The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale.

BACKGROUND: Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset. METHOD: Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA. RESULTS: Education, but not ethnicity/race, influenced the reporting of postpartum depression [difference between robust comparative fit indexes (∆*CFI) 0.01), but not between European countries (∆*CFI < 0.01). CONCLUSIONS: Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.

Pet therapy program for antepartum high-risk pregnancies: a pilot study.

OBJECTIVE: This pilot study evaluated the potential benefits of pet therapy on symptoms of anxiety and depression in antepartum hospitalized women with high-risk pregnancies. STUDY DESIGN: Eighty-two women in a hospital-based setting completed the State-Trait Anxiety Inventory and the Beck Depression Inventory before and after the pet therapy visit. For both questionnaires, paired t-test was used and adjusted P-values were obtained using the Hochberg step-up Bonferroni method. RESULT: The mean scores for depressive symptoms significantly improved from the pre-pet therapy (10.1 ± 6.3) compared with the post-pet therapy (6.3 ± 5.9) (P<0.0001). Likewise mean scores of the state anxiety significantly improved from the pre-pet therapy test (44.8 ± 11.7) compared with the post-pet therapy (34.5 ± 10.5) (P<0.001). CONCLUSION: Pet therapy significantly reduced anxiety and depression in antepartum hospitalized women with high-risk pregnancies.

Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling.

BACKGROUND: Postpartum depression (PPD) affects approximately 13% of women and has a negative impact on mother and infant, hence reliable biological tests for early detection of PPD are essential. We aimed to identify robust predictive biomarkers for PPD using peripheral blood gene expression profiles in a hypothesis-free genome-wide study in a high-risk, longitudinal cohort. METHOD: We performed a genome-wide association study in a longitudinal discovery cohort comprising 62 women with psychopathology. Gene expression and hormones were measured in the first and third pregnancy trimesters and early postpartum (201 samples). The replication cohort comprised 24 women with third pregnancy trimester gene expression measures. Gene expression was measured on Illumina-Human HT12 v4 microarrays. Plasma estradiol and estriol were measured. Statistical analysis was performed in R. RESULTS: We identified 116 transcripts differentially expressed between the PPD and euthymic women during the third trimester that allowed prediction of PPD with an accuracy of 88% in both discovery and replication cohorts. Within these transcripts, significant enrichment of transcripts implicated that estrogen signaling was observed and such enrichment was also evident when analysing published gene expression data predicting PPD from a non-risk cohort. While plasma estrogen levels were not different across groups, women with PPD displayed an increased sensitivity to estrogen signaling, confirming the previously proposed hypothesis of increased sex-steroid sensitivity as a susceptibility factor for PPD. CONCLUSIONS: These results suggest that PPD can be robustly predicted in currently euthymic women as early as the third trimester and these findings have implications for predictive testing of high-risk women and prevention and treatment for PPD.

Regulation of mRNA expression encoding chaperone and co-chaperone proteins of the glucocorticoid receptor in peripheral blood: association with depressive symptoms during pregnancy.

BACKGROUND: Major depressive disorder during pregnancy associates with potentially detrimental consequences for mother and child. The current study examined peripheral blood gene expression as a potential biomarker for prenatal depressive symptoms. METHOD: Maternal RNA from whole blood, plasma and the Beck Depression Inventory were collected longitudinally from preconception through the third trimester of pregnancy in 106 women with a lifetime history of mood or anxiety disorders. The expression of 16 genes in whole blood involved in glucorticoid receptor (GR) signaling was assessed using real-time polymerase chain reaction. In parallel, plasma concentrations of progesterone, estradiol and cortisol were measured. Finally, we assessed ex vivo GR sensitivity in peripheral blood cells from a subset of 29 women. RESULTS: mRNA expression of a number of GR-complex regulating genes was up-regulated over pregnancy. Women with depressive symptoms showed significantly smaller increases in mRNA expression of four of these genes - FKBP5, BAG1, NCOA1 and PPID. Ex vivo stimulation assays showed that GR sensitivity diminished with progression of pregnancy and increasing maternal depressive symptoms. Plasma concentrations of gonadal steroids and cortisol did not differ over pregnancy between women with and without clinically relevant depressive symptoms. CONCLUSIONS: The presence of prenatal depressive symptoms appears to be associated with altered regulation of GR sensitivity. Peripheral expression of GR co-chaperone genes may serve as a biomarker for risk of developing depressive symptoms during pregnancy. The presence of such biomarkers, if confirmed, could be utilized in treatment planning for women with a psychiatric history.

