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.     

Cardiac disorders and antidepressant medications

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have been associated with an increase in cardiovascular disorders, especially in depressed patients who have pre-existing cardiac disease. These disorders are less likely to occur when a therapeutic dosage is administered. Injuries because of falls are more likely in elderly depressed patients, and orthostatic hypotension occurs with the use of TCAs. Selective serotonin reuptake inhibitor (SSRI) antidepressants differ structurally and in side effects from TCAs and MAOIs. They appear to be effective for treatment of depression, and their side-effect profiles appear safer than those of earlier approved antidepressants used by depressed patients with cardiovascular disorders.     

Cardiac Disorders and Antidepressant Medications

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have been associated with an increase in cardiovascular disorders, especially in depressed patients who have pre-existing cardiac disease. These disorders are less likely to occur when a therapeutic dosage is administered. Injuries because of falls are more likely in elderly depressed patients, and orthostatic hypotension occurs with the use of TCAs. Selective serotonin reuptake inhibitor (SSRI) antidepressants differ structurally and in side effects from TCAs and MAOIs. They appear to be effective for treatment of depression, and their side-effect profiles appear safer than those of earlier approved antidepressants used by depressed patients with cardiovascular disorders.     

Indications for the Use of Atypical Antipsychotics in the Elderly

There has been an expanding role for the new generation atypical antipsychotic agents (clozapine, risperidone, olanzapine, and quetiapine) in elderly patients. Their efficacy in the treatment of psychoses associated with schizophrenia is now well established. But psychoses occur in other conditions. This paper will review the current research examining the use of the atypical agents in the treatment of psychoses in the elderly in three somewhat overlapping conditions: schizophrenia, dementia, and Parkinson's disease, as well as in the amelioration of a variety of movement disorders. In the elderly, any of the atypicals can be used to treat schizophrenia, although clozapine may be a second line agent because of its side effect profile. Risperidone may be the drug of choice for the treatment of psychoses and behavioral disturbances in dementia. Clozapine is a primary choice and quetiapine an alternative for the treatment of psychoses in Parkinson's disease; while clozapine and possibly risperidone may be preferred for the initial treatment of some movement disorders. The differential effectiveness of these agents across treatment indications may, in part, be related to their differing affinities at several neurotransmitter receptors. Examination of these relationships in large scale longitudinal studies may help in the development of effective tailored treatments for the elderly.     

Treatment-resistant posttraumatic stress disorder: strategies for intervention

The mainstay of treatment for chronic posttraumatic stress disorder (PTSD) is a combination of psychotherapy and medication treatments. The first-line medications for PTSD are antidepressants, with two selective serotonin reuptake inhibitors (sertraline and paroxetine) currently Food and Drug Administration-indicated for PTSD. However, many patients do not have an adequate response to antidepressants, therefore, combinations with other antidepressants or with other classes of psychotropic medication are often utilized to enhance the therapeutic response. Other agents that have been used include mood stabilizers, anti-adrenergics, anxiolytics, and atypical antipsychotics. The heterogeneity of symptom clusters in PTSD as well as the complex psychiatric comorbidities (eg, with depression or substance abuse) further support the notion that combinations of medications may be needed. To date, there is a paucity of data to support specific strategies for augmenting antidepressants in PTSD. This review will address representative existing studies and discuss several potential pharmacologic strategies for patients suffering from treatment-refractory PTSD.     

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.     

From Research to Practice: An Integrative Framework for the Development of Interventions for Children with Fetal Alcohol Spectrum Disorders

