Premenstrual Dysphoric Disorder

Premenstrual symptoms

Premenstrual Syndrome (PMS)

Premenstrual Dysphoric Disorder (PMDD)

Premenstrual symptoms

Commonly seen in most of the females

Physiological

Not much distressful

No treatment or intervention generally sought

Premenstrual Syndrome (PMS)

Severe than commonly experienced physiological symptoms

Around 40% of females experience this cluster of various symptoms

However, impairment in daily functioning is less as compared to PMDD

Premenstrual Dysphoric Disorder (PMDD)

Severe form of PMS

Around 3% to 8% females experience it

Impairment in functioning:Work, Social interaction, Academics and even Daily Routine

So we may encounter

Females with cyclical pattern of anxiety, depressive and physical symptoms

Symptoms appear for some days and disappear in the other days of a cycle

This may not be a very clear pattern

because:

Co morbidity with other psychiatric conditions

Worsening of psychiatric conditions in the premenstrual phase

Why do we bother?

There are more emotional and behavioral symptoms than physical

They respond to SSRIs

We are trained and we believe that we can handle those symptoms better than other professionals and have more experience with SSRIs!

What did our ancestors do with it?

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

November 1999,US FDA Neuropharmacology Advisory Committee supported this concept

FDA approvals

Fluoxetine (Sarafem- not Prozac ) – 2000Sertraline (Zoloft) – 2002Paroxetine controlled-release – 2003

Our guide!

2000In DSM-IV-TR, it is still in Appendix B.

This Appendix includes proposals for new diagnostic categories that are felt to require further study.

For the time being, the "official" DSM-IV coding of PMDD would be Depressive Disorder Not Otherwise Specified.

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).

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

The fact that you are willing to say,

“I do not understand, and it is fine”

Is the greatest understanding you could exhibit!

- Dr. Wayne Dyer

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

Observation:When these symptoms of anxiety and depression were treated by regular antidepressant like SSRIs,

patients improved!

What goes wrong?

Common sense assumption

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

Ovarian hormones (sex steroids)Serotonin

Other neurotransmitterBeta endorphins

AldosteroneProlactin

Ions and minerals

OvariesUterus

Limbic systemPrefrontal cortex

HippocampusHypothalamus

Pituitary?Kidney

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 PMS

Schmidt 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

Allopregnanolone-a metabolite of progesterone

Allopregnanolone-a metabolite of progesterone

Summary of various reviews and studiesAllopregnanolone levels are high in PMDDIncrease in allopregnanolone in response to stress is dampened in PMDD

Allopregnanolone to progesterone ratio is higher in PMDD following an oral progesterone dose (Klatzkin et al. Psychoneuroendocrinology 2006;31:1208-1219)

Shown to suppress hypothalamic GnRH release by interacting with GABA- A Receptor (Calogero et al. J Endocrinol 1998;158:121-125)

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?

Investigation

No mandatory laboratory investigation

If age is more than 40; investigation for menopausal status (Ref. to OB-GYN)

Prospective assessment of subjective experiences, using standard instrument is required for PMDD as per DSM-IV

In March 2001, a special report was published in Postgraduate Medicine titled "Treatment of Depression in Women 2001" (Altshuler et al. 2001).

Included in this Expert Consensus Guideline Series report was a section on Premenstrual Dysphoric Disorder (PMDD).

Opinions of 36 experts in women's mental health.

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).

Psychobehavioral approachesFirst-line treatmentAerobic exercise is the only First-line treatment recommended by experts

Second-line alternatives Cognitive Behavior Therapy Relaxation Therapy Interpersonal Therapy YogaMeditationNonspecific supportive psychotherapy

While there is a paucity of rigorous research involving psychobehavioral approaches to PMDD (what little has been done has been directed at less stringently defined PMS), benefit in PMS has been claimed not only for CBT but also for relaxation training, rational emotive therapy, coping skills training, and a variety of other even less defined approaches (Pearlstein. Psychiatric Annals 1996;26:590-594).

More studies for PMS than for PMDD

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)

Calcium

A large double blind placebo-controlled multi-center trial available

1200 mg daily

Effective in reducing PMS symptoms

A large double-blind multicenter trial (n=497 enrolled, n=466 evaluated) compared 1200 mg daily of elemental calcium (given as calcium carbonate in the form of TUMS E-X 2 tablets twice daily) to placebo over three menstrual cycles in women with moderate to severe PMS (Thys-Jacobs et al. Am J Obstet Gynecol 1998;179:444-452).

A significantly greater reduction in a 17-item daily self-rating scale score was noted in the calcium group for the second and third cycles. By the third cycle, the rating scale score was reduced by 49% in the calcium group versus 30% in the placebo group.

Magnesium

Few placebo-controlled trials availabe

200 mg daily

Improves fluid retention problem

In a crossover study of 38 women, 200 mg daily of magnesium in the form of magnesium oxide was more effective than placebo in reducing PMS symptoms related to fluid retention (Walker et al. J Womens Health 1998;7:1157-1165).

Total PMS symptoms and symptoms related to anxiety, depression and food cravings did not lessen with magnesium.

A small double-blind, placebo-controlled, crossover study found no evidence of a magnesium deficiency and no benefit on mood symptoms from intravenous magnesium infusion in women with PMDD (Khine et al. Biol Psychiatry 2006;59:327-333).

Multivitamin multimineral dietary supplementsUsed in PMS (some research support)??? for PMDD

Evening primrose oilRational: conversion of fatty acid into prostaglandin E1 little value even in PMS(Budeiri et al. Control Clin Trials 1996;17:60-68).

HerbsFemale Balance(a product widely sold on internet, containing unspecified amount of 16 herbs- as an effective, natural, gentle way for treating PMS)No scientific support

Hypericum perforatum (St. John’s Wart)Uncontrolled study available (small sample of 19 women)well designed controlled study needed(Stevinson and Ernst. BJOG 2000;107:870-876)

Kamishoyosan (a Japanese product containing 10 herbs)An open-label study showed benefitDouble-blind recommeded

Vitex agnus castus (chasteberry)

Effective than placebo

A single-blind study with Fluoxetine for 2 months. No difference in overall response rate. Fluoxetine better with mood symptomsHerb better for physical symptomsDouble-blind recommended

A randomized, placebo-controlled, double-blind study from Germany of 170 women with PMS found Vitex agnus castus (chaste tree) fruit extract to be effective (Schellenberg et al. BMJ 2001;322:134-137)

(Atmaca et al. Hum Psychopharmacol 2003;18:191-195)

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)

Other Agents Antidepressants

VenlafaxineClomipramine

AnxiolyticsAlprazolam

Analgesics for pain

Diureticsfor swelling

OC pills

Drospirenone 3 mg/Ehinyl Estradiol 20 mcg(YAZ)

We have JAZZ

As compared to previous OC pills use, it is said that this one improves not only physical symptoms but also mood features

Very severe symptoms

Danazole

GnRH agonists

Surgical removal of ovaries

Summary and Conclusion

Thank you