INT’L. J. PSYCHIATRY IN MEDICINE, Vol. 46(1) 39-55, 2013
DEPRESSION, IRRITABILITY, AND ANXIETY IN WOMEN WITH PREMENSTRUAL DYSPHORIC DISORDER* CHIH-HUNG KO Kaohsiung Medical University, and Kaohsiung Medical University Hospital, Taiwan CHENG-YU LONG Kaohsiung Municipal Hsiao-Kang Hospital, Taiwan SU-YIN CHEN I-JU CHEN Kaohsiung Medical University Hospital and Kaohsiung Medical University, Taiwan TZU-HUI HUANG Kaohsiung Medical University, Taiwan JU-YU YEN Kaohsiung Medical University Hospital, Taiwan, and Kaohsiung Municipal Ta-Tung Hospital, Taiwan
ABSTRACT
Objective: Depression, anxiety, and irritability are the three most studied symptoms of premenstrual dysphoric disorder (PMDD). This study aimed to assess the premenstrual exacerbation of these symptoms and their role in the *This study was supported by grants from the National Science Council (NSC 100-2629B-037 -001 -MY2) and the Kaohsiung Medical University Hospital (KMUH100-0R51). These institutions have no role in the design, process, analyses, and production of the present study. The other authors declare that they have no conflict of interest. 39 Ó 2013, Baywood Publishing Co., Inc. doi: http://dx.doi.org/10.2190/PM.46.1.d http://baywood.com
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diagnosis or functional impairment of PMDD. Methods: We recruited women with PMDD not undergoing any treatment and control subjects from the community. The diagnosis of PMDD was based on a positive score on the Premenstrual Symptoms Screening Tool and confirmed by psychiatric interviews and questionnaire follow-up for three menstrual cycles. A total of 67 women with PMDD and 75 control subjects participated the survey and reach the final analysis. They complete the Center for Epidemiological Studies, the Chinese Version of the Buss-Durkee Hostility Inventory-Short Form, and the Penn State Worry Questionnaire in both the premenstrual and follicular phases. Results: Women with PMDD, but no controls, demonstrate the premenstrual exacerbation of these three symptoms. Depression was the most prominent feature of the PMDD diagnosis while irritability was most frequently associated with functional impairment. Conclusions: Depression and irritability should be properly evaluated and treated among women with PMDD. (Int’l. J. Psychiatry in Medicine 2013;46:39-55)
Key Words: PMDD, depression, anxiety, irritability
INTRODUCTION Around 70%-90% of women of reproductive age have one or more signs of physical discomfort or emotional symptoms during the premenstrual phase of their menstrual cycle. About 20%-40% of the affected women have experienced premenstrual syndromes that are bothersome [1]. A small number, 3%-8%, of women of reproductive age experience more severe symptoms, which lead to substantial distress or functional impairment and meet the strict criteria for premenstrual dysphoric disorder (PMDD). The affected women have been estimated to experience almost 3,000 days of clinical symptoms during their reproductive age, resulting in a tough life burden and significant functional impairment [1]. The typical PMDD symptoms, including irritability, anger, mood swings, depression, tension/anxiety, abdominal bloating, breast pain, and fatigue, recur monthly and last for an average of 6 days per month during the majority of the reproductive years. The criteria demonstrate that PMDD includes the core symptoms of depression, irritability, anxiety, and tension in varying dimensions. However, the manner in which the symptoms of varying dimensions play a role in contributing to PMDD has not been thoroughly understood. Depression, anxiety, and irritability were the three most studied and prominent symptoms considered as criteria for PMDD [2, 3]. Earlier studies pay more attention to the connection between premenstrual symptoms and depression and anxiety [4, 5]. The results of co-morbidity study also support the association between them [6]. It has been suggested that severe premenstrual symptoms of a predominantly depressive nature are probably a manifestation of an underlying
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depressive disorder [7]. Further studies addressed the premenstrual exacerbations of psychiatric disorder and also supported the association between depression, anxiety, and premenstrual symptoms [7, 8]. Besides, the effect of selective serotonin reuptake inhibition (SSRI) on PMDD also supports the shared serotonin mechanism for PMDD, depression, and anxiety. The results mentioned above have suggested that PMDD is a variant of depressive disorder or anxiety disorder [3]. In the past decade, increasing attention has focused on the irritability symptoms of PMDD [9]. Irritability and aggression are frequent and prominent symptoms among women with PMDD [10-12]. Further, a recent study demonstrates that SSRI effectively improves the symptoms of irritability, as well as depression and anxiety [13]. Previous review also suggests that irritability is the cardinal symptom of PMDD [3]. Since irritability was a symptom independent of depression or anxiety, PMDD should be regarded as a distinct diagnostic entity, but not a variant of depressive or anxiety disorder [3]. However, the effect of depression, anxiety, or irritability on PMDD has not been well evaluated in a single data study to enable comparisons between them. Previous reports of treatment efficacy studies suggest that ovulation and ovulation-related processes may be a trigger for the onset of PMDD [14]. PMDD has been shown to be absent during menstrual cycles that are spontaneously anovulatory [15]. PMDD-like symptoms have been reported to be induced in postmenopausal women who received sequential hormonal replacement therapy (HRT) [16]. These observations and the menstrual cyclicity of symptoms are an indirect suggestion that gonadotropic hormones may play a role in the symptom formation of PMDD [17]. It has been suggested that the hormonal pattern of PMDD consists not in different levels of the hormones, but in different responses to normal hormonal levels [18]. However, a previous study did not find any significant association between estrogen or progesterone and depression and anxiety symptoms [19]. A study to evaluate the possible association between the gonadal hormone and these cardinal symptoms might shed light on the mechanism of PMDD. Thus, the aim of this study is to evaluate the depression, anxiety, and irritability symptoms among women and their relations to gonadotropic hormone with or without PMDD. Further, we investigate effects of these three symptoms on the diagnosis, functional impairment, and severity of PMDD. METHOD Participants Participants were recruited from an advertisement posted at a university campus specifically to attract PMDD patients not undergoing treatment and a control group from August, 2011 through October, 2012. The participants in the
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PMDD group had a positive response to five or more symptoms of the eleven DSM-IV-TR criteria of PMDD [24], and most symptoms relieved after menstruation. The control group had a positive response to fewer than 2 of the 11 DSM-IV-TR criteria of PMDD or had no functional impairment with mild symptoms. To prevent effects of psychotropic medication or gonadotropic medication on the function of serotonin or estrogen, subjects under current psychotropic or gonadotropic medication treatment were screened and excluded from the study. A total of 169 (90 in the PMDD group and 78 in the control group) women with at least a college education level were screened using the self-reported Premenstrual Symptoms Screening Tool (PSST) for moderate or severe premenstrual symptoms after informed consent was obtained. Eighty-six participants in the PMDD group and 75 in the control group were screened as positive and negative using the PSST, respectively. Participants were interviewed by one of two psychiatrists in order to make a diagnosis of PMDD based on the DSMIV-TR criteria [24]. Further, the psychotic disorder and bipolar I disorder were also excluded based on the Mini-International Neuropsychiatric Interview (MINI). Eighty-three subjects in the PMDD group and 75 subjects in the control group were diagnosed as having PMDD and not having PMDD, respectively. All agreed to participate in prospective investigation for three menstrual cycles. The study was approved by the Institutional Review Board (IRB) of Kaohsiung Medical University Hospital. Measures The Premenstrual Symptoms Screening Tool (PSST)
This tool was developed by Steiner and colleagues [20] and translated categorical DSM-IV criteria into a rating scale with degrees of severity. The PSST contains 14 4-point items to assess the severity of PMDD symptoms, ranging from not at all (1 point) to severe (4 points), as well as five 4-point items to assess functional impairment (work, relationships, social activities, and home responsibilities). We utilized the scale to screen women with moderate-to-severe premenstrual symptoms. They had to have: 1. at least one of the first four items of the 14 symptoms; 2. four or more items of the 14 items assessing PMDD symptoms; and 3. at least one of the five items assessing functional impairments that were classified as moderate-to-severe levels, with a score of 3 or 4 [20]. The 14 items for symptoms severity had a coefficient of internal consistency (Cronbach’s alpha) of 0.96 and the five items for functional impairment had a Cronbach’s alpha of 0.93 for this study. The total scores of the 14 items assessing PMDD symptoms and the five items assessing functional impairment were summed up to represent the severity and functional impairment of PMDD, respectively.
