychiatry, 1995;36:83–105. 823–33. 55. Kegeles L, Frankle WG, Gil R, et al., Schizophrenia Bull,
21. Crow T, Fed Proc, 1979;38:2462–7. 40. Pessiglione M, Seymour B, Flandin G, et al., Nature, 2007;33:294.
EUROPEAN PSYCHIATRIC REVIEW 23