Psychobiological Approaches for Anxiety Disorders E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: Wiley Series in Clinical Psychology
• Sprache: Englisch

Seitenzahl: 387

Veröffentlichungsjahr: 2012

Beschreibung

Psychobiological Approaches for Anxiety Disorders presents a comprehensive overview of the latest empirical evidence and research results on combining pharmacological agents and CBT techniques for the treatment of anxiety disorders.

• The first book to focus on the issue of enhancing CBT with pharmacological agents
• Features chapters from leading authors in the fields of psychiatry, pharmacology, clinical psychology, neuroscience, and emotion research
• Contributes significantly to the field by summarizing the contemporary research in combination treatments in anxiety disorders
• A valuable resource for clinicians in training, as well as experienced clinicians seeking to help patients with anxiety disorders

Leseprobe

Contents

Cover

Wiley Series in

Title Page

Copyright

About the Contributors

About the Editor

Introduction

Chapter 1: The Biology and Efficacy of Combination Strategies for Anxiety Disorders

Introduction

Psychobiology of Combination Treatments

Evidence for Combination Therapy in Anxiety Disorders

Conclusion

References

Chapter 2: Benzodiazepines

The Efficacy Of BZ Treatment for the Anxiety Disorders

Combination Treatment: The Wish and the Reality

Specific BZ Effects On Memory for CBT

Additional Negative Effects of Combination Treatment – Discontinuation Effects

A Model of Combined BZ and CBT

CBT for BZ Discontinuation

Summary and Conclusions

References

Chapter 3: Tricyclic Antidepressants and Monoamine Oxidase Inhibitors

Introduction

Why Combine Antidepressants and Psychotherapy?

Tricyclic Antidepressants for Panic Disorder and Agoraphobia

Tricyclic Antidepressants for Obsessive-Compulsive Disorder

Monoamine Oxidase Inhibitors for Panic Disorder and Agoraphobia

Monoamine Oxidase Inhibitors for Social Anxiety Disorder

Conclusion

References

Chapter 4: Selective Serotonin Reuptake Inhibitors, Reversible Inhibitors of Monoamine Oxidase-A, and Buspirone

Introduction

Methodological Issues

Meta-Analyses

Panic Disorder

Generalized Anxiety Disorder

Conclusion

References

Chapter 5: D-Cycloserine

Introduction

Basic Learning Processes in CBT

DCS Enhances the Extinction of Fear

The Effects of DCS on Fear Extinction in Animal Models

Clinical Applications of DCS in Humans

Implications of Research for Clinical Practice

Conclusion

References

Chapter 6: Yohimbine Hydrochloride

Introduction

Background and History of Yohimbine

Safety and Tolerability of Yohimbine Hydrochloride

Fear Conditioning and Extinction Learning

Yohimbine and Emotional Learning

Yohimbine in Animal Studies of Extinction

Yohimbine Augmentation of Exposure Treatment in Humans

Conclusion

References

Chapter 7: Cortisol

Introduction

Cortisol and the Regulation of Memory

The Impact of Fear Memories in Anxiety Disorders

Enhancing Exposure Therapy Effects with Cortisol

Possible Underlying Mechanisms for Glucocorticoid-Induced Fear Reduction

Conclusion

Acknowledgements

References

Chapter 8: Oxytocin

Introduction

Neurophysiological Bases of Oxytocin

Oxytocin and Human Social Behavior

Methodological Issues

Social Stress and Anxiety

Emotion Recognition

Social Cognition and Memory

Prosocial Behavior

Combining Oxytocin and Psychotherapy for the Treatment of ‘Social Disorders'

Conclusion

References

Chapter 9: Dietary Supplements

Introduction

The Potential of Dietary Supplements

AIMS of the Current Review

Nutritional Supplements

Herbal and Botanical Supplements

Conclusion

References

Chapter 10: A Roadmap for the Research and Practice of Combination Strategies

Moving Beyond the Horse Race Comparison of Clinical Trials and Toward Translational Medicine

Moving Toward Understanding the Mechanism of Treatment Change

Moving Toward Personalized Medicine Using Biomarkers

Conclusion

Acknowledgment

References

Index

Wiley Series in

CLINICAL PSYCHOLOGY

Adrian Wells (Series Advisor)School of Psychological Sciences, University of Manchester, UK

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Library of Congress Cataloging-in-Publication Data

Psychobiological approaches for anxiety disorders : treatment combination strategies / edited by Stefan G. Hofmann.

p.; cm.

Includes bibliographical references and index.

ISBN 978-0-470-97181-9 (cloth) – ISBN 978-0-470-97180-2 (pbk.)

I. Hofmann, Stefan G.

[DNLM: 1. Anxiety Disorders–therapy. 2. Combined Modality Therapy–methods. WM 172]

616.85′22–dc23

2011043015

About the Contributors

Gail Alvares is a PhD student at the Brain and Mind Research Institute, University of Sydney, working in the field of social anxiety and decision making. Her research explores some of the fundamental ways in which stress and anxiety influences learning and habit formation.

Dr Borwin Bandelow is Professor at the Department of Psychiatry and Psychotherapy at the University of Göttingen, Germany. He is the Managing Director of the clinic and head of the Anxiety Disorders Unit. As a psychiatry and neurology specialist, a psychologist, and a psychotherapist, Borwin Bandelow specializes in anxiety disorders (panic disorder, generalized anxiety disorder, and social phobia), schizophrenia, depression, psychotherapy, and psychopharmacology. He has authored or co-authored over 200 publications internationally in both books and scientific journals. Borwin Bandelow is President of the German Society for Anxiety Research. He is Editor-in-Chief of the German Journal of Psychiatry, one of the first on-line psychiatric journals.