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The Chinese Version of the Mini International Neuropsychiatric Interview (MINI) [21]
The modules of Psychotic Disorder and Bipolar Disorder in the Chinese version of MINI were utilized to exclude the existence of these two disorders. The Center for Epidemiological Studies’ Depression Scale (CES-D)
The 20-item Mandarin-Chinese version [22] of CES-D [23] is a selfadministered evaluation assessing the participants’ frequency of depressive symptoms over the previous week. The Cronbach’s alpha of CES-D in the present study was 0.78. In this study, the scale evaluates the level of depression. The Buss-Durkee Hostility Inventory-Chinese Version-Short Form (BDHIC-SF)
The 20-item 5-point Likert-type BDHIC-SF assessed the four dimensions of hostility construct, including hostility cognition, hostility affect, expressive hostility behavior, and suppressive hostility behavior. Cronbach’s alpha was 0.93 and the 4-week test-retest reliability was 0.80. Higher scores indicate higher hostility [24]. The Buss-Durkee Hostility Inventory was used to demonstrate the premenstrual exacerbation of PMDD irritability in this study [25]. The Penn State Worry Questionnaire (PSWQ)
This measure can discriminate between college samples that met all, some, or none of the DSM-III-R diagnostic criteria for generalized anxiety disorder [26]. It has good internal consistence and validity [27] and is a valid measure to assess anxiety symptoms [28]. The Cronbach’s alpha of PSWQ in the present study was 0.87. In this study, it was utilized to evaluate the anxiety symptoms. The Premenstrual Dysphoric Disorder (PMDD) Severity Questionnaire (PMDDSQ)
As the PSST is designed to assess symptoms only in the premenstrual phase, we developed the PMDDSQ to assess the severity of PMDD symptoms across the menstrual cycle. The questionnaire includes an 11-point Likert questionnaire that rates the severity of the 11 criteria of PMDD contained in the DSM IV-TR. Every symptom was rated as 0 to 10, representing no symptoms at all to extremely severe symptoms. Participants were asked to respond to the questions based on symptoms experienced when the questionnaire was completed. The total score of the 11 items was used to represent the severity. The questionnaire had a Cronbach’s alpha of 0.98 and the 4-week test-retest reliability was 0.92.
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The Level of Estrogen and Progesterone
To make hormonal determinations, blood samples were obtained directly from all subjects from a cannulated vein after test in both the premenstrual and follicular phases. The serum was separated by centrifugation, and stored at –80°C until further analysis. Estrogen and progesterone were measured with a Coat-A-count radioimmunoassay kit (SIEMENS Medical Solutions Diagnostics, Los Angeles, CA, United States). Procedures All participants took part in the investigation both in the premenstrual (one week before menstruation as predicted by the last menstruation cycle) and follicular phases (the week after the end of menstruation). The assessments included questionnaire evaluation, such as CESD, BDHIC-SF, and PSWQ, cognitive tasks, biochemistry and hormone evaluation. The analysis was focused on the result of the cardinal symptoms of PMDD. Half of the subjects (39 in the PMDD group and 39 in the control group in random) were assessed first in the luteal phase and were then assessed again in the follicular phase. The other subjects were assessed in the reverse phases. After the investigation during the first menstrual cycle as mentioned above, all participants were further followed-up and completed the PMDDSQ once a week for two menstrual cycles. According to the previously-defined criteria for a symptomatic cycle of PMDD [29], women with PMDD should have scores in the premenstrual phase that are 30% higher than the individual minimal score in the menstrual cycle. Further, the score during the premenstrual phase among women with PMDD should be higher than the mean plus two standard derivations of the control group. Subjects needed to fulfill these two criteria for two consecutive menstrual cycles in order to be classified as the PMDD group in this study. Statistics The score of CESD, BDHIC-SF, and PSWQ, both in the premenstrual and follicular phases, were compared between the PMDD and control groups with an independent t-test. The scale levels between the two phases were compared by paired t-test in each group. Then, the repeated measures of two-factor ANOVA were utilized to evaluate the scores of CESD, BDHIC-SF, and PSWQ as a function of the menstrual cycle phase and PMDD diagnosis. Further, the effect of CESD, BDHIC-SF, and PSWQ scores in the premenstrual phase on PMDD diagnosis were evaluated by forward logistic regression with controls of age and educational level and ROC curve. Moreover, the effect of CESD, BDHIC-SF, and PSWQ scores on the functional impairment of PMDD in the premenstrual phase was also evaluated with forward lineal regression among PMDD women. Lastly, the association between CESD, BDHIC-SF, and PSWQ scores and PMDD symptoms severity, functional impairment, and hormone level were analyzed by Cronbach’s
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alpha correlation analysis. A p-value lower than 0.05 was considered statistically significant for all the analyses. RESULTS A total of 16 symptomatic women were excluded from the PMDD group because they did not meet the criteria of two consecutive symptomatic cycles [29] according to prospective investigation using the PMDDSQ. A total of 67 women with PMDD and 75 normal subjects had entered into the final analysis. There were no significant differences in age or educational level (Table 1). The PMDD group has higher scores in CESD, BDHIC-SF, and PSWQ in both the premenstrual and follicular phases. Paired t-tests demonstrated that the score of CESD, BDHIC-SF, and PSWQ was higher in the premenstrual phase than in the follicular phase among the PMDD group, but not in the control group. The two-way ANOVA in Table 2 and Figure 1 demonstrated that there are significant premenstrual effects on the score of CESD, BDHIC-SF, and PSWQ. There is a significant interaction between the premenstrual effect and the PMDD effect on the score of CESD, BDHIC-SF, and PSWQ. This statistical interaction suggests that PMDD women had a higher premenstrual exacerbation effect on depression, hostility, and anxiety than the control group. The between-group
Table 1. The Depression, Anxiety, and Irritability Levels among PMDD and Control Group Variables
PMDD group (Mean ± SD)
Paired t-test
Control group (Mean ± SD)
Paired t-test
Independent t-test
Age
23.46 ± 3.21
23.60 ± 3.49
–0.24
Education level
16.12 ± 1.16
16.27 ± 1.73
–0.59
CESD Luteal Follicular
27.45 ± 10.00 17.91 ± 12.61
6.035***
10.36 ± 6.35 9.84 ± 6.05
0.836
11.995*** 4.771***
PSWQ Luteal Follicular
57.15 ± 10.94 50.63 ± 11.76
6.314***
44.95 ± 7.10 44.27 ± 7.46
1.170
7.782*** 3.798***
BDHIC-SF Luteal Follicular
64.72 ± 14.17 54.49 ± 15.47
5.897***
46.11 ± 10.85 45.73 ± 10.06
0.405
8.709*** 3.949***
Note: CESD = Center for Epidemiological Studies’ Depression Scale; PSWQ = Penn State Worry Questionnaire; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese VersionShort Form; ***p < 0.001.
