Striatal Volume Increase After Six Weeks of Selective Dopamine D2/3 Receptor Blockade in First-Episode, Antipsychotic-Naïve Schizophrenia Patients

Abstract

Patients with chronic schizophrenia often display enlarged striatal volumes, and antipsychotic drugs may contribute via the dopamine D_2/3 receptor (D_2/3R) blockade. Separating the effects of disease from medication is challenging due to the lack of a proper placebo-group. To address this, we conducted a longitudinal study of antipsychotic-naïve, first-episode schizophrenia patients to test the hypothesis that selective blockade of D_2/3R would induce a dose-dependent striatal volume increase. Twenty-one patients underwent structural magnetic resonance imaging (sMRI), single-photon emission computed tomography (SPECT), and symptom severity ratings before and after six weeks of amisulpride treatment. Twenty-three matched healthy controls underwent sMRI and baseline SPECT. Data were analyzed using repeated measures and multiple regression analyses. Correlations between symptom severity decrease, volume changes, dose and receptor occupancy were explored. Striatal volumes did not differ between patients and controls at baseline or follow-up, but a significant group-by-time interaction was found (p = 0.01). This interaction was explained by a significant striatal volume increase of 2.1% in patients (Cohens d = 0.45). Striatal increase was predicted by amisulpride dose, but not by either D_2/3R occupancy or baseline symptom severity. A significant reduction in symptom severity was observed at a mean dose of 233.3 (SD = 109.9) mg, corresponding to D_2/3R occupancy of 44.65%. Reduction in positive symptoms correlated significantly with striatal volume increase, driven by reductions in hallucinations. Our data demonstrate a clear link between antipsychotic treatment and striatal volume increase in antipsychotic-naïve schizophrenia patients. Moreover, the treatment-induced striatal volume increase appears clinically relevant by correlating to reductions in core symptoms of schizophrenia.

Keywords: SPECT; antipsychotic drug; dopamine receptor; first-episode antipsychotic-naïve; longitudinal; sMRI; schizophrenia; striatum.

FIGURE 1

MRI and SPECT images of one patient, treated with 300 mg amisulpride displaying a mean dopamine D₂ receptor occupancy of 56%. Panel (A) shows the sMRI image with the caudate nucleus (light blue), putamen (red) and accumbens (dark blue) from the subcortical Harvard-Oxford atlas depicted. Panels (B,C) show the co-registered SPECT image on top of the MRI image. The color scale corresponds to the specific binding potential before treatment (B) and after six weeks of treatment (C).

FIGURE 2

Scatter plot of the multiple regression model including dose, striatal receptor occupancy and PANSS positive score as predictive/independent variables. The dependent variable, striatal volume increase, is depicted on the y-axis, the independent variables on the x-axis. The model significantly predicted striatal volume increase (r² = 0.411, p = 0.026). Only dose was a unique predictor of volume increase when controlling for the other variables (r² = 0.553, p = 0.028). All model coefficients can be seen in Supplementary Table S1.