Gender differences in anxiety and depressive symptomatology determined by network analysis in panic disorder

Panic disorder (PD) is characterized by recurrent, unexpected panic attacks, significant maladaptive behavior change associated with the attacks (e.g., phobic avoidance), and social, familial, or occupational functional impairment (American Psychiatric Association and A.P.A.D.S.M.T.F., 2013; American Psychiatric Association and A.P.A.T.F.o.D.S.M.I.V., 2000; VandenBos, 2007). Further, depending on the clinical course, PD can usually be accompanied by other psychiatric conditions, such as agoraphobia, social phobia, or major depression (Bruce et al., 2005; Noyes et al., 1990). In particular, secondary depression may occur in approximately 57 % of patients with PD (Breier et al., 1984). Therefore, it is important to consider various psychiatric symptoms in addition to panic attacks simultaneously when evaluating patients with PD in a clinical setting.

Gender can play a role in the differences in clinical symptom presentation and functioning in PD as well as major depression (Piccinelli and Wilkinson, 2000; Sheikh et al., 2002). Female patients with PD tended to experience more stressful life events (SLEs), such as separation events, physical illness, or pregnancy-related issues than male patients (Kim et al., 2017). Additionally, female patients with PD were likely to exhibit more severe agoraphobia symptoms than their male counterparts (Kim et al., 2017). Additionally, women were more likely to experience high lifetime prevalence rates of comorbid secondary depression than men with anxiety disorder including PD (McLean et al., 2011). In other words, there are differences in vulnerability to SLEs, anxiety and depressive symptom patterns in clinical condition.

A neurochemical study of gender differences in patients with anxiety disorders, including PD, reported significant gender-dependent alterations in brain metabolites (i.e., glutamate or glycerophosphocholine plus phosphocholine) (Pigoni et al., 2020). These findings suggest the possibility of functional or structural changes as well as the neurochemical alterations in patients with PD (Cosgrove et al., 2007). A PET study in patients with PD revealed that in comparison with women, men showed a higher SERT availability in the brain stem raphe, temporal gyrus, anterior cingulate, insula, orbits frontal, prefrontal, and frontal cortices, but lower SERT availability in the hippocampus (Maron et al., 2011). A structural neuroimaging study demonstrated gender differences in the gray matter of PD patients. They also reported that women had lesser gray matter volume in the superior temporal gyrus compared to men (Asami et al., 2009). Neuroimaging hallmarks of PD include structural abnormalities in brain regions, including the corpus callosum, external capsule, cingulum, striatum, uncinate fasciculus, and insula (Asami et al., 2009; Han et al., 2008; Kim et al., 2014; Lai et al., 2013; van Velzen et al., 2020; Wang et al., 2021). However, to the best of our knowledge, the white matter (WM) differences according to gender in large samples of patients with PD have not been examined. Therefore, we investigated WM differences in patients of both genders in whole-brain areas.

In the traditional categorical or dimensional approaches in psychiatry, based on the Diagnostic and Statistical Manual of Mental Disorders (DSM), or International Classification of Diseases (ICD), a latent model has been used that considers the relationship between latent and observable variables (Lazarsfeld, 1959; Mellenbergh, 1994). This model assumes that the observable symptoms are influenced by the unobserved or underlying causes (e.g., mental disorders) that is, the model uses the “latent variable” to explain the directly unobserved psychiatric disorder (Bollen, 2002). Additionally, the model assumes that each observable variable related to the latent variable is equally importance (Bollen, 1989). This assumption can be helpful for conducting quantitative research. However, it is difficult to assess the causality or importance in the complex relationships between symptoms and mental disorders (Borsboom et al., 2003; Jones et al., 2017; McNally, 2021). As an alternative to overcoming the shortcomings of the traditional approach, a network approach to psychopathology has been proposed. The network approach can characterize dynamic interactions considering the importance of relationships among symptoms in the complex psychiatric network (Jones et al., 2017). The advantages of the network approach allow the investigation of the target symptoms within a psychiatric disorder and the associations between symptoms and the comorbidity of the psychiatric disease (Boschloo et al., 2015). Recently, in a comparison between the expanded network approach and traditional approach, nodes were not limited to symptoms but included biological, cognitive, or social variables (Jones et al., 2017). Through a network approach, a study experimentally revealed that relationships between symptoms and symptoms-related brain structure could be explored in patients with depression (Hilland et al., 2019). However, no network studies were conducted on patients with PD by evaluating the importance and patterns of the relationship between various variables—including anxiety and depressive symptomatology and WM neural correlates—according to gender.

We aimed to examine the gender differences of the importance and patterns in the networks consisting of PD-related symptomatology or WM neural correlates. The hypotheses of the present study were as follows: there will be gender differences in the central symptoms as the centrality measures in PD-related symptomatology network within patients with PD; and 2) there will be gender differences in the bridge centrality indices in the PD-related symptomatology and WM neural correlates network among patients with PD.

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