1 1
1 1
BDHIC-SF MC MC*PMDD
PSWQ MC MC*PMDD 917.848 603.947
1987.015 1716.874
1789.706 1438.706
Mean square
38.968*** 25.641***
30.873*** 26.676***
37.988*** 30.538***
F
0.218 0.155
0.181 0.160
0.213 0.179
h2
Intercept PMDD
Intercept PMDD
Intercept PMDD
1 1
1 1
1 1
df
686599.801 6096.829
788105.102 13253.609
76045.214 11198.946
Mean square
4455.730*** 39.566***
3045.264*** 51.212***
657.680*** 96.855***
F
Between-subject analysis
0.970 0.220
0.956 0.268
0.824 0.409
h2
Note: CESD = Center for Epidemiological Studies’ Depression Scale; PSWQ = Penn State Worry Questionnaire; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese Version-Short Form; ***p < 0.001.
1 1
CESD MC MC*PMDD
df
With-subject analysis
Table 2. The Two Factors Repeated Measures ANOVA for the Premenstrual and PMDD Effect on Depression, Anxiety, and Hostility
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PMDD SYMPTOMS / 47
Figure 1. Repeated measure ANOVA for PMDD and premenstrual effect on depression (CESD), irritability (BDHIC-SF), and anxiety (PSWQ).
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analysis demonstrated that PMDD women had higher scores in CESD, BDHIC-SF, and PSWQ across the menstrual cycle. The logistic regression in Table 3 demonstrated that the CESD score has a stronger effect on PMDD diagnosis. It indicates that depression is the most significantly associated factor of PMDD diagnosis. In this logistic regression model, the scores of PSWQ and BDHIC-SF were excluded when depression entered the regression model. The ROC curve analysis demonstrated the diagnostic accuracy (the area under ROC curve) of CIAS, BDHIC-SF, and PSWQ as 91.5%, 83.1%, and 79.5%. The correlation analysis in Table 4 revealed that all three symptoms correlate with the symptoms severity of PMDD. Only the score of CESD and BDHIC-SF correlate with functional impairment among women with PMDD. Further, the correlation analysis demonstrated that both depression and irritability correlated with work efficiency, coworker relationship, and social activity. The forward linear regression analysis revealed that only the BDHIC-SF score entered the regression model for functional impairment suggesting that irritability is the most significantly associated factor for functional impairment in the PMDD group. The estrogen and progesterone data were transformed to log nature data because they are not normally distributed. The correlation analysis in Table 4 demonstrate that there is no significant association between the cardinal symptoms and estrogen or progesterone level.
Table 3. The Forward Logistic Regression Model for Diagnosis of PMDD among All Subjects and Linear Regression Model for Symptoms Severity and Functional Impairment of PMDD among Women with PMDD in Premenstrual Phase Logistic regress For PMDD diagnosis
(All subjects) Wald
Exp(b)
50% CI
1.00 0.97 1.28
0.84-1.20 0.66-1.41 1.19-1.39
Age (yr) Education level (yr) CESD
0.000 0.031 37.222***
Linear regression
(Women with PMDD)
For functional impairment Age (yr) Education level (yr) BDHIC-SF
t
b
1.01 0.71 2.77*
0.13 0.25 0.07
Note: CESD = Center for Epidemiological Studies’ Depression Scale; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese Version-Short Form; *p < 0.05; **p < 0.01; ***p < 0.001.
–0.05 0.03
0.09 0.03
0.05 0.12
–0.16 –0.12
–0.13 –0.07
–0.16 –0.10
Estrogen
Progesterone
Note: CESD = Center for Epidemiological Studies’ Depression Scale; PSWQ = Penn State Worry Questionnaire; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese Version-Short Form; *p < 0.05; **p < 0.01; ***p < 0.001. The estrogen and progesterone levels are logarithmic transformed.
