title: Lack of association between dopaminergic antagonism and negative symptoms in schizophrenia: a positron emission tomography dopamine D2/3 receptor occupancy study.
abstract: Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial.
  
  
  
  The objective of this study was to examine the relationship between antipsychotic-related dopamine D2/3receptor occupancy and negative symptoms in patients with schizophrenia.
  
  
  
  Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [11C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40 % from the baseline dose.
  
  
  
  No significant relationship was found between antipsychotic-related dopamine D2/3receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship.
  
  
  
  Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.
authors: Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors: Gagan
authors: G
authors: Fervaha
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors: Fernando
authors: F
authors: Caravaggio
authors: Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.
authors: David C
authors: DC
authors: Mamo
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Benoit H
authors: BH
authors: Mulsant
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Bruce G
authors: BG
authors: Pollock
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Shinichiro
authors: S
authors: Nakajima
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Philip
authors: P
authors: Gerretsen
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Tarek K
authors: TK
authors: Rajji
authors: Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.
authors: Wanna
authors: W
authors: Mar
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Yusuke
authors: Y
authors: Iwata
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Eric
authors: E
authors: Plitman
authors: Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Jun Ku
authors: JK
authors: Chung
authors: Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors: Gary
authors: G
authors: Remington
authors: Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, ON, Canada. ariel.graff@camh.ca.|Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada. ariel.graff@camh.ca.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada. ariel.graff@camh.ca.|Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. ariel.graff@camh.ca.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada. ariel.graff@camh.ca.|Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada. ariel.graff@camh.ca.
authors: Ariel
authors: A
authors: Graff-Guerrero
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003430:Cross-Sectional Studies; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D020891:Raclopride; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; C581293:DRD2 protein, human; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D020891:Raclopride
keywords: Apathy; Dopamine; Extrapyramidal symptoms; Motivation; Negative symptoms; Schizophrenia; Side effects; Ventral striatum