Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.

This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines the landmark pharmacological journey of brexanolone as a first-in-class neurosteroid antidepressant with significant advantages over traditional antidepressants. PPD is a neuroendocrine disorder that affects about 20% of mothers after childbirth and is characterized by symptoms including persistent sadness, fatigue, dysphoria, as well as disturbances in cognition, emotion, appetite, and sleep. The main pathology behind PPD is the postpartum reduction of neurosteroids, referred to as neurosteroid withdrawal, a concept pioneered by our preclinical studies. We developed neurosteroid replacement therapy (NRT) as a rational approach for treating PPD and other conditions related to neurosteroid deficiency, unveiling the power of neurosteroids as novel anxiolytic-antidepressants. The neurosteroid, brexanolone (BX), is a progesterone-derived allopregnanolone that rapidly relieves anxiety and mood deficits by activating GABA-A receptors, making it a transformational treatment for PPD. In 2019, the FDA approved BX, an intravenous formulation of allopregnanolone, as an NRT to treat PPD. In clinical studies, BX significantly improved PPD symptoms within hours of administration, with tolerable side effects including headache, dizziness, and somnolence. We identified the molecular mechanism of BX in a neuronal PPD-like milieu. The mechanism of BX involves activation of both synaptic and extrasynaptic GABA-A receptors, which promote tonic inhibition and serve as a key target for PPD and related conditions. Neurosteroids offer several advantages over traditional antidepressants, including rapid onset, unique mechanism, and lack of tolerance upon repeated use. Some limitations of BX therapy include lack of aqueous solubility, limited accessibility, hospitalization for treatment, lack of oral product, and serious adverse events at high doses. However, the unmet need for synthetic neurosteroids to address this critical condition supersedes these limitations. Recently, we developed novel hydrophilic neurosteroids with a superior profile and improved drug delivery. Overall, approval of BX is a major milestone in the field of neurotherapeutics, paving the way for the development of novel synthetic neurosteroids to treat depression, epilepsy, and status epilepticus.

Estrogen administration and withdrawal in a model of hormone-simulated pregnancy lead to alterations in behavior and gene expression but do not induce depression-like phenotypes in mice.

Pregnancy and the post-partum period are associated with substantial fluctuations in hormone levels and are frequently associated with significant stress. Many individuals also experience affective disturbances during the peri­partum period, including anxiety, the 'baby blues,' and post-partum depression. However, the extent to which these affective changes result from rapidly altering hormone levels, increased stress, or the combination of both remains largely unknown. The current study sought to evaluate the consequences of pregnancy-like hormonal changes on behavior and gene expression in c57BL/6 mice in the absence of stress using a hormone-simulated pregnancy model. Our results reveal that animals receiving hormone injections to simulate the high levels of estrogen observed in late pregnancy and animals withdrawn from estrogen to mimic the rapid decline in this hormone following parturition both exhibit increased anxiety-like behavior compared to ovariectomized controls in the novel open field test. However, no other significant anxiety- or depression-like alterations were observed in either hormone-treated group compared to ovariectomized controls. Both hormone administration and estrogen withdrawal were shown to induce several significant alterations in gene expression in the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. In contrast to the estrogen withdrawal hypothesis of post-partum depression, our results suggest that this method estrogen withdrawal following hormone-simulated pregnancy in the absence of stress does not induce phenotypes consistent with post-partum depression in c57BL/6 mice. However, given that estrogen withdrawal does lead to significant gene expression changes in two stress-sensitive brain regions, it remains possible that estrogen withdrawal could still contribute to affective dysregulation in the peri-partum period by influencing susceptibility to stress. Future research is required to evaluate this possibility.

Factors Associated With Postpartum Smoking Relapse Among Women Who Quit in Early Pregnancy: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

