Efficacy of noradrenergic-selective agents in the treatment of neuropsychiatric diseases

In recent years, a number of antidepressants with varying degrees of selectivity for the noradrenergic neurotransmitter system have become available. However, these agents represent a pharmacologically heterogeneous group and differ in terms of their precise side-effect profile and, possibly, their clinical efficacy. Bupropion, which is thought to act on both the dopamine and norepinephrine (NE) systems, has not been widely used as an antidepressant and has more recently been licensed as adjunctive therapy for smoking cessation. The serotonin-NE reuptake inhibitors venlafaxine and nefazodone, the noradrenergic and specific serotonergic antidepressant mirtazapine, and the selective NE reuptake inhibitor reboxetine (the only truly NE-selective agent available) have all demonstrated efficacy in the treatment of depressive disorders. Evidence is now emerging for their use in the treatment of anxiety and panic disorders. There is some suggestion of a role for noradrenergic agents in other disorders, including attention-deficit/hyperactivity disorder and social phobia. The full range of disorders for which noradrenergic agents can be used remains to be seen and further research in this area is necessary.     

The role of glutamate in anxiety and related disorders

Anxiety, stress, and trauma-related disorders are a major public health concern in the United States. Drugs that target the gamma-aminobutyric acid or serotonergic system, such as benzodiazepines and selective serotonin reuptake inhibitors, respectively, are the most widely prescribed treatments for these disorders. However, the role of glutamate in anxiety disorders is becoming more recognized with the belief that drugs that modulate glutamatergic function through either ionotropic or metabotropic glutamate receptors have the potential to improve the current treatment of these severe and disabling illnesses. Animal models of fear and anxiety have provided a method to study the role of glutamate in anxiety. This research has demonstrated that drugs that alter glutamate transmission have potential anxiolytic action for many different paradigms including fear-potentiated startle, punished responding, and the elevated plus maze. Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.     

Overview of diagnosis and drug treatments of anxiety disorders

Anxiety disorders are common and often disabling. They fall into five main categories: panic disorder, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder and posttraumatic stress disorder, each of which have characteristic symptoms and cognitions. All anxiety disorders respond to drugs and psychological treatments. This review will focus on drug treatments. Recent research has emphasized the value of antidepressants especially the selective serotonin reuptake inhibitors, benzodiazepines, and related sedative-like compounds. The common co-existence of depression with all of the anxiety disorders means that the selective serotonin reuptake inhibitors are now generally considered to be the first-line treatments but the benzodiazepines have some utility especially in promoting sleep and working acutely to reduce extreme distress.     

Role of norepinephrine in the pathophysiology of neuropsychiatric disorders

The concatenation of convergent lines of evidence from basic to clinical research continues to reveal that norepinephrine (NE) is a crucial regulator of a myriad of behaviors ranging from stress response to memory formation. Furthermore, many neuropsychiatric disorders involve neurocircuitry that is directly modulated by NE. This report summarizes the physiological roles of NE, as well as the main findings implicating a role for NE system dysfunction in mood and anxiety disorders, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and Alzheimer's disease. In each of these disorders, there appears to be a complex dysregulation of NE function, with changes in locus ceruleus firing, NE availability, and both pre- and postsynaptic receptor regulation. Many symptoms of these disorders are attributable to abnormalities within distributed neural circuits regulated by NE. Appreciation of NE's role in modulating the neural circuitry mediating cognition and affect should help elucidate the pathophysiology of a variety of neuropsychiatric disorders and the development of novel treatments.     

The anaphase promoting complex is required for memory function in mice

Learning and memory processes critically involve the orchestrated regulation of de novo protein synthesis. On the other hand it has become clear that regulated protein degradation also plays a major role in neuronal plasticity and learning behavior. One of the key pathways mediating protein degradation is proteosomal protein destruction. The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets proteins for proteosomal degradation by the 26S proteasome. While the APC/C is essential for cell cycle progression it is also expressed in postmitotic neurons where it has been implicated with axonal outgrowth and neuronal survival. In this study we addressed the role of APC/C in learning and memory function by generating mice that lack the essential subunit APC2 from excitatory neurons of the adult forebrain. Those animals are viable but exhibit a severe impairment in the ability to extinct fear memories, a process critical for the treatment of anxiety diseases such as phobia or post-traumatic stress disorder. Since deregulated protein degradation and APC/C activity has been implicated with neurodegeneration we also analyzed the effect of Apc2 deletion in a mouse model for Alzheimer's disease. In our experimental setting loss of APC2 form principle forebrain neurons did not affect the course of pathology in an Alzheimer's disease mouse model. In conclusion, our data provides genetic evidence that APC/C activity in the adult forebrain is required for cognitive function.     

Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.     

The use of antidepressants in functional gastrointestinal disorders: new uses for old drugs

Since their introduction 50 years ago, antidepressants have been used in a wide variety of settings involving gastrointestinal (GI) disease. In the 1950s, antidepressants were shown to have some efficacy for the treatment of peptic ulcer disease. This is most likely due to their antihistaminic and anticholinergic effects. Since then, more efficacious and more disease-specific treatments have become available. In the last 20 years, antidepressants have been increasingly used for the treatment of functional gastrointestinal disorders such as irritable bowel syndrome, noncardiac chest pain, and other functional GI disorders. This article will review the rationale for the use of antidepressant drugs for the treatment of functional GI disorders. The role of psychiatric comorbidity in functional GI disorders, the impact of antidepressants on GI motility and visceral sensation, and the ability of these agents to produce improvements in the global well-being and overall quality of life will be reviewed. Finally, guidelines for prescribing and barriers to a patient's acceptance of these agents will be discussed.     

Pharmacotherapeutic options in the treatment of comorbid depression and anxiety

Although anxiety and mood disorders are listed as separate disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, they frequently coexist. They may be expressed phenotypically as comorbidities or as the provisional entity mixed anxiety-depressive disorder. Patients with both anxiety and depression are more symptomatic, use more health care resources, and have a worse prognosis than those with a single disorder. Recognizing and treating these patients are challenges for physicians because the symptoms of the two disorders often overlap. Administration of effective treatment, comprising both anxiolytic and antidepressant effects, can reduce patient distress and disability, as well as inappropriate utilization of medical services. Medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors, nefazodone, venlafaxine XR (extended release) and mirtazapine, are highly effective in treating comorbid depression and anxiety. These newer agents now represent the pharmacotherapeutic treatments of choice for the comorbid conditions.     

Anxiety, anxiety disorders, tobacco use, and nicotine: a critical review of interrelationships

Smoking is highly prevalent across most anxiety disorders. Tobacco use increases risk for the later development of certain anxiety disorders, and smokers with anxiety disorders have more severe withdrawal symptoms during smoking cessation than smokers without anxiety disorders. The authors critically examined the relationships among anxiety, anxiety disorders, tobacco use, and nicotine dependence and reviewed the existing empirical literature. Future research is needed to better understand the interrelationships among these variables, including predictors, moderators, and mechanisms of action. Increased knowledge in these areas should inform prevention efforts as well as the development and improvement of smoking cessation programs for those with anxiety and other psychiatric disorders.     

Idazoxan, an alpha-2 antagonist, facilitates memory retrieval in the rat

The role of the noradrenergic system in cognitive function was studied by using the alpha-2 adrenoceptor antagonist idazoxan to increase noradrenergic activity. Rats were trained in a complex maze task for food reward. They were left undisturbed for a 4-week "forgetting" period and were treated with idazoxan, just before the retention test. The dose of idazoxan used had previously been shown to enhance firing of units of the locus coeruleus and to increase noradrenaline (NE) turnover in the forebrain. This pharmacological treatment effectively alleviated forgetting, while control rats showed significant decrement compared to their performance at the last training trial. A control experiment showed that the facilitative effect was not on learning or on ongoing performance of the task, since there was no effect on simple acquisition. The results are taken as support for the notion that NE plays a role in memory retrieval processes.     

Substance abuse and panic-related anxiety: a critical review

The relationship between substance abuse and panic-related anxiety can be divided into two broad areas: the incidence of anxiety disorders in substance abuse patients and the incidence of substance abuse in patients with panic-related anxiety disorders. Studies indicate that approx. 10-40% of alcoholics have a panic-related anxiety disorder, and about 10-20% of anxiety disorder patients abuse alcohol or other drugs. The majority of patients with both an anxiety and alcohol disorder report that anxiety problems preceded alcohol problems. In some cases substance abuse (e.g. cocaine) triggers the onset of panic attacks. Most patients believe that self-medication is efficacious despite the fact that they appear to have a more serious clinical condition (e.g. higher rates of depression). Directions for future research are outlined, including the proposal for a study to examine the effects of an anxiety intervention procedure for anxious alcoholics to reduce relapse rates.     