0.29* 0.19 0.29*
0.14
0.15
0.21
Home responsibility
0.13 0.27*
0.20
0.25*
0.25*
0.35**
Social activity
0.27* 0.14
0.29*
0.09
0.21
0.17
Family relationship
0.14 0.19
0.25*
0.25*
0.35**
0.33**
0.32** 0.09
0.31**
Coworker relationships
0.32** 0.23
0.37**
0.20
0.32**
0.33**
Work efficiency
0.24
0.34**
0.36**
Functional impairment
0.38**
0.28*
0.48***
0.40**
0.36**
0.42***
Symptoms severity
Pan anxiety
CESD
Controls Hostility
Anxiety
Irritability
CESD
Pearson
PMDD
Table 4. The Correlation between Depression, Irritability, and Anxiety and Symptom Severity, Functional Impairment of PMDD, and Hormone Level among PMDD Group and Control Group in Premenstrual Phase
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DISCUSSION As per the criteria of PMDD set out in DMS VI-TR, our results support the observations that depression, anxiety, and irritability were all higher among women with PMDD than those among the control group. These results demonstrated that women with PMDD experience higher multiple dimension symptoms in the premenstrual phase. In line with a previous review [3], these results also support that PMDD is not a variant of depressive or anxiety disorder, which consisted of only one dimension of symptoms. The results might suggest PMDD is a distinct disorder with multiple dimensions of symptoms. Further, women with PMDD would experience their symptoms for more than 3,000 days in their life [30]. The complex and multiple dimension symptoms with such a long duration would bring a variety of life difficulties and severely affect their daily life, as suggested by previous reports [30, 31]. Further, our paired t-test results demonstrate that depression, anxiety, and irritability become more severe during the premenstrual phase among women with PMDD, but not in the control group. The repeated-measure ANOVA also revealed that women with PMDD are more subject to the menstrual effects of depression, anxiety, and irritability than controls. Previous studies suggest the premenstrual exacerbation of depression and other symptoms among women with PMDD [8, 32]. However, those results were based on retrospective investigation. The present results are based on prospective investigation and support the prevalence of premenstrual exacerbation of depression, anxiety, and irritability among women with PMDD. The results suggest that these symptoms follow the endocrine or neurobiological timing of the menstrual cycle in women with PMDD. A previous study demonstrated the premenstrual exacerbation of depression among women with major depressive disorder [7]. Two other studies demonstrated the premenstrual exacerbation of depression and anxiety in psychiatric disorders and found most of them shared co-morbidity with PMDD [8, 32]. In this present study, the premenstrual exacerbation of depression, anxiety, and irritability are only significant among women with PMDD, but not among women without PMDD. These results might support that the pathophysiology of PMDD plays a very important role in the premenstrual exacerbation of psychiatric symptoms. These results also indicate that the menstrual cycle effect on these symptoms is little among the control group. Thus, the pathology of premenstrual exacerbation was not simply the menstrual cycle effect on these symptoms, but the higher vulnerability of women with PMDD to the effect of the menstrual cycle on these symptoms. This claim, based on our results, is in line with a previous hypothesis that PMDD has a different response to normal hormone levels [18]. Our results demonstrate that women with PMDD had higher depression, anxiety, and irritability than the control group not only in the premenstrual phase, but also in the follicular phase. Although the severity of these three symptoms decreases significantly in the follicular phase in comparison to the premenstrual
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phase, their severity is still higher than in the control group. Although the criteria of PMDD in DSM IV-TR has suggested that its symptoms will become minimal or absent in the week post-menses, our study supported that the symptoms would become minimal, but not absent, in the follicular phase. Thus, women with PMDD do not totally remit in the follicular phase. These results might suggest that there must be factors other than menstrual-cycle related factors contributing to the psychopathology of PMDD in the follicular phase. Previous review has suggested that irritability is a more prominent symptom than depression or anxiety, based on its higher prevalence among PMDD women [3, 33, 34]. However, higher severity or prevalence could not conclude its importance because it might also be prevalent in the control group. In this study, we determined the most pathognomonic symptoms by logistic regression and ROC analysis. Although depression, anxiety, and irritability were all associated with PMDD, depression is the only variable to enter the forward regression model for PMDD. This suggests that depression is the most proximally associated symptom of PMDD diagnosis among these three cardinal symptoms. Further, depression has the highest diagnostic accuracy (91.5%) among these three symptoms. It indicates that higher depression contributes to a diagnosis of PMDD more than anxiety or irritability. This result might suggest that depression is the most pathognomonic symptom of PMDD among these three symptoms. However, these prominent effects might result from the fact that the four criteria—depression, concentration difficulty, fatigue, and sleep problem—of PMDD were similar to the criteria of depression. In any case, the significance of depression in the diagnosis and severity of PMDD would suggest that it should be well treated, such as SSRI or exercise, in the standard intervention of PMDD. Irritability was found to be the most significant factor contributing to the functional impairment of PMDD in this study. Previous reports have suggested that irritability was the most frequent PMDD symptom [33, 34]. Further, irritability impaired work efficiency, coworker relationship, and social activity in this study. Its effect on functional impairment may explain why irritability was more frequently experienced among women with PMDD seeking treatment [10]. Further, the result also shows that irritability might disturb the social interactions and decrease their social support. The social support is an important buffer for depression [35] and cardiac vascular risk, particularly in female patients [36]. The negative effect of irritability on cardiovascular effect [37], impaired buffer of social support, and cardiac dysregulation of PMDD [38] might make women with PMDD vulnerable to cardiovascular disorders. Thus, irritability is also an important factor that needs to be addressed during the treatment of PMDD. Although anxiety has been paid much attention in earlier studies [5, 6], in this study its severity did not correlate with the functional impairment of PMDD. Its role was not as prominent as that of irritability or depression in this present study. In line with previous results [18], our results demonstrate no significant correlation between cardinal symptoms of PMDD and estrogen and progesterone. Since a
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previous review had suggested that the fluctuation of gonodotropic hormone level in the luteal phase contribute to PMDD [14], our results testing in follicular or luteal phase fail to demonstrate the association between estrogen and progesterone and PMDD symptoms. Further study to investigate the hormone change in premenstrual phase is necessary to elucidate the mechanism. Limitations This study has three limitations that should be considered when interpreting its findings. First, it is a single study with a relatively small sample. It cannot be assumed that the present results will be representative of all samples of potential participants. Second, the diagnosis of PMDD was based only on diagnostic interviewing without any information from the family or diary symptoms check list. Third, the comorbidity with depression or anxiety disorder of PMDD were not controlled in the analysis in this presenting study.
CONCLUSION The present study demonstrates the premenstrual exacerbation of depression, anxiety, and irritability among women with PMDD, but not in those without PMDD. Depression is the most associated symptom of PMDD diagnosis. Irritability contributes to the functional impairment of PMDD. These results suggest that depression and irritability are two cardinal symptoms of PMDD. These symptoms should be addressed to attenuate symptom severity and functional impairment among women with PMDD.
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23. Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Applied Psychology Measure 1977;1(3):385-401. 24. Lin TK, Weng CY, Wang WC, Chen CC, Lin IM, Lin CL. Hostility trait and vascular dilatory functions in healthy Taiwanese. Journal of Behavioral Medicine 2008;31(6):517-524. 25. Yen JY, Chen CC, Chang SJ, Ko CH, Chen CS, Yen CF. Hostility, impulsivity, and behavior inhibition among women with PMDD. CNS Spectrum 2011;Sep 1:ii. 26. Meyer TJ, Miller ML, Metzger RL, Borkovec TD. Development and validation of the Penn State Worry Questionnaire. Behavioral Research Therapy 1990;28(6): 487-495. 27. Brown TA, Antony MM, Barlow DH. Psychometric properties of the Penn State Worry Questionnaire in a clinical anxiety disorders sample. Behavioral Research Therapy 1992;30(1):33-37. 28. Behar E, Alcaine O, Zuellig AR, Borkovec TD. Screening for generalized anxiety disorder using the Penn State Worry Questionnaire: A receiver operating characteristic analysis. Journal of Behavioral Therapy Experimental Psychiatry 2003; 34(1):25-43. 29. Smith MJ, Schmidt PJ, Rubinow DR. Operationalizing DSM-IV criteria for PMDD: Selecting symptomatic and asymptomatic cycles for research. Journal of Psychiatric Research 2003;37(1):75-83. 30. Rapkin AJ, Winer SA. Premenstrual syndrome and premenstrual dysphoric disorder: Quality of life and burden of illness. Expert Revised Pharmacoeconomic Outcomes Research 2009;9(2):157-170. 31. Dennerstein L, Lehert P, Heinemann K. Global study of women’s experiences of premenstrual symptoms and their effects on daily life. Menopause International 2011;17(3):88-95. 32. Miyaoka Y, Akimoto Y, Ueda K, Ujiie Y, Kametani M, Uchiide Y, et al. Fulfillment of the premenstrual dysphoric disorder criteria confirmed using a self-rating questionnaire among Japanese women with depressive disorders. Biopsychosocial Medicine 2011;5:5. 33. Hartlage SA, Arduino KE. Toward the content validity of premenstrual dysphoric disorder: Do anger and irritability more than depressed mood represent treatmentseekers’ experiences? Psycho Report 2002;90(1):189-202. 34. Qiao M, Zhang H, Liu H, Luo S, Wang T, Zhang J, et al. Prevalence of premenstrual syndrome and premenstrual dysphoric disorder in a population-based sample in China. European Journal of Obstetrics and Gynecological Reproductive Biology 2012;162(1):83-86. 35. Ibarra-Rovillard MS, Kuiper NA. Social support and social negativity findings in depression: Perceived responsiveness to basic psychological needs. Clinical Psychology Review 2011;31(3):342-352. 36. Christenfeld N, Gerin W. Social support and cardiovascular reactivity. Biomedical Pharmacotherapy 2000;54(5):251-257. 37. Deter HC, Micus C, Wagner M, Sharma AM, Buchholz K. Salt sensitivity, anxiety, and irritability predict blood pressure increase over five years in healthy males. Clinical Experiments in Hypertension 2006;28(1):17-27.
