Frontal D2/3 Receptor Availability in Schizophrenia Patients Before and After Their First Antipsychotic Treatment: Relation to Cognitive Functions and Psychopathology

Abstract

Background: We have previously reported associations between frontal D2/3 receptor binding potential positive symptoms and cognitive deficits in antipsychotic-naïve schizophrenia patients. Here, we examined the effect of dopamine D2/3 receptor blockade on cognition. Additionally, we explored the relation between frontal D2/3 receptor availability and treatment effect on positive symptoms.

Methods: Twenty-five antipsychotic-naïve first-episode schizophrenia patients were examined with the Positive and Negative Syndrome Scale, tested with the cognitive test battery Cambridge Neuropsychological Test Automated Battery, scanned with single-photon emission computerized tomography using the dopamine D2/3 receptor ligand [(123)I]epidepride, and scanned with MRI. After 3 months of treatment with either risperidone (n=13) or zuclopenthixol (n=9), 22 patients were reexamined.

Results: Blockade of extrastriatal dopamine D2/3 receptors was correlated with decreased attentional focus (r = -0.615, P=.003) and planning time (r = -0.436, P=.048). Moreover, baseline frontal dopamine D2/3 binding potential and positive symptom reduction correlated positively (D2/3 receptor binding potential left frontal cortex rho = 0.56, P=.003; D2/3 receptor binding potential right frontal cortex rho = 0.48, P=.016).

Conclusions: Our data support the hypothesis of a negative influence of D2/3 receptor blockade on specific cognitive functions in schizophrenia. This is highly clinically relevant given the well-established association between severity of cognitive disturbances and a poor functional outcome in schizophrenia. Additionally, the findings support associations between frontal D2/3 receptor binding potential at baseline and the effect of antipsychotic treatment on positive symptoms.

Keywords: SPECT; Schizophrenia; antipsychotic-naïve; cognition; epidepride; frontal dopamine D2/3 receptor; psychopathology.

Figure 1.

Example of axial image coregistration of single-photon emission computerized tomography (SPECT) and magnetic resonance (MR) images in a patient. Regions delineated are: (A) cerebellum (left in green and right in turquoise); (B) temporal cortex (left in blue and right in purple); (C) frontal cortex (left in red and right in yellow). SPECT spatial resolution in the trans-axial plain was 12mm full width half maximum (FWHM) with a 17-mm slice thickness. MR images were resliced to the planes defined by the SPECT images giving an in-plane resolution of 1x1mm in the MRI images and 10mm between slices.

Figure 2.

Correlation between left frontal dopamine D_2/3 receptor binding potential (BP_ND) in the antipsychotic-naïve state and treatment outcome. Improvement in Positive and Negative Syndrome Scale (PANSS) positive score (follow-up minus baseline) after 3 months of treatment: n=25, rho = 0.56, P<0.01. Linear regression shown as fully drawn line and confidence intervals as dashed lines.

Figure 3.

(A-B) Scatter plots showing correlations between dose and extrastriatal dopamine D_2/3 receptor occupancy in the 2 treatment groups. Patients treated with risperidone had significant correlations between dose and occupancy (n = 13, r = 0.68, P=.01). For patients treated with zuclopenthixol, no significant correlations were found (n = 9, r = 0.46, P=.2).

Figure 4.

Scatter plots showing correlations between extrastriatal dopamine D_2/3 receptor occupancy and cognitive measures. (A) Planning time at follow-up measured with CANTAB (Stockings of Cambridge initial thinking time) (n = 21, r = -0.436, P=.048). Extrastriatal occupancy is in percent, planning time in msek. (B) Improvement in attention measured with CANTAB (signal detection measure A’ from the Rapid Visual Information Processing test) (n = 21, r = -0.615, P=.003). Occupancy is in percent, and attention scores range from 0 to 1, with 1 indicating optimal signal detection.