Schizophrenia: Challenging the Orthodox (European Foundation for Psychiatry at the Maudsley) by Colm McDonald Katja Schulze Robin Murray Padraig Wright

Author:Colm McDonald, Katja Schulze, Robin Murray, Padraig Wright
Language: eng
Format: mobi
ISBN: 9781841843773
Publisher: CRC PRESS
Published: 2004-06-24T21:00:00+00:00

Why antipsychotics are anti-‘psychotic’

Shitij Kapur and David C Mamo

The history of the relation between dopamine, psychosis and antipsychotics starts with the discovery of antipsychotic drugs just over five decades ago. At that time

psychological theories of schizophrenia were prominent, and major biological theories

restricted to abnormal metabolism in the brain.1,2 It was in this context that Delay et al reported the discovery of the antipsychotic actions of chlorpromazine,3 followed by

reports of the efficacy of reserpine in the treatment of a variety of serious psychiatric disorders.4,5 However, these drugs were neither regarded as having specific efficacy in psychosis, nor restricted to the treatment of schizophrenia, assuming instead a broad

indication as ‘major tranquillizers’.6

Since then hundreds of compounds with putative antipsychotic activity have been

synthesized and dozens have made it to the clinic, with the more novel agents called

‘atypical’ antipsychotics referring to the absence of extrapyramidal side effects at

clinically effective doses. Nevertheless, despite years of research several important

questions remain unanswered, foremost being the mechanisms whereby these drugs

achieve their anti-‘psychotic’ effects. Patients suffering from schizophrenia are frequently reassured by their physicians that an antipsychotic drug will help clear the ‘chemical imbalance’. While this chemical imbalance model is quite widely used and accepted by

patients, we do not have a conceptual framework which addresses the complex issue of

how a drug, essentially a pharmacological agent that effects change in a biological

system, changes the personal experience of the patient. In this chapter we argue that not only is the modulation of dopaminergic neurotransmission key to the pharmacological

action of antipsychotics, but it is also central to the understanding of the psychological mechanisms involved in the resolution of psychotic symptoms during antipsychotic

treatment. The chapter draws heavily upon several previous articles by the first author.7–10

In the interest of succinctness, the reader will be referred to these articles for further discussion and primary references relevant to the respective sections below.

The discussion will start with an outline of the empirical evidence for the relation

between alteration in dopamine function and both antipsychotic drug action as well as the psychotic experience itself. We then discuss the involvement of dopamine as a mediator of motivational salience, a psychological construct referring to the involvement of

dopamine in mediating the conversion of neutral information into meaningful stimuli that have the potential to influence goal-directed behaviour. Within this framework, psychotic symptoms are derived from aberrant attribution of meaning (or ‘salience’) to neutral

Schizophrenia: Challenging the orthodox 98

stimuli, and the anti-psychotic effects of antipsychotic medications resulting from a

‘dampening’ of this aberrant salience through their actions on the mesolimbic

dopaminergic system (Figure 14.1). Finally, the implications of this hypothesis for future research will be discussed.

Dopamine, psychosis and antipsychotics

The story of dopamine and psychosis is closely linked to its involvement in the

mechanism of action of antipsychotic drugs, and the two have historically been subsumed under the umbrella of the dopamine hypothesis of schizophrenia.11–13 Nonetheless, the

evidence for dopamine’s involvement in psychosis and antipsychotic drug action stems

from two separate lines of research.

The lasting theories regarding the mechanism of action of antipsychotics were introduced by Carlsson and Lindquist, who showed that

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