Symptom-onset treatment for women with premenstrual dysphoric disorder

Symptoms of premenstrual dysphoric disorder (PMDD) respond to serotonin reuptake inhibitors when treatment is limited to 14 days of the menstrual cycle. Many women have less than a week of symptoms, and shorter treatment intervals would further reduce medication exposure and costs. METHODS: Twenty women with PMDD were randomly assigned to either paroxetine CR or placebo for 1 cycle and crossed over to the other condition for a second cycle. Subjects initiated treatment when premenstrual symptoms began and stopped within 3 days of beginning menses. RESULTS: Women took capsules for an average of 9 days (range, 3-15 days), including the first few days of menses. Moderate "PMDD level" symptoms occurred in 1 subject (6%) for 2 days and 4 subjects (24%) for 1 day before starting paroxetine or placebo. Daily Record of Severity of Problems scores were lower in the paroxetine group compared with the placebo group, although the differences were not statistically significant. However, the mean on-treatment Inventory of Depressive Symptomatology (clinician-rated) score for the paroxetine group was 17.9 +/- 8.3 compared with 31.5 +/- 11.2 in the placebo group (adjusted mean difference = 13.6, P = 0.009). Response (Clinical Global Impressions Scale score of 1 or 2) occurred in 70% of subjects randomized to paroxetine CR and 10% of those assigned to placebo (chi2(1) = 7.5, P = 0.006). Discontinuation symptoms did not differ in the groups. CONCLUSION: These data suggest the need to further evaluate symptom-onset treatment in a larger randomized clinical trial.     

SSRIs for premenstrual dysphoric disorder

Around 2-10% of women have premenstrual symptoms that severely disrupt daily living. When such symptoms are dominated by severe disturbances of mood and behaviour, the condition has been named premenstrual dysphoric disorder (PMDD). Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), is licensed in the UK for the treatment of PMDD. Here, we discuss the diagnosis of PMDD and the evidence for the efficacy of fluoxetine and other SSRIs in its treatment.     

Pharmacotherapy of premenstrual syndromes and premenstrual dysphoric disorder: current practices

Premenstrual syndromes (PMS) and especially premenstrual dysphoic disorder (PMDD) affect a large segment of the population of women of reproductive age. Treatment is necessary in approximately 2-10% of women with PMS and PMDD because of the degree of impairment and distress experienced. Treatment modalities are increasingly based on hypotheses concerning possible underlying biological mechanisms: mostly ovulation-related hormonal changes and serotonergic abnormalities. Two treatment modalities distinguish themselves as highly effective: suppression of ovulation and specific serotonin re-uptake inhibitor (SSRI) antidepressants. Suppression of ovulation is effective for a wide range of PMS, while SSRIs are effective for PMDD with some degree of efficacy for physical symptoms. The SSRIs are also efficacious when administered intermittently--only during the luteal phase of the menstrual cycle.     

Evaluation and management of premenstrual syndrome and premenstrual dysphoric disorder

OBJECTIVE: To review premenstrual disorders, their varied symptoms, possible etiology, and treatment options. DATA SOURCES: Published articles identified through MEDLINE (1966-2001) using the search terms premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) and the additional terms treatment and etiology. Additional references were identified from the bibliographies of the retrieved articles. DATA SYNTHESIS: PMS refers to a group of menstrually related disorders that are estimated to affect up to 40% of women of childbearing age. The varied symptoms of PMS include mood swings, tension, anger, irritability, headache, bloating, and increased appetite with food cravings. PMS symptoms occur during the luteal phase of the menstrual cycle and remit with the onset of menstruation or shortly afterward. Approximately 5% of women with PMS suffer from PMDD, a more disabling and severe form of PMS in which mood symptoms predominate. Because no tests can confirm PMS or PMDD, the diagnosis should be made on the basis of a patient-completed daily symptom calendar and the exclusion of other medical disorders. The causes of PMS and PMDD are uncertain, but are likely associated with aberrant responses to normal hormonal fluctuations during the menstrual cycle. For most women, symptoms can be relieved or reduced through lifestyle interventions, such as dietary changes and exercise, and drug therapy with hormonal or psychotropic agents. For PMDD, selective serotonin reuptake inhibitors have recently emerged as first-line therapy. Certain dietary supplements, including calcium, also may be an option for some women. CONCLUSION: PMS and PMDD are complex but highly treatable disorders. Pharmacists can improve the recognition and management of these common conditions by providing patient education on premenstrual symptoms and counseling women on lifestyle interventions and pharmacotherapy to relieve their discomfort.     

