Placebo-controlled trial comparing intermittent and continuous paroxetine in premenstrual dysphoric disorder.

Serotonin reuptake inhibitors (SRIs) do not have to be administered continuously to be effective for premenstrual dysphoric disorder (PMDD), but can be given during luteal phases only. This is of practical importance, but also of theoretical interest since it suggests that the onset of action of SRIs is shorter in PMDD than in, for example depression. In this study, both continuous and intermittent SRI administration was compared with placebo, with the special purpose of analyzing if different PMDD symptoms respond differently depending on the treatment regimen. To this end, women meeting slightly modified DSM-IV criteria for PMDD (mean+/-SD age, 37+/-6.3 years) were treated for three menstrual cycles with paroxetine continuously, paroxetine during the luteal phase only, or placebo, the population completing at least one treatment cycle comprising 55-56 subjects per group. Continuous treatment with paroxetine reduced premenstrual symptoms effectively with a response rate of 85%. The effect size was highest for irritability (1.4) and lowest for lack of energy (0.5). Intermittent treatment was as effective as continuous treatment in reducing irritability, affect lability, and mood swings, but had a somewhat weaker effect on depressed mood and somatic symptoms. The study indicates that the response rate when treating PMDD with SRIs is high, and that irritability is a key target symptom. Symptoms such as irritability, affect lability, and mood swings appear to be more inclined to respond rapidly to SRIs, enabling intermittent treatment, than are, for example, the somatic symptoms.     

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.     

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.     

Paroxetine controlled release

A controlled-release (CR) formulation of the SSRI paroxetine has been developed. This CR formulation delays the release of paroxetine until the tablet has passed through the stomach; the drug is then released over 4-5 hours. In well designed placebo-controlled trials in patients with major depressive disorder (including a study in the elderly), social anxiety disorder or premenstrual dysphoric disorder (PMDD), paroxetine CR was consistently superior to placebo with regards to primary endpoints (i.e. mean Hamilton Rating Scale for Depression total score [major depressive disorder], Liebowitz social anxiety scale total score and Clinical Global Impressions-Global Improvement score [social anxiety disorder] and Visual Analogue Scale-Mood score [PMDD]). The duration of treatment was 12 weeks or, in PMDD, over three menstrual cycles (intermittent or continuous administration). Paroxetine CR also demonstrated efficacy in three well designed studies in patients with panic disorder with or without agoraphobia. Paroxetine CR was generally well tolerated in clinical trials, with an adverse-event profile typical of SSRIs, although recipients of paroxetine CR experienced significantly less nausea than recipients of immediate-release paroxetine in the first week of treatment.     

Lack of beneficial effects of clonidine in the treatment of premenstrual dysphoric disorder: results of a double-blind, randomized study

OBJECTIVES: To test the effects of clonidine in comparison with active placebo on premenstrual symptoms, mood scores and norepinephrine (NE) concentration, in women with premenstrual dysphoric disorder (PMDD). METHODS: Twelve women with prospectively confirmed PMDD were randomly assigned to oral 0.3 mg/day clonidine, as an active treatment, or 10 mg/day loratadine, as an active placebo, for 2 months each using a double-blind, cross-over design. NE concentration, premenstrual symptom ratings and mood scales were measured on three occasions: at pretreatment, after clonidine treatment and after placebo treatment. All patients were free of current psychiatric co-morbidity and medication use. RESULTS: There were no significant differences between clonidine and placebo for mood scales or premenstrual symptom ratings, though clonidine significantly suppressed NE concentration and produced more side effects in comparison with placebo. CONCLUSION: Compared with an active placebo clonidine demonstrated no beneficial changes in mood and premenstrual symptoms in women with PMDD.     

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.     

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.     

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, double-blind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the low-dose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.     

Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator

Premenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopregnanolone is suggested to underlie PMDD symptomatology. Core mood symptoms include irritability and anger, with aggression being the behavioral outcome of these symptoms. The present study sought to investigate the neural correlates of reactive aggression during the premenstrual phase in women with PMDD, randomized to a selective progesterone receptor modulator (SPRM) or placebo. Self-reports on the Daily Record of Severity of Problems were used to assess PMDD symptoms and gonadal hormone levels were measured by liquid chromatography tandem mass spectrometry. Functional magnetic resonance imaging was performed in 30 women with PMDD, while performing the point subtraction aggression paradigm. Overall, a high SPRM treatment response rate was attained (93%), in comparison with placebo (53.3%). Women with PMDD randomized to SPRM treatment had enhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex during the aggressive response condition. The fronto-cingulate reactivity during aggressive responses depended on treatment, with a negative relationship between brain reactivity and task-related aggressiveness found in the placebo but not the SPRM group. The findings contribute to define the role of progesterone in PMDD symptomatology, suggesting a beneficial effect of progesterone receptor antagonism, and consequent anovulation, on top-down emotion regulation, i.e., greater fronto-cingulate activity in response to provocation stimuli.Subject terms: Neuroscience, Psychiatric disorders     

