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Intergenerational transmission of trauma occurs when the effects of childhood maltreatment (CM) influence the next generation's development and health; prenatal programming via maternal mood symptoms is a potential pathway. CM is a risk factor for bipolar disorder which is present in 1.8% of pregnant women. Mood symptoms are likely to increase during pregnancy, particularly for those with a history of CM. We examined whether there was evidence for intergenerational transmission of trauma in utero in this population, and whether maternal mood was a transmission pathway.CM and maternal mood were self-reported by N = 82 pregnant women in treatment for bipolar disorder. Fetal heart rate variability (FHRV) was measured at 24, 30, and 36 weeks' gestation. Gestational age at birth and birth weight were obtained from medical charts.A cluster analysis yielded two groups, Symptom+ (18.29%) and Euthymic (81.71%), who differed on severe mood symptoms (p 0.001) but not on medication use. The Symptom+ group had more CM exposures (p 0.001), a trend of lower FHRV (p = 0.077), and greater birth complications (33.3% vs. 6.07% born preterm p 0.01). Maternal prenatal mood mediated the association between maternal CM and birth weight in both sexes and at trend level for gestational age at birth in females.This is the first study to identify intergenerational effects of maternal CM prior to postnatal influences in a sample of pregnant women with bipolar disorder. These findings underscore the potential enduring impact of CM for women with severe psychiatric illness and their children.

The inclusion of somatic symptoms in assessing peripartum depression (PPD), which encompasses depression during pregnancy and the postpartum period, has remained controversial, as there is substantial overlap between somatic depression symptoms and normal features of pregnancy/postpartum. This study examined whether trajectories differed by PPD symptom subscale and whether PPD symptom networks changed as a function of the peripartum phase. 418 women with a history of neuropsychiatric illness participated in a longitudinal observational study, completing symptom questionnaires assessing affective, cognitive, and somatic symptoms throughout pregnancy and the first year postpartum. Assessments were grouped into five peripartum phases: three trimesters of pregnancy and early/late postpartum. Two analyses were performed. First, a series of multilevel spline regression models examined depression subscale trajectories over peripartum phase. Second, symptom networks and related metrics were estimated for each peripartum phase and compared. Somatic symptoms were most severe and had the most variable peripartum trajectory. The role of somatic symptoms within the networks also changed as a function of peripartum phase. Our results suggest that somatic symptoms can be severe and may play a crucial role in the maintenance of PPD. Thus, somatic symptoms should not be disregarded when assessing for PPD in obstetrical, psychiatric, and pediatric clinics, and clinical research.

This study examined positive affect (PA) trajectories over the first year of life among infants of mothers with a history of depression (N = 191) as well as predictors (i.e., maternal prenatal and postpartum depression symptoms, maternal parenting behaviors) of those trajectories. Infant PA was observed in play and feeding tasks during lab visits at 3, 6, and 12 months of age; parenting behaviors were observed at 3 months. Mothers completed questionnaires regarding their symptoms of depression throughout the prenatal period and during the first 3 months postpartum. Growth curve analyses indicated that infant PA increased across time, and this finding replicated across both the play and feeding tasks, though increases slowed over time. Neither maternal prenatal nor postpartum depression symptoms predicted infants’ PA trajectories, but mothers’ PA, positive parenting, and disengaged parenting were associated with infant PA during the play task. Our finding that infant PA increased over the first year postpartum suggests PA trajectories among infants of mothers with a history of depression may be indices of resilience, despite risks associated with their mothers’ history of depression. Furthermore, this study highlights parenting behaviors that may be important targets of prevention and early intervention efforts to bolster infant PA.

Background and objectives The factors associated with medication for opioid use disorder (MOUD) treatment retention among pregnant women with opioid use disorder (OUD) are largely unknown. This study sought to characterize factors associated with postpartum treatment retention. Methods A retrospective chart review from 2014 to 2017 was conducted among women with OUD in pregnancy treated with buprenorphine. Women were assigned to the treatment retention group if they attended an appointment within 10 to 14 weeks postpartum. Others were assigned to the dropout group. The groups were compared using bivariate analysis for sociodemographic variables, obstetrical and neonatal outcomes, clinical and subjective opioid withdrawal symptoms, buprenorphine dosage, urine drug toxicology (UDT) results, and other factors. Results A total of 64 pregnancies received treatment until delivery, and 47 (73.1%) were retained in treatment by 12 weeks postpartum. The treatment dropout group had lower buprenorphine doses at delivery, a higher percentage of benzodiazepine positive UDT, and number of UDT positive for benzodiazepine in the third trimester. Breastfeeding rates were higher in the treatment retention group. Discussion and conclusions Future research of variables related to postpartum treatment retention is needed to provide guidelines regarding MOUD during the perinatal period and to optimize maternal and fetal well-being. Scientific significance This study supports previous recommendations that aggressive treatment of withdrawal symptoms in pregnant women with OUD is needed to maximize treatment retention. This is the first study to find that breastfeeding was associated with postpartum treatment retention; while, increased use of benzodiazepines during pregnancy was associated with postpartum treatment dropout. (Am J Addict 2020;00:00-00).

