Pre-treatment brain structural associations with temporal evolution of extrapyramidal symptoms over 24-month of antipsychotic treatment in first-episode schizophrenia spectrum disorders

Background

Existing evidence indicates that both extrapyramidal symptoms (EPS) and structural brain differences are often present in treatment-naïve first episode schizophrenia. Pre-treatment EPS are associated with greater symptom severity and poorer treatment outcomes in first episode schizophrenia. Baseline structural brain differences have been linked to symptom severity, antipsychotic treatment response, and the occurrence of EPS. Our aim was to investigate the associations between pre-treatment brain structure and the temporal evolution of EPS over 24 months of assured antipsychotic treatment in patients with first episode schizophrenia (n = 95) compared to healthy controls (n = 97). We hypothesized that pre-treatment brain structural differences, particularly larger cerebral white matter and basal ganglia volumes, would be associated with the development of more severe EPS over 24 months of antipsychotic treatment.

Methods

The study was based in Cape Town, South Africa, and patients with first episode schizophrenia were recruited from hospitals and surrounding community clinics in a well-defined catchment area. This was a sub-study of a larger research project which examined different clinical, biological, and functional aspects of treatment outcome in first episode schizophrenia. EPS were assessed at baseline and again at regular 3-month intervals using the Extrapyramidal Symptom Rating Scale across the 24-month treatment period. Patients were treated with a fixed protocol using flupenthixol decanoate long-acting injectable antipsychotic. Structural magnetic resonance imaging (MRI) was performed at baseline in both patients and healthy controls. Global neuroimaging outcomes of interest were: total cortical thickness, cerebral white matter volumes, and subcortical grey matter volumes. FreeSurfer-generated regions-of-interest (ROIs) included prefrontal cortical thickness and basal ganglia volumes. Brain structure was compared between patients and healthy controls using ANCOVA models. Associations between baseline brain structure and EPS trajectories were examined using partial correlations, adjusting for age, sex, highest level of education, ethnic background, PANSS total scores at baseline, substance use, and cumulative antipsychotic dose, with correction for multiple comparisons.

Results

EPS were present at baseline in 22 patients (23%) and were observed in 63 patients (66%) over the 24-month follow-up period, with Parkinsonism features (n = 53) being the most common. Larger cerebral white matter and subcortical grey matter volumes were associated with a more pronounced increase in EPS from baseline to peak severity during antipsychotic treatment. Thinner right superior frontal cortical thickness was associated with greater increases in global EPS and Parkinsonism features. For our ROIs, larger proportion-adjusted putamen and pallidum volumes were associated with a more pronounced increase in Parkinsonism features over time. Larger proportion-adjusted putamen volumes were associated with the occurrence of dyskinesia, irrespective of timepoint.

Conclusions

Our findings suggest that pre-existing cortical and subcortical differences are associated with greater susceptibility to antipsychotic-induced EPS in first episode schizophrenia. Pre-treatment variations in cortical thickness, white matter, and putamen volumes may reflect a vulnerability to antipsychotic related extrapyramidal side effects. Our findings highlights the potential utility of neuroimaging markers for informing individualised treatment strategies aimed at minimising motor complications in first episode psychosis.

References

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