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38. Girdler SS, Pedersen CA, Straneva PA, Leserman J, Stanwyck CL, Benjamin S, et al. Dysregulation of cardiovascular and neuroendocrine responses to stress in premenstrual dysphoric disorder. Psychiatry Research 1998;81(2):163-178.
Direct reprint requests to: Ju-Yu Yen, MD, PhD Department of Psychiatry Kaohsiung Medical University Hospital 100, Tzyou 1st Road Kaohsiung, 80708 Taiwan e-mail: [email protected]
DEPRESSION, IRRITABILITY, AND ANXIETY IN WOMEN WITH PREMENSTRUAL DYSPHORIC DISORDER* CHIH-HUNG KO Kaohsiung Medical University, and Kaohsiung Medical University Hospital, Taiwan CHENG-YU LONG Kaohsiung Municipal Hsiao-Kang Hospital, Taiwan SU-YIN CHEN I-JU CHEN Kaohsiung Medical University Hospital and Kaohsiung Medical University, Taiwan TZU-HUI HUANG Kaohsiung Medical University, Taiwan JU-YU YEN Kaohsiung Medical University Hospital, Taiwan, and Kaohsiung Municipal Ta-Tung Hospital, Taiwan
ABSTRACT
Objective: Depression, anxiety, and irritability are the three most studied symptoms of premenstrual dysphoric disorder (PMDD). This study aimed to assess the premenstrual exacerbation of these symptoms and their role in the *This study was supported by grants from the National Science Council (NSC 100-2629B-037 -001 -MY2) and the Kaohsiung Medical University Hospital (KMUH100-0R51). These institutions have no role in the design, process, analyses, and production of the present study. The other authors declare that they have no conflict of interest. 39 Ó 2013, Baywood Publishing Co., Inc. doi: http://dx.doi.org/10.2190/PM.46.1.d http://baywood.com
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diagnosis or functional impairment of PMDD. Methods: We recruited women with PMDD not undergoing any treatment and control subjects from the community. The diagnosis of PMDD was based on a positive score on the Premenstrual Symptoms Screening Tool and confirmed by psychiatric interviews and questionnaire follow-up for three menstrual cycles. A total of 67 women with PMDD and 75 control subjects participated the survey and reach the final analysis. They complete the Center for Epidemiological Studies, the Chinese Version of the Buss-Durkee Hostility Inventory-Short Form, and the Penn State Worry Questionnaire in both the premenstrual and follicular phases. Results: Women with PMDD, but no controls, demonstrate the premenstrual exacerbation of these three symptoms. Depression was the most prominent feature of the PMDD diagnosis while irritability was most frequently associated with functional impairment. Conclusions: Depression and irritability should be properly evaluated and treated among women with PMDD. (Int’l. J. Psychiatry in Medicine 2013;46:39-55)
Key Words: PMDD, depression, anxiety, irritability
INTRODUCTION Around 70%-90% of women of reproductive age have one or more signs of physical discomfort or emotional symptoms during the premenstrual phase of their menstrual cycle. About 20%-40% of the affected women have experienced premenstrual syndromes that are bothersome [1]. A small number, 3%-8%, of women of reproductive age experience more severe symptoms, which lead to substantial distress or functional impairment and meet the strict criteria for premenstrual dysphoric disorder (PMDD). The affected women have been estimated to experience almost 3,000 days of clinical symptoms during their reproductive age, resulting in a tough life burden and significant functional impairment [1]. The typical PMDD symptoms, including irritability, anger, mood swings, depression, tension/anxiety, abdominal bloating, breast pain, and fatigue, recur monthly and last for an average of 6 days per month during the majority of the reproductive years. The criteria demonstrate that PMDD includes the core symptoms of depression, irritability, anxiety, and tension in varying dimensions. However, the manner in which the symptoms of varying dimensions play a role in contributing to PMDD has not been thoroughly understood. Depression, anxiety, and irritability were the three most studied and prominent symptoms considered as criteria for PMDD [2, 3]. Earlier studies pay more attention to the connection between premenstrual symptoms and depression and anxiety [4, 5]. The results of co-morbidity study also support the association between them [6]. It has been suggested that severe premenstrual symptoms of a predominantly depressive nature are probably a manifestation of an underlying
PMDD SYMPTOMS / 41
depressive disorder [7]. Further studies addressed the premenstrual exacerbations of psychiatric disorder and also supported the association between depression, anxiety, and premenstrual symptoms [7, 8]. Besides, the effect of selective serotonin reuptake inhibition (SSRI) on PMDD also supports the shared serotonin mechanism for PMDD, depression, and anxiety. The results mentioned above have suggested that PMDD is a variant of depressive disorder or anxiety disorder [3]. In the past decade, increasing attention has focused on the irritability symptoms of PMDD [9]. Irritability and aggression are frequent and prominent symptoms among women with PMDD [10-12]. Further, a recent study demonstrates that SSRI effectively improves the symptoms of irritability, as well as depression and anxiety [13]. Previous review also suggests that irritability is the cardinal symptom of PMDD [3]. Since irritability was a symptom independent of depression or anxiety, PMDD should be regarded as a distinct diagnostic entity, but not a variant of depressive or anxiety disorder [3]. However, the effect of depression, anxiety, or irritability on PMDD has not been well evaluated in a single data study to enable comparisons between them. Previous reports of treatment efficacy studies suggest that ovulation and ovulation-related processes may be a trigger for the onset of PMDD [14]. PMDD has been shown to be absent during menstrual cycles that are spontaneously anovulatory [15]. PMDD-like symptoms have been reported to be induced in postmenopausal women who received sequential hormonal replacement therapy (HRT) [16]. These observations and the menstrual cyclicity of symptoms are an indirect suggestion that gonadotropic