Clinical trial NCT03740009: Effects of a Tissue Selective Estrogen Complex (TSEC) on Depression and the Neural Reward System in the Perimenopause"
Official title: Effects of a Tissue Selective Estrogen Complex (TESC) on Depression and the Neural Reward System in the Perimenopause
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Perimenopausal Disorder
Depression
Keywords: Hormone Replacement Therapy
Estrogen
Depression
Mood Disorders
Estrogen Replacement Therapy
Depressive Disorder
Mental Disorders
Hormones
Physiological effects of drugs
Reproductive Control Agents
Tissue Selective Estrogen Complex
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Foundation of Hope, North Carolina
First posted: 2018-11-14
Enrollment: 20
Sex: FEMALE
Minimum age (years): 44
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Using neuroimaging, the investigator will study the effects of estrogen on mood and brain function in perimenopausal women with depression.

Detailed description: Despite decades of clinical research, depression continues to affect 20.9 million Americans each year and remains the leading cause of disability worldwide. Women are twice as likely as men to experience depression, and depression symptoms are particularly common during periods of hormone change. Depression risk increases 14-fold in the two years surrounding menopause, suggesting that hormone changes may cause depression during this time. Past research has shown that estrogen, in particular, plays an important role in depression during the transition to menopause ("the perimenopause") for the following reasons: 1) depression begins when estrogen levels plummet, 2) estrogen therapy reduces depression symptoms, and 3) when perimenopausal women who were treated with estrogen are taken off of estrogen (without their knowledge), their depression returns. Despite clear evidence that estrogen plays a role in depression during the perimenopause (DPM), the investigators don't know how estrogen affects the brain, which is important for developing effective medications to treat DPM and also for determining which patients are most likely to benefit from medication that replaces the estrogen lost during menopause (estrogen replacement therapy).

The investigator received a grant from the National Institutes of Health, which received preliminary support from the Foundation of Hope, to characterize the effect of estrogen replacement therapy on the brain in women with DPM and women without depression ("controls"). The brain pathway affected most by depression is the neural reward circuit, which consists of a number of different brain regions that act in concert to determine a person's response to rewards. Activity in the neural reward circuit depends on estrogen levels and is reduced in people with depression. The investigator's NIH-funded study will be the first to examine how the neural reward circuit is affected by DPM and estrogen replacement therapy. While estrogen replacement therapy acts as an antidepressant, many women elect not to take estrogen and many physicians discourage its use because of the risk of long-term negative health effects, including breast and uterine cancer. A new FDA-approved compound, Duavee, combines estrogen with another medication, bazedoxifene, which protects against breast and uterine cancer while reducing hot flashes. Duavee may therefore be more acceptable to women with DPM and their doctors than estrogen replacement therapy. However, the effects of Duavee on depression and the neural reward circuit have never been tested, and one can't infer that estrogen will have the same antidepressant effects in the presence of bazedoxifene (which partially blocks the effects of estrogen in certain tissues).

The purpose of the proposed project is to 1) test the antidepressant effects of Duavee, and 2) quantify the effects of Duavee on the neural reward circuit. The investigators expect that Duavee will reduce symptoms of depression and increase activity in the neural reward circuit. In this study, the investigators will recruit medically healthy, unmedicated women with DPM and administer Duavee for 3 weeks (a duration that has been shown in previous studies of estrogen replacement to be sufficient for treating depression). Eligibility will be assessed by an initial telephone screen and confirmed by a gynecologic exam, laboratory testing, and an interview about their current and past depression symptoms. Only women with depression that began during the menopause transition (i.e., when they started skipping periods) will be enrolled. Both before and after treatment, women will have a fMRI brain scan to determine the effects of the medication on the neural reward circuit. During the 3-week treatment, women will come into the clinic to have their blood drawn, refill their medication, and answer questions about their mood and menopause symptoms.This study is important because untreated DPM contributes to cardiac deaths. Many women are afraid to use estrogen replacement therapy because of the long-term risk of cancer and yet refuse to take antidepressants for fear of side effects and stigma. Because Duavee addresses the main potential problems of estrogen replacement therapy, this research stands to revolutionize treatment for DPM. The use of estrogen replacement therapy to treat DPM is a relatively new area of research and one of great importance given the large and increasing number of women who enter the perimenopause each year and are potentially at risk for depression. Women with DPM seek treatment from gynecologists, psychiatrists, and general practitioners, yet there is neither consensus nor practical guidelines for preventing and treating DPM.

