Depression and ‘the pill’: untangling the evidence

Use of the contraceptive pill in England is on the decline. NHS data published in June 2023 show that community pharmacies dispensed 7.2 million items of progestogen-only contraceptives and combined hormonal contraceptives in 2022/2023, a significant jump down from the 8.5 million dispensed in 2014/2015.

In that time, studies have raised concerns about the connection between ‘the pill’ and an increased risk of mood disorders. The potential link recently caught the wider public’s attention, with nearly 400,000 people tuning in to a Channel 4 documentary in June 2023 fronted by TV presenter Davina McCall, calling for further research in this area.

However, clinical guidelines maintain that there is no clear evidence linking the pill with depression in particular, creating a contradictory evidence base for its possible side effects.

Here, we examine the evidence for and against, to assess whether the pill is contributing to mood disorders in women or if other factors are at play. 

The case for:

One of the most recent — and largest — studies to look at the link between oral contraception and depression was led by researchers at Uppsala University in Sweden. The research, published in June 2023, used UK Biobank data from 264,557 women from birth to menopause, of whom 81% had taken combined contraception containing progestogen and oestrogen at some point in their lives. 

Results showed that the first two years of oral contraception use were associated with a 71% higher risk of developing depression compared with people who had never used oral contraception. 

Adolescents at greater risk 

The Swedish study also found that women who began to use contraceptive pills as teenagers had a 130% higher incidence of symptoms of depression.

“The powerful influence of contraceptive pills on teenagers can be ascribed to the hormonal changes caused by puberty,” says Therese Johansson, a PhD student at the Department of Immunology, Genetics and Pathology at Uppsala University, who co-led the study.

“As women in that age group have already experienced substantial hormonal changes, they can be more receptive not only to hormonal changes but also to other life experiences.”

Sofia Zettermark, a primary care physician who is currently completing a PhD in the oral contraceptive pill and women’s health at the Lund University in Sweden, agrees that there is a possible “biochemical rationale” for the increased susceptibility of adolescents.  

Zettermark’s research, published in 2018, examined the association between taking hormonal contraceptives as well as psychiatric medication. The study — which included people taking combined oral contraceptives, progesterone-only contraceptives and non-oral hormonal contraceptives, such as intravaginal rings — found adolescent girls using a hormonal contraceptive were more likely than adult women to subsequently need medication for low mood or anxiety. 

The study also revealed a stronger association between progesterone-only contraception and psychotropic drug use than with combined methods, regardless of how the contraception is administered.

Overall, the study suggested “an adverse effect of [hormonal contraception] on psychological health in this population”, having followed on from a 2016 Danish study, which also found “depression as a potential adverse effect of hormonal contraceptive use” among adolescents.  

Mitigating factors 

However, Zettermark says the association between depression and hormonal contraceptives in adolescents could owe to selective discontinuation, which is where older women are more likely to stop taking the pill earlier if they experience negative side effects. “Maybe the effect would be as real in adult women if they were new starters,” she says. 

Johansson’s study attempted to address this by distinguishing between new and current users. It found that women aged over 20 years were at a 92% increased risk of developing depression after starting the pill; less than adolescents but a clear association. 

The case against: 

The research produced by Zettermark, Johansson and others not only contrasts with several other studies and reviews that find no association between oral contraceptives and depression, but also with national guidance in the UK.

The Faculty of Sexual and Reproductive Healthcare (FSRH) produces National Institute for Health and Care Excellence-accredited clinical guidelines on contraception, as well as the UK Medical Eligibility Criteria for Contraceptive Use. Its guidance is clear that “the available evidence does not establish a causal relationship between [progestogen-only pill] use and depression”, nor is there “clear, consistent evidence that [combined hormonal contraception] use causes depression”. 

The evidence it cites includes a 2018 systematic review of 26 studies, which concluded that, “despite perceptions in the community of increased depression following the initiation of progestin contraceptives, the preponderance of evidence does not support an association.”

A more recent study, published in the British Journal of Obstetrics and Gynaecology in 2021, used Swedish register information on 739,585 women aged 15–25 years and found that those “on combined oral contraceptives and oral progestogen-only products had lower or no increased risk of depression”.

The FSRH concludes that current or previous depressive episodes do not contraindicate use of the contraceptive pill and instead advises healthcare professionals to “ensure an individualised approach to managing signs and symptoms of depression and explore other possible contributing factors whilst considering offering alternative contraception”.

“It is important to acknowledge that some individuals report mood change during use of hormonal contraception whether the hormonal contraception is the cause of these changes or not,” the guidelines say.

Limits of methodology 

The association between the pill and mental illness is “not something that has been shown to be a general effect,” acknowledges Zettermark, suggesting that one challenge may be study design. Most research in this field uses an observational design that can only find possible associations between contraceptive use and depression, rather than any causal relationships. 

Zettermark says that there are few randomised controlled trials on oral contraceptives, “which is often explained by ethical issues [as] giving placebo contraceptives is difficult” to justify.

Additionally, depression can be hard to measure using standardised scales. Zettermark says that some of the women she has studied would describe side effects such as being closer to tears than usual or “one women said she was robbed of several years of laughter”. 

“These women were not depressed but there was still an effect on their mental health that is relevant to [their] quality of life,” she says.

In contrast, “there is good research about cancer and blood clots”, Zettermark says, as scientific studies are able to capture “hard endpoints”, such as hospitalisation rates.

Our verdict

Despite the conclusions drawn by national guidelines and the limitations to research methodology in this area, more than three quarters (77%) of 4,000 women reported side effects from the pill when asked as part of a Channel 4 survey commissioned for McCall’s documentary. Some 57% said they were concerned about its impact on their mental health.

However, it is clear that more research is needed to reach a definitive conclusion and enable healthcare professionals to make more informed decisions when prescribing contraceptive pills. 

Johansson says that her study of UK Biobank data does not offer conclusions “about other contraceptive options, such as mini pills, contraceptive patches, hormonal spirals, vaginal rings or contraceptive rods”. 

“In a future study, we plan to examine different formulations and methods of administration,” she says. “Our ambition in comparing different contraceptive methods is to give women even more information to help them take well-informed decisions about their contraceptive options.”

But more funding is essential. “Women’s reproductive healthcare simply doesn’t receive adequate funding and prioritisation,” says Janet Barter, president of the FSRH. 

Without it, we are still in the dark on the true side effects of what she describes as “the medical intervention with the biggest impact on a woman throughout their life”.