hormones may play a role in the symptom formation of PMDD [17]. It has been suggested that the hormonal pattern of PMDD consists not in different levels of the hormones, but in different responses to normal hormonal levels [18]. However, a previous study did not find any significant association between estrogen or progesterone and depression and anxiety symptoms [19]. A study to evaluate the possible association between the gonadal hormone and these cardinal symptoms might shed light on the mechanism of PMDD. Thus, the aim of this study is to evaluate the depression, anxiety, and irritability symptoms among women and their relations to gonadotropic hormone with or without PMDD. Further, we investigate effects of these three symptoms on the diagnosis, functional impairment, and severity of PMDD. METHOD Participants Participants were recruited from an advertisement posted at a university campus specifically to attract PMDD patients not undergoing treatment and a control group from August, 2011 through October, 2012. The participants in the
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PMDD group had a positive response to five or more symptoms of the eleven DSM-IV-TR criteria of PMDD [24], and most symptoms relieved after menstruation. The control group had a positive response to fewer than 2 of the 11 DSM-IV-TR criteria of PMDD or had no functional impairment with mild symptoms. To prevent effects of psychotropic medication or gonadotropic medication on the function of serotonin or estrogen, subjects under current psychotropic or gonadotropic medication treatment were screened and excluded from the study. A total of 169 (90 in the PMDD group and 78 in the control group) women with at least a college education level were screened using the self-reported Premenstrual Symptoms Screening Tool (PSST) for moderate or severe premenstrual symptoms after informed consent was obtained. Eighty-six participants in the PMDD group and 75 in the control group were screened as positive and negative using the PSST, respectively. Participants were interviewed by one of two psychiatrists in order to make a diagnosis of PMDD based on the DSMIV-TR criteria [24]. Further, the psychotic disorder and bipolar I disorder were also excluded based on the Mini-International Neuropsychiatric Interview (MINI). Eighty-three subjects in the PMDD group and 75 subjects in the control group were diagnosed as having PMDD and not having PMDD, respectively. All agreed to participate in prospective investigation for three menstrual cycles. The study was approved by the Institutional Review Board (IRB) of Kaohsiung Medical University Hospital. Measures The Premenstrual Symptoms Screening Tool (PSST)
This tool was developed by Steiner and colleagues [20] and translated categorical DSM-IV criteria into a rating scale with degrees of severity. The PSST contains 14 4-point items to assess the severity of PMDD symptoms, ranging from not at all (1 point) to severe (4 points), as well as five 4-point items to assess functional impairment (work, relationships, social activities, and home responsibilities). We utilized the scale to screen women with moderate-to-severe premenstrual symptoms. They had to have: 1. at least one of the first four items of the 14 symptoms; 2. four or more items of the 14 items assessing PMDD symptoms; and 3. at least one of the five items assessing functional impairments that were classified as moderate-to-severe levels, with a score of 3 or 4 [20]. The 14 items for symptoms severity had a coefficient of internal consistency (Cronbach’s alpha) of 0.96 and the five items for functional impairment had a Cronbach’s alpha of 0.93 for this study. The total scores of the 14 items assessing PMDD symptoms and the five items assessing functional impairment were summed up to represent the severity and functional impairment of PMDD, respectively.
PMDD SYMPTOMS / 43
The Chinese Version of the Mini International Neuropsychiatric Interview (MINI) [21]
The modules of Psychotic Disorder and Bipolar Disorder in the Chinese version of MINI were utilized to exclude the existence of these two disorders. The Center for Epidemiological Studies’ Depression Scale (CES-D)
The 20-item Mandarin-Chinese version [22] of CES-D [23] is a selfadministered evaluation assessing the participants’ frequency of depressive symptoms over the previous week. The Cronbach’s alpha of CES-D in the present study was 0.78. In this study, the scale evaluates the level of depression. The Buss-Durkee Hostility Inventory-Chinese Version-Short Form (BDHIC-SF)
The 20-item 5-point Likert-type BDHIC-SF assessed the four dimensions of hostility construct, including hostility cognition, hostility affect, expressive hostility behavior, and suppressive hostility behavior. Cronbach’s alpha was 0.93 and the 4-week test-retest reliability was 0.80. Higher scores indicate higher hostility [24]. The Buss-Durkee Hostility Inventory was used to demonstrate the premenstrual exacerbation of PMDD irritability in this study [25]. The Penn State Worry Questionnaire (PSWQ)
This measure can discriminate between college samples that met all, some, or none of the DSM-III-R diagnostic criteria for generalized anxiety disorder [26]. It has good internal consistence and validity [27] and is a valid measure to assess anxiety symptoms [28]. The Cronbach’s alpha of PSWQ in the present study was 0.87. In this study, it was utilized to evaluate the anxiety symptoms. The Premenstrual Dysphoric Disorder (PMDD) Severity Questionnaire (PMDDSQ)
As the PSST is designed to assess symptoms only in the premenstrual phase, we developed the PMDDSQ to assess the severity of PMDD symptoms across the menstrual cycle. The questionnaire includes an 11-point Likert questionnaire that rates the severity of the 11 criteria of PMDD contained in the DSM IV-TR. Every symptom was rated as 0 to 10, representing no symptoms at all to extremely severe symptoms. Participants were asked to respond to the questions based on symptoms experienced when the questionnaire was completed. The total score of the 11 items was used to represent the severity. The questionnaire had a Cronbach’s alpha of 0.98 and the 4-week test-retest reliability was 0.92.
