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PMDD and Depression During the Menopausal Transition: New Insights

Laura Fagioli Petrillo, M.D.

Director of Training, The Ammon-Pinizzotto Center for

Women’s Mental Health, Massachusetts General

Hospital

Instructor in Psychiatry, Harvard Medical School

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Disclosures

Neither I nor my spouse/partner has a relevant financial relationship with a commercial interest to disclose.

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Depression and Anxiety Across the

Female Reproductive Cycle

Premenstrual depression/anxiety (eg,

PMDD)

Depression/anxiety

during pregnancy

Depression/anxiety during the

postpartum period

Menarche Menopause

Pregnancy

Depression/anxiety associated with infertility, miscarriage, or perinatal

loss

Depression/anxiety during the

perimenopausal period

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Premenstrual Mood Changes

• The majority of reproductive age women report unpleasant symptoms around the time of menstruation.

– Physical and psychological symptoms

– “More emotional”

– Minimal effect on functioning

Winer & Rapkin, Jnl Reproductive Med. 2006:51(4): 339-347.

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Prevalence of Premenstrual Conditions

PMS75%

Nothing20%

PMDD5%

(3-8% of women of childbearing age)

100%=all women of childbearing age.

Haskett RF. Prog Neuropsychopharmacol Biol Psychiatry. 1987;11(2-3):129-135.Johnson SR, et al. J Reprod Med. 1988;33(4):340-346.Rivera-Tovar AD, Frank E. Am J Psychiatry. 1990;147(12):1634-1636.Ramcharan S, et al. J Clin Epidemiol. 1992;45(4):377-392.

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Premenstrual Syndrome (PMS)

• Pattern of physical, emotional and behavioral symptoms occurring 1-2 weeks before menstruation

• Remit with the onset of menstruation

• 30-80% of women

• Significant in 3-8% of women

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PMS Symptoms

Psychological

Symptoms

Behavioral

Symptoms

Physical

Symptoms

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PMDD - DSM-V Criteria

• Criterion A: in most menstrual cycles during the past year, at least 5 of 11 symptoms (including at least 1 of the first 4 listed) were present:

• Markedly depressed mood, hopelessness, or self-deprecating thoughts • Marked anxiety, tension, feelings of being “keyed up” or “on edge” • Marked affective lability • Persistent/marked anger or irritability or interpersonal conflicts • Decreased interest in usual activities • Subjective sense of difficulty in concentrating • Lethargy, easy fatigability, or marked lack of energy • Marked change in appetite, overeating, or specific food cravings • Hypersomnia or insomnia • A subjective sense of being overwhelmed or out of control • Other physical symptoms, such as breast tenderness or swelling, headaches, joint

or muscle pain, a sensation of bloating, or weight gain • The symptoms must have been present for most of the time during the last week

of the luteal phase, begun to remit within a few days of the onset of menstrual flow, and absent in the week after menses.

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DSM-V Criteria

• Criterion B is that the symptoms must be severe enough to interfere significantly with social, occupational, sexual, or scholastic functioning.

• Criterion C is that the symptoms must be discretely related to the menstrual cycle and must not merely represent an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder

• Criterion D is that criteria A, B, and C must be confirmed by prospective daily ratings during at least 2 consecutive symptomatic menstrual cycles. The diagnosis may be made provisionally before this confirmation.

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Premenstrual Exacerbation (PME)

• Mood disorders can worsen premenstrually

• PMDD vs. PME

• 40% of women screened for PMDD have an underlying mood disorder with PME

• Charting to determine cyclicity of symptoms

Bailey & Cohen. J Womens Health Gender Based Med. 1999;8(9):1181.

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0

1

2

3

4

Sym

pto

m S

ever

ity

Menses Ovulation Menses

PME

PMDD

PMDD vs. Premenstrual Exacerbation (PME)

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Prospective Rating for Patient With PMS

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Prospective Rating for Patient With PMDD

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Prospective Rating for Patient With Depression

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Pathophysiology

• No clear evidence of “hormonal dysregulation”

• PMS/PMDD may represent an abnormal response to normal fluctuations of gonadal steroids

Schmidt et al., American Journal of Psychiatry:2017;174(10), 980-989.

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Differential sensitivityto normal changes in estrogen andprogesterone

GnRH agonists areeffective therapy

• Eliminate hormonal fluctuation

• PMS re-occurs withadd-back therapy

GnRH = gonadotropin-releasing hormone.

Schmidt et al. N Engl J Med. 1998;338:209.

Hormonal Basis of PMDD

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Hormonal Basis of PMDD

Schmidt PJ, Martinez PE, Nieman LK, et al. Am J Psychiatry. 2017;174:980-989.

