Antidepressants and pregnancy: risks and benefits for the mother and child

Depression, anxiety disorders, anorexia nervosa and bulimia, all indications for antidepressant use, are common disorders in women of childbearing age. Nevertheless, antidepressant use during the gestational period remains a controversial topic. Given that 50 % of pregnancies are unplanned, the safety of antidepressants during the first trimester of pregnancy, a critical period for foetal development, has become a major public health concern. Until now, most studies suggest that physicians may often under-prescribe or discontinue antidepressants at the time of conception and during pregnancy. This may be a consequence of the concern over the safety of these agents in pregnant women and the risks they may pose to the foetus. In fact, recent studies and warnings from Health Canada and the US Food and Drug Administration have reinforced this uncertainty regarding the adverse effects of antidepressant use on the foetus. On the other hand, discontinuation of antidepressant use during pregnancy was also recently associated with maternal relapse of depression and withdrawal symptoms, which is not optimal for the mother and her foetus. Consequently, women who wish to become pregnant and who suffer from psychiatric disorders are faced with the difficult task of deciding whether to continue or discontinue their antidepressant during pregnancy. At this time, it appears important to take into account all evidence-based data to evaluate the risks/benefits of using antidepressants during the gestational period in order to help mothers make the best choice for themselves, and their infants.     

The neurosteroid dehydroepiandrosterone sulfate,but not androsterone,enhances the antidepressant effect of cocaine examined in the forced swim test — Possible role of serotonergic neurotransmission

One of the mechanisms of cocaine's actions in the central nervous system is its antidepressant action. This effect might be responsible for increased usage of the drug by individuals with mood disorders. Higher endogenous levels of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS) were reported to correlate with successful abstinence from cocaine use in addicts, but a clinical trial showed that supplementation with a high dose of DHEA increased cocaine usage instead. Such ambiguous effects of DHEA(S) could potentially be linked to its influence on the antidepressant effect of cocaine. In this study we tested DHEAS and its metabolite, androsterone, for interactions with cocaine in animal model of depression (forced swim test) and examined the effects of both steroids and cocaine on serotoninergic neurotransmission. All substances were also tested for influence on locomotor activity. A cocaine dose of 5 mg/kg, which had no significant effect on locomotor activity, was chosen for the forced swim test. Neither DHEAS nor androsterone showed any antidepressant action in this test, while cocaine manifested a clear antidepressant effect. Androsterone slightly reduced the antidepressant influence of cocaine while DHEAS markedly, dose-dependently enhanced it. Such an effect might be caused by the influence of DHEAS on serotonin neurotransmission, as this steroid decreased serotonin concentration and turnover in the striatum. When DHEAS and cocaine were administered together, the levels of serotonin in the striatum and hippocampus remained unchanged. This phenomenon may explain the additive antidepressant action of DHEAS and cocaine and why co-administration of DHEAS and cocaine increases drug use.     

Treatment with Hypericum perforatum L. does not trigger decreased resistance in Staphylococcus aureus against antibiotics and hyperforin.

Most scientific investigations of Hypericum perforatum L. (Saint John's wort) concentrated on its antidepressant activity. Only recently, its antibacterial activity against multiresistant Staphylococcus aureus led to speculations regarding the use of hyperforin, an antibacterial principle of hypericum, as an antibiotic. In the present investigation, we show that Staphylococcus aureus is able to acquire a resistance against hyperforin which did not lead to a cross resistance against clinically used antibiotics. Resistance development does not take place, however, at concentrations as low as they are found in human blood plasma during antidepressant treatment with 900 mg Hypericum extract/day.     

Lower Frequency of Antidepressant Use in Patients on Renin-Angiotensin-Aldosterone System Modifying Medications

Both hypertension and depression are common disorders which may both involve components of the hypothalamic-pituitary-adrenal axis system and the Renin-Angiotensin-Aldosterone System (RAAS). These observations, coupled with growing evidence that RAAS-active drugs may have anti-depressant properties prompted us to study the frequency of anti-depressant medication usage in the patients receiving RAAS-active agents. A chart review was performed on 378 patients who were seen during a 3-month period in a primary care clinic and who were diagnosed with hypertension. Demographic information and data on the rates of co-administration of antihypertensive and anti-depressant medications was collected. Overall, 23.7% of the sample was on an antidepressant. 20% of the patients taking a RAAS-modifying medication were on an antidepressant, compared to 34% of those not taking a RAAS-modifying medication (Χ ² = 8.88, P = 0.003). The patients taking a beta-blocker alone had the highest rate of antidepressant usage (40%). The use of RAAS-modifying medications was associated with an even lower rate of anti-depressant usage in males compared with females. It was also observed that the patients taking an additional diuretic had a significantly lower rate of antidepressant use (17.6%, Χ ² = 5.81, P = 0.016) compared with the patients not taking a diuretic. The patients being treated with an ACE inhibitor or ARB showed significantly lower rates of antidepressant usage. The data is supportive of the hypothesis that these agents may possess anti-depressant effects.     