Frances S. Chen, PhD, is a postdoctoral fellow at the University of Freiburg, Germany. She completed her PhD in psychology at Stanford University. From 2009 to 2010, she was a Visiting Professor of Psychology at Deep Springs College in California. She currently conducts research at the University of Freiburg as a Fulbright Scholar and Alexander von Humboldt Postdoctoral Fellow. Her research focuses on neurobiological and psychological factors influencing social relationships, in particular attachment behavior and behavior within negotiation and conflict settings.

Michelle L. Davis is a research assistant for the Anxiety Research and Treatment Program at Southern Methodist University. She received a BSc in Biology at Texas Tech University. She is currently a project coordinator for a study funded by the National Institute of Drug Abuse examining exercise as an augment to cognitive behavioral treatment for smoking cessation.

Lindsey B. DeBoer is a clinical psychology doctoral candidate at Southern Methodist University. She received a BA in Psychology and in Child Development at The University of Texas at Dallas and an MA in clinical psychology at SMU. Ms. DeBoer is currently a research assistant for the Anxiety Research and Treatment Program at SMU. Her research focuses on the interplay between anxiety and health behaviors including eating behavior, exercise, and substance use, as well as augmenting empirically supported psychotherapy with exercise and dietary interventions.

Dr Dominique de Quervain is a full professor at the Faculty of Medicine and Faculty of Psychology and Director of the Division of Cognitive Neuroscience, University of Basel, Switzerland. He studied medicine at the University of Berne, Switzerland, and was a Postdoctoral Fellow at the University of California Irvine, USA, and at the universities of Basel and Zurich, Switzerland. He is interested in the effects of stress hormones on memory in health and disease and in the identification of memory-related genes in humans using behavioral genetics approaches together with neuroimaging techniques.

Dr Gregor Domes completed his PhD in psychology at the University of Tübingen, Germany, and his postdoctoral research at the University of Rostock, Germany and the University of Zurich, Switzerland. Currently, he is an assistant professor at the University of Freiburg, Germany and a member of the Freiburg Brain Imaging Center. His research focuses on the behavioral and neural effects of steroid hormones and neuropeptides in health and mental disorders.

Samantha G. Farris is a clinical psychology doctoral student at the University of Houston. She received her Bachelor's degree in psychology from Rutgers University, while working at the Center of Alcohol Studies. After completing her degree, Ms Farris worked as a research coordinator at the Center for the Treatment and Study of Anxiety, at the University of Pennsylvania. Her current research interests include the relationship between anxiety and substance use disorders, and dissemination of empirically-supported treatments.

Keith Ganasen, MD, is a resident in psychiatry. He has, during his training in psychiatry, embarked on research in the anxiety disorders, and is planning a career in academic psychiatry.

Dr Adam Guastella is Associate Professor, a clinical psychologist, and principal research fellow at the Brain and Mind Research Institute, University of Sydney. He manages the youth anxiety services at the institute. His research focuses on using translational models to improve social function in disorders of social deficit and to develop novel methods to reduce anxiety.

Bridget A. Hearon, MA, is a doctoral student in the Clinical Psychology Program at Boston University. Her research interests include the treatment of anxiety and substance use disorders as well as factors which influence health behaviors.

Dr Markus Heinrichs is a full Professor at the Faculty of Economics and Behavioral Sciences and at the Faculty of Medicine, Director of the Laboratory for Biological and Personality Psychology, and Director of the Outpatient Clinic for Stress-Related Disorders at the University of Freiburg, Germany. He received his PhD from the University of Trier, Germany, where he began his studies on oxytocin and social behavior. Prior to his position at the University of Freiburg, he spent 10 years at the University of Zurich, Switzerland, where he was a professor of clinical psychology and psychobiology from 2007 to 2009. His research topics include experimental therapy research on mental disorders with social deficits, neurobiology of social interaction, and stress- and anxiety-protective factors.

Michael W. Otto, PhD, is Professor of Psychology at Boston University. Michael Otto specializes in the cognitive-behavioral treatment of anxiety, mood, and substance use disorders. An enduring theme across these disorders is the role of exposure-based emotional tolerance/acceptance strategies in improving mental health and activity levels. His research focuses on difficult-to-treat populations, including interventions for patients who have failed to respond to previous treatments. He also focuses on health behavior promotion ranging from medication adherence to engagement in exercise, and has published over 300 articles, chapters, and books spanning his research interests.

Mark B. Powers, PhD, is Assistant Professor and Co-Director of the Anxiety Research and Treatment Program at Southern Methodist University. He received a BA at the University of California at Santa Barbara, an MA at Pepperdine University, and a PhD from the University of Texas at Austin. He also completed a pre-doctoral fellowship at Boston and Harvard universities and a residency at the University of Washington. He has over 70 publications and his current research focuses on mechanisms of change in anxiety disorders.

Markus Reitt is a clinical psychologist at the Department of Psychiatry and Psychotherapy at the University of Göttingen. He is trained in Cognitive Behavioral Therapy. In his research, he cooperates with the East China Normal University, Shanghai, China. He is currently working with the Task Force for Germany National Guidelines for Anxiety Disorders.

Franklin R. Schneier, MD, is Professor of Clinical Psychiatry at the Department of Psychiatry at Columbia University in New York and Research Psychiatrist in the Anxiety Disorders Clinic of New York State Psychiatric Institute. His research has focused on psychobiology, and cognitive-behavioral and pharmacological treatments for anxiety and mood disorders.

Jasper J. A. Smits, PhD, is Associate Professor and Co-director of the Anxiety Research and Treatment Program at Southern Methodist University. He is a federally funded investigator of intervention strategies to improve outcomes for adults suffering from anxiety and related disorders.

