Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.     

Pharmacotherapy of anxiety

The pharmacological treatment of anxiety has a long and chequered history, and recent years have seen a rich development in the options available to prescribers. Most of the currently used anxiolytic agents act via monoaminergic (chiefly serotonin) or amino acid (GABA or glutamate) neurotransmitters, and this chapter describes the pharmacology of the major drug groups. Clinical applications are discussed with respect to the five major anxiety disorders, as well as simple phobia and depression with concomitant anxiety. Prospective future developments in the field are considered.     

Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment.

Chronic stress is a risk factor for the development of many psychopathological conditions in humans, including major depression and anxiety disorders. There is a high degree of comorbidity of depression and anxiety. Moreover, cognitive impairments associated with frontal lobe dysfunction, including deficits in cognitive set-shifting and behavioral flexibility, are increasingly recognized as major components of depression, anxiety disorders, and other stress-related psychiatric illnesses. To begin to understand the neurobiological mechanisms underlying the cognitive and emotional consequences of chronic stress, it is necessary to employ an animal model that exhibits similar effects. In the present study, a rat model of chronic unpredictable stress (CUS) consistently induced a cognitive impairment in extradimensional set shifting capability in an attentional set shifting test, suggesting an alteration in function of the medial prefrontal cortex. CUS also increased anxiety-like behavior on the elevated plus-maze. Further, chronic treatment both with the selective norepinephrine reuptake blocker, desipramine (7.5 mg/kg/day), and the selective serotonin reuptake blocker, escitalopram (10 mg/kg/day), beginning 1 week before CUS treatment and continuing through the behavioral testing period, prevented the CUS-induced deficit in extradimensional set-shifting. Chronic desipramine treatment also prevented the CUS-induced increase in anxiety-like behavioral reactivity on the plus-maze, but escitalopram was less effective on this measure. Thus, CUS induced both cognitive and emotional disturbances that are similar to components of major depression and anxiety disorders. These effects were prevented by chronic treatment with antidepressant drugs, consistent also with clinical evidence that relapse of depressive episodes can be prevented by antidepressant drug treatment.     

Neurodevelopmental origins of depressive disorders

Depression is a common and devastating neuropsychiatric disorder, and a better understanding of its pathophysiology is needed to improve diagnosis, treatment and prevention. By considering the developmental dimensions of genetic and environmental factors, new insights have been found into the etiology and pathophysiology of depression. Specifically, we begin to understand how certain vulnerability factors affect the maturation of brain circuits involved in emotional function to increase the risk for depressive disorders later in life. These new findings might help us to better categorize and manage this complex disease.     

Behavioural genetics in mood and anxiety: a next step in finding novel pharmacological targets

The pharmacological treatment of mood and anxiety disorders has for long relied on the serendipitous findings of monoaminergic and benzodiazepine drugs more than 50 years ago. These treatments, however, are therapeutically insufficient and even though more recently developed drugs are particularly improving side effects, the efficacy or response rate of the drugs has fundamentally not improved. Therefore it is necessary to develop new methods to identify novel mechanisms not based on merely the symptomatology, but on biologically relevant (endo) phenotypes. This review examines the option of integrating mouse and human behavioural genetics to aid the identification of the putative underlying pathophysiological mechanisms and pharmacological targets for psychiatric disorders.     

Oral contraceptives and neuroactive steroids

A deregulation in the peripheral and brain concentrations of neuroactive steroids has been found in certain pathological conditions characterized by emotional or affective disturbances, including major depression and anxiety disorders. In this article we summarize data pertaining to the modulatory effects of oral contraceptive treatment on neuroactive steroids in women and rats. Given that the neuroactive steroids concentrations are reduced by oral contraceptives, together with the evidence that a subset of women taking oral contraceptives experience negative mood symptoms, we propose the use of this pharmacological treatment as a putative model to study the role of neuroactive steroids in the etiopathology of mood disorders. Moreover, since neuroactive steroids are potent modulators of GABA(A) receptor function and plasticity, the treatment with oral contraceptives might also represent a useful experimental model to further investigate the physiological role of these steroids in the modulation of GABAergic transmission.     

Serotonin and emotional processing: does it help explain antidepressant drug action?

