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1 online ML Comm 생물정신의학 Vol. 16, No. 4, November 2009 종설 폐경기관련우울증의평가와치료 * 양수진 김재민 Diagnosis and Treatment of Menopause-Related Depression * Su-Jin Yang, M.D., Ph.D., Jae-Min Kim, M.D., Ph.D. ABSTRACT R ecent Korean statistics show that a Korean woman can now expect to live until her mid-80s, which implies living at least one-third of her life after menopause. The menopausal transition is typically marked by intense hormonal fluctuations, accompanied by sleep disturbance, vasomotor symptoms(e.g., hot flashes, night sweats), increased risk for osteoporosis, cardiovascular disease, and developing depression as well as mood disturbances. These symptoms can affect a woman s quality of life negatively. Therefore, a comprehensive understanding of the accurate detection and appropriate treatment of various menopause-related symptoms including depression in the menopausal transitions and postmenopause is mandatory. This review primarily focused on the current knowledge about the treatment of menopause-related depression. KEY WORDS:Menopause Depression Diagnosis Therapy. 서론 폐경 (menopause) 이란병적인이유없이난소기능이중지된후 12 개월이상무월경이지속되는것을말한다. 1) 폐경은정상적인인생의단계이나여성들에게큰의미를주는사건으로여겨지며에스트로겐감소와관련되어심리적, 신체적으로다양한변화가일어나게된다. 폐경기증상은그발현시기및양상에따라구분되어 기술된다. 2) 먼저증상이발현되는시기에따라서급성기증상으로정신적증상과불규칙한월경, 홍조, 발한등의혈관운동증상이있고, 아급성증상으로생식기위축, 비뇨기위축, 피부위축등을보이며, 그리고만성증상으로골다공증, 심혈관질환, 치매등이나타난다. 2) 한편증상의양상에따라서는심리및행동증상으로기분변동, 불면증, 과민성, 긴장감, 에너지와욕구감소, 성욕감퇴, 불쾌감등이있고, 신체증상으로는혈관운동증상과근골격계증상등이있는데, 이와같은심리및신체증상이 * 본연구는보건복지부보건의료기술진흥사업의지원에의하여이루어진것임 ( 과제번호 :A050047). 전남대학교의과대학정신과학교실및전남대학교병원우울증임상연구센터 Department of Psychiatry, Chonnam National University Medical School and Department Clinical Research Center, Chonnam National University Hospital, Gwangju, Korea 교신저자 : 김재민, 광주광역시동구학 1 동 5 번지전화 ) (062) , 전송 ) (062) , ) jmkim@chonnam.ac.kr

2 동시에나타나는경우가많다. 3) 폐경기증상들은여성의삶의질과안녕감 (well-being) 에부정적영향을주는데 4) 여성의평균수명이증가하여폐경기이후의여명이늘어나고있으므로임상가는폐경기증후군의진단과치료에관심을기울여야한다. 본종설은폐경기증후군특히우울증에관한문헌들을고찰하고요약하여, 이의진단및치료에대한이해를증진시키고자하였다. 내용의구성은폐경기증후군의전반적증상, 폐경기우울증의검사및진단, 치료, 그리고향후연구방향이다. 폐경기증후군의개관 여성생애전반의생식주기및내분비계변화는그림 1에도식화되었다. 생식주기를시기별로보면, 월경이처음시작되는초경 (menarche) 에서폐경이행기 (menopausal transition) 까지가가임기 (reproductive) 인데그중폐경이임박하였지만월경주기가규칙적인기간을후기가임기또는폐경전기 (premenopause) 라고하고, 폐경기직전및무월경이있은지 1년동안의시기를폐경주변기 (perimenopause), 폐경이후의시기를폐경후기 (postmenopause) 라고한다. 흔히사용되는갱년기 (climacteric) 라는용어는난소기능이하강하는기간을일컫는것이고, 폐경이행기는폐경전에호르몬이변동되는시기이다. 5) 폐경이행이시작되는연령대는다양하지만대략 47.5 세이며대부분 4년후인 51.4 세경에폐경기가된다. 6) 흡연자와미분만부 (nullipara) 의경우좀더일 찍폐경이행기가시작된다. 7) 폐경이일어나는기전에대한다양한설명이있는데일반적으로관찰할수있는첫번째변화는인히빈 (inhibin) 감소와난포자극호르몬 (Follicle Stimulating Hormone, 이하 FSH) 농도상승이다. 8) 폐경이행기초기에는난소의기질부위에서에스트로겐의생산은계속되고난소- 시상하부- 뇌하수체축도유지된다. 