title: Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle-A double-blind, placebo-controlled randomized trial.
abstract: Ever since the introduction of combined oral contraception (COC), one of the major reasons for discontinuing the pill use has been mood-related side effects. Moreover, women who discontinue the pill turn to less effective methods whereby the probability of an unintended conception increases. Approximately 4-10% of COC users complain of depressed mood, irritability or increased anxiety, but drug-related causality has been difficult to prove. Given the lack of randomized controlled trials in this area, we aimed to prospectively estimate the severity of adverse mood in COC users that would be as representative of general users as possible.
  
  
  
  This investigator-initiated, multi-center, randomized, double-blinded, placebo-controlled study included 202 healthy women. Women were randomized to a COC (1.5mg estradiol and 2.5mg nomegestrolacetate) or placebo for three treatment cycles. Main outcome measure was the Daily Record of Severity of Problems (DRSP), which was filled out daily during one baseline cycle and the final treatment cycle.
  
  
  
  Results from 84 women in the COC group and 94 women in the placebo group were analysed. COC use was associated with small, but statistically significant, increases in mean anxiety (0.22; 95% CI: 0.07-0.37, p=0.003), irritability (0.23; 95% CI: 0.07-0.38, p=0.012), and mood swings scores (0.15; 95% CI: 0.00-0.31, p=0.047) during the intermenstrual phase, but a significant premenstrual improvement in depression (-0.33; 95% CI: -0.62 to -0.05, p=0.049). Secondary analyses showed that women with previous adverse hormonal contraceptive experience reported significantly greater mood worsening in the intermenstrual phase in comparison with healthy women, p<0.05. The proportion of women who reported a clinically relevant mood deterioration did not differ between those allocated to COC (24.1%) or placebo (17.0%), p=0.262.
  
  
  
  COC use is associated with small but statistically significant mood side effects in the intermenstrual phase. These findings are driven by a subgroup of women who clearly suffer from COC-related side effects. However, positive mood effects are noted in the premenstrual phase and the proportion of women with clinically relevant mood worsening did not differ between treatment groups.
authors.affiliation: Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lundin
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristina Gemzell
authors.initials: KG
authors.lastname: Danielsson
authors.affiliation: Department of Clinical Health, Obstetrics and Gynecology, Umeå University, Umeå, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Bixo
authors.affiliation: Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Moby
authors.affiliation: Department of Obstetrics and Gynecology, Örebro University, Örebro, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bengtsdotter
authors.affiliation: Department of Obstetrics and Gynecology, Örebro University, Örebro, Sweden.
authors.forename: Izabella
authors.initials: I
authors.lastname: Jawad
authors.affiliation: Department of Clinical Science and Education, Karolinska Institutet Södersjukhuset, Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Marions
authors.affiliation: Department of Obstetrics and Gynaecology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Brynhildsen
authors.affiliation: Department of Obstetrics and Gynaecology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Agota
authors.initials: A
authors.lastname: Malmborg
authors.affiliation: Department of Obstetrics and Gynecology, Sahlgrenska Academy at Gothenburg University, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Ingela
authors.initials: I
authors.lastname: Lindh
authors.affiliation: Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden. Electronic address: inger.sundstrom@kbh.uu.se.
authors.forename: Inger
authors.initials: I
authors.lastname: Sundström Poromaa
mesh_terms: D000293:Adolescent; D000328:Adult; D000342:Affective Symptoms / Q000139:chemically induced*; D001007:Anxiety / Q000139:chemically induced*; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000009:adverse effects*; D003863:Depression / Q000503:physiopathology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007508:Irritable Mood / Q000187:drug effects*; D008597:Menstrual Cycle / Q000502:physiology*; D017063:Outcome Assessment, Health Care; D055815:Young Adult
chemical_list: D003277:Contraceptives, Oral, Combined
keywords: Anxiety; Combined oral contraceptives; Depression; Estrogen; Irritability; Progestagen; Randomized clinical trial