Premenustrual Dysphoric Disorder and Post Menopausal Syndrome

Dr. Pavan Kumar.KAssistant Professor,Dept of Psychiatry

CAIMS

What is Premenstrual Dysphoric Disorder?

• PMDD• Severe PMS (Premenstrual

Syndrome)• Depression, tension and irritability

are common.

Hippocrates (460-377 B.C.)

Described a group of conditions that occurred prior to the onset of menses,

in which women might develop suicidal ideation and other severe symptoms

Frank (in 1931) Described 15 women experiencing severe premenstrual symptoms

and coined the term ‘Premenstrual Tension Syndrome

Green and Dalton (in 1953) coined the term ‘Premenstrual Syndrome’

PMDD is a relatively a new concept!

Our guide!1987DSM-III-R included criteria for Late Luteal Phase Dysphoric Disorder (in Appendix A, proposed diagnostics categories needing further studies)

1994In DSM-IV the name has been changed to Premenstrual Dysphoric DisorderIncluded as a Depressive Disorder Not Otherwise Specified (Appendix B, research criteria)

October 1998,A panel of experts evaluated the evidence then available, and a consensus was reached that PMDD was a distinct clinical entity

A review by a group of experts "reached the consensus that PMDD is a distinct entity with clinical and biological profiles dissimilar to those seen with other disorders"

(Endicott et al. J Womens Health Gend Based Med 1999;8:663-679).

PMDD - a Distinct Clinical Entity?

A distinct clinical presentation with characteristic symptoms

Cyclical course linked to the menstrual cycle

Unique physical symptoms such as bloating and breast tenderness

Cessation of symptoms during pregnancy and after menopause

Rapid response to selective serotonin reuptake inhibitors (SSRIs)—in contrast to

the slower onset in major depressive disorder

Normal hypothalamic-pituitary-adrenal axis functioning—in contrast to major

depression

Causes of PMDD• The Causes are NOT KNOWN.• Hormones play some sort of

role.• Symptoms Disappear if

ovaries are removed.• Ovarian function

may affect changes in brain chemistry.

Incidence of PMDD

• Occurs in in 8% of woman who are having their menstrual cycle.

• May have a genetic disposition. • Daughters of mothers with PMDD are likely to

have the disorder as well.• 93% of Identical twins will

both have PMDD.• 44% of Fraternal twins will

both have PMDD.

Risk Factors

• Anxiety• Major Depression• Seasonal affective disorder• Alcohol abuse• Overweight• Sedentary lifestyle• Family History

In most menstrual cycles during the past year, five (or more) of the following symptoms were present

for most of the time during the last week of the luteal phase,

began to remit within a few days after the onset of the follicular phase,

and were absent in the week post-menses, with at least one of the symptoms being either (1), (2), (3), or (4).

markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts

marked anxiety, tension, feelings of being "keyed up," or "on edge"

marked affective lability (e.g., feeling suddenly sad or tearful or increased sensitivity to rejection)

persistent and marked anger or irritability or increased interpersonal conflicts

(e.g. work, school, friends, hobbies)

Symptoms absent, the week after the onset of menses (Follicular

Phase)

Symptoms subside few days after the onset of menses

Symptoms present in the last week of Luteal Phase

In the most menstrual cycles during the past one year

The disturbance markedly interferes with work or school or with usual social activities and relationships with others (e.g., avoidance of social activities, decreased productivity and efficiency at work or school).

The disturbance is not merely an exacerbation of the symptoms of another disorder, such as Major Depressive Disorder, Panic Disorder, Dysthymic Disorder, or a Personality Disorder (although it may be superimposed on any of these disorders).

How to diagnose PMDD ?

• No physical exam or lab test can diagnose PMDD.• Psychiatric evaluation is used to rule out other

conditions.• Keep a calendar or diary of symptoms when they

occurred to help with a diagnosis and best course of treatment.

Diagnostic InstrumentsDRSP Daily Record of Severity of Problems

PSST Premenstrual Symptoms Screening Tool

COPE Calendar of Premenstrual Experiences

VAS Visual Analogue Scale

DSR Penn Daily Symptom Report Scale

The reliability and validity of the DRSP were confirmed recently in two studies reported by Endicott et al. (Arch Womens Ment Health 2006;9:41-49).

Symptoms

AnxietyDepressionIrritabilityLability of moodConcentration difficultySleep disturbanceFood cravings, overeatingAnhedonia

Breast tendernessBloatingBreast engorgementHeadachesMuscle or joint painWeight gain

ICD - 10

Requires only one physical or emotional symptom to make the diagnosis of PMS

ICD-10 does not include PMDD as a diagnosis

Differential Diagnosis

Premenstrual Syndrome

Premenstrual exacerbation of current mental disorder

Premenstrual exacerbation of general medical condition such as epilepsy, asthma or endocrine disorders

What goes wrong?