There is growing interest in the effects of antidepressant drug treatment on measures of emotional processing. Such actions may help us understand the role of monoamines in emotional dysfunction in depression and how antidepressant drug treatments work. Recent studies suggest that decreasing central serotonin function with tryptophan depletion can reinstate negative biases in recovered depressed patients, even at doses insufficient to induce changes in mood. Conversely, antidepressant drug administration increases the processing of positive emotional information in healthy volunteers and acutely depressed patients early in treatment. This increase in positive bias may provide a platform for subsequent cognitive restructuring and learning which contributes to the evolution of symptom change in depression. Functional neuroimaging studies suggest that these early antidepressant effects involve fronto-limbic and extra-striate circuitry suggestive of actions on both the initial appraisal and attentional processing of affective stimuli. This approach may therefore provide a framework for linking psychological and biological processes in emotional disorders and their treatment. Antidepressants may not directly modulate mood and anxiety but rather allow a different perspective for our ongoing evaluation of our self, the world and the future.     

Social vs. environmental stress models of depression from a behavioural and neurochemical approach

Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). However, while CMS reproduces specifically core depressive symptoms such as anhedonia and helplessness, CSDS studies rely on the analysis of stress-induced social avoidance, addressing different neuropsychiatric disorders. Here, we study comparatively the two models from a behavioural and neurochemical approach and their possible relevance to human depression. Mice (C57BL/6) were exposed to CMS or CSDS for six weeks and ten days. Anhedonia was periodically evaluated. A battery of test applied during the fourth week after the stress procedure included motor activity, memory, anxiety, social interaction and helplessness. Subsequently, we examined glutamate, GABA, 5-HT and dopamine levels in the prefrontal cortex, hippocampus and brainstem. CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety and social avoidance, signs also common to anxiety and posttraumatic stress disorders. While both models disrupted the excitatory inhibitory balance in the prefrontal cortex, CMS altered importantly this balance in the brainstem. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical and brain stem areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes.     

Neurotic Personality Traits and Risk for Adverse Alcohol Outcomes: Chained Mediation through Emotional Disorder Symptoms and Drinking to Cope

Background: Rates of alcohol abuse are high on Canadian postsecondary campuses. Individual trait differences have been linked to indices of alcohol use/misuse, including neurotic traits like anxiety sensitivity (AS) and hopelessness (HOP). We know little, though, about how these traits confer vulnerability. AS and HOP are related to anxiety and depression, respectively, and to drinking to cope with symptoms of those disorders. Neurotic personality may therefore increase risk of alcohol use/abuse via (1) emotional disorder symptoms and/or (2) coping drinking motives. Objectives: Allan and colleagues (2014) found chained mediation through AS-generalized anxiety-coping motives-alcohol problems and AS-depression-coping motives-alcohol problems. We sought to expand their research by investigating how emotional disorder symptoms (anxiety, depression) and specific coping motives (drinking to cope with anxiety, depression) may sequentially mediate the AS/HOP-to-hazardous alcohol use/drinking harms relationships among university students. Methods: This study used cross-sectional data collected in Fall 2014 as part of the Movember-funded Caring Campus Project (N = 1,883). The survey included the SURPS, adapted DMQ-R SF, and AUDIT-3. Results: AS and HOP were both related to hazardous alcohol and drinking harms via emotional disorder symptoms and, in turn, coping drinking motives. All indirect pathways incorporating both mediators were statistically significant, and additional evidence of partial specificity was found. Conclusions/Importance: The study's results have important implications for personality-matched interventions for addictive disorders.     