Intermittent, luteal phase nefazodone treatment of premenstrual dysphoric disorder

Three outpatients who fulfilled full DSM-IV diagnostic criteria for premenstrual dysphoric disorder (PDD) were successfully treated with intermittent (luteal phase) nefazodone. They received the medication at low doses of up to 100 mg/day (50 mg b.i.d.), for 2 weeks through the luteal phase of the menstrual cycle only. All the patients reported a marked symptomatic improvement, including full remission of their emotional symptoms, and two achieved in addition full remission of their somatic symptoms. Side-effects reported during the treatment were mild. The use of luteal phase nefazodone seems to be a promising treatment strategy for the management of PDD. It offers advantages over daily dosing throughout the menstrual cycle, such as reduced incidence and severity of side-effects, and avoids the stigma that may accompany the continuous use of psychopharmacological treatment, with the advantage that compliance may be improved.     

The pharmacologic management of premenstrual dysphoric disorder

Premenstrual dysphoric disorder (PMDD) is characterized by physical, affective and behavioral symptoms that are linked to the luteal phase of the menstrual cycle and relieved soon after the onset of menses. The disorder is chronic and exerts a major impact on personal relationships and occupational productivity for the estimated 6% of reproductive-aged women who fulfill strict PMDD criteria and the almost 20% of women who nearly meet these criteria. There are now various pharmacologic options that have demonstrated efficacy for PMDD and two of these approaches have an approved indication for treatment from the US FDA: three selective serotonin re-uptake inhibitors; and for women who also desire hormonal contraception, a low dose oral contraceptive pill containing the progestin drospirenone, in a new dosing regimen. Due to the unique pathophysiology of the disorder, the selective serotonin re-uptake inhibitors can be effectively administered intermittently, with dosing limited to the luteal phase of the cycle (2 weeks prior to menses). In the future, new pharmacotherapy will likely evolve from research evaluating other hormonal formulations that inhibit ovulation, without simulating PMDD-like symptoms, or novel pharmacologic agents that modulate the central neurotransmission.     

Paroxetine treatment of mood disorders in women: premenstrual dysphoric disorder and hot flashes

With the relatively recent introduction of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants, increased attention has been focused on the use of antidepressants in the treatment of mood disorders across the female life cycle. Evidence for the efficacy of antidepressants in the treatment of premenstrual dysphoric disorder (PMDD) and hot flashes associated with menopause and breast cancer has emerged. The clinical trials experience with paroxetine and the controlled-release (CR) formulation of paroxetine is reviewed.     

Luteal phase administration of agents for the treatment of premenstrual dysphoric disorder

This review focuses on current information about luteal phase administration (i.e. typically for the last 2 weeks of the menstrual cycle) of pharmacological agents for the treatment of premenstrual dysphoric disorder (PMDD). Compared with continuous administration, a luteal phase administration regimen reduces the exposure to medication and lowers the costs of treatment. Based on evidence from randomised clinical trials, SSRIs are the first-line treatment for PMDD at this time. Of these agents, sertraline, fluoxetine and paroxetine (as an extended-release formulation) are approved by the US FDA for luteal phase, as well as continuous, administration. Clinical trials of these agents and citalopram have demonstrated that symptom reduction is similar with both administration regimens. When used to treat PMDD, SSRI doses are consistent with those used for major depressive disorder. The medications are well tolerated; discontinuation symptoms with this intermittent administration regimen have not been reported. Other medications that have been examined in clinical trials for PMDD or severe premenstrual syndrome (PMS) using luteal phase administration include buspirone, alprazolam, tryptophan and progesterone. Buspirone and alprazolam show only modest efficacy in PMS (in some but not all studies), but there may be a lower incidence of sexual adverse effects with these medications than with SSRIs. Symptom reduction with tryptophan was significantly greater than with placebo, but the availability of this medication is strictly limited because of safety concerns. Progesterone has consistently failed to show efficacy for severe PMS/PMDD in large, randomised, placebo-controlled trials.     

Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder

Clinical trials have demonstrated that serotonin reuptake inhibitors (SRIs) and the extract of Vitex agnus castus are effective for the treatment of premenstrual dysphoric disorder (PMDD). However, to the best of our knowledge, there has been no study comparing the efficacy of the SRIs with Vitex agnus castus (AC) extract. Therefore, the aim of the present study was to compare the efficacy of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), with that of the AC extract, a natural choice. After a period of 2 screening months to screen the patients for suitability, 41 patients with PMDD according to DSM-IV were recruited into the study. The patients were randomized to fluoxetine or AC for 2 months of single-blind, rater- blinded and prospective treatment period. The outcome measures included the Penn daily symptom report (DSR), the Hamilton depression rating scale (HAM-D), and the clinical global impression-severity of illness (CGI-SI) and -improvement (CGI-I) scales. At endpoint, using the clinical criterion for improvement, a similar percentage of patients responded to fluoxetine (68.4%, n = 13) and AC (57.9%, n = 11). There was no statistically significant difference between the groups with respect to the rate of responders. This preliminary study suggests that patients with PMDD respond well to treatment with both fluoxetine and AC. However, fluoxetine was more effective for psychological symptoms while the extract diminished the physical symptoms.     