Background : The treatment of pregnant women with opioid use disorder is challenging due to the myriad of physical, mental, and social complications. Factors influencing adherence to buprenorphine during pregnancy have not been identified. Materials and methods : Pregnant women with opioid use disorder followed in a tertiary clinic were included in a retrospective chart review from buprenorphine induction through delivery. All women who had been evaluated and treated with buprenorphine from January 1, 2014, to September 31, 2016, were included. Adherence was defined as follows: 1) adherent: attended follow up visits, negative urine toxicology screens, and phase advancement; 2) moderately adherent: attended follow up visits until delivery, had not completed six negative urine toxicology screens, or had positive urine toxicology screens (i.e., no phase advancement); 3) non-adherent: missed follow up visits and did not stay in treatment until delivery. Sociodemographic characteristics, family psychiatric history, current and lifetime psychiatric and childhood trauma along with treatment factors were compared by category of adherence. Results : 64 women met criteria for inclusion in this study with 41 (64%) adherent; eight (13%) moderately adherent; and 15 (23%) non-adherent. In the non-adherent group compared to the adherent group, the clinician-rated opioid withdrawal scale score was significantly higher, and the daily buprenorphine dose at last visit was significantly lower. Conclusions : Women who were non-adherent to buprenorphine during pregnancy had higher severity of opioid withdrawal symptoms and lower doses of buprenorphine. These findings should be further explored with the goal of optimizing care without increasing risk for neonates.

Psychotropic medication use and psychiatric symptoms during pregnancy each are associated with adverse neurodevelopmental outcomes in offspring. Commonly, studies considering medication effects do not adequately assess symptoms, nor evaluate children when the effects are believed to occur, the fetal period. This study examined maternal serotonin reuptake inhibitor and polypharmacy use in relation to serial assessments of five indices of fetal neurobehavior and Bayley Scales of Infant Development at 12 months in N = 161 socioeconomically advantaged, non-Hispanic White women with a shared risk phenotype, diagnosed major depressive disorder. On average fetuses showed the expected development over gestation. In contrast, infant average Bayley psychomotor and mental development scores were low (M = 84.10 and M = 89.92, range of normal limits 85–114) with rates of delay more than 2–3 times what would be expected based on this measure's normative data. Controlling for prenatal and postnatal depressive symptoms, prenatal medication effects on neurobehavioral development were largely undetected in the fetus and infant. Mental health care directed primarily at symptoms may not address the additional psychosocial needs of women parenting infants. Speculatively, prenatal serotonin reuptake inhibitor exposure may act as a plasticity rather than risk factor, potentially enhancing receptivity to a nonoptimal postnatal environment in some mother–infant dyads.

Given high health costs of depression during pregnancy and the first postnatal year, it is important to understand mechanisms involved in the emergence and perpetuation of symptoms during this time. In a series of 2 studies, we aim to clarify bidirectional relations between mothers' physiological stress regulation-stress-related activation of the hypothalamic-pituitary-adrenal (HPA) axis-and their course of depressive symptoms. In Study 1, 230 pregnant women recruited from a women's mental health program gave 3 saliva samples in the context of psychosocial stress at 24, 30, and 36-weeks gestation. They self-reported depressive symptoms across the three trimesters of pregnancy and first year postpartum. Multilevel models revealed women with elevated salivary cortisol during pregnancy showed a course of escalating ante- and postnatal symptoms, implicating HPA hyperactivation as a precursor to worsening mood problems. In Study 2, 54 mothers from a community sample self-reported depressive symptoms at 3, 6, 12, and 18 months postnatal. At 18 months, they participated in a dyadic stress task with their infant and gave 4 saliva samples for cortisol assay. For mothers with a lifetime depression diagnosis, an escalating course of postnatal symptoms predicted a higher, flatter cortisol response profile. Together, the results of these studies suggest that for high-risk mothers, a trajectory of worsening depression may both follow from and give rise to neuroendocrine stress hyperactivation. These findings suggest greater attention is warranted to course of depressive symptoms across the ante- and postnatal period, rather than symptom levels at any given time, to characterize health risks. (PsycINFO Database Record

We examined the utility of screening instruments to identify risk factors for suicidal ideation (SI) in a population of women with neuropsychiatric illnesses at high risk for postpartum depression. Pregnant women with neuropsychiatric illness enrolled prior to 20 weeks of gestation. Follow-up visits at 4-8-week intervals through 13 weeks postpartum included assessment of depressive symptoms with both clinician and self-rated scales. A total of 842 women were included in the study. Up to 22.3% of postpartum women admitted SI on rating scales, despite the majority (79%) receiving active pharmacological treatment for psychiatric illness. Postpartum women admitting self-harm/SI were more likely to meet criteria for current major depressive episode (MDE), less than college education, an unplanned pregnancy, a history of past suicide attempt, and a higher score on the Childhood Trauma Questionnaire. In women with a history of neuropsychiatric illness, over 20% admitted SI during the postpartum period despite ongoing psychiatric treatment. Patient-rated depression scales are more sensitive screening tools than a clinician-rated depression scale for +SI in the postpartum period.

Objective To investigate the association, if any, of prenatal mental illness and psychotropic exposure with the risk of hypertensive disorders of pregnancy (HDP). Methods A case-cohort analysis was conducted of 686 pregnant women participating in prospective, longitudinal observational studies in a tertiary referral center between January 1998 and May 2012. Risk estimates were produced using multivariate logistic regression modeling. Medication- and diagnosis-specific data were utilized to conduct post hoc confirmatory analyses of the risk estimates. Results After adjustment for confounders, HDP were significantly associated with psychostimulant (odds ratio [OR] = 6.11; 95% CI, 1.79-20.9) and serotonin-norepinephrine reuptake inhibitor (SNRI) (OR = 2.57; 95%, 1.34-4.93) exposure following the 20th week of gestation and lifetime histories of cocaine dependence (OR = 2.99; 95% CI, 1.12-7.98) and panic disorder (OR = 1.78; 95% CI, 1.06-2.98) using DSM-IV diagnostic criteria. HDP risk was not associated with prenatal selective serotonin reuptake inhibitor exposure or other psychiatric disorders. Post hoc analyses demonstrated an increased risk for HDP with higher maternal daily doses of amphetamine psychostimulants and the SNRI venlafaxine. Conclusions These data indicate that psychostimulant and SNRI exposure following the 20th week of gestation conveys considerable risk for the emergence of HDP. Overall, the findings suggest that heightened vascular reactivity to noradrenergic, rather than serotonergic, stimulation may be pivotal to HDP risk among women with psychiatric illness.

