Nancy Byatt

Antidepressant Use in Pregnancy: A Critical Review Focused on Risks and Controversies

Conflicting data have led to controversy regarding antidepressant use during pregnancy. The objectives of this study are to i) review the risks of untreated depression and anxiety, ii) review the literature on risks of exposure to antidepressants during pregnancy, iii) discuss the strengths and weaknesses of the different study designs used to evaluate those risks, and iv) provide clinical recommendations.

Pharmacotherapy for Mood Disorders in Pregnancy: A Review of Pharmacokinetic Changes and Clinical Recommendations for Therapeutic Drug Monitoring

Objective Pharmacotherapy for mood disorders during pregnancy is often complicated by pregnancy-related pharmacokinetic changes and the need for dose adjustments. The objectives of this review are to summarize the evidence for change in perinatal pharmacokinetics of commonly used pharmacotherapies for mood disorders, discuss the implications for clinical and therapeutic drug monitoring (TDM), and make clinical recommendations. Methods The English-language literature indexed on MEDLINE/PubMed was searched for original observational studies (controlled and uncontrolled, prospective and retrospective), case reports, and case series that evaluated or described pharmacokinetic changes or TDM during pregnancy or the postpartum period. Results Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may result in lowered psychotropic drug levels and possible treatment effects, particularly in late pregnancy. Mechanisms include changes in both phase 1 hepatic cytochrome P450 and phase 2 uridine diphosphate glucuronosyltransferase enzyme activities, changes in hepatic and renal blood flow, and glomerular filtration rate. Therapeutic drug monitoring, in combination with clinical monitoring, is indicated for tricyclic antidepressants and mood stabilizers during the perinatal period. Conclusions Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.

Strategies for improving perinatal depression treatment in North American outpatient obstetric settings

Objective: To identify core barriers and facilitators to addressing perinatal depression and review clinical, programmatic, and system level interventions that may optimize perinatal depression treatment. Method: Eighty-four MEDLINE/PubMed searches were conducted using the terms perinatal depression, postpartum depression, antenatal depression, and prenatal depression in association with 21 other terms. Of 7768 papers yielded in the search, we identified 49 papers on barriers and facilitators, and 17 papers on interventions in obstetric settings aimed to engage women and/or providers in treatment. Results: Barriers include stigma, lack of obstetric provider training, lack of resources and limited access to mental health treatment. Facilitators include validating and empowering women during interactions with health care providers, obstetric provider and staff training, standardized screening and referral processes, and improved mental health resources. Conclusion: Specific clinical, program, and system level changes are recommended to help change the culture of obstetric care settings to optimize depression treatment.

Patient, provider, and system-level barriers and facilitators to addressing perinatal depression

Objective: To explore perinatal health care professionals’ perspectives on barriers and facilitators to addressing perinatal depression. Background: Perinatal depression is common and associated with deleterious effects on mother, foetus, child and family. Although the regular contact between mothers and perinatal health care professionals may make the obstetric setting ideal for addressing depression, barriers persist, and depression remains under-diagnosed and under-treated. Methods: Four 90-minute focus groups were conducted with perinatal health care professionals, including obstetric resident and attending physicians, licensed independent practitioners, nurses, patient care assistants, social workers and administrative support staff. Focus groups were transcribed, and resulting data were analysed using a grounded theory approach. Results: Participants identified patient-, provider- and system-level barriers and facilitators to addressing perinatal depression. Provider-level barriers included lack of resources, skills and confidence needed to diagnose, refer and treat perinatal depression. Limited access to mental health care and resources were identified as system-level barriers. Facilitators identified included targeted training for perinatal health care professionals’, structured screening and referral processes, and enhanced support and guidance from mental health providers. Conclusion: A complex set of interactions between women and perinatal health care professionals contributes to perinatal depression being untreated. Service gaps could be closed by addressing identified barriers through integrated obstetric and depression care and enhanced collaborations. Future intervention testing could include targeted training, improved access, and mental health provider support to empower perinatal health care professionals’ to address perinatal depression, and thereby improve delivery of depression treatment in obstetric settings.

Enhancing Participation in Depression Care in Outpatient Perinatal Care Settings: A Systematic Review