Efficacy and tolerability of premenstrual use of venlafaxine (flexible dose) in the treatment of premenstrual dysphoric disorder

The objective of this study was to examine the efficacy and tolerability of intermittent dosing of venlafaxine for the treatment of premenstrual dysphoric disorder. One hundred and twenty-four women aged 18 to 45 years, with regular menstrual cycles and who reported significant premenstrual symptoms, were assessed prospectively to confirm their diagnosis of premenstrual dysphoric disorder. Twenty subjects with confirmed premenstrual dysphoric disorder entered a single-blind, placebo phase (1 cycle). Placebo nonresponders (n = 12) received 2 cycles of intermittent (premenstrual) treatment with venlafaxine (75 to 112.5 mg/d). Subjects initiated treatment 14 days before the anticipated onset of menses and discontinued it on the second day of bleeding. Doses could be adjusted after cycle 1 based on subjects' response and tolerability. Response to treatment was assessed based on changes in the Daily Rating Severity of Problems and Premenstrual Tension Syndrome Questionnaire scores from baseline (before the placebo cycle), as well as Clinical Global Impression-Severity scores. Discontinuation symptoms were assessed between treatment cycles, using the Discontinuation-Emergent Signs and Symptoms questionnaire. Eleven subjects concluded 2 cycles of intermittent dosing with venlafaxine. Nine subjects (81.8%) showed satisfactory response based on Clinical Global Impression of < or = 2. Changes in Daily Rating Severity of Problems scores and subscores (depression, physical symptoms, and anger) and in Premenstrual Tension Syndrome Questionnaire scores were significant (P < 0.05 for all comparisons, Wilcoxon tests). Intermittent treatment was well tolerated. This preliminary report suggests that premenstrual use of venlafaxine is an efficacious and well-tolerated treatment for premenstrual dysphoric disorder.     

Fluctuating serotonergic function in premenstrual dysphoric disorder and premenstrual syndrome: findings from neuroendocrine challenge tests

Rationale Premenstrual dysphoric disorder (PMDD) has been assumed to be a subtype of premenstrual syndrome (PMS) with depressive symptoms, such as depressive mood, tension, anxiety, and mood liability during luteal phase. At present, no conclusion has been established about serotonergic function in PMDD. Objective The purpose of this study was to investigate the serotonergic function of PMDD subjects in comparison to PMS without PMDD subjects and normal controls via neuroendocrine challenge tests. Subjects and methods Twenty-four women (seven with PMDD, eight with PMS without PMDD, and nine normal controls) were tested on three occasions (follicular phase, early luteal phase, and late luteal phase) receiving paroxetine 20 mg orally as a serotonergic probe at 8:00 a.m. Plasma ACTH and cortisol were measured prior to the administration and every hour for 6 h thereafter. Results As a whole, there were significant differences in serotonergic function measured by ACTH and cortisol responses to paroxetine challenge across these three groups. PMDD subjects showed higher serotonergic function in follicular phase but lower serotonergic function in luteal phase, compared with women with PMS without PMDD and normal controls. Conclusion The present findings suggest that PMDD women have fluctuating serotonergic function across their menstrual cycles and that the pattern may be different from PMS without PMDD.     

Treatment of premenstrual dysphoric disorder with selective serotonin reuptake inhibitors

Premenstrual dysphoric disorder (PMDD) is considered a severe form of premenstrual syndrome. Symptoms of PMDD occur during the last week of the luteal phase of the menstrual cycle and usually abate at the onset of menses. About 3-8% of all menstruating women experience PMDD, which can lead to significant functional impairment. Several randomized, controlled trials have assessed the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of PMDD. The SSRIs were found to significantly improve symptoms, particularly psychological or behavioral symptoms, during the luteal phase in women with PMDD. Also, SSRIs were found to improve the quality of life in women with PMDD. Headache, fatigue, insomnia, and anxiety were often reported as adverse effects. A decrease in libido or sexual dysfunction also was reported. In recent studies, intermittent SSRI therapy was found to be effective treatment for PMDD and allows a woman to take the drug for only 14 days each month. Intermittent SSRI therapy should be recommended before continuous daily dosing of SSRIs in the treatment of PMDD.     

Review of fluoxetine and its clinical applications in premenstrual dysphoric disorder

The largest number of antidepressant treatment trials in premenstrual syndrome and premenstrual dysphoric disorder (PMDD) have been conducted with fluoxetine. Fluoxetine and other selective serotonin re-uptake inhibitors (SSRIs) clearly reduce premenstrual emotional and physical symptoms and improve premenstrual psychosocial functioning. Fluoxetine was the first SSRI to be approved by the FDA as a treatment for the emotional and physical symptoms of PMDD. Fluoxetine 20 mg has been reported to be effective for emotional and physical premenstrual symptoms with continuous daily dosing (every day of the menstrual cycle) and with luteal phase daily dosing (from ovulation to menses). In addition, premenstrual emotional symptoms have been reported to improve with fluoxetine 10 mg in luteal phase daily dosing and with 90 mg 2 and 1 weeks prior to menses. Fluoxetine is generally a well-tolerated treatment for PMDD and discontinuation effects have not been reported with intermittent dosing regimens.