BACKGROUND: While a wide range of predictors of postpartum smoking relapse have been suggested, population-based studies have rarely examined these factors exclusively among women who quit in early pregnancy. Furthermore, workplace secondhand smoke (SHS) exposure has never been examined. METHODS: We analyzed data from 10,466 pregnant women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Age, education, parity, breastfeeding, postpartum depression, SHS exposure at home, and SHS exposure at work (not working, working without SHS exposure, working with SHS exposure) were evaluated as possible predictors. Multiple logistic regression analyses were conducted to examine the associations between these factors and smoking relapse by 1 year postpartum among women who quit in early pregnancy. Analyses stratified by SHS exposure at home were also conducted. RESULTS: About one-fourth of early-pregnancy quitters had relapsed into smoking by 1 year postpartum. Lower education, multiparity, not breastfeeding, postpartum depression, and SHS exposure at home were associated with increased risks of smoking relapse. Working with SHS exposure was associated with an increased risk of smoking relapse; the multivariate-adjusted odds ratios of working without SHS exposure and working with SHS exposure compared with not working were 1.14 (95% confidence interval [CI], 0.82-1.59) and 2.18 (95% CI, 1.37-3.46), respectively. The significant association of workplace SHS exposure was observed only among women without SHS exposure at home. CONCLUSION: SHS exposure at work, as well as education, multiparity, breastfeeding, postpartum depression, and SHS exposure at home were associated with postpartum smoking relapse among early-pregnancy quitters.

The effects of omega-3 polyunsaturated fatty acids supplementation in pregnancy, lactation, and infancy: An umbrella review of meta-analyses of randomized trials.

We aimed to perform an umbrella review of systematic reviews and meta-analyses (SRMAs) of randomized clinical trials (RCT) of the effects of long-chain omega-3 fatty acid supplementation in pregnancy, lactation, and infancy. We searched PubMed, Scopus, and Web of Science to November 2020. Two independent investigators extracted the information, evaluated the methodological quality of SRMAs using A Measurement Tool to Assess Systematic Reviews-2 (AMSTAR2), and rated the certainty of evidence using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. Either a fixed-effects or a random-effects model was used to recalculate the effect sizes and 95%CIs, depending on the number of trials. Overall, 28 SRMAs of RCTs, reporting 124 outcomes from 672 RCTs with 273,523 participants were considered eligible for the present umbrella review. Our results demonstrated evidence of moderate to high certainty that omega-3 supplementation reduced the risk of pre-eclampsia and low-birth weight and improved head circumference when used in pregnant women, and reduced severe retinopathy of prematurity and cholestasis when used in infancy. There were also favorable effects on preterm delivery, pre-natal and post-partum depression, glycemic control and inflammation markers in pregnant women, and sensitization to peanuts, positive skin prick tests, anthropometric measures, language development, visual acuity, and duration of ventilation in infants (GRADE = low). Our findings suggested that omega-3 supplementation during pregnancy can exert favorable effects against pre-eclampsia, low-birth weight, pre-term delivery, and post-partum depression, and can improve anthropometric measures, immune system, and visual activity in infants and cardiometabolic risk factors in pregnant mothers.

Brexanolone: A Novel Drug for the Treatment of Postpartum Depression.

OBJECTIVES: To review the pharmacology, efficacy, and safety of Brexanolone and define its role in the treatment of postpartum depression. DATE SOURCES: A MEDLINE/PubMed search was conducted (1980-May 2020) using the following keywords: postpartum depression, antidepressants, pharmacologic therapy, drug therapy, and brexanolone to identify relevant articles. STUDY SELECTION/DATA EXTRACTION: Literature search was limited to human studies published in the English language. Phase I, II, and III studies evaluating the pharmacology, efficacy, safety of brexanolone for postpartum depression were included. Bibliographies of relevant articles evaluating postpartum depression and treatment were reviewed for additional citations and background information. DATA SYNTHESIS: Brexanolone is a soluble, proprietary, injectable formulation of allopregnanolone, a neuroactive steroid that modulates neuronal excitability. Allopregnanolone levels increase during pregnancy and decrease substantially after birth. These fluctuations have profound effects on anxiety and depression. Three clinical trials established the efficacy and safety of brexanolone in the treatment of postpartum depression. In all 3 trials, brexanolone had an acceptable safety profile and was well tolerated. The most common adverse effects were loss of consciousness, sedation, dry mouth, headache, dizziness, and flushing. Due to sudden loss of consciousness and excessive sedation, continuous pulse oximetry is recommended. CONCLUSION: Brexanolone has a novel mechanism of action and appears to be safe and effective for the treatment of moderate to severe postpartum depression. At present, high cost, serious adverse effects, and restricted access may limit its use in clinical practice.

Prenatal Exposure to Bisphenols and Phthalates and Postpartum Depression: The Role of Neurosteroid Hormone Disruption.

