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Denna Repaci
1Department of Psychiatry, School of Medicine, Kyungpook National University, Daegu, Korea.
2Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
3Department of Psychiatry, Gachon Medical School, Gachon University of Medicine and Science, Incheon, Korea.
4Department of Neuropsychiatry, Seoul Metropolitan Boramae Medical Center, Seoul, Korea.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( -nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Panic disorder (PD) and major depressive disorder (MDD) can occur concurrently, despite different clinical manifestations. Because MDD and PD patients tend to have more complicated conditions, understanding the co-occurrence and pattern of these conditions is important. Here, we investigated the influence of PD and MDD on each other, with respect to time interval.
Data from three national representative surveys were pooled (total 18,807 respondents), and the age of onset (AOO) of PD and MDD was analyzed. We performed Kaplan-Meier analysis to estimate separate survival functions, using the AOO of MDD and PD as the outcome. To understand the temporal effect of other disorders, we used a Cox proportional hazard model to estimate the hazard ratios for the onset of MDD/PD with other comorbidities as time-dependent covariates.
The comorbidity of panic disorder (PD) and major depressive disorder (MDD) is common in both clinical and general settings.1, 2 According to a previous study,2 55.6% of patients with PD and 11.2% of those with MDD experience the other disorder in their life. Although this comorbidity is very prevalent, few researchers and clinicians have pay attention to this. Moreover, we may not consider the association of them since the symptomatic and biological profiles of these two disorders are quite different.3, 4 However, the association between them is much stronger than any other comorbidities of psychiatirc disorders.1, 5 In a recent study, 98% patients with PD had one or more lifetime comorbidities and MDD was also the most common comorbidity.6 Despite this strong relevance, clinicians may not be aware of this comorbidity due to the different symptom profiles and the lack of information about this comorbidity. Furthermore, in this context this common comorbidity can remain untreated, which result in serious consequences such as hospitalization and suicide.7, 8 Patients with comorbidities of MDD and PD have poorer outcomes and higher suicidality than those with one of these conditions.2, 9, 10, 11 Therefore, it is crucial to focus on and understand the pattern of the co-occurrence of these disorders, which may facilitate the detection and management of this complicated condition in clinical settings.
Both PD and MDD may be present simultaneously or their onset may occur at a time interval. There are three possibilities of the occurrence of these comorbidities in a lifetime: first, PD precedes MDD; second, MDD precedes PD; third, PD and MDD are simultaneously present. Several studies have focused on a temporal priority between anxiety disorder and depressive disorder with respect to their onset order. The results revealed that anxiety disorder developed before depressive disorder.12, 13 Similar results were observed in case of PD and MDD.8 The results of these studies have reported unidirectionality in the comorbidity of anxiety and depressive disorders. However, in actual clinical settings, an opposite directionality has been reported.2, 8 Notably, the most recent meta-analysis has suggested bidirectional associations between anxiety disorder and depressive disorders, except for social and specific phobia and depressive disorder.14 In addition to the above directionality, the pattern of intensity of the occurrence can be analyzed with respect to the time point. A previous study has shown that the risk of comorbidity is the highest in the same year and decreases over time.8
In this study, we analyze the association between PD and MDD, with respect to the time interval, and verify the bidirectionality. First, we will examine the cumulative occurrence of MDD and PD, depending on the presence or absence of the other disease. Second, the hazard ratios (HRs) of the occurrence of PD or MDD was calculated by the time interval after the other disorder developed first. While most of previous studies have only focused on comorbidity rate and temporal priority, we try to find a clinical implication by focusing on time lag of first onset between PD and MDD. In particular, our study has strengths in that we analyzed the comorbidity between PD and MDD for the first time in Asian.
We extracted data from three nationwide epidemiological surveys: Korean Epidemiologic Catchment Area study (KECA),15 Korean Epidemiologic Catchment Area study replication (KECA-R),16 and 2011 Korean Epidemiologic Catchment Area study (KECA-2011).17 These three surveys investigated the prevalence of psychiatric disorders based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) in Korean adults aged 18 years and older. Each survey was conducted with the same design, but the sample of each was independent. Subjects were selected by multistage, cluster sampling of 18,807 adults across 12 catchment areas (6,275 in KECA; 6,510 in KECA-R; and 6,022 in KECA-2011). The subjects were interviewed using a full-structured diagnostic tool, the Korean version of the Composite International Diagnostic Interview (K-CIDI).18, 19 Data were pooled from all three surveys, and the respondents diagnosed with the onset of MDD and PD were examined.
