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