Effects of comorbid anxiety disorders on the course of bipolar disorder-I SADIYE VISAL BUTURAK, ORHAN MURAT KOÇAK

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Buturak SV, Koçak OM. Effects of comorbid anxiety disorders on the course of bipolar disorder-I. Nord J Psychiatry 2015;Early Online:1–5. Background and aims: Although comorbid anxiety disorders (AD) are quite frequent in bipolar disorders (BD), data on how this comorbidity affects BD are limited. In the present study, we aimed to investigate the frequency of comorbid AD in Turkish patients with bipolar disorder-I (BD-I) and the effects of comorbid AD on the course of BD-I. Methods: 114 patients with BD-I were included in the study. All patients were diagnosed by a psychiatrist. The patients were divided into two groups as BD-I patients with lifetime comorbid AD (BDI-CAD) or those without comorbid AD (BDI). Results: 37 (32.46%) patients had one or more comorbid lifetime AD. The numbers of admissions to the outpatient clinic within calendar year 2013 (P ⫽ 0.014), the number of lifetime mood episodes (P ⫽ 0.019) and the duration of BD (P ⫽ 0.007) were higher in the BDI-CAD group compared with the BDI group. There was a strong relationship between the duration of the disorder and the number of episodes (r ⫽ 0.583, P ⬍ 0.001). Partial correlation analyses showed that the number of admission to the outpatient clinic correlated significantly with the frequency of episodes (P ⫽ 0.007, r ⫽ 0.282). Conclusion: We found that the patients with BDI-CAD use the healthcare system more frequently than the BDI patients. This suggests that AD comorbidity may have a negative influence on the course of BD-I and it is a factor that should be considered in the clinical follow-up. • Anxiety disorders, Bipolar disorders, Bipolar disorder I, Comorbidity, Mood disorders. Sadiye Visal Buturak, Department of Psychiatry, Kirikkale University Faculty of Medicine, Yahsihan Yerleskesi, Kirikkale, Turkey, E-mail: [email protected]; Accepted 30 January 2015.

C

omorbidity is the co-occurrence of two or more diseases or disorders in the same patient (1). In psychiatry, particularly in mood and anxiety disorders (AD), comorbidity is the rule rather than the exception (2). Studies about the prevalence of AD comorbidity with bipolar disorders (BD) have found that the rate of comorbid AD with BD ranges from 15.7% to 88.1% (3, 4). In a comprehensive review by Vázquez et al., the average rates of comorbid AD in BD and bipolar disorder-I (BD-I) were reported as 46.8% and 48.2%, respectively (5). The frequency of the types of comorbid AD in BD-I patients differs in various studies. Tamam & Ozpoyraz found that obsessive–compulsive disorder (OCD) (39%) was the most common comorbid lifetime AD, followed by specific phobia (SPP) (26%) and social phobia (SP) (20%) in BD-I patients (6). In another study the ratio of types of comorbid AD in BD-I ranges as SP (51.6%), SPP (47.1%), generalized AD (GAD) (38.7%), post-traumatic stress syndrome (PTSD) (30.9%), panic disorder (PD) (29.1%), OCD (25.2%) (4). In their review, Vázquez et al. (5) reported the frequency rank-

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ing of comorbid AD types in BD-I patients as follows: SP and SPPⱖ PDⱖ GADⱖ PTSDⱖ OCD. As some symptoms overlap among disorders, especially among mood disorders and AD, the diagnosis of comorbid disorders is important in many respects (7–13). In addition, it has been shown that comorbid AD can negatively affect the clinical course and treatment of BD (14, 15). Young et al. (16) reported that BD patients with comorbid AD might have a higher number of mixed episodes. Another study reported early age at onset in condition of comorbid AD with BD (6). Moreover, longer stays in the hospital, more suicide attempts, resistance to pharmacotherapy (17) and higher treatment non-adherence rates (18) have been shown in bipolar patients with comorbid AD in the literature. Because comorbid AD with BD could influence the prognosis of BD, comorbid disorders in BD has drawn attention (19, 20). However, as aforementioned, the clinic properties of BD and AD comorbidity have not been sufficiently clarified to well manage the condition. Interestingly, it seems that the requirement of the clarification DOI: 10.3109/08039488.2015.1014835

S. V. BUTURAK & O. M. KOÇAK

has been out of the interest. In a recent review, it was shown that the number of literature about comorbid AD and BD increased gradually from 1990 until 2007 and then declined or reached a plateau (21). In present study, we aimed to detect the frequency of comorbid AD in BD-I patients in Turkish population and investigate the effects of comorbid AD on variables associated with the course of BD-I such as hospitalization, suicidality, number of episodes, age at onset and duration of the disorder.

