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Hot flashes are associated with psychological symptoms of anxiety and depression in peri- and post- but not premenopausal women
Maturitas 52 (2005) 119–126
Hot flashes are associated with psychological symptoms of anxiety and depression in periand post- but not premenopausal women Kai-Dih Juang a, c , Shuu-Jiun Wang b, c , Shiang-Ru Lu d , Shin-Jung Lee e , Jong-Ling Fuh b, c, ∗ a
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan c National Yang-Ming University School of Medicine, Taipei, Taiwan d Department of Neurology, Kaohsiung Medical University Chung-Ho Memorial Hospital, USA e Department of Biostatistics, Comprehensive Cancer Center, University of Michigan, MI, USA b
Received 8 October 2004; received in revised form 2 January 2005; accepted 11 January 2005
Abstract Objective: To explore the relationship between anxiety, depression, vasomotor symptoms, and menopausal status among middleaged women. Design: A population-based study involving a rural Taiwanese population. Participants received a structured questionnaire, which included the hospital anxiety and depression scale (HADS), gynecological history and a checklist of menopausal symptoms in the most recent 2 weeks. Results: A total of 1273 women with no history of surgical menopause and hormonal therapy history participated. The mean anxiety, depression, and total HADS scores were 4.3 ± 3.3, 3.3 ± 2.8 and 7.6 ± 5.3, respectively, and did not differ according to menopausal status. A total of 10.5% participants reported hot flashes within the previous 2 weeks. After controlling for educational status and insomnia, anxiety (6.0 ± 3.8 versus 4.1 ± 3.1) and depression scores (4.0 ± 3.3 versus 3.2 ± 2.7) were significantly higher (p < 0.001) compared with those without hot flashes. These differences were attributed to peri- and postmenopausal subjects. Conclusions: Hot flashes in peri- and postmenopausal women were associated with anxious and depressive symptoms in East Asian population with low prevalence of vasomotor symptoms. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Climacteric symptoms; Depression; Menopause; Anxiety; Vasomotor symptoms; Hot flashes
∗
Corresponding author. Tel.: +886 2 28762522; fax: +886 2 28765215. E-mail address: [email protected] (J.-L. Fuh).
0378-5122/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2005.01.005
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1. Introduction Whether depression is increased in peri- and postmenopausal women has been an issue of debate for decades. Earlier clinic-based studies found that depression is more frequent in postmenopausal women [1]. In contrast, large-scale community-based research shows that the prevalence of depression is not higher in peri- or postmenopausal women [2,3]. The divergence of results may result from different sampling methods. Since women with either menopausal syndrome or depression are more likely to seek help in clinical settings, subjects drawn from these clinics may be different from the general population in community settings. Recent studies have begun to find risk factors of depression during menopausal transition. For example, Bosworth et al. [4] suggested that it is the menopausal symptoms, rather than menopausal status, that are related to depression. The authors reported that a telephone interview of women wishing to discuss hormone therapy revealed that mood swing, troubled sleeping, and poor concentration can account for the association between menopausal status and depression. Furthermore, Joffe et al. [5] showed a more complicated relationship among vasomotor symptoms, menopausal status, and depression, by applying the Center for Epidemiological Studies Depression Scale (CES-D). In that study, perimenopausal women visiting general practice physicians were shown to experience increased frequencies of depression only if vasomotor symptoms were present. Pre-, postmenopausal, and perimenopausal women without vasomotor symptoms did not show an increased frequency of depression. It appears that the simultaneous presence of both vasomotor symptoms and menopausal changes is associated with depression in middle-aged women. However, these two studies were conducted among specific groups of women in clinical settings, and not in the general population. Since both hot flashes and depression may bring women to clinical settings, their association may be caused by sampling bias. More community-based studies are needed in order to elucidate the relationship between menopausal status, menopausal syndrome, and depression. In addition to sampling issues, measurement bias may also influence the investigation of depression and menopausal symptoms. When two methods of
measurement overlap in some area, they appear to be correlated even if they are not. Depression and certain physical conditions share some common symptoms, such as fatigue. Therefore, in the assessment of depression, these shared symptoms may overlap, resulting in confounding and measurement bias [6]. For example, night sweating may disturb sleep and thus increase depression scores that include insomnia as a symptom. A measurement of depression that accounts for these shared symptoms would potentially reduce confounding between depression and menopausal syndrome. Besides, none of the previous studies explored the relationship between anxiety and menopausal changes. The purpose of the current study was to explore the relationship between depression, vasomotor symptoms, and menopausal status in a community population. We adopted the hospital anxiety and depression scale (HADS) [7] as a measurement tool. The HADS is a depression and anxiety scale that excludes physical symptoms of depression and anxiety; therefore, it prevents physical symptoms from confounding the measure of depression. Because insomnia may be a possible mediator between vasomotor symptoms and emotional symptoms, we also tried to control insomnia in the analysis. The present study was conducted among middle-aged women in a community-based setting. We hypothesized that there would be higher scores of depression and anxiety among subjects with hot flashes.
2. Methods 2.1. Subjects The study is a part of the Kinmen Woman’s Health Investigation (KIWI) [8] that assessed the health condition of middle-aged women in the community of Kinmen, Taiwan. Kinmen is an island of 176 km2 located 248 km (154 miles) west of Taiwan and 41 km (25 miles) east of Mainland China. It consists of four townships, with a total population of 51,060 in 1998. Using the KIWI cohort, we surveyed all female citizens between ages 40 and 54 in 1998 who resided in two of the four townships in Kinmen Island. Fig. 1 shows the flow chart of recruiting subjects to the final population. We excluded subjects who have had hysterectomy or
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2.3. Definition of menopausal status According to the subjects’ reports, menopausal status was categorized into: (1) premenopausal: regular menstruation (regular menstruation is defined as cycles that vary in length by not more than 5 days for the preceding 3 months, and are between 23 and 35 days); (2) perimenopausal: cycles irregular (defined as cycles lasting less than 23 days, greater than 35 days or that vary by more than 5 days during the preceding 3 months) or ceased for less than 1 year; and (3) postmenopausal: no cycles for more than 1 year. 2.4. Vasomotor symptoms
Fig. 1. Flow chart of subject recruitment and exclusion.
bilateral oophorectomy and who are receiving hormone therapy to reduce the confounding effects of surgical menopause and exogenous hormones. More detailed methods are described in an earlier paper [8]. This study has been approved by the Institutional Review Board of Taipei Veterans General Hospital. Informed consent has been obtained from the subjects. 2.2. Assessment The participants received and completed the following self-administered questionnaires in the presence of well-trained interviewers: (1) personal information, (2) medical history, (3) menstrual and reproductive history, and (4) the menopause-related symptom checklist. Although KIWI is a longitudinal follow-up study, the present study is cross-sectional analysis of data of the first year that assessed menopausal status, menopausal symptoms, and mood at the same time.
