Divergent effects of first-generation and second-generation antipsychotics on cortical thickness in first-episode psychosis

Abstract

Background: Whether there are differential effects of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) on the brain is currently debated. Although some studies report that FGAs reduce grey matter more than SGAs, others do not, and research to date is limited by a focus on schizophrenia spectrum disorders. To address this limitation, this study investigated the effects of medication in patients being treated for first-episode schizophrenia or affective psychoses.

Method: Cortical thickness was compared between 52 first-episode psychosis patients separated into diagnostic (i.e. schizophrenia or affective psychosis) and medication (i.e. FGA and SGA) subgroups. Patients in each group were also compared to age- and sex-matched healthy controls (n = 28). A whole-brain cortical thickness interaction analysis of medication and diagnosis was then performed. Correlations between cortical thickness with antipsychotic dose and psychotic symptoms were examined.

Results: The effects of medication and diagnosis did not interact, suggesting independent effects. Compared with controls, diagnostic differences were found in frontal, parietal and temporal regions. Decreased thickness in FGA-treated versus SGA-treated groups was found in a large frontoparietal region (p < 0.001, corrected). Comparisons with healthy controls revealed decreased cortical thickness in the FGA group whereas the SGA group showed increases in addition to decreases. In FGA-treated patients cortical thinning was associated with higher negative symptoms whereas increased cortical thickness in the SGA-treated group was associated with lower positive symptoms.

Conclusions: Our results suggest that FGA and SGA treatments have divergent effects on cortical thickness during the first episode of psychosis that are independent from changes due to illness.

Keywords: Antipsychotics; cortical thickness; first-episode psychosis; first-generation; second-generation.

Fig. 1.

Comparisons of diagnostic subgroups. Brain surface maps show statistically significant areas of reduced cortical thickness (cluster-wise probability, p < 0.05) derived from pair-wise group comparisons. Each comparison is colour coded and overlap between clusters is represented as a linear combination of comparison colours. Reduced cortical thickness was found in the first-episode schizophrenia (Scz) group compared to controls (Ctrl; green areas) in the right inferior frontal gyrus, bilateral medial superior frontal gyri and left temporo-occipital cortex. Reduced thickness of the affective psychosis subgroup (Aff; blue) was found in the right temporo-occipital region and in a small area of the right cingulate sulcus. No significant differences were found when comparing schizophrenia and affective subgroups (red).

Fig. 2.

Comparisons of medication subgroups. Brain surface maps (left) show statistically significant (cluster-wise probability, p < 0.05) areas of reduced cortical thickness in comparisons of: subgroups treated with first-generation antipsychotics (FGAs) compared to second-generation antipsychotics (SGAs; red clusters), the FGA subgroup compared to control participants (Ctrl; green clusters), and the SGA subgroup compared to control participants (blue clusters). Overlap of clusters is represented as a linear combination of colours from pair-wise comparisons (see colour wheel on bottom left). Results demonstrated large areas of reduced cortical thickness in the subgroup treated with FGAs in superior frontal, pre- and postcentral and pericalcarine gyri. Compared to control participants, reductions were found in the FGA subgroup in the right superior lateral and medial frontal cortex, and in the SGA group in the right cingulate and temporo-occipital regions. Further investigation of the mean thickness from the clusters of the FGA versus SGA subgroups (right plots; a–f) demonstrated that the mean cortical thickness of the control group was interposed between patients treated with FGAs and those treated with SGAs in the following regions: (a) left superior frontal gyrus, (b) left precentral gyrus, (c) left pericalcarine gyrus, (d) right superior frontal gyrus, (e) right postcentral gyrus and (f) right pericalcarine gyrus. t tests with control group comparison: ¤, p < 0.05, † p < 0.01, ‡ p < 0.001.

Fig. 3.

Dose–response relationship. Relationship between cumulative first-generation antipsychotic (FGA) dose and average cortical thickness of the left superior frontal cortex cluster identified in Fig. 2 and Table 2. Note log scale of the x axis.