Dr Leila Maria Soravia is a Postdoctoral Fellow at the Department of Psychiatric Neurophysiology of the University Hospital of Psychiatry, University of Berne, Switzerland. She studied Psychology at the University of Berne, and obtained her PhD at the Department of Clinical Psychology and Psychotherapy of the University of Zürich, Switzerland. She has focused on the investigation of the neuroendocrinological mechanisms of anxiety disorders and the development of new treatment approaches, especially for social phobia and spider phobia. Her main interest is in the exploration of the HPA-axis, the glucocorticoid cortisol, and its influence on fear memory in phobic patients.

Dan J. Stein's MD, PhD, is Professor and Chairman of the Department of Psychiatry at the University of Cape Town in South Africa. His research focuses on the psychobiology of anxiety disorders, ranging from animal models, through clinical research, and on to epidemiological work.

Dr Dirk Wedekind is a senior consultant psychiatrist at the Department of Psychiatry at the University of Göttingen, Germany. He attended medical school in Göttingen, Germany and studied affective neuroscience in Maastricht, The Netherlands. His scientific work has focused on the neurobiology and neuropharmacology of anxiety disorders. He also worked on clinical and biological aspects of addiction disorders and did research on personality- and somatoform disorders. He has authored and co-authored more than 60 articles in scientific journals and books and is a frequent national speaker on pharmacological and clinical topics.

About the Editor

Stefan G. Hofmann, PhD, is Professor of Psychology at Boston University and the Director of the Psychotherapy and Emotion Research Laboratory. He is president-elect of the Association for Behavioral and Cognitive Therapies and president-elect of the International Association for Cognitive Psychotherapy. He is also a Board Member of the Academy of Cognitive Therapy and of the Anxiety Disorders Association of America. He is an advisor to the DSM-V Development Process. He is widely published with more than 200 peer-reviewed journal articles and book chapters, and 10 books, including “An Introduction to Modern CBT” (Wiley-Blackwell, 2012). His primary research interests center on treatment of anxiety disorders for which he has received many research awards. Weblink: http://www.bostonanxiety.org/

Introduction

Stefan G. Hofmann

Department of Psychology, Boston University, Boston, MA USA

Individuals with anxiety disorders show excessive fear when confronted with specific objects, situations, physical sensations, or other external or internal cues in the absence of any actual danger. As a consequence, people with these debilitating conditions often avoid these cues or endure their anxiety under great distress. This often leads to great personal suffering, diminished quality of life, and high economic cost to society (Olatunji et al. 2007).

Epidemiological studies indicate that the group of anxiety disorders, which includes specific phobias, social anxiety disorder, generalized anxiety, obsessive compulsive disorder, panic disorder, agoraphobia, and post-traumatic stress disorder, are the most prevalent class of mental disorders, with 12-month and lifetime prevalence rates of 18.1 and 28.8%, respectively (Kessler et al. 2005a; b2005b).

A large body of work supports the efficacy of cognitive behavioral therapy (CBT) (Hofmann and Smits 2008) and anxiolytic medication for treating anxiety disorders (Roy-Byrne and Cowley 2002). CBT combines cognitive strategies to target maladaptive beliefs about the fear-eliciting cues and exposure techniques aimed at helping patients reacquire a sense of safety around cues associated with anxiety disorders. In contrast to CBT, pharmacological interventions aim to directly target biochemical pathways underlying the anxiety elicited by disorder-specific cues (Bourine and Lambert 2002). Pharmacological agents that have demonstrated efficacy for a variety of anxiety disorders include benzodiazepines, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), reversible inhibitors of monoamine oxidase-A (RIMA), and buspirone (Baldwin et al. 2005; Bourine and Lambert 2002). There is some evidence to suggest that CBT may be more tolerable and more cost-effective, especially in the long-term, than some of these traditional anxiolytic agents (Otto et al. 2006). Although both treatment modalities are efficacious, there is clearly room for improvement (Hofmann and Smits 2008; Roy-Byrne and Cowley 2002).

Because these treatment modalities are less than perfect when administered as monotherapies, investigators have examined whether combining pharmacotherapy and psychotherapy is more effective than either of the monotherapies for reducing anxiety symptoms. Many of these studies show that combination strategies are not substantially more effective than monotherapies in the short term and may even be worse in the long term for some anxiety disorders. Thus some cases, adding conventional pharmacotherapy can even be detrimental to the success of psychological treatments, such as when using benzodiazepines in combination with exposure therapy for panic disorder (see Otto et al., 2006, for a review).

A more recent approach toward combination therapy is to enhance the mechanism of CBT using pharmacological agents. Some of these approaches are highly promising and support such augmentation strategies to further enhance the efficacy of CBT. Examples of those agents include D-cycloserine, yohimbine, cortisol, oxytocin, propranolol, and various nutritional supplements. Some of these agents appear to act as cognitive enhancers based on the mechanism through which they augment CBT (Hofmann et al. 2011).

The goal of this book is to discuss the evidence from the existing literature on conventional and novel combination therapies for anxiety disorders. For this purpose, a number of leading investigators were invited to present the evidence of combination strategies for treating anxiety disorders. The first chapter gives an overview of the biology and efficacy of combination strategies, which points to some of the limitations of the contemporary literature and recommends that future research should embrace a translational research approach. The following chapters 2, 3, and 4 discuss traditional combination strategies using benzodiazepines, tricyclic antidepressants, monoamine oxidase inhibitors, SSRIs, RIMA, and buspirone. Chapter 5 discusses the evidence of D-cycloserine as a cognitive enhancer of CBT. Similarly, yohimbine (Chapter 6), cortisol (Chapter 7), and oxytocin (Chapter 8) offer new combination strategies born out of a translational research approach. Chapter 9 discusses dietary supplements, which offer promising options that are worthy of further investigation. Chapter 10 provides a general roadmap for future research in combination treatments for anxiety disorders and recommends that the field of psychiatry and pharmacology should:

move beyond the traditional horse race comparison of clinical trials and toward translational research from ‘bench to bedside;’move closer toward understanding the mechanism of treatment change; andmove closer toward personalized medicine by tailoring the treatment to the client based on certain biomarkers.