Common sense assumption

Assumption 1There might be a different hormone status in females with PMDD than those who do not have these symptoms

What goes wrong?

Common sense assumption

Assumption 2There might be serotonin depletion in PMDD, mainly in the luteal phase of menstruation!??

What data has to say?

premenstrual syndrome is probably the result of a complex interaction between ovarian steroids and central neurotransmitters(N Engl J Med 1998;338:256-257)

Regular hormones levels

No consistent difference in blood and urine level of estrogen and progesterone in women with PMDD compared to those without disorder.

Why hormones involved?

If the fluctuation of hormones is somehow stopped,

the premenstrual symptoms improve!

GnRH agonists improves PMSSchmidt and colleagues used leuprolide, a GnRH agonist, to block endogenous production of estrogen and progesterone in 10 women with PMS

conclusion: There was a significant decrease in PMS symptoms compared to

baseline and compared to a placebo group. This was followed by a marked worsening of PMS symptoms when

estrogen or progesterone was added to leuprolide in the women who had benefited previously. (N Engl J Med 1998;338:209-216)

GnRH agonists improves PMS

Other supporting studiesFreeman EW, Sondheitjer SH, Rickets K. Gonadotropin-releasing hormone agonist in treatment of premenstrual symptoms with and without ongoing dysphorics: a controlled study. Psychopharmacol Bull. 1997;33:303-309

Hammarback S, Backstrom T.Induced anovulation as treatment of premenstrual tension syndrome: a double-blind cross-over study with GnRH-agonist versus placebo. Acta Obstet Gynecol Scand. 1988;67:159-166.

Progesterone alone Used for many yearsNo supporting evidence

Progesterone has not been demonstrated to work better than placebo for treatment of mood symptoms of PMS.

-Ford O, Lethaby A, Mol B, Roberts H. Progesterone for premenstrual syndrome. Cochrane Database Syst Rev. 2006;(4):CD003415.

-Wyatt K, Dimmock P, Jones P, Obhrai M, O'Brien E. Efficacy of progesterone and progestins in management of premenstrual symptoms: a systematic review. BMJ. 2001;323:776-780

OC pills to suppress ovulation

Neurotransmitters

Retrospective evidence of Serotonin involvement- as the symptoms improves with SSRIs

SerotoninIncrease allopregnanolone synthesis

Increase sensitivity to neurosteroids

SSRIsThe effect is unrelated to the serotonin uptake inhibiting property of these drugs

Genetic susceptibility

A preliminary study suggested that genetic variation in the estrogen receptor alpha gene is associated with increased risk for PMDD;

leading the authors to speculate that there might be a "genetic susceptibility to affective dysregulation induced by normal levels of gonadal steroids" (Huo et al. Biol Psychiatry 2007;62:925-933).

How can we go about helping her?

UpdateA brief update on diagnosis and treatment, "Expert Guidelines for the Treatment of Severe PMS, PMDD, and Comorbidities: The Role of SSRIs“published in 2006 by Steiner et al. (J Womens Health (Larchmt) 2006;15:57-69).

Recent review

A more recent overview on treatment of PMDD is provided by Yonkers and colleagues (Lancet 2008;371:1200-1210).

The pharmacologic treatment of PMDD was reviewed recently by Rapkin and Winer (Expert Opin Pharmacother 2008;9:429-445) and Steiner et al. (J Womens Health 2006;15:57-69).

CBT Comparision with Fluoxetine and combination of Fluoxetine

and CBT

all three equally effective; though the response with Fluoxetine faster

more sustained benefit from CBT after termination of treatment

(Hunter et al. J Psychosom Obstet Gynecol 2002;23:193-199).

Nutritional approaches

Dietary modifications are recommended widely to relieve symptoms of PMS, but whether they are effective for treating the more severe symptoms of PMDD has not been established

Again more studies for PMS; so ?? For severe symptoms of PMDD.Limitations:Poor study design, Vague definition of PMS, High placebo response(review by Bendich. J Am Coll Nutr 2000;19:3-12)

General nutritional recommendationLimit intake of alcohol, caffeine, salt, tobacco, and refined sugars

Increase complex carbohydrate and protein intake

Avoid overeating and weight gain

Consider frequent small meals

Pyridoxine (vitamin B6)

Despite the limitation of study designs.100 mg/day benefits in premenstrual symptoms

by Wyatt et al. (BMJ 1999;318:1375-1381)

Medication Treatment

SSRIsOther antidepressants

HormonesAnxiolyticsAnalgesicsDiureticsClonidineLithium

SSRIs

A thorough review of SSRIs by Dimmock and colleagues

Evaluated 15 high quality randomized placebo-controlled trials

(Lancet 2000;356:1131-1136)

SSRIsOverall, the SSRIs were 6.9 times more effective than placebo.

