Women taking hormonal contraceptives may be at increased risk of depression, especially from skin patches, a study has found.
Data from more than a million women in Denmark showed that those on the most popular type of Pill were 23% more likely to be prescribed an antidepressant than non-users.
Contraceptive patches delivering a synthetic version of the hormone progesterone through the skin doubled the risk, while the ring and coil raised it by 60% and 40% respectively.
Teenagers on the Pill appeared to be more vulnerable than older women.
Scientists suspect a link with progesterone, which has been shown to have a negative effect on mood during the menstrual cycle.
The Danish researchers, led by Dr Ojvind Lidegaard, from the University of Copenhagen, wrote in the journal Jama Psychiatry: "Further studies are warranted to examine depression as a potential adverse effect of hormonal contraceptive use."
Further studies are warranted to examine depression as a potential adverse effect of hormonal contraceptive use.
One British expert said the study raised "important questions" while another urged women not to be alarmed by the findings.
In 2000, nearly four million women in the UK were on the Pill according to the Family Planning Association (FPA) sexual health charity.
For the study, researchers analysed data from national registries in Denmark that included more than a million teenage girls and adult women aged 15 to 34.
Over an average period of six years, participants taking combined oral contraceptives containing a mixture of hormones were shown to be 23% more likely than non-users to be treated with antidepressants for the first time.
Users of progestin-only pills which rely on synthetic progesterone had a 34% increased risk. Women using contraceptive patches, also containing progestin, were twice as much at risk.
For teenagers aged 15 to 19, use of the combined Pill led to an 80% greater chance of being prescribed antidepressants.
The relative risks of having a diagnosis of depression mirrored those for being treated for the condition.
Dr Channa Jayasena, from the Society for Endocrinology and Imperial College London, said: "This study raises important questions about the Pill. In over a million Danish women, depression was associated with contraceptive Pill use.
"The study does not prove (and does not claim) that the Pill plays any role in the development of depression. However, we know hormones play a hugely important role in regulating human behaviour.
The study does not prove (and does not claim) that the Pill plays any role in the development of depression.
"Given the enormous size of this study, further work is needed to see if these results can be repeated in other populations, and to determine possible biological mechanisms which might underlie any possible link between the Pill and depression.
"Until then, women should not be deterred from taking the Pill."
Dr Ali Kubba, from the Royal College of Obstetricians and Gynaecologists, pointed out that despite known evidence that hormonal contraception can affect women's moods, the study did not demonstrate causation.
He added: "Women should not be alarmed by this study as all women react differently to different methods of contraception.
"There are a variety of contraception methods on offer including the Pill, implants, injections, intrauterine devices, and vaginal rings and we therefore advise women to discuss their options with a doctor, where they will discuss the possible side-effects and decisions around the most suitable method can be made jointly."
The study authors said both progesterone and its female sex hormone partner oestrogen were suspected of playing a role in depression.
Progesterone break down chemicals, or metabolites, have been shown to affect an important inhibitory system in the central nervous system.
Levels of the metabolites also increased after ovulation during the menstrual cycle and some women experienced negative moods at this time.
The findings supported the theory that progesterone might be linked to depression because "progestin dominates combined and progestin-only contraceptives", researchers said.
They added: "The high risk among women using the transdermal patch and vaginal ring compared with the corresponding Pill is probably a question of dose rather than the route of administration."
FPA chief executive Natika Halil said: "We welcome new research which can give us more understanding about contraception - ultimately, the more we know about different methods and what their effects may be, the more informed women are when it comes to making choices.
"We know many women are using hormonal contraception without problems, and we wouldn't want to see women worried by this study to suddenly stop using their hormonal method, as this will leave them at risk of unplanned pregnancy."