Specific Aims: The investigators currently are assessing the neural reward system in subjects with perimenopausal major depressive disorder (PM-MDD) and those without depression ("controls") using functional magnetic resonance imaging (fMRI) at baseline and following estrogen replacement therapy (ERT). The Foundation of Hope (FOH) award will allow us to add a Tissue Selective Estrogen Complex (TSEC) treatment condition in a separate group of PM-MDD. The investigators' central hypothesis is that the neural reward system is hypoactive in PM-MDD, and the antidepressant effects of a three-week TSEC intervention will be associated with increased activity in the neural reward system, assessed using functional magnetic resonance imaging (fMRI). The investigators will test the hypothesis by executing the following aims: Aim 1: Determine the extent to which TSEC reduces anhedonia and other depressive symptoms in PM-MDD. Anhedonia and other depressive symptoms will be assessed at baseline and following TSEC administration. The investigators also will compare the effects of TSEC and ERT in PM-MDD. Hypothesis 1: Women PM-MDD will report a significant reduction in depressive symptoms following TSEC administration, and the degree of symptom improvement will be associated with the change in frontostriatal responsivity to reward. Aim 2: Quantify the effect of TSEC on the neural reward system in PM-MDD. The investigators will use fMRI at baseline and following TSEC treatment in PM-MDD to probe frontostriatal reward circuitry. The investigator will also compare the effects of TSEC and ERT in PM-MDD. Hypothesis 2: PM-MDD will show increased activation of the frontostriatal circuit in response to reward following TSEC administration (compared with baseline).

Eligibility criteria: Inclusion Criteria:

Perimenopause Status: The investigators will employ the Stages of Reproductive Aging Workshop (STRAW) criteria to confirm perimenopausal status. The stages are primarily based on the characteristics of the menstrual cycle and secondarily on follicle stimulating hormone (FSH) levels. The anchor for the staging system is the last menstrual period (LMP). The investigators will enroll women who have \> 2 skipped cycles with an interval of amenorrhea \> 60 days and FSH values \> 14, consistent with the late menopause transition (stage-1)\*. Women who have taken oral contraceptives continuously for relief of perimenopausal symptoms will be exempt from our LMP criteria, and their perimenopausal status will be determined by FSH alone. Because extremes of body weight (BMI \< 18 or \> 35 kg/m2) or a history of chronic menstrual cycle irregularity can contribute to inaccurate reproductive staging, these will serve as additional exclusion criteria.

MDD Eligibility Criteria: Current diagnosis of MDD with an onset associated with menstrual cycle irregularity. Present or past mania, psychosis, suicide attempts, and alcohol or drug dependence, and current substance abuse, as determined by the Structure Clinical Interview for The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) for Axis I Disorders (SCID) are exclusionary.

\* Per the STRAW criteria, FSH values are highly variable in the late menopausal transition (stage -1), and clinicians should "carefully evaluate the appropriate FSH value, depending on the assay they use" (Harlow et al, 2012). For nearly two years following the LMP, FSH values can fluctuate between levels characteristic of the early reproductive years and levels characteristic of menopause (Hale et al, 2014). McLendon Labs at the University of North Carolina at Chapel Hill (UNC) uses an FSH assay that defines levels consistently above ? 21.5 IU/mL as post-menopausal (McLendon Labs, 2016). As FSH values do not stabilize at consistently high levels until post-menopause, the investigators are setting our minimum required FSH value at \> 14 IU/mL to carefully select for women in the perimenopause transition.

Exclusion Criteria:

* Patients will not be permitted to enter this protocol if they have any of the following:

  1. current medication use (i.e., psychotropics, anti-hypertensives, statins, hormonal preparations, or frequent use of anti-inflammatory agents (\> 10 times/month)). Women will be allowed to enroll who take medications without known mood effects (e.g. stable thyroid hormone replacement and occasional (\< 5 times/month) use of Ambien);

     * all reported prescription medications will be reviewed and cleared by a study physician prior to a participant's enrollment;
  2. pregnant, breastfeeding or trying to conceive;
  3. LMP more than 12 months prior to enrollment;

     * women who have recently taken oral contraceptives continuously for relief of perimenopausal symptoms will be exempt from the final menstrual period (FMP) criteria, and instead, the presence of menstrual irregularity prior to the use of oral contraceptives and elevated FSH will be used to determine their perimenopausal status;
  4. history of undiagnosed vaginal bleeding;
  5. undiagnosed enlargement of the ovaries;
  6. polycystic ovary syndrome;
  7. history of breast or ovarian cancer;
  8. first degree relative with ovarian cancer;
  9. first degree relative with premenopausal onset or bilateral breast cancer;
  10. 2+ first degree relatives with breast cancer (regardless of onset);
  11. 3+ relatives with postmenopausal breast cancer;
  12. abnormal finding in a provider breast exam and/or mammogram;

