Abstract
Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia. A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest. The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms. We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.
Highlights
Antipsychotics have been the mainstay of treatment for schizophrenia since the 1950s, and their beneficial effects are well documented (Leucht et al, 2012)
For the Positive and Negative Syndrome Scale (PANSS) domains, we found a significant effect for positive symptoms for both white matter volume and basal ganglia volume changes, respectively (F = 12.02, p = 0.0009 and F = 8.74, p = 0.004), but not for negative (F = 0.51, p = 0.4774 and F = 0.001, p = 0.9752) or disorganised (F = 1.27, p = 0.2634 and F = 0.25, p = 0.6194) symptoms
We found reductions in global cortical thickness and increases in white matter and basal ganglia volumes over time in patients, but not in controls, basal ganglia volumes were the only region to show a significant group × time interaction
Summary
Antipsychotics have been the mainstay of treatment for schizophrenia since the 1950s, and their beneficial effects are well documented (Leucht et al, 2012). Longitudinal studies in patients with schizophrenia have reported brain volume reductions that were associated with the estimated exposure to antipsychotic medication (Guo et al, 2015; Ho et al, 2011). Interpretation of the results of studies to date is made difficult by several methodological considerations (Guo et al, 2015) These studies seldom focused primarily on the relationship between antipsychotic medication and brain volume changes, and most were either cross-sectional or naturalistic. We hypothesised that, compared with healthy controls, the patients would experience reductions in cortical thickness and white matter volumes and increases in basal ganglia volumes, and that these changes would be differentially associated with antipsychotic dose, efficacy and adverse effects
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