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Patients This retrospective clinical study was performed in accordance with the guidelines for human subjects in research set by the Ethical Committee of Kirikkale University. All patients diagnosed as BD-I in the BD Outpatient Clinic in the Kirikkale University Faculty of Medicine Department of Psychiatry by psychiatrists from May 2011 until December 2012, were included in the study. The outpatient BD clinic of the Kirikkale University Faculty of Medicine Department of Psychiatry was established in May 2011. This is a tertiary medical center. All patients were followed up with using the Diagnostic and Follow-Up Form for Mood Disorders (SKIP-TURK form) (22, 23) and were diagnosed by an experienced psychiatrist according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (24) using the Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-I) (25, 26) in this clinic. Data about age, age at onset, number of episodes, duration of the disorder, presence of hospitalization, suicide attempts and comorbidity were obtained from SKIP-TURK form. In BD outpatient clinic, information about the patient is gathered from patients and their close relatives. If patients and relatives do not remember an information about past, this information is not registered to the SKIP-TURK form. All patients were divided into two groups as follows: • •

BD-I patients with lifetime comorbid AD (BDICAD); BD-I patients without comorbid AD (BDI).

The number of admission to the outpatient clinic of the patients within calendar year of 2013 has been identified from the hospital admission records and registered without the cause of the visit or the mental state as number of admission to the outpatient clinic. The person who counted the number of admissions to outpatient clinic was blinded to the patients. We thought that episode frequency is more important than the number of lifetime episodes in the course of the BD. For this reason, the number of lifetime episodes was divided by the duration of the illness (the number of months from the beginning of the BD) to determine the frequency of episodes.

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Materials SKIP-TURK FORM The SKIP-TURK form is a standardized form based on a national follow-up program for mood disorders (22, 23). This form includes socio-demographic variables (such as age, education, marital status and job) and data about the disorder (such as age at onset, number of episodes, hospitalization, suicide attempts, duration of the illness, comorbidities and family history of psychiatric disorders). STRUCTURED CLINICAL INTERVIEW FOR DSM-IV AXIS I DISORDERS (SCID-I) The SCID-I was designed for psychiatrists to use to determine DSM-IV Axis-I disorders (25). Turkish validity and reliability of the SCID-I had performed by Corapcioglu et al. (26). We used the Turkish version of the SCID-I to diagnose bipolar disorders and lifetime AD comorbidities.

Statistical analysis The Statistical Package for Social Sciences (SPSS/ PC 17.0) program was used to analyze the study results. The Mann–Whitney U test was performed to determine the statistical difference between the BDI-CAD and BDI groups for the variables with non-normal distributions as age of patients, age at onset, number of episodes, duration of the disorder, hospitalization, frequency of episodes and number of admission to the outpatient clinic in 2013. The chi-squared test was performed to analyze the differences between the BDI-CAD and BDI groups for gender, educational levels, marital status and suicide attempt, and P-values less than 0.05 were considered significant. A Spearman correlation test was carried out to assess the relationships among frequency of episodes, number of admission to the outpatient clinic, number of episode, age at onset and the duration of disorder. The correlations between number of admission to the outpatient clinic and number of episode, age at onset, the duration of disorder and frequency of episodes were assessed with partial correlation analyses by controlling the effects of AD. Correlation is significant at the 0.01 level (two-tailed).

Results Seventy-seven (67.54%) of the enrolled patients had no lifetime comorbid AD and 37 (32.46%) patients had one or more comorbid lifetime AD (Tables 1 and 2). Fortyone patients in BDI group and 25 patients in BDI-CAD group were female. The comparison of the two grouping terms of gender, education, marital status is shown in Table 1. The median ages of the BDI and BDI-CAD group were 39 and 43, respectively. The comparison of the ages of the two groups is shown in Table 2. NORD J PSYCHIATRY·EARLY ONLINE·2015

COMORBID ANXIETY DISORDERS IN BIPOLAR

Table 1. Comparison of socio-demographic variables between bipolar I patients with (BDI-CAD) and without (BDI) lifetime anxiety disorder.

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Variable Gender Female Male Marital status Married Other Suicidality None Yes Education ⬍ 11 years ⬎ 11 years

BDI

χ2

BDI-CAD

df

outpatient clinic was correlated with the frequency of episodes (P ⫽ 0.007, r ⫽ 0.282).

