In utero exposure to ADHD medication and long-term offspring outcomes.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Outcomes at the Motherhood Center: A Comparison of Virtual and On-Site Versions of a Specialized Perinatal Partial Hospitalization Program.

OBJECTIVES: Remotely administered mental health care is becoming increasingly common for treatment of a range of psychiatric disorders; however, there is a dearth of literature overviewing direct comparisons between remote and in-person interventions for treatment of Perinatal Mood and Anxiety Disorders (PMADs). The sudden advent of the Covid-19 pandemic in New York City forced an abrupt conversion for an intensive day treatment program for new mothers with PMADs, from an on-site to a remote program. METHODS: The current report compares outcomes of 81 women who completed the program in-person to those of 60 women who completed the program remotely. RESULTS: Improvement in depression scores was statistically superior in the remote program, and improvement in mother-infant bonding was statistically equivalent between the on-site and remote programs. DISCUSSION: These findings indicate that specialized partial hospitalization treatment for individuals with moderate to severe psychiatric illness can be effectively provided via telehealth, thus offering improved convenience, accessibility, and safety without compromising care. We conclude that remotely administered group psychotherapy is an effective intervention for women with moderate to severe PMADs.

Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants.

The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers' attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106 individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.

Risks and benefits of pre-delivery taper in pregnant women taking antidepressants.

BACKGROUND: Serotonin reuptake inhibitors are commonly used for treatment of mental health problems in pregnancy but may cause neonatal adaptation syndrome. It is unknown whether reduction or discontinuation of medication prior to delivery may mitigate this effect. METHODS: We present a case series of 38 women who either tapered their medication prior to delivery or maintained or increased their dose. RESULTS: Greater reductions in maternal antidepressant dose just prior to delivery were associated with fewer admissions to the neonatal intensive care unit (NICU) for infants. There was a slightly greater increase in depressive symptoms across delivery for women who tapered, which was not statistically significant. CONCLUSIONS: NICU admissions may be less frequent among neonates whose mothers tapered their medication prior to delivery. Large prospective randomized trials are needed to further study this practice.

Neurodevelopment in school-aged children after intrauterine exposure to antipsychotics.

OBJECTIVE: Antipsychotics are increasingly prescribed in pregnancy, yet little is known about potential long-term developmental effects on children. In this study, we investigated the effect of prenatal antipsychotic exposure on neurodevelopmental functioning in school-aged children. METHODS: We performed a cross-sectional neurodevelopmental assessment of 91 children aged 6-14 years whose mothers had severe mental illness and were either exposed or unexposed to antipsychotic medication during pregnancy. Neurodevelopmental outcomes were assessed using validated neurodevelopmental assessment instruments to examine the child's IQ and global cognitive functioning, and the presence of any psychiatric disorders and/or learning problems in the child was assessed by parental report. RESULTS: No statistically significant associations were found between antipsychotic exposure during pregnancy and either adverse neurodevelopmental outcomes (IQ, neuropsychological function), likelihood of psychiatric diagnosis, or learning problems based on parental report. Analyses were likely limited in power to detect subtler differences in neurodevelopmental functioning because of small sample size and heterogeneity of the sample. CONCLUSIONS: In this exploratory cohort study, intrauterine exposure to antipsychotics was not associated with any adverse effect on IQ or neurodevelopmental functioning in a cohort of school-aged children (6-14 years).

Breastfeeding Difficulties Predict Mothers' Bonding with Their Infants from Birth to Age Six Months.

OBJECTIVES: We examined the association between breastfeeding difficulties and trajectories of bonding in the first 6 months postpartum. METHODS: Each month for the first 6 months following birth, 121 mothers of newborn infants (age = 23-45 years, M = 32.31 ± 4.79, 57% White, 23% Asian, 11% Hispanic, 9% Multiracial, 1% Black/African American) were invited to complete self-assessments of bonding. At the first postpartum assessment, mothers who intended to breastfeed also reported whether breastfeeding was more difficult than they had anticipated. We conducted linear mixed modelling to test whether early breastfeeding difficulty was associated with bonding trajectories and examined whether effects remained when accounting for postnatal depression symptoms. RESULTS: We found main effects of breastfeeding difficulty (ß = - .20, 95% CI [ -  .34, - .06]) and postpartum month (ß = .13, 95% CI [.07, .20]) on bonding. On average, women who reported breastfeeding difficulty reported lower bonding than women who did not (Cohen's d = - 0.44, 95% CI [- 0.81, - 0.06]). Additional analyses indicated that, independent of breastfeeding difficulties, women who reported higher postnatal depressive symptoms across the first 6 months postpartum reported lower levels of bonding, on average. Further, within-individual decreases in postnatal depressive symptoms across the first six months were associated with relative improvements in bonding across this period. CONCLUSIONS FOR PRACTICE: Our findings suggest that mothers who experience breastfeeding difficulties are at risk for reduced bonding with their infants in the first 6 months after birth. Moreover, while postnatal depressive symptoms are also associated with reduced bonding, the effect of breastfeeding difficulties on bonding persists over and above the effect of postnatal depressive symptoms.