CONTEXT: Postpartum depression (PPD) is a serious psychiatric disorder. While causes remain poorly understood, perinatal sex hormone fluctuations are an important factor, and allopregnanolone in particular has emerged as a key determinant. Although synthetic environmental chemicals such as bisphenols and phthalates are known to affect sex hormones, no studies have measured allopregnanolone and the consequences of these hormonal changes on PPD have not been interrogated. OBJECTIVE: To investigate associations of repeated measures of urinary bisphenols and phthalates in early and midpregnancy with serum pregnenolone, progesterone, allopregnanolone, and pregnanolone concentrations in midpregnancy and PPD symptoms at 4 months postpartum. METHODS: Prospective cohort study of 139 pregnant women recruited between 2016 and 2018. Bisphenols and phthalates were measured in early and midpregnancy urine samples. Serum sex steroid hormone concentrations were measured in midpregnancy. PPD was assessed at 4 months postpartum using the Edinburgh Postnatal Depression Scale (EPDS). Multiple informant models were fit using generalized estimating equations. Serum levels of allopregnanolone, progesterone, pregnanolone, and pregnenolone were examined as log-transformed continuous variables. PPD symptoms were examined as continuous EPDS scores and dichotomously with scores ≥10 defined as PPD. RESULTS: Di-n-octyl phthalate (DnOP) and diisononyl phthalate (DiNP) metabolites were associated with reduced progesterone concentrations. Log-unit increases in ∑DnOP and ∑DiNP predicted 8.1% (95% CI -15.2%, -0.4%) and 7.7% (95% CI -13.3%, -1.7%) lower progesterone, respectively. ∑DnOP was associated with increased odds of PPD (odds ratio 1.48; 95% CI 1.04, 2.11). CONCLUSION: Endocrine disrupting chemicals may influence hormonal shifts during pregnancy as well as contribute to PPD.

Methyldopa as an inductor of postpartum depression and maternal blues: A review.

PURPOSE: Pregnancy and time period right after labour are connected with some dangerous states, such as: pregnancy-induced hypertension (PIH), which afflict 6-10 % of pregnant women and mood disorders where postpartum depression occurs among 10-15 % of women after labour and so-called baby blues afflicts around 43 % of them. Scientists tried to link those diseases which afflicts thousands of women per year, and the linking factor appears to be methyldopa which is the first choice treatment of PIH. Recent study showed that 778 % of pregnant women treated with methyldopa suffered to postpartum depression. Aim of this article is to delineate mechanisms through which methyldopa induce mood disorders. METHODS: Authors reviewed following databases for randomized controlled trials and review articles published up to February 2019: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. Keywords used to research were: postpartum depression, methyldopa, depression, baby blues, pregnancy-induced hypertension, gestational hypertension, VEGF, nitric oxide, prolactin, hyperprolactinaemia. Selection of studies was based on relevance, year of publication, and reliability of methodology. Authors included every study contributory to assessment of scale of the problem of postpartum depression and baby blues, along with connection of those diseases with usage of methyldopa. RESULTS: Methyldopa alterate neurotrophic factors levels, impairs cerebral blood flow, and through dopamine level reduction it impairs reward system and increase prolactin release. Moreover, methyldopa leads to catecholamines depletion which impairs neurons function and increase concentration of nitric oxide (NO) which have neurotoxic properties. CONCLUSIONS: Epidemiological, as well as pharmacological studies confirmed important role of methyldopa in induction of postpartum depression and baby blues through hormone alteration, reduced cerebral blood flow and neurons function impairment. This study proves how important for women's health is this problem and how complex is its mechanism.

Postpartum hormonal contraception use and incidence of postpartum depression: a systematic review.

PURPOSE: To evaluate the association between postpartum hormonal contraceptive use and postpartum depression. MATERIALS AND METHODS: We searched the literature through March 2018 on the association between postpartum hormonal contraception use and incident postpartum depression. We used the United States Preventive Services Task Force framework to assess study quality. RESULTS: Of 167 articles identified, four met inclusion criteria. Two studies found no differences in rates of postpartum depression between women using postpartum depot medroxyprogesterone and those not using hormonal contraception; however, a study of women receiving injectable norethisterone enanthate immediately postpartum found a 2-3-fold increased risk of depression at 6 weeks, though not at 3 months. One study compared combined hormonal contraception, progestin-only pills (POPs), etonogestrel implants and levonorgestrel intrauterine devices (LNG-IUDs) with no hormonal contraception, and found a 35-44% decreased risk of postpartum depression with POPs and LNG-IUDs, a small increased risk of postpartum antidepressant use among women using the etonogestrel implant and vaginal ring, and a decreased risk of antidepressant use with POPs. CONCLUSIONS: Limited evidence found no consistent associations between hormonal contraceptive use and incidence of postpartum depression. Future research would be strengthened by using validated diagnostic measures, careful consideration of confounders, and ensuring adequate follow-up time.