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Pathophysiology

ESTROGEN PROGESTERONE

CENTRAL NEUROTRANSMISSION

SEROTONERGIC/NORADRENERGIC/DOPAMINERGIC

SEROTONIN TRANSMISSION ABNORMALITY PMDD

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Pathophysiology

Role of gamma amino-butyric acid (GABA)

Allopregnanolone enhances effects of GABA

-Metabolite of progesterone

-Positive modulator of GABAA receptor

Treatment with allopregnanolone antagonist during the luteal phase reduced PMDD scores on the DRSP.

Bixo et al. Psychoneuroendocrinology:2017;80:46-55.

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PMS/PMDD Longitudinal Course

– Women seek treatment in their late 20s/early 30s

– Peaks around 30-39 years old1

– Physical/mood symptoms stable from cycle to cycle2

– Diagnosis appears stable over time3

– Chronic course; symptoms may worsen over time [with age4, pregnancy5]

1Johnson. Clin Obstet Gynecol. 1987;30:369.2Block. Am J Psychiat. 1997;154:1741. 3Roca et al. J Clin Psychiatry. 1999;60:763.

4Ramcharan. J Clin Epidemiol. 1992;45:377. 5Campbell. J Reprod Med. 1997;42:637.

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1. van den Akker OB, et al. Acta Genet Med Gemellol (Roma ). 1987;36(4):541-548. 2. Kendler KS, et al. Psychol Med. 1992;22(1):85-100. 3. Warner P, et al. J Affect Disord. 1991;23(1):9-23. 4. Bancroft J, et al. Psychosom Med. 1994;56(3):225-231. 5. Graze KK, et al. Acta Psychiatr Scand. 1990;81(2):201-205.

Risk Factors for PMDD and PMS

• Family history of PMS and PMDD1,2

• History of postpartum depression3

• Major depression past3,4 or future5

• Mood changes induced by oral contraceptives

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Pharmacologic Treatment

SSRIs are first line treatment– Low dose– Rapid response– Fluoxetine, sertraline, and controlled release paroxetine

are FDA approved

Antidepressants with serotonergic activity are also effective:

clomipraminevenlafaxineduloxetine

Sundblad et al. Acta Psychiatr Scand. 1992;85:39-47.Freeman et al. Obstet Gynecol. 2001;98:737-44.Ramos & Hara. Int J Neuropsychopharmacol. 2009;12(8):1081-8.

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Antidepressant Dosing

• Continuous

– Steady dose throughout the month

• Intermittent

– Luteal phase

• Luteal phase increase

– Continuous with luteal phase “bump up”

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Who is a Candidate for Intermittent Treatment?

• Women who have premenstrual symptoms that require pharmacologic treatment

• Women without additional psychiatric co-morbidity that would require daily treatment

• Women with fairly regular menstrual cycles who can estimate when to initiate treatment

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1.de la Gandara Martin JJ. Actas Luso Esp Neurol Psiquiatr Cienc Afines.1997;25(4):235-242. 2. Pearlstein TB, Stone AB. J Clin Psychiatry. 1994;55(8):332-335.3. Elks ML. South Med J. 1993;86(5):503-507. 4. Yonkers KA. Psychopharmacol Bull. 1998;34(3):261-266. 5. Freeman EW, et al. Am J Psychiatry. 1992;149(4):531-533.

Duration of Treatment in PMDD

• Many women relapse when they stop treatment–as early as 1 to 2 cycles1-5

• Well tolerated and efficacious when used longer than 6 months in open-label studies1-3

• Patients should be reevaluated regularly

– Chronic treatment may be necessary

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Oral Contraceptives (OC)and PMS/PMDD

Evidence from double-blind, randomized, placebo-controlled trials supports use of some OCs for treatment of PMDD.

OCs containing drosperinone may be more effective.

• derivative of spironolactone versus testosterone derived progestins

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OCP Dosing

• Cyclic

– 21 days active pill, 7 days placebo

• Continuous

– Consecutive pill packs without a placebo

– Efficacy greater than cyclic dosing

Consider: medical risks of OCP

OCP can increase suicide risk

Freeman et al. Contraception. 2012;85(5): 437-445Skovlund et al. Am Jnl Psychiatry. 2018;175(4): 336-342

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Mortola JF et al. J Clin Endocrinol Metab. 1991; 72: 252A–252F. Ripps BA et al. J Reprod Med. 2003;48:761–766. Wyatt et al. Br J Obstet Gynaecol. 2004; 111: 585-593

Gonadotropin-ReleasingHormone Agonists for PMDD

Leuprolide/buserelin

Down-regulate gonadotrophin receptors in pituitary to create a hypogonadotropic state

Induce a reversible medical menopause

Administered by nasal spray or subcutaneously

Treatment usually restricted to six months

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• Side effects: hot flashes, vaginal dryness, osteoporosis