Synthesis and antidepressant-like activity evaluation of sulphonamides and sulphonyl-hydrazones

In this study a series of sulphonamides and sulphonyl hydrazones of maleimide, naphthalimide and phthalimide derivatives was synthesized. The antidepressant effect of these compounds was evaluated by the forced-swimming test in mice. The behavioural parameter observed in this test is a reduction in the immobility time, which is indicative of antidepressant activity. All compounds, except 8, 11 and 24, were active as antidepressants. The most active compound was the sulphonyl-hydrazone 10 which showed an activity of around 72.02% at 60 mg/kg, it thus being more active than imipramine (10mg/kg, ip), a commercial antidepressant. Other important results were obtained for the benzylnaphthalimide derivatives, the sulphonamides 21 and 22 showing activity of 64% at 10mg/kg, also being more active than imipramine. These results indicate that the sulphonamides and sulphonyl-hydrazone cyclic imide derivatives are potential compounds for use in the designing of new candidates for the treatment of depression.     

Antidepressant drugs: imipramine, mianserin and trazodone

The advent of newer antidepressant drugs (second generation) during the past two decades has provided an alternative to the use of tricyclic antidepressants in the alleviation of depression. These antidepressants have not been proven to be superior in the therapy of depression to the tricyclic antidepressants but they have been reported to cause fewer cardiac effects. Most of the reported adverse cardiac reactions elicited by antidepressant drugs are based on observations from clinical studies. The possible underlying mechanisms by which these adverse reactions arise have for the large part been proposed on the basis of clinical findings which have been extrapolated back to the known pharmacological actions of such drugs. There is a paucity of hard experimental data in this respect.     

Medical implications from the crystal structure of a copper-containing amine oxidase complexed with the antidepressant drug tranylcypromine

The X-ray crystal structure of the copper-containing quinoprotein amine oxidase from E. coli has been determined in complex with the antidepressant drug tranylcypromine to 2.4 A resolution. The drug is a racemic mix of two enantiomers, but only one is seen bound to the enzyme. The other enantiomer is not acting as a substrate for the enzyme as no catalytic activity was detected when the enzyme was initially exposed to the drug. The inhibition of human copper amine oxidases could be a source of side-effects in its use as an antidepressant to inhibit the flavin-containing monoamine oxidases in the brain.     

Tricyclic Antidepressants Amitriptyline and Desipramine Induced Neurotoxicity Associated with Parkinson’s Disease

Recent studies report that a history of antidepressant use is strongly correlated with the occurrence of Parkinson’s disease (PD). However, it remains unclear whether antidepressant use can be a causative factor for PD. In the present study, we examined whether tricyclic antidepressants amitriptyline and desipramine can induce dopaminergic cell damage, both in vitro and in vivo. We found that amitriptyline and desipramine induced mitochondria-mediated neurotoxicity and oxidative stress in SH-SY5Y cells. When injected into mice on a subchronic schedule, amitriptyline induced movement deficits in the pole test, which is known to detect nigrostriatal dysfunction. In addition, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta was reduced in amitriptyline-injected mice. Our results suggest that amitriptyline and desipramine may induce PD-associated neurotoxicity.     

Getting closer to affective disorders: the role of CRH receptor systems

Depressive disorders are a leading cause of morbidity and mortality worldwide. Current antidepressant drugs targeting monoamine neurotransmitter systems have a delayed onset of action, and fewer than 50% of the patients attain complete remission after therapy with a single antidepressant. A large body of preclinical and clinical evidence points to a key role of the corticotropin-releasing hormone (CRH) receptor 1 subtype (CRHR1) in mediating CRH-elicited effects in anxiety, depressive disorders and stress-associated pathologies. Genetic modification of CRHR1 function in mice by the use of conventional and conditional knockout strategies enables further analysis of specific elements in the CRH circuitry. The recent characterisation of several selective small-molecule CRHR1 antagonists offers new possibilities for the treatment of anxiety and depression.     

