Pregnant women with bipolar disorder who have a history of childhood maltreatment: Intergenerational effects of trauma on fetal neurodevelopment and birth outcomes.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Rating scale item assessment of self-harm in postpartum women: a cross-sectional analysis.

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.

Obsessive-compulsive disorder in pregnancy and the postpartum period: course of illness and obstetrical outcome.

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 (ß = -0.5161, p = .0378). Cesarean section was associated with increased OCSs in the postpartum period compared to vaginal delivery (ß = 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.

Test-retest reliability of retrospective self-reported maternal exposure to childhood abuse and neglect.

Retrospective reports of exposure to childhood trauma indicate it is common. There is growing interest in relationships between maternal exposure to childhood adversity, perinatal mental health, and pregnancy outcomes. The goal of this study was to describe the self-reported prevalence and test-retest reliability of exposure to childhood maltreatment using the Childhood Trauma Questionnaire among adult women around the time of pregnancy. A substantial proportion of women reported exposure to maltreatment and reliability was generally at least moderate, indicating consistent reporting.

Associations between mothers' and fathers' depression and anxiety prior to birth and infant temperament trajectories over the first year of life: Evidence from diagnoses and symptom severity.

BACKGROUND: Developmental shifts in infant temperament predict distal outcomes including emerging symptoms of psychopathology in childhood. Thus, it is critical to gain insight into factors that shape these developmental shifts. Although parental depression and anxiety represent strong predictors of infant temperament in cross-sectional research, few studies have examined how these factors influence temperament trajectories across infancy. METHODS: We used latent growth curve modeling to examine whether mothers' and fathers' anxiety and depression, measured in two ways - as diagnostic status and symptom severity - serve as unique predictors of developmental shifts in infant temperament from 3 to 12 months. Participants included mothers (N = 234) and a subset of fathers (N = 142). Prior to or during pregnancy, both parents were assessed for lifetime diagnoses of depression and anxiety as well as current severity levels. Mothers rated their infants' temperament at 3, 6, and 12 months of age. RESULTS: Mothers' depression and anxiety primarily predicted initial levels of temperament at 3 months. Controlling for mothers' symptoms, fathers' depression and anxiety largely related to temperament trajectories across infancy. Lifetime diagnoses and symptom severities were associated with distinct patterns. LIMITATIONS: Infant temperament was assessed using a parent-report measure. Including an observational measure would provide a more comprehensive picture of the infants' functioning. CONCLUSIONS: These results indicate that mothers' and fathers' mental health are uniquely associated with infant temperament development when measured using diagnostic status and/or symptom severity. Future studies should examine whether these temperament trajectories mediate intergenerational transmission of risk for depression and anxiety.

Maternal expectations of postpartum social support: validation of the Postpartum Social Support Questionnaire during pregnancy.

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.

The severity and role of somatic depressive symptoms in psychological networks in a longitudinal sample of peripartum women.

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.

Postpartum depression in women with epilepsy: influence of antiepileptic drugs in a prospective study.

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.

Drug screening during pregnancy: Urine dip cups measure up.

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.

Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes.

OBJECTIVES: There are limited data regarding the use of atypical antipsychotic medications in pregnancy. The objectives of the current study were to quantify placental permeability to antipsychotic medications and to document obstetrical outcomes for women taking these agents proximate to delivery. METHOD: The authors conducted a prospective observational study of women treated with an atypical antipsychotic or haloperidol during pregnancy. Maternal and umbilical cord plasma samples collected at delivery were analyzed for medication concentrations. Placental passage was defined as the ratio of umbilical cord to maternal plasma concentrations (ng/ml). Obstetrical outcome was ascertained through maternal reports and reviews of obstetrical records. RESULTS: Fifty-four pregnant women with laboratory-confirmed antipsychotic use proximate to delivery were included in the analysis. Complete maternal-infant sample pairs were available for 50 participants. Placental passage ratio was highest for olanzapine (mean=72.1%, SD=42.0%), followed by haloperidol (mean=65.5%, SD=40.3%), risperidone (mean=49.2%, SD=33.9%), and quetiapine (mean=23.8%, SD=11.0%). There were tendencies toward higher rates of low birth weight (30.8%) and neonatal intensive care unit admission (30.8%) among neonates exposed to olanzapine. CONCLUSIONS: All four antipsychotics demonstrated incomplete placental passage. Quetiapine demonstrated the lowest placental passage of the medications studied. These novel data provide an initial quantification of the placental passage of antipsychotics and fetal exposure in humans, demonstrating significant differences between individual medications.

Prospective Longitudinal Study of Predictors of Postpartum-Onset Depression in Women With a History of Major Depressive Disorder.

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.

Prenatal Psychostimulant and Antidepressant Exposure and Risk of Hypertensive Disorders of Pregnancy.

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.

Temperament and behavior in toddlers of mothers with bipolar disorder: a preliminary investigation of a population at high familial risk for psychopathology.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Maternal depression and anxiety differentially impact fetal exposures during pregnancy.

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.

Comparison of women with confirmed versus presumably misdiagnosed bipolar disorder.

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.

DNA methylation in neonates born to women receiving psychiatric care.

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.

Prenatal antiepileptic exposure associates with neonatal DNA methylation differences.

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.

Neonatal DNA methylation patterns associate with gestational age.

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.

Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals?

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.

Venlafaxine in human breast milk and nursing infant plasma: determination of exposure.

OBJECTIVE: Venlafaxine use during pregnancy has increased over the past decade in concert with accumulating reproductive safety data; however, systematic data on venlafaxine during lactation remain sparse. The current study characterizes the level and determinants of venlafaxine and desvenlafaxine concentrations in breast milk and in nursing infant plasma. METHOD: Women participating in a prospective investigation of perinatal pharmacokinetics from January 2001 through July 2006 who were treated with venlafaxine and who chose to continue venlafaxine during lactation 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 were collected over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Venlafaxine and desvenlafaxine concentrations were determined using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. RESULTS: Thirteen women and their nursing infants participated, providing 106 breast milk samples. The mean milk/plasma ratio was 275.3% (95% CI = 144.8% to 405.7%). There were statistically significant time courses of excretion for venlafaxine (R = 0.36, F = 6.82, P < .02), desvenlafaxine (R = 0.48, F = 4.41, P < .009), and combined venlafaxine/desvenlafaxine (R = 0.51, F = 5.16, P < .004), with the highest venlafaxine and desvenlafaxine concentrations in the breast milk occurring 8 hours after maternal ingestion. Infant plasma concentrations for combined venlafaxine/desvenlafaxine were 37.1% of maternal plasma concentrations. The theoretical infant venlafaxine/desvenlafaxine dose was 0.208 mg/kg/d, and the relative infant venlafaxine/desvenlafaxine dose was 8.1%. The theoretical and relative infant doses for desvenlafaxine were 197% and 224% higher, respectively, than those for venlafaxine. No adverse events were observed or reported in the nursing infants. CONCLUSIONS: Consistent with previous investigations of medications in breast milk, the venlafaxine and desvenlafaxine milk/plasma ratios were highly variable. The rate of venlafaxine/desvenlafaxine excretion into human breast milk is relatively higher than that observed for other antidepressants, largely due to higher desvenlafaxine excretion. These data expand the extant literature on venlafaxine and desvenlafaxine in lactation.