그래서난소부전에반응하여뇌하수체는난포를자극하기위해좀더많은 FSH 를분비하게되어 FSH 는상승하고, 난소에서대부분세포사에따른이차적현상인난소난포의결여가생겨난소가더이상뇌하수체성선자극호르몬인 FSH 와황체형성호르몬 (luteinizing hormone, 이하 LH) 에반응할수없게되면에스트로겐이나프로게스테론의생산이멈추어지게되면서무배란의주기의빈도가늘어난다. 7)8) 과거에는호르몬생성이점진적으로감소된다고생각하였으나연구에의하면폐경이행기때는성호르몬의변동이심해지면서간헐적으로임상증상이발생한다. 9) 폐경이행기동안호르몬변화는혈관운동성증상, 질건조증, 유방통과관련이있었다. 폐경이행기후반기때상대적으로큰에스트로겐의감소와 FSH 의증가로인해홍조, 질건조증상, 야간발한, 불면증은증가하고유방통은감소하였다. 10) 증상이발생되는시기로보면생식기의후반기 (late reproductive phase) 에유방통, 홍조및혈관운동증상, 불면, 편두통, 생리전불쾌감 (dysphoria) 등의증상이시작되고폐경이행기의후반기 (late menopausal transition phase) 에생식기위축과성기능문제가발생한다. 5) 특히홍조는폐경기이행기증상중에서 M Reproductive Menopausal transition FMP Terminology Early Peak Late Early Late Early Late Premenopause Perimenopause Postmenopause Menstrual cycles Variable to regular Regular Variable(>7days different from normal) 2 skipped cycles and an interval of amenorrhea Amenorrhea None Duration Variable Variable 1year 4years Variable Normal FSH FSH FSH FSH Endocrine Normal estrogen Estrogen Estrogen Estrogen Normal inhibin A & B Inhibin B Inhibin B Inhibin A Inhibin A & B Age(years) 10 s 20 s 30 s 40 s 50 s Over 50 s Fig. 1. Reproductive life cycle. FMP:final menstrual period, FSH:Follicle Stimulating Hormone, M:menarche

3 가장괴로움을주는신체증상으로알려져있다. 4) 홍조는폐경이후 1~2년간지속되는데 25% 가량은 5년이상지속된다. 35~55 세여성을 3년간추적관찰한 Seattle Midlife Women s Health Study 에의하면혈관운동증상은시간이지나면서안정적이되는데증상의정도는에스트로겐의감소를반영한다. 2) 폐경기증상에대한국내자료는드문편이다. 향후국내에서도많은환자를대상으로한보다잘고안된체계적연구가시행될필요가있다. 폐경기우울증 1. 폐경기우울증의유병률정신과적진단기준에맞는폐경과연관된기분장애의외국유병률은지역사회에서 15% 미만, 병원에서는 30% 를넘는다. 10) 최근여성의주기에따른우울증상유병률을정리한연구에따르면폐경전기가 8~37%, 폐경주변기 11~47%, 자연적폐경기 8~47%, 수술적폐경기 8~38% 였다. 11) 단, 폐경기우울증상에대한연구에는새로생긴기분증상과과거기분증상의악화인지구분하는데있어서몇가지방법론적제한이있다. 즉, 연구기간의선택, 진단의신뢰도와민감도등에서한계점을가지고있으며이상적인연구를위해대규모코호트연구에신뢰할수있는측정도구로자주기분증상과호르몬수치를측정하는장기적인전향적연구가필요하다. 폐경이행기가우울증상과유의한연관성이있는지에대해서는특성화된폐경클리닉인지, 임상상황인지, 일반인구대상인지등의연구대상과설문조사방법, 그리고폐경이행기의정의에따라결론이달랐다. 폐경주변기의우울증의유병률은어떤우울측정방법을사용하였느냐에따라다양하다. 으로무작위로선택한군에서 CES-D 16점이상이폐경전기여성보다폐경주변기여성에서 4배이상, 우울장애로진단되는것은 2.5 배였으며, CES-D 가 16점이상여성에서에스트로겐농도의변화가더다양하다는연구가있다. 15) 최근에는내분비계변화에대한측정과함께표준화된우울장애진단도구인 CES-D 16) 와 Hamilton Rating Scale for Depression( 이하 HAM-D) 17) 을사용한전향적역학연구가진행이되어우울증상과관련된요인으로과거우울증의과거력, 심한생리전증후군 (premenstrual syndrome) 등을보고하였으며 16) 우울증상이폐경이행기에증가하고폐경후에감소되는경향을보인다고하였다. 17) 대규모역학연구인 Study of Women s Health Across the Nation 에의하면폐경전기여성보다폐경주변기여성에서기분증상이지속되는비율이높았다. 18) 이러한기분증상은비관적인기분 (blue) 이라기보다는주로과민성 (irritability), 긴장감 (nervousness), 잦은기분변화등이었다. 19) 임상가는폐경주변기여성에서과민성, 긴장감, 잦은기분변화를보일때폐경기증후군과연관된우울장애의가능성을염두에두어야하는데현재로서는폐경기우울증을선별진단하는특정도구가개발되어있지않으므로 CES-D와 HAM-D 등의일반적인우울증척도들을사용하며, FSH 와 estradiol 의농도가진단에반드시포함되어야하는것은아니므로평가과정에서기분과폐경주변기의시간적경과, 우울증후군의식별, 홍조와수면평가를통해폐경기증후군과우울장애에대한진단을해야한다. 20) 폐경기증후군을보이는여성에대한체계적평가법은그림 2에도식화되었다. 3. 폐경기우울증발병의위험인자 ( 표 1) 2. 