Article

Schizophrenia as a disorder of too little dopamine: Implications for symptoms and treatment

University of Toronto, Toronto, Ontario, Canada.
Expert Review of Neurotherapeutics (Impact Factor: 2.83). 04/2011; 11(4):589-607. DOI: 10.1586/ern.10.191
Source: PubMed

ABSTRACT Antipsychotics represent the first effective therapy for schizophrenia, with their benefits linked to dopamine D2 blockade. Schizophrenia was soon identified as a hyperdopaminergic disorder, and antipsychotics proved to be reasonably effective in controlling positive symptoms. However, over the years, schizophrenia has been reconceptualized more broadly, now defined as a heterogeneous disorder with multiple symptom domains. Negative and cognitive features, not particularly responsive to antipsychotic therapy, have taken on increased importance--current thinking suggests that these domains predate the onset of positive symptoms and are more closely tied to functional outcome. That they are better understood in the context of decreased dopamine activity suggests that schizophrenia may fundamentally represent a hypodopaminergic disorder. This shift in thinking has important theoretical implications from the standpoint of etiology and pathophysiology, but also clinically in terms of treatment and drug development.

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    • " 2012 ; Perez et al . , 2012 ) and recent - onset schizophrenia ( Perez et al . , 2012 ) . Importantly , in exploratory analyses of a small subsample of unmedicated schizophrenia patients , we found that the ERN was intact . Circumstantial evidence suggests that the altered cortical dopamine ( DA ) signaling proposed in schizophrenia ( reviewed in Remington et al . , 2011 ) may impact action monitoring , and a reinforcement learning - based model of error monitoring would predict that a deficit in phasic DA responsiveness during action monitoring would lead to an ERN reduced in amplitude , by attenuating DA signal transmission in the mesocortical DA path - way ( Holroyd and Coles , 2002 ) . There is some"
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    ABSTRACT: Schizophrenia patients experience cognitive control disturbances, manifest in altered neural signatures during action monitoring. It remains unclear whether error- and conflict-monitoring disturbances co-occur, and whether they are observed in recent-onset psychosis patients with schizophrenia or bipolar disorder. We tested electrophysiological measures of action monitoring in these patients. 73 schizophrenia patients (SZ), 26 bipolar disorder type I patients (BP), each within one year of psychosis onset, and 54 healthy control subjects (HC) underwent EEG during Stroop task performance. In the trial-averaged EEG at three midline scalp electrodes, the error-related negativity (ERN), error positivity (Pe) and conflict-related N450 were determined. Compared to HC, 1) SZ exhibited an attenuated ERN and N450, and a larger Pe, and 2) BP exhibited an attenuated ERN but normal Pe and N450. Between patient groups, SZ showed an attenuated N450 and trend toward a larger Pe; ERN was not significantly different. A small (n=10) SZ subgroup that was not receiving antipsychotic medication showed normal ERPs. Altered error- and conflict-monitoring occur together in first-episode schizophrenia patients, and these measures are comparable in patients with first-episode bipolar disorder. Antipsychotic medication may contribute to altered measures of error-monitoring in schizophrenia.
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    • "GBR-12909 is a blocker of the dopamine transporter and an indirect agonist at dopamine receptors, providing a condition of sustained hyper-dopaminergia, which has considered to occur in psychosis, mostly in striatal sites (Howes and Kapur, 2009). SCH-23390 is a D1R selective antagonist, mimicking a condition of D1R- mediated hypo-dopaminergia that has been hypothesized to occur in psychosis (Remington et al., 2011), mostly in cortical sites. Haloperidol is a D2R selective antagonist, since blockade of D2Rs is considered the necessary mechanism of antipsychotic action (Seeman, 2006). "
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    • "In a first episode cohort assessed during the first year of illness, DUP was also shown to predict PNS [3]. Furthermore, some studies have proposed that negative symptoms appear prior to the onset of positive symptoms, occurring in the prodromal period [69,70]. The current study did not replicate these findings; no significant group differences were found for DUP or length of the prodromal period. "
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