Childhood maltreatment is common and has been increasingly studied in relation to perinatal outcomes. While retrospective self-report is convenient to use in studies assessing the impact of maltreatment on perinatal outcomes, it may be vulnerable to bias. We assessed bias in reporting of maltreatment with respect to women’s experiences of adverse perinatal outcomes in a cohort of 230 women enrolled in studies of maternal mental illness. Each woman provided a self-reported history of childhood maltreatment via the Childhood Trauma Questionnaire at two time points: 1) the preconception or prenatal period and 2) the postpartum period. While most women’s reports of maltreatment agreed, there was less agreement for physical neglect among women experiencing adverse perinatal outcomes. Further, among women who discrepantly reported maltreatment, those experiencing adverse pregnancy outcomes tended to report physical neglect after delivery but not before, and associations between physical neglect measured after delivery and adverse pregnancy outcomes were larger than associations that assessed physical neglect before delivery. There were larger associations between post-delivery measured maltreatment and perinatal outcomes among women who had not previously been pregnant and in those with higher postpartum depressive symptoms. Although additional larger studies in the general population are necessary to replicate these findings, they suggest retrospective reporting of childhood maltreatment, namely physical neglect, may be prone to systematic differential recall bias with respect to perinatal outcomes. Measures of childhood maltreatment reported before delivery may be needed to validly estimate associations between maternal exposure to childhood physical neglect and perinatal outcomes.

There are no published studies examining concurrent associations between temperament and behavior during toddlerhood in offspring of parents with bipolar disorder (OBD), a population at high familial risk for psychopathology. Better understanding of early determinants contributing to well-being or mental illness in this high-risk population has the potential to aid in the identification of problem domains to be targeted clinically, and facilitate the development of early intervention and prevention initiatives for an appropriate subgroup of children at the youngest possible age.A total of 30 offspring of mothers with BD (mean age=25.4±4.9 months) participated in this study at Emory University. The mothers completed the Early Childhood Behavior Questionnaire (ECBQ) and the Child Behavior Checklist (CBCL).The results of the correlational analyses indicated that the broad temperament dimension Negative Affectivity and the individual ECBQ scales Sadness and Shyness were positively associated with the broad CBCL dimension Internalizing Problems, whereas Sociability was negatively associated with Internalizing Problems. In addition, the temperament scales Soothability and Frustration were negatively and positively associated with Internalizing Problems, respectively. All ECBQ scales included in the broad temperament dimension Effortful Control, except for Cuddliness, were significantly negatively associated with the broad CBCL dimension Externalizing Problems. A significant sex difference was found for the ECBQ scale Positive Anticipation and the CBCL scale Sleep Problems, with a higher mean rank score for girls than for boys.This is the first systematic investigation of temperament and behavior and concurrent associations between these two domains in toddlers of mothers with BD. The present findings provide a platform for future investigations of the contribution of temperament and early behavior to potential well-being or mental illness in OBD.

The aims of this study were to characterize the alterations in total and free carbamazepine (CBZ) and in total and free carbamazepine-epoxide (CBZ-EPO) clearances during pregnancy, to calculate the change in free fractions of CBZ and CBZ-EPO during pregnancy, and to determine whether seizure worsening is associated with a low ratio to nonpregnant baseline concentration of total or free CBZ or CBZ-EPO. Women on CBZ were enrolled before conception or during pregnancy in this prospective, observational study. Concomitant medications and seizure frequency were recorded. Serum total and free CBZ and CBZ-EPO were collected at each visit. Changes in the clearance of all four compounds and free fractions of CBZ and CBZ-EPO were compared with nonpregnant baseline. During pregnancy, the ratios to baseline concentrations of total and free CBZ and CBZ-EPO were compared for months with and without increased seizure frequency. Total and free CBZ and CBZ-EPO clearances were calculated in 15 pregnancies in 12 women. Clearances did not change for any of these compounds during pregnancy. The free fraction of CBZ increased from 0.23 at baseline to a maximum of 0.32 in the third trimester (p=0.008). In the six women on CBZ monotherapy with adequate seizure diaries and blood sampling, seizure worsening did not correspond to a ratio to baseline concentration of less than 0.65 for total or free CBZ or CBZ-EPO. In conclusion, total and free CBZ and CBZ-EPO clearances did not change substantially during pregnancy, and seizure frequency worsening was not associated with decreased concentrations of total or free CBZ; therefore, therapeutic drug monitoring may not be necessary for all women on CBZ during pregnancy. Further studies with larger sample sizes are needed before definitive recommendations can be made. Carbamazepine monotherapy may be a relatively safe and cost effective treatment option for women with focal epilepsy syndromes during pregnancy.

