Treating Depression in Perimenopause

TCPR: Dr. Brizendine, as the director of the UCSF Women’s Mood and Hormone Clinic, you receive many referrals of women who are having difficulty with menopause. What are the typical problems that women have during this period?

Dr. Brizendine: First, it’s important to be clear about some definitions, because many people think of menopause as encom- passing a several-year time span. In actuality, menopause lasts for one single day – the day 12 months after a woman has had her last period. After this, we use the term “postmenopausal.” Perimenopause, which is also termed “the menopausal transition,” refers to the several-year period leading up to menopause and usually begins in the mid 40s. Most of the troubling physical and psychological symptoms occur during perimenopause.

TCPR: Clinically, how do we determine if a woman is in perimenopause?

Dr. Brizendine: The first clue is a change in the menstrual cycle. Early in perimenopause, the menstrual cycle begins to shorten; and later, it lengthens progressively until there are no more periods. Physiologically, the ovaries are becoming progressively less responsive to gonadotrophic hormones such as FSH (follicular stimulating hormone). Estrogen levels go down, and this leads to the menstrual irregularities, as well as a host of perimenopausal symptoms such as hot flashes, night sweats, insomnia, vaginal dryness, and lowered libido.

TCPR: What is the connection between perimenopause and depression?

Dr. Brizendine: A number of studies have suggested that perimenopause is a trigger for depression in some women, even women who have had no prior history of depression at all. Most recently, for example, researchers from Harvard published a study in which they enrolled 460 premenopausal women who had no history ofdepression (Cohen L et al., Arch Gen Psychiatry 2006;63:385-390). These womenwere interviewed by researchers periodically for the next several years, allowing themto ascertain correlations between onset of perimenopause and onset of psychiatricsymptoms.

TCPR: And what did they find?

Dr. Brizendine: They found that women who entered perimenopause during thestudy were twice as likely to develop significant depressive symptoms thanwomen who remained premenopausal. The odds of becoming depressed wereeven higher for women who also reported hot flashes. This study, combined withothers, is pretty strong evidence that perimenopause is a high-risk time fordepression.

TCPR: Is this consistent with your clinical experience?

Dr. Brizendine: Yes. In the UCSF Mood and Hormone Clinic, we see two differenttypes of depressed perimenopausal women: those with no prior history of depression, and those with a depressive history. And we tend to treat these two categories of women differently.

TCPR: In what ways?

Dr. Brizendine: Women who have a perimenopausal worsening of depression do well on antidepressants, which is no surprise. One comment that I will add, however, is that these women tend to be very sensitive to possible sexual side effects of meds, because they are already suffering lowered sex drive due to perimenopause. So we very often start with Wellbutrin (bupropion) rather than SSRIs.

TCPR: Are women at higher risk for perimenopausal depression if they have a history of either PMDD (premenstrual dysphoric disorder) or postpartum depression?

Dr. Brizendine: That’s still very much an open question in the field. While it would make sense that having had one hormonally related mood disorder would predict another, thus far the data have not been clear on this, and it is being intensively researched.

TCPR: What about the women with no prior depression history? How do you treat them in your clinic?

Dr. Brizendine: These women make up about half of those we see in the clinic and we think of their depression as hormonally induced. Up to 50% of women who have a depression during perimenopause will have never had a depression in their life before. Therefore, we believe that hormonal treatments are appropriate, and I usually prescribe the estradiol patch, either with or without antidepressants.

TCPR: But isn’t hormone replacement therapy thought to be quite risky in light of the results from the Women’s Health Initiative study?

Dr. Brizendine: Yes, but it’s important to be clear about what these risks actually are, and to what extent these risks actually apply to a given patient. First of all, the WHI study did not enroll any women in perimenopause at all. Instead, the study followed 16,000 postmenopausal women between the ages of 50 and 79; the average age was 63 at study enrollment. These women were randomized to either Prempro (estrogen + progestin) or placebo, and were followed for an average of about five years before the study was halted in 2002.

TCPR: And why was the study halted?

Dr. Brizendine: Because a preliminary analysis of the data showed that women in the Prempro arm of the study (who were taking both progesterone and estrogen) had increased risks of breast cancer, heart disease, stroke, and pulmonary embolism. But this group actually showed a decreased risk of colon cancer and hip fracture (Rossouw J et al., JAMA 2002;288:321-333). And for those women who were less than five years postmenopausal, this group actually reduced the heart disease risk. It’s also important to note that in another part of the WHI study, women who were assigned to estrogen alone showed a reduced breast cancer risk.

TCPR: Are these results generalizable to the younger perimenopausal women whom we have been discussing?

Dr. Brizendine: We don’t know for sure, but most of us believe that these health risks are much lower when estrogen-only preparations are taken for a relatively short period (less than five years) by younger women. That’s not to say that there is no risk, and before I start any woman on estrogen, I establish that she is not a smoker, that she doesn’t have a personal or family history of breast cancer, and that she has not had a stroke, clotting disorder, or significant heart disease.

TCPR: As a “psychiatrists”, do you feel comfortable starting these women on estrogen yourself, or do you refer them to their OB-GYN for that decision?

Dr. Brizendine: After having worked with this group of women for 15 years along with OB-GYNs at UCSF, I feel comfortable handling the discussion of risks versus benefits, but I do comanage these women with their OB-GYN.

TCPR: Has estrogen been tested specifically for the treatment of depression?

Dr. Brizendine: Yes, one placebo-controlled trial of the estradiol patch for perimenopausal women reported a 68% remission rate of depressive symptoms vs. a 20% remission rate on placebo (Soares C et al., Arch Gen Psychiatry 2001;58:529-534). This was a small trial that enrolled only 50 women, but the results were statistically significant. On the other hand, one controlled trial of the estrogen patch for postmenopausal women showed no effect (Morrison M et al., Biol Psychiatry 2004;55(4):406-12), so I view it as helpful primarily in perimenopause.

TCPR: Is there any particular brand that you favor?

Dr. Brizendine: We usually prescribe the Vivelle-Dot patch (estradiol transdermal system), because it is small and women don’t experience as much skin irritation with it. Vivelle-Dot comes in several strengths, ranging from 0.025 mg to 0.1 mg, and we usually start with the 0.1 mg/day version. Patients change the patch twice a week, and I tell them that we are going to do this for the next 12 to 24 months to try to get a hold of their mood, irritability, and insomnia.

TCPR: And what sort of results do you see?

Dr. Brizendine: We often see improvements in all of the psychiatric symptoms I already mentioned, as well as improvements in hot flashes and vaginal dryness.

TCPR: And why do you prefer to use the patch over oral estrogen?

Dr. Brizendine: Because oral estrogen undergoes first pass metabolism in the liver, and this stimulates the production of sex hormonebindingglobulin(SHBG). SHBG’sfavoritevictimisfreetestosterone,andwithin30daysofgoingonanoralestrogenthe free testosterone level plummets. This, in turn, causes the sex drive to go into the basement. It may take up to six months after stopping oral estrogen for the SHBG level to normalize.

TCPR: Dr. Brizendine, thank you for this whirlwind course in perimenopause, and I also have found your new book, The Female Brain, very helpful clinically.

Dr. Brizendine: It was my pleasure. And if your readers would like more information on some of these issues, they can contact me through my Web site, www.thefemalebrain.com.

General Psychiatry