Benzodiazepine use before conception and risk of ectopic pregnancy.

STUDY QUESTION: Are women who fill a benzodiazepine prescription before conception at increased risk of ectopic pregnancy? SUMMARY ANSWER: Risk of ectopic pregnancy is 50% higher among women who fill a benzodiazepine prescription before conception. WHAT IS KNOWN ALREADY: Benzodiazepine use in pregnancy increases the risk of miscarriage, adverse birth outcomes and adverse child development outcomes. STUDY DESIGN, SIZE, DURATION: Using data from US commercial insurance claims, we performed a cohort study of 1 691 366 pregnancies between 1 November 2008 and 30 September 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified ectopic pregnancies using diagnosis and procedure codes and used unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models to calculate relative risks (RR) of ectopic pregnancy for pregnant women who did and did not fill any prescriptions for benzodiazepines in the 90 days before conception. Two sub-groups of women with specific indications for benzodiazepine use were also examined-women who had a least one diagnosis for anxiety disorder and women who had at least one diagnosis of insomnia in the year before conception. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1 691 366 pregnancies, 1.06% filled at least two benzodiazepine prescriptions totaling at least 10 days supply in the 90 days before conception. Among women with a benzodiazepine prescription, there was an excess of 80 ectopic pregnancies per 10 000 pregnancies, and their IPT-weighted risk of ectopic pregnancies was 1.47 (95% CI 1.32 to 1.63) times greater relative to women without benzodiazepine prescriptions before conception. The IPT-weighted RR between ectopic pregnancy and benzodiazepine use was 1.34 (95% CI 1.18 to 1.53) among women with anxiety disorder diagnoses and 1.28 (95% CI 0.99 to 1.68) among women with an insomnia diagnosis. LIMITATIONS, REASONS FOR CAUTION: We relied on outpatient prescription data to identify benzodiazepine use before conception, which could result in over- or under-estimation of actual benzodiazepine consumption. We relied on medical claim codes to identify pregnancies and conception date, which may result in misclassification of pregnancy outcomes and gestational length. WIDER IMPLICATIONS OF THE FINDINGS: This study found that women who have a benzodiazepine prescription before conception are at an increased risk of ectopic pregnancy. This information can help women, and their healthcare providers make more fully informed decisions about benzodiazepine use in their reproductive years. STUDY FUNDING/COMPETING INTEREST(S): Funding for this project was provided by a Banting Postdoctoral Fellowship and a Stanford Maternal and Child Health Research Institute Postdoctoral Award. Data access for this project was provided by the Stanford Center for Population Health Sciences Data Core. The PHS Data Core is supported by a National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and internal Stanford funding. The authors have no competing interest. TRIAL REGISTRATION NUMBER: N/A.

Antidepressant Use around Conception, Prepregnancy Depression, and Risk of Ectopic Pregnancy.

OBJECTIVE: To compare the risk of ectopic pregnancy among women with and women without antidepressant prescriptions around conception and examine whether this risk differs by prepregnancy depression status. METHODS: We conducted a cohort study of all pregnancies between November 1, 2008, and September 30, 2015, identified in the nationwide (American) IBM® MarketScan® Databases. At least one day's supply of antidepressants in the 3 weeks after a woman's last menstrual period defined active antidepressant use around conception. At least one depression diagnosis in the year before the last menstrual period defined prepregnancy depression. Relative risk (RR) of ectopic pregnancy was estimated using unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models. RESULTS: Of the 1,703,245 pregnancies, 106,788 (6.3%) women had a prepregnancy depression diagnosis. Among women with a depression diagnosis, 40,287 (37.7%) had an active antidepressant prescription around conception; the IPT-weighted risk of ectopic pregnancy was similar among women who did and did not fill an antidepressant prescription around conception (IPT-weighted RR = 1.01; 95% CI, 0.93 to 1.10). Overall, the risk of ectopic pregnancy was higher among women who had a prepregnancy depression diagnosis than women who did not have a prepregnancy depression diagnosis (IPT-weighted RR = 1.09; 95% CI, 1.04 to 1.15). CONCLUSIONS: This study's findings suggest that women who have a prepregnancy depression diagnosis are at a slightly increased risk of ectopic pregnancy, and among women who have a prepregnancy depression diagnosis, the use of antidepressants around conception does not increase the risk of ectopic pregnancy.