Background Substance use during pregnancy is a major medical and public health concern. Determination of the most appropriate screening protocol remains a clinical conundrum. Interviews and/or laboratory drug screens may be costly, inaccurate, and are frequently inadequate to identify patterns of substance use for a given population or geographic area. We compared commercially available urine “dip cup” toxicology screens obtained in the clinic to university hospital drug toxicology results. Methods 267 observed urine samples were collected from pregnant women with known substance use disorders enrolled in a specialized treatment program that included access to buprenorphine medication-assisted treatment. Each urine sample was tested by commercial dip cup with temperature confirmation and then sent to the university hospital laboratory for analyses. The number of substances detected and cost for each screening method were compared. Results Uniformly, the dip cup had comparable detection of amphetamines, barbiturates, cocaine, methadone, opiates, and tetrahydrocannabinol to the university hospital laboratory with the exception of benzodiazepines. In addition, the dip cup detected use of buprenorphine (a commonly misused opiate receptor ligand not included in the hospital screen) and was significantly less expensive. Conclusions Commercially available urine dip cups are cost-effective, equally comparable to hospital based screening, and provide ‘real time’ results germane to clinical care and treatment planning.

Background Accumulating evidence suggests that fetal exposure to maternal psychiatric symptoms is associated with future risk for psychopathology. One potential pathway is distress-linked constriction in uterine or umbilical blood flow (UBF). With approximately 6.6% of pregnant women taking an antidepressant, an ecologically valid investigation of this hypothesis must consider the potential concomitant influence of pharmacotherapy on UBF. Methods Pregnant women (n = 101) with lifetime histories of mental illness were evaluated every 4 to 6 weeks during gestation for mood symptoms and medication use; women underwent an ultrasound examination for UBF at approximately 25 weeks gestation. Results No associations were observed between UBF and three assessments of maternal prenatal depression and anxiety (acute: coincident with the UBF scan; proximal: within 2 weeks of the scan; chronic: serial symptom ratings). Chronic and acute use of bupropion was associated with reduced UBF, even after controlling for pregnancy complications. Chronic use of atypical antipsychotics also was associated with decreased UBF. There were no associations between serotonergic antidepressant use and UBF. Conclusions Contrary to a popular hypothesis, depression and anxiety-associated reductions in UBF may not be a pathway by which risk is conferred during prenatal development. However, while requiring replication, our findings suggest that prenatal bupropion exposure may be associated with reductions in UBF.

Prenatal exposure both to maternal psychiatric illness and psychiatric medication has been linked with adverse child outcomes that affect physiological, emotional and psychiatric development. Studies suggest that epigenetic mechanisms, such as DNA methylation, may facilitate these effects. In this report, we explore the association between maternal psychiatric illness and treatment during pregnancy and neonatal DNA methylation patterns in a prospectively-characterized clinical cohort of 201 dyads. Associations between the percent of umbilical cord blood DNA methylated at 27,578 CpG sites and maternal psychiatric diagnosis, symptoms and antidepressant use were evaluated by fitting a separate linear mixed effects model for each CpG site. There were no significant changes in neonatal DNA methylation attributable to maternal psychiatric diagnosis or depressive symptoms during pregnancy. Exposure to an antidepressant medication was associated with differential methylation of CpG sites in TNFRSF21 and CHRNA2 (false discovery rate < 0.05), but the average difference in methylation for both CpG sites was less than 3% between each group. The results were not specific to type of antidepressant or duration of the exposure. This study suggests that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal exposure to antidepressants on neonatal DNA methylation. Delineation of the influence of maternal psychiatric illness and pharmacological exposures on the developing fetuses has critical implications for clinical care during pregnancy.

International audience; Background Cytokines of the innate immune response may contribute to behavioral alterations that resemble major depression as manifested in medically healthy individuals. Methods To explore potential similarities and differences between cytokine-induced depression and idiopathic major depression in healthy subjects, dimensional analyses comparing specific symptom dimensions of depression were conducted in 20 patients with malignant melanoma administered the innate immune cytokine, interferon (IFN)-alpha, and 28 medically healthy subjects with major depression of similar age and gender distribution. The Hamilton Rating Scale for Depression was used to assess severity of individual depressive symptoms. Results Severity of symptoms of anxiety, depressed mood, and impaired work/activities were comparable between patients with IFN-alpha-induced depression and medically healthy depressed patients. Interestingly, however, compared to medically healthy patients with major depression, patients with IFN-alpha-induced depression reported significantly greater psychomotor retardation and weight loss and significantly less severe feelings of guilt. Limitations The relatively small sample size limited statistical power to detect small differences in symptom expression among groups. Conclusions The data suggest that there is considerable overlap in symptom expression between cytokine-induced depression and idiopathic depression in medically healthy subjects. Nevertheless, differences in isolated symptom domains suggest that cytokines may preferentially target neurocircuits relevant to psychomotor activity (e.g. basal ganglia), while having a limited effect on cognitive distortions regarding self-appraisal.

Patients with epilepsy are at high risk for major depressive disorder (MDD) and, according to one report, postpartum depression (PPD) as well. The study described here sought to determine the prevalence and risk factors for PPD among women with epilepsy. Fifty-six women with epilepsy participating in a prospective study of perinatal antiepileptic drug (AED) pharmacokinetics were included. Participants completed the Beck Depression Inventory (BDI) during pregnancy and the postpartum period. Fourteen participants (25.0%) had a postnatal BDI score > or =12 indicative of PPD. Logistic regression indicated that significant risk factors for PPD among women with epilepsy included multiparity (odds ratio=12.5) and AED polytherapy (odds ratio=9.3). The rate of PPD was unaffected by the use of specific AEDs. In conclusion, PPD rates are higher among women with epilepsy than the general population, particularly those who are multiparous or receiving AED polytherapy, and there is no evidence that AED selection modifies this risk.

