premenstrual%20dysphoric%20disorder
PREMENSTRUAL DYSPHORIC DISORDER
Premenstrual dysphoric disorder is a cyclical disorder presenting with distressing mood and behavioral symptoms that occur during the late luteal phase of the ovulatory cycle; it is a severe form of premenstrual syndrome.
It results in considerable impairment of the patient's personal functioning that occurs in approximately 5% of women of reproductive age.

Principles of Therapy

Goals of Therapy

  • Reduce symptoms
  • Improve social and occupational performance needed for improved quality of life

Pharmacotherapy

Selective Serotonin Reuptake Inhibitors (SSRIs)

  • Considered the 1st-line treatment for severe PMDD
  • Selective blockers of the reuptake of serotonin at presynaptic neurons with little, if any, effect on muscarinic, histaminergic, adrenergic or serotonergic receptors
  • Treatment regimen can be given continuously throughout the menstrual cycle, during the luteal phase or at the start of symptoms and choice would depend on patient preference, predictability of symptom manifestation or physician evaluation that symptoms are present and worsen during the premenstrual phase
    • Timing of treatment during the luteal phase and that wherein dosing is done for the whole cycle are both effective
    • If given continuously, SSRIs should be stopped gradually to prevent withdrawal symptoms 
  • Potential adverse effects with treatment include decreased libido, fatigue, insomnia, nausea, and somnolence, though these can be reduced with use of luteal-phase regimens 
  • As PMS symptoms will subside during pregnancy, SSRI therapy should be stopped before and during pregnancy due to possible congenital malformations 

Fluoxetine

  • Clinical studies have shown that Fluoxetine is superior to placebo in decreasing both emotional and physical symptoms of PMDD
    • Shown to have significant rate of response during the 1st treatment cycle
    • Efficacy of Fluoxetine is the same whether used only during the luteal phase (intermittent dosing) or throughout the full menstrual cycle (continuous dosing)
  • The use of Fluoxetine in PMDD is approved by the US Food and Drug Administration (USFDA)

Sertraline

  • Sertraline has shown similar efficacy to Fluoxetine
  • Clinical studies have shown improvement in both emotional and physical symptoms
    • Improvement in symptoms has been noted within the 1st cycle
    • A significantly effective treatment using intermittent or continuous dosing
  • The use of Sertraline in PMDD is approved by the USFDA

Other SSRIs that have shown efficacy

  • Citalopram and Paroxetine have demonstrated efficacy in PMS and PMDD clinical trials
    • One study with Citalopram showed that intermittent dosing may be preferred over continuous treatment, though both were superior to placebo therapy
    • Citalopram has been used in doses of 10-30 mg/day continuously or intermittently during the luteal phase
    • Paroxetine has been used in doses of 10-30 mg/day continuously or intermittently during the luteal phase
      • Risk for congenital abnormalities is increased when taken during the 1st trimester of pregnancy
  • Fluvoxamine has shown mixed results in treatment of PMDD
  • Escitalopram appears to demonstrate similar efficacy as that of Citalopram

Other Antidepressants

Clomipramine

  • Serotonergic tricyclic antidepressant
  • Shown to be more effective than placebo in the treatment of PMDD using either continuous or intermittent dosing

Venlafaxine

  • Serotonin and noradrenaline reuptake inhibitor
  • Daily dosing of immediate-release Venlafaxine was reported to be superior to placebo in reducing emotional and physical symptoms of PMDD

Anxiolytics

Alprazolam

  • Alprazolam is an intermediate-acting benzodiazepine considered 2nd-line in PMDD treatment
  • Results of clinical studies were mixed and use is restricted by risk of dependence and withdrawal
  • Use should be limited to luteal-phase dosing
    • One study found no withdrawal symptoms when intermittent luteal-phase dosing was used

Buspirone

  • A serotonergic agonist that appears to have weak beneficial effects on premenstrual symptoms
  • Decreases irritability symptoms in women with PMDD

Hormonal Therapy

  • Hormonal intervention is considered if treatment with other methods was unsuccessful
  • Symptoms of PMDD may resolve if ovulation is suppressed, inducing anovulation and amenorrhea
  • Use is limited by occurrence of menopausal symptoms such as hot flushes, vaginal dryness, fatigue, irritability, cardiac problems, and ostopenia
    • Add-back therapy with Estradiol and Progestogen is used to avoid above side effects but may cause premenstrual disorder-like symptoms  
Oral Contraceptives (OCs)
  • May be considered 2nd-line therapy in patients unresponsive to SSRIs  
  • Women, whose priority is contraception, prefer an OC rather than an SSRI as 1st-line treatment
    • If OC monotherapy provides inadequate relief of symptoms, an SSRI may be added 
  • Drospirenone/Ethinyl estradiol in a 24/4 regimen improved mood and physical symptoms in patients with PMDD
  • Patients with PMS may be effectively treated with Drospirenone-containing combined oral contraceptives 
  • Continuous rather than cyclical use of contraceptive pill is suggested by current data in those with PMS