KECA, KECA-R, and KECA-2011 diagnosed MDD and PD according to the mood and anxiety sections in the K-CIDI. In these sections, the subjects were retrospectively asked about the age of onset (AOO) according to the K-CIDI question series. The retrospective diagnostic AOO report in the CIDI has a limitation of acceptability, but revealed a good test-retest reliability.20
Sociodemographic and clinical characteristics of the subjects are summarized in Table 1 and Fig. 1. Among the 18,807 respondents, 1,415 and 118 were diagnosed as having at least one episode of MDD and PD, respectively. The lifetime prevalence of MDD and PD was 7.0% and 0.6%, respectively; the prevalence of these comorbidities was 0.3%.
Fig. 2Cumulative occurrence of MDD over time in patients with and without PD (adjusted by age and gender).All other disorders: alcohol use disorder, eating disorder, obsessive-compulsive disorder, post-traumatic stress disorder, psychotic disorder, bipolar disorder, dysthymic disorder, social phobia, generalized anxiety disorder, specific phobia.PD = panic disorder, MDD = major depressive disorder.
Fig. 3Cumulative occurrence of PD over time in patients with and without MDD (adjusted by age and gender).All other disorders: alcohol use disorder, eating disorder, obsessive-compulsive disorder, post-traumatic stress disorder, psychotic disorder, bipolar disorder, dysthymic disorder, social phobia, generalized anxiety disorder, specific phobia.PD = panic disorder, MDD = major depressive disorder.
The findings of the present study revealed that PD was significantly associated with an elevated risk of subsequent MDD. PD elevated the risk of subsequent MDD by 9.6-fold; after adjustment for the previous onset of all other disorders, this risk was reduced to 1.5-fold, but was still statistically significant. Previous studies have only shown that PD increased the risk of subsequent MDD, whereas our results show additional evidence that MDD increased the risk of subsequent PD. MDD elevated the risk of subsequent PD by 14.7-fold. After adjustment for the previous onset of all other disorders, the risk was decreased to 3.8-fold. The reasons for this difference in finding cannot apparently be explained in this study, but we may consider culture and ethnicity as influencing factors. Notably, the patterns of disease occurrence and prevalence rate of MDD and PD vary according to race, ethnicity, and country; their prevalence was actually lower in Asian countries than in Western countries.15, 21, 22, 23, 24 Therefore, further research is needed to explain the difference in our results compared with those of previous studies. Nevertheless, in actual clinical settings, we could meet a substantial number of patients with PD having a previous history of depression. In addition, this type of patients have existed even in several studies that did not statistically present the directionality from MDD to PD. Therefore, it seems necessary to focus on this directional relationship. In fact, there have been studies showed the association between PD and MDD. Stein and Uhde25 argued that PD and MDD are non- identical disorders with a lot of neurobiological similarities. PD and MDD have several shared risk factors such as the exposure to childhood abuse26, 27 and information-processing bias.28, 29 Cox et al.30 showed that negative affectivity, neuroticism, low positive affect and anxious arousal could be worked as shared risk factors between PD and MDD based on the tripartite model. As an extension of this study, large-scale genetics studies were conducted afterward and found that PD and MDD shared genetic variation which was related with personality trait of neuroticism.31, 32 Although there have been studies supporting the bidirectional association, it is still difficult to confirm the pathogenesis of association between PD and MDD since the precise pathophysiology of each disorders are not even understood fully. These shared factors can be considered as acceptable to explain the comorbidity in that they make individuals vulnerable to stress or many psychopathologies. However, further and well-designed researches are needed on this issue because these may also be risk factors for other psychiatric disorders. To our knowledge, this study is the first to reveal the bidirectional relationship between MDD and PD by analyzing large epidemiological data.
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