Search

We sought to determine whether premenstrual mood symptoms exhibit familial aggregation in bipolar disorder or major depression pedigrees. Two thousand eight hundred seventy-six women were interviewed with the Diagnostic Interview for Genetic Studies as part of either the NIMH Genetics Initiative Bipolar Disorder Collaborative study or the Genetics of Early Onset Major Depression (GenRED) study and asked whether they had experienced severe mood symptoms premenstrually. In families with two or more female siblings with bipolar disorder (BP) or major depressive disorder (MDD), we examined the odds of having premenstrual mood symptoms given one or more siblings with these symptoms. For the GenRED MDD sample we also assessed the impact of personality as measured by the NEO-FFI. Premenstrual mood symptoms did not exhibit familial aggregation in families with BP or MDD. We unexpectedly found an association between high NEO openness scores and premenstrual mood symptoms, but neither this factor, nor NEO neuroticism influenced evidence for familial aggregation of symptoms. Limitations include the retrospective interview, the lack of data on premenstrual dysphoric disorder, and the inability to control for factors such as medication use.

Psychiatric conditions (including substance misuse disorders) are serious, potentially life threatening illnesses that can be successfully treated by psychotropic drugs, even during pregnancy. Because few rigorously designed prospective studies have examined the safety of these drugs during pregnancy, the default clinical recommendation has been to discontinue them, especially during the first trimester. However, in the past decade, as more evidence has accumulated, it seems that most psychotropic drugs are relatively safe to use in pregnancy and that not using them when indicated for serious psychiatric illness poses a greater risk to both mother and child, including tragic outcomes like suicide and infanticide. This review presents an up to date and careful examination of the most rigorous scientific studies on the effects of psychotropic drugs in pregnancy. The lack of evidence in several areas means that definite conclusions cannot be made about the risks and benefits of all psychotropic drug use in pregnancy.

Clinical studies over the past decades have attempted to uncover the biological factors mediating the pathophysiology of bipolar disorder (BD) utilizing a variety of biochemical and neuroendocrine strategies. Indeed, assessments of cerebrospinal fluid chemistry, neuroendocrine responses to pharmacological challenge, and neuroreceptor and transporter binding have demonstrated a number of abnormalities in the amine neurotransmitter systems in this disorder. However, recent studies have also implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of BD, in addition to a growing body of data suggesting that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of the disorder. It is thus noteworthy that mood stabilizers and antidepressants indirectly regulate a number of factors involved in cell survival pathways - including MAP kinases, CREB, BDNF and bcl-2 protein - and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects.

Background While major depressive disorder (MDD) is familial, it is not clear whether distinct familial-genetic factors influence vulnerability to depression during or after pregnancy. Here we examine familial aggregation of perinatal major depression (PND, any episode during pregnancy or the month after childbirth) and the subset of post-partum depression (PPD) in families with multiple cases of recurrent, early-onset MDD from the Genetics of Recurrent Early-Onset Depression dataset. Methods The dataset included 691 childbearing women who could be classified as PND (27.6%) or non-PND (NPND), of whom 328 were members of 148 sibships with two or more PND or NPND women. PND and NPND subjects were compared for differences in putative predictors. Prediction of sibling PND or PPD by the proband's history was examined using logistic regression and general estimating equation methods. Results PND was associated with fewer episodes and younger current age. Odds ratios for prediction of sibling status were significant for PND (2.28) and PPD (3.96), particularly when current age was under 46 (2.87 and 4.39, respectively). ORs for PPD were not significantly different from those for PND. The OR for PPD (3.52), but not for PND, remained significant after current age was introduced as a covariate, but not when both current age and number of episodes were included in the model. Limitations Because detailed data were not collected for all pregnancies, we cannot determine whether current age and number of episodes mediated the observed effects due to recall bias or other factors (cohort effect, number of episodes). Conclusions A familial component to PND, and particularly PPD, is suggested by the results. However more systematic study is needed to confirm this result. A greater understanding of both genetic and non-genetic familial factors could lead to improved prevention and clinical management.

