Anxiety Disorders: Nutt DJ

Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU, Anonymous00170. · Division of Clinical Neurosciences, University of Southampton, Southampton, UK. · J Psychopharmacol. · Pubmed #16272179 No free full text.

Abstract: These British Association for Psychopharmacology guidelines cover the range and aims of treatment for anxiety disorders. They are based explicitly on the available evidence and are presented as recommendations to aid clinical decision making in primary and secondary medical care. They may also serve as a source of information for patients and their carers. The recommendations are presented together with a more detailed review of the available evidence. A consensus meeting involving experts in anxiety disorders reviewed the main subject areas and considered the strength of evidence and its clinical implications. The guidelines were constructed after extensive feedback from participants and interested parties. The strength of supporting evidence for recommendations was rated. The guidelines cover the diagnosis of anxiety disorders and key steps in clinical management, including acute treatment, relapse prevention and approaches for patients who do not respond to first-line treatments.

Allgulander C, Bandelow B, Hollander E, Montgomery SA, Nutt DJ, Okasha A, Pollack MH, Stein DJ, Swinson RP, Anonymous00175. · Department of Psychiatry, Harvard University School of Medicine, Boston, Massachusetts, USA. · CNS Spectr. · Pubmed #14767398 No free full text.

Abstract: What are the current recommendations for the long-term treatment of generalized anxiety disorder (GAD)? GAD is a common disorder with a lifetime prevalence of 4% to 7% in the general population. GAD is characterized by excessive, uncontrollable worry or anxiety about a number of events or activities that the individual experiences on more days than not over a 6-month period. Onset of GAD symptoms usually occurs during an individual's early twenties; however, high rates of GAD have also been seen in children and adolescents. The clinical course of GAD is often chronic, with 40% of patients reporting illness lasting >5 years. GAD is associated with pronounced functional impairment, resulting in decreased vocational function and reduced quality of life. Patients with GAD tend to be high users of outpatient medical care, which contributes significantly to healthcare costs. Currently, benzodiazepines and buspirone are prescribed frequently to treat GAD. Although both show efficacy in acute treatment trials, few long-term studies have been performed. Benzodiazepines are not recommended for long-term treatment of GAD, due to associated development of tolerance, psychomotor impairment, cognitive and memory changes, physical dependence, and a withdrawal reaction on discontinuation. The antidepressant venlafaxine extended-release (XR) has received approval for the treatment of GAD in the United States and many other countries. Venlafaxine XR has demonstrated efficacy over placebo in two randomized treatment trials of 6 months' duration as well as in other acute trials. Paroxetine is the first of the selective serotonin reuptake inhibitors (SSRIs) to receive US approval for the treatment of GAD. Paroxetine demonstrated superiority to placebo in short-term trials, and investigations into the use of other SSRIs are ongoing. This suggests that other SSRIs, and serotonin and noradrenaline reuptake inhibitors, are likely to be effective in the treatment of GAD. Of the psychological therapies, cognitive-behavioral therapy (CBT) shows the greatest benefit in treating GAD patients. Treatment gains after a 12-week course of CBT may be maintained for up to 1 year. Currently, no guidelines exist for the long-term treatment of GAD.

Van Ameringen M, Allgulander C, Bandelow B, Greist JH, Hollander E, Montgomery SA, Nutt DJ, Okasha A, Pollack MH, Stein DJ, Swinson RP, Anonymous00174. · Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada. · CNS Spectr. · Pubmed #14767397 No free full text.

Abstract: What is the best approach for treating patients with social phobia (social anxiety disorder) over the long term? Social phobia is the most common anxiety disorder, with reported prevalence rates of up to 18.7%. Social phobia is characterized by a marked and persistent fear of being observed or evaluated by others in social performance or interaction situations and is associated with physical, cognitive, and behavioral (ie, avoidance) symptoms. The onset of social phobia typically occurs in childhood or adolescence and the clinical course, if left untreated, is usually chronic, unremitting, and associated with significant functional impairment. Social phobia exhibits a high degree of comorbidity with other psychiatric disorders, including mood disorders, anxiety disorders, and substance abuse/dependence. Few people with social phobia seek professional help despite the existence of beneficial treatment approaches. The efficacy, tolerability, and safety of the selective serotonin reuptake inhibitors (SSRIs), evidenced in randomized clinical trials, support these agents as first-line treatment. The benzodiazepine clonazepam and certain monoamine oxidase inhibitors (representing both reversible and nonreversible inhibitors) may also be of benefit. Treatment of social phobia may need to be continued for several months to consolidate response and achieve full remission. The SSRIs have shown benefit in long-term treatment trials, while long-term treatment data from clinical studies of clonazepam are limited but support the drug's efficacy. There is also evidence for the effectiveness of exposure-based strategies of cognitive-behavioral therapy, and controlled studies suggest that the effects of treatment are generally maintained at long-term follow-up. In light of the chronicity and disability associated with social phobia, as well as the high relapse rate after short-term therapy, it is recommended that effective treatment be continued for at least 12 months.