Estrogen

  • Relatively straightforward and effective therapy
  • Transdermal Estrogen (gel or patch) or SC implants are recommended over oral therapy
  • Progestogen is necessary unless the patient has had a hysterectomy
    • Prevents irregular bleeding and endometrial hyperplasia (oral or vaginal progesterone at a cyclical 10-12 day treatment course) 
    • Combination of percutaneous Estradiol and cyclical progestogen has been effective in managing severe PMS 
    • Use lowest possible dose to reduce adverse effects of progestogen when transdermal Estrogen is used 
    • Investigate immediately any unscheduled bleeding in patients on short courses of progestogen treatment or those receiving low doses 
    • Micronized progesterone is preferred over progestogen for progestogenic opposition as it has less potential for causing PMS-like symptoms
  • Levonorgestrel intrauterine system (LNG-IUS) protects against endometrial hyperplasia
    • When ovulation is suppressed with Estradiol, use intrauterine methods of contraception 
    • Low levels of Levonorgestrel can initially cause PMS-type adverse effects and bleeding 
  • Treatment with opposed Estradiol therapy should be individualized with the benefits and risks of therapy considered 

Progesterone/Progestogens

  • Limited benefit has been shown in efficacy studies done with progesterone or progestogens in the treatment of PMS

Gonadotropin-releasing Hormone (GnRH) Agonists

  • Act on the hypothalamus to decrease follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion resulting in anovulation and decreased estrogen and progesterone synthesis
  • May be given to patients for 3 months to aid in the diagnosis of PMS if charted symptoms are inconclusive 
  • Highly effective and should be given to patients with severe PMS symptoms that do not respond to other treatment options
  • Have been shown to be superior to placebo in alleviation of PMS complaints such as irritability and depression along with physical symptoms
  • Cause typical menopausal symptoms (eg flushing, osteoporosis) so treatment should be limited to 6 months
    • If to be given for >6 months in patients with severe PMS, addback therapy should be utilized, eg Tibolone or continuous combined hormone replacement therapy 
    • Stop treatment if there is a significant decline in bone density from annual BMD measurements

Danazol

  • Efficacy in reducing PMDD symptoms is linked to induction of anovulation
    • Low-dose administration during the luteal phase helps with mastalgia
  • Use is limited by occurrence of side effects (eg amenorrhea, weight gain, acne, facial hair and nausea)
    • Long-term use leads to masculinization; hence, Danazol is currently rarely used but if it is, it must be given in low doses
    • Advise patient regarding contraception use due to possible virilization of the female fetus
Symptom-Focused Therapy

Analgesics
  • Effective treatment for dysmenorrhea
  • Ibuprofen, at doses of up to 1,000 mg/day, can reduce breast pain, headaches, back pain

Dopamine Agonist

  • Bromocriptine may offer relief to women with cyclic mastalgia

Diuretic (Spironolactone)

  • Spironolactone has antimineralocorticoid and antiandrogenic properties
    • When dosed at 100 mg/day, was shown by a study to be more effective than placebo in reducing irritability, depression, somatic symptoms, craving for sweets, and breast tenderness
    • May also improve premenstrual bloating and weight gain
    • Recommended to be given only during the luteal phase

Non-Pharmacological Therapy

Other Methods

  • In conjunction with pharmacological therapy, the following techniques may offer significant improvement in premenstrual symptoms:
    • Relaxation and stress reduction, cognitive behavioral therapy, light therapy, yoga, guided imagery, reflexology, massage therapy, biofeedback, acupuncture, counseling
      • A study showed long-term efficacy of cognitive behavioral therapy for premenstrual disorders
  • Adopting a regular sleep-wake pattern may alleviate distress and discomfort associated with sleep irregularities
  • Avoiding stressful activities during the premenstrual period may be helpful

Complementary Therapy

Dietary Supplements

Calcium

  • Clinical trial showed that 1200 mg of calcium carbonate (CaCO3) per day can offer significant reduction in symptoms such as pain and food cravings as well as improvement of negative affect
  • Supplementation with calcium and vitamin D may relieve symptoms of PMS or PMDD

Magnesium, Tryptophan, Vitamin E

  • Limited data shows some benefits of using these supplements in women with PMDD

Vitamin B6

  • Clinical studies have shown that daily doses of 50-100 mg of vitamin B6 can reduce severity of premenstrual depressive and physical symptoms of PMS and PMDD
  • Caution patient on the risk of developing peripheral neuropathy at high doses (≥200 mg/day)

Herbal Therapy

  • Herbal therapies have been tried on women with PMS and may have some positive effects

Chaste Tree Berry

  • Chaste tree berry (Vitex agnus castus) may reduce prolactin levels and offer relief for breast engorgement, irritability, anger, mood swings and headache
    • Has a dopaminergic effect and indirect anti-prolactin effect
  • May have efficacy similar to that of the antidepressant Fluoxetine

Evening Primrose Oil

  • Has been shown by some studies to have some benefit in women with PMS and those with cyclical breast symptoms 

Ginkgo Biloba

  • A placebo-controlled randomized controlled trial showed significant reduction in the physical and psychological effects in women with PMS in the first cycle of treatment
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