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The Level of Estrogen and Progesterone
To make hormonal determinations, blood samples were obtained directly from all subjects from a cannulated vein after test in both the premenstrual and follicular phases. The serum was separated by centrifugation, and stored at –80°C until further analysis. Estrogen and progesterone were measured with a Coat-A-count radioimmunoassay kit (SIEMENS Medical Solutions Diagnostics, Los Angeles, CA, United States). Procedures All participants took part in the investigation both in the premenstrual (one week before menstruation as predicted by the last menstruation cycle) and follicular phases (the week after the end of menstruation). The assessments included questionnaire evaluation, such as CESD, BDHIC-SF, and PSWQ, cognitive tasks, biochemistry and hormone evaluation. The analysis was focused on the result of the cardinal symptoms of PMDD. Half of the subjects (39 in the PMDD group and 39 in the control group in random) were assessed first in the luteal phase and were then assessed again in the follicular phase. The other subjects were assessed in the reverse phases. After the investigation during the first menstrual cycle as mentioned above, all participants were further followed-up and completed the PMDDSQ once a week for two menstrual cycles. According to the previously-defined criteria for a symptomatic cycle of PMDD [29], women with PMDD should have scores in the premenstrual phase that are 30% higher than the individual minimal score in the menstrual cycle. Further, the score during the premenstrual phase among women with PMDD should be higher than the mean plus two standard derivations of the control group. Subjects needed to fulfill these two criteria for two consecutive menstrual cycles in order to be classified as the PMDD group in this study. Statistics The score of CESD, BDHIC-SF, and PSWQ, both in the premenstrual and follicular phases, were compared between the PMDD and control groups with an independent t-test. The scale levels between the two phases were compared by paired t-test in each group. Then, the repeated measures of two-factor ANOVA were utilized to evaluate the scores of CESD, BDHIC-SF, and PSWQ as a function of the menstrual cycle phase and PMDD diagnosis. Further, the effect of CESD, BDHIC-SF, and PSWQ scores in the premenstrual phase on PMDD diagnosis were evaluated by forward logistic regression with controls of age and educational level and ROC curve. Moreover, the effect of CESD, BDHIC-SF, and PSWQ scores on the functional impairment of PMDD in the premenstrual phase was also evaluated with forward lineal regression among PMDD women. Lastly, the association between CESD, BDHIC-SF, and PSWQ scores and PMDD symptoms severity, functional impairment, and hormone level were analyzed by Cronbach’s
PMDD SYMPTOMS / 45
alpha correlation analysis. A p-value lower than 0.05 was considered statistically significant for all the analyses. RESULTS A total of 16 symptomatic women were excluded from the PMDD group because they did not meet the criteria of two consecutive symptomatic cycles [29] according to prospective investigation using the PMDDSQ. A total of 67 women with PMDD and 75 normal subjects had entered into the final analysis. There were no significant differences in age or educational level (Table 1). The PMDD group has higher scores in CESD, BDHIC-SF, and PSWQ in both the premenstrual and follicular phases. Paired t-tests demonstrated that the score of CESD, BDHIC-SF, and PSWQ was higher in the premenstrual phase than in the follicular phase among the PMDD group, but not in the control group. The two-way ANOVA in Table 2 and Figure 1 demonstrated that there are significant premenstrual effects on the score of CESD, BDHIC-SF, and PSWQ. There is a significant interaction between the premenstrual effect and the PMDD effect on the score of CESD, BDHIC-SF, and PSWQ. This statistical interaction suggests that PMDD women had a higher premenstrual exacerbation effect on depression, hostility, and anxiety than the control group. The between-group
Table 1. The Depression, Anxiety, and Irritability Levels among PMDD and Control Group Variables
PMDD group (Mean ± SD)
Paired t-test
Control group (Mean ± SD)
Paired t-test
Independent t-test
Age
23.46 ± 3.21
23.60 ± 3.49
–0.24
Education level
16.12 ± 1.16
16.27 ± 1.73
–0.59
CESD Luteal Follicular
27.45 ± 10.00 17.91 ± 12.61
6.035***
10.36 ± 6.35 9.84 ± 6.05
0.836
11.995*** 4.771***
PSWQ Luteal Follicular
57.15 ± 10.94 50.63 ± 11.76
6.314***
44.95 ± 7.10 44.27 ± 7.46
1.170
7.782*** 3.798***
BDHIC-SF Luteal Follicular
64.72 ± 14.17 54.49 ± 15.47
5.897***
46.11 ± 10.85 45.73 ± 10.06
0.405
8.709*** 3.949***
Note: CESD = Center for Epidemiological Studies’ Depression Scale; PSWQ = Penn State Worry Questionnaire; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese VersionShort Form; ***p < 0.001.
1 1
1 1
BDHIC-SF MC MC*PMDD
PSWQ MC MC*PMDD 917.848 603.947
1987.015 1716.874
1789.706 1438.706
Mean square
38.968*** 25.641***
30.873*** 26.676***
37.988*** 30.538***
F
0.218 0.155
0.181 0.160
0.213 0.179
h2
Intercept PMDD
Intercept PMDD
Intercept PMDD
1 1
1 1
1 1
df
686599.801 6096.829
788105.102 13253.609
76045.214 11198.946
Mean square
4455.730*** 39.566***
3045.264*** 51.212***
657.680*** 96.855***
F
Between-subject analysis
0.970 0.220
0.956 0.268
0.824 0.409
h2
Note: CESD = Center for Epidemiological Studies’ Depression Scale; PSWQ = Penn State Worry Questionnaire; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese Version-Short Form; ***p < 0.001.
1 1
CESD MC MC*PMDD
df
With-subject analysis
Table 2. The Two Factors Repeated Measures ANOVA for the Premenstrual and PMDD Effect on Depression, Anxiety, and Hostility
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PMDD SYMPTOMS / 47
Figure 1. Repeated measure ANOVA for PMDD and premenstrual effect on depression (CESD), irritability (BDHIC-SF), and anxiety (PSWQ).
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analysis demonstrated that PMDD women had higher scores in CESD, BDHIC-SF, and PSWQ across the menstrual cycle. The logistic regression in Table 3 demonstrated that the CESD score has a stronger effect on PMDD diagnosis. It indicates that depression is the most significantly associated factor of PMDD diagnosis. In this logistic regression model, the scores of PSWQ and BDHIC-SF were excluded when depression entered the regression model. The ROC curve analysis demonstrated the diagnostic accuracy (the area under ROC curve) of CIAS, BDHIC-SF, and PSWQ as 91.5%, 83.1%, and 79.5%. The correlation analysis in Table 4 revealed that all three symptoms correlate with the symptoms severity of PMDD. Only the score of CESD and BDHIC-SF correlate with functional impairment among women with PMDD. Further, the correlation analysis demonstrated that both depression and irritability correlated with work efficiency, coworker relationship, and social activity. The forward linear regression analysis revealed that only the BDHIC-SF score entered the regression model for functional impairment suggesting that irritability is the most significantly associated factor for functional impairment in the PMDD group. The estrogen and progesterone data were transformed to log nature data because they are not normally distributed. The correlation analysis in Table 4 demonstrate that there is no significant association between the cardinal symptoms and estrogen or progesterone level.
Table 3. The Forward Logistic Regression Model for Diagnosis of PMDD among All Subjects and Linear Regression Model for Symptoms Severity and Functional Impairment of PMDD among Women with PMDD in Premenstrual Phase Logistic regress For PMDD diagnosis
(All subjects) Wald
Exp(b)
50% CI
1.00 0.97 1.28
0.84-1.20 0.66-1.41 1.19-1.39
Age (yr) Education level (yr) CESD
0.000 0.031 37.222***
Linear regression
(Women with PMDD)
For functional impairment Age (yr) Education level (yr) BDHIC-SF
t
b
1.01 0.71 2.77*
0.13 0.25 0.07
Note: CESD = Center for Epidemiological Studies’ Depression Scale; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese Version-Short Form; *p < 0.05; **p < 0.01; ***p < 0.001.
–0.05 0.03
0.09 0.03
0.05 0.12
–0.16 –0.12
–0.13 –0.07
–0.16 –0.10
Estrogen
Progesterone
Note: CESD = Center for Epidemiological Studies’ Depression Scale; PSWQ = Penn State Worry Questionnaire; BDHIC-SF = Buss-Durkee Hostility Inventory-Chinese Version-Short Form; *p < 0.05; **p < 0.01; ***p < 0.001. The estrogen and progesterone levels are logarithmic transformed.
