Antidepressants a New Option for Managing Hot Flashes

CHICAGO—A low daily dose of venlafaxine (Effexor)—an antidepressant agent that affects reuptake of serotonin and norepinephrine—resulted in a 60% reduction in the "median hot flash score," a measure of the severity and frequency of hot flashes. The therapeutic dose range for treatment of depression is 75 to 225 mg/d; the 60% reduction in the hot flash score was achieved with only 75 mg/d. Charles Loprinzi, MD, director of medical oncology, Mayo Clinic, Rochester, Minnesota, reported the results at the Lynn Sage Breast Cancer Symposium.

Hot flashes are a common menopausal symptom and a greater problem in women with breast cancer due to several factors. First, chemotherapy for premenopausal women can cause an abrupt menopause that results in hot flashes. Second, tamoxifen is frequently used in the treatment of breast cancer, and its most common side effect is hot flashes. Third, Dr. Loprinzi said, "we have been reticent to use estrogen itself for hot flashes in patients with breast cancer."

Over the past decade, Dr. Loprinzi explained, many medications have been tested for their effect on the frequency and severity of hot flashes. Researchers at the Mayo Clinic and those working through the North Central Cancer Treatment Group (NCCTG) have studied clonidine, megestrol acetate (Megace), vitamin E, a soy phytoestrogen preparation, venlafaxine, fluoxetine (Prozac), and other agents (see Figure).

Hot flashes are measured using the hot flash score, Dr. Loprinzi said: 1 point is assigned for mild hot flashes, 2 for moderate, 3 for severe, and 4 for very severe. For example, if a woman has 10 severe hot flashes and 1 very severe hot flash in a day, the hot flash score is 34.

The basic study design for testing the effects of various agents on hot flashes, Dr. Loprinzi said, is to stratify eligible patients and randomize them to the agent being tested or placebo in a double-blind manner. If the baseline week represents 100% hot flashes, then over a 4-week period of time with a placebo, there is approximately a 20% to 30% reduction in hot flashes. "We have seen this in several studies," Dr. Loprinzi said.

To test the selective serotonin reuptake inhibitor (SSRI) class of antidepressants, Dr. Loprinzi’s group started with venla-faxine (which also inhibits norepinephrine reuptake) at a very low dose. "We used 25 mg/d in our pilot trial, and there was a 50% reduction in hot flashes, compared with the baseline week," he said.

That result led to a placebo-controlled trial through the NCCTG comparing several venlafaxine doses. The treatment arms were placebo, venlafaxine 37.5 mg/d, venlafaxine 37.5 mg/d for 1 week increasing to 75 mg/d for 3 additional weeks, and venlafaxine 37.5 mg/d for 1 week increasing to 75 mg/d for the second week and then to 150 mg/d for the final 2 weeks. The placebo produced a 27% reduction in hot flashes, compared with the baseline week; 37.5 mg/d venlafaxine resulted in a 40% reduction in hot flashes; 75 mg/d venlafaxine produced a 60% reduction; the 150 mg/d dose seemed to be somewhat less effective than the 75 mg/d dose. There were about 50 patients per study arm.

Some alimentary track toxicity was noted, including toxicity, dry mouth, decreased appetite, nausea (the largest problem), and constipation. About 5% to 10% of patients cannot tolerate this medication due to nausea/vomiting, he said.

Fluoxetine Trial

The Mayo Clinic researchers conducted a randomized, double-blind trial of another antidepressant, the SSRI fluoxetine. Patients received 20 mg/d of fluoxetine or placebo. All patients crossed over to the other treatment after 4 weeks.

The result was a statistically significant reduction in hot flashes in the fluoxetine study arm, compared with placebo, thus demonstrating a class effect with the newer antidepressants. The magnitude of the benefit with fluoxetine was not as great as that seen in the venlafaxine trial. However, he said, only one dose of fluoxetine was tested.

Dr. Loprinzi also described a pilottrial of gabapentin (Neurontin), an antiseizure agent, that showed a 50% to 60% reduction in hot flashes. Several other agents have been studied at the Mayo Clinic in phase II trials, he said. Preliminary information indicates that St. John’s Wort did not help. Additional antidepressants, as well as the herb black cohesh, appeared to have produced some benefit.

There are now several therapeutic options in actual clinical practice. "My first approach is to use venlafaxine," Dr. Loprinzi said. "Other antidepressants seem to be effective, but the magnitude of benefit has not yet been as well defined." When using venlafaxine, he said, start with 37.5 mg/d for a week, and if there is not good hot flash control, then increase the dose to 75 mg/d for a week.

If the newer antidepressants don’t work, Dr. Loprinzi said that he then tries gabapentin, and if that doesn’t work, a progestational agent. For example, 40 mg/d of megestrol acetate produces an 80% reduction in hot flashes and is well tolerated. "However," he said, "there is some concern with giving this to breast cancer patients."

Other agents to consider include vitamin E. Dr. Loprinzi explained that "this is a nice alternative because it allows patients to get the placebo effect, and maybe a little more, and it is inexpensive, readily available, and nontoxic." Cloni-dine will work to some degree, he said, but there are problems with side effects. Soy has shown no significant efficacy, and Bellergal (a migraine treatment containing belladonna, ergotamine, and phenobarbital) is an older agent without much effect.

He concluded that the availability of the newer antidepressant agents provides several new options for the nonestrogenic management of hot flashes in cancer survivors.