Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age

To investigate whether prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure affects behavior in 3-year-olds of antenatally anxious or depressed mothers and whether risk was moderated by the serotonin transporter promoter (SLC6A4) genotype.

Hypothalamic-pituitary-adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure

Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic-pituitary-adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown.

Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy

To evaluate attentional and activity behaviors in 4-year-olds following prenatal selective serotonin reuptake inhibitor (SSRI) exposure.

Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure

In this prospective study, we examined biobehavioral responses to acute procedural pain at 2 months of age in infants with prenatal and postnatal selective serotonin reuptake inhibitor (SSRI) medication exposure. Based on previous findings showing reduced pain responses in newborns after prenatal exposure, we hypothesized that altered pain reactivity would also be found at 2 months of age.

Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment

Background Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans. Methods We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment. Results Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key “punishment” areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect. Conclusions Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment.

Brugada syndrome ECG provoked by the selective serotonin reuptake inhibitor fluvoxamine

A patient with an SCN5A p.W822X nonsense mutation, localized in the transmembrane region DII-S4 of the Na(v)1.5 sodium channel and leading to a non-expression of the mutant allele, was prescribed the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Floxyfral), 100 mg per day. His normal baseline ECG changed to a characteristic Brugada-Type-1-ECG pattern. To investigate whether fluvoxamine may reduce the cardiac sodium current, the effect of this drug was studied on the wild-type voltage-gated cardiac sodium channel Na(v)1.5 stably expressed in HEK293 cells. Patch-clamp recording showed a 50% inhibition of the current at a concentration of 57.3 microM. In our patient, no arrhythmia occurred but the proarrhythmic potential of SSRI in patients with SCN5A mutations cannot be excluded. Therefore, we advise 12-lead ECG control after administering SSRI in these patients.

Síndrome do climatério

The climateric is characterized by progressive hipoestrogenism and by tissue and functional alterations that leads the women to aging. The diagnosis approach needs to consider the symptoms originated by estrogenic deficiency and by the more prevalent chronic diseases in this lifetime, for instance, among others, the cardiovascular and osteoporosis diseases, witch need a systematic screening. The therapeutic management must consider the proposition of healthy life habits and, when indicated, pharmacological treatment for estrogenic deficiency or for anothers comorbidities existent. The estroprogestative hormonal therapeutic is a valuable tool to provide health and better quality of life, once obeyed the individualized criterion of the cases, doses, hormonal composition and mainly of the opportunity of intervention. There are nonhormonal alternatives to treat the menopausal symptoms, as the antidepressives and phytoestrogens. It's also advised to combine with regular physical activities and adequate calcium intake. © Copyright Moreira Jr. Editora. Todos os direitos reservados.

Role of stressful and traumatic life events in obsessive-compulsive disorder

Whilst genetic factors are thought to contribute to the development of obsessive-compulsive disorder (OCD), the role of environmental factors in OCD is only beginning to be understood. In this article, we review the influence of stress-related factors in OCD. Overall, studies indicate that: patients with OCD frequently report stressful and traumatic life events before illness onset, although these rates do not seem to be significantly different from those described in other disorders; the association between OCD and post-traumatic stress disorder (PTSD) might result from symptom overlap, although cases of patients developing OCD after PTSD and showing obsessive-compulsive symptoms that were unrelated to trauma have been described fairly consistently; it is unclear whether patients with OCD and a history of stress-related factors (including stressful life events, traumatic life events or comorbid PTSD) may respond better or worse to the available treatments; and comorbid PTSD may modify the clinical expression of OCD-although controlled studies comparing pre-versus post-traumatic OCD patients are still unavailable. In conclusion, there is a growing evidence to suggest a role for stress-related factors in OCD. Although the available literature does not confirm the existence of a post-traumatic subtype of OCD, it does call for further systematic research into this topic. © 2011 Future Medicine Ltd.

An exploratory dimensional approach to premenstrual manifestation of obsessive-compulsive disorder symptoms: A multicentre study

Objective: In women with obsessive-compulsive disorder (OCD), symptom severity appears to fluctuate over the course of the menstrual cycle. The objective of this paper was to compare female OCD patients with and without premenstrual worsening of obsessive-compulsive symptoms (OCS), in terms of the clinical characteristics of OCD. Methods: This was a cross-sectional study involving 455 women with OCD, of whom 226 (49.7%) had experienced premenstrual OCS worsening and 229 (50.3%) had not (PMOCS-worse and PMOCS-same groups, respectively). Data were collected with the original and dimensional versions of the Yale-Brown Obsessive-Compulsive Scale, as well as with the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). Results: We found significant differences between the PMOCS-same and PMOCS-worse groups, the latter showing a higher frequency of suicidal ideation (P<.001), suicide attempts (P=.027), current use of selective serotonin reuptake inhibitors (P=.022), lifetime use of mood stabilisers (P=.015), and sexual/religious obsessions (P<.001; OR. =1.90), as well as higher scores on the BDI (P<.001) and BAI (P<.001). Conclusion: Underscoring the fact that OCD is a heterogeneous disorder, there appears to be a subgroup of female OCD patients in whom the premenstrual period is associated with a higher frequency of sexual/religious obsessions, depression, anxiety, and suicidality. This might be attributable to hormonal fluctuations. Further studies are warranted in order to investigate this hypothesis by evaluating such patients at different phases of the menstrual cycle, as well as measuring hormonal levels. © 2012 Elsevier Inc.

Vitamin E reduces antidepressant-related beta-adrenoceptor down-regulation in cultured cells. Comparable effects on St. John's wort and tricyclic antidepressant treatment

The mode of action of antidepressants is still a matter of debate. Acute inhibition of neurotransmitter reuptake in central neuronal synapses, followed by a down-regulation of central postsynaptic beta-adrenoceptor (beta-AR) numbers were consistently observed in vivo, while a reduction in surface beta-AR density was found in cell cultures. Effects of the tricyclic antidepressant desipramine (DMI) were abolished by vitamin E (alpha-TOC) in vitro as well as in vivo. Alpha-TOC interfered with antidepressant-induced changes of cellular plasma membrane properties and with recycling of beta-AR. St. John's wort (SJW) extract reduced beta-AR numbers in cultured cells to a similar extent as DMI or the selective serotonin re-uptake inhibitor fluoxetine. We chronically co-exposed cell cultures to SJW extract and to alpha-TOC. Receptor down-regulation following exposure to the plant extract was inhibited in the presence of alpha-TOC suggesting a mode of action of SJW extract comparable to that of synthetic antidepressants. Inhibition of cell proliferation by the plant extract was also significantly reduced by alpha-TOC.

A single serine residue controls the cation dependence of substrate transport by the rat serotonin transporter

The serotonin transporter (SERT) is a member of the Na+/Cl−-dependent neurotransmitter transporter family and constitutes the target of several clinically important antidepressants. Here, replacement of serine-545 in the recombinant rat SERT by alanine was found to alter the cation dependence of serotonin uptake. Substrate transport was now driven as efficiently by LiCl as by NaCl without significant changes in serotonin affinity. Binding of the antidepressant [3H]imipramine occurred with 1/5th the affinity, whereas [3H]citalopram binding was unchanged. These results indicate that serine-545 is a crucial determinant of both the cation dependence of serotonin transport by SERT and the imipramine binding properties of SERT.

Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities

Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF+/− mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF+/− mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF+/− mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF+/− mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.