Elsevier

Schizophrenia Research

Volume 79, Issue 1, 1 November 2005, Pages 59-68
Schizophrenia Research

From dopamine to salience to psychosis—linking biology, pharmacology and phenomenology of psychosis

https://doi.org/10.1016/j.schres.2005.01.003Get rights and content

Abstract

How does an excess in a neurochemical lead someone to being paranoid about the intentions of their neighbour? And why does blocking a dopamine receptor improve this symptom? In this article we present a heuristic framework which attempts to link the biology, phenomenology and pharmacology of psychosis. Focussing on dopamine's role in reward prediction and motivational salience we propose that psychosis arises from an aberrant assignment of novelty and salience to objects and associations. Antipsychotics block dopamine receptors and decrease dopamine transmission, which leads to the attenuation of aberrant novelty and salience. This ‘salience’ framework accounts for existing data and questions several current assumptions about the speed of onset phenomenological effects of antipsychotics and their behavioral effects in animal models. We review new data to show that in contrast to the prevailing idea of a “delayed onset” of antipsychotic action, the improvement is evident in the first few days. Antipsychotics do not eradicate symptoms, but create a state of “detachment” from them. And the actions of antipsychotics in the conditioned avoidance response model, one of the best established animal models for identifying antipsychotic action, are consistent with the idea that they dampen aberrant as well as normal motivational salience. The article discusses the caveats, limitations as well as the clinical implications of the salience framework.

Introduction

The introduction of chlorpromazine in the 1950s opened the era of modern antipsychotics, and since then dozens of antipsychotics have been developed and tested. In the 1960s, the idea that these antipsychotics were acting on the dopamine system took hold, and this was finally confirmed in the 1970s by the finding that the antipsychotics act on the dopamine D2 receptors. In the 1980s and 1990s the role of dopamine in psychosis, and that antipsychotics block the dopamine D2 receptors, was firmly established using neuroimaging studies. While several efforts have been made to develop antipsychotics which bypass the dopamine system, a blockade of the dopamine D2 receptor remains a necessary and sufficient condition for antipsychotic activity to this day (Kapur and Mamo, 2003, Sanger, 2004).

Thus while the role of dopamine in the biology of psychosis and the anti-D2 mechanism of antipsychotics is widely accepted—it still remains unclear how one links these neurobiological and pharmacological or “brain-level” findings with the essentially phenomenological “mind-level” nature of psychosis and its resolution. In this article we try and provide a heuristically useful framework, derived from the role of dopamine in salience and psychosis, that allows one to bring together these two levels of analysis. Any effort at a brain–mind synthesis can easily get bogged down in the complex ontological issues that relate to this topic (Kendler, 2001). For the purposes of this article it is sufficient to assume that brain-level and mind-level phenomena both constitute empirical regularities that can be measured and related to each other, without entering deeper debates about their essential nature (Gabbard, 1994).

We begin with a brief review of the current accounts about the role of dopamine in emotion and behavior, with a particular emphasis on notions of reward, reward prediction and salience. We use these concepts to then develop a framework that can potentially explain the phenomenology of psychosis and the phenomenological nature of antipsychotic response. The framework then leads to a number of natural questions—about the speed of onset of antipsychotic action, the experience of patients and what implications this has for preclinical animal models. We provide data from some recent studies from our group and that of others—which answer some of these questions. The article summarizes a talk presented at the 4th International Early Psychosis Meeting (Vancouver, Canada, September 2004) and builds upon earlier reviews (Kapur, 2003, Kapur, 2004) and recently published articles from our group (Agid et al., 2003, Kapur et al., 2005)—where appropriate the reader is referred to these original articles for details.

Section snippets

Roles of dopamine in “reward” and “salience”

There is near universal agreement for a central role of dopamine in “reward” and “reinforcement”. However, precisely what these terms mean and what dopamine contributes to their realization is a subject of competing hypotheses. Original ideas suggested that dopamine mediates hedonic pleasure (Wise et al., 1978). However, subsequent studies suggested that dopamine is involved not only in appetitive events but also in aversive ones (Salamone, 1994); and the release of dopamine often precedes the

The paradox of delayed onset

Given that an abnormally active dopamine system is implicated in psychosis and antipsychotics block this dopamine system—the relationship between the two ought to be an immediate and straightforward one. The paradox has been that while dopamine blockade happens within hours of starting medications (Tauscher et al., 2002), it is claimed that the antipsychotic response is delayed by 2 to 3 weeks. This idea of a “delayed onset” of antipsychotic action gained favor in the 1970s and is now firmly