폐경기우울증의진단폐경기우울증상에대한진단과대부분의연구는한달전의우울증상을평가하는 20문항의 Center for Epidemiologic Studies Depression Scale( 이하 CES-D) 12) 을사용하여 16점이상일때우울장애의가능성이높은것으로보았다. 한연구에의하면 CED-D 16 점이상으로했을때주요우울장애진단의 33% predictive value를보였다. 13) CES-D 로측정한우울기분의유병률이폐경후보다폐경주변기때가더높았다. 14) 일반인구를대상 1) 호르몬변화여성에서우울증의위험이가장큰시기가초경과폐경사이라는연구는여성가임기때기분장애에호르몬변화가중요한역할을한다는것을알려준다. 21)22) 가임기변화기간중특히생리전기간 (premenstrual period), 산욕기 (puerperium), 폐경이행기가우울증발생의위험기간이다. 특히폐경이행기는수년간지속되므로여성들이우울증위험에노출되는시간도길어진다. 23)24) 이행기가 27개월이상길어질경우우울장애의위험도가증

4 가하거나좀더많은신체증상이동반된다. 14) 규칙적인생리주기를보이는 29명의여성이 6개월이상무월경을경험할때까지평균 5년간추적관찰한연구에따르면, 폐경주변의 2년기간이규칙적인생리주기라기보다는우울증의위험도가 14배이상증가하였다. 25) 전향적코호트연구인 Harvard Study of Moods and Cycles 에의하면, 과거우울증의과거력이없는 460명의폐경주변기여성이폐경전기여성에비해우울증상발생위험이 2배높았다. 26) 이연구에따르면폐경이행기 는과거기분장애의재발뿐만아니라새로운기분장애발생의위험시기이다. 2) 폐경이행기우울증에서홍조의역할홍조는폐경이행기의주요증상이다. 홍조는난소부전과에스트로겐감소상황에서시상하부온도조절중추의조절곤란으로생긴다. 27) 야간홍조와열감은수면중에짧지만반복적인각성과관련이있다. 28) 그러나수면중단의정도가중요하지않다는연구도있다. 29) 홍조와열 Middle-age woman(40-60years), depressed, anxious, and sleep disturbance Full assessment of somatic symptoms, menstrual pattern, past psychiatry history(including reproductive-related history), TSH, and current psychosocial issues Vasomotor symptoms? Yes No Perimenopause(does not rule out psychiatric comorbidity) 1. Educate menopause, HRT 2. Refer to gynecologist 3. Offer psychotherapy(group, individual) 1. Consider psychiatric disorder 2. Consider standard psychiatric treatment Symptoms remit? Symptoms remit? Yes No No Yes No further psychiatric treatment needed Begin psychiatric treatment Yes Evaluate FSH, E2 Increased FSH Decreased E2 No Continue psychiatric treatment Fig. 2. Psychiatric evaluation for the middle-age woman. E2:estradiol, FSH:Follicle Stimulating Hormone, HRT: Hormone-Replacement Therapy, TSH:thyroid-stimulating hormone. Table 1. Summary of factors associated with dysphoric mood symptoms in studies Factors Study Bad lifestyle(smoking, little exercise) Freeman(2006), 15) Dennerstein(2000) 68) Early natural menopause(before age 40years) Harlow(1995) 69) Health problems Kaufert(1992), 36) McKinlay(1992), 6) Woods(1999) 18) History of depressed mood or depression, including post- Woods(2008) 70) partum depression and premenstrual mood symptoms Lower education level Bromberger(2003) 19) Lack of partner and single parenting Walters(1993) 71) Negative attitudes to aging and menopause Woods(1996, 1997), 18)72) Avis(1991), 1) Matthews(1990) 73) Premenstrual symptoms(age 36-44years) Harlow(1999) 13) Stressors Amick(1998) 74), Cheung(2000) 75) Stressful life events Schmidt(2004), 34) Hunter(1986, 1992), 76)77) Avis(1994), 38) Kaufert(1992) 36), Woods(2008) 70) Vasomotor and somatic symptoms Dennerstein(1979, 1999), 14)78) Hunter(1992), 77) Bromberger(1996), 24) Baker(1997), 79) Freeman(2001) 80)