In the menopause-related symptom checklist, the subjects reported whether they experienced symptoms within the most recent 2 weeks. The list of symptoms that we used were modified from the Kupperman index [9] that includes hot flashes, night sweating, insomnia, headache, joint pain, back pain, muscle pain, dizziness, fatigue, vaginal dryness, and frequency of urination. Since only the vasomotor symptoms were considered to be clearly associated with menopause in our own and previous studies [8,10], and the relationship of night sweats and depression might be confounded by insomnia, we chose only hot flashes for analysis. According to Kupperman index, we asked the frequency of hot flashes in recent 2 weeks, and recorded the frequency as: (1) having no hot flashes occurring in the most recent 2 weeks; (2) hot flashes having occurred once in these 2 weeks; (3) once a week; and (4) more than once a week. The latter three groups were regrouped into one group with the presence of any hot flashes in recent 2 weeks for analysis because of the relatively low number of subjects in each group. The data of insomnia was also taken from the Kupperman index, in which the frequency of insomnia was explored by the question “Do you have insomnia in recent 2 weeks?” 2.5. Assessment of depression and anxiety We adopted the Chinese version of HADS [11] to measure participants’ anxiety and depression. The HADS is a self-administered rating scale that was designed to avoid the confounding effects of somatic condition in the study of medical patients by excluding physical symptoms of anxiety and depression. Hence,
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the HADS focuses on psychological and emotional symptoms of anxiety and depression. The depression subscale of the HADS focuses on the feelings of anhedonia [7]. The depression subscale inquires depressed mood, hopelessness, and enjoyment, similar to CESD that has been used by many studies in menopausal women. Unlike CES-D, the HADS did not ask about appetite, sleep, fatigue, and concentration of mind, which are easily affected by physical discomfort. The anxiety subscale of the HADS focuses on worry and restlessness [7]. It also excludes items of physical symptoms, such as sweating, tremor and palpitation. The HADS includes 14 items: 7 for anxiety and 7 for depression, yielding total anxiety, and depression scores. Each of the 14 items is followed by four descriptions. The description that indicates “no distress” was scored 0, followed by descriptions scored 1 and 2; and the description that indicates the highest distress is scored 3. The anxiety score is the sum of the 7 anxiety items and the depression score is the sum of the 7 depression items. The total HADS score is the sum of anxiety and depression scores. Hence, the range of the total HADS score is 0–42, while the range of anxiety score and depression score is 0–21. In this study we used a cut-off point of 7/8 in anxiety and depression scores as clinically significant cases [12]. We followed some previous studies in adopting the 7/8 cut-off points although some studies suggest that optimal cut-off points varies among different samples and that different cut-off points should be used in each sample [12]. In our previous study in patients with severe headache, we found that a total HADS score of 10 or more was the optimal cut-off point for depressive disorders. The sensitivity was 85.7%, and the specificity 33.3%. A total score of at least 13 was the optimal cut-off point for anxiety disorder. The sensitivity was 84.2%, while the specificity was 41.9% [11]. 2.6. Statistical methods The mean and standard deviations (S.D.) of the various parameters were calculated for each menopausal group. The χ2 -test was used for comparing the rates of each symptom in the pre-, peri-, and postmenopausal groups. The differences among means were compared by one-way analysis of variance (ANOVA) and by Scheffe’s pairwise comparison where appropriate. Pearson’s correlation was used to test the correlation
between scores and other variables of interested. The linear regression model and logistic regression model were used to adjust for confounding factors in the analysis of scores. Education and age were coded in years as a continuous variable. The level of significance chosen was p < 0.05.
3. Results 3.1. Characteristics of the study population Of the 2256 targeted women, 1497 (66%) participated in the study. Most of the non-participants actually live in Taiwan and return to Kinmen occasionally, so we could not find them even after several house calls. The participants and non-participants did not differ in age (45.5 ± 4.0 versus 45.8 ± 4.2 years; t = −1.3, d.f. = 2.54, p = 0.19). After excluding subjects with incomplete data (n = 56), mental retardation (n = 5), past history of hysterectomy (n = 50) and/or bilateral oophorectomy (n = 42), and HT users (n = 86), the remaining 1273 women constituted the final sample for analysis. Of the 1273 subjects, 728 (57%) were premenopausal, 351 (28%) perimenopausal, and 194 (15%) postmenopausal, with a mean menopause duration of 4.1 years (S.D. = 3.6; median = 3 years). The mean age of the total sample was 45.3 ± 4.0 years, and the mean years of education was 5.9 ± 4.7. Basic demographic data of the subjects in these three menopausal categories are shown in Table 1. 3.2. Anxiety and depression scores The mean anxiety score was 4.3 ± 3.3, and the mean depression score was 3.3 ± 2.8. The mean total HADS score was 7.6 ± 5.3. The anxiety and depression scores correlated with each other (r = 0.57, p < 0.001). Fifteen point eight percent (15.8%) of the subjects had a clinically significant level of anxiety (anxiety score of 8 or higher), while 8.4% had a clinically significant level of depression (depression score of 8 or higher). Anxiety and depression scores of subjects in the three different menopausal groups are shown in Table 1. According to the ANOVA analysis, there was no significant difference among any one of the total HADS, anxiety, and depression scores.
