1. Premenstrual Dysphoric Disorder

2. Premenstrual symptomsPremenstrual Syndrome (PMS)Premenstrual Dysphoric Disorder (PMDD)

3. Premenstrual symptoms Commonly seen in most of the females Physiological Not much distressful No treatment or intervention generally sought

4. 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

5. 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

6. 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

7. This may not be a very clear pattern because: Co morbidity with other psychiatric conditions Worsening of psychiatric conditions in the premenstrual phase

9. 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!

10. What did our ancestors do with it?

11. 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

12. 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’

13. PMDD is a relatively a new concept!

14. Our guide! 1987 DSM-III-R included criteria for Late Luteal Phase Dysphoric Disorder (in Appendix A, proposed diagnostics categories needing further studies) 1994 In DSM-IV the name has been changed to Premenstrual Dysphoric Disorder Included as a Depressive Disorder Not Otherwise Specified (Appendix B, research criteria)

15. 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).

16. PMDD - a Distinct Clinical Entity?

18. November 1999, US FDA Neuropharmacology Advisory Committee supported this concept

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

20. Our guide! 2000 In 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.

22. 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).

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

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

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

26. persistent and marked anger or irritability or increased interpersonal conflicts

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

28. Symptoms subside few days after the onset of menses Symptoms present in the last week of Luteal Phase Symptoms absent, the week after the onset of menses (Follicular Phase)

29. In the most menstrual cycles during the past one year

30. 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).

31. 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).

32. Diagnostic Instruments 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).

34. Symptoms Anxiety Depression Irritability Lability of mood Concentration difficulty Sleep disturbance Food cravings, overeating Anhedonia Breast tenderness Bloating Breast engorgement Headaches Muscle or joint pain Weight gain

38. ICD - 10 Requires only one physical or emotional symptom to make the diagnosis of PMS ICD-10 does not include PMDD as a diagnosis

39. Differential Diagnosis Premenstrual Syndrome Premenstrual exacerbation of current mental disorder Premenstrual exacerbation of general medical condition such as epilepsy, asthma or endocrine disorders

42. What goes wrong? Common sense assumption Assumption 1 There might be a different hormone status in females with PMDD than those who do not have these symptoms

43. Observation: When these symptoms of anxiety and depression were treated by regular antidepressant like SSRIs, patients improved!

44. What goes wrong? Common sense assumption Assumption 2 There might be serotonin depletion in PMDD, mainly in the luteal phase of menstruation!??

45. Ovarian hormones (sex steroids) Serotonin Other neurotransmitter Beta endorphins Aldosterone Prolactin Ions and minerals

46. Ovaries Uterus Limbic system Prefrontal cortex Hippocampus Hypothalamus Pituitary ?Kidney

47. 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)

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

49. Why hormones involved? If the fluctuation of hormones is somehow stopped, the premenstrual symptoms improve!

51. 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)

52. GnRH agonists improves PMS Other supporting studies Freeman 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. ActaObstetGynecol Scand. 1988;67:159-166.

53. Progesterone alone Used for many years No 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

54. OC pills to suppress ovulation

55. Allopregnanolone-a metabolite of progesterone

56. Allopregnanolone-a metabolite of progesterone Summary of various reviews and studies Allopregnanolone levels are high in PMDD Increase 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)

57. Neurotransmitters Retrospective evidence ofSerotonin involvement- as the symptoms improves with SSRIs Serotonin Increase allopregnanolone synthesis Increase sensitivity to neurosteroids SSRIs The effect is unrelated to the serotonin uptake inhibiting property of these drugs

58. Genetic susceptibility A preliminary study suggested that genetic variation in the estrogen receptor alpha geneis 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).

59. How can we go about helping her?

60. 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

62. 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.

63. Update A 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).

64. 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 OpinPharmacother 2008;9:429-445) and Steiner et al. (J Womens Health 2006;15:57-69).

66. Relaxation Therapy

67. Interpersonal Therapy

68. Yoga

69. Meditation

70. Nonspecific supportive psychotherapyMore studies for PMS than for PMDD

71. 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 PsychosomObstetGynecol 2002;23:193-199).

72. 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 CollNutr 2000;19:3-12)

73. General nutritional recommendation Limit intake of alcohol, caffeine, salt, tobacco, and refined sugars Increase complex carbohydrate and protein intake Avoid overeating and weight gain Consider frequent small meals

74. 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)

75. 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 ObstetGynecol 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.

76. 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).

77. Multivitamin multimineral dietary supplements Used in PMS (some research support) ??? for PMDD Evening primrose oil Rational: conversion of fatty acid into prostaglandin E1 little value even in PMS (Budeiri et al. Control Clin Trials 1996;17:60-68).

78. Herbs Female 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 Hypericumperforatum (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 benefit Double-blind recommeded

79. Vitexagnuscastus (chasteberry) Effective than placebo A single-blind study with Fluoxetine for 2 months. No difference in overall response rate. Fluoxetine better with mood symptoms Herb better for physical symptoms Double-blind recommended A randomized, placebo-controlled, double-blind study from Germany of 170 women with PMS found Vitexagnuscastus (chaste tree) fruit extract to be effective (Schellenberg et al. BMJ 2001;322:134-137) (Atmaca et al. Hum Psychopharmacol 2003;18:191-195)

80. Medication Treatment SSRIs Other antidepressants Hormones Anxiolytics Analgesics Diuretics Clonidine Lithium

81. SSRIs A thorough review of SSRIs by Dimmock and colleagues Evaluated 15 high quality randomized placebo-controlled trials (Lancet 2000;356:1131-1136)

82. SSRIs Overall, 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)

86. Other Agents Antidepressants Venlafaxine Clomipramine Anxiolytics Alprazolam Analgesics for pain Diuretics for swelling

87. OC pills Drospirenone 3 mg/EhinylEstradiol 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

88. Very severe symptoms Danazole GnRH agonists Surgical removal of ovaries

89. Summary and Conclusion

90. Thank you