The pharmacological treatment of anxiety disorders in children and adolescents

As the recognition of paediatric and adolescent anxiety disorders improves, so does the number of recommended treatments. Newer medications (chiefly serotonergic antidepressants) have emerged as the pharmacological treatment of choice and have largely replaced benzodiazepines and tricyclic antidepressants (TCAs) for these disorders. This review will focus on placebo-controlled and open-label studies concerning the treatment of anxiety in children and adolescents, comparing data from newer antidepressant medications (plus buspirone) with data on TCAs and benzodiazepines in this population. There are few randomised, placebo-controlled trials of medications for anxiety in children and adolescents, with most data coming from open-label trials and case series. Moreover, there are no studies comparing pharmacological versus behavioural treatments. Most recent data concerning the efficacy of selective serotonin reuptake inhibitors suggests that these agents will be effective and safe in the treatment of paediatric anxiety disorders. The potential side effect profiles of these newer agents also makes them an attractive first choice for anxiety when compared to the benzodiazepines or TCAs, each of which poses its own potentially serious adverse effects. More research is needed in the area of psychopharmacological treatments for paediatric and adolescent anxiety, not only to substantiate the current beliefs that serotonergic agents are effective and safe but to pinpoint the factors that might predict responses to particular agents or classes of medications. Future investigations should focus on treatments which have already proven effective for adult anxiety disorders (both medications and psychotherapies), given the apparent links between paediatric and adult anxiety disorders.     

The pharmacological treatment of anxiety disorders in children and adolescents

As the recognition of paediatric and adolescent anxiety disorders improves, so does the number of recommended treatments. Newer medications (chiefly serotonergic antidepressants) have emerged as the pharmacological treatment of choice and have largely replaced benzodiazepines and tricyclic antidepressants (TCAs) for these disorders. This review will focus on placebo-controlled and open-label studies concerning the treatment of anxiety in children and adolescents, comparing data from newer antidepressant medications (plus buspirone) with data on TCAs and benzodiazepines in this population. There are few randomised, placebo-controlled trials of medications for anxiety in children and adolescents, with most data coming from open-label trials and case series. Moreover, there are no studies comparing pharmacological versus behavioural treatments. Most recent data concerning the efficacy of selective serotonin reuptake inhibitors suggests that these agents will be effective and safe in the treatment of paediatric anxiety disorders. The potential side effect profiles of these newer agents also makes them an attractive first choice for anxiety when compared to the benzodiazepines or TCAs, each of which poses its own potentially serious adverse effects. More research is needed in the area of psychopharmacological treatments for paediatric and adolescent anxiety, not only to substantiate the current beliefs that serotonergic agents are effective and safe but to pinpoint the factors that might predict responses to particular agents or classes of medications. Future investigations should focus on treatments which have already proven effective for adult anxiety disorders (both medications and psychotherapies), given the apparent links between paediatric and adult anxiety disorders.     

Motivation for treatment preceding and following a substance abuse program

BACKGROUND: Motivation for treatment is generally considered a powerful predictor of treatment seeking and success in patients with alcohol and drug dependence disorders. Objective measures have seldom been used, however, to assess how motivation is altered during treatment, or the impact of depression/anxiety on motivation. METHODS: We assessed motivation using the Treatment Motivation Questionnaire (TMQ) in 78 male alcohol- and drug-dependent veterans immediately preceding and following an intensive, 2-week residential substance abuse program. The TMQ assesses four domains of motivation: internal motivation, external motivation, interpersonal help-seeking, and nonconfidence in treatment. RESULTS: Following treatment, only external motivation changed (decreased), whereas the other dimensions of motivation retained the high levels observed pretreatment. Depression (as measured by the Beck Depression Inventory, BDI) was highly correlated with three of the four domains of motivation, while anxiety (as measured by the Spielberger State-Trait Anxiety Inventory, STAI) was highly correlated solely with internal motivation. CONCLUSIONS: Our findings suggest that depression and anxiety may differentially effect motivation and that external motivation may be quite transient; treatment implications of these findings are discussed. The usefulness of the TMQ in a residential population was also explored.     

Longitudinal investigation of the impact of anxiety and mood disorders in adolescence on subsequent substance use disorder onset and vice versa

Objective

A large body of epidemiological research indicates that anxiety and mood disorders are highly comorbid with substance use disorders (SUDs). However, longitudinal research regarding their temporal relations is limited. The goal of this study was to assess whether emotional disorders (i.e., anxiety and mood disorders) predict the onset of SUDs, whether SUDs predict the onset of emotional disorders, or both.

Method

The current study used data from baseline assessment (N = 627) and four years of follow-up assessments from the NU/UCLA Youth Emotion Project to examine this question.