A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD).

Generalised anxiety disorder (GAD) is defined as excessive and uncontrollable worry and anxiety about everyday life situations. It is a chronic disorder, and is associated with substantial somatisation, high rates of comorbid depression and other anxiety disorders, and significant disability. The evidence base for pharmacotherapy and psychotherapy has continued to grow, and a wide range of drug choices for GAD now exists. Current guidelines for GAD generally restrict themselves to presentation of the evidence for various treatments, which, as a result, generally do not offer detailed discussion or recommendation of strategies beyond the first level of treatment, or take into account the individual circumstances of the patient. Thus, there is a lack of algorithm-based treatment guidelines for GAD. Our aim is, therefore, to present an algorithm for the psychopharmacologic management of GAD, intended for all clinicians who treat patients with GAD, where issues of pharmacotherapy are under consideration. We also hope that these GAD algorithms and other guidelines can help to identify high-priority areas that need further study. In this algorithm, we provide a sequenced approach to the pharmacotherapy of GAD, taking into account salient symptomatology and comorbidity, levels of evidence and extent of response. Special issues, including comorbidity, insomnia, suicidality, substance abuse, treatment adherence, pregnancy and lactation, cross-cultural issues, use of medication in the elderly, psychosocial treatment and dosing issues are also addressed.

Maternal depression and medication exposure during pregnancy: comparison of maternal retrospective recall to prospective documentation.

OBJECTIVE: Outcome investigations of prenatal maternal depression and psychotropic exposure rely extensively on maternal retrospective recall. This study compared postnatal recall to prospective documentation of illness and medication exposures. DESIGN: Prospective cohort and retrospective case-control studies. SETTING: Emory Women's Mental Health Program (prospective study) and Emory University Department of Psychology (retrospective study). SAMPLE: A total of 164 women who participated in both the prospective and retrospective studies. METHODS: Women with a history of mental illness were followed during pregnancy for prospective prenatal assessments of depression and medication exposures. At 6 months postpartum, some of these women also participated in a retrospective study during which they were asked to recall prenatal depression and medication use. Agreement between prospective and retrospective documentation of exposures was analysed. MAIN OUTCOME MEASURES: Occurrence of maternal depression during pregnancy and maternal use of pharmacological agents during pregnancy. RESULTS: There was only moderate agreement (k = 0.42) in prospective versus retrospective reporting of prenatal depression. Positive predictive value for recalling depression was 90.4%; however, negative predictive value for denying depression was only 53.8%. Participants accurately recalled psychotropic use but significantly underreported use of nonpsychotropic medications. CONCLUSIONS: Studies using retrospective data collection may be susceptible to systematic recall bias with underreporting of maternal depression and use of nonpsychotropic agents during pregnancy.

Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency.

OBJECTIVE: To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity. METHODS: A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency. RESULTS: Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52). CONCLUSIONS: These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.

Suicidal ideation in pregnancy: assessment and clinical implications.

The objectives of this study were 1) to determine the prevalence of suicidal ideation (SI) in pregnant women with a history of neuropsychiatric illness, 2) to assess the relative sensitivity of commonly used depression rating scales for detecting SI, and 3) to examine the sociodemographic and clinical predictors of SI in pregnant women. Demographic data, Beck Depression Inventory [BDI] and Hamilton Rating Scale for Depression [HRSD] questionnaires, and SCID interviews were obtained from 383 pregnant women presenting to the Emory Women's Mental Health Program or the Emory Women's Epilepsy Program. Among those who completed both scales, 29.2% endorsed SI on the BDI and 16.9% on the HRSD, with 33.0% endorsing SI on at least one of the rating scales and 13.1% on both rating scales. The rate of SI endorsement on the BDI was 73.3% higher than the HRSD. Multivariate logistic regression demonstrated that SI in pregnant women was associated with unplanned pregnancy (OR = 2.97), current major depression (OR = 4.12), and comorbid anxiety disorder (OR = 4.17). Further studies are warranted to identify additional predictors of perinatal suicidality and to clarify the nature of the association between such factors and the presence of SI in pregnant women.

Relapse of depression during pregnancy following antidepressant discontinuation: a preliminary prospective study.