Risk analysis of suicidal ideations and postpartum depression with antenatal alpha methyldopa use.

Out of the various risk factors for postpartum depression, use of pharmacotherapy during pregnancy is the most poorly understood. The present study aimed to establish risk of postpartum depression and suicidal ideations with antenatal use of alpha methyldopa. Out of the 100 postpartum women assessed, 77.78% of the women who were prescribed alpha methyldopa had significant postpartum depression. There was statistically significant risk of postpartum depression associated with alpha methyldopa (p = 0.026, OR = 6.45). There was no increased suicidal risk with use of alpha methyldopa in these women (p = 1.00).

Selective Serotonin Reuptake Inhibitors during Pregnancy: Do We Have Now More Definite Answers Related to Prenatal Exposure?

Despite extensive studies, there still seems to be uncertainty as to the possible reproductive risk of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs) in pregnancy. We, therefore, assess the current data on the risk/benefit of SSRI use in pregnancy. As the neurodevelopmental effects of SSRIs are discussed in another paper in this issue, we will not address the possible neurodevelopmental effects. Special emphasis is given to the newer, large population-based studies. Most studies have shown that the overall risk of major malformations is similar to that in unexposed children, except for some small increased risk for cardiac anomalies. Persistent pulmonary hypertension of the newborn has also been described with a low absolute risk of <1%, less than twice that observed in nonexposed newborns. Poor neonatal adaptation was described in up to 25% of exposed neonates. However, newer population-based studies have also shown similarly high rates among offspring of women with untreated depression. There is a higher risk for psychiatric problems possibly related to the maternal psychiatric disease for which SSRIs were prescribed. Judging from the new population registry-based studies with comparison to disease controls, there seems to be no demonstrable increase in the rate of major anomalies, prematurity, small for gestational age, or miscarriage. Therefore, the risk associated with treatment discontinuation (e.g., higher frequency of relapse, and postpartum depression) appears to outweigh the fetal and neonatal risks of maternal treatment. Thus, following appropriate explanation regarding possible risks, treatment should continue during pregnancy with minimal effective doses. Birth Defects Research 109:898-908, 2017. © 2017 Wiley Periodicals, Inc.

Organochlorine pesticide residues in breast milk and maternal psychopathologies and infant growth from suburban area of Ankara, Turkey.

We aimed to determine the levels of organochlorine pesticides (OCPs) in the breast milk; to assess the effect of detectable OCPs on maternal-infant characteristics and; to evaluate the relation between OCPs and the maternal psychopathologies [Brief Symptom Inventory (BSI), Postpartum Bonding Questionnaire (PBQ), Mother-to-Infant Bonding Scale (MIBS) and Edinburgh Postnatal Depression Scale (EPDS)] and infant growth. DDT, beta-hexachlorocyclohexane (HCH), aldrin and heptachlor were detected in 89.3, 70.7, 58.7 and 34.7 % of the samples, respectively. Mothers with low monthly family income had detectable DDTs less frequently. The frequencies of detectable heptachlor epoxide were significantly higher in mothers with gestational nausea. Anaemic mothers had more frequently detectable alpha-HCH. Z scores of head circumference were inversely correlated with beta-HCH and DDT levels. The heptachlor epoxide levels were positively correlated with PBQ, MIBS and indexes of BSI. No relation was detected between EPDS and OCPs. Further studies are needed for changes in maternal psychopathologies.

Antidepressant-like effects of omega-3 fatty acids in postpartum model of depression in rats.