抑郁症易感基因和抗抑郁药物靶点相关[]神经细胞类型及相互作用网络分析

基于抑郁症的全基因组关联分析研究(GWAS),对于获得的单核苷酸多态性位点(SNP)使用Haploreg软件进行基因注释,得到SNP注释的102个易感基因.。使用MAGMA软件对GWAS的汇总统计数据做基因水平的分析,获得了270个校正之后显著的基因,两者合并共得到320个抑郁症易感基因。通过药物数据库Drugbank获取133个抗抑郁药物靶点基因。使用EWCE包对抑郁症易感基因和抗抑郁药物靶点在三套脑组织单细胞测序数据中,分别进行神经细胞类型富集分析。结果发现大脑皮质的GABA神经元(抑制性神经元)和谷氨酸能神经元(兴奋性神经元)是抑郁症易感基因和抗抑郁药物靶点共同的神经元。这两种类型的神经细胞可能是抗抑郁药物与抑郁症易感基因相互作用的神经细胞,另外少突胶质前体细胞可能是抑郁症特有的易感神经细胞。使用Network Calculator软件构建网络并进行进行网络拓扑学参数分析。结果表明抑郁症易感基因与抗抑郁药物靶点组成了一个具有显著的相互连接的网络。本研究从单细胞层面揭示抑郁症的遗传机制,在网络层面为寻找新的抗抑郁药物靶点提供了一定的启示。     

Antidepressants versus placebo in major depression: an overview

Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug‐placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non‐profit agencies. This narrowing of the drug‐placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM‐III and the broadening of the definition of major depression have led to the inclusion of mildly to moderately ill patients into antidepressant trials. These patients may experience a smaller magnitude of antidepressant‐placebo differences. Second, drug development regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, have had a significant, albeit underappreciated, role in determining how modern antidepressant clinical trials are designed and conducted. Their concerns about possible false positive results have led to trial designs that are poor, difficult to conduct, and complicated to analyze. Attempts at better design and patient selection for antidepressant trials have not yielded the expected results. As of now, antidepressant clinical trials have an effect size of 0.30, which, although similar to the effects of treatments for many other chronic illnesses, such as hypertension, asthma and diabetes, is less than impressive.     

Sleep deprivation in depression stabilizing antidepressant effects by repetitive transcranial magnetic stimulation

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed mood. However, the transient antidepressant effect of PSD - most patients relapse after one night of recovery sleep - is limiting the clinical use of this method. Using a controlled, balanced parallel design we studied, whether repetitive transcranial magnetic stimulation (rTMS) applied in the morning after PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to receive either active or sham stimulation during the following 4 days after PSD. Active stimulation prolonged significantly (p < 0.001) the antidepressant effect of PSD up to 4 days. This finding indicates that rTMS is an efficacious method to prevent relapse after PSD.     

Effects of intranasal administration of the peptide antagonist of type I vaniloid receptor (TRPV1) in the rodent central nervous system

Intranasal administration of the polypeptide APHC3, an antagonist of the TRPV1 receptor, had acute anxiolytic and antidepressant effects, as well as an ability to modify the microglial response to proinflammatory stress and cytokine profile of the hippocampus. However, the acute antidepressant effect of the polypeptide was not related to the attenuation of neuroiflammation and probably had a different mechanism. The use of intranasal administration of the APHC3 peptide as a therapeutic approach aimed at decreasing depression symptoms needs additional studies in order to find the mechanism of action of this polypeptide in the central nervous system (CNS).     

Cell atrophy and loss in depression: reversal by antidepressant treatment

Depression is associated with structural alterations in limbic brain regions that control emotion and mood. Studies of chronic stress in animal models and postmortem tissue from depressed subjects demonstrate that these structural alterations result from atrophy and loss of neurons and glial cells. These findings indicate that depression and stress-related mood disorders can be considered mild neurodegenerative disorders. Importantly, there is evidence that these structural alterations can be blocked or even reversed by elimination of stress and by antidepressant treatments. A major focus of current investigations is to characterize the molecular signaling pathways and factors that underlie these effects of stress, depression, and antidepressant treatment. Recent advances in this research area are discussed and potential novel targets for antidepressant development are highlighted.     

Serotonin receptor changes after chronic antidepressant treatments: ligand binding, electrophysiological, and behavioral studies

Early biochemical research on antidepressant treatments provided evidence that the treatments alter catecholaminergic and serotonergic activity. The mechanisms of action proposed by the resulting biogenic amine hypotheses of affective disorders, however, are not consistent with the delayed onset of therapeutic effects of antidepressant treatments nor with the acute effects of more recently developed antidepressant drugs. Recent investigation of chronic antidepressant treatments using ligand binding, electrophysiological, and behavioral techniques have attempted to identify subgroups of receptors that might be affected uniquely and specifically by chronic antidepressant treatments. Such receptor changes have been suggested to form a basis for the mechanism of action of antidepressants. At the present time, however, the data produced by ligand binding experiments and electrophysiological experiments investigating serotonergic functioning do not fit together. In addition, interpretational problems and internal contradictions exist within each of the three bodies of data when straightforward hypotheses regarding a serotonergic role in antidepressant treatment are formulated. In order to clarify the serotonergic role in antidepressant drug and ECS effects the functional significance of observed changes in putative serotonergic receptors must be discovered. Unfortunately, putative receptors identified by ligand binding cannot be directly compared to those identified by electrophysiological techniques, because these two methods require the disassembly of the organism in mutually incompatible ways. In order to prove that either or both techniques do in fact identify functional serotonin receptors, investigators need to proceed both more microscopically and also more globally. Further anatomical and physiological studies are necessary to locate putative receptors and to demonstrate their place in existing serotonergic networks. Further behavioral studies must be done to relate alterations in receptor characteristics to the functioning of the intact organism.     

Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: comparison with antidepressant drugs

Neurokinin-1 (NK1) receptor antagonists have been reported to possess antidepressant and anxiolytic properties in controlled trials. Since antidepressant and anxiolytic drugs act mainly by enhancing serotonin (5-HT) and norepinephrine (NE) neurotransmission in forebrain areas, the main focus of the present review is to critically examine the electrophysiological effects of NK1 receptor antagonists on serotoninergic and noradrenergic neurons, and then hippocampal neurons. It is concluded that NK1 antagonists increase the firing and burst activity of 5-HT neurons, increase burst activity of NE neurons, and modulate postsynaptic transmission at the hippocampus level. Further research is needed in order to develop more selective ligands for the human NK1 receptor and to gain better knowledge of required brain penetration and optimal pharmacodynamic conditions for their use in patients.     

Iatrogenic epilepsy due to antidepressant drugs

An analysis of the case histories of nine patients who developed epileptic fits shortly after starting tricyclic antidepressant drugs showed that all of them had one or more of the following factors: previous or family history of epilepsy, pre-existing brain damage, cerebral arteriosclerosis, alcoholism, withdrawal of barbiturates, and history of previous electric convulsive therapy. Before prescribing antidepressant drugs these factors should be sought for in the history, and if any are present prophylactic anticonvulsant medication is indicated. From a limited experience we do not think that chlordiazepoxide is adequate to counteract the convulsant effect of antidepressant drugs.     

Mammalian cystatin and protagonists in brain diseases

Abstract

Cystatins are the thiol Proteinase inhibitors, present ubiquitously in mammalian body. They prevent unwanted proteolysis and play important role in several diseases. Regulation of cysteine Proteinase and their inhibitors is of utmost importance in neurodegenerative diseases like Alzheimer, amyloid angiopathy and in many other diseases. The action of these cysteine proteases is biologically controlled by proteinase inhibitors namely cystatins(cys) they constitute a superfamily of homologous proteins. The major role of cystatins is to protect the organism against endogenous proteases released from lysosomes, invading microorganisms and parasites that use cysteine proteases to enter the body. An enormous progress has been made in understanding of protein degradation process under normal and pathological conditions; in fact proteases are now clearly viewed as important drug targets. Some studies have suggested that cystatin C is a target for intervention in neurological disorders because its expression increases in response to human neurological disorders and in animal models of neurodegenerative states. Although, these studies did not clarify whether CysC up-regulation is a pathogenic factor in neurodegenerative disorders or whether it represents a neuroprotective compensatory response of the organisms aimed to prevent progression of the disease. However, for other diseases in some cases cystatins other than cys C are up regulated and in some it is down regulated.

Cystatins have been implicated in the processes of neuronal degeneration and repair of the nervous system. Both CysC and CysB are potent, reversible inhibitors of most of the currently known cathepsins. The extent of proteolytic activity at any given time and location is the result of a balance between active proteases and physiological inhibitors. Uncontrolled proteolysis as a result of imbalance between active proteases and their endogenous inhibitors has been associated with neuronal cell death in different neuronal diseases, including brain tumors, stroke, some forms of epilepsy, Alzheimer’s disease, and neurological autoimmune diseases.

An antidepressant is a psychiatric medication used to alleviate mood disorders, major depression and other brain diseases. Drugs including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are most commonly used antidepressant. They are also used to treat other conditions, such as anxiety disorders, obsessive compulsive disorder, eating disorders, and chronic pain. Although the mechanisms of the action of these antidepressants are not precisely understood, their principal target of action is at the monoamine transporter proteins located at nerve endings. Monoamine neurotransmitter transporters act to terminate synaptic neurotransmission. Selective serotonin reuptake inhibitors or SSRIs are also most widely used class of antidepressants. They work by increasing the level of serotonin in the brain. SSRIs have fewer and milder side effects, fewer drug interactions, and are much less likely to be associated with suicide than TCAs.

These antidepressants shows binding when incubated with cystatin, presenting the involvement of these antidepressant in cascade of disease, as leaving no cystatin to inhibit the cathepsin showing the myriad side effect after the administration of antidepressant. This might be one of the reason in the mechanism of action of antidepressant.

So this review expound about the role of cystatins in neurological diseases which is considered to be highly significant as it pave the way for commanding tool in the drug design.

Communicated by Ramaswamy H. Sarma