Stein DJ, Bandelow B, Hollander E, Nutt DJ, Okasha A, Pollack MH, Swinson RP, Zohar J, Anonymous00173. · Medical Research Council Research Unit on Anxiety Disorder, University of Stellenbosch, Cape Town, Tygerberg, South Africa. · CNS Spectr. · Pubmed #14767396 No free full text.

Abstract: Posttraumatic stress disorder (PTSD) is a common and disabling condition. In addition to combat-related PTSD, the disorder occurs in civilians exposed to severe traumatic events, with the community prevalence rate for the combined populations reaching as high as 12%. If left untreated, PTSD may continue for years after the stressor event, resulting in severe functional and emotional impairment and a dramatic reduction in quality of life, with negative economic consequences for both the sufferer and society as a whole. Although PTSD is often overlooked, diagnosis is relatively straightforward once a triggering stressor event and the triad of persistent symptoms-reexperiencing the traumatic event, avoiding stimuli associated with the trauma, and hyperarousal have been identified. However, comorbid conditions of anxiety and depression frequently hamper accurate diagnosis. Treatment for PTSD includes psychotherapy and pharmacotherapy. The latter includes selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Only SSRIs have been proven effective and safe in long-term randomized controlled trials. Current guidelines from the Expert Consensus Panel for PTSD recommend treatment of chronic PTSD for a minimum of 12-24 months.

Pollack MH, Allgulander C, Bandelow B, Cassano GB, Greist JH, Hollander E, Nutt DJ, Okasha A, Swinson RP, Anonymous00172. · Division of Psychiatry, Huddinge University Hospital, Stockholm, Sweden. · CNS Spectr. · Pubmed #14767395 No free full text.

Abstract: What are the symptoms of panic disorder and how is the disorder most effectively treated? One of the most commonly encountered anxiety disorders in the primary care setting, panic disorder is a chronic and debilitating illness. The core symptoms are recurrent panic attacks coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Patients with panic disorder have medically unexplained symptoms that lead to overutilization of healthcare services. Panic disorder is often comorbid with agoraphobia and major depression, and patients may be at increased risk of cardiovascular disease and, possibly, suicide. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors have emerged as the most favorable treatment, as they have a beneficial side-effect profile, are relatively safe (even if taken in overdose), and do not produce physical dependency. High-potency benzodiazepines, reversible monoamine oxidase inhibitors, and tricyclic antidepressants have also shown antipanic efficacy. In addition, cognitive-behavioral therapy has demonstrated efficacy in the acute and long-term treatment of panic disorder. An integrated treatment approach that combines pharmacotherapy with cognitive-behavioral therapy may provide the best treatment. Long-term efficacy and ease of use are important considerations in treatment selection, as maintenance treatment is recommended for at least 12-24 months, and in some cases, indefinitely.

Greist JH, Bandelow B, Hollander E, Marazziti D, Montgomery SA, Nutt DJ, Okasha A, Swinson RP, Zohar J, Anonymous00171. · Healthcare Technology Systems, Inc., Madison, Wisconsin 53717, USA. · CNS Spectr. · Pubmed #14767394 No free full text.