The relationship between comorbid personality disorders and treatment received in patients with anxiety disorders

Few studies have addressed the relationship between the presence of a comorbid personality disorder and the amount of psychiatric treatment received by patients with an Axis I disorder. This issue has not been studied in patients with anxiety disorders. In a prospective, naturalistic, longitudinal study of anxiety disorders, 526 subjects were assessed with the Personality Disorder Examination, and types of treatment received in 1991 and 1996 were identified. In 1991, compared to subjects without a personality disorder, subjects with a personality disorder were as likely to receive medication and they received a greater number of medications. Subjects with borderline personality disorder were more likely to receive heterocyclic antidepressants and interventions characteristic of psychodynamic psychotherapy and cognitive therapy; they also reported receiving a greater number of medications and types of psychosocial treatment than other subjects. In 1996, subjects with borderline personality disorder were more likely to receive psychodynamic interventions. These findings suggest that in patients with an anxiety disorder, the presence of a comorbid personality disorder is associated with receiving a greater number of medications but not with a greater likelihood of receiving pharmacologic or psychosocial treatment. However, the presence of borderline personality disorder is associated with a greater likelihood of receiving, and receiving a greater number of, certain types of somatic and psychosocial treatments.     

5-HT2A: its role in frontally mediated executive function and related psychopathology

Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.     

Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma

The goal of these experiments was to evaluate the effects of some drugs affecting noradrenergic (NE) synaptic transmission, commonly prescribed following stroke or traumatic brain injury, on functional recovery. Measurement of recovery from a transient hemiplegia produced by a traumatic unilateral focal contusion in sensorimotor cortex (SMCX) of rats was used to assess the effects of chronic haloperidol (HAL) treatment begun early (1 day) or late (18 days to recovered animals) after injury. Additionally, using the same model, the effects of a single administration of drugs with selective action at NE receptors were also evaluated early or late (30 days) after injury. These drugs were: phenoxybenzamine (PBZ), an alpha 1-NE antagonist; prazosin (PRAZ), an alpha 1-NE antagonist; yohimbine (YOH), an alpha 2-NE antagonist; propranolol (PROP), a beta 1- and 2-NE receptor antagonist; methoxymine (METHOX), an alpha 1-NE agonist; and clonidine (CLON), an alpha 2-NE agonist. The data indicate that drugs with antagonistic effects at alpha 1 NE receptors, including HAL and PRAZ but not PROP, administered early after SMCX contusion retard locomotor recovery. Beneficial effects of enhancing NE transmission by METHOX or YOH were not observed. In animals recovered from beam walk (BW) deficits, a single administration of PBZ or PRAZ (alpha 1 NE antagonists) or CLON (alpha 2 NE agonist) transiently reinstated hemiplegic symptoms. The nonspecific beta NE receptor antagonist PROP had no effect in recovered animals. A single dose of HAL had no effect in recovered animals, but a BW deficit transiently developed in some animals following chronic treatment. The data are discussed with reference to drug contraindications noted in clinical studies of recovery from poststroke aphasia and cognition in demented patients with degenerative brain disease.     

Angstzustände bei Patienten mit schweren Persönlichkeitsstörungen

States of anxiety are very common problems in patients with severe personality disorders. All phenomena of anxiety can be observed. In this connection a continuum of the severity of impairment of structural personality organisation can be postulated. In many cases proper anxiety disorders exist as comorbid disorders. Anxiety is esteemed to be the central affective problem of borderline patients. In spite of these relations, states of anxiety in patients with personality disorders are often underdiagnosed or misdiagnosed. For the treatment of neurotic anxiety disorders (for example panic disorders), there exist disorder-specific therapy manuals that proceed from behavioural as well as psychodynamic perspectives. Nevertheless, for the treatment of anxiety states in personality disordered patients, the techniques that focus heavily on symptomatology appear often contraindicated. In our opinion, treatment of these typically severe anxieties must be contained within a therapeutic framework, which essentially takes into account the personality organisation of this group of patients. Such treatment makes special demands on the therapist for working with transference and countertransference processes. From a disorder-specific psychodynamic perspective recommendations are given for psychotherapy.     

Mirror neurons, the representation of word meaning, and the foot of the third left frontal convolution

Previous neuroimaging research has attempted to demonstrate a preferential involvement of the human mirror neuron system (MNS) in the comprehension of effector-related action word (verb) meanings. These studies have assumed that Broca's area (or Brodmann's area 44) is the homologue of a monkey premotor area (F5) containing mouth and hand mirror neurons, and that action word meanings are shared with the mirror system due to a proposed link between speech and gestural communication. In an fMRI experiment, we investigated whether Broca's area shows mirror activity solely for effectors implicated in the MNS. Next, we examined the responses of empirically determined mirror areas during a language perception task comprising effector-specific action words, unrelated words and nonwords. We found overlapping activity for observation and execution of actions with all effectors studied, i.e., including the foot, despite there being no evidence of foot mirror neurons in the monkey or human brain. These "mirror" areas showed equivalent responses for action words, unrelated words and nonwords, with all of these stimuli showing increased responses relative to visual character strings. Our results support alternative explanations attributing mirror activity in Broca's area to covert verbalisation or hierarchical linearisation, and provide no evidence that the MNS makes a preferential contribution to comprehending action word meanings.     

