Hormonal contraception use among teenagers linked to depression
BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i5289 (Published 29 September 2016) Cite this as: BMJ 2016;354:i5289
All rapid responses
Millions of women worldwide use hormonal contraception (HC) and it is recognised that some women report that they experience mood changes associated with HC (1) . But is there an increased frequency (or risk) of depression among women using HC compared to non-users? If so, would this imply a causal link between HC and depression? Would it then be reasonable to expect that stopping contraceptive use would reverse the symptoms in many women who suffer from depression?
Based on data collected from a large registry-based cohort study of more than one million women in Denmark, Skovlund et al (1) assessed the influence of HC on the risk of subsequent use of antidepressants and subsequent diagnosis of depression at a psychiatric hospital. They found that women who used combined oral contraceptives had a risk of first use of antidepressants that was increased by 23% compared with non-users (adjusted RR = 1.23, 95% CI 1.22 – 1.25), independent of age, calendar year, educational level, history of polycystic syndrome and endometrioses. A “slightly lower” increase by 10% in the risk of a first confirmed diagnosis of depression was found for women on combined oral contraceptives compared to non-users (adjusted RR = 1.10, 95% CI 1.08 – 1.31). In adolescents, the relative risk increases were even more dramatic: HC was associated with an increase in the risk of antidepressant use of 80% (adjusted RR = 1.8, 95% CI 1.75 – 1.84) and an increase by 70% in the risk of having a confirmed diagnosis of depression (adjusted RR = 1.7, 95% CI 1.63 –1.81). The authors implied a causal link by stating in their abstract that these findings are “suggesting depression as a potential adverse effect of HC use”.
Within few days following its publication in JAMA Psychiatry, the study grabbed much attention in the media and alarming headlines made it in the news , such as “If you take hormonal contraceptives, you need to know about this new study” (Business Insider UK, 11/10/2016) or “The pill: From sexual revolution to cancer and depression links (The Independent, 2/11/2016)” or even “‘It’s not in your head’: Striking new study links birth control to depression” (The Washington Post, 5/10/2016)”. The study also attracted the attention of the British Medical Journal (2), but readers’ rapid responses were conflicting. One gynaecologist wrote that “it is not new news that HC can cause depression” and then referred to findings of studies performed in the 1960s that “have mostly been ignored for 50 years” (3). Another gynaecologist prudently noted that the Skovlund et al findings may show over-prescription of antidepressants in Denmark and cause concern that local psychiatrists may be overlooking indications for these drugs (4). The Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists issued a rapid statement to acknowledge that the Skovlund et al study only “adds to the existing conflicting evidence regarding a potential association between HC and depression, but does not demonstrate any causal association” (5). The latter was because the study was “an observational study and not a randomised controlled trial and other significant confounding factors cannot be excluded” (5).
Intricate issues in study design are of major importance in making causal inferences, but these were not the reason why the Skovlund et al study has caught our attention. What seems to have fuelled our interest in this study is that it reported that HC is associated with an increase in the risk of first use of antidepressants by 23%, which rises to 80% for adolescents. And this sounds terrifyingly high.
However, the 23% (or the 80%) is a relative risk increase and does not help us assess the actual risk of someone on HC subsequently using antidepressants - because it doesn’t tell us how many women would be using antidepressants anyway. Looking at the raw data reported in Skovlund et al (1), the actual baseline risk of subsequent use of antidepressants was 1.66 cases per 100 women per year for those not using HC, which increased to 2.11 cases per 100 women per year for users of any oral HC. This corresponds to an impressive relative risk increase of 27% (that reduces to 23% after accounting for the effect of factors other than HC). But the absolute risk increase is only 0.45 cases per 100 women per year, i.e. an ultimately unimpressive risk of 0.45% in a year. Even more unimpressive is the absolute risk increase for a confirmed diagnosis of depression: 0.04%.
The Royal College of Obstetricians & Gynaecologists recommended that women should be informed by their contraceptive provider that there is no clear evidence that HC causes depression (5). However, an honest doctor would simply have to tell her patient that, on average, only 1 in 221 women exposed to HC over a year is likely to subsequently be prescribed an antidepressant because of HC (number needed to harm [NNH] is 1/0.045 = 221), and only 1 in 2,441 women is likely to be diagnosed with depression at a psychiatric hospital (NNH is 1/0.0004 = 2441). For adolescents, the NNH is 1 in 92 for use of antidepressants and 1 in 556 for depression diagnosis (Table).