OBJECTIVE: Pregnancy has frequently been referred to as a time of emotional well-being for patients. However, systematic data about the risk for relapse of depression during pregnancy are sparse. METHOD: We completed a longitudinal cohort study of thirty-two (N = 32) women with histories of depression who were euthymic at conception and who either discontinued or attempted to discontinue antidepressant therapy proximate to conception. Subjects were prospectively followed across pregnancy once per trimester using structured clinical interviews. Rates of relapse and time to relapse were examined. Factors distinguishing the population with respect to risk for relapse including demographic characteristics and illness history were also examined. RESULTS: Seventy-five percent (N = 24) of patients relapsed during pregnancy. The majority of relapses (79%, N = 19) occurred in the first trimester, and relapse was more prevalent in women with histories of more chronic depression. CONCLUSIONS: Pregnancy is not "protective" with respect to risk for relapse of depression. Careful treatment planning is necessary for those women on antidepressants who plan to conceive or who become pregnant.

The impact of pregnancy and childbirth on the metabolism of lamotrigine.

This study was performed to clarify alterations in lamotrigine (LTG) clearance during pregnancy and childbirth. Fourteen women on LTG monotherapy had LTG concentration samples obtained before conception and monthly. LTG apparent clearance, weight-adjusted relative clearance, and percentages of baseline clearance significantly differed between preconception baseline and each trimester and between trimesters. LTG clearance progressively increased until 32 weeks' gestational age, reaching a peak of >330% of baseline, and then began to decline.

Negative affect in offspring of depressed mothers is predicted by infant cortisol levels at 6 months and maternal depression during pregnancy, but not postpartum.

This study tests the hypothesis that maternal depression during pregnancy predicts temperament in offspring aged 6 m to 5 y. Previous studies have shown that maternal depression is related to negative affect and that certain temperament factors, such as negative affect and behavioral inhibition, in children predict affective disorders. Here, maternal depression is divided into depression during pregnancy vs. depression postpartum. Maternal depression was determined by the Beck Depression Inventory (BDI) throughout pregnancy and postpartum (prospectively) and by a diagnostic interview (SCID) at 6 months postpartum. The data show that maternal depression during pregnancy, but not postpartum, predicted the ratings of negative affect in the offspring. Importantly, symptoms of depression in the mother (BDI) were used as a control variable in the analyses in order to control for potential bias related to the mother's mood. In addition, cortisol levels in response to a mild stressor at 6 months of age predicted negative affect in infants and toddlers. We conclude that the effects of maternal depression on behavioral problems and vulnerability to mental illness may be mediated by altered temperament and enhanced stress responsiveness.

Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk.

BACKGROUND: This study's goal was to characterize nursing infants' exposure to fluoxetine through breast milk and to identify variables for minimizing such exposure. METHODS: Nursing women on stable daily doses of fluoxetine were recruited into the study. Breast milk, maternal and infant serum concentrations of fluoxetine and norfluoxetine were determined with high-performance liquid chromatography. RESULTS: Nineteen nursing women one with a pair of dizygotic twins participated in the study. The women were on stable daily doses of fluoxetine (10-60 mg/day) and all but two took the medication during the last trimester of pregnancy. Fluoxetine was detectable in 30% (n = 6) of the nursing infant sera (< 1-84 ng/mL), whereas norfluoxetine was found in 85% (N = 17) (< 1-265 ng/mL). Peak breast milk concentrations occurred approximately 8 hours after maternal dosing and predicted norfluoxetine concentrations in infant serum. Maternal serum fluoxetine and norfluoxetine concentrations correlated highly with infant norfluoxetine concentrations. A daily maternal fluoxetine dosage of 20 mg or lower was significantly less likely to produce detectable concentrations of either fluoxetine or norfluoxetine in infants compared to higher daily dosages. No adverse effects were reported in any infant. CONCLUSIONS: Our findings demonstrate that maternal serum and peak breast milk concentrations of fluoxetine and norfluoxetine predict nursing infant serum norfluoxetine concentrations. In nursing women taking 20 mg/day or less of fluoxetine, infant serum concentrations were typically low.

Antidepressants during pregnancy and lactation: defining exposure and treatment issues.

The majority of psychiatric illness onsets early in an individual's life, typically before or during the reproductive years. The increased incidence of major depression, dysthymia, and panic disorder in women compared with men underscores the likelihood that the clinician will encounter the clinical dilemma of medication use during pregnancy and lactation. The emergence of specialized clinics at several academic centers specifically to investigate and address issues in Perinatal psychiatry illustrates this conundrum best. The extant literature derived from human studies suggests that maternal mental illness and stress may have an adverse impact on obstetrical outcome. These clinical investigations are complemented by a burgeoning series of laboratory studies in rodents and nonhuman primates, showing the profound deleterious impact of maternal stress during the perinatal and neonatal periods on the development of the offspring. Data obtained from pharmaceutical registries, cohort studies, toxicology centers, and case series have consistently failed to show an adverse effect associated with in utero antidepressant exposure. Despite these advances and treatment guidelines proposed by the various academic leaders, investigations describing the extent of fetal/neonatal exposure, clinical methods for minimizing such exposure, and clinical treatment guidelines that include the physiological impact of pregnancy are sparse. The available literature shows distinct pharmacokinetic profiles of the selective serotonin reuptake inhibitors in placental passage and breast milk. Preliminary animal studies have shown higher than expected central nervous system concentrations associated with exposure during pregnancy and mathematical modelling for calculating infant exposure when nursing. The clinical import of these data will require further investigations of central nervous system bioavailability in the fetus and neonate.

Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women.

BACKGROUND: Pregnancy and the postpartum period are a time of increased risk for women to develop mood disorders. As such, the reproductive safety data on antidepressant use during pregnancy have rapidly expanded over the last decade; however, there is relatively sparse information on maternal/fetal exchange of these medications and no data reporting their concentrations in amniotic fluid. METHODS: We report on three women treated during pregnancy with fluvoxamine, sertraline, and venlafaxine, respectively. Amniotic fluid at amniocentesis and umbilical cord blood and maternal blood at delivery were collected and analyzed for antidepressant concentrations using high performance liquid chromatography with UV detection. RESULTS: Antidepressant and metabolite concentrations were detectable in all amniotic fluid samples, though parent compound concentrations were less than maternal serum and umbilical cord blood concentrations. No adverse effects of the medication were reported. CONCLUSIONS: The presence of these antidepressants in amniotic fluid suggests that fetal exposure to these medications is continual and may occur through a variety of paths, thus accounting for increased fetal exposure. These paths include circulatory via placental passage, gastrointestinal via fetal swallowing, and respiratory secondary to fetal lung absorption.

Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications.

The use of antidepressants during pregnancy has undergone considerable scrutiny with respect to safety issues, though limited data with respect to dose management and symptom resolution is available. Previous reports on tricyclic antidepressants (TCAs) have demonstrated the need to adjust maternal dose later in pregnancy to maintain therapeutic serum concentrations. However, there is no data on the dosage of selective serotonin uptake inhibitors (SSRIs) required to maintain symptom resolution in women treated for major depression during pregnancy. The purpose of this study, then, was to assess the medication dosage requirements of SSRIs during this time. In this naturalistic study, pregnant women with a primary diagnosis of major depression were followed prospectively through pregnancy at monthly intervals with symptom assessment. Subjects were included in data analysis if they presented prior to 28 weeks gestation, were treated with SSRI monotherapy, received all psychiatric treatment during the pregnancy at the Emory Pregnancy and Postpartum Mood Disorders Program, and achieved euthymia after initial treatment intervention (CGI = 1 and Beck Depression Inventory (BDI) < 9) during pregnancy or failed to respond after eight weeks of treatment. Medication selection was based on personal treatment history or family treatment history (if any), and the published data on SSRIs in pregnancy. All medication dose adjustments were based on depressive symptoms as measured by the BDI and a psychiatric interview (ZNS). Thirty-four pregnant women were included in final analysis. Two thirds of the subjects (n = 22) required an increase in their daily dose of medication to maintain euthymia. The dose increases occurred at 27.1 +/- 7.1 weeks gestation, with mean BDI scores of 16.4 +/- 9.6, compared to a mean treatment response BDI of 6.9 +/- 5.4. Subject's age, education, past personal and familial psychiatric history were not significantly associated with dose adjustment. These novel data on SSRI daily dose in pregnancy parallels the extant literature with tricyclic antidepressants (TCA). Further work to determine the predictors of dose adjustments will provide guidelines for minimizing fetal exposure to both medication and maternal mental illness.

Paroxetine in human breast milk and nursing infants.

OBJECTIVE: The purpose of this study was to determine the extent of infant medication exposure through breast-feeding during maternal treatment with paroxetine. METHOD: Breast milk and paired maternal and infant sera were collected after 10 days of maternal treatment with paroxetine at a stable daily dose (10-50 mg/day). All samples were analyzed by means of high-performance liquid chromatography with ultraviolet detection and a limit of detection of 2 ng/ml. RESULTS: Breast milk paroxetine concentrations were highly variable (2-101 ng/ml) and were present in all breast milk samples (N=108). A significant gradient effect was observed, with greater paroxetine concentrations found in later portions of breast milk (hind milk) than in early portions (fore milk). No clear time course of paroxetine excretion into breast milk was demonstrated, although maternal paroxetine daily dose reliably predicted both trough and peak breast milk concentrations over a 24-hour period. In 16 mother and infant serum pairs, no detectable concentrations of paroxetine were found in the serum of the nursing infants. CONCLUSIONS: This study extends previous data by demonstrating the presence of paroxetine in the breast milk of nursing women treated with this medication. The low concentrations of paroxetine in infant serum and lack of any observable adverse effects after maternal use of this medication while breast-feeding parallels the available data on other selective serotonin reuptake inhibitors.

