Pilot validation of blood-based biomarkers during pregnancy and postpartum in women with prior or current depression.

Major depressive disorder (MDD) is more common in women than in men, and evidence of gender-related subtypes of depression is emerging. Previously identified blood-based transcriptomic biomarkers distinguished male and female subjects with MDD from those without the disorder. In the present pilot study, we investigated the performance of these biomarkers in pregnant and postpartum women with prior major depressive episodes, some of whom had current symptomatology. The symptom scores of 13 pregnant and 15 postpartum women were identified by the Inventory of Depressive Symptoms (IDS-SR-30) at the time of blood sampling. Blood levels of the 20 transcriptomic biomarkers and that of estrogen receptor 2 (ESR2), membrane progesterone receptor alpha and beta (mPRα, mPRß) were measured. In pregnant women, transcript levels of ADCY3, ASAH1, ATP11C, CDR2, ESR2, FAM46A, mPRß, NAGA, RAPH1, TLR7, and ZNF291/SCAPER showed significant association with IDS-SR-30 scores, of which ADCY3, FAM46A, RAPH1, and TLR7 were identified in previous studies for their diagnostic potential for major depression. ASAH1 and ATP11C were previously also identified as potential markers of treatment efficacy. In postpartum women, transcript levels of CAT, CD59, and RAPH1 demonstrated a trend of association with IDS-SR-30 scores. Transcript levels of ADCY3, ATP11C, FAM46A, RAPH1, and ZNF291/SCAPER correlated with ESR2 and mPRß expressions in pregnant women, whereas these associations only existed for mPRß in postpartum women. These results suggest that a blood biomarker panel can identify depression symptomatology in pregnant women and that expression of these biomarker genes are affected by estrogen and/or progesterone binding differently during pregnancy and postpartum.

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.

Rationale and design for an investigation to optimize selective serotonin reuptake inhibitor treatment for pregnant women with depression.

The physiological changes of pregnancy can affect the pharmacokinetics of a drug, thereby affecting its dose requirements. Because pharmacokinetic (PK) studies in pregnant women have rarely been conducted, evidence-based dosing adjustments are seldom available. In particular, despite the fact that the use of antidepressants has become increasingly common, pregnancy-associated PK changes of the selective serotonin reuptake inhibitors (SSRIs) are largely unknown.

Pharmacologic evidence to support clinical decision making for peripartum methadone treatment.

RATIONALE: Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum. OBJECTIVES: Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D. METHODS: Methadone dose changes and timed plasma samples were obtained for women on methadone (n = 25) followed prospectively from third trimester of pregnancy to 3 months postpartum. RESULTS: Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase = 23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase = 19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7-24.9 h; S-methadone, 8.02-18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1-2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum. CONCLUSIONS: Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery.

Pharmacotherapy for depressed pregnant women: overcoming obstacles to gathering essential data.

Approximately 3% of pregnant women take antidepressant medications. Information on the impact of antidepressants on short- and long-term maternal and offspring outcomes is highly desirable but neglected. The position that the dearth of treatment information is of greater concern than the risks to pregnant subjects involved in medical research is gaining support. Mandating the collection of reproductive outcome data in exposed childbearing women is an overdue step toward societal responsibility to our most vulnerable members.

Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression.

OBJECTIVE: Postpartum depression (PPD) affects 10-15% of mothers. Omega-3 fatty acids are an intriguing potential treatment for PPD. METHOD: The efficacy of omega-3 fatty acids for PPD was assessed in an 8-week dose-ranging trial. Subjects were randomized to 0.5 g/day (n = 6), 1.4 g/day (n = 3), or 2.8 g/day (n = 7). RESULTS: Across groups, pretreatment Edinburgh Postnatal Depression Scale (EPDS) and Hamilton Rating Scale for Depression (HRSD) mean scores were 18.1 and 19.1 respectively; post-treatment mean scores were 9.3 and 10.0. Percent decreases on the EPDS and HRSD were 51.5% and 48.8%, respectively; changes from baseline were significant within each group and when combining groups. Groups did not significantly differ in pre- or post-test scores, or change in scores. The treatment was well tolerated. CONCLUSION: This study was limited by small sample size and lack of placebo group. However, these results support further study of omega-3 fatty acids as a treatment for PPD.

Lesbian perinatal depression and the heterosexism that affects knowledge about this minority population.

The medical literature about homosexuality and mental health is expanding; however, a paucity of research about lesbian mental health remains. No research about lesbian perinatal depression has been published. This paper highlights the heterosexism that perpetuates research and health care disparities between heterosexual and lesbian/gay/bisexual individuals. We acknowledge barriers that distance lesbian women from research and health care, and emphasize the importance of moving beyond these barriers to fill in gaps of knowledge about the specific health care needs of this minority population. We use an analysis of stress factors as a framework to generate hypotheses about perinatal depression in lesbian women. We conclude with suggestions for future study in the form of questions that should be asked and pursued in research.