Do any of these absolute risk increases counterweight the benefits from birth control?
References:
1. Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of Hormonal Contraception With Depression. JAMA Psychiatry 2016;73(11):1154-1162. doi:10.1001/jamapsychiatry.2016.2387.
2. Wise J. Hormonal contraception use among teenagers linked to depression. Bmj [Internet]. 2016;5289(September):i5289. Available from: http://www.bmj.com/lookup/doi/10.1136/bmj.i5289
3. Grant EC. Increased MAO activity with progestogens. Bmj [Internet]. 2016;5289(September):i5289. Available from: http://www.bmj.com/content/354/bmj.i5289/rr-0
4. Saripanidis S. Questionable conclusions in this study [Internet]. Bmj. 2016. p. i5289. Available from: http://www.bmj.com/content/354/bmj.i5289/rr
5. Clinical Effectiveness Unit Royal College of Obstetricians & Gynaecologists. Association of Hormonal Contraception With Depression [Internet]. 2016. Available from: https://www.fsrh.org/documents/ceu-response-to-published-study-associati...
Competing interests: No competing interests
It is not new news that hormonal contraceptives can cause depression.1,2
We discovered in the 1960s that depressive mood changes and loss of libido affected 10% to 44% of women taking oral contraceptives (OCs) in the London trial.3,4 The incidence of depression increased as progestin doses increased and oestrogen doses decreased. Also endometrial glandular mono amine oxidase (MAO) activity increased with increasing progestogen potency. Normally, MAO activity increases in the endometrium, platelets, and, brain, for a few days only during the short premenstrual phase increasing the risk of premenstrual tension.5 MAO inhibitor drugs have long been used as antidepressants.
Oestrogen doses were lowered and often omitted to lower the risk of thrombosis but newer progestins became even more powerful increasing the incidence of depression and weight gain. In the UK, NHS data reveals that 26% of young women aged 16 to 24 are now suffering from mental health problems compared with 9.1% of young men.6
The highest risk rates for antidepressant use are in adolescent girls, aged 15 to 19 years, who had 1.8 times higher risk of first use of an antidepressant using combined oral contraceptives and 2.2 times higher risk with progestin only pills. A three times higher risk was seen in adolescent girls using non-oral products,2
Our very important discoveries have mostly been ignored for 50 years. Suicides, accidents or violence became the commonest causes of death in current users of hormonal contraception..7
1 Jacqui Wise. Hormonal contraception use among teenagers linked to depression. BMJ 2016;354:i5289.
2 Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Sep 28. doi: 10.1001/jamapsychiatry.2016.2387
3 Grant ECG, Mears E. Mental effects of oral contraceptives. Lancet 1967;1:945-46
4 Grant ECG, Pryce Davies J. Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases. BMJ 1968;3:777-80.
5 Robinson DS, Davies JM, Nies A, Ravaris CL, Sylwester D. Relation of Sex and Aging to Monoamine Oxidase Activity of Human Brain, Plasma, and Platelets. Arch Gen Psychiatry 1971;24(6):536-539.
6 Digital NHS. Mental health and wellbeing in England: Adult psychiatric morbidity survey 2014. September 2016. http://content.digital.nhs.uk/searchcatalogue?productid=21938&topics=0%2....
7 Beral V, Hermon C, Kay C, et al. Mortality in relation to method of follow-up in the Royal College of General Practitioners’ Oral Contraception Study. In: Hannaford PC, Webb AMC, eds. Evidence guided Prescribing of the Pill. New York: Parthenon Publishing, 1996.
Competing interests: No competing interests
SSRIs should be administered only in severe cases of depression, according to NICE guidance and International clinical guidelines. [1][2]
133,178 out of the 1,061,997 young women in Denmark followed were prescribed antidepressant medications, 12.54%.
This percentage of adolescent girls and young women suffering from a depression so severe that antidepressant drugs are needed, seems elevated.
Were other effective methods of treatment, like CBT, CCBT, Behavioural Activation, even tried before resulting in prescription pharmacotherapy?
If not, we must conclude that the study design is flawed, because local Psychiatrists prescribe too many antidepressants to young women and girls, overlooking indications.
In addition, if such causation was suspected, stopping contraceptive use would reverse depression symptoms, without the need to proceed in specific antidepressant medications.
Were contraceptives discontinued before initiating antidepressant drugs?
