A study linking data from a collection of nationwide Danish population and health registries has found menopausal women prescribed oral hormone therapy were more likely to receive a hospital diagnosis of depression soon afterward. The researchers reported the risk was highest in women aged 45 to 50 years and in the first years after starting hormone therapy, but the association declined gradually with time. However, international experts outside the study are speaking up about the limitations of population studies like this – which cast into stark relief how little is known about menopause and depression – especially when hormone therapies can be incredibly effective for some women experiencing perimenopausal depression. "Many women begin taking hormone therapy precisely because of negative changes in their mood – which fits with the report that the incidence of depression was greatest after initiation and then gradually declined," says neuroscientist Ciara McCabe of the University of Reading. With this kind of study, it's just not possible to separate out mood changes related to depression from any changes associated with medication, nor look at what precipitated the use of hormone therapy. "This is not a randomized controlled trial. It isn't possible to tell whether the factors that drive the decision to start hormone therapy are connected to the outcomes of interest here," says Matt Sydes of the UK Medical Research Council Clinical Trial Unit in London. Psychiatrist Jayashri Kulkarni of Monash University in Australia, an expert in perimenopausal depression, shares the concern that large population studies such as these "can be misinterpreted by women and their clinicians, leading to potentially worse outcomes for women already struggling with menopausal depression and needing hormone treatment." Dramatic reductions in hormonal prescriptions in response to confusion over women's health studies has happened before, such as in the early 2000s. "So many women have suffered as a result," Kulkarni told ScienceAlert. Being a retrospective observational study, there is an awful lot the Danish dataset does not capture – which serves as a good reminder of the limitations of these kinds of epidemiology studies, so let's take a look. Kulkani says the study lumps all estrogen hormone therapies together, when, for example, some forms of estrogen designed to treat menopausal hot flushes don't reach the brain and so would have little effect on mood. Changing levels of hormones in the brain affect mood, and menopause hormone medications – containing synthetic versions of sex hormones, estrogen, and progesterone, either alone or in combination – work to stabilize those fluctuations. The study also only had data on hospitalized cases of depression, and without capturing the granular details of the depression women experienced and their personal history, it says nothing about other factors affecting their mental health. "It does not consider the very important nuances of the diagnosis of depression … nor does it consider the large variation in the forms of hormone treatments or the frequent fluctuations in mental health due to menopause," Kulkarni told ScienceAlert. As Kalkani highlighted to ScienceAlert, the diagnosis of depression has changed substantially in the two decades the study covers, from 1995 to 2017. And many new menopause hormone medications have been and continue to be developed, she says. Depression is also a spectrum condition, one that comes in many forms, is related to individual life events and responds differently to treatment. "Women have a whole range of differences in what symptoms they get, what happens [after their diagnosis] and what the causalities are. In many women, trauma is the biggest factor that creates depression." Put simply, Kulkarni says these types of retrospective studies probing decades-old data are not the type of research that's needed to move the field forward. It's clinical trials that carefully diagnose depression and follow women through treatment, specifying the type, timing, and dose, and neuroscience studies looking at how hormones affect the brain that will help better our understanding of menopausal depression and the most effective treatments for women, Kulkani explains. "Research in this area is desperately needed – but what is really needed is a big, prospective detailed clinical trial," comparing hormone therapies to standard antidepressants. And that's the larger issue here at risk of being overlooked: Women's health in general, but especially menopause, is terribly understudied. The vast majority of people with depression also aren't getting the bare minimum of treatment they need. As Kulkarni writes in the recent Nature Outlook perspective, obtaining a diagnosis of depression can be particularly difficult for women, not least because depression in women is so misunderstood. This is a reflection of systemic sexism that pervades biomedical research and which in turn affects the care women receive, she says. "Many health-care professionals do not recognize menopause as the underlying causal factor in women with mid-life depression, and so do not prescribe hormone therapy," writes Kulkarni. "A big part of clinicians' reluctance to prescribe [hormone therapy] for menopausal depression is the lack of knowledge about menopause – particularly how it affects the brain." For some women, trans men, and non-binary people, menopause could be the first time they are diagnosed with depression. Others with a past history of depression may face a resurgence of depressive symptoms during menopause. Either way, the incidence of depression peaks in the years around menopause. Suicide rates, too. But perimenopause depression is often diagnosed years later, if at all. Complicating matters is the fact that psychological symptoms such as mood changes can precede physical symptoms of menopause by up to five years. Clearly, far more research is needed to delve into the complexities of menopause and depression – and much more funding is needed to make that research a reality.
