Clinical Context

Oral contraceptive pills (OCPs) are commonly used by women to prevent pregnancy or to alleviate menstrual symptoms, but 32% to 60% of women discontinue OCP use within 6 months for various reasons, including mood changes. Evidence is conflicting regarding OCP use and concurrent mood changes, which may include better mood, fewer mood swings, worse mood, or no effect.

Although oral contraceptive use in adolescents has been linked to increased risk for subsequent clinical depression, the association of OCP use with concurrent depressive symptoms is still undetermined. The goals of this prospective cohort study were to examine the association between oral contraceptive use and depressive symptoms, the effect of age on this association, and which specific symptoms are associated with oral contraceptive use.

Study Synopsis and Perspective

Use of oral contraceptives is associated with an increased risk for depressive and other psychiatric symptoms in young women, new research shows.

A large prospective cohort study showed that individuals who took OCPs reported experiencing more crying, eating problems, and hypersomnia compared with their counterparts who did not take OCPs.

Such symptoms, the investigators note, can affect quality of life and can lead to nonadherence, potentially resulting in an unwanted pregnancy.

It is important to monitor for depressive symptoms in these teenagers, study investigator Hadine Joffe, MD, executive director, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

"Young women should know that if they have a mood issue when on the pill, it can be addressed so it doesn't interfere with their functioning, with their relationships and their schoolwork, or their ability to take the medicine, if that's the treatment of choice," she added.

Dr Joffe suggested that young, sexually active teenagers need to be made aware of alternatives to oral contraception.

The study was published online October 2 in JAMA Psychiatry.

A Reproductive Right

Many teenagers and young women are sexually active, and their access to birth control is "an important reproductive right," said Dr Joffe.

Discussions about contraceptive choice should include information regarding the risks and benefits of the various options. Benefits of OCPs include period regulation, the control of painful periods, and the prevention of unwanted pregnancy. Potential risks include worsening mood and, although rare in young people, blood clots and increased blood pressure.

Researchers used data on 1010 persons from the Tracking Adolescents' Individual Lives Survey (TRAILS), a Dutch population survey that investigates the psychological, social, and physical development of adolescents.

Study participants were recruited from primary schools. Participants underwent a baseline assessment (mean age, 11 years); follow-up assessments were conducted at median ages of 13, 16, 19, 22, and 25 years. For all follow-up assessments, retention rates were 80% or higher. The study included girls and young women aged 16 to 25 years. On at least 1 occasion during the study period, each participant filled out a form that assessed use of oral contraceptives and depressive symptoms.

Researchers used well-validated instruments to assess depression. For participants aged 16 years, the researchers used the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV)-oriented affective problems scale of the Youth Self-Report, a version of the Child Behavior Checklist.

At ages 19, 22, and 25 years, the investigators used a scale that includes 2 additional items: indecisiveness and feeling unable to succeed.

The researchers conducted all analyses both with and without adjusting for age, socioeconomic status, and ethnicity.

As a whole, OCP use was not associated with higher adjusted mean scores on depressive symptoms (β coefficient, 0.006; 95% confidence interval [CI], −0.013 to 0.025; P=.52).

Age Dependent

However, at age 16 years, girls who used OCPs had higher depressive symptom scores compared with those who did not use OCPs (mean score, 0.40 vs 0.33; β coefficient, 0.075; 95% CI, 0.033-0.120; P<.001).

For participants in this age group, compared with nonuse of OCPs, OCP use was associated with more crying (odds ratio [OR], 1.89; 95% CI, 1.38-2.58; P<.001), eating problems (OR, 1.54; 95% CI, 1.13-2.10; P =.009), and hypersomnia (OR, 1.68; 95% CI, 1.14-2.48; P=.006).

"This study showed that these girls, whose brains are still developing, so they're at a different state than a 22-year-old or 25-year-old, appear to have more of a connection with these mood symptoms than the girls who aren't on the pill," said Dr Joffe.

Anhedonia and sadness, which are symptoms required for the diagnosis of depression, were unaffected. The authors note that in contrast to adult depression, the diagnosis of which focuses more on anhedonia, the emphasis in teenage depression is more on vegetative or physical disturbances, such as loss of energy, as well as changes in weight, appetite, and sleep.

For 16-year-old girls, the association was weakened after adjusting for depressive symptoms before use of OCPs, but the findings remained significant. This suggests that the relationship between OCP use and depressive symptoms could be bidirectional.

"Because of the way the study was designed, we can't determine that the pill caused the depressive symptoms," said Dr Joffe. "But based on the kind of analysis we did, it looks like the relationship goes both ways, that people who had more mood symptoms earlier in their teen years were more likely to be on the pill when they were 16, and vice versa; girls who were on the pill at age 16 were more likely to have mood symptoms."

The authors pointed to a previous study that showed that worsening of mood among individuals using OCPs was more likely in users who had a history of depression.

The use of OCPs affects hormone levels, including levels of androgens and stress hormones. Some women may be particularly sensitive to the hormonal fluctuations in these contraceptives.