Since fetal alcohol syndrome was first described over 35 years ago, considerable progress has been made in the delineation of the neurocognitive profile in children with prenatal alcohol exposure. Preclinical investigators have made impressive strides in elucidating the mechanisms of alcohol teratogenesis and in testing the effectiveness of pharmacological agents and dietary supplementation in the amelioration of alcohol-induced deficits. Despite these advances, only limited progress has been made in the development of evidence-based comprehensive interventions for functional impairment in alcohol-exposed children. Having performed a search in PubMed and PsycINFO using key words, interventions, treatment, fetal alcohol syndrome, prenatal alcohol exposure, and fetal alcohol spectrum disorders, we found only 12 papers on empirically-based interventions. Only two of these interventions had been replicated and none met the criteria of “well-established,” as defined by Chambless and Hollon (Journal of Consulting and Clinical Psychology 66(1):7–18, 1998). There has been only limited cross-fertilization of ideas between preclinical and clinical research with regard to the development of interventions. Therefore, we propose a framework that allows integrating data from preclinical and clinical investigations to develop comprehensive intervention programs for children with fetal alcohol spectrum disorders. This framework underscores the importance of multi-level evaluations and interventions.     

Response of the norepinephrine system to antidepressant drugs

Environmental stimuli and drugs affect the norepinephrine (NE) system and may be linked to the manifestation and treatment of anxiety and affective disorders. The activity of locus ceruleus NE neurons in the brainstem can alter the function of forebrain structures associated with several psychiatric disorders. In particular, NE neurons send and receive projections from sensory afferents, limbic areas, and cortical areas implicated in higher-order brain malfunctions and the symptomatology of anxiety and affective disorders. In turn, anxiolytic and antidepressant drugs are able to offset perturbations of NE activity and forebrain structures with a time course congruent with their therapeutic action. All antidepressants, even the agents selective for other biogenic amines or peptides, act on the NE system. In the present review, the effects of antidepressants on NE neurons are summarized and applied to the treatment of neuropsychiatric disorders, with emphasis placed on mechanisms of action.     

Pharmacological treatment effects on eye movement control

The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson’s disease, and Huntington’s disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.     

Pharmacological treatment effects on eye movement control

The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson’s disease, and Huntington’s disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.     

Anxiety, Sensory Over-Responsivity, and Gastrointestinal Problems in Children with Autism Spectrum Disorders

Children with autism spectrum disorders (ASD) experience high rates of anxiety, sensory processing problems, and gastrointestinal (GI) problems; however, the associations among these symptoms in children with ASD have not been previously examined. The current study examined bivariate and multivariate relations among anxiety, sensory over-responsivity, and chronic GI problems in a sample of 2,973 children with ASD enrolled in the Autism Treatment Network (ages 2–17 years, 81.6 % male). Twenty-four percent of the sample experienced at least one type of chronic GI problem (constipation, abdominal pain, bloating, diarrhea, and/or nausea lasting three or more months). Children with each type of GI problem had significantly higher rates of both anxiety and sensory over-responsivity. Sensory over-responsivity and anxiety were highly associated, and each provided unique contributions to the prediction of chronic GI problems in logistic regression analyses. The results indicate that anxiety, sensory over-responsivity and GI problems are possibly interrelated phenomenon for children with ASD, and may have common underlying mechanisms.     

Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?

Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials (both pre-approval and post-approval). However, two recent meta-analyses question this picture. The first meta-analysis used data that were submitted to FDA for the approval of 12 antidepressant drugs. While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results. The average benefit of these drugs based on the FDA data was of small magnitude, while the published literature suggested larger benefits. A second meta-analysis using also FDA-submitted data examined the relationship between treatment effect and baseline severity of depression. Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinically important only in the very small minority of patient populations with severe major depression. In severe major depression, antidepressants did not become more effective, simply placebo lost effectiveness. These data suggest that antidepressants may be less effective than their wide marketing suggests. Short-term benefits are small and long-term balance of benefits and harms is understudied. I discuss how the use of many small randomized trials with clinically non-relevant outcomes, improper interpretation of statistical significance, manipulated study design, biased selection of study populations, short follow-up, and selective and distorted reporting of results has built and nourished a seemingly evidence-based myth on antidepressant effectiveness and how higher evidence standards, with very large long-term trials and careful prospective meta-analyses of individual-level data may reach closer to the truth and clinically useful evidence.     

