1. Introduction
Psychiatric comorbidities are common among patients with schizophrenia. One of the foremost comorbid conditions are obsessive–compulsive symptoms (OCS), reported in 30% of cases, with about 13% fulfilling the criteria of an obsessive–compulsive disorder (OCD) [
1,
2]. Co-occurring OCS results in a lower quality of life [
3], more severe depressive symptoms [
4], higher rates of suicidality [
5] and an unfavorable prognosis [
6,
7].
The clinical presentation of OCS in schizophrenia is diverse with onset prior to, simultaneously with or subsequent to the onset of psychosis. This heterogeneity suggests multiple interacting pathways [
8]. For the subgroup of patients, who develop OCS subsequent to their first psychotic episode and initiation of antipsychotic treatment, increasing evidence strongly suggests a “pro-obsessive” effect of certain second-generation antipsychotics (SGAs), especially clozapine [
9,
10] and olanzapine [
11]. Clozapine, and similarly olanzapine, exerts its effects via a relatively low affinity to dopamine D
2 receptors combined with strong antagonism at 5-HT
1C, 5-HT
2A and 5HT
2C receptors [
12,
13]. In contrast, predominantly dopaminergic SGAs such as amisulpride [
14] or the partial dopaminergic/serotonergic agonist aripiprazole [
15] are two substances that rather seem to have a beneficial or at least neutral effect on OCS [
16‐
20]. Hence, differences in receptor binding profiles of clozapine/olanzapine vs. amisulpride/aripiprazole might explain diverging effects on co-occurring OCS [
21]. The assumption that SGAs aggravate OCS via an antiserotonergic mechanism also seems plausible, because treatment with selective serotonin reuptake inhibitors (SSRIs) has been proven effective in the treatment of OCD [
22]. Furthermore, CBT treatment of OCD exerts a serotonergic normalization and several clinical trials revealed positive effects of serotonergic antidepressants for comorbid OCD in schizophrenia [
23].
The neural mechanisms of how antipsychotics change brain functioning are poorly understood. Röder et al. reviewed literature on antipsychotic influence on the blood-oxygenation-level-dependent (BOLD)-signal and suggested that functional magnetic resonance imaging (fMRI) can be a useful approach to provide information about differential drug effects [
24]. In a prior study, we investigated differential effects of SGAs on OCS in schizophrenia by comparing patients treated with clozapine or olanzapine to a group treated with aripiprazole or amisulpride [
25,
26]. FMRI analyses showed aberrant orbitofrontal cortex (OFC) activation during a flanker task in the clozapine/olanzapine group. OFC activation mediated the association between SGA treatment and co-occurring OCS [
27]. To the best of our knowledge, four other fMRI studies investigated neural correlates of OCS in schizophrenia, but did not specifically focus on OCD-related brain regions, nor did they account for possible underlying pharmacodynamic mechanisms [
28‐
30].
Apart from the fronto-striato-thalamocortical (CSTC) circuitry, which is known to be involved in OCD pathogenesis [
31,
32], recent findings proposed to extend research to limbic regions [
33‐
35], and highlighted the role of the amygdala,[
36,
37].
In their review, Wood and Ahmari [
37] discussed the potential role of a corticolimbic-ventral striatum network, extending the traditional OCD model with an important aspect, namely affective dysregulation. This circuit connecting frontal and limbic brain regions, specifically the amygdala with the ventral striatum plays a particularly important role in the emotional appraisal of situations and the generation of emotional responses and reward-based behaviors. The circuit has been found altered in OCD explaining increased anxiety and repetitive behaviors [
34,
37].
Accordingly, a number of fMRI studies reported increased amygdala activation [
38] and enhanced amygdala-prefrontal connectivity during emotion recognition tasks [
39], whereas others showed attenuated amygdala responsivity to emotional stimuli in OCD patients relative to healthy controls [
40,
41].
Differences in amygdala activity and corticolimbic connectivity during emotion processing have also been found in patients with schizophrenia [
42,
43]. Meta-analytic findings suggest hypoactivation of the amygdala in response to emotional facial expressions compared to healthy controls [
44], whereas more recent studies reported hyperactivation in response to neutral facial expressions [
45,
46].
Hence, aberrant amygdala activation and connectivity to regions of the corticolimbic-ventral striatum network during emotion processing might indicate a neural correlate of both OCD and schizophrenia and might play a role in the co-occurrence of the two disorders. However, additive effects and modulations due to therapeutic interventions seem possible. Accordingly, pharmacological treatment affects brain activation involved in emotional processing [
24,
47,
48]. Effects of antipsychotic agents should be considered when investigating OCS-related aberrations in brain activation in schizophrenia.
The aim of the present study was to investigate whether SGAs with different pharmacodynamic profiles differentially affect functioning of brain regions known to be involved in emotional processing. We assumed to find differences in brain activation and connectivity especially of the amygdala between SGA groups. On a secondary level, we intended to investigate associations between task-specific activation and the severity of OCS.