I hope that this volume will inspire researchers, clinicians, policy makers, funding agencies, and the pharma industry to move beyond conventional paradigms of combination therapies for anxiety disorders.

References

Baldwin, D. S., Anderson, I. M., Nutt, D. J. et al. (2005). British Association for Psychopharmacology: Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology, 19: 567–596.

Bourine, M. and Lambert, O. (2002). Pharmacotherapy of anxiety disorder. Human Psychopharmacology, 17: 383–400.

Hofmann, S. G. and Smits, J. A. J. (2008). Cognitive-behavioral therapy for adult anxiety disorders: A meta-analysis of randomized placebo-controlled trials. Journal of Clinical Psychiatry, 69: 621–632.

Hofmann, S. G., Smits, J. A. J., Asnaani, A., Gutner, C. A., and Otto, M. W. (2011). Cognitive enhancers for anxiety disorders. Pharmacology, Biochemistry, and Behavior, 99: 275–284.

Kessler, R. C., Berglund, P. A., Demler, O., Jin, R., and Walters, E. E. (2005a). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry, 62, 593–602.

Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R., and Walters, E. E. (2005b). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62: 617–627.

Olatunji, B. O., Cisler, J. M., and Tolin, D. F. (2007). Quality of life in the anxiety disorders: A meta-analytic review. Clinical Psychology Review, 27: 572–581.

Otto, M. W., Smits, J. A. J., and Reese, H. E. (2006). Combined psychotherapy and pharmacotherapy for mood and anxiety disorders in adults: Review and analysis. Clinical Psychology: Science and Practice, 12: 72–86.

Roy-Byrne, P. P. and Cowley, D. S. (2002). Pharmacological treatments for panic disorder, generalized anxiety disorder, specific phobia, and social anxiety disorder. In P. E. Nathanand J. M. Gorman (eds), A Guide To Treatments that Work, 2nd edn. New York, Oxford University Press: 337–365.

Chapter 1

The Biology and Efficacy of Combination Strategies for Anxiety Disorders

Keith A. Ganasen and Dan J. Stein

Department of Psychiatry, University of Cape Town, Cape Town, South Africa

Introduction

Optimal treatment of anxiety disorders is important as they are the most prevalent psychiatric disorders in community studies, and generalized anxiety disorder is the most prevalent psychiatric disorder in primary care (Kessler et al. 2010). In addition, anxiety disorders begin early in life, and predispose to the development of comorbid disorders such as depression and substance use disorders; early and robust treatment may therefore be important in secondary prevention (Goodwin and Gorman 2002). Anxiety disorders are not only associated with significant suffering in affected individuals and families, but also contribute enormously to the societal burden of disease; a number are among the most disabling of all medical conditions (Lopez et al. 2006).

Fortunately, there have been significant advances in the treatment of anxiety disorders. A range of medications have been approved in the past few decades for the major anxiety disorders on the basis of randomized controlled trials showing efficacy and safety. Similarly, during the same period, a number of psychotherapies have been rigorously studied, and shown to have both short-term and longer-term efficacy. Expert guidelines, often incorporating systematic meta-analyses of the research literature, have been developed, and highlight the evidence base for first-line interventions, such as selective serotonin uptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) (Ipser and Stein 2009). The majority of patients with anxiety disorders can be expected to respond to such first-line interventions.

At the same time, underdiagnosis and undertreatment of, and resistance to treatment in, anxiety disorders remain significant problems. Underdiagnosis and undertreatment may reflect a range of structural and attitudinal barriers, including insufficient numbers of well-trained therapists and insufficient mental health literacy in both the general population and primary care practitioners. First-line treatments may work in the majority of cases, but even when appropriately diagnosed and treated, 40% or more of patients may fail to respond (Pallanti et al. 2002; Bandelow and Ruther 2004). There is a relative lack of effectiveness trials in anxiety disorders, but in real-world settings, where patients may have increased comorbidity, and where clinicians are required to be generalists rather than specialists, treatment response rates may be lower, and tolerability concerns more obvious, particularly over the longer term.

Combination treatment is an important consideration in attempts to improve the efficacy and effectiveness of intervention in anxiety disorders. Given the multiple factors, including neurobiological and psychological variables, involved in anxiety disorder pathogenesis, there is a prima facie case for a comprehensive treatment approach including pharmacotherapy and psychotherapy. Indeed, early thinking suggested pharmacotherapy was useful for a rapid treatment response, while psychotherapy was valuable for a maintained response, even after discontinuation of short-term intervention (Riba and Ballon 2005). It has therefore been surprising to see a growing evidence base suggesting relatively little advantage in combining pharmacotherapy and psychotherapy for anxiety disorders (Foa et al. 2002; Otto et al. 2005; Black 2006; Bandelow et al. 2007; Hofmann et al. 2009).