Depression precedes, but does not follow, gestational diabetes.

OBJECTIVES: To determine whether past history of depression is associated with increased rates of gestational diabetes, and whether history of gestational diabetes is associated with increased rates of postpartum depression. RESEARCH DESIGN: Data for this case-control study consisted of de-identified chart records for 1439 women who received pregnancy care at a large university hospital between 1998 and 2017. RESULTS: A history of depression prior to pregnancy was associated with gestational diabetes requiring insulin, although not with subtler degrees of gestational hyperglycemia. Diabetes in pregnancy was not associated with an increased risk of postpartum depression. Trauma history was associated with both impaired glucose tolerance in pregnancy and postpartum depression. CONCLUSIONS: Past episodes of depression increase risk for the most severe form of gestational diabetes; however, gestational diabetes does not contribute significantly to risk for postpartum depression. This suggests a unidirectional association, unlike the bidirectional association of diabetes with depression among the general population. History of trauma increases risk for both gestational hyperglycemia and postpartum depression, suggesting important health effects of trauma that may differ measurably from those associated with depression.

Optimistic outlook regarding maternity protects against depressive symptoms postpartum.

The transition to motherhood is a time of elevated risk for clinical depression. Dispositional optimism may be protective against depressive symptoms; however, the arrival of a newborn presents numerous challenges that may be at odds with initially positive expectations, and which may contribute to depressed mood. We have explored the relative contributions of antenatal and postnatal optimism regarding maternity to depressive symptoms in the postnatal period. Ninety-eight pregnant women underwent clinician interview in the third trimester to record psychiatric history, antenatal depressive symptoms, and administer a novel measure of optimism towards maternity. Measures of depressive symptoms, attitudes to maternity, and mother-to-infant bonding were obtained from 97 study completers at monthly intervals through 3 months postpartum. We found a positive effect of antenatal optimism, and a negative effect of postnatal disconfirmation of expectations, on depressive mood postnatally. Postnatal disconfirmation, but not antenatal optimism, was associated with more negative attitudes toward maternity postnatally. Antenatal optimism, but not postnatal disconfirmation, was associated with reduced scores on a mother-to-infant bonding measure. The relationships between antenatal optimism, postnatal disconfirmation of expectations, and postnatal depression held true among primigravidas and multigravidas, as well as among women with prior histories of mood disorders, although antenatal optimism tended to be lower among women with mental health histories. We conclude that cautious antenatal optimism, rather than immoderate optimism or frank pessimism, is the approach that is most protective against postnatal depressive symptoms, and that this is true irrespective of either mood disorder history or parity. Factors predisposing to negative cognitive assessments and impaired mother-to-infant bonding may be substantially different than those associated with depressive symptoms, a finding that merits further study.

Familial risk of postpartum psychosis.

Objective: Postpartum psychosis, a mood disorder triggered by childbirth, is one of the most severe psychiatric conditions, with high risks of suicide and infanticide if untreated. While it is evident that genetic factors play a crucial role in disorder risk, the exact extent of their importance is yet to be determined. Methods: This cohort study consisted of 1,648,759 women from the Swedish nationwide registers, of whom 2,514 (0.15%) experienced postpartum psychosis within three months of their first-ever childbirth. We estimated the relative recurrence risk of postpartum psychosis for female full siblings and cousins as a measure of familial, genetic, and environmental risk. Results: Relative recurrence risk of postpartum psychosis in full siblings was 10.69 (95% CI=6.60-16.26) when adjusted for year of and age at childbirth. Although cousins showed an elevated relative recurrence risk, these results did not reach statistical significance (1.78, 95% CI=0.70-3.62). Despite the higher familial risk of postpartum psychosis among full siblings, the absolute risk for women with an affected sibling is relatively low, estimated at 1.55% within the entire population. Conclusions: The observed increased risk of postpartum psychosis in full siblings suggests both genetic and shared environmental influences. However, the lack of significant results in cousins hampers a definitive distinction between these factors. Furthermore, despite increased relative recurrence risk in siblings, their overall likelihood of developing postpartum psychosis remains low. Our study underscores the need for further research to better understand the intricate interplay of genetics and environment in the development of postpartum psychosis.