Radioligands for PET and SPECT Imaging of the central noradrenergic system

In the central nervous system, the neurotransmitter norepinephrine is involved in normal physiology, neuropsychiatric disorders, and the effects of numerous drugs. Although alterations of the central noradrenergic system are involved in the pathophysiology and pharmacotherapy of mood disorders, the basis and nature of these changes remain unresolved. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging agents will be valuable for further elucidating the roles of norepinephrine in health and disease. This review discusses PET and SPECT radioligands that have been developed for the enzymes, receptors, and transporters involved in noradrenergic neurotransmission. Currently, imaging agents that exhibit specific in vivo uptake in the brain have been described for monoamine oxidase A and beta-adrenergic receptors, but have not undergone detailed evaluation or experimental application. Based on the successful development and utilization of in vivo imaging agents for elements of the central dopaminergic and serotoninergic systems, PET and SPECT radioligands are expected to serve as new tools for studying the physiology, pathophysiology, and pharmacology of the central noradrenergic system.     

Non-stimulant treatment of attention-deficit/hyperactivity disorder

Stimulants are a highly efficacious and safe treatment for attention-deficit/hyperactivity disorder (ADHD), with 75% to 90% of patients responding well if two different stimulants (amphetamine and methylphenidate) are used. Nonetheless, a subset of ADHD patients will either fail to respond to stimulants or have side effects that preclude their use (tics, severe loss of appetite, marked insomnia). For such patients, there are a number of non-stimulant agents that serve as second-line treatments. Tricyclic antidepressants (TCAs) are the most studied of these drugs. They are superior to placebo in the treatment of ADHD and may reduce abnormal movements in patients with ADHD/tic disorder. TCAs often produce side effects of sedation, dry mouth, and constipation. Bupropion is superior to placebo in the treatment of ADHD and has a more favorable side-effect profile than the TCAs. A new selective norepinephrine reuptake inhibitor, atomoxetine, has been shown to be efficacious in the treatment of ADHD and has recently received an approvable letter from the Food and Drug Administration. The a-agonists clonidine and guanfacine have also been used as alternative agents in ADHD, though the controlled data are more limited. A recent controlled clinical trial suggests a combination of methylphenidate and clonidine has advantages in the treatment of comorbid ADHD and tics over either medication alone. Clinical guidelines for each of these agents, as well as their use in combination with stimulants in comorbid conditions, will be discussed.     

Generality of the practical functional assessment and skill‐based treatment among individuals with autism and mental health disorders

A practical functional assessment format was recently developed that informed a skill‐based treatment for the problem behavior of children diagnosed with autism spectrum disorder. Since its inception there have been multiple replications of the procedures; however, the comprehensive model has rarely been applied to populations with more complex comorbid disorders and severe problem behavior such as those diagnosed with anxiety or depression. We conducted the current study to systematically replicate the entire practical functional assessment and skill‐based treatment model with two participants diagnosed with multiple mental health disorders admitted to a severe behavior outpatient unit. The practical functional assessment identified reinforcers that were provided contingent on increasingly complex forms of communication. Problem behavior remained low for both participants after reinforcement was thinned by increasing a response requirement of completing difficult tasks. Furthermore, the results were socially validated by the parents and teachers and the treatment was extended to the home setting.     

Current trends in neuropathic pain treatments with special reference to fibromyalgia

Neuropathic pain and fibromyalgia are prevalent diseases which have major consequences on healthcare resources and the individual. From the clinical point of view neuropathic pains represent a heterogeneous group of aetiologically different diseases ranging from cancer to diabetes. Patients with fibromyalgia also display clinical features common in neuropathic pain suggesting that there might be some overlap. The mechanisms responsible for symptoms and signs in both diseases are still unknown. Recently, there have been numerous reports of various pharmacological treatments of neuropathic pain and fibromyalgia with often disappointing results. Most of the studies were of short duration, had high attrition rates, and displayed other methodological problems. Some compounds had high rates of adverse effects which makes it often difficult for the patients to tolerate the treatment, especially in the long-term. At present, the best options for medication treatment are tricyclic antidepressants in lower dosage than usual in psychiatric disorders and a wide range of anticonvulsants. Opioids are sometimes recommended but have been found to have minor efficacy. Recently, there have been more controlled trials, which are reported here if they had been published between 2002 and 2004. Various compounds have been tested in different studies. Treatment of fibromyalgia, which has many features in common with depressive symptoms, became the focus of interest. New promising studies with dual serotonin-norepinephrine reuptake inhibitors (duloxetine and milnacipram) and a newer antiepileptic drug (pregabalin) are in progress. Future research will have to apply new approaches (e.g., using a mechanism-based classification of neuropathic pain and carrying out studies in populations with the same symptom but not necessarily the same disease) in order to find effective treatments for these common and often debilitating diseases.     