Perhaps one of the most exciting developments in combination treatment of anxiety disorders, if not in all of medicine, has been the adoption of a rigorous translational neuroscience approach (Davis et al. 2006; Otto et al. 2007; Hofmann et al. 2011; Kaplan and Moore 2011). Advances in a range of basic neuroscience areas, including animal models of anxiety disorders, have allowed combination interventions to be studied in the laboratory. Rather than relying on standard first-line pharmacotherapies, such work has focused on targets (e.g. in glutamatergic systems) that may be specifically relevant to enhancing cognitive-behavioral interventions. Such work provides a rigorous foundation for moving findings through to the bedside, in the form of proof-of-principle clinical studies. This approach appears to have significant potential and has therefore attracted considerable interest from researchers, making this book extremely timely.

This chapter will briefly focus on a number of background issues relevant to combination treatment in anxiety disorders. First, we will review some of the psychobiology relevant to an understanding of how combined treatments work. Second, we will review some of the findings addressing, and issues concerning, the efficacy of such combined treatments.

Psychobiology of Combination Treatments

There is a growing understanding of the neurocircuitry underlying the fear response in animals and anxiety disorders in humans. Advances in structural and functional neuro-imaging have been key in developing our understanding of such circuitry in clinical conditions (Shin and Liberzon 2010). Thus, a growing body of evidence suggests that anxiety disorders are characterized by abnormalities in both prefrontal and subcortical (e.g. amygdala, hippocampus) circuitry (Grillon 2002; Anderson and Insel 2006). Neurotransmitters involved in such pathways include serotonergic, noradrenergic, glutamatergic, gamma-aminobutyric acid (GABA)ergic, and neuropeptide systems, and many available pharmacotherapies act on such systems (Charney 2003).

One approach to understanding the psychobiology of combined pharmacotherapy and psychotherapy is to argue that pharmacotherapy acts predominantly on bottom-up neurotransmitter-mediated mechanisms, while psychotherapy acts mainly on top-down cognitive-affective processes. Medications, such as SSRIs, may act on the amygdala and its efferent pathways (e.g. to hypothalamus and brainstem) to reduce panic attacks, which in turn leads to reduced anticipatory anxiety and phobic avoidance (Gorman et al. 2000). However, interventions such as CBT, may act upstream of the amgydala, strengthening the ability of medial prefrontal areas to inhibit sub-cortically mediated processes, by decreasing cognitive misattributions and deconditioning the fear response (Mayberg 2002).

While such an approach may be heuristically useful, it may entail some over-simplification. First, neurocircuitry alterations following psychotherapy are not limited to prefrontal areas; instead they may be widespread (Roffman et al. 2005; Frewen et al. 2008). Conversely, the effects of pharmacotherapy are unlikely to be limited to sub-cortical neurotransmitter activity; rather they may lead to significant changes in high-level cognitive and affective processing. Furthermore, such an approach does not explain why certain combinations of pharmacotherapy and psychotherapy appear ineffective or even contra-indicated (Otto et al. 2005). Indeed, both pharmacotherapy and psychotherapy are interventions that have complex and interactive effects on the brain-mind.

Another question that requires a more complex approach is whether combination strategies are likely to be similar across different anxiety disorders, or whether specific combined treatment approaches will be needed for each disorder. On the one hand, imaging studies suggest that there are a number of overlapping mechanisms that cut across different anxiety disorders. A recent meta-analysis of brain imaging studies in anxiety disorders, for example, found an increase in the activity of the amygdala and insula in participants with post-traumatic stress disorder (PTSD), social anxiety disorder, and with specific phobia, relative to healthy control subjects (Etkin and Wager 2007). Thus, it may be predicted that SSRIs act to decrease insula activity, while CBT acts to decrease amygdala activity, in a number of these conditions (Furmark et al. 2002; Carey et al. 2004). On the other hand, there is also involvement of distinctive neurocircuitry in different anxiety disorders (Etkin and Wager 2007). Furthermore, within a particular disorder, different neuronal circuitry may be involved in different symptom presentations (Lueken et al. 2011). Thus, it is possible that different forms of combined treatment may be effective, not only for different anxiety disorders, but also for different subtypes of particular anxiety disorders.

Imaging studies in humans will no doubt continue to be important in answering such questions. For example, particular neurocircuitry findings predict response to pharmacotherapy, while others predict response to psychotherapy, or to combined treatment (Brody et al. 1998; Furmark et al. 2002; 2005). Data from studies that address the impact of particular gene variants on neuro-imaging findings are also likely to be important in developing more integrative models. Also, in order to develop more complex models of combined treatments, it would be helpful to have good laboratory models of anxiety disorders and interventions. Fortunately, there is a range of ongoing work in this area. We briefly review some of the relevant work targeting neurotransmitter systems (e.g. glutamatergic, noradrenergic, and adenosine systems), neuroendocrine systems (e.g. glucorticorticoids), and social neuropeptides (e.g. oxytocin (OT)).

Neurotransmitter Systems

Laboratory research has suggested the glutamatergic system as a target for combined pharmacotherapy and psychotherapy; this research demonstrated that the N-methyl-D-aspartate (NMDA)-glutamate receptor of the lateral and basolateral amygdaloid nuclei was involved in fear conditioning and fear extinction in rodents (Davis et al. 1993). Given that antagonists of the NMDA receptor prevented both the acquisition and extinction of fear (Lee and Kim 1998), the question arose of whether an NMDA agonist would facilitate the extinction of conditioned fear (Walker et al. 2002). Indeed, rats that received the partial NMDA agonist D-cycloserine (DCS), in combination with repeated exposure to the conditioned stimulus, had enhanced extinction of their fear as compared to the rats that received DCS alone (Walker et al. 2002). The work provided a solid foundation for clinical trials of combined DCS and CBT; the first of these seminal proof-of-principle clinical studies was undertaken in acrophobia (Ressler et al. 2004), and several others soon followed.