OBJECTIVE. Although lamotrigine use during pregnancy has substantially increased over the past decade secondary to accumulated reproductive safety data, systematic data on lamotrigine during breastfeeding remains sparse. We sought to characterize the determinants of lamotrigine concentrations in breast milk and nursing-infant plasma. PATIENTS AND METHODS. Women who enrolled in a prospective investigation of perinatal medication pharmacokinetics, were treated with lamotrigine, and chose to continue lamotrigine while breastfeeding were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient and serial samples over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Lamotrigine concentrations in all of the samples were determined by using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. RESULTS. Thirty women and their nursing infants participated in the study, providing a total of 210 breast milk samples. The mean milk/plasma ratio was 41.3%. There was a nonsignificant trend for higher lamotrigine concentrations in breast milk 4 hours after the maternal dose. Infant plasma concentrations were 18.3% of maternal plasma concentrations. The theoretical infant lamotrigine dose was 0.51 mg/kg per day, and the relative infant lamotrigine dose was 9.2%. Mild thrombocytosis was present in 7 of 8 infants at the time of serum sampling. No other adverse events were observed or reported in the breastfed infants. CONCLUSIONS. Consistent with previous investigations of medications in breast milk, the lamotrigine milk/plasma ratio is highly variable. The rate of lamotrigine excretion into human breast milk is similar to that observed with other antiepileptic drugs. These data expand the extant literature on lamotrigine in breastfeeding and demonstrate relatively comparable nursing-infant exposure to lamotrigine compared with other antiepileptic drugs.

Objective: Clinical management of bipolar disorder (BPD) patients during pregnancy is a major challenge. The high risk of bipolar depression during pregnancy encourages consideration of lamotrigine (LTG). We therefore compared recurrence risks among pregnant women with BPD treated with LTG to those discontinuing mood stabilizer therapies. Methods: We compared risks and weeks to new DSM-IV illness-episodes among 26 initially clinically stable pregnant women diagnosed with DSM-IV BPD who continued LTG treatment to those discontinuing all mood stabilizer treatment during pregnancy. Results: The risk of new illness-episodes with LTG was 30% versus 100% after discontinuing mood stabilizers, and survival-computed time-to-25%-recurrence was 28.0 versus 2.0 weeks (χ2 = 17.3, p

OBJECTIVE Risk factors for postpartum depression in euthymic pregnant women with histories of major depressive disorder (MDD) were evaluated. METHODS From April 2003 to March 2009, 343 pregnant women with a history of Structured Clinical Interview for DSM-IV (SCID)-diagnosed major depressive disorder were prospectively assessed from the third trimester into the postpartum period using the SCID mood module and 17-item Hamilton Depression Rating Scale (HDRS). Data from 300 subjects who completed at least 2 mood module assessments (1 within 60 days before and the other within 60 days after delivery) were analyzed for predictive associations between variables assessed in the third trimester and the development of a postpartum depression. RESULTS The majority of women were euthymic in pregnancy by SCID criteria. Women with third trimester SCID-diagnosed depression (n = 45) versus euthymia (n = 255) had a significantly higher risk for having depression after delivery (24% vs 11%, P = .013). For pregnant euthymic women, third trimester total HDRS scores significantly predicted postpartum depression (P < .0001); specifically, scores on 3 HDRS items alone-work activities, early insomnia, and suicidality-significantly predicted postpartum depression. Antidepressant use in the third trimester in euthymic women did not confer protection against the onset of postpartum depression. CONCLUSIONS Among women with a history of MDD who are euthymic in the third trimester, 3 HDRS items-work activities, early insomnia, and suicidality-may be useful as screening items for clinicians working with pregnant women with histories of MDD to identify a group at risk for developing postpartum depression. Additionally, in euthymic women with a history of MDD, antidepressant use in the third trimester may not reduce the risk of developing postpartum depression.

This study attempted to define further the neural processing events underlying social anxiety in patients with social anxiety disorder (SAD) and their response to pharmacotherapy. Social anxiety-related changes in regional cerebral blood flow were defined by [15O]H2 positron emission tomography (PET) in medication-free individuals with generalized SAD (gSAD), and age- and sex-matched comparison subjects, and analyzed using a linear mixed effects model. PET studies were again acquired in the gSAD individuals following an 8-week, flexible dose treatment trial of nefazodone. Both script-guided mental imagery of an anxiogenic social situation and a confrontational mental arithmetic task were associated with marked increases in self-rated anxiety in both subject groups. For gSAD subjects, social anxiety induced by guided mental imagery was associated with increased activity in the left postcentral gyrus and lenticulate, and the right inferior frontal and middle temporal gyri. Social anxiety induced by the mental arithmetic task was associated with activation of the medial and left dorsolateral prefrontal cortex, cerebellum, thalamus, insula, and ventral striatum. Both tasks were associated with relative decreases in activity in the right amygdala and the hippocampus. A direct group comparison indicated that comparison subjects exhibited a differing pattern of social anxiety-related neural activations. Nefazodone treatment was associated with marked clinical improvement. Comparison of social anxiety-related neural activations prior to and after nefazodone administration indicated greater activity in the precentral gyrus, insula, midbrain/hypothalamus, and middle frontal and anterior cingulate gyrus prior to treatment, and greater activity in the left middle occipital and bilateral lingual gyri, postcentral gyrus, gyrus rectus, and hippocampus after treatment. The results of an analysis relating neural activity and treatment-related changes in symptom severity indicated differential neural responses associated with states of symptom remission vs partial response. The observed social anxiety-related changes in distributed neural activity are consistent with cognitive models of SAD and adaptive decreases in amygdala activity in response to social anxiogenics, and support the association of altered frontal cortical responses with treatment response.