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Table 1 Demographic data and hospital anxiety and depression scale in different menopausal status Parameter
p-Value
Menopausal status
Total subjects
Premenopause
Perimenopause
Postmenopause
728
351
194
Age (years) Education (years) Married w/o separation (%)a Unemployed (%) Body mass index Hot flashes (%) Night sweating (%) Insomnia (%) Anxiety score Anxiety score ≥8 (%) (clinically significant anxiety) Depression score Depression score ≥8 (%) (clinically significant depression)
43.6 ± 2.9†,‡
6.7 ± 4.6†,‡ 93.4 55.9 23.9 ± 3.4†,‡ 8.2 3.0 38.4 4.2 ± 3.1 14.4 3.1 ± 2.7 7.8
46.1 ± 3.7*,‡
5.5 ± 4.7*,‡ 88.3 63.8 24.4 ± 3.8* 12.5 7.1 36.5 4.4 ± 3.3 17.7 3.4 ± 2.7 8.0
50.6 ± 3.0*,† 3.7 ± 4.2*,† 82.5 68.6 24.6 ± 3.6* 15.5 11.9 42.8 4.1 ± 3.7 17.5 3.6 ± 3.0 11.3
0.00 0.00 0.000 0.001 0.004 0.01 0.000 0.35 0.67 0.303 0.07 0.277
ANOVA and followed by Scheffe’s test, as a post hoc procedure when needed for the comparison of means and the χ2 -test for the variable of proportion. a Women who were married without separation from their husband. It excludes those who were single, widows, divorced and who were married but in separation. † p < 0.05 vs. perimenopause. ‡ p < 0.05 vs. postmenopause. * p < 0.05 vs. premenopause.
3.3. Hot flashes and mood A total of 10.5% (n = 134) of participants reported hot flashes within the previous 2 weeks. Anxiety scores were higher in subjects with hot flashes than those without (6.0 ± 3.8 versus 4.1 ± 3.1, p < 0.001). Women
with hot flashes also had higher depression scores than those without (4.0 ± 3.3 versus 3.2 ± 2.7, p < 0.001). To ascertain if the hot flashes are independently associated with the anxiety, depression and/or the total HADS scores, we conducted stepwise linear regression analysis. The independent variables were chosen be-
Table 2 Stepwise regression model of variables and their association with the anxiety, depression and total scores of the hospital anxiety and depression scale Parameter estimate (95% confidence interval)
S.E.
p-Value
Anxiety score (R2 = 0.110) Intercept Presence of insomnia Presence of hot flashes Years of education
2.72 (2.39–3.05) 1.41 (1.062–1.758) 1.746 (1.193–2.299) 0.113 (0.076–0.15)
0.168 0.177 0.282 0.019
0.000 0.000 0.000 0.000
Depression score (R2 = 0.037) Intercept Presence of insomnia Presence of hot flashes
2.784 (2.568–3.0) 0.875 (0.57–1.181) 0.701 (0.214–1.189)
0.11 0.156 0.214
0.000 0.000 0.005
Total scores (R2 = 0.090) Intercept Presence of insomnia Presence of hot flashes Years of education
5.339 (4.796–5.883) 2.338 (1.67–2.816) 2.512 (1.599–3.425) 0.142 (0.081–0.203)
0.277 0.292 0.465 0.031
0.000 0.000 0.000 0.000
Age and menopausal status were entered into the model, but no significant association with the HADS scale was found.
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cause they might be related to anxiety and depression. The presence of insomnia was the strongest associated factor, followed by the presence of hot flashes in the anxiety, depression, and total HADS scores (Table 2). Years of education were associated with anxiety and the total scores, but not the depression score. The remaining variables, years of age and menopausal status, were not significantly associated with these three scores. 3.4. The relationship of hot flashes, mood and menopausal status The anxiety score for subjects with and without hot flashes in the three menopausal groups is shown in Fig. 2. A similar graph for the depression score is shown in Fig. 3. The relationships between hot flashes, anxiety, and depression scores were different across the three menopausal groups. In the premenopausal group, when comparing subjects with hot flashes with those without, there were no significant differences in anxiety scores (4.9 ± 3.2 versus 4.2 ± 3.1, p = 0.07) and depression scores (3.0 ± 2.7 versus 3.1 ± 2.7, p = 0.78). However, the differences in anxiety scores between subjects with, and those without, hot flashes were significant in the perimenopausal (6.7 ± 3.8 versus 4.1 ± 3.1, p < 0.01) and postmenopausal (7.2 ± 4.4 versus 3.5 ± 3.3, p < 0.01)
Fig. 2. Anxiety score between women with and without hot flashes in different menopausal groups. The differences between subjects with, and those without, hot flashes were significant in the perimenopausal and postmenopausal groups (p < 0.01).
groups. Depression scores were also significantly different between those with and without hot flashes in the perimenopausal (4.9 ± 3.4 versus 3.2 ± 2.5, p < 0.01) and postmenopausal (4.9 ± 3.5 versus 3.4 ± 2.9, p < 0.01) groups. Among the 1139 subjects without hot flashes, anxiety and depression scores were not different across the three menopausal groups (p = 0.08 and 0.50, respectively). In contrast, among the remaining 134 subjects with hot flashes, anxiety and depression scores differ significantly across different menopausal groups (both p = 0.01, one-way ANOVA). A logistic regression model of clinically significant anxiety and depression as dependent variables and hot flashes, menopausal status, and several demographic factors as independent variables was performed. The presence of hot flashes is a risk factor of clinically significant anxiety, with an odds ratio 3.09 (95% C.I. = 2.05–4.64, p < 0.001) after menopausal status, age, education, body mass index, unemployment and marital status were controlled. In a similar model, the presence of hot flashes is also associated with clinically significant depression, with an odds ratio of 2.01 (95% C.I. = 1.18–3.43, p = 0.01). To examine whether insomnia mediates the association between hot flashes and anxiety or depression, we further put insomnia into these models. The odd ratio of hot flashes
Fig. 3. Depression score between women with and without hot flashes in different menopausal groups. The differences between subjects with, and those without, hot flashes were significant in the perimenopausal and postmenopausal groups (p < 0.01).