Biologically based treatment approaches to the patient with resistant perinatal depression.

This study aims to summarize the current state of knowledge regarding approaches to treatment-resistant depression in pregnancy and the postpartum period and to develop algorithms for ante- and postnatal management in cases of refractory major depression. PubMed, Scopus, Google Scholar, and the Cochrane Library databases were searched without temporal restriction. Search terms included pregnancy and depression, perinatal depression, postnatal depression, treatment resistance and depression, antipsychotics and pregnancy, antidepressants and pregnancy, and mood stabilizers and pregnancy. Abstracts were reviewed for relevance, and further articles were obtained from bibliographic citations. There is a significant subpopulation of patients in pregnancy and postpartum whose depressive symptoms do not respond to first-line treatments. No research studies have focused specifically on this population. Data extracted from studies on women with depressive symptoms in pregnancy suggest that in the absence of evidence on which to base clinical decisions, many are receiving combinations of psychotherapeutic medications that have not been specifically studied for use in pregnancy. Antidepressant use in pregnancy is well studied, but studies specifically addressing the case of the patient who does not respond to first-line treatments are absent. Research in this area is urgently needed. The authors review a number of possible therapeutic approaches to treatment-resistant depression in pregnancy and the postpartum period.

Insulin resistance and accelerated cognitive aging.

Insulin resistance may be an early sign of metabolic dysfunction with the potential to lead to neuropsychiatric sequelae in the long term. In order to identify whether insulin resistance in otherwise healthy young and middle-aged adults is associated with preclinical signs of neuropsychiatric impairment, we recruited 126 overweight but nondiabetic, nondepressed individuals who completed an insulin suppression test for direct measurement of insulin resistance as well as a battery of cognitive and neuropsychiatric measures. Insulin resistance was associated with weaker performance on a fine motor task (Purdue Pegboard) as well as increases in subclinical symptoms of depression. We submit that insulin resistance in early to mid-adulthood may be an important predictor of long-term risk for metabolic, psychiatric, and neurobehavioral dysfunction.

Past Psychiatric Conditions as Risk Factors for Postpartum Depression: A Nationwide Cohort Study.

OBJECTIVE: To compare risk for postpartum depression across prior psychiatric diagnoses. METHODS: The deidentified Optum© Clinformatics Data Mart of national commercial insurance claims was used to identify 1,166,577 women of reproductive age with first-observed incidence of pregnancy across all 50 United States from 2003 to 2016. Women with insurance coverage for at least 6 months prior to conception and following delivery were eligible (n = 336,522). Psychiatric diagnoses prior to pregnancy were identified by ICD-9-CM and ICD-10-CM codes, including depression, anxiety and panic disorders, bipolar disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and eating disorders. Primary outcomes included postpartum depression diagnosis at 2 months and 1 year after delivery. Multiple variable logistic regression analysis assessed for independent associations between predictors and outcomes. RESULTS: Among 336,522 pregnancies, 9.4% of women were diagnosed with postpartum depression (n = 31,610). Five percent of women with no depression history developed postpartum depression, compared to 65% of women with depression prior to and during pregnancy. Among women with history of depression who were euthymic during pregnancy, 20% were diagnosed with postpartum depression. A major risk factor was a history of depression (OR = 2.7; 95% CI, 2.6-2.8; P < .001), and depression in pregnancy was a risk factor for continued depression in the postpartum period (OR = 13.1; 95% CI, 12.6-13.6; P < .001). All other psychiatric conditions, including anxiety and panic disorders, bipolar disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and eating disorders, conferred risk for postpartum depression, independent of a comorbid depression history. CONCLUSIONS: We report that all psychiatric diagnoses investigated independently increase risk for postpartum depression and suggest that care providers inquire about psychiatric history to identify and closely monitor women at increased risk for postpartum depression.

DNA methylation patterns in T lymphocytes are generally stable in human pregnancies but CD3 methylation is associated with perinatal psychiatric symptoms.