P

Conclusion 41 36

25 12

2.103

1

0.147

38 39

24 13

2.425

1

0.119

64 13

26 11

2.500

1

0.115

56 21

25 12

0.323

1

0.570

df, degree of freedom.

Some patients did not remember age at onset (n ⫽ 1), number of lifetime episodes (n ⫽ 21) and number of hospitalization (n ⫽ 2). These patients were not included to the statistical analysis. The number of episodes, the duration of the disorder and the number of hospital visits in 2013 were higher in the BDI-CAD group (Table 2). There was a strong relationship between the duration of the disorder and the number of episodes (Table 3). The Spearman correlation analyses showed that the number of admission to the outpatient clinic was not correlated with the frequency of episodes, the number of episodes and the duration of the disorder (Table 3). However, when the effect of AD was controlled in partial correlation analyses, the number of admission to the

Table 2. Comparison of number of episodes, disorder duration and the number of admission to the outpatient clinic during the last year between bipolar I patients with (BDI-CAD) and without (BDI) lifetime anxiety disorder. Variable

DISORDER-I

Groups

Number of admission to the BDI outpatient clinic BDI-CAD Age BDI BDI-CAD Age at onset BDI BDI-CAD Duration of disorder BDI BDI-CAD Number of episodes BDI BDI-CAD Hospitalization BDI BDI-CAD Frequency of episodes BDI BDI-CAD

NORD J PSYCHIATRY·EARLY ONLINE·2015

n

Median

P

77

4.0 (1.0–9.0)

0.014

37 77 37 76 37 76 37 59 34 75 37 58 34

8.0 (3.0–12.0) 39.0 (25.0–49.0) 43.0 (32.5–50.5) 23.5 (19.0–30.0) 24.0 (20.0–30.5) 8.0 (4.0–19,0) 15.0 (8.5–25.0) 5.0 (3.0–10.0) 7.5 (4.0–14.0) 0.0 (0.0–2.0) 1.0 (0.0–2.0) 0.80 (0.50–1.30) 0.66 (0.37–1.0)

0.102 0.504 0.007 0.019 0.528 0.120

In the present study, lifetime AD comorbidity in BD-I patients was found to be 32.46%. The most common AD type detected in our study population was GAD (21.05%), followed by OCD (14.04%), social phobia (11.04%) and PD (1.75%). In the literature, there are inconsistent results about the rates of AD comorbidity with BD. For example, Merikangas et al. (4) reported 86.7% AD comorbidity in a US population. On the other hand, Brieger et al. (3) reported a lower comorbidity rate, 15.7%, in Germany. A recent study reported that lifetime prevalence rate of AD comorbidity in Korean BD patients was 30.2%. The authors of the study attributed the variability of the results to social, genetic, ethnic and cultural factors (27). These factors may explain the dissimilar study results. However, the results of studies about frequency of the AD comorbidity in BD that conducted in the same country are also different. For example there are two other studies (6, 28) focused on frequency of the AD comorbidity in Turkish BD patients. Tamam & Ozpoyraz (6) reported the rate of lifetime AD comorbidity with BD was 61.4% in 70 bipolar patients with a prospective study design. However, Ibilo lu & Caykoylu (28) found that the rate of current AD comorbidity with BD was 24% in a prospective study. Thus it can be concluded that the frequency of AD comorbidity is not affected by the population properties but also influenced by methodology of studies. In addition, difficulty of distinguishing AD from anxiety symptoms that can be seen in mood disorders (16) may have an effect on variability of the results. Further researches are needed to determine the likely causes of different results. There were no statistical differences between the groups in terms of socio-demographic variables in this study, which is consistent with literature (29). However, in some studies, researchers found an association between comorbid AD with BD and being female (6, 19). Results of the studies on the effects of AD comorbidity on the course of BD are controversial. This study showed that BDI-CAD patients had a higher number of mood episodes and had significantly longer durations of illness than BDI patients. These results could indicate that comorbid AD deteriorates the course of BD-I. In the literature, other studies found a relationship between comorbid AD with BD and early age at onset, duration of hospitalization, postpartum onset, suicide attempts and moderate to severe manic/depressive episodes (5). In our study severity, duration of episodes, duration of hospitalization could not be assessed because of retrospective design. This study did not show statistical differences between the two groups for hospitalization, age at onset,

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S. V. BUTURAK & O. M. KOÇAK

Table 3. The correlation analyses of the frequency of episodes, number of episodes, duration of disorder, age at onset, number of admission to the outpatient clinic.