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for clinically significant anxiety became 2.54 (95% C.I. = 1.67–3.87, p < 0.001) and that for depression became 1.76 (odds ratio = 1.76, 95% C.I. = 1.03–3.04, p = 0.041) after insomnia was controlled.
4. Discussion In the present study, conducted with a community population of middle-aged women, we found that both anxiety and depression are associated with hot flashes but not menopausal status. The association remains significant even after insomnia has been controlled. The results are compatible with our hypothesis that the presence of hot flashes is a risk factor for psychological symptoms of anxiety and depression. The lack of association between hot flashes and anxiety and/or depression in the premenopausal women suggests that hot flashes are associated with anxiety and/or depression only in the peri- and postmenopausal women. This community-based study confirms the Joffe et al.’s clinic-based study [5] that demonstrates the interplay between vasomotor symptoms and perimenopausal depression in middle-aged women. In addition to depression, we also found that anxiety is associated with hot flashes. While most previous studies focused on depression, the status of anxiety in perimenopausal women has been less well investigated. In the present study, we found that anxiety is also related to the menopausal status and hot flashes. Our findings suggest that anxiety in climacteric women deserves more attention in future research and in clinical practice. Although we found that the average anxiety and depression scores were higher in the presence of hot flashes, whether these results reflected a clinical significance is unknown. However, in the logistic regression analyses, which used a high cut-off score as clinical significance of depression or anxiety, we also found significant association between both anxiety and depression and the presence of hot flashes. More research is needed to determine whether the presence of hot flashes can be a useful indicator to remind clinicians to be aware of possible co-existing psychiatric conditions among perimenopausal and postmenopausal patients. The prevalence of vasomotor symptoms is relatively low in East Asia [8,13]. Only one-tenth of our subjects had hot flashes within the most recent 2-week study period. Whether our results could apply
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to populations with high vasomotor symptoms is in doubt and deserves further comparison. The study was also done in a rural area with low educational achievement (mean educational year = 6.7). The implication of our study results to different population is still unknown. At present, our findings are similar to those of Joffe et al. in a clinical sample at Boston [5]. These authors also found an association between hot flashes in perimenopausal women. However, they did not find the association in postmenopausal women as indicated in our study. The discrepancy may be related to the relatively younger age of menopausal women in our study. We recruited only women below 55 years of age. Most of our postmenopausal women were still early in their postmenopausal period. The mean menopausal duration was only 4.1 years, with a median of 3 years, in our sample. When the total sample was divided into those with hot flashes and those without hot flashes, we found different patterns of relationship between menopausal status and mood. In the presence of hot flashes, peri-and postmenopausal status were associated with higher HADS scores. There was no such association in the absence of hot flashes. Those who suffer from and are troubled by hot flashes may be more likely to seek medical help in clinical settings. Hence, women with hot flashes may be over-represented in the clinical sample. Early clinic-based investigation of mood and menopause may have detected the association while many of their subjects were experiencing hot flashes [1]. More recent community-based studies [2,3] avoided the confounding effect of hot flashes and found no association between menopause and mood, as found in our study population. The mechanism of hot flashes is generally thought to be the prominent change of gonadal hormones, such as a decline of estrogen, in climacteric women. Earlier studies have shown that change in gonadal hormones can induce depression in some susceptible women [14]. Therefore, hormonal change may be the underlying mechanism of the link between psychological change and hot flashes. There is now growing evidence indicating that antidepressants such serotonin-specific uptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) are effective in reducing hot flashes [15–17]. These findings suggest that hot flashes may be related to neuronal serotonergic and norepinephrine systems. Since these neuronal systems
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also play important roles in depression and anxiety, serotonin and norepinephrine may also explain the link between hot flashes and emotional disturbance in climacteric women. Other factors such as diet and exercise may also play some role in the link between mood and hot flashes. Further research is needed to elucidate the mechanism underlying the link. In the present study of the relationship between menopausal status, vasomotor symptoms, anxiety, and depression, we found a complicated interplay between menopausal status and vasomotor symptoms and their association with anxiety as well as with depression. We have tried to rigorously avoid sampling bias by using a community-based study. We also adopted the HADS to avoid the phenomenon of shared symptoms between mood and vasomotor symptoms. Our results confirm findings of previous studies conducted in clinical practice [5]. These findings may also shed light on the investigation of the mechanism of both hot flashes and emotional disturbance in climacteric women. Because the presence of hot flashes is associated with emotional disturbance in women during the menopausal transition, hot flashes may be helpful in screening anxiety and depression in public health and clinical settings.
Acknowledgements This study was supported by grants from the National Health Research Institutes (NHRI-GTEX89P923C, NHRI-GT-EX90-8923PC and NHRIEX91-8923PC) and Taipei VGH.
References [1] Ihezue UH, Kumaraswamy N. Prevalence of depressive symptoms among patients attending a general outpatient clinic. Acta Psychiatr Scand 1986;73:395–8.