0.29* 0.19 0.29*
0.14
0.15
0.21
Home responsibility
0.13 0.27*
0.20
0.25*
0.25*
0.35**
Social activity
0.27* 0.14
0.29*
0.09
0.21
0.17
Family relationship
0.14 0.19
0.25*
0.25*
0.35**
0.33**
0.32** 0.09
0.31**
Coworker relationships
0.32** 0.23
0.37**
0.20
0.32**
0.33**
Work efficiency
0.24
0.34**
0.36**
Functional impairment
0.38**
0.28*
0.48***
0.40**
0.36**
0.42***
Symptoms severity
Pan anxiety
CESD
Controls Hostility
Anxiety
Irritability
CESD
Pearson
PMDD
Table 4. The Correlation between Depression, Irritability, and Anxiety and Symptom Severity, Functional Impairment of PMDD, and Hormone Level among PMDD Group and Control Group in Premenstrual Phase
PMDD SYMPTOMS / 49
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DISCUSSION As per the criteria of PMDD set out in DMS VI-TR, our results support the observations that depression, anxiety, and irritability were all higher among women with PMDD than those among the control group. These results demonstrated that women with PMDD experience higher multiple dimension symptoms in the premenstrual phase. In line with a previous review [3], these results also support that PMDD is not a variant of depressive or anxiety disorder, which consisted of only one dimension of symptoms. The results might suggest PMDD is a distinct disorder with multiple dimensions of symptoms. Further, women with PMDD would experience their symptoms for more than 3,000 days in their life [30]. The complex and multiple dimension symptoms with such a long duration would bring a variety of life difficulties and severely affect their daily life, as suggested by previous reports [30, 31]. Further, our paired t-test results demonstrate that depression, anxiety, and irritability become more severe during the premenstrual phase among women with PMDD, but not in the control group. The repeated-measure ANOVA also revealed that women with PMDD are more subject to the menstrual effects of depression, anxiety, and irritability than controls. Previous studies suggest the premenstrual exacerbation of depression and other symptoms among women with PMDD [8, 32]. However, those results were based on retrospective investigation. The present results are based on prospective investigation and support the prevalence of premenstrual exacerbation of depression, anxiety, and irritability among women with PMDD. The results suggest that these symptoms follow the endocrine or neurobiological timing of the menstrual cycle in women with PMDD. A previous study demonstrated the premenstrual exacerbation of depression among women with major depressive disorder [7]. Two other studies demonstrated the premenstrual exacerbation of depression and anxiety in psychiatric disorders and found most of them shared co-morbidity with PMDD [8, 32]. In this present study, the premenstrual exacerbation of depression, anxiety, and irritability are only significant among women with PMDD, but not among women without PMDD. These results might support that the pathophysiology of PMDD plays a very important role in the premenstrual exacerbation of psychiatric symptoms. These results also indicate that the menstrual cycle effect on these symptoms is little among the control group. Thus, the pathology of premenstrual exacerbation was not simply the menstrual cycle effect on these symptoms, but the higher vulnerability of women with PMDD to the effect of the menstrual cycle on these symptoms. This claim, based on our results, is in line with a previous hypothesis that PMDD has a different response to normal hormone levels [18]. Our results demonstrate that women with PMDD had higher depression, anxiety, and irritability than the control group not only in the premenstrual phase, but also in the follicular phase. Although the severity of these three symptoms decreases significantly in the follicular phase in comparison to the premenstrual
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phase, their severity is still higher than in the control group. Although the criteria of PMDD in DSM IV-TR has suggested that its symptoms will become minimal or absent in the week post-menses, our study supported that the symptoms would become minimal, but not absent, in the follicular phase. Thus, women with PMDD do not totally remit in the follicular phase. These results might suggest that there must be factors other than menstrual-cycle related factors contributing to the psychopathology of PMDD in the follicular phase. Previous review has suggested that irritability is a more prominent symptom than depression or anxiety, based on its higher prevalence among PMDD women [3, 33, 34]. However, higher severity or prevalence could not conclude its importance because it might also be prevalent in the control group. In this study, we determined the most pathognomonic symptoms by logistic regression and ROC analysis. Although depression, anxiety, and irritability were all associated with PMDD, depression is the only variable to enter the forward regression model for PMDD. This suggests that depression is the most proximally associated symptom of PMDD diagnosis among these three cardinal symptoms. Further, depression has the highest diagnostic accuracy (91.5%) among these three symptoms. It indicates that higher depression contributes to a diagnosis of PMDD more than anxiety or irritability. This result might suggest that depression is the most pathognomonic symptom of PMDD among these three symptoms. However, these prominent effects might result from the fact that the four criteria—depression, concentration difficulty, fatigue, and sleep problem—of PMDD were similar to the criteria of depression. In any case, the significance of depression in the diagnosis and severity of PMDD would suggest that it should be well treated, such as SSRI or exercise, in the standard intervention of PMDD. Irritability was found to be the most significant factor contributing to the functional impairment of PMDD in this study. Previous reports have suggested that irritability was the most frequent PMDD symptom [33, 34]. Further, irritability impaired work efficiency, coworker relationship, and social activity in this study. Its effect on functional impairment may explain why irritability was more frequently experienced among women with PMDD seeking treatment [10]. Further, the result also shows that irritability might disturb the social interactions and decrease their social support. The social support is an important buffer for depression [35] and cardiac vascular risk, particularly in female patients [36]. The negative effect of irritability on cardiovascular effect [37], impaired buffer of social support, and cardiac dysregulation of PMDD [38] might make women with PMDD vulnerable to cardiovascular disorders. Thus, irritability is also an important factor that needs to be addressed during the treatment of PMDD. Although anxiety has been paid much attention in earlier studies [5, 6], in this study its severity did not correlate with the functional impairment of PMDD. Its role was not as prominent as that of irritability or depression in this present study. In line with previous results [18], our results demonstrate no significant correlation between cardinal symptoms of PMDD and estrogen and progesterone. Since a
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previous review had suggested that the fluctuation of gonodotropic hormone level in the luteal phase contribute to PMDD [14], our results testing in follicular or luteal phase fail to demonstrate the association between estrogen and progesterone and PMDD symptoms. Further study to investigate the hormone change in premenstrual phase is necessary to elucidate the mechanism. Limitations This study has three limitations that should be considered when interpreting its findings. First, it is a single study with a relatively small sample. It cannot be assumed that the present results will be representative of all samples of potential participants. Second, the diagnosis of PMDD was based only on diagnostic interviewing without any information from the family or diary symptoms check list. Third, the comorbidity with depression or anxiety disorder of PMDD were not controlled in the analysis in this presenting study.
CONCLUSION The present study demonstrates the premenstrual exacerbation of depression, anxiety, and irritability among women with PMDD, but not in those without PMDD. Depression is the most associated symptom of PMDD diagnosis. Irritability contributes to the functional impairment of PMDD. These results suggest that depression and irritability are two cardinal symptoms of PMDD. These symptoms should be addressed to attenuate symptom severity and functional impairment among women with PMDD.
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