• Add-back estrogen and progesterone may reduce the effectiveness of the GnRH agonist treatment of PMS due to the induction of mood and anxiety symptoms

Gonadotropin-ReleasingHormone Agonists

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1. Brown CS, et al. Obstet Gynecol. 1994;84(5):779-786. 2. Freeman EW, et al. Psychopharmacol Bull. 1997;33(2):303-309. 3. Hammarback S, Backstrom T. Acta Obstet Gynecol Scand. 1988;67(2):159-166. 4. Hussain SY, et al. Gynecol Endocrinol. 1992;6(1):57-64. 5. Leather AT, et al. Gynecol Endocrinol. 1999;13(1):48-55. 6. Muse KN, et al. N Engl J Med. 1984;311(21):1345-1349. 7. Schmidt PJ, et al. N Engl J Med. 1998;338(4):209-216. 8. Sundstrom I, et al. Acta Obstet Gynecol Scand. 1999;78(10):891-899. 9. Helvacioglu A, et al. J Reprod Med. 1993;38(11):864-870. 10. West CP, Hillier H. Hum Reprod. 1994;9(6):1058-1063.

Gonadotropin-ReleasingHormone Agonists

• Double-Blind, placebo-controlled trials

– Several show superiority of GnRH agonists over placebo1–8

– Some show GnRH agonists equal to placebo9,10

– Not first line

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Non-Pharmacologic Treatment

• Mood Charting

• Lifestyle Modification

• Psychotherapy

• Nutritional Supplements

• CAM

Andrzej, M & Diana, J. Maturitas. 2006;55:S47-S54.

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Nutritional Supplements

Calcium (1200 mg daily)

Vitamin B6 (50-100 mg daily)

Magnesium (200-460 mg daily)

Vitamin E (400 IU daily)

Thys-Jacobs S et al. Am J Obstet Gynecol. 1998;179: 444–52. Chocano-Bedoya P et al. The Am Jnl Clin Nutr. 2011;93(5):1080-1086. Fathizadeh N et al. Iran J Nurs Midwifery Res. 2010;15:401-5.

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Herbal Remedies

• Vitex Agnus Castus (Chasteberry)– Association of Reproductive Health Professionals

includes VAC as a treatment option– Data are inconclusive– Potential benefits– Unclear mechanism: D2 receptor, estrogen receptor

• St. John’s Wort– Physical symptoms > emotional symptoms– 13-15% reduction in the level of OCP

Cerqueira RO, et al. Arch Womens Ment Health. 2017;20:713-719.Verkaik S, et al. Am J Obstet Gynecol. 2017;217:150-166Jang SH, et al. BMC Complement Altern Med. 2014;14:11.

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Summary

• Premenstrual symptoms are common.

• A smaller percentage of women experience severe physical and emotional symptoms that interfere with their ability to function.

• Screening for these symptoms is important as it may lead to treatments that can be beneficial.

• Treatments can be non-pharmacologic or pharmacologic.

– Hormonal or psychotropic

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What is Menopause?

• 12 months without menses

• Menopausal transition– endocrinologic, somatic, psychological changes

• Average age is 51 (lower for smokers)

• Severity, frequency and variety of symptoms vary widely

• Perimenopause = passage from reproductive to non-reproductive life

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MENOPAUSAL TRANSITION

Longo et al. Harrison’s Principles of Internal Medicine, 18th edition.

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Symptoms

• Hot flashes

• Vaginal dryness

• Depression/anxiety

• Osteopenia/osteoporosis

• Sleep changes

• Fatigue

• Concentration difficulty

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Hot Flashes

Sensation of warmth of the upper bodyLast 30 seconds – 5 minutesAccompanied palpitations, anxiety, dizzinessMay result in a cold sensation and/or chillsDaytime and/or nightCan occur from perimenopause through post menopause45-85% of women

Severe in 10-15% of womenAssociated sleep disruption

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Hot Flashes

• Natural menopause

– Vasomotor symptoms decrease over a few years

• Surgical menopause

– Severe vasomotor symptoms post-surgery

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Depression-Risks

• History of depression

– Women without lifetime MDD = lower risk of developing MDD during midlife vs women with prior MDD (28% v. 59%)

• History of postpartum depression

• Higher BMI

• Vasomotor symptoms

• Surgical menopause

• Estrogen itself may also have an antidepressant as well as a direct sleep effect

Eichling, P.S. and Sahni, J. J Clin Sleep Med. 2005;1(3), 291-300. Bromberger, JT, et al. Psychol

Med. 2015;45:1653-64. Georgakis MK, et al. JAMA Psychiatr. 2016;6:1-12.

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Depression

Meta-analysis of 14 observational studiesLower likelihood of postmenopausal depression with longer duration of reproductive age

– Age at menopause minus age at menarche

Premature menopause associated with higher rates of depression

Georgakis MK. JAMA Psychiatry. 2016;73:139-149.