Results

In line with the self-medication hypothesis of emotional disorder/SUDs comorbidity, anxiety and unipolar mood disorders at baseline assessment were associated with later onsets of SUDs. In particular, social anxiety disorder (SAD) at baseline predicted onset of alcohol use disorders and PTSD predicted the onset of all SUDs. SUDs did not predict any anxiety or unipolar mood disorders with the exception that alcohol use disorders predicted the onset of obsessive compulsive disorder (OCD).

Conclusions

These findings, as well as the clinical implications and future directions for research, are discussed.     

Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date

Depression and anxiety disorders are highly prevalent forms of mental illness that are considered to be stress-related disorders because some form of stressful life event often triggers their symptoms. Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide involved in mediating neuroendocrine, autonomic and behavioural responses to stress, and clinical studies provide evidence for the role of CRF in the development of depression and anxiety disorders. Two CRF receptor subtypes have been identified to date - the CRF(1) receptor and the CRF(2) receptor. Preclinical models provide evidence of a role for CRF(1) receptors in the activation of the stress response. Data from these experiments suggest that antagonism of CRF(1) receptor activity may provide an effective pharmacological treatment for stress-related psychiatric disorders.This review highlights progress to date with the development of CRF(1) receptor antagonists as potential pharmacotherapies for depression and anxiety disorders. Although additional research is needed to fully investigate the efficacy and safety profiles of CRF(1) receptor antagonists as candidate medications for these disorders, the results of preclinical experiments and clinical trials are encouraging. Further development of these compounds is warranted.     

脑梗死患者早期情绪干预方法及效果评价

目的探讨脑梗死的早期情绪干预方法,并分析其对脑梗死的临床效果。方法选择62例脑梗死后患者,随机分为两组,观察组使用情绪干预方法,并与单纯使用药物治疗、心理护理、辅助功能锻炼指导等的对照组比较,比较两组患者治疗前后睡眠功能的变化,并采用综合医院焦虑抑郁情绪自评量表评价两组的患者焦虑、抑郁情绪。结果干预后观察组存在睡眠障碍的比率显著低于对照组（P〈0.05）,干预后观察组焦虑评分和抑郁评分均显著低于对照组（P〈0.05）。结论对脑梗死患者实施早期情绪干预,注重患者心理健康,改善患者肢体功能以及睡眠质量,可以有效减少患者焦虑、抑郁的发生。     

Managing the patient with co-morbid depression and an anxiety disorder

Depression and anxiety disorders frequently co-occur. This type of co-morbidity is associated with higher severity, suicidality, chronicity and treatment resistance. However, available treatment guidelines mainly focus on treatment for singular disorders. The current paper describes diagnostic and treatment issues relevant for adequately addressing patients with depression and an anxiety disorder, using information from both guidelines and a search of recent literature. Apart from differential diagnosis, the diagnostic evaluation should include a thorough assessment of the symptoms of both disorders, preferably by using a structured clinical interview, and an assessment of depression severity in terms of suicidality, psychotic symptoms and impairment. Treatment should first address the primary disorder in terms of severity and risk. As a rule, severe depression should be treated before the anxiety disorder, using antidepressant medication or combined treatment (plus psychotherapy). In less severe pathology, the primary focus may be determined by examining the temporal pattern and the subjective burden of each disorder as experienced by the patient. Treatment is often sequential. Treatment of the primary disorder may or may not relieve the co-morbid disorder as well. If the primary disorder is an anxiety disorder, co-morbid depression generally implies earlier use of an antidepressant. Co-morbid mild depression may also react favourably to psychotherapeutic treatment of the anxiety disorder. Recent literature on concurrent treatment of both depression and anxiety shows that modern antidepressants such as sertraline, paroxetine, fluoxetine, venlafaxine, nefazodone and bupropion have demonstrated efficacy in relieving both depressive and anxiety symptoms compared with placebo. Head-to-head comparisons, although relatively scarce, tend to show superiority over tricyclic antidepressants. Venlafaxine was found to be more effective than fluoxetine in some studies. However, these results should be interpreted with caution because studies vary considerably in terms of patient selection, assessment of anxiety and primary outcome measures. Only one randomized controlled trial compared atypical antipsychotics with placebo. Psychotherapy was generally shown to have a beneficial effect on the co-morbid conditions, and available evidence appears to favour combined treatment. The results should be interpreted with caution because the number of studies on this issue was relatively small, with considerable clinical and methodological heterogeneity.     