Animal research has also questioned the extent to which the effects of DCS on fear extinction are generalized. Rats given DCS and fear extinction training to one stimulus, also exhibited reduced fear to another stimulus (Ledgerwood et al. 2005). Furthermore, some animal work has indicated that DCS may prevent the relapse of learned fear (Ledgerwood et al. 2004). However, it has also been suggested that if DCS enhances fear extinction by improving learning, then it may also facilitate recall of aversive memories (Lee et al. 2006). Perhaps, to reduce the potential for sensitization of negative memories, it will prove preferable to administer DCS after an exposure session that is determined by the clinician to be successful (Hofmann et al. 2011).

There is also some concern about developing tolerance to DCS, thereby reducing efficacy of combined treatment over time. Perhaps DCS should be used on an acute rather than chronic basis (Hofmann et al. 2006). Indeed, poorer results have been found in studies that used DCS at higher or more frequent doses (Kushner et al. 2007; Wilhelm et al. 2008; Storch et al. 2010). Ultimately, additional clinical research is needed to determine the extent of precise benefits and risks of using DCS in combined treatments (Krystal 2007). Combination strategies using DCS are further discussed in Chapter 5 of this book.

Ongoing animal research has provided additional insight into the specific mechanisms whereby DCS exerts its effects. DCS acts on the NMDA receptor complex's strychnine-insensitive glycine-recognition binding site, facilitating the movement of calcium, which in turn initiates intracellular processes that are involved in learning. The effects of DCS appear to be mediated in particular by intra-amygdala signaling cascades involving mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI-3K), both of which are known to play a role in fear conditioning (Yang and Lu 2005). Such work may ultimately lead to additional pharmacological interventions for use in clinical employment of combined treatment.

A range of neurotransmitter systems, other than the glutamatergic system, are also likely involved in facilitating prefrontally-mediated fear extinction. The noradrenergic system, for example, plays a key role in prefrontal processes. Yohimbine hydrochloride is a selective competitive alpha2-adrenergic receptor antagonist that stimulates c-Fos expression in the medial prefrontal cortex (Singewald 2003). Administration of yohimbine hydrochloride in rats enhanced extinction learning and improved the time needed to reduce conditioned fear, providing a foundation for subsequent translation to human studies (Cain 2004; Powers 2009). Combination strategies using yohimbine hydrochloride in the treatment of anxiety disorders are further discussed in Chapter 6.

Various neutraceuticals may also act on neurotransmitters mediating fear and anxiety. Caffeine, a psychostimulant that acts on adenosine receptors, is one of the most widely used. It induces positive feelings such as alertness and increased mental performance. However, individuals with a history of anxiety disorders, particularly panic disorder, experience more unpleasant physical symptoms, suggesting adenosine receptor sensitivity; hence the hypothesis that administration of caffeine during exposure based treatment might enhance and sustain fear extinction. Neutraceutical combination treatments are discussed further in Chapter 9.

Neuroendocrine Systems

Glucocorticoids are steroid hormones that are synthesized in the adrenal cortex, and are released along with catecholamines as part of the hypothalamic-pituitary-adrenal neuroendocrine response to stress. Laboratory research has shown that adrenalectomy and administration of corticosteroid synthesis inhibitors reduces the unconditioned startle response and increases time spent in a fearful environment (Cordero 1998; Takehashi 1998). Conversely, administration of GR agonists prior to fear extinction facilitates fear extinction on repeated exposure of the stimulus, an effect that is blocked by co-administration of a GR antagonist (Yang et al. 2006). This work again provides a foundation for clinical trials of GR agonists together with psychotherapy (see below).

Laboratory research again suggests particular clinical research directions. For example, administration of a GR agonist after the extinction phase continues to have a facilitatory effect, suggesting that glucocorticoids influence memory consolidation (Yang et al. 2006), a finding that may be particularly relevant in the context of a condition such as PTSD. Further extensions of laboratory research may ultimately lead to additional clinical targets. It is notable, for example, that it is glucocorticoid receptors, rather than mineralocorticoid receptors, which are associated with memory consolidation (Oitzl and de Kloet 1992; Roozendaal and McGaugh 1996). As the neurobiology of these receptors becomes increasingly better understood, so additional clinical routes of investigation open up (Cahill and McGaugh 1996; Lupien and McEwen 1997). A broad range of other neuroendocrine targets (e.g. gonal hormonal systems) may also be relevant to combined treatments.

One important area of glucorticorticoid research lies in developmental psychobiology. The effects of early adversity of the developing brain-mind, for example, are mediated by a range of neurochemical and neuroendocrine pathways, including the glucocorticoid system (Stein et al. 2005). Administration of an SSRI may reverse some of these effects in rodent models of early life trauma (Uys et al. 2006). Although there has been some literature on both the pharmacotherapy and psychotherapy of patients presenting with psychopathology in the context of a history of early adversity (Nemeroff et al. 2003; Stein et al. 2003), much further work is needed to establish optimal combined treatments for such patients. Combination strategies using glucocorticoids are further discussed in Chapter 7.

Social Neuropeptides

OT and arginine vasopressin (AVP) are highly conserved neuropeptides that play an important role in social interaction, including parental care, pair-bonding, sexual behavior, and social memory. Across species, OT often mediates female-specific behavior such as parturition and lactation, while AVP often mediates male-specific behavior including aggression (Donaldson and Young 2008). Both OT and AVP appear critical for linking social signals to mesocorticolimbic reward circuitry (Insel 2003). These basic scientific findings raise the question of whether such social neuropeptides may be usefully incorporated into combined treatments of clinical disorders. A broad range of other peptide systems (e.g. opioid system) may also be relevant to the clinical setting (Stein et al. 2007).