[2] Mathews KA, Wing RR, Kuller LH, et al. Influences of natural menopause on psychological characteristics and symptoms of middle-aged healthy women. J Consult Clin Psychol 1990;58:345–51. [3] Mitchell ES, Woods NF. Symptom experiences of midlife women: observations from the Seattle Midlife women’s health study. Maturitas 1996;25:1–10. [4] Bosworth HB, Bastian LA, Kuchibhatla MN, et al. Depressive symptoms, menopausal status, and climacteric symptoms in women at midlife. Psychosom Med 2001;63:603–8. [5] Joffe H, Hall JE, Soares CN, et al. Vasomotor symptoms are associated with depression in perimenopausal women seeking primary care. Menopause 2002;9:392–8. [6] Beck AT, Steer R, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 1988;8:77–100. [7] Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–70. [8] Fuh JL, Wang SJ, Lu SR, Juang KD, Chiu LM. The Kinmen women-health investigation (KIWI): a menopausal study of a population aged 40–54. Maturitas 2001;39:117–24. [9] Blatt MHG, Wiesbader H, Kupperman HS. Vitamin E and climacteric syndrome: failure of effective control as measured by menopausal index. Arch Int Med 1953;91:792–9. [10] Studd JWW, Whitehead MI. The menopause. Blackwell Scientific: United Kingdom, Oxford; 1988. p. 24–42. [11] Juang KD, Wang SJ, Lin CH, Fuh JL. Use of the hospital anxiety and depression scale as a screening tool for patients with headache. J Chin Med Assoc 1999;62:749–55. [12] Leung CM, Ho S, Kan CS, Hung CH, Chen CN. Evaluation of the Chinese version of the hospital anxiety and depression scale. A cross-cultural perspective. Int J Psychosom 1993;40:29–34. [13] Boulet MJ, Oddens BJ, Lehert P, Vemer HM, Visser A. Climacteric and menopause in seven southeast Asian countries. Maturitas 1994;19:157–76. [14] Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 1998;338:209–16. [15] Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003;289:2827–34. [16] Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578–83. [17] Schober CE, Ansani NT. Venlafaxine hydrochloride for the treatment of hot flashes. Ann Pharmacother 2003;37:1703–7.
Hot flashes are associated with psychological symptoms of anxiety and depression in periand post- but not premenopausal women Kai-Dih Juang a, c , Shuu-Jiun Wang b, c , Shiang-Ru Lu d , Shin-Jung Lee e , Jong-Ling Fuh b, c, ∗ a
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan c National Yang-Ming University School of Medicine, Taipei, Taiwan d Department of Neurology, Kaohsiung Medical University Chung-Ho Memorial Hospital, USA e Department of Biostatistics, Comprehensive Cancer Center, University of Michigan, MI, USA b
Received 8 October 2004; received in revised form 2 January 2005; accepted 11 January 2005
Abstract Objective: To explore the relationship between anxiety, depression, vasomotor symptoms, and menopausal status among middleaged women. Design: A population-based study involving a rural Taiwanese population. Participants received a structured questionnaire, which included the hospital anxiety and depression scale (HADS), gynecological history and a checklist of menopausal symptoms in the most recent 2 weeks. Results: A total of 1273 women with no history of surgical menopause and hormonal therapy history participated. The mean anxiety, depression, and total HADS scores were 4.3 ± 3.3, 3.3 ± 2.8 and 7.6 ± 5.3, respectively, and did not differ according to menopausal status. A total of 10.5% participants reported hot flashes within the previous 2 weeks. After controlling for educational status and insomnia, anxiety (6.0 ± 3.8 versus 4.1 ± 3.1) and depression scores (4.0 ± 3.3 versus 3.2 ± 2.7) were significantly higher (p < 0.001) compared with those without hot flashes. These differences were attributed to peri- and postmenopausal subjects. Conclusions: Hot flashes in peri- and postmenopausal women were associated with anxious and depressive symptoms in East Asian population with low prevalence of vasomotor symptoms. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Climacteric symptoms; Depression; Menopause; Anxiety; Vasomotor symptoms; Hot flashes
∗
Corresponding author. Tel.: +886 2 28762522; fax: +886 2 28765215. E-mail address: [email protected] (J.-L. Fuh).
0378-5122/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2005.01.005
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1. Introduction Whether depression is increased in peri- and postmenopausal women has been an issue of debate for decades. Earlier clinic-based studies found that depression is more frequent in postmenopausal women [1]. In contrast, large-scale community-based research shows that the prevalence of depression is not higher in peri- or postmenopausal women [2,3]. The divergence of results may result from different sampling methods. Since women with either menopausal syndrome or depression are more likely to seek help in clinical settings, subjects drawn from these clinics may be different from the general population in community settings. Recent studies have begun to find risk factors of depression during menopausal transition. For example, Bosworth et al. [4] suggested that it is the menopausal symptoms, rather than menopausal status, that are related to depression. The authors reported that a telephone interview of women wishing to discuss hormone therapy revealed that mood swing, troubled sleeping, and poor concentration can account for the association between menopausal status and depression. Furthermore, Joffe et al. [5] showed a more complicated relationship among vasomotor symptoms, menopausal status, and depression, by applying the Center for Epidemiological Studies Depression Scale (CES-D). In that study, perimenopausal women visiting general practice physicians were shown to experience increased frequencies of depression only if vasomotor symptoms were present. Pre-, postmenopausal, and perimenopausal women without vasomotor symptoms did not show an increased frequency of depression. It appears that the simultaneous presence of both vasomotor symptoms and menopausal changes is associated with depression in middle-aged women. However, these two studies were conducted among specific groups of women in clinical settings, and not in the general population. Since both hot flashes and depression may bring women to clinical settings, their association may be caused by sampling bias. More community-based studies are needed in order to elucidate the relationship between menopausal status, menopausal syndrome, and depression. In addition to sampling issues, measurement bias may also influence the investigation of depression and menopausal symptoms. When two methods of
measurement overlap in some area, they appear to be correlated even if they are not. Depression and certain physical conditions share some common symptoms, such as fatigue. Therefore, in the assessment of depression, these shared symptoms may overlap, resulting in confounding and measurement bias [6]. For example, night sweating may disturb sleep and thus increase depression scores that include insomnia as a symptom. A measurement of depression that accounts for these shared symptoms would potentially reduce confounding between depression and menopausal syndrome. Besides, none of the previous studies explored the relationship between anxiety and menopausal changes. The purpose of the current study was to explore the relationship between depression, vasomotor symptoms, and menopausal status in a community population. We adopted the hospital anxiety and depression scale (HADS) [7] as a measurement tool. The HADS is a depression and anxiety scale that excludes physical symptoms of depression and anxiety; therefore, it prevents physical symptoms from confounding the measure of depression. Because insomnia may be a possible mediator between vasomotor symptoms and emotional symptoms, we also tried to control insomnia in the analysis. The present study was conducted among middle-aged women in a community-based setting. We hypothesized that there would be higher scores of depression and anxiety among subjects with hot flashes.