Postpartum depression (PPD) is a psychiatric disorder that occurs in 10-15% of childbearing women. It is hypothesized that omega-3 fatty acids, which are components of fish oil, may attenuate depression symptoms. In order to examine this hypothesis, the animal model of postpartum depression was established in the present study. Ovariectomized female rats underwent hormone-simulated pregnancy (HSP) regimen and received progesterone and estradiol benzoate or vehicle for 23 days, mimicking the actual rat's pregnancy. The days after hormone termination were considered as the postpartum period. Forced feeding of menhaden fish oil, as a source of omega-3, with three doses of 1, 3, and 9g/kg/d, fluoxetine 15mg/kg/d, and distilled water 2ml/d per rat started in five postpartum-induced and one vehicle group on postpartum day 1 and continued for 15 consecutive days. On postpartum day 15, all groups were tested in the forced swimming test (FST) and open field test (OFT), followed by a biochemical assay. Results showed that the postpartum-induced rats not treated with menhaden fish oil, exhibited an increase in immobility time seen in FST, hippocampal concentration of corticosterone and plasmatic level of corticosterone, and pro-inflammatory cytokines. These depression-related effects were attenuated by supplementation of menhaden fish oil with doses of 3 and 9g/kg. Moreover, results of rats supplemented with menhaden fish oil were comparable to rats treated with the clinically effective antidepressant, fluoxetine. Taken together, these results suggest that menhaden fish oil, rich in omega-3, exerts beneficial effect on postpartum depression and decreases the biomarkers related to depression such as corticosterone and pro-inflammatory cytokines.

Estradiol modulates anhedonia and behavioral despair in rats and negative affect in a subgroup of women at high risk for postpartum depression.

In an effort to address inconsistencies in the literature, we tested a cross-species estrogen withdrawal model of postpartum depression (PPD) with a series of rodent experiments and a prospective, naturalistic human study. All rats were ovariectomized prior to experimentation. The first rat experiment examined the effects of low- and high-dose estradiol administration and withdrawal on lateral-hypothalamic self-stimulation, a behavioral index of anhedonia, in experimental (n=7) and vehicle-only control animals (n=7). The second rat experiment examined the effects of high-dose estradiol withdrawal on activity and immobility during the forced swim test, an index of behavioral despair, in a separate group of experimental (n=8) and vehicle-only control animals (n=8). In the human study, women with (n=8) and without (n=12) a history of PPD completed mood ratings and collected saliva samples (to assess estradiol levels) daily during the third trimester of pregnancy through 10 days postpartum. The presence of PPD was assessed at one month postpartum. In the animal studies, rats in the estradiol withdrawal group demonstrated significantly greater immobility and less swimming than controls. Estradiol withdrawal resulted in reduced responding for electrical stimulation (multiple intensities) relative to estradiol administration. In the human study, there was no significant association between estradiol and negative affect among women with or without a history of PPD. However, there was a correlation between daily estradiol levels and negative affect in the women with incident PPD at one month postpartum. Despite important cross-species differences, both the rat and human studies provided evidence of the effects of estradiol on perinatal depressive symptoms.

Testing of a prototype Web based intervention for adolescent mothers on postpartum depression.

PURPOSE: This article describes testing of a prototype Web site for adolescent mothers with postpartum depression; providing proof of concept. METHODS: Participants (N=138) were recruited from a public school-based program for adolescent parents and completed the Mental Health Acceptability Scale, Stigma Scale for Receiving Psychological Help, and Attitudes Towards Seeking Professional Psychological Help Scale before, and after, the Web site intervention. They also provided feedback on the usability of the Web site. RESULTS: Attitudes related to depression and treatment (ATSPPH) improved after viewing the Web site (p=.023). Feedback on the Web site indicated that it was easy to use (77%), reflecting highly acceptable score for product usability. CONCLUSIONS: The data provide the foundation for the launch of the Web site from prototype to product and more comprehensive testing. The creation and testing of informational text messages will be added to the Web site to increase the interactivity and dose of the intervention.

Chronic corticosterone during pregnancy and postpartum affects maternal care, cell proliferation and depressive-like behavior in the dam.

