Contraceptives, Hormones, and… Depression?

For many years, researchers have been trying to clarify the association between estrogen, progesterone, and depression. We know that women are twice as likely as men to become depressed (likely due to hormones). We know that changes in the level of estradiol (a type of estrogen) are associated with depression. Furthermore, fluctuating hormones in the days before menstruation are believed to be the cause of premenstrual syndrome (PMS) and can even cause its angrier sister, premenstrual dysphoric disorder (PMDD).

Combined oral contraceptives include synthetic forms of both progesterone and estrogen. These hormones (given in specific doses and at certain times during a woman’s cycle) inhibit ovulation and prevent pregnancy. Interestingly, external progestins (more than endogenous progestins) seem to increase levels of monoamine oxidase, leading to more serotonin breakdown. Degrading more serotonin may lead to depression and irritability. [If you’ll remember from this article, one of the major classes of antidepressants blocks monoamine oxidase. External progestins seem to do the opposite.] 1

Looking back, I remember many of my friends taking birth control in college for the first time. Incidentally, many of these same friends also began to take antidepressants for mood changes or anxiety. After I started my first hormonal contraceptive, I too felt uncontrollably moody. I have always been prone to ups and downs, but certain types of contraceptives have made me feel as though I cannot regulate my feelings.

On to the data. Similar to the research on statins and SSRIs, Denmark has published another large study examining the rates of depression in women who use hormonal contraception. Over 1 million women from ages 15-34 were observed for 14 years. Women who had used antidepressants or who had been diagnosed with depression prior to study initiation were excluded. Both the first diagnosis of depression and the initiation of an antidepressant after starting hormonal contraceptives were tracked and were used to estimate the increased risk of depression with hormonal contraceptives.

The relative risks (RR) of first-use of antidepressants for users of hormonal contraceptives versus women not taking hormonal contraceptives are outlined below.

Combined oral contraceptives 1.2
Progestin-only pills 1.3
Vaginal ring (Nuva Ring) 1.6
Implant (Implanon) 2.1
Levonorgestrel IUD (Mirena) 1.4
Medroxyprogesterone depot (Depot-Provera) 2.7

RR can be understood as the number of “times” more likely you are to experience an effect. For example, an RR of 1.2 means that users of combined oral contraceptives are 20% more likely to use an antidepressant for the first time than women not taking combined oral contraceptives.

Clearly the use of hormonal contraceptives was associated with antidepressant use and also a diagnosis of depression. Interestingly, the relative risk decreased with age (i.e. adolescents had significantly higher relative risks: up to an RR of 3.2 for adolescent users of Mirena). For both age groups, the RR peaked at 6 months of hormonal contraceptive use.

This article should be taken with a grain of salt. Hormonal contraceptives play an incredibly important role in many women’s lives and have provided an independence that wasn’t present before. Women have more control over their health than ever and birth control plays a large role in this gain. Regardless, it is important to be aware of the possible side effects and to make informed decisions about your health care [and to seek help should you need it].


In Pop Culture: Is your birth controlling depressing the hell out of you?


  1. External Progestins and MAO
  2. Association of Hormonal Contraception with Depression 


Inflammation, Depression, and … Statins?

There are multiple theories regarding the pathophysiology of depression. The most common (and the one you’ve probably heard about) is the monoamine hypothesis. This theory posits that depression is an imbalance (or depletion) of certain key neurotransmitters in the brain. The imbalance of these key neurotransmitters, namely dopamine, serotonin, and norepinephrine, is believed to cause depression. As such, most common antidepressants fit into classes that limit the uptake and/or breakdown of serotonin (SSRIs), serotonin and norepinephrine (SNRIs and TCAs), or serotonin, norepinephrine, and dopamine (MAOIs).

Today, we’re interested in a different hypothesis involving inflammatory proteins called cytokines. Cytokines are increased within our body when we are having an immune response and with inflammation in general. In patients with depression, certain cytokines have been found to be elevated before treatment (associated with a pro-inflammatory state) and decreased after treatment 1. This implies that cytokines and other inflammatory molecules may cause a pro-inflammatory state that causes our brain to be “inflamed,” thus causing depression. If there were a way to decrease inflammation in our body, perhaps depressive symptoms would improve as well.

On to statins. Statins (think Lipitor, Crestor) are commonly prescribed to treat high cholesterol. Incidentally, they are also believed to have anti-inflammatory properties. This is believed to be the reason why statins decrease the risk for stroke and heart attack independent of their cholesterol lowering effect.

A recent study in Denmark followed 872,216 SSRI users (of whom 113,108 (13.0%) used a statin concomitantly) over the course of 15 years 2. It found that patients who took SSRIs while on a statin had fewer depression-related hospital visits and depression-related hospitalizations. As such, the article concluded that “concomitant treatment with SSRIs and statins resulted in robust advantages compared with SSRIs alone.”

So does this prove the cytokine hypothesis of depression? Should you be taking a statin if you’re depressed? Not quite. Statins are not benign drugs, and the evidence isn’t there yet to recommend augmenting antidepressant treatment with a statin. Regardless, this study represents one more step in the right direction. Here’s to eventually finding a cure (and a satisfying explanation) for the millions of people worldwide who are afflicted with depression.

  1. Cytokines and Depression
  2. Statins and Depression