Estradiol in premenstrual asthma: a double-blind,randomized, placebo-controlled,crossover study

STUDY OBJECTIVES: To characterize asthma symptoms and pulmonary function throughout two menstrual cycles, with and without exogenous estradiol administration, in women with premenstrual asthma, and to determine the effect of estradiol administration on asthma symptoms, pulmonary function, quality of life, and biomarkers of airway inflammation. DESIGN: Double-blind, randomized, placebo-controlled, crossover study. SETTING: Respiratory clinic and clinical research center. SUBJECTS: Twelve women with documented premenstrual asthma (> or = 20% premenstrual worsening of asthma symptoms and/or of peak expiratory flow [PEF] during a 1-month screening phase). INTERVENTION: Each woman received either estradiol 2 mg or placebo orally between cycle days 23 and 28 (i.e., premenstrually, or before the onset of menses) in the first cycle and then crossed over to the other arm in the second cycle. Throughout both cycles, the women recorded daily morning and evening PEF readings and asthma symptoms. MEASUREMENTS AND MAIN RESULTS: Spirometry testing and measurement of serum estradiol and biomarkers of airway inflammation were performed on days 8 (follicular phase), 22 (luteal phase), and 28 (premenstrually) of both the estradiol and placebo cycles. During the two premenstrual visits, the Asthma Quality of Life Questionnaire was administered. No notable differences were observed between the estradiol and placebo cycles in daily PEF recordings or composite asthma symptoms scores. The area under the curve (AUC) for the composite asthma symptoms versus time profile was numerically, but not statistically, lower (denoting less severe symptoms) during the estradiol cycle than during the placebo cycle. Likewise, no significant difference in AUC values for morning PEF or evening PEF was found between the estradiol cycle and the placebo cycle. Despite differences (p<0.05) in day-28 estradiol concentrations for estradiol and placebo cycles, no significant differences were found in forced expiratory volume in 1 second, serum endothelin-1, serum and urine eosinophil protein X, urine leukotriene E4, or quality-of-life scores. CONCLUSION: Exogenously administered estradiol did not have a significant effect in women with premenstrual asthma whose asthma was classified predominantly as mild and under excellent control. As in the case of premenstrual syndrome, the placebo effect may be prominent in premenstrual asthma. Further trials, involving women with more severe asthma under poorer control, are warranted to discern underlying mechanisms for the worsening of asthma in relation to menstruation.     

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.     

Selective serotonin reuptake inhibitors for premenstrual dysphoric disorder: the emerging gold standard?

There have been a large number of studies conducted investigating the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of patients with premenstrual dysphoric disorder (PMDD). The 12 randomised, controlled trials with continuous dose administration of SSRIs and the eight randomised, controlled trials with luteal phase dose administration (from ovulation to menses) are reviewed. All the treatment studies on fluoxetine, sertraline, paroxetine and citalopram have reported positive efficacy. Fluoxetine and sertraline have the largest literature, with a smaller number of studies endorsing paroxetine and citalopram. Mixed efficacy results have been reported with fluvoxamine. In general, adverse effects from the use of SSRIs in women with PMDD are the usual mild and transient adverse effects from SSRIs including anxiety, dizziness, insomnia, sedation, nausea and headache. Sexual dysfunction and weight gain can be problematic long-term adverse effects of SSRIs, but these effects have not been systematically evaluated with long-term SSRI use in women with PMDD. Serotonergic antidepressants have differential superiority over nonserotonergic antidepressants in the treatment of PMDD. Treatments that enhance serotonergic action improve premenstrual irritability and dysphoria with a rapid onset of action, suggesting a different mechanism of action than in the treatment of depression. It is possible that neurosteroids, such as progesterone metabolites, are involved in the rapid action of serotonergic antidepressants in PMDD. Future research needs to address less frequent dose administration regimens, such as 'symptom-onset' dose administration, and the recommended length of treatment.     

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.     

Escitalopram administered in the luteal phase exerts a marked and dose-dependent effect in premenstrual dysphoric disorder

This is the first placebo-controlled trial evaluating the efficacy of the selective serotonin reuptake inhibitor (SSRI), escitalopram, in the treatment of premenstrual dysphoric disorder (PMDD). Women with PMDD (intention-to-treat population, n = 151) were treated intermittently for 3 months, during luteal phases only, with 10 mg/d escitalopram, 20 mg/d escitalopram, or placebo. Escitalopram was found to exert a marked and a dose-dependent symptom-reducing effect, 20 mg/d being clearly superior to 10 mg/d. Although the primary outcome parameter, that is, the sum of the symptoms irritability, depressed mood, tension, and affective lability, was decreased by 90% with 20 mg/d escitalopram, the effect of active treatment on breast tenderness, food craving, and lack of energy was more modest and not significantly different from that of placebo; this outcome supports our previous assumption that the former symptoms are more inclined to respond to intermittent administration of an SSRI than are the latter. Although the placebo response was high, the difference between the placebo group and the 20-mg/d escitalopram group with respect to the percentage of subjects displaying 80% or greater reduction in the rating of the cardinal symptom of PMDD, that is, irritability, was considerable: 30% versus 80%. Adverse events were those normally reported in SSRI trials, such as nausea and reduced libido, and were not more common in patients given 20 mg/d of escitalopram than in patients given the lower dose. This study supports the usefulness of escitalopram for the treatment of PMDD and sheds further light on how different components of this syndrome are differently influenced by intermittent administration of an SSRI.     

