J Psychiatry Neurosci 2016;41(2):133-141
Bjørn H. Ebdrup, MD, PhD*; Jayachandra M. Raghava, PhD*; Mette Ø. Nielsen, MD, PhD; Egill Rostrup, MD, DMSc; Birte Glenthøj, MD, DMSc
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, antipsychoticnaive 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).
Limitations: Smoking and a previous diagnosis of substance abuse were potential confounders. Long-term effects of amisulpride on white matter were not evaluated.
Conclusion: 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.
*These authors contributed equally to this work.
Submitted Jan. 30, 2015; Revised May 27, 2015; Accepted July 14, 2015; Early-released Nov. 24, 2015
Affiliations: 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.
Funding: This work was supported by a grant from the University of Copenhagen/Mental Health Services, Capital Region of Denmark awarded to B. Ebdrup. The Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS is funded by Lundbeck Foundation grant number R25-A2701.
Competing interests: B. Ebdrup declares lecture fees from Bristol- Myers Squibb, Otsuka Pharma Scandinavia AB and Eli Lilly, and he is on the advisory boards of Eli Lilly Danmark A/S and Takeda Pharmaceutical Company Ltd. No other competing interests declared.
Contributors: B. Ebdrup, J. Raghava, E. Rostrup and B. Glenthoj designed the study. M. Nielsen acquired the data, which B. Ebdrup, J. Raghava, E. Rostrup and B. Glenthoj analyzed. B. Ebdrup and J. Raghava wrote the article, which all authors reviewed and approved for publication.
Correspondence to: B.H. Ebdrup, Centre for Neuropsychiatric Schizophrenia Research, CNSR & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Copenhagen University Hospital, Mental Health Centre, Glostrup, Nordre Ringvej 29-67, DK-2600, Glostrup, Denmark; email@example.com