Schizophrenia: From developmental deviance to dopamine dysregulation

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Abstract

Two major theories of schizophrenia are respectively, the neurodevelopmental hypothesis and the dopamine hypothesis. Each of these has recently been revised. Firstly, the classical neurodevelopmental hypothesis has been modified to include the pathogenic effects of psychostimulants and cannabis abuse, and also of chronic social adversity; it is perhaps now more appropriately termed, the developmental hypothesis. Secondly, recent amendments to the dopamine hypothesis suggest that excess striatal dopamine is responsible for increased salience being given to insignificant events and thoughts, and that this underpins the development of psychotic symptoms. Traditionally, it has been thought that this striatal dopamine dysregulation might be secondary to frontal dysfunction. However, recent animal research shows that over-expression of striatal D2 receptors results in frontal dysfunction manifesting as cognitive difficulties and animal equivalents of so-called negative symptoms. This raises the question whether early intervention may prevent the development of these latter problems. Finally, the two theories are beginning to be integrated through the growing evidence that all the developmental risk factors which increase risk of schizophrenia appear to act by facilitating 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.

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