Journal Article Annotations
2020, 4th Quarter

Women’s health

Annotations by Liliya Gershengoren, MD, Mary Burke, MD
December, 2020

Ulipristal Acetate for Treatment of Premenstrual Dysphoric Disorder: A Proof-of-Concept Randomized Controlled Trial
The impact of major depressive disorder and antidepressant medication before and during pregnancy on obstetric and neonatal outcomes; a nationwide population-based study
Indirect psychiatric consultation for perinatal bipolar disorder: A scoping review

PUBLICATION #1 — Women’s health

Ulipristal Acetate for Treatment of Premenstrual Dysphoric Disorder: A Proof-of-Concept Randomized Controlled Trial

Erika Comasco, Helena Kopp Kallner, Marie Bixo, Angelica L Hirschberg, Sara Nyback, Haro de Grauw, C Neill Epperson, Inger Sundström-Poromaa

Abstract: Am J Psychiatry. 2020 Dec 10;appiajp202020030286. doi: 10.1176/appi.ajp.2020.20030286. Online ahead of print.

Objective:
Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD.

Methods:
The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures.

Results:
The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference -18%; 95% CI=-29, -8). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference).

Conclusions:
If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.

Keywords:
Neuroendocrinology; Premenstrual Dysphoric Disorder; Progesterone; Selective Progesterone Receptor Modulator; Ulipristal Acetate.

Annotation

The finding:
Ulipristal acetate (UPA) is a selective progesterone receptor modulator that acts as a progesterone antagonist; continuous therapy can lead to anovulation and decrease the progesterone concentration in amygdala which is associated with the symptoms of PMDD. In this study, a total of 95 women with PMDD were randomized to either UPA (N=48) or placebo (N=47). UPA was found to be effective to improve Daily Recover of Severity of Problems (DRSP) scores, depressive symptoms, and anger/irritability symptoms. However, UPA group did not demonstrate beneficial effects on the physical symptoms of PMDD.

Strength and weaknesses:
This trial is a proof-of-concept multicenter randomized controlled trial with notable patient adherence to treatment and daily symptom charting. The study included three-cycle durations thus capturing the persistence of response and efficacy of treatment over time. Since UPA treatment can lead to irregular menses or amenorrhea, it is possible that blinding of the study was compromised. The study is unable to ascertain whether UPA exerts its impact through low progesterone levels or another action at the progesterone receptor.

Relevance:
Consult psychiatrists working in obstetrics/gynecology or primary care settings may be asked to weigh in on the treatment of PMDD. This finding can lead to the use of an alternative medication for patients who do not respond to or could not tolerate selective serotonin reuptake inhibitors.

Type of study (EBM guide):
Randomized controlled trial

PUBLICATION #2 — Women’s health

The impact of major depressive disorder and antidepressant medication before and during pregnancy on obstetric and neonatal outcomes; a nationwide population-based study

Emelie Wolgast, Caroline Lilliecreutz, Gunilla Sydsjö, Marie Bladh, Ann Josefsson

Abstract: Eur J Obstet Gynecol Reprod Biol. 2020 Nov 25;257:42-50. doi: 10.1016/j.ejogrb.2020.11.062. Online ahead of print.

Objective
To investigate the impact of major depressive disorder (MDD) and antidepressant medication before and during pregnancy on obstetric and neonatal outcomes.

Study design
A national register‐based cohort study of pregnant women born in Sweden, and their first child born in 2012-2015 (n = 262 329). Women diagnosed with MDD and who had redeemed an antidepressant one year before becoming pregnant (“before pregnancy”) and women who were diagnosed with MDD and who had redeemed an antidepressant both before and during pregnancy (“before and during pregnancy”) were compared with each other and with women who had neither been diagnosed with MDD nor been prescribed antidepressants (population controls).

Results
In comparison to population controls, the “before pregnancy” and the “before and during pregnancy” groups had increased likelihoods of operative childbirth (aOR = 1.19, 95% CI 1.12-1.27, aOR = 1.38, 95% CI 1.28-1.48 respectively), and with an increased likelihood for the child being admitted to a neonatal intensive care unit (NICU) (aOR = 1.51, 95% CI 1.17-1.95, aOR = 1.55, 95% CI 1.14-2.11). Children born to mothers in the “before and during pregnancy” group had an increased likelihood of preterm birth (aOR = 1.72, 95% CI 1.52-1.95,), while children to mothers in the “before pregnancy” group had an increased likelihood of low birthweight (aOR = 1.15, 95% CI 1.00-1.33) compared to population controls. Women in the “before and during pregnancy” group had an increased likelihood for hyperemesis during pregnancy (OR = 1.93, 95% CI = 1.60-2.32), having an operative childbirth (OR = 1.17, 95% CI = 1.06-1.29) or a preterm birth (OR = 1.53, 95% CI = 1.28-1.81) compared to the “before pregnancy” group.