2. Methods 2.1. Subjects The study is a part of the Kinmen Woman’s Health Investigation (KIWI) [8] that assessed the health condition of middle-aged women in the community of Kinmen, Taiwan. Kinmen is an island of 176 km2 located 248 km (154 miles) west of Taiwan and 41 km (25 miles) east of Mainland China. It consists of four townships, with a total population of 51,060 in 1998. Using the KIWI cohort, we surveyed all female citizens between ages 40 and 54 in 1998 who resided in two of the four townships in Kinmen Island. Fig. 1 shows the flow chart of recruiting subjects to the final population. We excluded subjects who have had hysterectomy or
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2.3. Definition of menopausal status According to the subjects’ reports, menopausal status was categorized into: (1) premenopausal: regular menstruation (regular menstruation is defined as cycles that vary in length by not more than 5 days for the preceding 3 months, and are between 23 and 35 days); (2) perimenopausal: cycles irregular (defined as cycles lasting less than 23 days, greater than 35 days or that vary by more than 5 days during the preceding 3 months) or ceased for less than 1 year; and (3) postmenopausal: no cycles for more than 1 year. 2.4. Vasomotor symptoms
Fig. 1. Flow chart of subject recruitment and exclusion.
bilateral oophorectomy and who are receiving hormone therapy to reduce the confounding effects of surgical menopause and exogenous hormones. More detailed methods are described in an earlier paper [8]. This study has been approved by the Institutional Review Board of Taipei Veterans General Hospital. Informed consent has been obtained from the subjects. 2.2. Assessment The participants received and completed the following self-administered questionnaires in the presence of well-trained interviewers: (1) personal information, (2) medical history, (3) menstrual and reproductive history, and (4) the menopause-related symptom checklist. Although KIWI is a longitudinal follow-up study, the present study is cross-sectional analysis of data of the first year that assessed menopausal status, menopausal symptoms, and mood at the same time.
In the menopause-related symptom checklist, the subjects reported whether they experienced symptoms within the most recent 2 weeks. The list of symptoms that we used were modified from the Kupperman index [9] that includes hot flashes, night sweating, insomnia, headache, joint pain, back pain, muscle pain, dizziness, fatigue, vaginal dryness, and frequency of urination. Since only the vasomotor symptoms were considered to be clearly associated with menopause in our own and previous studies [8,10], and the relationship of night sweats and depression might be confounded by insomnia, we chose only hot flashes for analysis. According to Kupperman index, we asked the frequency of hot flashes in recent 2 weeks, and recorded the frequency as: (1) having no hot flashes occurring in the most recent 2 weeks; (2) hot flashes having occurred once in these 2 weeks; (3) once a week; and (4) more than once a week. The latter three groups were regrouped into one group with the presence of any hot flashes in recent 2 weeks for analysis because of the relatively low number of subjects in each group. The data of insomnia was also taken from the Kupperman index, in which the frequency of insomnia was explored by the question “Do you have insomnia in recent 2 weeks?” 2.5. Assessment of depression and anxiety We adopted the Chinese version of HADS [11] to measure participants’ anxiety and depression. The HADS is a self-administered rating scale that was designed to avoid the confounding effects of somatic condition in the study of medical patients by excluding physical symptoms of anxiety and depression. Hence,
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the HADS focuses on psychological and emotional symptoms of anxiety and depression. The depression subscale of the HADS focuses on the feelings of anhedonia [7]. The depression subscale inquires depressed mood, hopelessness, and enjoyment, similar to CESD that has been used by many studies in menopausal women. Unlike CES-D, the HADS did not ask about appetite, sleep, fatigue, and concentration of mind, which are easily affected by physical discomfort. The anxiety subscale of the HADS focuses on worry and restlessness [7]. It also excludes items of physical symptoms, such as sweating, tremor and palpitation. The HADS includes 14 items: 7 for anxiety and 7 for depression, yielding total anxiety, and depression scores. Each of the 14 items is followed by four descriptions. The description that indicates “no distress” was scored 0, followed by descriptions scored 1 and 2; and the description that indicates the highest distress is scored 3. The anxiety score is the sum of the 7 anxiety items and the depression score is the sum of the 7 depression items. The total HADS score is the sum of anxiety and depression scores. Hence, the range of the total HADS score is 0–42, while the range of anxiety score and depression score is 0–21. In this study we used a cut-off point of 7/8 in anxiety and depression scores as clinically significant cases [12]. We followed some previous studies in adopting the 7/8 cut-off points although some studies suggest that optimal cut-off points varies among different samples and that different cut-off points should be used in each sample [12]. In our previous study in patients with severe headache, we found that a total HADS score of 10 or more was the optimal cut-off point for depressive disorders. The sensitivity was 85.7%, and the specificity 33.3%. A total score of at least 13 was the optimal cut-off point for anxiety disorder. The sensitivity was 84.2%, while the specificity was 41.9% [11]. 2.6. Statistical methods The mean and standard deviations (S.D.) of the various parameters were calculated for each menopausal group. The χ2 -test was used for comparing the rates of each symptom in the pre-, peri-, and postmenopausal groups. The differences among means were compared by one-way analysis of variance (ANOVA) and by Scheffe’s pairwise comparison where appropriate. Pearson’s correlation was used to test the correlation
between scores and other variables of interested. The linear regression model and logistic regression model were used to adjust for confounding factors in the analysis of scores. Education and age were coded in years as a continuous variable. The level of significance chosen was p < 0.05.