Stress during pregnancy and the postpartum can influence the well-being of both the mother and her offspring. Prolonged elevated levels of glucocorticoids are associated with depression and we developed an animal model of postpartum depression/stress based on high levels of corticosterone (CORT) during the postpartum. Gestational stress is a risk factor for postpartum depression and prenatal and/or postnatal high levels of CORT may have differential effects on the mother. Thus the present study was conducted to investigate the effects of low (10mg/kg) or high levels of CORT (40mg/kg) given to dams either during gestation, postpartum or across both gestation and postpartum on maternal care, depressive-like behavior and hippocampal cell proliferation in the dam. Only the high dose of CORT administered during the postpartum increased depressive-like behavior in the dam. Furthermore the high dose of CORT altered maternal care (reduced time spent on the nest and nursing) regardless of whether administration of CORT was during gestation or postpartum. Gestational and/or postpartum treatment with high CORT and postpartum low CORT reduced cell proliferation in the dentate gyrus of postpartum dams compared to oil-treated controls. Thus prolonged treatment with high levels of CORT postpartum reduced maternal care, hippocampal cell proliferation and induced depressive-like behavior in the dam and therefore might be considered an animal model of postpartum depression. More research is needed to understand the effects of stress hormones during different phases of reproduction and how they affect the brain and behavior of the mother and her offspring.

GABA(A) receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat.

Postpartum mammals show suppressed anxiety, which is necessary for their ability to appropriately care for offspring. It is parsimonious to suggest that the neurobiological basis of this reduced anxiety is similar to that of non-parturient animals, involving GABA(A) receptor activity in sites including the midbrain periaqueductal gray (PAG). In Experiment 1, postpartum and diestrous virgin female rats received an intraperitoneal injection of the GABA(A) receptor antagonist (+)-bicuculline (0, 2 and 4 mg/kg) and anxiety-related behavior was assessed with an elevated plus maze. The 4 mg/kg dose of (+)-bicuculline significantly increased anxiety-related behavior, particularly in the postpartum females. Experiment 2 revealed that bicuculline's action was within the central nervous system, because anxiety in neither dams nor virgins was significantly affected by intraperitoneal injection of bicuculline methiodide (0, 2 and 6 mg/kg), which does not readily cross the blood-brain-barrier. In Experiment 3, bicuculline methiodide (2.5 ng/side) was directly infused into the ventrocaudal PAG (cPAGv) and significantly increased dams' anxiety compared to saline-infused controls. These studies expand our knowledge of how GABA(A) receptor modulators affect anxiety behaviors in postpartum rats to the widely-used elevated plus maze, and indicate that the postpartum suppression of anxiety is in part a consequence of elevated GABAergic neurotransmission in the cPAGv.

Current issues: women and bipolar disorder.

While the treatment of bipolar disorder (BD) is typically complex, the treatment of women with bipolar disorder is even more challenging because clinicians must also individualize treatment based on the potential for pregnancy, drug interactions with oral contraceptives, and an increased risk of endocrine diseases that can either impact the course of illness or become manifest with some treatments. Women with BD should be checked for hypothyroidism, and if prescribed antidepressants, carefully watched for rapid cycling or a mood switch to mania, hypomania, or a mixed state. Several medications interact with oral contraceptives or increase the risk of developing polycystic ovary syndrome. Consideration of possible pregnancy is essential, and should be planned in advance whenever possible. Rates of recurrence have been shown to be equal in pregnant and nonpregnant women with BD. Risks of medication to the fetus at various points of development must be balanced against the risks of not treating, which is also detrimental to both fetus and mother. The postpartum period is a time of especially high risk; as many as 40% to 67% of women with BD report experiencing a postpartum mania or depression. The decision to breastfeed must also take into account the adverse impact of sleep deprivation in triggering mood episodes. In order to best address these issues, clinicians must be familiar with the data and collaborate with the patient to assess risks and benefits for the individual women and her family.

Ovarian hormone withdrawal-induced "depression" in female rats.

Approximately 15% of child-bearing women develop postpartum depression (PPD), and many women with PPD experience anxious symptoms. It has been proposed that PPD is precipitated by the dramatic decline in reproductive hormones that occurs just after childbirth. To examine this hypothesis, ovariectomized female Sprague-Dawley rats underwent a hormone-simulated pregnancy (HSP) regimen; during the subsequent hormone withdrawal period, rats were tested in the forced swim test or elevated plus-maze, animal models of depression and anxiety, respectively. The HSP regimen consisted of injections with progesterone and escalating doses of estradiol benzoate for 22 days; control rats received daily vehicle injections. One, two, four or seven days after the last hormone injection, separate groups of rats were tested once on either the forced swim test or the elevated plus-maze. To examine any hormone withdrawal-induced changes in activity levels, spontaneous locomotor activity was measured at the same time points. At 2 and 4 days after the last hormone injection, HSP-treated females displayed significant increases in immobility relative to vehicle-treated females in the forced swim test. Behavior on the elevated plus-maze did not differ between the HSP and control groups at any of the withdrawal time points. There were also no differences in spontaneous locomotor activity between the HSP and control females at any of the withdrawal time points. The results of this study suggest that postpartum hormone withdrawal may contribute to depressive symptoms experienced after giving birth, and that the HSP-hormone withdrawal protocol may provide a useful animal model of PPD.