      * participants will be given the opportunity to describe these conditions in the online screening survey. Reported conditions that were acute in nature and have resolved completely (as indicated by the medical record or follow-up testing) and/or benign will be reviewed by a study physician prior to enrollment. All chronic conditions will be exclusionary.
  13. known carrier of BRCA1 or 2 mutation;
  14. endometriosis;
  15. blood clots in the legs or lungs;
  16. porphyria;
  17. diabetes mellitus;
  18. malignant melanoma;
  19. Hodgkin's disease;
  20. recurrent migraine headaches that are preceded by aura;
  21. gallbladder or pancreatic disease;

      * participants will be given the opportunity to describe these conditions in the online screening survey. Reported conditions that were acute in nature and have resolved completely (as indicated by the medical record or follow-up testing) and/or benign will be reviewed by a study physician prior to enrollment. All chronic conditions will be exclusionary.
  22. heart or kidney disease;

      * participants will be given the opportunity to describe these conditions in the online screening survey. Reported conditions that were acute in nature and have resolved completely (as indicated by the medical record or follow-up testing) and/or benign will be reviewed by a study physician prior to enrollment. All chronic conditions will be exclusionary.
  23. liver disease;
  24. cerebrovascular disease (stroke);
  25. current cigarette smoking;
  26. current suicidal ideation, mania, psychosis, or alcohol/drug abuse/dependence;
  27. past suicide attempts, mania, alcohol/drug dependence, or psychotic episodes;
  28. chronic depression (i.e., episode(s) lasting 3+ years);
  29. depressive episode(s) within 2 years of enrollment;
  30. self-reported claustrophobia;
  31. peanut allergy;
  32. HIV/AIDS

