Antidepressants to treat menopausal hot flashes

One of the most debilitating aspects of menopause for women is severe hot flashes which often cause high levels of insomnia, discomfort and contribute to depression overall.  The mainstay of treatment has always been hormone replacement in the form of estrogen.  However estrogen can increase some types of cancers  so many women and doctors alike are reluctant to use them.  Using antidepressants to treat hot flashes has been looked into off and on over the years in a variety of smaller studies but no clear guidelines have emerged that are based on Grade 1 level evidence.

Although still unclear how antidepressants work in general, including for depression, it may be even more a mystery why they work in menopausal hot-flashes.  While the mechanism is not clear, only the serotonergic antidepressants appear to have efficacy compared to medications like Wellbutrin which have a unique mechanism that does not utilize serotonergic pathways.

Another finding without a clear reason, is that seemingly lower doses (suboptimal doses if treating depression) are much more effective than higher doses of antidepressant. Higher doses actually not uncommonly cause sweating and thermoregulatory problems causing heat retention and pseud0 hot flashes via a non-estrogenic mechanism.

We already know that 5-HT2A and to a lesser degree 5-HT2C serotonergic receptors are involved in the regulation of the hypothalamic thermoregulatory heat-loss circuitry.  This circuitry regulates our core body temperature, how fast or slow our body compensates to properly dissipate heat, and monitors this heat loss to adjust our temperature. Estrogen activates these receptors whereas loss of estrogen causes a deficiency of activity at these receptors.

It is likely than that the serotonergic antidepressants are effective in large part due to their ability to strongly modulate serotonin 5ht2A and C receptors in the hypothalamus.  5-HT2 receptors appear to be more sensitive than other receptors in the same vicinity and therefore low-doses off an antidepressant most likely activates the necessary 5-HT2 receptors to regulate our body temperature without activating other nearby receptors. At higher doses however, the relative number of 5-HT2 receptors activated become outnumbered by the activation of several other receptors now active with more serotonin available. These other receptors can have a dominant action to accelerate heat production and worsen the feeling of hot-flashes.

While the exact mechanism is unclear, it would be consistent with how other medications effect our thermoregulation. Antipsychotics for example such as abilify, Seroquel, Risperdal or Geodon for example are potent 5-ht2A antagonists and are known to cause potent heat retention and loss of thermoregulation leading to elevated body temperatures.

Although antidepressants carry their own risk of side-effects, they generally are extremely tolerable at low doses such as Prozac 2.5-5mg, Lexapro 2.5mg, Celexa 5mg, Effexor 25-50mg and offer an alternative to estrogen for women who either want to avoid the increased risk of cancer or for women who already have had breast cancer and cannot be on estrogen.

Michael Yasinski MD