Mirtazapine: Hot Flashes

Background

Hot flashes often occur during and after menopause (either spontaneous or surgically induced), in breast cancer survivors and in men undergoing androgen deprivation therapy with gonadotropin-releasing hormone analogues (eg, leuprolide, goserelin) or postorchiectomy. Although the etiology of hot flashes is multifactorial, in men it may be related to a lack of hypothalamic feedback from decreased serum testosterone.^1-3 Approximately 75% of men will develop significant hot flashes within 1 to 12 months after therapy has been initiated, which may continue for as long as 30 months or until the time of death. ⁴ Whatever the reason, hot flashes, although not life threatening, are disruptive during the day and night and may affect the ability to function and quality of life.

Although estrogens have been widely used to treat vasomotor symptoms associated with menopause, alternative therapies are often needed for women with breast cancer. Megestrol acetate, a progestin, has also been effective in both breast cancer survivors and in men postorchiectomy or on androgen ablation therapy. Nonhormonal therapies have also included clonidine, vitamin E, methyldopa, and belladonna alkaloids. Antidepressants that inhibit the reuptake of serotonin and/or norepinephrine have also been evaluated as possible therapy. Although the mechanism of action is not clear, initial beneficial reports with other serotonin reuptake inhibitors have prompted investigations with mirtazapine.^3,5

Study Design

One prospective open trial: 27 women (16 completed the trial). One case series: 4 women.

Patient Population

Adult women experiencing hot flashes/flushes related to menopause.

Dosage and Duration

Mirtazapine has been administered as 7.5 to 60 mg per day. In an open trial, the drug was administered at night to avoid drowsiness effects. It was administered for 4 weeks in trial data and up to 3 months in case reports.

Results

Mirtazapine has been studied in a limited number of women for the treatment of hot flashes related to menopause. In the open trial and case reports, mirtazapine offered some relief of symptoms, both in frequency and severity. In the open trial, median reductions occurred in both total-daily hot flash frequency and total-weekly hot flash scores (52.5% and 59.5%, respectively). Onset of relief usually occurred within the first week.

Safety

Side effects reported in these reports included somnolence, an increased appetite, and dry mouth. Patient withdrawals were due to excessive somnolence, dry mouth, headache, flu-like syndrome, and aching arms.

OPEN IN VIEWER

Study of Clinical Literature on the Use of Mirtazapine for the Treatment of Hot Flashes

Citation	Indication	Study Design	Patient Population/Profile	Drug (Route) Dose (Duration)	Results		Safety	Author Conclusion
IMMEDIATE-RELEASE FORMULATIONS
Perez, et al. 20046	Hot flashes in women (with or without a history of breast cancer)	Prospective pilot trial	27 adult women with ≥ 14 hot flashes/wk for at least 1 mo Patients could continue stabilized doses of tamoxifen, raloxifene, or aroma-tase inhibitors. Other therapy for hot flashes was discontinued 2 wk prior study enrollment. Mean age: 56 y Median age: 53 y (range: 43 to 74 y) Duration of symptoms: < 9 months: 23% ≥ 9 months: 77% Mean frequency/day: 2 to 3: 18% 4 to 9: 59% ≥ 10 : 23% Breast cancer history: 59% Raloxifene: 9% Tamoxifen: 45% Mean weight: 79.1 kg Median weight: 75.8 kg	Mirtazapine (PO): Baseline assessment Wk 1: 7.5 mg nightly Wk 2: 15 mg nightly Wk 3: 30 mg nightly Wk 4: 15 or 30 mg nightly At wk 4: 30 mg nightly: 5 patients 22.5 mg nightly: 1 patient 15 mg nightly: 10 patients	Clinical outcomes: Withdrawals Before receiving meds Did not return surveys During study: ADRs Unknown Did not report data Results Mean HF reduction/day Median reductions  Total daily HF  Total weekly HF scores Patients reported statisticallysignificant improvements in tension, distress from H F, sleep sproblems, HF control, overall quality if life, and abnormal sweating. A total of 38% continued the medication after the completion of the trial. HF: hot flash	2 3 2 2 2 4 52.5% 59.5%	ADR profile: Patients reported a significant increase in appetite and dry mouth. Two patients withdrew because of excessive somnolence, dry mouth, and headache, and the other because of excessive somnolence, flulike symptoms, and aching arms.	Mirtazapine may be a reasonable choice in the treatment of hot flashes. Additional controlled trials are required to validate these results.
Waldinger, etal. 20007	Hot flashes in peri- or postmenopausal women	Case reports	4 adult women with hot flashes related to menopause Age range: 39 to 60 y	Mirtazapine (PO): 15 to 60 mg daily	Clinical outcomes: Most patients reported partial or complete response within 1 week. One patient achieved better results with an increase in dose. Two patients experienced recurrence of symptoms (eg, flushing, sweating) to pretreatment levels when the drug was stopped. Symptoms recurred as early as 2 days after the drug was stopped. Follow-up hot flashes occurred up to 3 months in 1 patient.		ADR profile: One patient reported drowsiness on the first day of treatment.	Mirtazapine alleviated hot flash symptoms related to menopause in 4 women.

Therapeutic Considerations

Initial data note a partial benefit of mirtazapine in the treatment of hot flashes related to menopause. Additional long-term controlled studies will be needed to validate these trial results and determine if mirtazapine will be useful as monotherapy or as adjunctive therapy to existing treatment modalities.