Commentary on: Hayes RM, Wu P, Shelton RC, et al. Maternal antidepressant use and adverse outcomes: a cohort study of 228 876 pregnancies. Am J Obstet Gynecol 2012; 207: 49.e1– 9.[OpenUrl][1][CrossRef][2][PubMed][3] Approximately 10–20% of women will meet the criteria for major depressive disorder (MDD) during their lifetime, including during pregnancy.1 Rates of antidepressant exposure … [1]: {openurl}?query=rft.jtitle%253DAmerican%2Bjournal%2Bof%2Bobstetrics%2Band%2Bgynecology%26rft.stitle%253DAm%2BJ%2BObstet%2BGynecol%26rft.aulast%253DHayes%26rft.auinit1%253DR.%2BM.%26rft.volume%253D207%26rft.issue%253D1%26rft.spage%253D49.e1%26rft.epage%253D49.e9%26rft.atitle%253DMaternal%2Bantidepressant%2Buse%2Band%2Badverse%2Boutcomes%253A%2Ba%2Bcohort%2Bstudy%2Bof%2B228%252C876%2Bpregnancies.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.ajog.2012.04.028%26rft_id%253Dinfo%253Apmid%252F22727349%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1016/j.ajog.2012.04.028&link_type=DOI [3]: /lookup/external-ref?access_num=22727349&link_type=MED&atom=%2Febnurs%2F16%2F3%2F74.atom

COMMENTARY ON: Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med 2014;370:2397–407[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4]. Previous studies have had conflicting and inconsistent findings regarding the rates of cardiac malformations in infants exposed to antidepressant medications during the first trimester. Concerns remain, particularly with regard to paroxetine, which has been associated with ventricular outflow tract obstruction,1 and sertraline, which has been associated with ventral septal defects.1 ,2 It has remained unclear if these associations are causal or if risk factors having to do with the underlying illness, depression, play a role. The goal of this study … [1]: {openurl}?query=rft.jtitle%253DN%2BEngl%2BJ%2BMed%26rft.volume%253D370%26rft.spage%253D2397%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa1312828%26rft_id%253Dinfo%253Apmid%252F24941178%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa1312828&link_type=DOI [3]: /lookup/external-ref?access_num=24941178&link_type=MED&atom=%2Febmental%2F18%2F2%2F48.atom [4]: /lookup/external-ref?access_num=000337353000008&link_type=ISI

A somatic mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene causes the loss of glycosyl phosphatidylinositol (GPI)-linked proteins on blood cells from patients with paroxysmal nocturnal hemoglobinuria. Because all blood cell lineages may be affected it is thought that the mutation occurs in a hematopoietic stem cell. In transgenic mice, germline transmission of an inactive Piga gene is embryonic lethal. To inactivate the murine Piga gene in early hematopoiesis we therefore chose conditional gene inactivation using the Cre/loxP system. We expressed Cre recombinase under the transcription regulatory sequences of the human c-fes gene. FES-Cre inactivated PIGA in hematopoietic cells of mice carrying a floxed Piga allele (LF mice). PIGA− cells were found in all hematopoietic lineages of definitive but not primitive hematopoiesis. Their proportions were low in newborn mice but subsequently increased continuously to produce for the first time mice that have almost exclusively PIGA− blood cells. The loss of GPI-linked proteins occurred mainly in c-kit+CD34+Lin− progenitor cells before the CFU-GEMM stage. Using bone marrow reconstitution experiments with purified PIGA− cells we demonstrate that LF mice have long-term bone marrow repopulating cells that lack GPI-linked proteins, indicating that recombination of the floxed Piga allele occurs in the hematopoietic stem cell.