Identifying environmental contributions to autism: provocative clues and false leads

The potential role of environmental factors in autism spectrum disorders (ASD) is an area of emerging interest within the public and scientific communities. The high degree of heritability of ASD suggests that environmental influences are likely to operate through their interaction with genetic susceptibility during vulnerable periods of development. Evaluation of the plausibility of specific neurotoxicants as etiological agents in ASD should be guided by toxicological principles, including dose-effect dependency and pharmacokinetic parameters. Clinical and epidemiological investigations require the use of sufficiently powered study designs with appropriate control groups and unbiased case ascertainment and exposure assessment. Although much of the existing data that have been used to implicate environmental agents in ASD are limited by methodological shortcomings, a number of efforts are underway that will allow more rigorous evaluation of the role of environmental exposures in the etiology and/or phenotypic expression of the disorder. Surveillance systems are now in place that will provide reliable prevalence estimates going forward in time. Anticipated discoveries in genetics, brain pathology, and the molecular/cellular basis of functional impairment in ASD are likely to provide new opportunities to explore environmental aspects of this disorder.     

Explicative models of musculoskeletal disorders (MSD): From biomechanical and psychosocial factors to clinical analysis of ergonomics

Following the apparition of new working schemes and work organization in companies, a so-called “reactive productivism” was set up at the worker level. This is characterized by an increased workload, flexibility efforts and productivity requirements, which show noticeable impacts on the worker’s health in their own professional environment. Among these consequences are musculoskeletal disorders (MSD) which have become the most current form of professional disease in France. Such troubles and disorders, in relation to working conditions, are complex mechanisms, often expressed by chronic pain and associated with functional troubles and even disability. The majority of researchers are currently in agreement in affirming the multidimensional aspect of these disorders in biomechanical and psychological terms. The purpose of this paper is to list and review the main risk factors leading to such consequences. These epidemiological and psychological factors will be related to francophone clinical and ergonomic concepts and positions. This perspective is oriented more towards the “meaning of activity” with a clinical and a psychodynamic approach. In our conclusion, we present a predictive model on musculoskeletal pain in relation to maneuver margins, workload and work recognition.     

A Review of Recent FDA Drug Safety Communications for Pediatric Psychotropics

To alert professionals and consumers about safety risks associated with approved drugs, the U.S. Food and Drug Administration (FDA) periodically issues Drug Safety Communications, or DSCs (previously known as advisories, warnings, and health care professional letters). This review consolidates balanced information from 22 DSCs issued over the last 15 years by the FDA for drugs with pediatric indications (for any disorder) that are used to treat pediatric emotional and behavioral disorders (ADHD drugs, antipsychotics, antidepressants, and antiepileptics/anticonvulsants). A single-source document of pediatric DSCs for these drugs was needed because none existed previously; finding DSC information on the FDA website can be challenging; and other information sources (e.g., manufacturer or advocacy websites, blogs, other media reports) may lack the objectivity or accuracy that the FDA is charged to maintain. This consolidation is intended to enable better informed risk-benefit analysis around treatment selection and drug safety monitoring. For the 22 DSCs, we summarize the safety concerns, the populations affected, and when available from the FDA, the incidence of the adverse events, precursors, and factors that may increase or mitigate the risk of these very serious (e.g., sudden death, life-threatening rash, liver failure), but typically low incidence (<1 %) adverse events (cardiometabolic complications with atypical antipsychotics and suicidality with antidepressants are more common). This review does not address the far more common, but usually less serious, side effects that also accompany these drugs. Implications of this review for research and practice are discussed.