In humans, intranasal administration of OT increases feelings of trust (Kosfeld et al. 2005) and enhances emotion recognition (Domes et al. 2007). OT attenuates behavioral or amygdala responses to breaches of trust, aversive stimuli, or fear-conditioned responses to social stimuli (Kirsch et al. 2005; Domes et al. 2007; Baumgartner et al. 2008; Petrovic et al. 2008). Depending on the paradigm studied, there may also be reduced coupling of amygdala to brainstem regions involved in the fear response (Kirsch et al. 2005), or decreased activation in regions involved in facial recognition (Petrovic et al. 2008). However, further work is needed to determine whether such effects are also seen during combined treatment of clinical disorders.

While laboratory studies give insight into general cognitive-affective processes, they may not necessarily be devised with specific clinical conditions in mind. Given the role of OT and AVP in social interaction, these peptides have been postulated to play a role in autism (Hammock and Young 2006). OT may be decreased in autism and association studies have suggested a role for OT receptor variants in autism (Israel et al. 2008). Arginine vasopressin 1a receptor (AVPR1a) knockout mice have social dysfunction that is redolent of autism, and both linkage and association data in clinical samples have pointed to involvement of AVPR1a in autism (Hammock and Young 2006). However, there is also some evidence that these neuropeptides or their receptors may play a role in a broad range of other psychiatric conditions, including schizophrenia, post-traumatic stress disorder, obsessive-compulsive disorder, depression, and substance use disorders (Stein 2009). Thus, should OT be found useful as part of combined treatment, study of a broad range of conditions may be relevant. Combination strategies using OT are further discussed in Chapter 8.

Evidence for Combination Therapy in Anxiety Disorders

Although a psychobiological perspective may be used to support the combination of some pharmacotherapies and psychotherapies, and although laboratory research has provided a basis for the development of specific agents to augment exposure based therapies in the clinic, ultimately the proof of the pudding is, of course, in the eating. In this section, we briefly review some of the clinical data on combined treatments in anxiety disorders, in order to draw some general conclusions regarding work in this area. Later chapters in this book will discuss combination strategies with specific agents in further detail; Chapter 2 will discuss benzodiazepines, Chapter 3 will discuss tricyclics and monoamine oxidase inhibitors, and Chapter 4 will discuss selective serotonin re-uptake inhibitors, reversible inhibitors of monomine oxidase-A, and buspirone.

Panic Disorder

A relatively large number of studies of combined pharmacotherapy (i.e. antidepressants or benzodiazepines, plus CBT) have been undertaken in panic disorder. An early meta-analysis indicated that 20 studies provided data on the efficacy of combined treatment compared to psychotherapy. Combined treatment was found to be slightly more effective than CBT alone. However, in those studies which included a follow-up, there was no significant difference between a combination approach and CBT alone (Mitte 2005). A subsequent meta-analysis reviewing trials, combining antidepressants with CBT for panic disorder (Furukawa et al. 2007), confirmed that during short-term treatment, combination therapy was more effective than single modality treatment, and found that during long-term follow-up, combined treatment was as effective as psychotherapy alone, and was more effective than pharmacotherapy alone.

Bandelow et al. (2007) have emphasized that by using different methods, meta-analyses of treatments in anxiety disorders may reach different conclusions. In their meta-analysis of combined treatments for different anxiety disorders, they restricted their analysis to studies which directly compared pharmacotherapy, psychotherapy, or the combination of these therapeutic modalities. Furukowa et al. concluded that combined pharmacological and psychological treatment was superior to monotherapy for panic disorder. Effect sizes range between d = 0.23 and d = 0.61 (which corresponds to small to medium effect sizes, Cohen 1988), thus indicating that combined therapy is the most effective treatment strategy.

Medications studied in combination with CBT for panic disorder are, however, heterogenous, including various antidepressants, buspirone, and benzodiazepines (Marks et al. 1993; Cottraux et al. 1995; Barlow et al. 2000). Although there are arguably too few studies of combined benzodiazepines and CBT in panic disorder to draw definitive conclusions (Watanabe et al. 2009), a study with alprazolam showed that improvements made early in combined treatment were lost when alprazolam was tapered off (Barlow et al. 2000). However, improvements made in the groups receiving CBT alone, or placebo alone, were maintained. This finding suggests that alprazolam weakens the effects of CBT, perhaps due to interference with learning or suppression of affect during exposure therapy (Black 2006; Hofmann 2006; Otto et al. 2010).

More recently, DCS has been combined with exposure-based CBT for panic disorder (Otto et al. 2010). The results indicated large effect sizes for the additive benefit of DCS augmentation, consistent with the view that DCS consolidates extinction memory. The authors also emphasized that this was the first DCS study to have emphasized exposure to feared internal sensations (i.e. interoceptive exposure). Furthermore, the treatment targeted participants who in most cases were refractory to previous pharmacotherapy. A more recent trial was unable to show a significant additive benefit of DCS to panic disorder due to the fact that patients responded well to CBT; however, there was evidence that in more severely measure ill patients, DCS accelerated symptom reduction in the primary outcome (Siegmund et al. 2011).

Social Anxiety Disorder

Sertraline, fluoxetine, phenelzine, and moclobemide are some of the medications that have been studied in combination with CBT for the treatment of social anxiety disorder (Blomhoff et al. 2001; Davidson et al. 2008; Prasko et al.2006; Blanco et al. 2010). Early meta-analysis found that there was insufficient data to demonstrate an advantage for combined over unimodal treatment (Bandelow et al. 2007). However, in the largest of the comparative studies, combined phenelzine and CBT treatment was superior to either treatment alone (Blanco et al. 2010). Furthermore, as discussed below, combined treatment is more effective than unimodal therapy in children and adolescents with social anxiety disorder (Walkup et al. 2008).