OBJECTIVE: To examine a wide range of study designs and outcomes to estimate the extent to which interventions in outpatient perinatal care settings are associated with an increase in the uptake of depression care. DATA SOURCES: PubMed, CINAHL, PsycINFO, ClinicalTrials.gov, and Scopus (EMBASE) were searched for studies published between 1999 and 2014 that evaluated mental health care use after screening for depression in perinatal care settings. METHODS OF STUDY SELECTION: Inclusion criteria were: 1) English language; 2) pregnant and postpartum women who screened positive for depression; 3) exposure (validated depression screening in outpatient perinatal care setting); and, 4) outcome (mental health care use). Searches yielded 392 articles, 42 met criteria for full-text review, and 17 met inclusion criteria. Study quality was assessed using a modified Downs and Black scale. TABULATION, INTEGRATION, AND RESULTS: Articles were independently reviewed by two abstractors and consensus reached. Study design, intervention components, and mental health care use were defined and categorized. Seventeen articles representing a range of study designs, including one randomized controlled trial and one cluster randomized controlled trial, were included. The average quality rating was 61% (31.0–90.0%). When no intervention was in place, an average of 22% (13.8–33.0%) of women who screened positive for depression had at least one mental health visit. The average rate of mental health care use was associated with a doubling of this rate with patient engagement strategies (44%, 29.0–90.0%), on-site assessments (49%, 25.2–90.0%), and perinatal care provider training (54%, 1.0–90.0%). High rates of mental health care use (81%, 72.0–90.0%) were associated with implementation of additional interventions, including resource provision to women, perinatal care provider training, on-site assessment, and access to mental health consultation for perinatal care providers. CONCLUSION: Screening alone was associated with 22% mental health care use among women who screened positive for depression; however, implementation of additional interventions was associated with a two to fourfold increased use of mental health care. Although definitive studies are still needed, screening done in conjunction with interventions that target patient, health care provider, and practice-level barriers is associated with increased improved rates of depression detection, assessment, referral, and treatment in perinatal care settings.

Polypharmacy prevalence rates in the treatment of unipolar depression in an outpatient clinic

OBJECTIVE Unipolar depression is a complex illness with an ever increasing number of pharmacological treatments available. As the number of available medication options increases, so does the potential for polypharmacy, a practice with possible complications. Such complications include a greater number of side effects with the initiation of additional medications and the consequences of drug-drug interactions. Therefore, it is important to understand the effects of polypharmacy on efficacy of treatment as well as whether polypharmacy is instituted after appropriate initial monotherapy trials. This study attempts to answer these questions. METHODS Patient names for this investigation were provided by residents in the UMass Medical School Psychiatry Residency program. The charts of these patients were analyzed to collect data regarding demographics, clinical data about the illness, medication names, types, duration of use and to access efficacy using the Clinical Global Impression (CGI). RESULTS Of 160 reviewed charts, 135 subjects were included in the final analyses (others excluded due to incomplete data or no depression diagnosis). Patients were on average on 2.0 medications (SD=0.5) with 2.1 past trials. A greater number of current antidepressant medications did not correlate with a greater improvement in CGI, implying that polypharmacy did not necessarily lead to greater efficacy. The impact of illness severity, as measured by comorbidities, substance abuse, and trauma history, were included in the analysis, and did not significantly change this outcome. Additionally, prescription patterns themselves were examined, including reasons for termination of medication trials, the impact of side-effects, and the number of patients that had complete monotherapy trials before transitioning to polypharmacy. STUDY LIMITATIONS Small sample size, retrospective review, one CGI rater. CONCLUSIONS First, many patients did not receive an adequate monotherapy trial, as defined by dose and duration, before progressing to polypharmacy. Secondly, the use of two or more medications concurrently did not appear to increase efficacy as measured by CGI. Due to study limitations, direct comparison of the efficacy of one and two medications was not significant; however the study did demonstrate a general correlation between polypharmacy and greater depressive symptomatology. This suggests the need for optimizing monotherapy regimens before initiating polypharmacy that may not lead to improvement in symptoms.

Depression and anxiety among high-risk obstetric inpatients☆

OBJECTIVE To assess the following among women hospitalized antenatally due to high-risk pregnancies: (1) rates of depression symptoms and anxiety symptoms, (2) changes in depression symptoms and anxiety symptoms and, (3) rates of mental health treatment. METHODS Sixty-two participants hospitalized for high-risk obstetrical complications completed the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder 7-item scale (GAD-7) and Short-Form 12 weekly until delivery or discharge, and once postpartum. RESULTS Average length of total hospital stay was 8.3 ± 7.6 days for women who completed an initial admission survey (n = 62) and 16.3 ± 8.9 (n = 34), 25.4 ± 10.2 (n = 17) and 35 ± 10.9 days (n = 9) for those who completed 2, 3 and 4 surveys, respectively. EPDS was ≥ 10 in 27% (n=17) and GAD-7 was ≥ 10 in 13% (n = 8) of participants at initial survey. Mean anxiety (4.2 ± 6.5 vs. 5.2 ± 5.1, p = .011) and depression (4.4 ± 5.6 vs. 6.9 ± 4.8, p = .011) scores were lower postpartum compared to initial survey. Past mental health diagnosis predicted depression symptoms [odds ratio (OR) = 4.54; 95% confidence interval (CI) 1.91-7.17] and anxiety symptoms (OR = 5.95; 95% CI 3.04-8.86) at initial survey; however, 21% (n = 10) with no diagnostic history had EPDS ≥ 10. Five percent (n = 3) received mental health treatment during pregnancy. CONCLUSION Hospitalized high-risk obstetrical patients may commonly experience depression symptoms and/or anxiety symptoms and not receive treatment. A history of mental health treatment or diagnosis was associated with depression symptoms or anxiety symptoms in pregnancy. Of women with an EPDS ≥ 10, > 50% did not report a past mental health diagnosis.