The patients' perspective on how antipsychotics act

While a considerable amount of scientific effort has been expended at describing how symptoms or clusters of symptoms change (Casey et al., 1960a, Casey et al., 1960b, Johnstone et al., 1978, Ceskova and Svestka, 1993)–almost all of this work entails the clinicians' assessment of how the drugs impact the patient. Alternatively, studies have focused on drug side-effects and their acceptability as well as studying the impact of drugs on the quality of life for their users (Van Putten et al., 1981

Relating the salience framework to traditional animal models

Selective disruption of conditioned avoidance response (CAR) in rats is a hallmark of all antipsychotics. In this test, usually conducted in a two-sided chamber, an innocuous tone is paired with an aversive electrical shock to the feet. The animals can shut off the tone or the shock by running over to the other side of the chamber. Because of conditioning association between tone and shock, over time the animals start shuttling to the other side to avoid the tone itself, hence the term

Caveats and implications

The explanation above accounts for the “positive” symptoms of schizophrenia—and not the negative or cognitive ones. Thus, as we note in the title, this is more an account of psychosis (in schizophrenia), rather than an account for schizophrenia itself. Further, while dopamine is central to this account, the dopamine pathology itself may be secondary to some kind of a neurodevelopmental or glutamate-driven pathology (Lewis and Levitt, 2002). As is well known, many patients do not respond despite

Acknowledgements

SK's research in this area is supported by the Canada Research Chair in Schizophrenia and Therapeutic Neuroscience and grants from the Ontario Mental Health Foundation and the Canadian Institutes of Health Research. The article is based on the talk presented by SK to the 4th International Early Psychosis Meeting, Vancouver, Canada, September 2004.

References (63)

  • M. Li et al.

    Effects of typical and atypical antipsychotic drugs on maternal behavior in postpartum female rats

    Schizophr. Res.

    (2004)
  • J.D. Salamone

    The involvement of nucleus accumbens dopamine in appetitive and aversive motivation

    Behav. Brain Res.

    (1994)
  • W. Schultz

    Getting formal with dopamine and reward

    Neuron

    (2002)
  • P. Shizgal

    Neural basis of utility estimation

    Curr. Opin. Neurobiol.

    (1997)
  • J.M. Stern et al.

    Maternal motivation of lactating rats is disrupted by low dosages of haloperidol

    Behav. Brain Res.

    (1999)
  • K. Thompson et al.

    Reliability and validity of a new Medication Adherence Rating Scale (MARS) for the psychoses

    Schizophr. Res.

    (2000)
  • L.N. Voruganti et al.

    Personal evaluation of transitions in treatment (PETiT): a scale to measure subjective aspects of antipsychotic drug therapy in schizophrenia

    Schizophr. Res.

    (2002)
  • A. Abi-Dargham et al.

    Increased baseline occupancy of D2 receptors by dopamine in schizophrenia

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • O. Agid et al.

    Delayed-onset hypothesis of antipsychotic action—a hypothesis tested and rejected

    Arch. Gen. Psychiatry

    (2003)
  • M.A. Aguilar et al.

    Different inhibition of conditioned avoidance response by clozapine and DA D1 and D2 antagonists in male mice

    Behav. Neurosci.

    (2000)
  • A.G. Awad

    Subjective response to neuroleptics in schizophrenia

    Schizophr. Bull.

    (1993)
  • A.G. Awad et al.

    Subjective response to neuroleptics and the quality of life: implications for treatment outcome

    Acta Psychiatr. Scand., Suppl.

    (1994)
  • A.G. Awad et al.

    Quality of life and new antipsychotics in schizophrenia. Are patients better off?

    Int. J. Soc. Psychiatry

    (1999)
  • A.G. Awad et al.

    Patients' subjective experiences on antipsychotic medications: implications for outcome and quality of life

    Int. Clin. Psychopharmacol.

    (1995)
  • K.C. Berridge

    Pleasure, pain, desire and dread: hidden core processes of emotion

  • G. Bignami

    Effects of neuroleptics, ethanol, hypnotic-sedatives, tranquilizers, narcotics, and minor stimulants in aversive paradigms

  • M.B. Bowers

    Pathogenesis of acute schizophrenic psychosis. An experimental approach

    Arch. Gen. Psychiatry

    (1968)
  • J.F. Casey et al.

    Drug therapy in schizophrenia. A controlled study of the relative effectiveness of chlorpromazine, promazine, phenobarbital, and placebo

    Arch. Gen. Psychiatry

    (1960)
  • J.F. Casey et al.

    Treatment of schizophrenic reactions with phenothiazine derivatives. A comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazine, perphenazine, and phenobarbital

    Am. J. Psychiatry

    (1960)
  • E. Ceskova et al.

    Double-blind comparison of risperidone and haloperidol in schizophrenic and schizoaffective psychoses

    Pharmacopsychiatry

    (1993)
  • D.E. Clody et al.

    Stimulus efficacy, chlorpromazine, and schizophrenia

    Psychopharmacology

    (1980)
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