Abstract: What are the latest psychotherapeutic and pharmacotherapeutic treatment recommendations for obsessive-compulsive disorder (OCD)? OCD is a relatively common disorder with a lifetime prevalence of approximately 2% in the general population. It often has an early onset, usually in childhood or adolescence, and frequently becomes chronic and disabling if left untreated. High associated healthcare utilization and costs, and reduced productivity resulting in loss of earning, pose a huge economic burden to OCD patients and their families, employers, and society. OCD is characterized by the presence of obsessions and compulsions that are time-consuming, cause marked distress, or significantly interfere with a person's functioning. Most patients with OCD experience symptoms throughout their lives and benefit from long-term treatment. Both psychotherapy and pharmacotherapy are recommended, either alone or in combination, for the treatment of OCD. Cognitive-behavioral therapy is the psychotherapy of choice. Pharmacologic treatment options include the tricyclic antidepressant clomipramine and the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. These have all shown benefit in acute treatment trials; clomipramine, fluvoxamine, fluoxetine, and sertraline have also demonstrated benefit in long-term treatment trials (at least 24 weeks), and clomipramine, sertraline, and fluvoxamine have United States Food and Drug Administration approvals for use in children and adolescents. Available treatment guidelines recommend first-line use of an SSRI (ie, fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) in preference to clomipramine, due to the latter's less favorable adverse-event profile. Further, pharmacotherapy for a minimum of 1-2 years is recommended before very gradual withdrawal may be considered.

Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Borkovec TD, Rickels K, Stein DJ, Wittchen HU. · Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, SC 29425-0742, USA. · J Clin Psychiatry. · Pubmed #11414552 No free full text.

Abstract: OBJECTIVE: To provide primary care clinicians with a better understanding of management issues in generalized anxiety disorder (GAD) and guide clinical practice with recommendations on the appropriate treatment strategy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R.T. Davidson, Yves Lecrubier, and David J. Nutt. Four additional faculty members invited by the chair were Karl Rickels, Hans-Ulrich Wittchen, Dan J. Stein, and Thomas D. Borkovec. EVIDENCE: The consensus statement is based on the 6 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed the review articles and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSIONS: GAD is the most common anxiety disorder in primary care and is highly debilitating. Furthermore, it is frequently comorbid with depression and other anxiety disorders, which exacerbates functional impairment. Antidepressants (serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and nonsedating tricyclic antidepressants) are generally the most appropriate first-line pharmacotherapy for GAD, since they are also effective against comorbid psychiatric disorders and are suitable for long-term use. Cognitive-behavioral therapy is the preferred form of psychotherapy for GAD, although when GAD is comorbid with depression, pharmacotherapy is increasingly indicated.

Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Foa EB, Kessler RC, McFarlane AC, Shalev AY. · Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, Charleston 29425-0742, USA. · J Clin Psychiatry. · Pubmed #10761680 No free full text.

Abstract: OBJECTIVE: To provide primary care clinicians with a better understanding of management issues in posttraumatic stress disorder (PTSD) and guide clinical practice with recommendations on the appropriate management strategy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Other faculty invited by the chair were Edna B. Foa, Ronald C. Kessler, Alexander C. McFarlane, and Arieh Y. Shalev. EVIDENCE: The consensus statement is based on the 6 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed the review articles and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSION: PTSD is often a chronic and recurring condition associated with an increased risk of developing secondary comorbid disorders, such as depression. Selective serotonin reuptake inhibitors are generally the most appropriate choice of first-line medication for PTSD, and effective therapy should be continued for 12 months or longer. The most appropriate psychotherapy is exposure therapy, and it should be continued for 6 months, with follow-up therapy as needed.

Reul JM, Nutt DJ. · No affiliation provided · J Psychopharmacol. · Pubmed #18701640 No free full text.

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Allgulander C, Nutt DJ. · No affiliation provided · J Psychopharmacol. · Pubmed #18635714 No free full text.

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Nutt DJ, Sharpe M. · No affiliation provided · J Psychopharmacol. · Pubmed #18187527 No free full text.

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Davies SJ, Lowry CA, Nutt DJ. · No affiliation provided · J Psychopharmacol. · Pubmed #17901092 No free full text.

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Robinson HM, Hood SD, Bell CJ, Nutt DJ. · No affiliation provided · Rev Bras Psiquiatr. · Pubmed #17242803 links to  free full text

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Nutt DJ. · No affiliation provided · J Psychopharmacol. · Pubmed #14513912 No free full text.

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Argyropoulos SV, Hood SD, Nutt DJ. · No affiliation provided · Acta Psychiatr Scand. · Pubmed #11328235 No free full text.

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Bailey JE, Nutt DJ. · Psychopharmacology Unit, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK. · Pharmacol Biochem Behav. · Pubmed #18485466 No free full text.

