To the best of our knowledge, this is the first study to date investigating the impact of long-term monotherapy of clozapine and risperidone on callosal structure in chronic schizophrenia. Our analyses demonstrated significant deficits of micro- and macrostructure of the CC in never-treated patients that were mainly located in anterior and mid-anterior CC. Moreover, patients receiving antipsychotic medications showed significantly increased FA values in the anterior CC region in comparison with NT-SCZ, and only patients with risperidone treatment had larger volume in the mid-anterior CC region compared with NT-SCZ. Together, these findings suggest that chronic exposure to clozapine and risperidone may have different effects on callosal structure in schizophrenia.
The findings of our present study agree well with other studies in the literature demonstrating that chronic patients were associated with smaller CC volume or FA value in comparison with healthy comparison subjects [3, 12, 21–23]. As an extension of prior findings, one important observation here is that callosal deficits were mainly located in anterior and mid-anterior CC. White matter fibers passing through these subregions are responsible for connecting the frontal lobes [24, 25]. Therefore, anatomical alterations in the anterior and mid-anterior region of the CC may be related to structural and functional abnormalities of the frontal lobe in schizophrenia, which generate delusions and hallucinations [26, 27]. However, other studies showed that chronic schizophrenia patients had more widespread deficits that were located in both anterior and posterior region of the CC [3, 21, 22]. This discrepancy may be due to sample heterogeneities related to race, handedness, sex, and age, and to methodological differences [3]. Apart from anterior and mid-anterior CC, we also observed significant volume reduction in central CC in patients, which is in line with findings from Collinson et al [12]. Notably, dynamical alterations of this subregion in schizophrenia are associated with stage of illness [12]. Thus, it is interesting to explore whether structural alterations in central CC are a stable biomarker to predict the developmental trajectory of schizophrenia in future studies.
The observation that micro- and macrostructural abnormalities of the CC in schizophrenia were located in different subregions is in line with several previous studies [21, 26]. Here, we found that alterations of callosal volume were in the mid-anterior and central region, and abnormalities of white matter integrity were only in the anterior region of the CC. It has been proposed that changes in the number of axons and the degree of myelination may lead to the changes in white matter volume but not anisotropy [12, 28, 29]. Since the index of anisotropy is related with fiber integrity [30, 31], its change in schizophrenia patients may relate to disruptions of oligodendrocytes and/or myelin surrounding axons because of inflammation or dysregulations of neuroinflammatory responses [32–35]. Our findings suggest different pathophysiological processes in these subregions of the CC.
The current findings, together with findings from previous studies, suggest that chronic exposure to antipsychotics may have an impact on anatomical organization of the CC in schizophrenia [15, 36]. In this study, both CT-SCZ and RT-SCZ showed significantly increased FA values in the anterior CC region in comparison with NT-SCZ. A series of studies have demonstrated that antipsychotic medications, such as clozapine and risperidone, may modulate inflammations and immune responses through reduced activation of microglia and macrophages, increased level of anti-inflammatory cytokines, and inhibition of the release of proinflammatory cytokines [37–39]. Therefore, clozapine and risperidone may repair white matter microstructures of the CC by reducing inflammation or immune responses. Interestingly, only patients receiving long-term risperidone, not clozapine, showed significantly increased volume of mid-anterior CC. It has been suggested that dopamine D2 receptor signal pathway may indirectly activate Akt and glycogen synthase kinase 3 (GSK3) to inhibit myelination by regulating a β-arresting 2 (βArr2)/protein phosphatase 2A (PP2A) signaling complex [40]. Evidences from gene expression profiling and neuroimaging studies also support the hypothesis that dysregulation of the dopaminergic system in psychiatric disorders is associated with aberrant dopamine receptor signaling on oligodendrocytes, further leading to myelination impairment [40, 41]. Bartzokis et al found that typical and atypical antipsychotics differently mitigated myelination deficits in schizophrenia depending on their affinities to dopamine D2 receptors [8, 42, 43]. Since risperidone has a stronger affinity for dopamine D2 receptors than clozapine [10], our findings may suggest that different impacts of two drugs on CC are related to their different abilities in modulating the dopaminergic system.
There are several limitations in the present study. First, because that this study is a cross-sectional design and it lack of random assignments to different antipsychotic medications for schizophrenia patients, it should be careful to interpret our current findings. However, it is unethical and challenging to request the patients to receive a single antipsychotic treatment for over five years in a longitudinal study with a randomize design. Therefore, our cross-sectional design may be a feasible method to explore the effects of long-term usage of antipsychotic medications on human brain. Second, the sample size in this study is relatively small, and may be not completely representative. Third, the usage of non-antipsychotic medications was not controlled according to individual clinical condition.