Serum concentrations of antidepressants and benzodiazepines in nursing infants: A case series.

OBJECTIVE: The relative risk of psychotropic medication use in women with puerperal psychiatric illness who are breastfeeding has yet to be quantified adequately. Although the emotional and medical benefits of breastfeeding and adverse effects of maternal depression on infant development are well described, how these absolute benefits weigh against the potential effects of psychotropic drug use during lactation to ultimately guide clinical decisions is still unclear. The objective of this report was to evaluate the extent that psychotropic medications were present in the serum of infants breastfed by mothers treated with antidepressants and benzodiazepines. DESIGN: Serum samples were obtained from 35 nursing infants whose mothers were treated with psychotropic medications while breastfeeding. When a detectable concentration of medication was reported, information regarding infant behavior was obtained by maternal report. SETTING: The Perinatal and Reproductive Psychiatry Program at Massachusetts General Hospital serves as a regional consultation center for the treatment of psychiatric disorders during pregnancy and the postpartum period. PATIENTS: Subjects were mothers referred to the Perinatal Psychiatry Program for consultation regarding the relative safety of psychotropic medication use while breastfeeding. PRIMARY OUTCOME MEASURES: Presence of detectable levels of medication in infants whose mothers breastfed while taking psychotropic medications during pregnancy and/or during the puerperium and the well-being (based on maternal report) of infants who had detectable serum concentrations of medication. RESULTS: Seventy-four percent (n = 26) of infants had serum medication concentrations below the laboratory limit of detection (assay sensitivity 5-50 ng/mL). In the remaining 26% of the sample (n = 9), serum concentrations of psychotropic medications and/or active metabolites were detected. In each of these cases, infants had been exposed to the medication during pregnancy. Medications were not detected in infant serum when mothers had taken these agents solely during the postpartum period. No readily apparent difficulties with the infants were reported by mothers. CONCLUSIONS: These data support the low incidence of infant toxicity and adverse effects associated with antidepressant and benzodiazepine use during breastfeeding. These data also suggest that infant serum monitoring is helpful in the assessment of medication exposure in children of mothers who breastfeed while using psychotropic medications. Given the limited accumulated data regarding serum concentrations of psychotropic medications in breastfeeding infants, no single agent seems to be safer than another. Therefore, choice of pharmacologic treatment should be guided by the likelihood that it will result in restoration of maternal psychiatric well-being.

Treatment issues during pregnancy and lactation.

The lifetime incidence of mood disorders is twice as great in women compared with men, with the highest risk occurring during the childbearing years. The management of mental illness during pregnancy and lactation is a particularly complex clinical situation. The cornerstone of such a clinical decision is a completion of an assessment of the risks of the illness vs the risks of treatment. The following article reviews the factors influencing infant outcome and outlines the essential elements of the process of determining risk for the use of psychotropics in women during pregnancy and lactation. As the available data rapidly change, the facets of the risk benefit assessment are consistent and often the issue of specific medication is decided by prior history and exposure.

The use of lithium and management of women with bipolar disorder during pregnancy and lactation.

The introduction of lithium salts almost a century ago and the subsequent approval of lithium carbonate for the treatment of patients with bipolar disorder represent one of the cornerstones of modern psychopharmacology. The onset of bipolar disorder in women often occurs during the childbearing years, which complicates the treatment decisions secondary to the possibility of conception while taking medication. The establishment of the lithium registry for fetal teratogenesis in the late 1960s ushered in a heightened level of concern for the use of lithium during the reproductive years; although, in the years to come, it has become apparent that alternative pharmacologic treatments for bipolar disorder may exceed the teratogenic risk of lithium monotherapy. In this paper, the available data on the use of antimanic medications during pregnancy and lactation are reviewed with an emphasis on providing a realistic risk/benefit assessment for medication selection and management of these patients. Treatment strategies are discussed for (1) women who are contemplating pregnancy (2) women who inadvertently conceive while taking medications (3) women who choose to become pregnant while taking medication, and (4) women who intend to breastfeed while taking medications.