Abstract: The mechanisms by which the inhalation of carbon dioxide (CO(2)) produces anxiety and panic are not fully understood, although more recently there is evidence to suggest the involvement of a neural 'fear circuit'. We have suggested that this neural fear circuit is partly mediated by the brain noradrenaline network [Bailey, J.E., Argyropoulos, S.V., Lightman, S.L. and Nutt, D.J., (2003) Does the brain noradrenaline network mediate the effects of the CO(2) challenge? J Psychopharmacol 17(3): 252-259.]. However, we now review evidence that GABA-A may also play an important role in the modulation of CO(2)-induced anxiety. The review of this evidence starts with a key publication showing that 1 min of 35% CO(2)/65% air produced anxiogenic effects in a rat model of anxiety, to a similar extent to the anxiogenic betacarboline derivative FG7142, a benzodiazepine receptor inverse agonist. The effects of both anxiogenic stimuli were abolished with pre-treatment with alprazolam (0.5 mg/kg), but only those of FG7142, not CO(2), was blocked by a benzodiazepine antagonist [Cuccheddu, T., Floris, S., Serra, M., Porceddu, L., Sanna, E., Biggio, G., (1995) Proconflict effect of carbon dioxide inhalation in rats. Life Sci 56: PL 321-324.]. Although the evidence from this study did not conclusively prove that CO(2) had an action to reduce GABA function, it was an experiment designed to be translational to compare what was known about CO(2)-induced anxiety in patients, and to also to explore if GABA mechanisms are involved. Additional evidence from the literature is found in the association between GABA and chemoreceptors, both in laboratory and human studies and GABA and anxiety disorders. Evidence of this association is found across species from stress-induced change in GABA levels in plants and insects to humans, where there is now much evidence of abnormalities in GABA/benzodiazepine receptors in anxiety and other psychiatric disorders. This paper reviews some of the evidence and attempts to relate and compare these findings across species from the human to the Drosophila.

Kalueff AV, Nutt DJ. · Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland, USA. · Depress Anxiety. · Pubmed #17117412 No free full text.

Abstract: This review assesses the parallel data on the role of gamma-aminobutyric acid (GABA) in depression and anxiety. We review historical and new data from both animal and human experimentation which have helped define the key role for this transmitter in both these mental pathologies. By exploring the overlap in these conditions in terms of GABAergic neurochemistry, neurogenetics, brain circuitry, and pharmacology, we develop a theory that the two conditions are intrinsically interrelated. The role of GABAergic agents in demonstrating this interrelationship and in pointing the way to future research is discussed.

Nutt DJ, Stein DJ. · Psychopharmacology Unit, University of Bristol, Bristol, United Kingdom. · CNS Spectr. · Pubmed #17008826 links to  free full text

Abstract: Anxiety and depression are common disorders that frequently co-exist. Both disorders show good response to antidepressants, especially the selective serotonin reuptake inhibitors. Some suggest that these disorders are variants of the same underlying brain pathology. This review examines the similarities and differences between anxiety and depression in terms of the known neurobiological etiologic mechanisms as well as their biological underpinnings and response to treatment. Sufficient and significant differences between these disorders support the view that they are independent entities. Shared abnormalities in the 5HT1A receptor function, for example, may help explain some of the comorbidity.

Bell CJ, Hood SD, Nutt DJ. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, New Zealand. · Aust N Z J Psychiatry. · Pubmed #15996137 No free full text.

Abstract: OBJECTIVE: This is the second of two articles reviewing the modern dietary technique of acute tryptophan depletion (ATD), a method of transiently reducing central serotonin levels in both healthy volunteers and clinical populations. This article details the clinical studies to date and discusses the implications of this research methodology. METHOD: The authors present a review of clinical ATD studies collated from a MEDLINE search, unpublished communications and the authors' considerable experience with this paradigm. RESULTS: Following from the initial use of ATD in subjects with depressive illness, studies of anxiety disorders and other psychiatric illnesses have been reported. Sleep, aggressive and cognitive effects are also active areas of research and are reviewed here. CONCLUSIONS: Acute tryptophan depletion remains a useful psychiatric research tool. The findings from the clinical studies reviewed here are summarized and implications for future research detailed.