Method
Study design and participants
This neuroimaging approach was part of a multimodal assessment [
25,
26]. Patients were divided into two groups, those with an inherent antiserotonergic profile (group I: olanzapine and clozapine) and those with a primarily dopaminergic treatment profile (group II: amisulpride and aripiprazole) [
15,
49]. As described earlier [
27], participants were aged 18–60 years, diagnosed with a schizophrenia spectrum disorder according to DSM-IV-TR, received stable monotherapy with clozapine, olanzapine, amisulpride or aripiprazole and showed stable psychopathology over a period of at least 2 weeks with constant severity scores in psychosocial functioning (PSP) and the Positive and Negative Syndrome Scale (PANSS). Exclusion criteria included a history of alcohol or drug addiction or current treatment with antidepressants (except for reboxetine and bupropion—substances without marked serotonergic effects). Benzodiazepine intake was no exclusion criteria, but only one patient was prescribed clonazepam on demand. The investigation was approved by the ethical committee of the University of Heidelberg (no. 2008-235N-MA) and performed in agreement with the guidelines of good clinical practice. All participants provided written informed consent prior to study inclusion.
Clinical assessment
Sociodemographic and clinical variables were assessed using questionnaires and structured clinical interviews by a trained and certified rater (FS). The Yale–Brown Obsessive–Compulsive Scale (YBOCS) was applied to assess OCS severity, which has been validated in schizophrenia populations [
50,
51]. The YBOCS allows the rating of compulsions and obsessions on 5-point Likert scales (0–4), yielding subtotal scores ranging from 0 to 20. According to the interpretation guidelines of the original authors [
52], total scores of ≤ 7 are likely to be subclinical, whereas scores of ≥ 8 are likely to represent at least a mild case of OCD.
In addition, the Hamburger Zwangsinventar (HZI) was applied as a self-rating questionnaire to measure the presence of obsessions and different types of compulsions. The severity of psychotic symptoms was rated with the PANSS positive, negative and general psychopathology subscale. Subdomains of negative symptoms were further explored with the five subscales of the Scale for the Assessment of Negative Symptoms (SANS). Comorbid depressive symptoms were rated with the Calgary Depression Scale for Schizophrenia (CDSS). General and social functioning was assessed with the Personal and Social Performance Scale (PSP).
Functional MRI
To elicit amygdala response, we used the classical implicit emotion recognition face-matching paradigm of Hariri et al. [
53]. In this task, participants see three items on a screen: either faces showing emotional states such as anger or fear in the experimental condition or geometrical figures in the control condition. A reference item is shown at the top and two items for comparison left and right below the target item. The task is to indicate which of the two comparison items is identical to the target item. Each face and object was presented for 5 s in an A–B block design. Each block lasted around 30 s with a total experimental duration of 4.5 min. The task was presented with presentation (neurobehavioral systems) and responses were given via button press (current design).
Data acquisition and analyses
Sociodemographic characteristics and clinical variables at baseline were compared between groups using parametric Student t test and χ2 test. In case the assumption of normal distribution was violated, non-parametric Mann–Whitney U test was applied. Effect-sizes were calculated for between-group differences using Cohens’ d for normally distributed and Rosenthals’ r for non-normally distributed data. Statistical analyses were performed using the Statistical package for Social Sciences (SPSS version 24.0, Chicago, IL, US), assuming a two-sided significance levels of α < 0.05.
Functional imaging data was acquired with a 3 T Siemens Tim TRIO (Siemens Erlangen). An echo-planar imaging (EPI) sequence was used with the following parameters: 28 axial slices, field of view 19.2 cm, matrix 64 × 64, voxel size 3 × 3 × 5 mm3, repetition time 2000 ms, echo time 30 ms. Scans were acquired in descending order. 134 scans were acquired for the face-matching task. The first four volumes were discarded to account for saturation effects.
Functional imaging data was analyzed using SPM8 (
http://www.fil.ion.ucl.ac.uk/spm/software/spm8/). Pre-processing involved realignment, slice time correction, normalization to the standard MNI-EPI-template (Montreal Neurological Institute [MNI] EPI template) with resampling to an isotropic 3 × 3 × 3 mm voxel size and smoothing with a 9 mm full-width at half-maximum Gaussian filter.
To estimate individual neural activity, the general linear model (GLM) was applied to the BOLD-signal change. BOLD changes for each condition (faces, geometrical shapes) were modeled as a convolution of the canonical hemodynamic response function with a box-car function of the corresponding condition. Additionally, head movement was taken into account by means of six regressors (three translations, three rotations) obtained from realignment. For functional connectivity analyses with the left amygdala (seed region), eigenvariate time series were extracted from this region, and used as an additional regressor in the second GLM analysis. Further, eigenvariate time series from white matter and cerebrospinal fluid were extracted and used as covariates. To avoid confounding effects of task activation, amygdala’s eigenvariates were calculated after task activations were regressed out of the data in the first GLM.
For activity analyses of the contrast faces > geometrical figures, second-level group statistics were conducted by one-sample and two-sample t tests, and regression analyses. Second-level connectivity analyses were achieved with two-sample t test. Significance threshold at the voxel level was set to p < 0.05 FWE corrected, k = 10 for whole brain analyses. In addition, region of interest (ROI) analyses for activity differences were conducted for left and right amygdala. Furthermore, to investigate differences between groups in connectivity of the amygdala with the corticolimbic-ventral striatal circuitry, we applied ROIs for left and right ventral striatum. Masks were taken from the Wake Forest University (WFU)-Pickatlas. The ROI of the left amygdala was also taken for eigenvariate extraction for functional connectivity. Significance threshold for the ROI analyses at the voxel level was set to p < 0.05, small volume corrected (svc), k = 10.