Women’s perspectives on postpartum depression screening in pediatric settings: a preliminary study

This preliminary study is the first to identify mothers’ perspectives on barriers and facilitators to addressing postpartum depression (PPD) in pediatric settings. We conducted four 90-min focus groups with women (n = 27) who self-identified a history of perinatal depression and/or emotional complications. Barriers reported included stigma and fear among women and lack of provider knowledge/skills regarding depression. Participants recommended non-stigmatizing approaches to depression screening/referral. Future PPD screening efforts should leverage the pediatrician–mother relationship to mitigate mothers’ fears and encourage help-seeking.

Infertility and Perinatal Loss: When the Bough Breaks

Infertility and perinatal loss are common, and associated with lower quality of life, marital discord, complicated grief, major depressive disorder, anxiety disorders, and post-traumatic stress disorder. Young women, who lack social supports, have experienced recurrent pregnancy loss or a history of trauma and / or preexisting psychiatric illness are at a higher risk of experiencing psychiatric illnesses or symptoms after a perinatal loss or during infertility. It is especially important to detect, assess, and treat depression, anxiety, or other psychiatric symptoms because infertility or perinatal loss may be caused or perpetuated by such symptoms. Screening, psychoeducation, provision of resources and referrals, and an opportunity to discuss their loss and plan for future pregnancies can facilitate addressing mental health concerns that arise. Women at risk of or who are currently experiencing psychiatric symptoms should receive a comprehensive treatment plan that includes the following: (1) proactive clinical monitoring, (2) evidence-based approaches to psychotherapy, and (3) discussion of risks, benefits, and alternatives of medication treatment during preconception and pregnancy.

Fetal cardiac arrhythmia during bupropion use

Sir, Depression is estimated to complicate as many as 18% of pregnancies (1). Untreated depression has been associated with unfavorable outcomes for the mother and baby, making safe and effective treatment imperative (2). There is little information on the use of atypical antidepressants such as bupropion in pregnancy, and we would like to call attention to a possible link to fetal cardiac arrhythmia. A 29-year-old G2P1 woman with a history of postpartum depression was referred to psychiatry at 24 + 6 weeks gestation secondary to symptoms of major depression, including neurovegetative signs, irritability and mood swings. She was started on sertraline 25 mg twice a day and cognitive behavioral therapy. This was discontinued at 30 weeks gestation due to side effects of fatigue and headaches. Bupropion was then started at 100 mg daily as a family member had responded well to this medication. Two weeks later an irregular fetal heart rhythm was noted by Doppler auscultation during a routine prenatal exam. The patient reported frequent fetal movement and short episodes of contractions approximately 2–3 times per day. A urine toxicology screen was negative. Fetal heart tracing showed a fetal heart rate in the 150s with accelerations and episodes of hyper-variability suggestive of premature atrial contractions. An echocardiogram the following day showed no major cardiac anomalies, but occasional single premature atrial contractions (approximately 5–10% of all beats) with what appeared to be 1:1 atrioventricular conduction. The patient’s psychiatrist raised the possibility that bupropion may have precipitated the arrhythmia given an onset immediately following initiation of the drug and the structural similarity between bupropion and psychostimulants such as amphetamine, which have known cardiotoxic effects. Bupropion was immediately discontinued and no further arrhythmia was noted on follow up examination. From that point forward she was treated by psychotherapy alone and the remainder of her pregnancy was uncomplicated. The newborn infant had no evidence of cardiac disease or arrhythmia. The etiology of premature atrial contractions (PACs) is unknown or idiopathic (3) and PACs are not dangerous to the fetus, but can lead to bradyor tachyarrhythmias. Prolonged bradycardia in the fetus may lead to asphyxia and prolonged tachyarrhythmia to cardiovascular failure. Maternal abstinence from caffeine, alcohol and nicotine intake and/or other potential inciting agents is often suggested (4). Bupropion is currently labeled pregnancy category C by the Food and Drug Administration in the USA; however, there is a paucity of data on its safety. The manufacturer of the drug, GlaxoSmithKline, has concluded from their own registry that there is no evidence of a major teratogenic effect, but the sample size was small and did not report on fetal arrhythmia (5). Two studies on the safety of bupropion during pregnancy have neither confirmed nor disproven teratogenicity (6,7). The above case suggests a correlation between bupropion use during pregnancy and fetal cardiac arrhythmia; however, a causal relationship cannot be concluded. Given the unfavorable outcomes associated with untreated depression in pregnancy, it is crucial that concerns about medication effects on the fetus should not overly cloud clinical judgment when considering treatment.