Unraveling the diagnostic clues of depression and GAD: the primary care challenge

Anxiety and depression are commonly encountered in primary care, with a prevalence ranging from 5% to 10%. These disorders are associated with significant and persistent impairment in functioning, risk of suicide, and substantial economic cost. Comorbidity of depression and anxiety is frequent and intensifies the burden of illness. However, patients with anxiety and depression often present to primary care physicians (PCPs) with ill-defined somatic symptoms, and both disorders are under-recognized and under-treated. PCPs should be aware that the typical presentation of anxiety and depression may not be with classical psychological symptoms, but rather with vague somatic symptoms that are often hard to treat and result in frequent repeat visits. Once anxiety and depression are accurately recognized, most patients can successfully be managed in primary care. A wide range of effective drugs is available, allowing selection of an optimal treatment for each patient. Antidepressants are effective as monotherapy in comorbid patients, and newer agents such as selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors have been shown to be effective in the treatment of anxiety and depression. Adherence to medication can be improved if drug treatment is integrated into a package of patient education and support. PCPs have a vital role to play in identifying anxiety and depression amongst their patients, and building a therapeutic partnership to achieve successful treatment.     

Selective serotonin reuptake inhibitors in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a complex psychiatric condition, which can be triggered by a variety of traumatic events. Lifetime prevalence rates range from 1.3% to 10.4%, with women twice as likely as men to be affected. The clinical management of this condition is complex, since PTSD is associated with high rates of comorbid psychiatric disorders, particularly major depression, other anxiety and panic disorders, substance abuse and antisocial behaviour. Broadly, there are two main approaches to treatment: pharmacotherapy and cognitive or behavioural therapy. This paper reviews available pharmacological approaches for the treatment of PTSD and comorbid disorders. Although the optimal pharmacological approach has yet to be established, there is increasing evidence to support the use of antidepressants, and particularly selective serotonin reuptake inhibitors (SSRIs), as first-line therapy. In addition to alleviating the core symptoms of PTSD, some SSRIs are also effective for the treatment of common comorbidities, such as depression, panic disorder and social anxiety disorder; a fact which would appear to have important implications for patient management.     

The active alkaloids of Gelsemium elegans Benth are potent anxiolytics

OBJECTIVE To investigated whether acute subcutaneous administration of G.elegans alkaloids(eg,gelsemine,koumine,gelsevirine,gelsenicine) were capable of exerting anxiolytic and antidepressant effects in mouse models of these disorders.METHODS We used two mouse models of anxiety(elevated plus-maze and light-dark transition model),and two mouse models of depression(forced swim test and tail suspension test) to examine whether the G.elegans alkaloids are capable of attenuating anxiety-and depressive-like behaviors.RESULTS Gelsemine,koumine and gelsevirine exhibited potent anxiolytic effects in both the elevated plus-maze and the light-dark transition model.Gelsenicine,on the other hand,had no effect on the behavioural response in either of the anxiety models.None of the G.elegans alkaloids exerted antidepressant effects in the forced swim test and the tail suspension test.Importantly,none of the G.elegans alkaloids impaired spontaneous motor activities.CONCLUSION Gelsemine,koumine and gelsevirine might serve as potential candidates for the treatment of anxiety-related disorders in clinical trials with human patients.     

A cognitive dysfunction in anxiety and its amelioration by effective treatment with SSRIs

There is extensive research suggesting an abnormal selective attention to threat in anxiety disorders. We assessed the processing of emotional cognitions of physical anxiety, psycho-social fears, depression and positive affect in a cohort of 15 patients with active anxiety disorder (mostly panic) in comparison with a group of 15 depressed patients and 15 recovered panic patients after treatment with antidepressants (all selective serotonin re-uptake inhibitors) and an age- and sex-matched normal control group. Anxious patients showed delayed processing of emotional words (both negative and positive) compared with depressed patients. The successfully treated group showed no such interference and their responses were indistinguishable from controls. It would therefore appear that anxious patients (panic and generalized anxiety disorder) are affected primarily (but not exclusively) by themes of self-harm and psycho-social fears, and that this cognitive dysfunction in pathological anxiety is a state rather than trait feature of the condition, which is responsive to pharmacological intervention.