Stiff-person syndrome: autoimmunity and the central nervous system

Stiff-person syndrome (SPS) is a rare disease of severe progressive muscle stiffness in the spine and lower extremities with superimposed muscle spasms triggered by external stimuli. Patients with SPS are often referred for psychiatric evaluation and the psychiatrist may be the first to diagnosis SPS. Psychosocial stressors often precede the first manifestations of the disease; depression, anxiety, and alcohol abuse are comorbid illnesses. The identification of an association with antibodies to glutamic acid decarboxylase (GAD) was invaluable for definitively establishing a pathological basis for the disease; antibodies to amphiphysin and gephyrin are also found in cases of SPS but at much lower frequencies. Whether the antibodies inhibit GAD activity in vivo, target GAD-expressing neurons for immune-mediated destruction, are part of a wider immune process, or are merely a marker for destruction of GAD-expressing neurons by an independent neurodegenerative process is not yet clear. Both electromyography and the detection of GAD antibodies are useful in establishing a diagnosis of SPS. Treatment of SPS includes the use of immunomodulating therapies (plasmapheresis and intravenous immunoglobulins) and symptomatic treatment with benzodiazepines and baclofen. The use of tricyclic antidepressants and rapid withdrawal from therapy should be avoided.     

镜像神经元的意义

镜像神经元是一种感觉–运动神经元。它的典型特征是在动作观察和动作执行两个阶段皆被激活。多年来, 由于研究伦理的限制, 研究恒河猴时使用的单细胞电极植入方式无法应用于人类, 因而不能确定人类大脑皮层是否也存在着具有同样功能的神经细胞。但是通过脑成像技术, 神经科学家确定人类大脑皮层存在着具有相同或类似功能的脑区, 称为“镜像神经系统”。文章对镜像神经元及其人类镜像神经系统的意义进行了深入分析, 指出：(1)由于镜像机制把动作知觉和动作执行进行匹配, 观察者仅仅通过他人行为的知觉, 就激活了执行这一动作的神经环路, 产生了一种他人动作的具身模拟, 因而可以直接把握他人的行为意图; (2)镜像神经元所表现出来的那种动作知觉与动作执行的双重激活功能支持了身心一体说, 从方法论上证明了身心二元论的缺陷, 为身心的整体观提供了神经生物学的证据; (3)镜像神经机制把他人的动作与自己的运动系统相匹配, 以自身动作的神经环路对他人的动作做出回应, 促进了人际理解和沟通, 成为社会沟通的“神经桥梁”。     

Toward a clinically-oriented model of anxiety disorders

The Diagnostic and Statistical Manual of Mental Disorders (DSM) model of psychopathology has generally been the accepted standard in North America for understanding and diagnosing psychological disorders for over half a century. This classification model, particularly since DSM-III, has been formulated around the goals of aiding diagnosis, enhancing communication among professionals, fostering psychopathology research and informing treatment. However, all classification systems are inherently dependent on the purpose for the classification. In this paper, an argument is made for a clinically-relevant diagnostic system of mental disorders to support a primary goal of informing treatment. Several lines of research are examined, including studies on diagnostic reliability, dimensional vs categorical nature of anxiety disorders, co-morbidity, and psychotherapeutic and pharmacological treatment outcome as they relate to current and proposed diagnostic models of anxiety disorders. Based on the evidence, suggestions are made for revising diagnostic models of anxiety, and key lines of future research are proposed.     

Conceptual,methodological, and clinical issues in the assessment of anxiety disorders

Many conceptual, methodological, and clinical issues remain unresolved in the assessment of anxiety disorders. Despite the prevalence, incidence, chronicity, and severity of anxiety disorders, research efforts and funding have fallen behind with regard both to other disorders and to addressing critical issues in the field. The primary objective of this paper is to provide a scientific critique regarding a number of often ignored yet salient considerations in anxiety-disorders assessment. Critical analyses of and recommendations regarding the multidimensional nature of anxiety, comorbidity, uniformity myths, synchrony, normative comparisons, psychometric properties of measures, and treatment integrity are offered. Finally, promising areas of clinical research are presented to enhance further the current understanding of the complexities inherent in assessing anxiety disorders.Preparation of this paper was supported in part by NIMH Grant MH36299.