Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are first line agents for premenstrual dysphoric disorder treatment. Recommended treatment guidelines for SSRI use in premenstrual dysphoric disorder are included in Table Continuous (daily) SSRI/SNRI dosing and treatment strategies for premenstrual dysphoric disorder. Numerous double-blind, randomized controlled clinical trials have shown that almost all SSRIs are superior to placebo for treatment of the emotional and physical symptoms of premenstrual dysphoric disorder. The majority of these trials have shown symptom improvement within three cycles of active treatment. Fluoxetine and sertraline are the most studied selective serotonin reuptake inhibitors in premenstrual dysphoric disorder.

Fluoxetine has consistently proven more effective than placebo in randomized studies. In a study including 277 patients who would meet current criteria for premenstrual dysphoric disorder, fluoxetine at doses of 20 mg or 60 mg daily was superior to placebo in reducing premenstrual emotional and physical symptoms. This study found a statistically significant difference in response rate during the first treatment cycle with 52 percent of patients on fluoxetine demonstrating moderate improvement (defined as at least 50 percent reduction in baseline symptoms) compared to 22 percent of patients on placebo. The 60 mg daily dose, however, produced more side effects and 1 higher dropout rates without superior efficacy compared to the 20 mg daily dose. Other randomized controlled trials of daily and/or intermittent (luteal) dosing of fluoxetine have found it to be more effective than placebo in the treatment of severe premenstrual syndrome. Cohen and colleagues found that fluoxetine was more effective in the reduction of overall premenstrual syndrome symptoms, particularly emotional symptoms and social functioning at doses of 10 mg and 20 mg administered during the premenstrual time. Twenty milligrams of fluoxetine was shown to be more effective than both the 10 mg dose and placebo in the treatment of physical symptoms. Fluoxetine has been found to improve physical symptoms, work functioning and quality of life associated with premenstrual dysphoric disorder as well.

Table Continuous (daily) SSRI/SNRI dosing and treatment strategies for premenstrual dysphoric disorder

SSRI Starting Dose (mg) Therapeutic Dose (mg) Common Side Effects1
Fluoxetine 10-20 20 Insomnia, nausea, fatigue
Sertraline 25-50 50-1502 Nausea,diarrhea, insomnia
Paroxetine 10-20 20-30 Dry mouth, constipation, nausea, sedation
Citalopram 10-20 20-30 Headache, sweating, dry mouth, sedation
Venlafaxine 50 50-2003 Nausea, dizziness, insomnia, decreased libido

1) Sexual dysfunction (anorgasmia and decreased libido), sleep alterations (insomnia, sedation, hypersomnia) and gastrointestinal distress (nausea and diarrhea) are common side effects across all SSRIs. Specific side effects that may be more likely to occur with the identified SSRI are listed. 2) Patients with premenstrual dysphoric disorder will typically demonstrate a response to sertraline doses of 50-1 00 mg daily. However, a subset of patients may require slightly higher doses (up to 1 50 mg). If a patient is taking another SSRI and tolerating it well, but has a partial response at the dosages listed, it would be appropriate to raise the dose of the specific SSRI prior to switching to another agent. 3) Patients with premenstrual dysphoric disorder typically respond to lower venlafaxine doses of 50-1 00 mg daily. However, a subset of patients may require venlafaxine doses of 225 or 300 mg daily.

Sertraline has also been found to be more effective than placebo for premenstrual dysphoric disorder in multiple randomized controlled trials. In a study of 243 women with premenstrual dysphoric disorder, sertraline at 50 to 150 mg daily was more effective than placebo for premenstrual emotional and physical symptoms. Overall response rate (defined by clinician observer ratings of “much” or “very much” improved) in this study was significantly different with a 62% response in the sertraline group and a 34% response in the placebo group. Additional double-blind studies of sertraline have also shown that doses of 50 to 150 mg administered daily or just during the luteal phase are effective in improving overall function and reducing a range of premenstrual symptoms.

Paroxetine and citalopram have also been found to be effective for the treatment of premenstrual dysphoric disorder. Recent studies of controlled release paroxetine at doses of 12.5 mg and 25 mg daily revealed significant improvement in emotional symptoms of premenstrual syndrome compared to placebo. Physical symptoms were noted to improve with continuous and luteal phase administration of the 25 mg paroxetine CR dose compared to 12.5 mg daily and placebo. In an early study of daily paroxetine treatment compared with maprotoline, a noradrenergic antidepressant, and placebo, immediate release paroxetine was found to be significantly better than maprotoline or placebo for improvement of premenstrual mood and physical symptoms.