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Sleep

• Sleep disruption is the hallmark of menopause• Nighttime vasomotor symptoms correlate with increased

sleep fragmentation– Depression is more common in this group

• Sleep disordered breathing more common during menopause (weight gain, unknown endocrine reasons)

• Also increase in fibromyalgia and insomnia/depression• Menopausal sleep disruption can exacerbate other

conditions, i.e. circadian disorders and RLS

.Joffe H, Crawford S, Economu N, Kim S, Regan S, Jalle JE, White D. Sleep. 2013 Dec 1;36(12):1977-85. doi:

10.5665/sleep.3244. Eichling, P.S. and Sahni, J. J Clin Sleep Med. 2005:1(3), pp.291-300

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Treatment

• Hormone replacement therapy

• Antidepressants

• Other psychotropics

• Complementary and alternative medications

• Non-pharmacologic treatment

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Hormone Replacement Therapy

• Gold standard until late 1990s

• Results from WHI changed practice

– Higher rates of CVA, coronary artery disease, breast cancer

– Worsening cognition

– Benefit: colorectal cancer and endometrial cancer

– Average age mid-60s

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HRT and Depression

• Rates of depression double to triple in the menopausal transition compare to pre and late menopause

• Estrogen +/- progesterone may alleviate depression

– Eliminate fluctuations in estrogen levels

Bromberger et al. Psychol Med. 2011;4:1879-88. Gleason et al. PLoS Med. 2015;12(6):e1001833.Joffe at al. J Clin Endocrinol Metab. 2011;96(7):E1044-E1054.

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HRT and Depression

• Estrogen replacement may be effective in preventing depression during the menopausal transition

• RTC of 172 perimenopausal and early postmenopausal women

• Transdermal estrogen + intermittent micronized progesterone vs. placebo

• Hormone therapy reduced the risk for depression by half

Gordon et al. JAMA Psychiatry. 2018;75(2):149-157.

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HRT and Mortality

• 27,000 postmenopausal women

• HRT with conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) median of 5.6 years

• or with CEE alone for a median of 7.2 years

• No increased risk of all-cause, cardiovascular, or cancer mortality– Did not prevent CV disease, other chronic diseases, or

reduce mortality

Manson JE, et al. JAMA. 2017;318:927-938.

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Antidepressants

• SSRIs/SNRIs – helpful

• Depression and vasomotor symptoms

– Paroxetine is FDA approved for hot flashes

– Fluoxetine, escitalopram, venlafaxine also helpful

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Antidepressants and Fractures

• Antidepressants linked to bone loss in the past

• Women with higher anxiety levels had a greater number of fractures over 10 years

• 192 postmenopausal women, avg. age 68

• 20% of women with lowest anxiety levels had a fracture vs 25% of those with highest anxiety– Higher anxiety associated with lower bone mineral density

in the lumbar spine and femoral neck

Catalano A, et al. Menopause. 2018

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Other Psychotropics

• Gabapentin

– Improvement in sleep and hot flashes

– Dose 100-3600 mg

• Sleep meds

– Zolpidem, eszopiclone improve sleep and hot flashes. ? Low dose TCAs (e.g. doxepin)

• Clonidine– Improves hot flashes

• Armodafinil

– Improves fatigue

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CAM

• Black cohosh – limited data, mixed results

• Omega-3 – improvement in hot flashes

• Soy – mixed results; significant placebo response

Mintziori G, Lambrinoudaki I, Goulis DG, et al. Maturitas. 2015

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Non-pharmacologic

• CBT

• Yoga

• Exercise

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CBT

CBT-Meno

psychoeducation

cognitive behavioral strategies VMS

depressive symptoms

anxiety

sleep

sexual concerns

Improvement sustained at 3 months post-treatment

Green et al. Menopause.2019;9:972-80.

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Effect of CBT on Sleep

Guthrie et al. Effects of Pharmacologic and Nonpharmacologic Interventions on Insomnia Symptoms and Self-reported Sleep Quality in Women With Hot Flashes: A Pooled Analysis of Individual Participant Data From Four MsFLASH Trials. Sleep, 2018:41.

Sleep disturbance is a common among peri- and post-menopausal women7 interventions for sleep were assessed as part of MS-FLASH, RTCs for insomnia

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Yoga and Hot Flashes

• Meta-analysis, of 13 RTCs with a total of 1306 participants

• Improvements in psychological, somatic, vasomotor, and urogenital symptoms

Cramer H, Peng w, Lauche R. Maturitas, March 2018

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Summary

• It is important to identify mood symptoms during the menopausal transition

• Menopausal symptoms other than mood (sleep, vasomotor) can significantly affect quality of life

• Symptoms are treatable with pharmacologic and non-pharmacologic interventions