Primary outcomes:
measure: Change in Frontostriatal Reactivity to Reward During MID fMRI Task
timeFrame: Baseline to 3 weeks
measure: Depressive Symptoms as Measured by the MASQ-AD
timeFrame: Baseline, week 2, week 3, week 4 (post treatment)
Secondary outcomes:
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill School of Medicine
state: North Carolina
Study officials:
affiliation: UNC Dept of Psychiatry
name: Crystal E Schiller, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005 Jun;62(6):617-27. doi: 10.1001/archpsyc.62.6.617.
citation: Kessler RC. Epidemiology of women and depression. J Affect Disord. 2003 Mar;74(1):5-13. doi: 10.1016/s0165-0327(02)00426-3.
citation: Schiller CE, Johnson SL, Abate AC, Schmidt PJ, Rubinow DR. Reproductive Steroid Regulation of Mood and Behavior. Compr Physiol. 2016 Jun 13;6(3):1135-60. doi: 10.1002/cphy.c150014.
citation: Schmidt PJ, Haq N, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry. 2004 Dec;161(12):2238-44. doi: 10.1176/appi.ajp.161.12.2238.
citation: Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH, Rubinow DR. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol. 2000 Aug;183(2):414-20. doi: 10.1067/mob.2000.106004.
citation: Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR. Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2015 Jul;72(7):714-26. doi: 10.1001/jamapsychiatry.2015.0111.
citation: Forbes EE, Hariri AR, Martin SL, Silk JS, Moyles DL, Fisher PM, Brown SM, Ryan ND, Birmaher B, Axelson DA, Dahl RE. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatry. 2009 Jan;166(1):64-73. doi: 10.1176/appi.ajp.2008.07081336. Epub 2008 Dec 1.
citation: Bless EP, McGinnis KA, Mitchell AL, Hartwell A, Mitchell JB. The effects of gonadal steroids on brain stimulation reward in female rats. Behav Brain Res. 1997 Jan;82(2):235-44. doi: 10.1016/s0166-4328(96)00129-5.
citation: Schiller, C. The hormone withdrawal hypothesis of postpartum depression: a translational approach. Theses Diss. (2011).
citation: Thomas J, Metereau E, Dechaud H, Pugeat M, Dreher JC. Hormonal treatment increases the response of the reward system at the menopause transition: a counterbalanced randomized placebo-controlled fMRI study. Psychoneuroendocrinology. 2014 Dec;50:167-80. doi: 10.1016/j.psyneuen.2014.08.012. Epub 2014 Sep 1.
citation: Kenna HA, Rasgon NL, Geist C, Small G, Silverman D. Thalamo-Basal Ganglia connectivity in postmenopausal women receiving estrogen therapy. Neurochem Res. 2009 Feb;34(2):234-7. doi: 10.1007/s11064-008-9756-z. Epub 2008 Jun 6.
citation: 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 Jan 22;338(4):209-16. doi: 10.1056/NEJM199801223380401.
citation: Pinkerton JV, Thomas S. Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol. 2014 Jul;142:142-54. doi: 10.1016/j.jsbmb.2013.12.011. Epub 2013 Dec 25.
citation: U.S. Census Bureau. Age and Sex Composition: 2010. (2011).
citation: Gold EB, Bromberger J, Crawford S, Samuels S, Greendale GA, Harlow SD, Skurnick J. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemiol. 2001 May 1;153(9):865-74. doi: 10.1093/aje/153.9.865.
citation: Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006 Apr;63(4):385-90. doi: 10.1001/archpsyc.63.4.385.
citation: Bromberger JT, Matthews KA, Schott LL, Brockwell S, Avis NE, Kravitz HM, Everson-Rose SA, Gold EB, Sowers M, Randolph JF Jr. Depressive symptoms during the menopausal transition: the Study of Women's Health Across the Nation (SWAN). J Affect Disord. 2007 Nov;103(1-3):267-72. doi: 10.1016/j.jad.2007.01.034. Epub 2007 Feb 28.
citation: Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ; WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA. 2003 May 28;289(20):2673-84. doi: 10.1001/jama.289.20.2673.
citation: Thase ME, Entsuah R, Cantillon M, Kornstein SG. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005 Sep;14(7):609-16. doi: 10.1089/jwh.2005.14.609.
citation: Grigoriadis S, Kennedy SH, Bagby RM. A comparison of antidepressant response in younger and older women. J Clin Psychopharmacol. 2003 Aug;23(4):405-7. doi: 10.1097/01.jcp.0000085415.08426.c6.
citation: Masand PS, Gupta S. Long-term side effects of newer-generation antidepressants: SSRIS, venlafaxine, nefazodone, bupropion, and mirtazapine. Ann Clin Psychiatry. 2002 Sep;14(3):175-82. doi: 10.1023/a:1021141404535.
citation: Gyllstrom ME, Schreiner PJ, Harlow BL. Perimenopause and depression: strength of association, causal mechanisms and treatment recommendations. Best Pract Res Clin Obstet Gynaecol. 2007 Apr;21(2):275-92. doi: 10.1016/j.bpobgyn.2006.11.002. Epub 2006 Dec 12.
citation: First, M. B., Spitzer, R. L., Gibbon, M. & Williams, J. B. W. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition. (SCID-I/NP). (Biometrics Research, New York State Psychiatric Institute, 2002).
citation: Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, Sherman S, Sluss PM, de Villiers TJ; STRAW + 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Fertil Steril. 2012 Apr;97(4):843-51. doi: 10.1016/j.fertnstert.2012.01.128. Epub 2012 Feb 16.
citation: Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol. 1988 Jun;54(6):1063-70. doi: 10.1037//0022-3514.54.6.1063.
citation: HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56-62. doi: 10.1136/jnnp.23.1.56. No abstract available.
citation: Watson D, O'Hara MW, Simms LJ, Kotov R, Chmielewski M, McDade-Montez EA, Gamez W, Stuart S. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol Assess. 2007 Sep;19(3):253-68. doi: 10.1037/1040-3590.19.3.253.
citation: Clark LA, Watson D, Mineka S. Temperament, personality, and the mood and anxiety disorders. J Abnorm Psychol. 1994 Feb;103(1):103-16.
citation: Greene JG. Constructing a standard climacteric scale. Maturitas. 2008 Sep-Oct;61(1-2):78-84. doi: 10.1016/j.maturitas.2008.09.011.
citation: Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4.
citation: Knutson B, Fong GW, Adams CM, Varner JL, Hommer D. Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport. 2001 Dec 4;12(17):3683-7. doi: 10.1097/00001756-200112040-00016.
citation: Dichter GS, Kozink RV, McClernon FJ, Smoski MJ. Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes. J Affect Disord. 2012 Feb;136(3):1126-34. doi: 10.1016/j.jad.2011.09.048. Epub 2011 Oct 28.
citation: Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, Sherman S, Sluss PM, de Villiers TJ; STRAW 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause. 2012 Apr;19(4):387-95. doi: 10.1097/gme.0b013e31824d8f40.
citation: Hale GE, Robertson DM, Burger HG. The perimenopausal woman: endocrinology and management. J Steroid Biochem Mol Biol. 2014 Jul;142:121-31. doi: 10.1016/j.jsbmb.2013.08.015. Epub 2013 Oct 14.
citation: McLendon Labs. (2016). Follicle Stimulating Hormone (FSH). Retrieved from: http://www.uncmedicalcenter.org/mclendon-clinical-laboratories/available-tests/follicle-stimulating-hormone-fsh/
citation: Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH; Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010 Jul;95(7 Suppl 1):s1-s66. doi: 10.1210/jc.2009-2509. Epub 2010 Jun 21.
citation: ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014 Jan;123(1):202-216. doi: 10.1097/01.AOG.0000441353.20693.78.