Morphine pretreatment increases opioid inhibitory effects on maternal behavior.

Ongoing maternal behavior in rats is under the inhibitory influence of opiates. Exposure to drugs of abuse may result in a progressive and enduring enhancement of their reinforcing effects. Little attention has been paid to the possibility that puerperal treatment with morphine may lead to sensitization to this drug, ultimately influencing the effects of opiates on maternal behavior. The aim of the present study was to investigate if the abrupt withdrawal of repeated treatment with morphine chlorhydrate (MC) during late pregnancy and early lactation may influence maternal behavior in lactating rats. The premise that a possible change in sensitivity to the inhibitory effect of MC on maternal behavior would last at least until day 17 of lactation without any reinforcement was tested. In addition, the hypothesis that the MC-induced inhibition would be reversed by the opioid antagonist naloxone was also tested. In all experiments female Wistar rats were treated with MC (5.0 mg/kg/day, subcutaneous [s.c.]) or saline for 7 days starting on the 17th day of pregnancy. After the abrupt discontinuation of long-term treatment, animals were acutely challenged with MC (5.0 mg/kg, s.c.) or saline and tested for maternal behavior in three different experimental situations: first, on days 5, 10, and 17 postpartum (Experiment 1); second, on day 17 postpartum (Experiment 2); third, on day 6 postpartum following naloxone pretreatment (1.0 mg/kg; Experiment 3). In Experiment 1, animals were treated for 7 days with morphine and acutely challenged with MC (group MM). Experimental MM animals showed significantly longer latencies for all maternal behavior parameters than all other groups during all observation days. The other groups (treated with MC for 7 days and acutely challenged with saline, group MS; treated with saline for 7 days and acutely challenged with MC, group SM; and treated with saline for 7 days and acutely challenged with saline, group SS) did not differ significantly from one another. In Experiment 2, in which rats were submitted to a single test on day 17 of lactation, the MM group showed significantly longer latencies for all behavioral parameters as compared to group SM. Previous acute naloxone treatment (Experiment 3) reversed the inhibitory effects of MC on maternal behavior in lactating rats. These data suggest that repeated administration of MC to female rats during late pregnancy sensitizes the animals to the inhibitory effects of opioids on rat ongoing maternal behavior.

Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression.

The effect of hormone withdrawal following hormone-simulated "pregnancy" on "depressive-like behavior" in the Forced Swim Test (FST) was investigated in female Long-Evans rats. Females were randomly assigned to "pregnant", "pregnant"+estradiol benzoate (EB), and control groups. Both the "pregnant" and "pregnant"+EB groups received daily injections of the hormones estradiol and progesterone to simulate the 23-day gestational period in the rat. However, the "pregnant"+EB group continued to receive daily estradiol injections after "pregnancy". All groups were tested 48 h after the last injection of the pregnancy period in the FST and subsequently in the Open Field Test (OFT). Results revealed that the "pregnant" rats exhibited significantly increased immobility and decreased struggling and swimming behaviors as compared to the "pregnant"+EB and control groups. These findings could not be explained by an overall depression in general locomotor activity among "pregnant" rats, as the "pregnant" rats made more area crossings in the OFT. Thus "pregnant" rats exhibited behaviors consistent with "depressive-like" symptoms "post-partum" (after their hormone regime was discontinued). Continual treatment with high levels of estradiol in the "pregnant"+EB group, however, reversed the exhibition of these behaviors. These results imply that withdrawal from chronic high levels of pregnancy-associated hormones (estradiol and progesterone) can produce depressed symptomology in rodents, which can be prevented by prolonging exposure to high levels of estradiol through the post-partum period. These findings are the first demonstration of "depressive-like" symptoms in a rodent model of post-partum pregnancy and the ability of high levels of estradiol to attenuate these "depressive-like" symptoms.