Increased orbitofrontal cortex activation associated with "pro-obsessive" antipsychotic treatment in patients with schizophrenia

Abstract

Background: Patients with schizophrenia have an approximately 10-fold higher risk for obsessive-compulsive symptoms (OCS) than the general population. A large subgroup seems to experience OCS as a consequence of second-generation antipsychotic agents (SGA), such as clozapine. So far little is known about underlying neural mechanisms.

Methods: To investigate the role of SGA treatment on neural processing related to OCS in patients with schizophrenia, we stratified patients according to their monotherapy into 2 groups (group I: clozapine or olanzapine; group II: amisulpride or aripiprazole). We used an fMRI approach, applying a go/no-go task assessing inhibitory control and an n-back task measuring working memory.

Results: We enrolled 21 patients in group I and 19 patients in group II. Groups did not differ regarding age, sex, education or severity of psychotic symptoms. Frequency and severity of OCS were significantly higher in group I and were associated with pronounced deficits in specific cognitive abilities. Whereas brain activation patterns did not differ during working memory, group I showed significantly increased activation in the orbitofrontal cortex (OFC) during response inhibition. Alterations in OFC activation were associated with the severity of obsessions and mediated the association between SGA treatment and co-occurring OCS on a trend level.

Limitations: The main limitation of this study is its cross-sectional design.

Conclusion: To our knowledge, this is the first imaging study conducted to elucidate SGA effects on neural systems related to OCS. We propose that alterations in brain functioning reflect a pathogenic mechanism in the development of SGA-induced OCS in patients with schizophrenia. Longitudinal studies and randomized interventions are needed to prove the suggested causal interrelations.

Fig. 1

Differential activation of the orbitofrontal cortex (OFC) during response inhibition. Unmasked display of increased OFC activation in the no-go > neutral contrast for group I (clozapine/olanzapine) compared to group II (amisulpride/aripiprazole; p < 0.005, uncorrected, k = 20).

Fig. 2

Mediation analyses. (A) A posteriori analysis exploring a mediating effect of orbitofrontal cortex (OFC) activation on the association between antipsychotic treatment and obsessive–compulsive symptom (OCS) severity. Path a represents the effect of treatment with second-generation antipsychotics (SGA) on OFC activation, whereas path b represents the effect of OFC activation on symptom severity, partialling out the effect of SGA treatment. In addition to a direct effect of group affiliation on OCS severity (path c), statistically significant and trend results of both paths a and b indicate an indirect effect of OFC activation on this association. All of these paths are quantified with unstandardized regression coefficients. (B) Analysis exploring a mediating effect of performance in the go/no-go task on the association between OFC activation and OCS severity. Analysis did not reveal a significant direct effect of OFC activation (c), but the statistically significant results of both paths a and b indicate an indirect effect through cognitive performance in the inhibitory control task on OCS severity. All of the paths are quantified with unstandardized regression coefficients. Group I = clozapine/olanzapine; group II = amisulrpide/aripiprazole, Y-BOCS = Yale–Brown Obsessive–Compulsive Scale.