Childhood Stress, Serotonin Transporter Gene and Brain Structures in Major Depression

The underlying neurobiology of major depression (MD) is likely to represent an interaction between genetic susceptibility and environmental factors such as stress. We investigated, in a multimodal high-resolution magnetic resonance imaging (MRI) genetic study, whether reduced hippocampal volumes and other brain alterations are associated with the tri-allelic polymorphism of the serotonin transporter and childhood stress in patients with MD and healthy subjects. Patients with MD and healthy participants were investigated using high-resolution MRI and genotyping for serotonin transporter polymorphism in the promoter region of the serotonin transporter gene (SLC6A4, 5-HTTLPR). Region of interest analysis of the hippocampus, whole-brain voxel-based morphometry (VBM), and assessment of childhood stress were carried out. Patients carrying the risk S-allele developed smaller hippocampal volumes when they had a history of emotional neglect compared with patients who only had one risk factor (environmental or genetic). In patients, childhood stress also predicted further hippocampal white matter alterations independently from the genotype. Moreover, the left prefrontal cortex was smaller in patients, whereby childhood stress resulted in larger prefrontal volumes in those subjects carrying the non-risk L-allele, suggesting preventive effects. The findings indicate that subjects with both environmental and genetic risk factors are susceptible to stress-related hippocampal changes. Structural brain changes due to stress represent part of the mechanism by which the illness risk and outcome might be genetically mediated.     

老年心肌梗塞后抑郁与5-HT的关系

目的 探讨老年急性心肌梗塞后抑郁与血浆5羟色胺(5-HT)浓度的关系。方法 利用HAMD对抑郁进行评定,同时使用HPLC-EC法检测30例心梗后伴有明显抑郁症状患者的血浆5羟色胺浓度,并与30例不伴明显抑郁症状的患者以及30例健康人进行对照。结果 血浆5-HT含量抑郁组为46.37±24.47(ng/ml),非抑郁组为44.08±13.03(ng/ml),健康对照组为37.01±5.92(ng/ml)。结论　老年急性心肌梗塞患者HAMD与血浆5-HT浓度无相关。     

基于药物基因组学的选择性5-羟色胺再摄取抑制剂个体化治疗抑郁症

选择性5-羟色胺再摄取抑制剂(SSRIs)是当前治疗抑郁症的一线药物,CYP2D6、CYP2C19基因多态性会影响SSRIs的代谢,进而影响其疗效与安全性.目前我国临床医师对抑郁症患者基于基因多态性的SSRIs个体化治疗实践相对较少.该文就CYP2D6、CYP2C19基因型及其对SSRIs治疗的影响进行综述,以期为抑郁...     

Serotonin, stress and corticoids

There is evidence for stressor- and brain region-specific selectivity in serotonergic transmission responses to aversive stimuli. The aim of the present review is to provide an overview of the effects of different acute and repeated/chronic stressors on serotonin (5-HT) release and reuptake, extracellular 5-HT levels, and 5-HT pre- and postsynaptic receptors in areas tightly linked to the control of fear and anxiety, namely the dorsal and median raphe nuclei, the frontal cortex, the amygdala and the hippocampus. In addition, our knowledge of the impacts of corticoids on serotonergic systems in these brain areas is also briefly provided to examine whether the hypothalamo-pituitary-adrenal axis may play a role in stress-induced alterations in 5-HT neurotransmission. Taken together, the data presented reinforce the hypothesis that stress affects such a transmission, partly through the actions of corticoids. However, we are still left with unanswered, albeit crucial questions. First, the question of the specificity of the serotonergic responses to stress, with regard to the site of action and the nature of the stressor still remains open due to the heterogeneity of the results obtained so far. This could indicate that environmental factors, other than the stressor itself, may have enduring consequences on 5-HT sensitivity to stress. Second, the question regarding the role of stress-elicited changes in 5-HT transmission within coping processes finds in most cases no clearcut answer. In keeping with human symptomatology, the need to consider the environment (including the early one) and the genetic status when assessing the effects of stress on 5-HT neurotransmission is underlined. Such a consideration could help to answer the questions raised.     

Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis

Background:

Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).

Methods:

Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review.

Results:

All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily).

Conclusions:

All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.     

Serotonin,memory, and the aging brain

Six rhesus monkeys self-administered orally-delivered phencyclidine (PCP) and water under concurrent fixed-ratio (FR) 8 schedules. Liquids were available during three 6.5-h periods daily preceded by 1-h components when food was available under an FR 64 (lever press) schedule. After 10 days of stable behavior, water was substituted for PCP for 8 days. PCP was subsequently reinstated, and this PCP withdrawal sequence was repeated using different food FR values (64, 128, 256, 512 and 1024). Each time the food FR was changed behavior was allowed to stabilize for at least 10 days. Under all FR values food-maintained responding decreased markedly during PCP withdrawal, with a gradual recovery over the next 8 days. As the FR value increased from 64 to 1024 there was a parallel shift downward in food-maintained performance. When PCP was reinstated, food-reinforced responding generally returned to baseline rates during the first few days. In a second experiment monkeys were tested for PCP withdrawal effects under relatively food deprived or food satiated conditions under both an FR 512 and 1024 schedule of food delivery. The results showed that the decrease in food-maintained responding during withdrawal was inversely related to the total amount of food consumed during the control period. The results of these experiments indicate that manipulation of both the response requirements for food (FR) and the total amount of food available (food deprivation/satiation) alters the magnitude of response disruptions during PCP withdrawal.     