Conclusions
Women with MDD and antidepressant medication prior to becoming pregnant are at increased risk for adverse obstetric and neonatal outcomes compared to women without an MDD. Continuation of antidepressant medication during pregnancy somewhat increased the risk for adverse obstetric and neonatal outcomes

Annotation

The finding:
This study demonstrated that adverse birth outcomes were statistically associated with depression during pregnancy, in women who had received antidepressants (ADS) in the year prior to pregnancy and had stopped; and in women who continued to take ADS during pregnancy, compared to healthy controls. In comparing the two depressed groups, there was a statistically significant increase in adverse outcomes in for women who continued to take ADS compared to those who stopped. However, the absolute differences were small (PTB 1-4 days earlier, LBW 20-100 grams less. Women who were depressed prior to pregnancy had co-morbid risks including higher rates of obesity, smoking, DM and chronic conditions, however when these and other factors were adjusted for the findings were the same, except for rates of LBW.

Strength and weaknesses:
This study examined a large cohort (262,329 women) from the Swedish health registry that included all first-born children between 2012-2015 born to Swedish women born 1973-1993. It tracked multiple relevant outcomes and analysed the data in two regressions including and excluding comorbid risk factors. However, the study only included women of Swedish birth, excluding immigrants thus representing a more homogenous population. Because only women taking ADS were included in the depression group, the study likely only captures those with more serious depressive illnesses. The investigators were not able to specify or clarify the course of medication treatment for women who had discontinued ADS.

Relevance:
Because of the known risks to mother and baby of peripartum depression, psychiatrists and obstetricians face constant questions about which treatments are best. SSRIs are standard and commonly used but not without risks. The study confirms the peripartum risks associated with ADS use; however, it also demonstrates that the risks do not increase dramatically for women who have severe depression and remain on medications. This study reinforces the importance of psychotherapy as a first-line treatment and supports reserving medication for women who do not respond. Moreover, the risks of discontinuing ADS in women with severe depression may outweigh the benefits as the absolute risk of ADS between the two groups was small.

Type of study (EBM guide):
Cohort study

PUBLICATION #3 — Women’s health

Indirect psychiatric consultation for perinatal bipolar disorder: A scoping review

Amelia C Wendt, Gabriella Stamper, Molly Howland, Joseph M Cerimele, Amritha Bhat

Abstract: Gen Hosp Psychiatry. 2020 Nov 25;68:19-24. doi: 10.1016/j.genhosppsych.2020.11.011. Online ahead of print.

Objective: To synthesize the literature and develop guidance on supports needed for primary care and perinatal providers in screening, initial management, triage, and bridging treatment for perinatal bipolar disorder. Methods: We conducted a scoping review by searching six electronic databases using keywords related to perinatal bipolar disorder. We summarized descriptive statistics on settings and extracted information on care approaches. We synthesized the literature on indirect care models and extracted data on screening, follow-up, referrals, and management. Results: 1169 articles were retrieved. 51 articles were included after review. Most papers were reviews. Fewer addressed care in obstetric (n = 20, 39%), primary care (n = 10, 20%), and paediatric settings (n = 2, 4%). Most papers (n = 30, 59%) discussed using screening instruments for bipolar disorder. Articles were mixed on recommendations for bipolar disorder screening. Conclusions: Varied strategies for structured assessment exist and are influenced by practice setting. There remains uncertainty about optimal strategies for screening and management of perinatal bipolar disorder. We recommend screening for bipolar disorder in the perinatal period in select circumstances (with depression screening, known bipolar disorder risk factors, and prior to starting antidepressants). If specialty mental health care is unavailable, we recommend enhancing usual care through integrated care strategies such as indirect consultation

Annotation

The finding:
Despite the risks of perinatal bipolar disorder and the challenges for many women in accessing specialty care, there are not consistent evidence-based strategies for providing indirect psychiatric consultation to primary care and obstetric practices. In addition, paediatric clinics are a potential site for connecting mothers with mental health care. The majority of review articles addressing this problem are not specific in offering treatment guidelines.

Strength and weaknesses:
The article highlights disparities in access to mental health care and concludes with five specific steps for managing perinatal BAD in non-mental health settings. The paper is a comprehensive review of extant literature and free of commercial bias. A table would have been useful for visualising results.

Relevance:
The majority of childbearing women with major mental illness do not have access to specialty mental health care. Developing and standardizing best practices for perinatal mental health care is of urgent importance

Type of study (EBM guide):
Librarian-assisted scoping review