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: 2.78). 04/2011; 11(4):589-607. DOI: 10.1586/ern.10.191
Source: PubMed


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.
    Psychiatry Research: Neuroimaging 12/2014; 221:114=121. · 2.42 Impact Factor
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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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    ABSTRACT: A relevant role for dopamine-glutamate interaction has been reported in the pathophysiology and treatment of psychoses. Dopamine and glutamate may interact at multiple levels, including the glutamatergic postsynaptic density (PSD), an electron-dense thickening that has gained recent attention as a switchboard of dopamine-glutamate interactions and for its role in synaptic plasticity. Recently, glutamate-based strategies, such as memantine add-on to antipsychotics, have been proposed for refractory symptoms of schizophrenia, e.g. cognitive impairment. Both antipsychotics and memantine regulate PSD transcripts but sparse information is available on memantine's effects under dopamine perturbation. We tested gene expression changes of the Homer1 and PSD-95 PSD proteins in models of sustained dopamine perturbation, i.e. subchronic treatment by: a) GBR-12909, a dopamine receptor indirect agonist; b) haloperidol, a D2R antagonist; c) SCH-23390, a dopamine D1 receptor (D1R) antagonist; and d) SCH-23390+haloperidol. On the last day of treatment, rats were acutely treated with vehicle or memantine. The Homer1a immediate-early gene was significantly induced by haloperidol and by haloperidol+SCH-23390. The gene was not induced by SCH-23390 per se or by GBR-12909. Expression of the constitutive genes Homer1b/c and PSD-95 was less affected by these dopaminergic paradigms. Acute memantine administration significantly increased Homer1a expression by the dopaminergic compounds used herein. Both haloperidol and haloperidol+SCH-23390 shifted Homer1a/Homer1b/c ratio of expression toward Homer1a. This pattern was sharpened by acute memantine. Dopaminergic compounds and acute memantine also differentially affected topographic distribution of gene expression and coordinated expression of Homer1a among cortical-subcortical regions. These results indicate that dopaminergic perturbations may affect glutamatergic signaling in different directions. Memantine may help partially revert dopamine-mediated glutamatergic dysfunctions.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2014; 54. DOI:10.1016/j.pnpbp.2014.07.003 · 3.69 Impact Factor
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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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    ABSTRACT: Background Although persistent negative symptoms (PNS) are known to contribute significantly to poor functional outcome, they remain poorly understood. We examined the heuristic value of various PNS definitions and their respective prevalence in patients with first episode psychosis (FEP). We also contrasted those definitions to the Proxy for the Deficit Syndrome (PDS) to identify deficit syndrome (DS) in the same FEP cohort. Methods One hundred and fifty-eight FEP patients were separated into PNS and non-PNS groups based on ratings from the Scale for Assessment of Negative Symptoms (SANS). PNS was defined in the following ways: 1) having a score of 3 or greater on at least 1 global subscale of the SANS (PNS_1); 2) having a score of 3 or more on at least 2 global subscales of the SANS (PNS_2); and 3) having a score of 3 or more on a combination of specific SANS subscales and items (PNS_H). For all three definitions, symptoms had to be present for a minimum of six consecutive months. Negative symptoms were measured upon entry to the program and subsequently at 1,2,3,6,9 and 12 months. Functional outcome was quantified at first assessment and month 12. Results PNS prevalence: PNS_1 (27%); PNS_2 (13.2%); PNS_H (13.2%). The prevalence of DS was found to be 3% when applying the PDS. Regardless of the definition being applied, when compared to non-PNS, patients in the PNS group were shown to have significantly worse functioning at month 12. All three PNS definitions showed similar associations with functional outcome at month 12. Conclusion Persistent negative symptoms are present in about 27% of FEP patients with both affective and non-affective psychosis. Although there has previously been doubt as to whether PNS represents a separate subdomain of negative symptoms, the current study suggests that PNS may be more applicable to FEP when compared to DS. Although all three PNS definitions were comparable in predicting functional outcome, we suggest that the PNS definition employed is dependent on the clinical or research objective at hand.
    BMC Psychiatry 12/2012; 12(1):224. DOI:10.1186/1471-244X-12-224 · 2.21 Impact Factor
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