Furthermore, responsible women on antidepressant pharmacotherapy should postpone pregnancies, using various contraceptives, to avoid congenital malformations and other adverse neonatal outcomes. [3][4][5][6][7][8][9][10]
References
[1] CCBT is considered a low-intensity psychosocial intervention, which should be the first-line therapy for people with mild depression (NICE, 2009)
[2] http://www.bmj.com/content/344/bmj.e4211 Reserve antidepressants for cases of severe depression, Dutch doctors are told
[3] http://www.bmj.com/content/339/bmj.b3569 Selective serotonin reuptake inhibitors in pregnancy and congenital malformations
[4] http://www.bmj.com/content/344/bmj.d8012 Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn
[5] http://www.bmj.com/content/350/bmj.h1798 Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects
[6] http://www.bmj.com/content/346/bmj.f2059 Maternal antidepressant use during pregnancy, and risk of autism spectrum disorders
[7] https://www.ncbi.nlm.nih.gov/pubmed/27239775 SSRI use during pregnancy and risk of preterm birth
[8] https://www.ncbi.nlm.nih.gov/pubmed/27193296 SSRIs during pregnancy linked to cardiovascular birth defects
[9] https://www.ncbi.nlm.nih.gov/pubmed/27138915 Exposure to SSRIs in pregnancy has been associated with miscarriage, premature delivery, neonatal complications, birth defects-specifically cardiac defects, neurodevelopmental disorders in childhood
[10] https://www.ncbi.nlm.nih.gov/pubmed/26148560 Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies
Competing interests: No competing interests
Reply to Evangelos I Kritsotakis
Thanks to Evangelos I. Kritsotakis for giving us the opportunity to clarify the absolute risk of developing depression with use of hormonal contraception.
First, all the one million included women were free of previous mental disease when they entered the study, implying a lower “baseline risk of depression” than seen in a random sample of young women.
Women 15-34-years old
The absolute risk of getting a first prescription of antidepressants among all women 15-34 years old without use of any antidepressants was 1.66% per year or 8.3% per five years, which was the mean duration of use of hormonal contraception in our study
If these women used combined oral contraceptives, their absolute risk was 2.11% per year. If 100 women thus use combined oral contraceptives for five years, their absolute risk of getting a first prescription of antidepressants is 10.5%. Thus, after 5 years of combined oral contraceptive use the absolute risk increase due to hormonal contraception is 2.2 per 100 women.
The corresponding figures for a first depression diagnosis treated in a psychiatric unit was 0,31% per year among non-users and 0,35% per year in users of combined oral contraceptives, and in five years 1.55% and 1.75%, respectively.
Women 15-19-years old
The absolute risk of getting a first prescription of antidepressants in non-users was 0,94% per year and among users of oral combined pills 2.03% per year, and in five years 4.7% and 10.1.%, respectively. Thus 5.4 additional women out of 100 women using the pill for five years from 15 to 19 years of age, have a first prescription of antidepressants due this use.
For depression diagnosis the figures are 0.23% per year in non-users and 0.4% per year in users of oral contraceptives. The figures for five-year use thus 1.1% in non-users and 2.0% in users of combined pills. The absolute increase thus 0.9 per 100.
The reference population
In our main analysis, the reference population was non-users of hormonal contraception which includes those former users of hormonal contraception who after year 2000 stopped their use due to adverse effects including depression. Many of these women continue their antidepressant use, making the use of antidepressants higher than among never-users. If current uses are compared to never-users, the relative risk of a first prescription of antidepressants increased from 1.2 to 1.7. That will not change the absolute risk among users of hormonal contraception, but suggests that the absolute risk increases with 70% in current users as compared to never-users of hormonal contraception.
Is this a clinically significant risk?
There is no doubt that hormonal birth control has several benefits. This is not an argument for downplaying potential side effects of this medication, however. Serious adverse events affecting 1 to 10% are generally considered as clinically significant. The decision of whether to use hormonal contraceptives or an alternative non-hormonal contraception should be based on information about both benefits and risks. The final decision has to be taken by each woman after appropriate information by her doctor.
Competing interests: Øjvind Lidegaard has within the last three years received honoraria for talks on pharmaco-epidemiological issues. Lars Vedel Kessing has been a consultant for Lundbeck and AstraZeneca and has received honoraria for this work. Charlotte Wessel Skovlund and Lina Steinrud Mørch have no conflicts of interests to declare.