Low-dose Paroxetine (7.5 mg) Improves Sleep in Women With Vasomotor Symptoms Associated With Menopause

JoAnn V. Pinkerton, MD; Hadine Joffe, MD, MSc; Kazem Kazempour, PhD; Hana Mekonnen, MA; Sailaja Bhaskar, PhD; Joel Lippman, MD


Menopause. 2015;22(1):50-58. 

In This Article

Abstract and Introduction


Objective. Sleep disturbances are common among women in midlife; prevalence increases among perimenopausal/ postmenopausal women with vasomotor symptoms. Paroxetine 7.5 mg is the only nonhormonal treatment that has been approved in the United States for moderate to severe vasomotor symptoms associated with menopause. In two pivotal phase 3 studies evaluating its efficacy and safety, improvements in sleep disturbances were also prospectively evaluated.

Methods. Postmenopausal women with moderate to severe vasomotor symptoms were randomly assigned to paroxetine 7.5 mg (n = 591) or placebo (n = 593) once daily for 12 weeks (both studies) or 24 weeks (24-wk study). Predefined assessments on weeks 4, 12, and 24 included number of nighttime awakenings attributed to vasomotor symptoms, sleep-onset latency, sleep duration, and sleep-related adverse events. The two studies’ data for weeks 1 to 12 were pooled.

Results. At baseline, participants reported a mean of 3.6 awakenings/night attributed to vasomotor symptoms. Nighttime awakenings attributed to vasomotor symptoms were significantly reduced within 4 weeks of initiating paroxetine 7.5 mg treatment (39% reduction vs 28% for placebo; P = 0.0049), and reductions were sustained through 12 or 24 weeks of treatment. Paroxetine 7.5 mg treatment also significantly increased nighttime sleep duration (week 4, +31 vs +16 min for placebo; P = 0.0075), but no significant between-group differences in sleep-onset latency or sleep-related adverse events such as sedation were observed.

Conclusions. In postmenopausal women treated for menopausal vasomotor symptoms, paroxetine 7.5 mg significantly reduces the number of nighttime awakenings attributed to vasomotor symptoms and increases sleep duration without differentially affecting sleep-onset latency or sedation.


Disturbances in sleep (eg, sleep induction, sleep maintenance, nighttime awakenings, and early morning wakefulness) are common among women during midlife. The prevalence of sleep disturbances increases with age and menopause status, with up to half of women aged 40 to 59 years reporting poor sleep quality.[2,3] Targeting the specific causal factors/conditions of sleep disturbances, rather than treating the sleep problem nonspecifically with sedative or hypnotic medications, is important given that these medications are recommended for short-term situational sleep problems rather than for long-term disorders because of their addictive potential.[4]

Hot flashes and night sweats, collectively termed vasomotor symptoms (VMS), occur in up to 80% of perimenopausal and postmenopausal women.[5,6] VMS can be bothersome and may negatively impact functioning[7] and activities of daily living, including work, social, and leisure activities.[8] Furthermore, VMS have been linked to increased prevalence of sleep disturbances and nighttime awakenings during menopause.[9,10,11,12,13] Because sleep disturbance is a risk factor for impaired daytime functioning, development of medical and affective disorders, and increased health care costs,[14,15] sleep disturbances associated with menopause may negatively affect the health and safety of postmenopausal women and persons with whom they interact.

Hormone therapy is effective for treating VMS associated with menopause[16,17] and improves sleep disturbances related to VMS in perimenopausal and early postmenopausal women.[1,4,18] However, hormone therapy is contraindicated in, or is not acceptable for use by, some postmenopausal women[19,20,21]; this has led researchers to evaluate the efficacy of nonhormonal treatments of VMS.[22,23,24,25,26,27,28,29]

Paroxetine 7.5 mg capsules (Brisdelle; formerly low-dose mesylate salt of paroxetine), which consist of a low dose of the mesylate salt of paroxetine, were specifically developed for the treatment of women with moderate to severe VMS associated with menopause. In two multicenter, randomized, double-blind, placebo-controlled phase 3 studies,[30] paroxetine 7.5 mg once daily significantly reduced the mean weekly frequency (P < 0.0001) and severity (P ≤ 0.0110) of VMS on weeks 4 and 12 in postmenopausal women compared with placebo. Paroxetine 7.5 mg was generally well tolerated; most treatment-emergent adverse events (TEAEs) were mild or moderate in severity.[30] Unlike higher doses of paroxetine that have been approved for the treatment of psychiatric conditions (which require gradual dose reduction before drug cessation to reduce the risk of discontinuation syndrome),[31,32] paroxetine 7.5 mg could be stopped without the need for tapering; minimal acute discontinuation symptoms were reported upon stopping study drug in phase 3studies.[30] Furthermore, treatment with paroxetine 7.5 mg did not result in adverse events (AEs) such as weight gain and sexual dysfunction, which are commonly associated with higher-dose selective serotonin reuptake inhibitors (SSRIs).[33]

Although some SSRIs (and serotonin-norepinephrine reuptake inhibitors) are known to worsen sleep in individuals with depression,[34,35] recent data suggest that the SSRI escitalopram may improve nighttime sleep disturbances among nondepressed women receiving treatment of VMS.[36] The underlying cause of sleep disturbances (whether psychiatric in origin or attributed to VMS) and the population type treated may be factors in how individuals’ sleep outcomes are affected by treatment with SSRIs. The impact of higher (psychiatric) doses of paroxetine on sleep has been inconsistent across studies[37,38,39]; therefore, improvements in sleep disturbances with paroxetine 7.5 mg were evaluated a priori in the two phase 3studies in women with menopausal VMS. Sleep parameters were assessed using predefined sleep diary measures for nighttime awakenings, sleep-onset latency and duration, interference of symptoms with daily living, and difficulty sleeping. AEs related to sleep during the treatment period and after discontinuation of treatment were also evaluated. We now report the impact of paroxetine 7.5 mg/day on these self-reported sleep parameters in an analysis of data from the two pivotal phase 3 studies.