3. Results 3.1. Characteristics of the study population Of the 2256 targeted women, 1497 (66%) participated in the study. Most of the non-participants actually live in Taiwan and return to Kinmen occasionally, so we could not find them even after several house calls. The participants and non-participants did not differ in age (45.5 ± 4.0 versus 45.8 ± 4.2 years; t = −1.3, d.f. = 2.54, p = 0.19). After excluding subjects with incomplete data (n = 56), mental retardation (n = 5), past history of hysterectomy (n = 50) and/or bilateral oophorectomy (n = 42), and HT users (n = 86), the remaining 1273 women constituted the final sample for analysis. Of the 1273 subjects, 728 (57%) were premenopausal, 351 (28%) perimenopausal, and 194 (15%) postmenopausal, with a mean menopause duration of 4.1 years (S.D. = 3.6; median = 3 years). The mean age of the total sample was 45.3 ± 4.0 years, and the mean years of education was 5.9 ± 4.7. Basic demographic data of the subjects in these three menopausal categories are shown in Table 1. 3.2. Anxiety and depression scores The mean anxiety score was 4.3 ± 3.3, and the mean depression score was 3.3 ± 2.8. The mean total HADS score was 7.6 ± 5.3. The anxiety and depression scores correlated with each other (r = 0.57, p < 0.001). Fifteen point eight percent (15.8%) of the subjects had a clinically significant level of anxiety (anxiety score of 8 or higher), while 8.4% had a clinically significant level of depression (depression score of 8 or higher). Anxiety and depression scores of subjects in the three different menopausal groups are shown in Table 1. According to the ANOVA analysis, there was no significant difference among any one of the total HADS, anxiety, and depression scores.
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Table 1 Demographic data and hospital anxiety and depression scale in different menopausal status Parameter
p-Value
Menopausal status
Total subjects
Premenopause
Perimenopause
Postmenopause
728
351
194
Age (years) Education (years) Married w/o separation (%)a Unemployed (%) Body mass index Hot flashes (%) Night sweating (%) Insomnia (%) Anxiety score Anxiety score ≥8 (%) (clinically significant anxiety) Depression score Depression score ≥8 (%) (clinically significant depression)
43.6 ± 2.9†,‡
6.7 ± 4.6†,‡ 93.4 55.9 23.9 ± 3.4†,‡ 8.2 3.0 38.4 4.2 ± 3.1 14.4 3.1 ± 2.7 7.8
46.1 ± 3.7*,‡
5.5 ± 4.7*,‡ 88.3 63.8 24.4 ± 3.8* 12.5 7.1 36.5 4.4 ± 3.3 17.7 3.4 ± 2.7 8.0
50.6 ± 3.0*,† 3.7 ± 4.2*,† 82.5 68.6 24.6 ± 3.6* 15.5 11.9 42.8 4.1 ± 3.7 17.5 3.6 ± 3.0 11.3
0.00 0.00 0.000 0.001 0.004 0.01 0.000 0.35 0.67 0.303 0.07 0.277
ANOVA and followed by Scheffe’s test, as a post hoc procedure when needed for the comparison of means and the χ2 -test for the variable of proportion. a Women who were married without separation from their husband. It excludes those who were single, widows, divorced and who were married but in separation. † p < 0.05 vs. perimenopause. ‡ p < 0.05 vs. postmenopause. * p < 0.05 vs. premenopause.
3.3. Hot flashes and mood A total of 10.5% (n = 134) of participants reported hot flashes within the previous 2 weeks. Anxiety scores were higher in subjects with hot flashes than those without (6.0 ± 3.8 versus 4.1 ± 3.1, p < 0.001). Women
with hot flashes also had higher depression scores than those without (4.0 ± 3.3 versus 3.2 ± 2.7, p < 0.001). To ascertain if the hot flashes are independently associated with the anxiety, depression and/or the total HADS scores, we conducted stepwise linear regression analysis. The independent variables were chosen be-
Table 2 Stepwise regression model of variables and their association with the anxiety, depression and total scores of the hospital anxiety and depression scale Parameter estimate (95% confidence interval)
S.E.
p-Value
Anxiety score (R2 = 0.110) Intercept Presence of insomnia Presence of hot flashes Years of education
2.72 (2.39–3.05) 1.41 (1.062–1.758) 1.746 (1.193–2.299) 0.113 (0.076–0.15)
0.168 0.177 0.282 0.019
0.000 0.000 0.000 0.000
Depression score (R2 = 0.037) Intercept Presence of insomnia Presence of hot flashes
2.784 (2.568–3.0) 0.875 (0.57–1.181) 0.701 (0.214–1.189)
0.11 0.156 0.214
0.000 0.000 0.005
Total scores (R2 = 0.090) Intercept Presence of insomnia Presence of hot flashes Years of education
5.339 (4.796–5.883) 2.338 (1.67–2.816) 2.512 (1.599–3.425) 0.142 (0.081–0.203)
0.277 0.292 0.465 0.031
0.000 0.000 0.000 0.000
Age and menopausal status were entered into the model, but no significant association with the HADS scale was found.
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cause they might be related to anxiety and depression. The presence of insomnia was the strongest associated factor, followed by the presence of hot flashes in the anxiety, depression, and total HADS scores (Table 2). Years of education were associated with anxiety and the total scores, but not the depression score. The remaining variables, years of age and menopausal status, were not significantly associated with these three scores. 3.4. The relationship of hot flashes, mood and menopausal status The anxiety score for subjects with and without hot flashes in the three menopausal groups is shown in Fig. 2. A similar graph for the depression score is shown in Fig. 3. The relationships between hot flashes, anxiety, and depression scores were different across the three menopausal groups. In the premenopausal group, when comparing subjects with hot flashes with those without, there were no significant differences in anxiety scores (4.9 ± 3.2 versus 4.2 ± 3.1, p = 0.07) and depression scores (3.0 ± 2.7 versus 3.1 ± 2.7, p = 0.78). However, the differences in anxiety scores between subjects with, and those without, hot flashes were significant in the perimenopausal (6.7 ± 3.8 versus 4.1 ± 3.1, p < 0.01) and postmenopausal (7.2 ± 4.4 versus 3.5 ± 3.3, p < 0.01)
Fig. 2. Anxiety score between women with and without hot flashes in different menopausal groups. The differences between subjects with, and those without, hot flashes were significant in the perimenopausal and postmenopausal groups (p < 0.01).
