Antidepressants as a Treatment for Hot Flashes in Women

Denise R. Kockler; Michelle W. McCarthy


Am J Health Syst Pharm. 2004;61(3) 

In This Article


Hot flashes are one of the most bothersome problems for many menopausal women and breast cancer survivors. They are described as transient occurrences of flushing and extreme warmth, often in conjunction with palpitations and anxiousness, followed by profuse sweating and occasionally chills and shaking.[1,2] The frequency, duration, and intensity of hot flashes vary. In the majority of women, they are prevalent during the first two years of menopause.[2] While the exact pathogenesis of hot flashes has not been fully established, hot flashes are vasomotor symptoms thought to originate within the anterior hypothalamus and are associated with a lack of thermoregulation due to estrogen withdrawal.[3] A relationship also seems to exist between the onset of hot flashes and the release of luteinizing hormone, though hot flashes have been reported in patients with diminished or absent levels of this hormone. Other theories suggest that, in addition to estrogen withdrawal, other centrally acting mediators (i.e., 3-methoxy-4-hydroxyphenylglycol [a metabolite of norepinephrine], dopamine, and serotonin) may be responsible for or associated with the development of hot flashes.[5,6]

Hormone therapy has long been recognized as the primary treatment for hot flashes and reduces their frequency in postmenopausal women by 70-90%.[7,8,9] This therapy, however, is generally contraindicated in patients with breast cancer because of possible hormonal effects on tumor growth and progression.[10,11] Available data suggest a 5% increase in breast cancer-related events when hormone therapy is given to women with breast cancer.[11] In May 2002, interim results of the Women's Health Initiative clinical trial revealed that long-term use (five years or more) of hormone therapy in healthy postmenopausal women increased risk of stroke, thromboembolic events, heart disease, and breast cancer.[12] Given these growing concerns and subsequent risks, other nonhormonal pharmacologic alternatives are necessary for the long-term treatment of hot flashes.

Previous trials have evaluated the ability of numerous nonhormonal agents to alleviate hot flashes, including clonidine,[13,14] methyldopa,[15,16] propranolol,[17] vitamin E,[18] belladonna alkaloids,[19] and gabapentin.[20,21] The results of these trials have demonstrated variable benefits, and adverse effects often limit the use of these agents. Several complementary and alternative medicines frequently used by patients have also been studied for the treatment of hot flashes. These include black cohosh, chaste tree berry, dong quai, ginseng, evening primrose oil, motherwort, red clover, licorice, Chinese herb mixture, soy and soy extracts, acupuncture, and behavioral therapies.[22] However, results of these studies are conflicting. In general, clinical trials do not support the use of complementary and alternative medicines because of insufficient long-term safety data and the lack of purity standardization to pharmaceutical grade required by the Food and Drug Administration.[22,23]

Several antidepressants, specifically venlafaxine (Effexor, Wyeth), fluoxetine (Prozac, Eli Lilly), and paroxetine (Paxil, GlaxoSmith-Kline), that are primarily indicated for the treatment of depression, major depressive disorders, and generalized anxiety disorders have been identified as medications that may be beneficial for managing hot flashes in women.[6,24,25,26,27,28,29] The mechanism by which these agents reduce hot flashes is not fully understood. Reduced serum serotonin (5-HT) levels, possibly due to estrogen withdrawal, have been documented in women with spontaneous or surgical menopause.[30] It has been suggested that 5-HT, specifically the subtypes 5-HT1a and 5-HT2a, may be a factor in thermoregulation in mammals. These subtypes must be in balance to maintain optimal thermoregulation. The upregulation of 5-HT receptor sites in the hypothalamus may alter the set point temperature, thereby activating an autonomic function to decrease body temperature. This action results in an elevation in skin temperature and sweating.[30,31,32] The results of animal studies have demonstrated that agents with 5-HT-reuptake-inhibition activity resemble these 5-HT receptor subtypes and may alter the thermoregulatory response.[32,33]

Primary and review articles published in English were identified by a MEDLINE (1966-June 2003) search using the MeSH terms "hot flashes," "hot flushes," "menopause," and "serotonin reuptake inhibitor." References of identified articles were subsequently reviewed for additional data. This article reviews the published literature on the use of venlafaxine, fluoxetine, and paroxetine for the treatment of hot flashes.


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