As well, important emotion-related regions of the brain, such as the amygdala, the prefrontal cortex, and the hippocampus, are still maturing during adolescence.

"Teens are dealing with lots of issues, which makes them more sensitive to many things they take that affect their body and their brain," said Dr Joffe.

IUDs a Better Choice for Teenagers?

The researchers investigated whether the association between OCP use and depressive symptoms may be explained by preexisting differences.

For instance, 16-year-old OCP users were more sexually active and had more stressful events, as well as more menstruation-related pain and acne, than their counterparts in the nonuser group. Analyses showed that all these factors weakened the association, although none diminished it.

The researchers wondered what role, if any, the "healthy survivor effect" played. Women who experience psychological adverse effects may be more likely to discontinue oral contraceptives, which could lead to an under estimation of the association between OCP use and depressive symptoms.

Comparing only first-time OCP users with nonusers strengthened the association between OCP use and depressive symptoms for the whole cohort (β coefficient for first-time OCP use, 0.021; 95% CI, −0.005 to 0.046; P=.11).

"This means that if you remove the group who took the pill before and maybe went off it because of a side effect, it looks like the pattern was still evident, and the association was even stronger," said Dr Joffe.

Clinicians should be aware that adolescents who use OCPs may have mood problems, the authors note. Teenagers may attribute their depressive symptoms to the contraceptives and stop taking them, which could result in an unwanted pregnancy.

To lower this risk, long-acting reversible contraceptives, such as intrauterine devices (IUDs), are recommended as a first-line option. "We definitely encourage consideration of other means of birth control" in this age group, said Dr Joffe.

An advantage of the IUD is that it can be inserted and left in for many years and "doesn't rely on somebody taking something like a pill consistently and reliably," she said.

The investigators do not recommend limiting OCP use to counterbalance the risk for depressive symptoms. They point out that OCPs have benefits, including beneficial effects on dysmenorrhea and premenstrual syndrome, and are much safer than pregnancy and associated postpartum depression risks.

This new longitudinal analysis does not provide information about specific OCPs. However, the researchers checked which OCPs were used in a comparable cohort of girls born in the same year and whose addresses were of the same postal code as the girls included in this study. They found most of these participants were using the same type of progestin.

It is unclear whether the findings are generalizable to the US population because of the differences in the acceptability of, and access to, contraception. For example, unlike Dutch teenagers, not all US teenagers have access to no-cost contraception, the authors note.

Definite Correlation

Commenting for Medscape Medical News, Maureen Sayres Van Niel, MD, who is president of the American Psychiatric Association Women's Caucus and is a reproductive psychiatrist in Cambridge, Massachusetts, described the study as "important" and "well done."

"This study collected data over a long period of time, which is exactly the kind of data we need," she said.

Scandinavian countries and the Netherlands "are better able to do these kinds of studies than the US because they have every person's medical data on record, beginning at birth and continuing until death," said Dr Van Niel.

Previous "excellent" studies, 1 from Sweden and 1 from Denmark, showed a "definite correlation" between use of hormonal contraceptives and depression and antidepressant use later in life, said Dr Van Niel. She noted that this new analysis is different in that it assessed the occurrence of depressive symptoms while girls were actually taking oral contraceptives.

Dr Van Niel agreed that the new results do not mean that teenage girls should not use OCPs. She noted that the overall incidence of depression in young oral contraceptive users is "still low."

Dr Van Niel said that although sexually active girls need effective contraception, in her experience, "they are less likely to use a nonoral form of contraceptive that older women use, such as the ring or IUD."

Some vulnerable young girls may be predisposed to depressive symptoms and may be particularly sensitive to hormonal fluctuations, said Dr Van Niel. Researchers are working on genetic markers and biomarkers to identify such susceptible individuals, she added.

TRAILS has been financially supported by the Netherlands Organization for Scientific Research NOW, the Dutch Ministry of Justice, the European Science Foundation, the European Research Council, the European Science Foundation, Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL, the Gratama Foundation, the Jan Dekker Foundation, participating universities, and the Accare Center for Child and Adolescent Psychiatry. The authors' relevant financial relationships are listed in the original article. Dr Van Niel has disclosed no such financial relationships.

JAMA Psychiatry. Published online October 2, 2019.^[1]

Clinical Implications

• A cohort study of 1010 adolescents followed up for 9 years showed that 16-year-old OCP users had higher concurrent depressive symptom scores than nonusers, especially for crying, eating problems, and hypersomnia.
• Clinicians should monitor adolescent OCP users for depressive symptoms, as these may affect their quality of life and put them at risk for nonadherence.
• Implications for the Healthcare Team: Long-acting reversible contraceptives such as IUDs are recommended as a first-line option to reduce the risk for unintended conception, but these are used by only a minority of adolescents in the Netherlands and United States. Clinicians should have honest conversations with adolescents and encourage consideration of other means of birth control as needed if IUDs are not indicated.

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