Schizophrenia: From developmental deviance to dopamine dysregulation
Introduction
Dopamine dysregulation has long been known to be central to the pathogenesis of schizophrenia—based on the evidence that dopamine D2 receptor modulation is the single most important pharmacological action of antipsychotic medications, and that dopamine agonists elicit positive symptoms in individuals with schizophrenia. Dopamine dysregulation appears to be one of the final steps in a complex developmental cascade towards schizophrenia that starts early in life and ends with the onset of full-blown psychosis. In order to treat, or even prevent the development of dopamine dysfunction, it is important to understand all the factors that have an impact along the 20-year-long pathway to developing schizophrenia, and how the resulting dopaminergic dysregulation translates into psychotic symptoms.
Section snippets
Early developmental factors
Schizophrenia is an aetiologically complex disorder that arises from the interaction of a range of factors acting at various stages of life (Fig. 1). Susceptible individuals appear to inherit a number of deviant genetic traits, each of which is also present in the general population, but which, together, render an individual vulnerable to schizophrenia.
Two types of susceptibility genes have recently been associated with schizophrenia (Harrison and Owen, 2003). Firstly, neurodevelopmental genes,
Dopamine as the ‘wind of psychotic fire’
The neurodevelopmental hypothesis helps us to understand the pathway to becoming an at-risk adolescent, but does not explain what converts a socially isolated individual with cognitive deficits and quasi-psychotic ideas into an overtly psychotic individual. It is dopamine dysregulation which appears to be the final pathway to psychotic illness of susceptible individuals.
The ‘classical’ dopamine hypothesis of schizophrenia was proposed over 40 years ago, it states that schizophrenia is
Treating positive symptoms
Antipsychotic medications reduce the underlying dopaminergic drive. They attenuate the abnormal attribution of salience, leading to the prevention of new psychotic experiences. Many individuals also report, after receiving antipsychotic medication, that they are no longer bothered by issues that previously concerned them and that the voices they hear cause them less distress. However, the core belief in the truth of the memory of the delusion often persists. Antipsychotic medication provides a
Summary and conclusions
Dopamine dysregulation is central to the genesis of positive, negative, and cognitive symptoms of schizophrenia and represents the final stage of a 20-year-long pathway towards psychosis in genetically susceptible individuals. Early developmental factors interact with environmental and social pressures during childhood and adolescence and result in dopaminergic dysregulation that, ultimately, turns normal beliefs into delusions.
Antipsychotic medications, in combination with psychosocial
Role of the funding source
Marta Di Forti received funding from DOH.
This supplement was supported by H. Lundbeck A/S. Editorial support for the preparation of this manuscript was provided by Cambridge Medical Communication Limited.
Conflict of interest
Robin M. Murray received honoraria from AstraZenica, Janssen, Lilli and BMS. Marta Di Forti and Julia Lappin declare that they have no conflicts of interest.
References (63)
- et al.
Positive and negative symptoms of schizophrenia. Their course and relationship over time
Schizophr. Res.
(1991) - et al.
Cannabis and schizophrenia
Lancet
(1988) - et al.
What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?
Brain Res. Rev.
(1998) - et al.
Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family
Am. J. Hum. Genet.
(2001) - et al.
Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction
Biol. Psychiatry
(2005) - et al.
Isolation rearing in rats: pre- and postsynaptic changes in striatal dopaminergic systems
Pharmacol. Biochem. Behav.
(1998) - et al.
Genes for schizophrenia? Recent findings and their pathophysiological implications
Lancet.
(2003) - et al.
The pre-synaptic dopaminergic system before and after the onset of psychosis: initial results
Eur. Neuropsychopharmacol.
(2006) - et al.
Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort
Lancet
(1994) - et al.
Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning
Neuron
(2006)