Although the majority of clinical trials of SSRIs have examined continuous administration of medication throughout the menstrual cycle, SSRIs may also be administered only when the patient is symptomatic. This method, called luteal phase or “intermittent” dosing, involves initiating medication at the time of ovulation and discontinuing it at the time of onset of menses. Several double blind, controlled trials have documented the effective use of luteal phase dosing strategies with SSRIs including fluoxetine, sertraline, controlled-release paroxetine, and citalopram. Some data support intermittent dosing as the preferred strategy. One study compared several dosing strategies for citalopram in patients with severe premenstrual syndrome: continuous, “semi-intermittent” (low dose in the follicular phase and full dose in the luteal phase) and intermittent (full dose in the luteal phase only). As compared with placebo (given continuously), all active treatment groups significantly reduced premenstrual symptoms, but intermittent and “semi-intermittent” dosing strategies were more effective than continuous dosing. The efficacy of intermittent dosing is an important finding because many patients would prefer to take medication only during their symptomatic period. Both continuous and intermittent dosing studies with SSRIs have demonstrated symptomatic reduction during the initial treatment cycle with further improvement over the course of active treatment.

To help women with premenstrual syndrome and regular menstrual cycles initiate intermittent or luteal phase dosing, clinicians may instruct patients to begin the antidepressant 2 weeks prior to the time their period is expected. Patients should remain on the medication over the two weeks and discontinue medications on the day of menses onset. Interestingly, patients do not experience discontinuation symptoms after stopping the SSRIs, nor do they develop adverse effects with start up of medication at the time of each new cycle.

Other antidepressant agents have been studied for the treatment of premenstrual dysphoric disorder. Venlafaxine, a serotonergic and noradrenergic reuptake inhibitor, has been found to be efficacious in treatment of premenstrual dysphoric disorder. In one trial, 60% of women treated with venlafaxine (continuous dosing) had at least a 50% reduction in total symptoms compared to 35% of women on placebo. Many women experienced rapid relief of symptoms within the first treatment cycle on a dose of 50 mg of venlafaxine. An open-trial of luteal phase administration of venlafaxine at doses of 75-112.5 mg demonstrated efficacy in the treatment of premenstrual mood and physical symptoms. Symptomatic improvement at these doses may be secondary to the fact that venlafaxine has greater serotonergic activity than noradrenergic activity at lower doses compared to the higher doses.

Fluvoxamine, another SSRI, approved for the treatment of obsessive compulsive disorder has also been studied in the treatment of PMS, but results are inconsistent suggesting the need for further study. Clomipramine, a tricyclic antidepressant, has been found to be more effective than placebo for premenstrual dysphoric disorder in both continuous and luteal phase dosing studies. Open label studies have suggested that nortriptyline and nefazodone are effective for premenstrual symptoms, but these agents have not been tested in randomized controlled trials. Antidepressants that are not SSRIs are currently considered second-line therapies due to the limited data as well as reduced tolerability and side effect profile.

Importantly, several comparative studies have found antidepressant agents with increased serotonergic activity to be more effective than those with primary noradrenergic activity, such as desipramine and maprotoline or dopaminergic action, such as bupropion. These medications with minimal, if any, serotonergic activity, have limited, or no, efficacy in the management of premenstrual dysphoric disorder compared to placebo.

Anxiolytics

Alprazolam, a triazolobenzodiazepine anxiolytic agent, has also been studied in the treatment of premenstrual syndrome. Of five randomized controlled trials, four found alprazolam to be more effective than placebo. In positive studies, alprazolam was particularly effective for management of premenstrual anxiety. Clinicians should remain cautious when prescribing alprazolam given its risk of tolerance and dependence.

Buspirone, a nonbenzodiazepine anxiolytic agent, has not been found to be better than placebo for the treatment of premenstrual syndrome (PMS).

Hormonal Treatments

If treatment is unsuccessful with a SRI or a second-line psychotropic agent, hormonal therapies should be considered. Spironolactone, a diuretic and steroid antagonist, has been shown to reduce premenstrual bloating, weight gain and negative emotions. Oral contraceptives are frequently used for treatment of mild to moderate premenstrual symptoms. There are several open trials supporting the efficacy of an oral contraceptive containing drospirenone, a progestogen that is also an analogue of spironolactone, for moderate to severe premenstrual symptoms.

Progesterone has also been used for the treatment of premenstrual syndrome, but a recent meta-analysis found that progesterone and other progestogens were no more effective than placebo. In contrast, gonadotropin releasing hormone (GnRH) agonists, including leuprolide and buserelin, were superior to placebo in the reduction of premenstrual emotional (irritability, depression) and physical (bloating, breast tenderness) symptoms in four double-blind controlled studies. Although gonadotropin releasing hormone agonists may be effective for premenstrual dysphoric disorder, the parenteral route of administration (for leuprolide), cost, and potential side effects, including hot flushes and vaginal dryness, make them a third line treatment strategy.

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