OBJECTIVES: To determine whether DNA methylation patterns in genes coding for selected T-lymphocyte proteins are associated with perinatal psychiatric distress or with complications of pregnancy. METHODS: T lymphocyte DNA was obtained from pregnant women across three time points in pregnancy and the postpartum period and epigenetic patterns were assessed using Illumina 450 â€‹K Methylation Beadchips. Seven selected genes critical for T cell function were analyzed for methylation changes during pregnancy and for associations of methylation patterns with psychiatric distress or with pregnancy complications, with particular attention paid to spatial aggregations of methyl groups, termed 'hotspots,' within the selected genes. RESULTS: In the candidate gene approach, DNA methylation density within a single cluster of 9 contiguous CpG loci within the CD3 gene was found to be strongly associated with anxiety and depression in mid- and late pregnancy, and weakly associated with the presence of complications of pregnancy. Average DNA methylation density across each of the seven genes examined, and assay-wide, was found to be relatively stable across pregnancy and postpartum, but methylation within the CD3 hotspot was more malleable and changes over time were coordinated across the nine cytosines in the hotspot. CD3 CpGs did not pass array-wide tests for significance, but CpG clusters in two other genes, DTNBP1 and OXSR1, showed array-wide significant associations with anxiety. CONCLUSIONS: Despite the need for tolerating the fetal hemi-allograft, overall DNA methylation patterns in T lymphocytes are generally stable over the mid to late course of human pregnancies and postpartum. However, site-specific changes in DNA methylation density in CD3 appear linked to both symptoms of depression and anxiety in pregnancy and, less strongly, to adverse pregnancy outcomes.

Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression.

Early life adversity and insecure attachment style are known risk factors for perinatal depression. The biological pathways linking these experiences, however, have not yet been elucidated. We hypothesized that overlap in patterns of DNA methylation in association with each of these phenomena could identify genes and pathways of importance. Specifically, we wished to distinguish between allostatic-load and role-transition hypotheses of perinatal depression. We conducted a large-scale analysis of methylation patterns across 5 × 106 individual CG dinucleotides in 54 women participating in a longitudinal prospective study of perinatal depression, using clustering-based criteria for significance to control for multiple comparisons. We identified 1580 regions in which methylation density was associated with childhood adversity, 3 in which methylation density was associated with insecure attachment style, and 6 in which methylation density was associated with perinatal depression. Shorter telomeres were observed in association with childhood trauma but not with perinatal depression or attachment insecurity. A detailed analysis of methylation density in the oxytocin receptor gene revealed similar patterns of DNA methylation in association with perinatal depression and with insecure attachment style, while childhood trauma was associated with a distinct methylation pattern in this gene. Clinically, attachment style was strongly associated with depression only in pregnancy and the early postpartum, whereas the association of childhood adversity with depression was time-invariant. We concluded that the broad DNA methylation signature and reduced telomere length associated with childhood adversity could indicate increased allostatic load across multiple body systems, whereas perinatal depression and attachment insecurity may be narrower phenotypes with more limited DNA methylation signatures outside the CNS, and no apparent association with telomere length or, by extension, allostatic load. In contrast, the finding of matching DNA methylation patterns within the oxytocin receptor gene for perinatal depression and attachment insecurity is consistent with the theory that the perinatal period is a time of activation of existing attachment schemas for the purpose of structuring the mother-child relationship, and that such activation may occur in part through specific patterns of methylation of the oxytocin receptor gene.

Management of perinatal depression with non-drug interventions.

Perinatal depression is a common disorder that has been associated with serious risks to mother and child. Recently, screening for depression in pregnant and postpartum women has increased, as has the development of new psychotherapy and non-drug treatment modalities. Matching patients to treatments can be challenging, and although research into personalized treatment of major depression in the general population has increased, no published guidelines focus on personalized treatment approaches to perinatal depression. In particular, guidelines on non-drug treatments are lacking. This review summarizes the evidence on personalized non-drug treatment of perinatal depression, how to incorporate patients' preferences, novel treatments under investigation, and the potential role of biomarkers in matching patients to treatment. The review provides recommendations for future research in personalized care of perinatal depression.

Early life adversity blunts responses to pioglitazone in depressed, overweight adults.

PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression. PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression. FINDINGS: We found that early life adversity significantly impaired the metabolic response to pioglitazone. Effects on depressive symptoms did not reach significance, but nonetheless suggested that pioglitazone could mitigate the depressant effects of childhood adversity, only among those insulin resistant at baseline. CONCLUSIONS: We conclude that a history of early life adversity may impair the body's ability to respond to insulin sensitizing pharmacotherapy, and furthermore that its contribution to resistant depression may function in part via the generation of an insulin resistant phenotype.