Psychiatric disorders during pregnancy.

Treating women with psychiatric disorders during pregnancy is a challenge for numerous reasons. Balancing the risks and benefits of symptoms and treatments is particularly important during pregnancy because both medication and maternal illness may have adverse effects on the fetus. Communication of options in the management of psychiatric disorders in pregnancy is vital to optimal treatment. One barrier to effective communication has been a paucity of research from which clinicians can draw information, particularly in the area of pharmacological treatment. However, emerging evidence points to the low risk of many psychotropic medications during pregnancy. Uncertainty must not prevent frank risk-benefit discussions from occurring between treating physicians and their pregnant patients. Psychiatrists can prepare themselves for management decisions by reviewing the current literature.

Diminished response to pleasant stimuli by depressed women.

This study examined the self-report and facial expressions of emotional response to pictorial stimuli and the incidental learning of pleasant and unpleasant words by depressed (n = 20) and nondepressed (n = 20) women. Depression was associated with reports of diminished emotional response and reduced frequency and intensity of facial expressions only to pleasant stimuli. The 2 groups did not differ in response to hedonically unpleasant stimuli, even those specifically relevant to the emotion of sadness. In a similar vein, depressed and nondepressed participants showed differences in incidental recall for only pleasant self-referential terms. There was no difference in recall of unpleasant words. These findings suggest the importance of hedonic deficits on psychological processes in clinical depression.

Serum fluvoxamine levels in breastfed infants.

BACKGROUND: Between 10% and 15% of new mothers will experience an episode of postpartum depression. Although antidepressants are effective agents for the treatment of postpartum depression, minimal data are available to support their safety in infants of breastfeeding mothers. METHOD: In this article, we present 2 cases of nursing mother-infant pairs in which the mother was treated with fluvoxamine and in which infant serum fluvoxamine levels were obtained. Both mothers began the fluvoxamine treatment postpartum, and serum levels were obtained from mothers and infants after a minimum of 7 days on a stable maternal dose. One level was obtained from the infant in case 1, and 2 levels were obtained from the infant in case 2. RESULTS: Each of the infant serum fluvoxamine levels obtained was too low to quantify (at a limit of detection of 2.5 ng/mL). Neither of the infants experienced adverse events related to the mother's treatment with fluvoxamine. Each of the infants is reportedly healthy 2 to 3 years after the exposure. CONCLUSION: While these results are encouraging, they are limited and cannot be generalized to all cases of infants exposed to fluvoxamine. Additional mother-infant serum fluvoxamine levels and infant behavioral observations will facilitate the risk-benefit decision-making process for women who choose to breast-feed while taking fluvoxamine.

Prevention of recurrent postpartum depression: a randomized clinical trial.

BACKGROUND: Women who have suffered one episode of postpartum-onset major depression (PPMD) comprise a high-risk group for subsequent episodes. We conducted a double-blind, randomized clinical trial to test the efficacy of nortriptyline in the prevention of recurrent PPMD. METHOD: Nondepressed women who had at least one past episode of PPMD (Research Diagnostic Criteria) were recruited during pregnancy. Subjects were randomly assigned to nortriptyline or placebo. Treatment began immediately postpartum. Each subject was assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression and Research Diagnostic Criteria for recurrence of major depression. RESULTS: No difference was found in the rate of recurrence in women treated with nortriptyline compared with those treated with placebo. Of 26 subjects who took nortriptyline preventively, 6 (0.23, 95% exact confidence interval [CI] = 0.09 to 0.44) suffered recurrences. Of 25 subjects who took placebo, 6 (0.24, 95% exact CI = 0.09 to 0.45) suffered recurrence (Fisher exact p = 1.00). CONCLUSION: Nortriptyline did not confer additional preventive efficacy beyond that of placebo. The rate of recurrence of PPMD (one fourth of women) was unacceptably high.

Risk-benefit decision making for treatment of depression during pregnancy.

OBJECTIVE: The Committee on Research on Psychiatric Treatments of the American Psychiatric Association identified treatment of major depression during pregnancy as a priority area for improvement in clinical management. The goal of this article was to assist physicians in optimizing treatment plans for childbearing women. METHOD: The authors' work group developed a decision-making model designed to structure the information delivered to pregnant women in the context of the risk-benefit discussion. Perspectives of forensic and decision-making experts were incorporated. RESULTS: The model directs the psychiatrist to structure the problem through diagnostic formulation and identification of treatment options for depression. Reproductive toxicity in five domains (intrauterine fetal death, physical malformations, growth impairment, behavioral teratogenicity, and neonatal toxicity) is reviewed for the potential somatic treatments. The illness (depression) also is characterized by symptoms of somatic dysregulation that compromise health during pregnancy. The patient actively participates and provides her evaluation of the acceptability of the various treatments and outcomes. Her capacity to participate in this process provides evidence of competence to consent. Included in the decision-making process are the patient's significant others and obstetrical physician. The process is ongoing, with the need for incorporation of additional data as the pregnancy and treatment response progress. CONCLUSIONS: The conceptual model provides structure to a process that is frequently stressful for both patients and psychiatrists. By applying the model, clinicians will ensure that critical aspects of the risk-benefit discussion are included in their care of pregnant women.

