title: Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade.
abstract: BACKGROUND
  Psychotic symptoms are core clinical features of schizophrenia. We tested recent hypotheses proposing that psychotic, or positive, symptoms stem from irregularities in long-range white matter tracts projecting into the frontal cortex, and we predicted that selective dopamine D2/3 receptor blockade would restore white matter.
  
  
  METHODS
  Between December 2008 and July 2011, antipsychotic-naive patients with first-episode schizophrenia and matched healthy controls underwent baseline examination with 3 T MRI diffusion tensor imaging and clinical assessments. We assessed group differences of fractional anisotropy (FA) using voxelwise tract-based spatial statistics (TBSS) and anatomic region of interest (ROI)-based analyses. Subsequently, patients underwent 6 weeks of antipsychotic monotherapy with amisulpride. We repeated the examinations after 6 weeks.
  
  
  RESULTS
  We included 38 patients with first-episode schizophrenia and 38 controls in our analysis, and 28 individuals in each group completed the study. At baseline, whole brain TBSS analyses revealed lower FA in patients in the right anterior thalamic radiation (ATR), right cingulum, right inferior longitudinal fasciculus and right corticospinal tract (CT). Fractional anisotropy in the right ATR correlated with positive symptoms (z = 2.64, p= 0.008). The ROI analyses showed significant associations between positive symptoms and FA of the frontal fasciculi, specifically the right arcuate fasciculus (z = 2.83, p= 0.005) and right superior longitudinal fasciculus (z = -3.31, p= 0.001). At re-examination, all correlations between positive symptoms and frontal fasciculi had resolved. Fractional anisotropy in the ATR increased more in patients than in controls (z = -4.92, p< 0.001). The amisulpride dose correlated positively with FA changes in the right CT (t= 2.52, p= 0.019).
  
  
  CONCLUSIONS
  Smoking and a previous diagnosis of substance abuse were potential confounders. Long-term effects of amisulpride on white matter were not evaluated.
  
  
  CONCLUSIONS
  Antipsychotic-naive patients with schizophrenia displayed subtle deficits in white matter, and psychotic symptoms appeared specifically associated with frontal fasciculi integrity. Six weeks of amisulpride treatment normalized white matter. Potential remyelinating effects of dopamine D2/3 receptor antagonism warrant further clarification.
authors.affiliation: From the Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Copenhagen University Hospital, Mental Health Centre (Ebdrup, Raghava, Nielsen, Glenthøj); and the Functional Imaging Unit, Department of Diagnostics, Glostrup University Hospital (Raghava, Rostrup), Glostrup, Denmark.
authors.forename: Bjørn H
authors.initials: BH
authors.lastname: Ebdrup
authors.affiliation: From the Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Copenhagen University Hospital, Mental Health Centre (Ebdrup, Raghava, Nielsen, Glenthøj); and the Functional Imaging Unit, Department of Diagnostics, Glostrup University Hospital (Raghava, Rostrup), Glostrup, Denmark.
authors.forename: Jayachandra M
authors.initials: JM
authors.lastname: Raghava
authors.affiliation: From the Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Copenhagen University Hospital, Mental Health Centre (Ebdrup, Raghava, Nielsen, Glenthøj); and the Functional Imaging Unit, Department of Diagnostics, Glostrup University Hospital (Raghava, Rostrup), Glostrup, Denmark.
authors.forename: Mette Ø
authors.initials: MØ
authors.lastname: Nielsen
authors.affiliation: From the Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Copenhagen University Hospital, Mental Health Centre (Ebdrup, Raghava, Nielsen, Glenthøj); and the Functional Imaging Unit, Department of Diagnostics, Glostrup University Hospital (Raghava, Rostrup), Glostrup, Denmark.
authors.forename: Egill
authors.initials: E
authors.lastname: Rostrup
authors.affiliation: From the Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Copenhagen University Hospital, Mental Health Centre (Ebdrup, Raghava, Nielsen, Glenthøj); and the Functional Imaging Unit, Department of Diagnostics, Glostrup University Hospital (Raghava, Rostrup), Glostrup, Denmark.
authors.forename: Birte
authors.initials: B
authors.lastname: Glenthøj
mesh_terms: D000208:Acute Disease; D000328:Adult; D000077582:Amisulpride; D016880:Anisotropy; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects*; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D018492:Dopamine Antagonists / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D066127:White Matter / Q000000981:diagnostic imaging / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; C581293:DRD2 protein, human; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013469:Sulpiride; D000077582:Amisulpride