Hood SD, Bell CJ, Nutt DJ. · Psychopharmacology Unit, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, England, UK. · Aust N Z J Psychiatry. · Pubmed #15996136 No free full text.

Abstract: OBJECTIVE: Acute tryptophan depletion (ATD) is an experimental technique that has been widely used over the last decade to investigate the role of serotonin (5-HT) in a variety of disorders. This review, the first of two articles, describes the rationale behind this technique and provides detail on how it is applied in research settings. METHOD: The authors outline the development of this technique with reference to the seminal literature and more recent findings from neuroimaging and neuroendocrine studies. This is supplemented by the authors' clinical experience of over 5 years of continuous experimental work with this paradigm in over 50 subjects. RESULTS: Acute tryptophan depletion is a method that significantly reduces central 5-HT in human subjects. Non-serotonergic explanations of the effects of ATD have not been confirmed, supporting the specificity of this method. CONCLUSIONS: The ATD technique is a valid method of manipulating central 5-HT levels. The second article in this series will review the application of ATD in depression, anxiety and other psychiatric conditions.

Nutt DJ. · Psychopharmacology Unit, University of Bristol, Bristol, UK. · CNS Spectr. · Pubmed #15618947 links to  free full text

Abstract: 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.

Kaluev AV, Nutt DJ. · No affiliation provided · Eksp Klin Farmakol. · Pubmed #15500054 No free full text.

Abstract: Data on the role of gamma-aminobutyric acid (GABA) in pathogenesis of anxiety and depression are critically assessed. Clinical and experimental results indicative of an important role of GABA as the neurotransmitter involved in these mental states and their integration within a common pathogenic process are considered. The general neurochemical, pharmacological, and neurophysiological aspects of anxiety and depression are analyzed in the context of GABAergic system involvement in this process and the possibility of using GABAergic agents for the therapy of various related disorders.

Davies SJ, Jackson PR, Potokar J, Nutt DJ. · Psychopharmacology Unit, Dorothy Hodgkin Building, Bristol BS1 3NY. · BMJ. · Pubmed #15087342 links to  free full text

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Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Marshall RD, Nemeroff CB, Shalev AY, Yehuda R. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA. · J Clin Psychiatry. · Pubmed #14728098 No free full text.

Abstract: OBJECTIVE: To provide an update to the "Consensus Statement on Posttraumatic Stress Disorder From the International Consensus Group on Depression and Anxiety" that was published in a supplement to The Journal of Clinical Psychiatry (2000) by presenting important developments in the field, the latest recommendations for patient care, and suggestions for future research. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Other faculty who were invited by the chair were Randall D. Marshall, Charles B. Nemeroff, Arieh Y. Shalev, and Rachel Yehuda. EVIDENCE: The consensus statement is based on the 7 review articles in this supplement and the related scientific literature. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed topics to be represented by the 7 review articles in this supplement, and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all faculty. CONCLUSION: There have been advancements in the science and treatment of posttraumatic stress disorder. Attention to this disorder has increased with recent world events; however, continued efforts are needed to improve diagnosis, treatment, and prevention of posttraumatic stress disorder.

Nutt DJ, Malizia AL. · Psychopharmacology Unit, University of Bristol,Bristol, United Kingdom. · J Clin Psychiatry. · Pubmed #14728092 No free full text.

Abstract: Posttraumatic stress disorder (PTSD) is a highly disabling condition that is associated with intrusive recollections of a traumatic event, hyperarousal, avoidance of clues associated with the trauma, and psychological numbing. The field of neuroimaging has made tremendous advances in the past decade and has contributed greatly to our understanding of the physiology of fear and the pathophysiology of PTSD. Neuroimaging studies have demonstrated significant neurobiologic changes in PTSD. There appear to be 3 areas of the brain that are different in patients with PTSD compared with those in control subjects: the hippocampus, the amygdala, and the medial frontal cortex. The amygdala appears to be hyperreactive to trauma-related stimuli. The hallmark symptoms of PTSD, including exaggerated startle response and flashbacks, may be related to a failure of higher brain regions (i.e., the hippocampus and the medial frontal cortex) to dampen the exaggerated symptoms of arousal and distress that are mediated through the amygdala in response to reminders of the traumatic event. The findings of structural and functional neuroimaging studies of PTSD are reviewed as they relate to our current understanding of the pathophysiology of this disorder.