Carbohydrates and dietary fiber

The most widely spread eating habit is characterized by a reduced intake of dietary fiber, an increased intake of simple sugars, a high intake of refined grain products, an altered fat composition of the diet, and a dietary pattern characterized by a high glycemic load, an increased body weight and reduced physical activity. In this chapter the effects of this eating pattern on disease risk will be outlined. There are no epidemiological studies showing that the increase of glucose, fructose or sucrose intake is directly and independently associated with an increased risk of atherosclerosis or coronary heart disease (CHD). On the other hand a large number of studies has reported a reduction of fatal and non-fatal CHD events as a function of the intake of complex carbohydrates--respectively 'dietary fiber' or selected fiber-rich food (e.g., whole grain cereals). It seems that eating too much 'fast' carbohydrate [i.e., carbohydrates with a high glycemic index (GI)] may have deleterious long-term consequences. Indeed the last decades have shown that a low fat (and consecutively high carbohydrate) diet alone is not the best strategy to combat modern diseases including atherosclerosis. Quantity and quality issues in carbohydrate nutrient content are as important as they are for fat. Multiple lines of evidence suggest that for cardiovascular disease prevention a high sugar intake should be avoided. There is growing evidence of the high impact of dietary fiber and foods with a low GI on single risk factors (e.g., lipid pattern, diabetes, inflammation, endothelial function etc.) as well as also the development of the endpoints of atherosclerosis especially CHD.     

Plasticity of Presynaptic and Postsynaptic Serotonin 1A Receptors in an Animal Model of Epilepsy-Associated Depression

Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients'' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo–pituitary–adrenocortical (HPA) axis and/or diminished raphe–hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.     

Serotonin Transporter Genotype and Action Monitoring Dysfunction: A Possible Substrate Underlying Increased Vulnerability to Depression

A variable number of tandem repeats (short (S) vs long (L)) in the promoter region of the serotonin transporter gene (5-HTTLPR) and a functional variant of a single-nucleotide polymorphism (rs25531) in 5-HTTLPR have been recently associated with increased risk for major depressive disorder (MDD). In particular, relative to L/L or L_A homozygotes (hereafter referred to as L′ participants), S carriers or L_g-allele carriers (S′ participants) have been found to have a higher probability of developing depression after stressful life events, although inconsistencies abound. Previous research indicates that patients with MDD are characterized by executive dysfunction and abnormal activation within the anterior cingulate cortex (ACC), particularly in situations requiring adaptive behavioral adjustments following errors and response conflict (action monitoring). The goal of this study was to test whether psychiatrically healthy S′ participants would show abnormalities similar to those of MDD subjects. To this end, 19 S′ and 14 L′ participants performed a modified Flanker task known to induce errors, response conflict, and activations in various ACC subdivisions during functional magnetic resonance imaging. As hypothesized, relative to L′ participants, S′ participants showed (1) impaired post-error and post-conflict behavioral adjustments; (2) larger error-related rostral ACC activation; and (3) lower conflict-related dorsal ACC activation. As similar behavioral and neural dysfunctions have been recently described in MDD patient samples, the current results raise the possibility that impaired action monitoring and associated ACC dysregulation may represent risk factors increased vulnerability to depression.     

Effects of Serotonin on the Induction of Long-term Depression in the Rat Visual Cortex

Long-term potentiation (LTP) and long-term depression (LTD) have both been studied as mechanisms of ocular dominance plasticity in the rat visual cortex. In a previous study, we suggested that a developmental increase in serotonin [5-hydroxytryptamine (5-HT)] might be involved in the decline of LTP, since 5-HT inhibited its induction. In the present study, to further understand the role of 5-HT in a developmental decrease in plasticity, we investigated the effect of 5-HT on the induction of LTD in the pathway from layer 4 to layer 2/3. LTD was inhibited by 5-HT (10 µM) in 5-week-old rats. The inhibitory effect was mediated by activation of 5-HT₂ receptors. Since 5-HT also regulates the development of visual cortical circuits, we also investigated the role of 5-HT on the development of inhibition. The development of inhibition was retarded by chronic (2 weeks) depletion of endogenous 5-HT in 5-week-old rats, in which LTD was reinstated. These results suggest that 5-HT regulates the induction of LTD directly via activation of 5-HT₂ receptors and indirectly by regulating cortical development. Thus, the present study provides significant insight into the roles of 5-HT on the development of visual cortical circuits and on the age-dependent decline of long-term synaptic plasticity.     

