Q&a attempts to provide balanced answers to those curly-yet-common questions in obstetrics and gynaecology for the broader O&G Magazine readership, including Diplomates, Trainees, medical students and other health professionals.
A 21-year-old woman is concerned that in the days leading up to her period she becomes depressed, irritable, cries easily and has difficulty sleeping. Her breasts become very tender and she feels bloated and tired. Introduction of the oral contraceptive pill six months ago has not provided any relief. What are the current treatment options for premenstrual dysphoric disorder?
The diagnosis in this woman is almost definitely premenstrual syndrome (PMS). This is a condition evidenced by the presence of physical and behavioural symptoms occurring repetitively in the second half of the menstrual cycle that have a negative impact on some aspects of the woman’s life. Approximately 30 per cent of women with regular menstrual cycles are affected by PMS, although some form of premenstrual symptomatology is observed in 75 per cent of women.1 Premenstrual dysphoric disorder (PMDD) is a severe form of PMS, defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)2 as having prominence of psychological symptoms including anger, irritability and internal tension. An estimated three to eight per cent of those women with PMS are actually affected by PMDD.3 Most practitioners would recognise this patient as suffering from PMDD, the more extreme form of PMS.
It is important to accurately determine the timing of these symptoms to ensure that there is not another psychiatric diagnosis underlying them. To fit the criteria for PMDD, symptoms should be completely resolved by day four of the cycle and not recommence until after day 12. It should also be remembered that certain other conditions will exhibit premenstrual exacerbations, such as migraine and irritable bowel syndrome, and every attempt should be made to exclude these alternative causes of cyclical symptoms.
Cyclic changes in serum estrogen and progesterone levels result in changes in certain neurotransmitter systems, with the serotonin, GABA (gamma-aminobutyric acid) and opioid systems most affected.4 The aetiology of PMDD is likely based in these neurotransmitter changes. The main treatments that have been studied for PMDD, therefore, have aimed at manipulation of the neuroregulatory systems, particularly serotonin, as this is most strongly implicated in the aetiology of PMDD, or amelioration of the estrogen and progesterone fluctuations.
Selective serotonin reuptake inhibitors (SSRIs) have been shown in systematic reviews to be effective in management of PMDD5,6, with overall response rates of 60 to 75 per cent. Fluoxetine is the most extensively studied, in a dose of 20 mg/day; higher doses do not appear to enhance therapeutic effect, but are associated with more side effects. Sertraline (50 to 150 mg/day), paroxetine (20 to 30 mg/day) and citalopram (20 to 30 mg/day) also appear to be effective, as does venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI).7 Luteal phase dosing is often used initially, targeting therapy to the symptomatic window and reducing the potential for side effects, however, this is less effective at controlling symptoms (OR 0.55 for intermittent dosing versus 0.28 for continuous dosing, both with statistical significance).8 Other classes of antidepressants, such as tricyclic antidepressants and monoamine oxidase inhibitors, are not effective therapies for PMDD.
There are a few studies suggesting alprazolam, a benzodiazepine, is effective therapy for PMDD. Given the addictive potential of this agent, it is best reserved as a second-line therapy.
There is some early evidence that a new antiepileptic medication, levetiracetam, is effective in reducing the symptoms of PMDD.9 Further investigation is required before this agent can be recommended as a treatment modality.
Manipulation of ovarian hormones can also improve PMDD symptoms. GnRH agonists have been shown to be effective, particularly for depressive symptoms, presumably by creating a medical oophorectomy and therefore preventing the cascade of events triggered by fluctuating ovarian steroids.10 The possible side effect of loss of bone mineral density with these agents can be ameliorated by the use of continuous add-back estrogen and progesterone – continuous rather than cyclical use ensures no recurrence of symptoms. Danazol can be effective if given in doses sufficient to result in anovulation, but its androgenic side effects limit it to a second- or third-line agent.11
Oral contraceptives have also been used for PMDD management, with initially discouraging results. More recent evidence has supported the use of an oral contraceptive containing progestin and drosperinone, used with a four-day rather than a seven-day pill-free interval.12
Various alternative therapies have also been suggested for the management of PMDD. Calcium supplementation at a dose of 600 mg twice daily appears to be effective.13 There is limited evidence for beneficial roles of vitamin B6 (up to 100 mg/day), magnesium and vitamin E supplementation. Some low-quality evidence suggests possible usefulness of exercise, relaxation, reflexology, light therapy, non-steroidal anti-inflammatory drugs and diuretics, specifically spironolactone.14 Further evidence is required before any of these can definitively be said to be of use. Progesterone, beta blockers, evening primrose oil and numerous dietary supplements and herbal remedies have not been shown to be effective. While surgical oophorectomy with or without hysterectomy appears to be effective therapy, this is an extreme solution that should be considered only for those women with symptoms refractory to all other treatment modalities.10
In this patient, my first approach would be to discuss the importance of lifestyle factors including stress reduction, diet and exercise, and I would commence calcium and vitamin B6 supplementation. Continuation of the oral contraceptive pill would depend on the patient’s requirement for contraception. The implications of any therapy in the setting of unplanned conception should be addressed. A low dose of an SSRI would be the best option, after discussion with the patient. This could initially be used intermittently if preferred by the patient to daily use, but if symptoms persist with luteal phase dosing, then an increase to daily use would be recommended. If the first agent used proved ineffective, a trial with an alternative SSRI would be appropriate prior to resorting to second-line therapies. The patient should be warned of the 15 per cent incidence of side effects, most prominently nausea, headache and jitteriness. The patient should also be counselled not to be disheartened if there is no response with her first cycle, as it may take three or four cycles for the therapeutic effect to be established.