Postpartum depression (PPD) affects between 10 and 20% of women in the general population, but the risk is much higher in women with a history of major depression (MDD) or bipolar disorder (BP) with at least 30% developing PPD (Payne et al, 2007). There is evidence that women with a history of PPD are affectively susceptible to hormonal change: Bloch et al (2000) demonstrated that women with a history of PPD developed mood symptoms in response to a blinded withdrawal of supraphysiological levels of estrogen and progesterone compared to none of controls. We used a cross-species translational design to identify estrogen-mediated epigenetic changes associated with PPD (Guintivano et al, 2013). DNA methylation profiles were generated from whole blood using methylation microarrays in a sample of PPD high-risk women who were followed prospectively through pregnancy and after delivery. These profiles were cross-referenced with syntenic locations, which demonstrated murine hippocampal DNA methylation changes in response to long-term treatment with 17β-estradiol (E2). Initially, we investigated only DSM-4 defined PPD where women suffered a major depressive episode within 4 weeks of delivery. Using this group, we identified two biomarker loci at HP1BP3 and TTC9B, which predicted PPD with an area under the receiver operator characteristic curve (AUC) of 0.87. In a replication analysis, these biomarkers also functioned to segregate PPD status in women who developed depression during the antenatal period with 88% accuracy; however intriguingly, the prediction was in the opposite direction. There is controversy in the literature as to whether PPD as defined by DSM-4 is a unique entity from depression that begins during pregnancy and continues postpartum. In light of previous reports demonstrating depression-associated changes in white blood cell type compositions (Lutgendorf et al, 2008), we compared the two groups and found a decrease in the ratio of monocytes to lymphocytes and granulocytes in the antenatally depressed women that correlated with HP1BP3 DNA methylation status. Incorporation of cellular composition into the model enabled a prediction of PPD status with an AUC of 82% independent of antenatal depression status. Our results further suggested that there is an enhanced sensitivity to estrogen-based DNA methylation reprogramming in the hippocampus in those at risk for PPD, independent of antenatal depression status. Our findings are consistent with the hypotheses of hormone sensitivity-mediated PPD risk put forth by Bloch et al, as well as previous work implicating an increased sensitivity of the stress system with antenatal depression (Katz et al, 2012). As estrogen is closely tied to both the hypothalamic pituitary adrenal (HPA) axis as well as inflammation, it is conceivable that our findings represent a first step in unifying the disparate definitions of PPD into a common etiology of estrogen sensitivity and possibly a continuum of vulnerability to its downstream consequences. Whether our identified biomarkers represent a mere proxy of estrogen sensitivity or are involved in PPD pathophysiology will require further study. TTC9B may be linked to regulation of AMPA receptor levels, which in turn have been shown to be associated with resilience or vulnerability to stress (Schmidt et al, 2010). If the molecular changes exhibited by the biomarkers indicate a biological vulnerability, these may interact with stress occurring in the postnatal period and ultimately lead to depression. The use of animal models to either alter brain biomarker expression or to simulate hormone sensitivity differences may be used to test these mechanistic hypotheses. Further research will be needed to determine whether the identified biomarkers will display PPD predictive alterations at periods of low circulating estrogen in non-pregnant women; however, as high estrogen levels are a feature of normal pregnancy, these biomarkers are capable of early screening for PPD during pregnancy independent of whether they represent trait or state biological variation. In conclusion, we have identified biomarkers for postpartum mood status that correctly identify whether or not a woman will be depressed during the postpartum time period, regardless of whether or not she is depressed during pregnancy. Future work is needed to confirm these findings and to determine whether identification of women at risk will allow successful prevention of PPD.

It has been shown that K + channels, Cp20 (a 20kD GTP-binding protein), and intracellular calcium release, play a key role in associative memory storage. These same elements have been shown to be altered in fibroblasts from Alzheimer's Disease (AD) patients. In addition, it has been shown that PKC, also implicated in memory storage and closely related to the above mentioned components, is also altered in AD fibroblasts. Moreover, β-amyloid was capable of inducing an AD-like phenotype for K + channels and Cp20 in otherwise normal fibroblasts, providing additional evidence for the potential involvement of these components in AD and suggesting a possible pathological consequence of soluble β-amyloid elevation in AD. Preliminary evidence shows that comparable changes in potassium channel function are also present in human olfactory neuroblasts from AD patients. These results indicate that the observed changes not only occur in peripheral tissues such as fibroblasts, but also in neural tissue, the primary site of AD pathology.

Patients with clinical diagnoses of Alzheimer's disease, vascular dementia, or undifferentiated dementia were rated on standardized measures of depression, cognitive impairment, and functional impairment. Logistic regression was used to evaluate the relationship between functional or cognitive impairment, as well as their interaction, and depressive features in each group. This analysis revealed notable differences by type of dementia. The results imply that the mechanisms underlying depression in Alzheimer's disease may be different from those in vascular and other types of dementia. These results also provide indicators to the clinician for further evaluation of depression in different dementia subtypes.