However, few of these studies of combined treatment for social anxiety disorder have compared outcomes in acute and long-term treatment. The sertraline study suggested that a combination of treatment and exposure therapy had enhanced efficacy (Blomhoff et al. 2001), but this did not hold true over a 1-year follow-up (Haug et al. 2003). The moclobemide study followed-up participants over 2 years (Prasko et al.2006). Although there were no significant advantages between the groups in the first 3 months, the combined treatment group had quicker onset of symptom reduction. The moclobemide group showed a greater reduction in subjective anxiety over the 3 months, while the CBT group showed a greater reduction in avoidant behavior. However, by 6 months, there was no significant difference in outcomes between the groups.

Social anxiety disorder, like other anxiety disorders, is a heterogeneous condition. Most pharmacotherapy studies have focused on patients with generalized social anxiety disorder. Nevertheless, there are reports of the efficacy of both pharmacotherapy and psychotherapy in patients with specific performance phobia, and it would be useful to assess the relative efficacy of combined treatments in this condition.

Of particular interest to translational medicine, two studies have now found that DCS has an additive advantage to exposure-based CBT for social anxiety disorder (Hofmann et al. 2006; Guastella et al. 2008). Controlled effect sizes in this work were in the medium to large range. In their meta-analysis of the early literature on DCS in the augmentation of CBT, Norberg et al. (2008) suggested that DCS may be useful early in treatment. However, further work with larger samples is clearly needed to fully demonstrate the therapeutic profile of DCS in social anxiety disorder, and to determine predictors of response.

Generalized Anxiety Disorder

There are too few studies that have combined psychotherapy and pharmacotherapy in the treatment of generalized anxiety disorder to reach definitive conclusions (Bandelow et al. 2007). In a study of buspirone and various forms of anxiety treatment, combined treatment conferred some additional benefits (Lader and Bond 1998). In one study of diazepam and CBT, the combined treatment was superior to the drug alone, but with a smaller effect in comparison to CBT plus placebo, and inconsistent findings for the combined treatment in comparison to CBT alone (Power et al. 1990). Additional work is clearly needed in this area.

Walkup et al. (2008) conducted a study of combination treatment in children and adolescents with various anxiety disorders, including GAD, separation anxiety disorder, and social anxiety disorder. In this study, the combination of CBT and sertraline was significantly more effective than either treatment modality alone for each of these anxiety disorders. This finding raises the important question of whether combined treatments are equally effective at different development stages; it may, for example, be hypothesized that combined treatments are most effective at developmental periods when neuroplasticity is highest.

The literature on combined treatment for GAD also questions the use of an integrated approach to help improve outcomes of benzodiazepine discontinuation. Cognitive-behavioral treatment has shown efficacy in preventing relapse and facilitating BZ discontinuation in panic disorder (Otto et al. 1993; 2002; Spiegel et al. 1994). CBT provides specific efficacy for the successful discontinuation from BZs, even when controlling for therapist contact and relaxation training (Otto et al. 2010). Similarly, CBT appears useful in preventing relapse and increasing the tolerability of withdrawal in patients with GAD (Gosselin et al. 2006).

Post-traumatic Stress Disorder

A meta-analysis of trials of combined pharmacotherapy and psychotherapy for post-traumatic stress disorder found four trials eligible for inclusion (Hetrick et al. 2010). All used an SSRI and prolonged exposure or a cognitive behavioral intervention. Two trials compared combination treatment with pharmacological treatment and two compared combination treatment with psychological treatment. There was no strong evidence to show group differences. The authors concluded that there is not enough evidence available to support or refute the effectiveness of combined psychological therapy and pharmacotherapy compared to either of these interventions alone.

The literature on combined treatment in PTSD also questions how the sequencing of combined treatments affects outcome. In one study, CBT was added to sertraline in PTSD subjects who had already demonstrated a poor response to sertraline alone, and combined treatment was effective in these treatment-refractory patients (Otto et al. 2003). However, in PTSD patients who were symptomatic after prolonged exposure therapy, the addition of paroxetine was no more effective than placebo (Simon et al. 2008). Further work is needed to determine what specific individual factors predict response to combined and sequenced treatments. In the interim, when combining modalities, clinicians need to weigh up a range of considerations, including issues of counter-transference, and the possible symbolic meaning of medications for both therapists and patients (Southwick and Yehuda 1993).

The developmental of good animal models of PTSD will hopefully facilitate the translation of combined treatment approaches from ‘bench to bedside’ (Harvey et al. 2004; Cohen and Zohar 2004). Clearly, there is a prima facie case for considering the use of DCS in the combined treatment of PTSD (Choi et al. 2010; Ganasen et al. 2010). In addition, approaches which focus on the use of glucorticoid and other neuroendocrine and neuropeptide targets are worthy of further investigation in the clinical setting (Cohen et al. 2008; Kaplan and Moore 2011).

Obsessive-Compulsive Disorder

Medications studied in combination with CBT in treatment of obsessive-compulsive disorder include clomipramine and fluvoxamine (Marks et al. 1980; Cottraux et al. 1990; Hohagen et al. 1998; van Balkom et al. 1998; Foa et al. 2005). The combined results from these studies provide little evidence that combined treatment is better than monotherapy in obsessive-compulsive disorder (OCD). Nevertheless, individual studies have suggested that combined treatment, perhaps with more intensive CBT, may be more effective (Hohagen et al. 1998; Foa et al. 2005). As with PTSD, it may be particularly relevant to consider the use of an augmentation approach in those patients who are treatment-refractory.

Unfortunately, studies of DCS in OCD have also not been entirely persuasive (Kushner et al. 2007; Storch et al. 2007; Wilhelm et al