A double-blind placebo-controlled study of controlled release fluvoxamine for the treatment of generalized social anxiety disorder

This was a randomized double-blind placebo-controlled multicenter study to assess the efficacy, safety, and tolerability of fluvoxamine in a controlled release (CR) formulation for treatment of generalized social anxiety disorder (GSAD). A total of 300 subjects with GSAD were randomly assigned to receive either fluvoxamine CR (N = 149) or placebo (N = 151) for 12 weeks. Mean changes from baseline to end point in Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression Severity of Illness Scale (CGI-S), Sheehan Disability Scale (SDS), as well as the mean end point scores in Clinical Global Impression Improvement Scale (CGI-I) and Patient Global Impression of Improvement Scale (PGI) were compared between the fluvoxamine CR and placebo treatment groups. Arizona Sexual Experience Scale (ASEX), adverse event, and other safety parameters were also assessed. The results demonstrated that fluvoxamine CR was significantly superior to placebo in decreasing LSAS total score (primary measure) starting at week 4. At end point, there was a mean change from baseline of -36.1 +/- 2.7 (37% reduction) in the LSAS total score in the fluvoxamine CR group compared with -27.3 +/- 2.4 (28% reduction) in the placebo group (P = 0.020 for mean change). Fluvoxamine CR was also significantly superior to placebo in SDS, CGI-S, CGI-I at end point (secondary measures). When compared with placebo, fluvoxamine CR did not cause any significant weight gain or clinically significant sexual dysfunction as measured by ASEX. In summary, fluvoxamine CR is an efficacious, safe, and well-tolerated treatment of generalized social anxiety disorder.     

Diagnosis and treatment of premenstrual dysphoric disorder: an update

Premenstrual dysphoric disorder (PMDD) appears in the appendix of the DSM-IV under the heading 'depressive disorder not otherwise specified'. Yet, recently, a group of experts reached a consensus that PMDD is a distinct clinical entity with characteristic symptoms of irritability, anger, internal tension, dysphoria, and mood lability. PMDD is the more severe form of premenstrual symptomatology, whereas premenstrual syndrome (PMS) is milder and more prevalent and both must be differentiated from premenstrual magnification/exacerbation of an underlying major psychiatric disorder or a medical condition. Accurate assessment and diagnosis of significant premenstrual symptomatology is paramount and can be influenced by subjective perception, retrospective versus prospective reporting, and cultural context. The serotonergic system, which is in a close reciprocal relationship with the gonadal hormones, has been identified as the most plausible target for intervention. Results from randomized placebo-controlled trials in women with PMDD have clearly demonstrated that serotonin reuptake inhibitors (SSRIs), with daily or intermittent dosing, have excellent efficacy and minimal adverse effects and should be considered first-line treatment. Luteal phase only SSRI administration may offer an attractive treatment option for a disorder that is itself intermittent. Hormonal interventions, in particular the suppression of ovulation will eliminate premenstrual symptomatology; however, the benefits-risk ratio of these approaches should be carefully evaluated with the patient.     

Treatment of premenstrual dysphoria with selective serotonin re-uptake inhibitors: focus on safety

Many women experience physical or mood symptoms associated with the menstrual cycle. For approximately 3 – 8% of women, the symptoms are severe enough to significantly affect social, domestic and occupational functioning. This cluster of primarily emotional and behavioural symptoms is now labelled premenstrual dysphoric disorder (PMDD). Women who meet criteria for PMDD do not usually respond to conservative interventions; selective serotonin re-uptake inhibitors (SSRIs) taken either daily or intermittently are considered to be an effective first-line therapy for this population. In this paper, the authors report on the efficacy and tolerability of SSRIs that are currently recognised as the treatment of choice for PMDD.     

Treatment of premenstrual dysphoria with selective serotonin re-uptake inhibitors: focus on safety

Many women experience physical or mood symptoms associated with the menstrual cycle. For approximately 3 - 8% of women, the symptoms are severe enough to significantly affect social, domestic and occupational functioning. This cluster of primarily emotional and behavioural symptoms is now labelled premenstrual dysphoric disorder (PMDD). Women who meet criteria for PMDD do not usually respond to conservative interventions; selective serotonin re-uptake inhibitors (SSRIs) taken either daily or intermittently are considered to be an effective first-line therapy for this population. In this paper, the authors report on the efficacy and tolerability of SSRIs that are currently recognised as the treatment of choice for PMDD.