The study aimed to examine the course of obsessive-compulsive disorder (OCD) across pregnancy and its impact on obstetric and neonatal outcomes. Women enrolled prior to 20-week gestation in a prospective, observational study. The Structured Clinical Interview for DSM-IV was completed to obtain lifetime Axis I diagnoses. A total of 56 women with OCD were followed at 1 to 3-month intervals through 52 weeks postpartum. Each visit, the Yale-Brown Obsessive Compulsive Scale (YBOCS), clinical assessment, and medication/exposure tracking were performed. Obstetric and neonatal data were abstracted from the medical record. In subjects with OCD, associations between perinatal obsessive-compulsive symptoms (OCSs) and outcomes were examined. Additionally, outcomes were compared to 156 matched psychiatric patients without OCD. Maternal age inversely correlated with the YBOCS scores across the study period (β = −0.5161, p = .0378). Cesarean section was associated with increased OCSs in the postpartum period compared to vaginal delivery (β = 5.3632, p = 0.043). No associations were found between severity of perinatal obsessions or compulsions and any specific obstetric or neonatal complications. Subjects without OCD had higher frequency of fetal loss compared to mothers with OCD (χ 2 = 4.03, p = 0.043). These novel prospective data fail to identify an association of OCSs with adverse outcomes. In contrast, there is an association of delivery method and younger maternal age with increased postnatal symptoms of OCD. Psychiatric subjects without OCD may have a higher risk of miscarriage and intrauterine fetal demise compared to subjects with OCD.

BackgroundPostpartum 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.MethodWe 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.ResultsWe 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.ConclusionsThese 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.

Objective: This study iizvestigated whether depressed patients exhibit exaggerated platelet reactivity. Method: In vivo platelet activatioiz, secretioz, and dose-response aggregation were measured in 12 depressed patients and eight normal comparison subjects after overizight bed rest aizd following orthostatic challenge. Results: The depressed patients exhibited increased platelet activation at baseli,ze, demonstrated by increased binding of monoclonal antibody (moAb) annexin V protein reacting with prothrombinase complex binding sites. Followizg orthostatic challeizge, the depressed patients exhibited increases in binding of moAbs PACI a,zd anti-LIBS1 agaiizst actii'atedglycoprotein Jib/lila and GEI2 against P-selecti,z expressed 111)01? secretion. The normal comparison subjects exhibited increases in platelet activatioz only with GE I 2. Conclusions: Depressed patients exhibit enhazced baseline platelet activation and respozsiveness in comparisoz with normal subjects. Heightened susceptibility to platelet acti- vation flltlV he a mechanism b�' which depression is a significant risk factor for ischemic heart azd cerebrovascular disease and/or mortality after myocardial infarction. (AmJ Psychiatry 1996; 153:1313-1317)

Thirteen percent of women experience postpartum depression. Prenatal screening for anticipated postpartum social support, a postpartum depression risk factor, may allow for early intervention. We sought to validate use of a modified version of the Postpartum Social Support Questionnaire (PSSQ) in pregnant women at increased risk for postpartum depression. Factor analysis using orthogonal varimax rotation was used. The modified PSSQ, administered during pregnancy, yields similar loading patterns as observed in postpartum administration of the original PSSQ.

Antiepileptic drugs (AEDs) are used to treat a variety of neuropsychiatric illnesses commonly encountered in women during their reproductive years, including epilepsy and bipolar disorder. Despite their widespread use, the impact of prenatal exposure on fetal development remains obscure. To evaluate whether AEDs taken by pregnant mothers influence DNA methylation patterns in their neonates, DNA was extracted from the umbilical cord blood of 201 neonates whose mothers were treated for neuropsychiatric illness during pregnancy and interrogated across 27,578 CpG sites using the Illumina HumanMethylation27 BeadChip. The association of each methylation value with the cumulative duration of prenatal AED exposure was examined using a linear mixed model. The average methylation level across all CpG sites was calculated for each subject, and this global methylation measure was evaluated similarly. Neonates with a longer duration of AED exposure in pregnancy showed a decrease in average global methylation (p = 0.0045). Further, DNA methylation of CpG sites in 14 genes significantly decreased with the duration of prenatal AED exposure even after adjusting for multiple comparisons (FDR < 0.05). For a small subset (n = 19) of these neonates, a second tissue, placenta, was available in addition to cord blood. Methylation of 3 of these 14 CpG sites was also significantly decreased in placental tissue. These novel data suggest decreased DNA methylation in neonates of mothers who took AEDs during pregnancy. The long-term stability and potential impact of these changes warrant further attention, and caution may be warranted before prescribing AEDs to pregnant women.

Risk for adverse neonatal outcome increases with declining gestational age (GA), and changes in DNA methylation may contribute to the relationship between GA and adverse health outcomes in offspring. To test this hypothesis, we evaluated the association between GA and more than 27,000 CpG sites in neonatal DNA extracted from umbilical cord blood from two prospectively-characterized cohorts: (1) a discovery cohort consisting of 259 neonates from women with a history of neuropsychiatric disorders and (2) a replication cohort consisting of 194 neonates of uncomplicated mothers. GA was determined by obstetrician report and maternal last menstrual period. The associations between proportion of DNA methylated and GA were evaluated by fitting a separate linear mixed effects model for each CpG site, adjusting for relevant covariates including neonatal sex, race, parity, birth weight percentile and chip effects. CpG sites in 39 genes were associated with GA (false discovery rate < 0.05) in the discovery cohort. The same CpG sites in 25 of these genes replicated in the replication cohort, with each association replicating in the same direction. Notably, these CpG sites were located in genes previously implicated in labor and delivery (e.g., AVP, OXT, CRHBP and ESR1) or that may influence the risk for adverse health outcomes later in life (e.g., DUOX2, TMEM176A and CASP8). All associations were independent of method of delivery or induction of labor. These results suggest neonatal DNA methylation varies with GA even in term deliveries. The potential contribution of these changes to clinically significant postnatal outcomes warrants further investigation.