Carbohydrates in therapeutics

Awareness of the importance of carbohydrates in living systems and medicine is growing due to the increasing understanding of their biological and pharmacological relevance. Carbohydrates are ubiquitous and perform a wide array of biological roles. Carbohydrate-based or -modified therapeutics are used extensively in cardiovascular and hematological treatments ranging from inflammatory diseases and anti-thrombotic treatments to wound healing. Heparin is a well-known and widely used example of a carbohydrate-based drug but will not be discussed as it has been extensively reviewed. We will detail carbohydrate-based and -modified therapeutics, both those that are currently marketed or in various stages of clinical trials and those that are potential therapeutics based on promising preclinical investigations. Carbohydrate-based therapeutics include polysaccharide and oligosaccharide anti-inflammatory, anti-coagulant and anti-thrombotic agents from natural and synthetic sources, some as an alternative to heparin and others which were designed based on known structure-functional relationships. Some of these compounds have multiple biological effects, showing anti-adhesive, anti-HIV and anti-arthrithic activities. Small molecules, derivatives or mimetics of complement inhibitors, are detailed for use in limiting ischemia/ reperfusion injuries. Monosaccharides, both natural and synthetic, have been investigated for their in vivo anti-inflammatory and cardioprotective properties. Modification by glycosylation of natural products, or glycosylation-mimicking modification, has a significant effect on the parent molecule including increased plasma half-life and refining or increasing desired functions. It is hoped that this review will highlight the vast therapeutic potential of these natural bioactive molecules.     

Atypical antipsychotic drugs,diabetes and ethnicity

There are 17 million people affected by diabetes in the US. It is a syndrome consisting of metabolic abnormalities, microvascular and macrovascular disease leading to cardiac, renal and neurological abnormalities. Obesity is the most common public health problem in developed nations. Diabetes and obesity-related illnesses are common in ethnic minorities such as African–Americans, Hispanics and Asians related to both genetics and lifestyle patterns. In all ethnic minorities in the US, an increase in Type 2 diabetes has been observed. However, the Asian group experienced the highest rate of increase in prevalence between the years 1990 and 1998. The changing ethnic composition of the US population may contribute significantly to the worsening of the diabetes epidemic in this country. Atypical antipsychotic drugs can induce diabetes, as well as obesity. All atypical antipsychotic drugs can produce diabetes, but drugs such as olanzapine and clozapine have been known to produce diabetes more often than other drugs. As ethnic minority patients including Asians, Hispanics and African–Americans are predisposed to develop diabetes, antipsychotics become a burden by precipitating diabetes. Such a situation poses a problem in treating ethnic minority psychiatric patients. In clinical situations, close monitoring is necessary to prevent metabolic side effects of these drugs.     

Atypical antipsychotic drugs, diabetes and ethnicity

There are 17 million people affected by diabetes in the US. It is a syndrome consisting of metabolic abnormalities, microvascular and macrovascular disease leading to cardiac, renal and neurological abnormalities. Obesity is the most common public health problem in developed nations. Diabetes and obesity-related illnesses are common in ethnic minorities such as African-Americans, Hispanics and Asians related to both genetics and lifestyle patterns. In all ethnic minorities in the US, an increase in Type 2 diabetes has been observed. However, the Asian group experienced the highest rate of increase in prevalence between the years 1990 and 1998. The changing ethnic composition of the US population may contribute significantly to the worsening of the diabetes epidemic in this country. Atypical antipsychotic drugs can induce diabetes, as well as obesity. All atypical antipsychotic drugs can produce diabetes, but drugs such as olanzapine and clozapine have been known to produce diabetes more often than other drugs. As ethnic minority patients including Asians, Hispanics and African-Americans are predisposed to develop diabetes, antipsychotics become a burden by precipitating diabetes. Such a situation poses a problem in treating ethnic minority psychiatric patients. In clinical situations, close monitoring is necessary to prevent metabolic side effects of these drugs.     

Quetiapine,an Atypical Antipsychotic

The discovery of antipsychotic agents in the 1950s revolutionized the treatment of schizophrenia. A large body of evidence supports the dopamine D₂ receptor antagonist's efficacy in the treatment of psychotic symptoms. However, the advent of newer agents seems to point to a more complex interaction of neurotransmission in the pathophysiology of schizophrenia. In fact, a defining characteristic of atypical agents is a higher ratio of serotonin (5HT₂) receptor blockade to D₂ receptor blockade. Clozapine was the first atypical agent to be introduced; it was followed by risperidone, olanzapine, and now quetiapine, which is a dibenzothiazepine derivative structurally related to clozapine and olanzapine.