Serum valproate levels in 6 breastfeeding mother-infant pairs.

BACKGROUND: Women with bipolar disorder are at high risk for recurrence of an affective episode in the postpartum period, and treatment with a mood stabilizer may be indicated. Few data are available to inform the risk-benefit decision regarding the use of valproate for women with bipolar disorder who elect to breast-feed. METHOD: Serum valproate levels were obtained from 6 breastfeeding mother-infant pairs. All mothers had a diagnosis of bipolar disorder (Research Diagnostic Criteria) and were taking divalproex sodium as prophylaxis for or treatment of a recurrent affective episode. None of the mothers received valproate during pregnancy. RESULTS: The mothers had serum valproate levels near or within the therapeutic range (39.4 to 79.0 microg/mL). Infant serum levels were low, ranging from 0.7 to 1.5 microg/mL (0.9%-2.3% of maternal serum levels). No adverse clinical effects were observed in the infants. CONCLUSION: Serum valproate levels were low in nurslings of mothers treated with valproate. These data can be used to inform clinical decisions regarding the use of valproate during breastfeeding.

Gonadal steroids in the treatment of mood disorders.

UNLABELLED: Increased interest in the complex interplay between gonadal steroids and neurotransmitter systems involved in mood has led investigators to question the role of gonadal steroids in the treatment of affective disorders, especially in women. OBJECTIVES: The purpose of this article is to provide a rationale for using gonadal hormones in the treatment of depression in women. METHODS: The literature is reviewed regarding 1) sex-specific phenomenologic and epidemiologic differences in the manifestation of psychiatric illness, 2) sex-specific differences in the therapeutic and adverse effects of psychotropic medications, 3) the complex interplay between gonadal steroids and neurotransmitter systems implicated in psychiatric disorders, and 4) the growing literature regarding the use of estrogen and progesterone in the treatment of mood disorders in women and androgens in the treatment of depression and sexual dysfunction in both men and women. RESULTS: Findings from pharmacologic trials of estrogen and androgens are encouraging, albeit mixed, in the treatment of mood disorders and decreased libido in women, respectively. Controlled studies have failed to confirm early open-label reports of the effectiveness of progesterone in the treatment of premenstrual syndrome. CONCLUSIONS: Pending replication, estrogen may become an important pharmacologic agent in the treatment of postnatal and perimenopausal depression, whereas androgens have been shown to improve libido in postmenopausal women and hypogonadal men. Progesterone cannot be recommended as a treatment for premenstrual syndrome or postnatal depression.

Pharmacologic treatment of depression during pregnancy.

CONTEXT: Despite the frequency of depression in women of childbearing age, information to guide patients and physicians through a consideration of treatment during pregnancy is limited. OBJECTIVE: To identify risk factors associated with treatment of major depression during pregnancy to help physicians develop treatment plans that optimize clinical care. DATA SOURCES: Reports of prospective controlled trials in English were identified from MEDLINE and Health STAR using the search terms antidepressant during pregnancy and depression during pregnancy, by manually searching bibliographies of review articles, and through discussions with investigators for 1989-1999. STUDY SELECTION: We selected studies in which maternal and infant health outcomes associated with antidepressant exposure were compared with those of non-teratogen-exposed controls. Four studies published since 1993 were identified and included in the analysis. DATA EXTRACTION: We abstracted information about identification of subjects, comparison groups, pregnancy, and birth outcomes. We organized the data along 5 domains of reproductive toxicity: intrauterine fetal death, morphologic teratogenicity, growth impairment, behavioral teratogenicity, and neonatal toxicity. DATA SYNTHESIS: Data were available for tricyclic antidepressants (collectively), fluoxetine, and newer selective serotonin reuptake inhibitors (collectively). Exposure to these agents did not increase risk for intrauterine death or major birth defects. Decreased birth weights of infants exposed to fluoxetine in the third trimester were identified in 1 study. The development of children whose mothers took tricyclics or fluoxetine during gestation did not differ from that of controls. Direct drug effects and withdrawal syndromes occurred in some neonates whose mothers were treated with antidepressants near term. CONCLUSIONS: Although few in number, new information from prospective studies provides a welcome change from decision making based on nonprospective data. Monitoring and interventions for patients with identified risks (eg, poor weight gain) are recommended.