OBJECTIVE Because bipolar disorder can be difficult to diagnose, we compared characteristics of women with confirmed versus presumably misdiagnosed bipolar disorder. METHOD This cohort study was conducted from July 2005 to January 2010 in the outpatient clinic of the Emory Women's Mental Health Program, Atlanta, Georgia. Young adult women (mean age = 32 years) who were either pregnant or planning to conceive and who reported having previous clinical diagnoses of bipolar disorder completed 2 independent diagnostic assessments: the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) and an evaluation by a perinatal mood-disorder expert who was masked to the SCID findings. We compared clinical characteristics of women with confirmed versus presumably misdiagnosed bipolar disorder by bivariate testing followed by multivariate logistic regression modeling. RESULTS Of 199 participants, 141 (70.9%) had confirmed DSM-IV bipolar disorder on the basis of concordant assessments, 23 (11.6%) were considered misdiagnosed, and 35 (17.6%) who had discordant diagnostic assessments were excluded from further analysis. Multivariate modeling indicated that confirmed bipolar disorder was associated with a history of antidepressant-associated mania/hypomania (OR = 13.30; 95% CI, 3.32-53.20; P = .0003), psychotic symptoms (OR = 12.40; 95% CI, 2.14-71.10; P = .005), and sustained euthymia during mood-stabilizer treatment (OR = 4.53; 95% CI, 1.32-15.60; P = .02); presumably misdiagnosed bipolar disorder was associated with childhood physical abuse (OR = 8.73; 95% CI, 2.33-32.70; P = .001) and comorbid obsessive-compulsive disorder (OR = 7.26; 95% CI, 1.86-28.30; P = .004). CONCLUSIONS Several clinical factors found to distinguish women with confirmed versus presumably misdiagnosed bipolar disorder may help to refine clinical diagnosis.

OBJECTIVE To examine the association between severity of maternal depression and anxiety during pregnancy and the maternal use of medicinal agents and habit-forming substances. METHOD Participants in a prospective study of prenatal DSM-IV depressive and anxiety disorders at the Emory Women's Mental Health Program who completed weekly documentation of prenatal drug exposure and ≥ 3 administrations of the Hamilton Depression Rating Scale (HDRS) or Hamilton Anxiety Rating Scale (HARS) were included. The primary outcome measures were the HDRS and HARS. Correlation coefficients were computed for cumulative drug exposure with HDRS area under the curve (AUC) and HARS AUC. Data collection was completed between January 2007 and June 2010. RESULTS Among 195 participants, both HDRS AUC and HARS AUC were negatively correlated with prenatal vitamin exposure (r = -0.22 [P = .002] and r = -0.26 [P = .0003], respectively) and positively correlated with tobacco (r = 0.21 [P = .003] and r = 0.20 [P = .006], respectively) and hypnotic (r = 0.28 [P < .0001] and r = 0.19 [P = .008], respectively) exposure. Only HDRS AUC correlated with exposure to antiemetics (r = 0.14 [P = .05]), opioid analgesics (r = 0.14 [P = .05]), and all prescription drugs (r = 0.16 [P = .02]). Only HARS AUC correlated with benzodiazepine exposure (r = 0.17 [P = .02]). CONCLUSIONS Both prenatal depression and anxiety are associated with decreased prenatal vitamin compliance and increased use of hypnotics and tobacco, but only depression is associated with exposure to a broader array of medications targeting physical symptoms that often accompany depression. These findings confirm and extend previous studies, underscoring the importance of addressing prenatal depression and anxiety.

The objective of the current study was to delineate the optimal cutpoints for depression rating scales during pregnancy and the postpartum period and to assess the perinatal factors influencing these scores. Women participating in prospective investigations of maternal mental illness were enrolled prior to 28 weeks gestation and followed through 6 months postpartum. At each visit, subjects completed self-rated depression scales--Edinburgh Postnatal Depression Scale (EPDS) and Beck Depression Inventory (BDI) and clinician-rated scales--Hamilton Rating Scale for Depression (HRSD(17) and HRSD(21)). These scores were compared to the SCID Mood Module for the presence of fulfilling diagnostic criteria for a major depressive episode (MDE) during 6 perinatal windows: preconception; first trimester; 2nd trimester; 3rd trimester; early postpartum; and later postpartum. Optimal cutpoints were determined by maximizing the sum of each scale's sensitivity and specificity. Stratified ROC analyses determined the impact of previous pregnancy and comparison of initial to follow-up visits. A total of 534 women encompassing 640 pregnancies and 4025 follow-up visits were included. ROC analysis demonstrated that all 4 scales were highly predictive of MDE. The AUCs ranged from 0.857 to 0.971 and were all highly significant (p.0001). Optimal cutpoints were higher at initial visits and for multigravidas and demonstrated more variability for the self-rated scales. These data indicate that both clinician-rated and self-rated scales can be effective tools in identifying perinatal episodes of major depression. However, the results also suggest that prior childbirth experiences and the use of scales longitudinally across the perinatal period influence optimal cutpoints.

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.