5 감은폐경이행기후반기와폐경후초기에가장흔하게발생하며 30) 홍조와우울증은강한연관성을보인다. 31) 연구자들은폐경이행기의우울증이홍조와연관된수면중단의간접적인결과라고제안하기도하고어떤연구자는뇌에서에스트라디올변화에대한민감도때문이라고제안하기도한다. 32) 후군의과거력도역시우울증의예측인자이다. 16) 폐경이행기의우울증과생리전증후군은이두질환이호르몬변화와중추신경의신경조절변화와같은효과에대한기저의취약성을반영하는것이다. 폐경기우울증의치료 3) 폐경기우울증에서정신사회적요인폐경이행기동안정서적안녕감과사회경제적수준, 인종, 결혼만족도, 가족관계의질이관계가있다. 33) 수십년간폐경은여성의모성 (maternity) 역할을잃게만드는파괴적인사건으로여겨왔으며, 빈둥지증후군 은폐경이행기동안정신사회적요인으로인한우울증상을표현하는용어로광범위하게사용되었다. 그러나 빈둥지증후군 과폐경주변기우울증과관련이없다는연구와 34) 최근사회적으로활동적인여성이증가하면서아동이돌아오는것이오히려스트레스요인이된다는연구도있다. 35) 한편, 우울증의과거력은폐경이행기에서우울증재발의강력한예측인자라는연구가있다. 36) 이시기의우울증상발생에영향을주는다른요인으로건강, 사회적지지, 일상적스트레스등이있다 ) 생리전증 폐경기우울증에대한치료는항우울제약물치료, 에스트로겐치료를중심으로한생물학적치료와비생물학적치료로나누어생각해볼수있다. 40) 1. 생물학적치료연구들에의하면폐경주변기의우울증에에스트로겐치료 (estrogen therapy, 이하 ET) 가효과가있었지만나이가많은폐경후우울증에는효과가없었다. 41) 1) 호르몬치료 ( 표 2) ET는폐경기증후군에서많이사용되고있으며특히홍조에효과가좋다. 42) 폐경주변기우울증에대한이중맹검무작위위약대조시험 (double-blind, randomized placebo-controlled trial) 이시도되었다. 43)44) 이들연구 Table 2. Estrogen therapy for menopause-related depression Study Design n Population Regimen Main findings Schmidt et al. Double-blind (2000) 44) Placebocontrolled 6weeks Soares et al. Double-blind (2001) 43) Placebocontrolled 12weeks Cohen et al. Open-label (2003) 45) 4weeks Morrison et al. Double-blind (2004) 41) Placebocontrolled 8weeks Rasgon et al. Open-label (2001) 42) 4weeks Estrogen as monotherapy 36 Perimenopausal women Transdermal with depressive disorders estrogen 50mg/d 50 Perimenopausal women Transdermal with depressive disorders estrogen 100mg/d 22 Mixed menopausal status Transdermal with depressive disorders estrogen 100mg/d 57 Postmenopausal women with depressive disorders 10 Perimenopausal women with major depression Transdermal estrogen 100mg/d Oral estrogen 0.3mg/d Partial and full response 80% with estrogen, 22% with placebo No association with hot flashes Remission 68% with estrogen, 20% with placebo:sustained antidepressant response despite recurrence of hot flashes Remission 66% in perimenopausal women, 18% in postmenopausal women Response to estrogen was similar to placebo(40% vs. 44%) Remission in 60% of patients treated with estrogen Morgan(2005) 56) Double-blind Placebocontrolled 6weeks Estrogen as augmentation agent to antidepressants 17 Perimenopausal women with major depression Oral estrogen 0.625mg/d Women receiving estrogen had a larger decrease in depression scale than women receiving placebo