groups. Depression scores were also significantly different between those with and without hot flashes in the perimenopausal (4.9 ± 3.4 versus 3.2 ± 2.5, p < 0.01) and postmenopausal (4.9 ± 3.5 versus 3.4 ± 2.9, p < 0.01) groups. Among the 1139 subjects without hot flashes, anxiety and depression scores were not different across the three menopausal groups (p = 0.08 and 0.50, respectively). In contrast, among the remaining 134 subjects with hot flashes, anxiety and depression scores differ significantly across different menopausal groups (both p = 0.01, one-way ANOVA). A logistic regression model of clinically significant anxiety and depression as dependent variables and hot flashes, menopausal status, and several demographic factors as independent variables was performed. The presence of hot flashes is a risk factor of clinically significant anxiety, with an odds ratio 3.09 (95% C.I. = 2.05–4.64, p < 0.001) after menopausal status, age, education, body mass index, unemployment and marital status were controlled. In a similar model, the presence of hot flashes is also associated with clinically significant depression, with an odds ratio of 2.01 (95% C.I. = 1.18–3.43, p = 0.01). To examine whether insomnia mediates the association between hot flashes and anxiety or depression, we further put insomnia into these models. The odd ratio of hot flashes
Fig. 3. Depression score between women with and without hot flashes in different menopausal groups. The differences between subjects with, and those without, hot flashes were significant in the perimenopausal and postmenopausal groups (p < 0.01).
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for clinically significant anxiety became 2.54 (95% C.I. = 1.67–3.87, p < 0.001) and that for depression became 1.76 (odds ratio = 1.76, 95% C.I. = 1.03–3.04, p = 0.041) after insomnia was controlled.
4. Discussion In the present study, conducted with a community population of middle-aged women, we found that both anxiety and depression are associated with hot flashes but not menopausal status. The association remains significant even after insomnia has been controlled. The results are compatible with our hypothesis that the presence of hot flashes is a risk factor for psychological symptoms of anxiety and depression. The lack of association between hot flashes and anxiety and/or depression in the premenopausal women suggests that hot flashes are associated with anxiety and/or depression only in the peri- and postmenopausal women. This community-based study confirms the Joffe et al.’s clinic-based study [5] that demonstrates the interplay between vasomotor symptoms and perimenopausal depression in middle-aged women. In addition to depression, we also found that anxiety is associated with hot flashes. While most previous studies focused on depression, the status of anxiety in perimenopausal women has been less well investigated. In the present study, we found that anxiety is also related to the menopausal status and hot flashes. Our findings suggest that anxiety in climacteric women deserves more attention in future research and in clinical practice. Although we found that the average anxiety and depression scores were higher in the presence of hot flashes, whether these results reflected a clinical significance is unknown. However, in the logistic regression analyses, which used a high cut-off score as clinical significance of depression or anxiety, we also found significant association between both anxiety and depression and the presence of hot flashes. More research is needed to determine whether the presence of hot flashes can be a useful indicator to remind clinicians to be aware of possible co-existing psychiatric conditions among perimenopausal and postmenopausal patients. The prevalence of vasomotor symptoms is relatively low in East Asia [8,13]. Only one-tenth of our subjects had hot flashes within the most recent 2-week study period. Whether our results could apply
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to populations with high vasomotor symptoms is in doubt and deserves further comparison. The study was also done in a rural area with low educational achievement (mean educational year = 6.7). The implication of our study results to different population is still unknown. At present, our findings are similar to those of Joffe et al. in a clinical sample at Boston [5]. These authors also found an association between hot flashes in perimenopausal women. However, they did not find the association in postmenopausal women as indicated in our study. The discrepancy may be related to the relatively younger age of menopausal women in our study. We recruited only women below 55 years of age. Most of our postmenopausal women were still early in their postmenopausal period. The mean menopausal duration was only 4.1 years, with a median of 3 years, in our sample. When the total sample was divided into those with hot flashes and those without hot flashes, we found different patterns of relationship between menopausal status and mood. In the presence of hot flashes, peri-and postmenopausal status were associated with higher HADS scores. There was no such association in the absence of hot flashes. Those who suffer from and are troubled by hot flashes may be more likely to seek medical help in clinical settings. Hence, women with hot flashes may be over-represented in the clinical sample. Early clinic-based investigation of mood and menopause may have detected the association while many of their subjects were experiencing hot flashes [1]. More recent community-based studies [2,3] avoided the confounding effect of hot flashes and found no association between menopause and mood, as found in our study population. The mechanism of hot flashes is generally thought to be the prominent change of gonadal hormones, such as a decline of estrogen, in climacteric women. Earlier studies have shown that change in gonadal hormones can induce depression in some susceptible women [14]. Therefore, hormonal change may be the underlying mechanism of the link between psychological change and hot flashes. There is now growing evidence indicating that antidepressants such serotonin-specific uptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) are effective in reducing hot flashes [15–17]. These findings suggest that hot flashes may be related to neuronal serotonergic and norepinephrine systems. Since these neuronal systems
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also play important roles in depression and anxiety, serotonin and norepinephrine may also explain the link between hot flashes and emotional disturbance in climacteric women. Other factors such as diet and exercise may also play some role in the link between mood and hot flashes. Further research is needed to elucidate the mechanism underlying the link. In the present study of the relationship between menopausal status, vasomotor symptoms, anxiety, and depression, we found a complicated interplay between menopausal status and vasomotor symptoms and their association with anxiety as well as with depression. We have tried to rigorously avoid sampling bias by using a community-based study. We also adopted the HADS to avoid the phenomenon of shared symptoms between mood and vasomotor symptoms. Our results confirm findings of previous studies conducted in clinical practice [5]. These findings may also shed light on the investigation of the mechanism of both hot flashes and emotional disturbance in climacteric women. Because the presence of hot flashes is associated with emotional disturbance in women during the menopausal transition, hot flashes may be helpful in screening anxiety and depression in public health and clinical settings.
Acknowledgements This study was supported by grants from the National Health Research Institutes (NHRI-GTEX89P923C, NHRI-GT-EX90-8923PC and NHRIEX91-8923PC) and Taipei VGH.
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