With the exception of one negative study with fluvoxamine, results with SSRIs for PMDD have been uniformly positive

Drugs evaluated: Fluoxetine, Sertraline

Full cycle-more, few intermittent- same benefit

Unable to determine dose-response relationship (Lancet 2000;356:1131-1136)

Very severe symptoms

Danazole

GnRH agonists

Surgical removal of ovaries

Treatment of PMDD

• A healthy lifestyle is the first step to managing PMDD.

• Eat a Balanced Diet• Get sufficient sleep• Exercise• Keep a track of your symptoms

• Other Treatments:» Birth control Pills» Diuretics» Nutritional supplements» Antidepressants» CBT (Congenital behavioral Therapy)

POST MENOPAUSAL SYNDROME

• The average age of menopause in India is 47.5years with an average life expectancy of 71years.

• So.., Indian women are likely to spend 23 years in menopause.– Indian menopause Society, 2007

• Prakash and Murthy etal..– A study done in 1981, observed the relationship

between menopause and psychiatric morbidity by using GHQ, Psychiatric interview found highest psychiatric morbidity in the menopausal group.

• Menopause is the permanent cessation of menstruation resulting in the loss of ovarian follicle development.

• Factors that are toxic to the ovary often result in an earlier age of menopause.

• Premature ovarian failure is defined as menopause before the age of 40 years

• Although menopause is associated with changes in the hypothalamic and pituitary hormones that regulate the menstrual cycle, menopause is not a central event, but rather a primary ovarian failure.

• Menopausal transition or perimenopause is a defined period of time beginning with the onset of irregular menstrual cycles until the last menstrual period and is marked by fluctuation in reproductive harmones.

• This period is characterised by menustrual irregularities, prolonged and heavy menustruation intermixed with episodes of amenorrhea, decreased fertility, vasomotor symptoms and insomnia.

• Menopause is defined retrospectively as the time of the final menustrual period , followed by 12months of amenorrhea.

• Post menopause describes the period following the final menses.

• Vasomotor symptoms• Urogenital symptoms• Osteoporosis• Psychological problems

VASOMOTOR SYMPTOMS

• Affects upto 75% of perimenopausal women.• May last usually upto 1-2yrs but in some upto

10years.• Hot Flushes • Fatigue• Should be differentiated from thyroid

abnormalities.

• Probably initiated in hypothalamus, which drives an increased core body temperature, metabolic rate and skin temperature, resulting in peripheral vasodilatation and sweating.

• This may be triggered by 5HT, NE, DA activation.

• These symptoms are managed by • Estrogen • Progesterone MPA (20mg/day)• Clonidine• SSRIS

ACOG updated Practice Bulletin- treating vasomotor symptoms and vaginal atrophy-JAN

2014

• more evidence to support nonhormonal alternatives (SSRI & SNRI) for management of vasomotor symptoms.(paroxetine-only FDA approved)

• transdermal delivery is safer than oral.(ACOG2013)

Urogenital atrophy

• Vaginal dryness, pruritis, dyspareunia, dysuria and urgency.

• Treatment: • These symptoms respond to estrogen therapy.

May be given orally/local application of creams / vaginal suppository.

Osteoporosis

• Backache, fractures, decreased mobility are common due to osteoporosis.

• Women should recieve 1000-1500 mg calcium supplementation

• 400-800 IU of Vit D daily.• HRT is effective in preventing and treating

osteoporosis.• SERM : RAL0XIFEN 60MG• BISPHOSPHONATES

Psychological symptoms

• Depression • Cognitve problems• Sleep problems

Depression

• Because of fluctuating and declining estrogen levels in part.

• Steroid hormones like estrogens act by stimulating the synthesis of neurotransmitters, expression of receptors and influence membrane permeability.

• Estrogen increases the effect of serotonin and nor epinephrine which mediate mood.

• Alternate mechanism is estrogen decreases MAO.

• Although precise mechanisms are not known, fluctuations in estrogen levels affect the regulation of serotonin and norepinephrine.

• LIFE STRESSORS• EMPTY NEST SYNDROME• LOSS OF FERTILITY

Treatment

• SSRI• ESTROGEN • MPA

COGNITIVE FUNCTIONS

• Memory problems are common in menopausal transition rather than aging process.

• Cognitive difficulties may be a consequence of sleep disruptions secondary to nocturnal hot flushes.

• Women are at greater risk for Alzheimer’s disease than men.

Sleep disorders

• Insomnia occurs in 40-50% women during the menopausal transition.

• Age related???• Decrease in melatonin may be one of the

reason.

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