6 에의하면 transdermal 17beta estradiol 50~100μg/ day 를 4~12 주사용하였을경우 60~75% 에서우울증상의부분또는완전관해 (remission) 를보였으며, 위약에서는 20~30% 의반응을보였다. ET는사용한달안에효과를보였으나임상가가안정적인항우울제효과를얻기위해서기간을어느정도 ET를유지해야하는지는자료가부족하다. 45) 프로게스틴 (progestin) 을사용했을경우기분에미치는영향에대한연구는부족한편이다. 과민성과피곤감이증가한다는임상적소견과주기적인프로게스틴의사용이 ET에반응했던우울증을악화시킬수있다는연구가있다. 46)47) 2002 년도에폐경기때호르몬대체요법을받은군에서관상동맥질환, 유방암, 뇌졸중, 정맥혈전색전증의위험도가증가한다는 Women s Health Initiative( 이하 WHI) 결과 48) 가발표된후에스트로겐사용기간에대한걱정과함께에스트로겐사용을하지않는것을선호하는여성이있다. 49) WHI 발표이후지속하였던 ET를중단하는여성들도있었는데, 심한홍조, 수면중단등의폐경기증상이빠르게재출현하는경우가있었다. 50)51) 많은수에서 ET를재시도하거나세로토닌계열의새로운대체치료법을고려하기도한다. 52) 2) 항우울제치료폐경주변기와폐경후여성우울증치료에서항우울제는효과적이다 ) 개방표지시험 (open-label trial) 에서 citalopram과 escitalopram이단독요법으로효과가있었으며, citalopram 과 mirtazapine 이 ET에반응하지않는우울증상치료에보조적치료로효과가있었다. 54)55) 한이중맹검위약대조시험에서항우울제를사용하여부분관해를보였던 40~60세주요우울장애여성에게 g/d 의에스트로겐을추가하였을때위약에비해우울호전정도가의미있게컸다. 56)57) Escitalopram과에스트로겐과프로게스틴병합요법과의차이를비교한무작위 9주개방연구에서우울증상완전관해가 escitalopram 75%, 병합요법 25% 였고, 폐경관련증상관해가 escitalopram 56%, 병합요법 31.2% 였다. 55) ET를중단한여성에서 paroxetine CR을사용했을때위약에비해우울증상의개선과함께홍조등의혈관운동성증상의감소도있었다. 52) 일차위약으로반응하지않았던폐경후주요우울장애여성을대상으로 8주 duloxetine 개방표지 시험을했을때우울증상, 혈관운동증상, 불안, 수면질, 통증에모두유의한호전을보였다. 58) 폐경상태가항우울제반응에미치는영향에대한연구가있다 ) 대부분의연구에서연령군을나이가많은군과 45세, 50세, 52세, 56세등으로폐경후상태에근접한군으로나누었다. 연구에따르면나이가많은여성군에서삼환계항우울제에좀더반응이좋았다. 나이가보다젊은여성군에서는 SSRIs 군이효과가있었다는연구 60) 와연령에따른반응차이가없었다는연구즉, 여성의폐경전기, 폐경주변기, 폐경후상태와항우울제의치료반응에큰차이가없다는연구가있다. 61) 세로토닌제제항우울제는부작용이적은편이지만치료로유발된성기능장애와체중증가가제한점이될수있다. 62) 3) 기타일반인구에서는우울증치료에효과적이지않지만, 홍조로인한수면중단으로인해우울증이발생한다는가설하에수면제종류중하나인 zolpidem 의효과에대한연구가있다. 63) 콩류에서추출한식물성에스트로겐인 isoflavone 60mg 효과에대한이중맹검 3개월추적연구에서 57% 에서홍조, 43% 에서야간발한이감소하였다. 64) 2. 비생물학적치료폐경이행기우울증에대한비생물학적치료즉, 특정정신치료가체계적으로연구된것은없다. 폐경이행기와폐경후에우울증상을완화시키거나예방하는데이완반응훈련 (relaxation response training) 과운동이효과적이라는몇몇보고가있다. 65)66) 유산소균형감훈련 (aerobic training on balance) 과에스트로겐과프로게스틴병합치료를 18개월간비교한연구에서는병합치료가좀더나은효과를보였다. 67) 결론및향후연구방향 폐경기무렵에여성은급격한호르몬변화로인한수면장애, 홍조, 야간발한, 우울증등다양한폐경기증상을경험하게된다. 만약폐경기무렵의여성의변화가간과된다면, 환자는삶의질저하뿐아니라장기간다양한영역에서고통을겪게된다. 따라서폐경기와관련된증상에대한조기진단및조기치료가절실하다. 선행연구를통해진단및치료에대한필요성과지식이늘어나기는

7 하였지만, 통제된임상시험결과는아직부족하다. 폐경기우울증상과혈관운동성증상에효과적이었던호르몬치료에대한우려가대두되면서항우울제나다른치료방법에대한연구의필요성도커지고있다. 폐경기여성의기분장애에대한국내의연구가매우부진한데, 국내에서는먼저증상학과유병률과같은기초적인연구부터시행되어야한다. 앞으로폐경기기분증상의진단및치료에대한국내연구가활성화되기를기대한다. 중심단어 : 페경 우울 진단 치료. 참고문헌 1. Avis NE, McKinlay SM. A longitudinal analysis of women s attitudes toward the menopause: results from the Massachusetts Women s Health Study. Maturitas 1991;13: Mitchell ES, Woods NF. Symptom experiences of midlife women: observations from the Seattle Midlife Women s Health Study. Maturitas 1996;25: Steiner M, Yonkers K. Mood disorders associated with the menopause. In: Depression in Women. London: Martin Dunitz;1998. p Oldenhave A, Jaszmann LJ, Haspels AA, Everaerd WT. Impact of climacteric on well-being. A survey based on 5213 women 39 to 60 years old. Am J Obstet Gynecol 1993;168: Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, et al. Executive summary: stages of Reproductive Aging Workshop(STRAW). Climacteric 2001;4: McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14: Burger HG, Dudley EC, Hopper JL, Groome N, Guthrie JR, Green A, et al. Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women. J Clin Endocrinol Metab 1999;84: Burger H, Woods NF, Dennerstein L, Alexander JL, Kotz K, Richardson G. Nomenclature and endocrinology of menopause and perimenopause. Expert Rev Neurother 2007;7:S35-S Metcalf MG, Donald RA, Livesey JH. Pituitary-ovarian function in normal women during the menopausal transition. Clin Endocrinol(Oxf) 1981;14: Schmidt PJ, Rubinow DR. Menopause-related affective disorders: a justification for further study. Am J Psychiatry1991;148: Nelson H, Haney E, Humphrey L, Miller J, Nedrow, Nicolaidis C, et al. Management of menopause-related symptoms. Evid Rep Technol Asses(Summ) 2005;120: Roberts RE, Vernon SW. The Center for Epidemiologic Studies Depression Scale: its use in a community sample. Am J Psychiatry 1983;140: Harlow BL, Cohen LS, Otto MW, Spiegelman D, Cramer DW. Prevalence and predictors of depressive symptoms in older premenopausal women: the Harvard Study of Moods and Cylces. Arch Gen Psychiatry 1999;56: Dennerstein L, Lehert P, Burger H, Dudley E. Mood and the menopausal transition. J Nerv Ment Dis 1999;187: Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 2006;63: Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry 2004;61: Harlow BL, Wise LA, Otto MW, Soares CN, Cohen LS. Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles. Arch Gen Psychiatry 2003;60: Woods NF, Mitchell ES. Pathways to depressed mood for midlife women: observations from the Seattle Midlife Women s Health Study. Res Nurs Health 1997;20: Bromberger JT, Assmann SF, Avis NE, Schocken M, Kravitz HM, Cordal A. Persistent mood symptoms in a multiethnic community cohort of pre- and perimenopausal women. Am J Epidemiol 2003;158: Burt VK, Hendrick VC. Perimenopuase and menopause. In: Concise Guide to Women s Mental Health. Washington DC: American Psychiatric Press;1997. p Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence. J Affect Disord 1993;29: Joffe H, Cohen LS. Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge? Biol Psychiatry 1998;44: Richards M, Rubinow DR, Daly RC, Schmidt PJ. Premenstrual symptoms and perimenopausal depression. Am J Psychiatry 2006;163: Bromberger JT, Matthews KA. A longitudinal study of the effects of pessimism, trait anxiety, and life stress on depressive symptoms in middle-aged women. Psychol Aging 1996;11: Schmidt PJ, Haq N, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry 2004;161: Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the meno

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