Background Alterations in platelet reactivity have been previously posited to underlie the increased vulnerability of patients with depression to ischemic heart disease (IHD). The present study sought to determine whether the increased platelet reactivity associated with major depression is reduced after antidepressant treatment. Methods Patients diagnosed as having DSM-IV major depression (n = 15) (mean age, 37 ± 7 years; range, 23-48 years) and 12 normal comparison subjects (mean age, 36 ± 7; range, 23-48 years) were recruited. None of the controls or depressed group had evidence of IHD; 10 of 15 patients who were depressed had 1 or more traditional IHD risk factors. In vivo platelet activation, secretion, and dose-response aggregation of the controls and patients was measured after overnight bedrest under basal conditions, and after a mild exercise challenge. After 6 weeks of open-label treatment with the selective serotonin reuptake inhibitor paroxetine (20 mg/d), the patients with depression were readmitted and procedures of the first General Clinical Research Center admission repeated. Results In comparison with the control group, the depressed group exhibited greater procoagulant activity as detected by increased platelet binding of the monoclonal antibodies anti–ligand-induced binding site and GA6, and increased plasma concentrations of platelet factor 4 under basal conditions. After paroxetine treatment, the patients with depression exhibited significant reductions in all 3 parameters. Conclusions Normalization of platelet activation is associated with paroxetine treatment of patients with depression. Because this study design did not allow for the determination of whether this effect of paroxetine on platelet function is caused by a direct effect of the drug or placebo or, alternatively, because of recovery from depression, studies containing a placebo and/or psychotherapy treatment arm may resolve this issue.

Compulsive buying is a syndrome characterized by the impulsive and/or compulsive buying of unneeded objects that results in personal distress, impairment in vocational or social functioning, and/or financial problems. Results from a two-site, double-blind, placebo-controlled 13-week trial of fluvoxamine are presented. Subjects had problematic buying behavior that they could not control for the previous 6 months or longer and met DSM-IV criteria for impulse control disorder-not otherwise specified (ICD-NOS) and the University of Cincinnati criteria for compulsive buying. Assessments included clinician-rated scales-the Yale-Brown Obsessive Compulsive Scale modified for compulsive buying, the Clinical Global Impression Scale, the Global Assessment of Functioning, and the Hamilton Rating Scale for Depression-and patient self-reports using daily diaries, which measured episodes of compulsive buying. Forty-two subjects gave informed consent, with 37 subjects providing evaluable information and 23 completing the study. Current or past psychiatric comorbidity was present in 74% of subjects. Intent-to-treat and completer analyses failed to show a significant difference between treatments on any measures of outcome. A high placebo-response rate, possibly from the behavioral benefits of maintaining a daily diary, prevents any definitive statement on the efficacy of fluvoxamine in treating compulsive buying.

Background: The major treatments reported to be effective in the treatment of trichotillomania are cognitive-behavioral therapy (CBT) with habit reversal and serotonin-norepinephrine reuptake inhibitors such as clomipramine. However, the 2 treatments have not been previously compared with each other. This study examines the efficacy of CBT and clomipramine compared with placebo in the trcatment of trichotillomania. Method: Twenty-three patients with trichotillomania as determined by the Structured Clinical Interview for DSM-III-R entered and 16 completed a 9-week, placebo-controlled, randomized. parallel-treatment study of CBT and clomipramine. Efficacy was evaluated by the Trichotillomania Severity Scale, the Trichotillomania Impairment Scale, and the Clinical Global Impressions-Improvement scale, which were conducted by an independent assessor blinded to the treatment condition. Results: CBT had a dramatic effect in reducing symptoms of trichotillomania and was significantly more effective than clomipramine (p = .016) or placebo (p = .026). Clomipramine resultcd in symptom reduction greatcr than that with placebo, but the difference fell short of statistical significance. Placebo response was minimal. Conclusion: Clinicians should be aware of the potential treatments available for trichotillomania. A larger and more definitive study comparing CBT and a serotonin-norepinephrine reuptake inhibitor is indicated.

1. 1. Several factors, including age, gender, and season of the year, have been reported to affect physiologic indices of central serotonergic function, although some of these findings have not been consistent across groups of subjects and types of serotonergic measures. 2. 2. The authors investigated the role that each of these variables might play in the neuroendocrine response to acute intravenous challenge with the serotonin reuptake inhibitor clomipramine (CMI) in healthy volunteers. 3. 3. Thirty seven healthy subjects (17 women and 20 men), with an age range of 19 to 50 years, received 12.5 mg of CMI intravenously under standardized conditions. 4. 4. The maximum change from baseline in plasma prolactin concentrations (“delta-max”) was significantly related to age, after controlling for gender and season. 5. 5. In contrast, neither gender nor season was significantly related to prolactin delta-max, after controlling for the other two variables. 6. 6. Although the age range and sample size are relatively limited, the results from this study suggest that age, but not gender or season, may influence serotonergic function, as measured by the prolactin response to CMI challenge.

The effect of an initial challenge with the serotonin (5-HT) uptake inhibitor clomipramine (CMI) on subsequent rechallenge was studied in healthy men who served as volunteers. Carefully screened volunteers were assigned to one of three conditions: (1) CMI challenge followed 2 weeks later by CMI rechallenge; (2) placebo challenge followed 2 weeks later by CMI challenge; and (3) CMI challenge followed 4 weeks later by CMI rechallenge. We found significant blunting of the prolactin response to CMI rechallenge 2 weeks (Signed Rank = −12, p = 0.05), but not 4 weeks after an initial challenge. Placebo challenge did not affect CMI challenge 2 weeks later. These findings suggest that a single exposure to IV CMI may cause 5-HT receptor changes that are present 2, but not 4 weeks later. The ramifications of this finding with regard to the use of 5-HT challenge paradigms in a test-retest design are discussed.