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Number of admission to the Number of Duration outpatient clinic episodes of disorder Number of admission to the outpatient clinic r P Number of episodes r P Duration of disorder r P Age at onset r P Frequency of episodes r P

Age at onset

1.000 –

0.062 0.558

⫺ 0.095 0.316

0.062 0.558

1.000 –

0.583** ⬍ 0.001

⫺ 0.095 0.316

0.583** ⬍ 0.001

1.000 –

⫺ 0.052 0.581

⫺ 0.115 0.223

0.313** 0.002

⫺ 0.052 0.581

1.000 –

0.213* 0.041

0.247* 0.018

⫺ 0.605** ⬍ 0.001

0.213* 0.041

1.000 –

0.166 0.115

⫺ 0.115 0.223

Frequency of episodes

0.313** 0.002

0.166 0.115 0.247* 0.018 ⫺ 0.605** ⬍ 0.001

r, correlation coefficient.

frequency of episodes and presence of suicide attempts. Parallel to previous studies, the results of this study also show that AD comorbidity can affect the course of BD-I negatively. However, unlike other studies, an objective variable (the number of admissions to the psychiatry outpatient clinic) was compared between the BDI-CAD and BDI groups. The number of admissions to the psychiatry outpatient clinic was significantly higher in BDI-CAD group. This shows that comorbid AD affects not only the course of BD-I but also the use of mental health services. Because BD with comorbid AD has been considered to have a poor prognosis (21), a higher number of admissions to the psychiatry clinic might be indicative of a natural consequence of poor clinical course of BDICAD. When the effect of AD comorbidity was controlled in partial correlation analysis, it was found that the number of admissions to the psychiatry clinic was strongly related to the frequency of episodes. This factor is associated with severity of BD. This finding suggests that the higher number of admissions to the psychiatry outpatient clinic is associated with a poor clinical course of BDICAD. These results support the previous study outcomes that AD comorbidity negatively affects the course and severity of BD-I (5). Such variables as presence of suicide attempts, hospitalizations and number of episodes may provide information about the clinical course of the disorder. In this study, there were no statistical differences between the two groups with respect to number of hospitalizations or presence of suicide attempts. However, the number of lifetime mood episodes was significantly higher in BDI-

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CAD patients, which may explain the higher rate of psychiatric outpatient admissions observed in patients with AD comorbidity. Based on this finding, one might suggest that comorbid AD in patients with BD-I lead to an increase in number of mood episodes. On the other hand, more mood episodes in these patients may be a function of duration of disorder, which was found to be longer in BDI-CAD group. This led us to the thought that the frequency of mood episodes may provide more valuable information concerning the effect of comorbid AD on clinical course. Then we evaluated frequency of mood episodes to determine whether AD comorbidity affects the clinical course negatively or facilitates staying in clinical follow-up. If mood episodes were more frequent in the BDI-CAD patients than the patients without comorbid AD, we could think that the higher number of mood episodes was independent of the total duration of disorder and that comorbid AD in BD-I patients might be associated with more frequent mood episodes. However, we found that episode frequencies were not statistically different between the two groups of patients. Although their mood episodes were not more frequent, BDI-CAD patients showed a statistically higher number of psychiatric outpatient admissions. Thus, the results can be interpreted as indicating that anxiety symptoms may be a factor pushing the patients for more frequent outpatient visits. Alternatively, it seems that AD may be a consequence of a more chronic disorder. Overall, our data show that the decision about the effect of AD comorbidity on the clinical course of BD-I is not straightforward, which supports idea that it is not clear enough whether treatment of comorbid AD diminishes the severity of bipolar disorder (30). NORD J PSYCHIATRY·EARLY ONLINE·2015

COMORBID ANXIETY DISORDERS IN BIPOLAR

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Retrospective study design is one of the limitations of this study. Because of the study design, we did not evaluate why the BD-I patients with comorbid AD had higher admissions to psychiatric outpatient clinic in comparison with BD patients without AD. In summary, the present study found that BD-I patients with comorbid AD are much more likely to use the mental healthcare system than BD-I patients without comorbid AD. This study calls attention to the need for further studies about the effect of comorbid AD in clinical course of BD and the usage of the healthcare system by BDI-CAD patients. Acknowledgement—The authors would like to express their thanks and gratitude to Professor Kemal Yazici, M.D., and Associate Professor Bulent Bakar, M.D., for his skilled assistance during the study.

Conflict of interest statement: The authors declare that they have no conflict of interest.

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Effects of comorbid anxiety disorders on the course of bipolar disorder-I.

Although comorbid anxiety disorders (AD) are quite frequent in bipolar disorders (BD), data on how this comorbidity affects BD are limited. In the pre...
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