Dr. Zylowska is resident in training in the Department of Psychiatry at the UCLA Neuropsychiatric Institute in Los Angeles, and a former fellow at the UCLA Center for East-West Medicine.

Dr. Hui is professor of clinical medicine in the Department of Medicine and director of the Center for East-West Medicine at the UCLA School of Medicine in Los Angeles.

Acknowledgments: The authors would like to thank Regina R. Chinsio and Mai K. Ho for their intellectual contribution and assistance in preparing this manuscript. They also thank the Oppenheimer Family Foundation for its generous support of their work, including preparation of this article and Dr. Zylowska’s fellowship.



An increasing number of patients are using complementary and alternative medicine for both medical and psychiatric conditions. Do our patients know something we do not? Can clinicians and scientists in search of novel treatment strategies benefit from understanding the principles of other healing traditions? This article introduces the general framework of Chinese medicine and outlines its view of emotions in health and disease. The article briefly describes Chinese medicine’s approach to patients with anxiety, reviews available research on acupuncture in the treatment of anxiety disorders, and suggests potential benefits of incorporating Chinese medicine into clinical practice and research.



Oriental medicine and its most representative member, Chinese medicine, is a collection of ancient healing traditions with over 3,000 years of use and refinement in the Far East, predominantly China, Japan, and Korea. Chinese medicine represents a complete system of healing that, for centuries, evolved independently of Western cultural influences. In contrast to Western medicine, which describes the human body in terms of anatomical organs and structural and quantitative markers of disease, Chinese medicine conceptualizes the human body as a functional and energetic system and describes illness as an imbalance within these systems. Chinese medicine has its own conceptual framework, unique diagnostic methods (eg, tongue and pulse diagnosis), distinctive diagnostic formulations (eg, liver qi stagnation), and specialized treatment methods (eg, acupuncture, herbal medicine, massage, and qigong).

Although there is no separate discipline of psychiatry in Chinese medicine, this medical tradition has long recognized the importance of mental and emotional factors in health and disease, and it has been used to treat psychiatric illness. The theoretical, cultural, and linguistic differences between Chinese and Western medicine make it challenging to integrate the two systems of healing, yet such endeavors may yield improved clinical and research results.1 In this review, we outline the general framework of Chinese medicine, discuss the role of emotions in health in Chinese medicine, introduce some therapeutic approaches to emotional distress, and review available scientific evidence on treatment of anxiety disorders using acupuncture. For further information on psychiatry-related topics and Chinese medicine, the reader is referred to other, more comprehensive discussions.2-6


History of Chinese Medicine

Despite dominance of the Western medical paradigm in most countries, Chinese medicine remains a vital medical tradition—more than one fourth of people worldwide use it for promotion of health and treatment of disease. This healing system underwent a revival in the 1950s when the Chinese government began to support the development of Chinese medicine and encourage its integration with modern medicine. Over the last several decades, researchers in China and throughout the world have applied modern scientific techniques, including molecular biology, immunology, and pharmacology, to elucidate Chinese medicine theory and treatment methods. Modern ways of applying Chinese medicine techniques, such as laser acupuncture and using herbs to lower side effects of chemotherapy, have emerged. In the Western world, Chinese medicine remained obscure until President Nixon’s trip to China in the 1970s—a trip that spurred American interest in Chinese medicine, particularly acupuncture.7

The research evidence generated over the last several decades has revealed the role of the endogenous opioid system in acupuncture analgesia and suggested involvement of autonomic and neuroendocrine pathways in its other applications.8-12 Of relevance to psychiatry, studies have implicated changes in serotonergic, noradrenergic, and dopaminergic neurotransmitters with acupuncture, and two recent magnetic resonance imaging studies demonstrated acupuncture modulation of brain regions including the limbic system.11,13

Brief Overview of Chinese Medicine Theory

The Chinese medicine paradigm represents a comprehensive collection of theory, observations, and insights from consecutive generations of traditional Chinese physicians. More recently, researchers and physicians have proposed modern descriptions of ancient concepts. Chinese medicine framework is rooted in principles of energy-matter transformation, cyclical movement, relativity, and interdependence in nature. Within this framework, the human body is described in terms of functional and energetic properties and represents a “microcosm” with laws, rhythms, and properties analogous to those observed in the natural environment. Consequently, Chinese medical terminology uses analogies and metaphors borrowed from nature to describe complex physiological processes of the human body. For example, mania may be described as “excess of heat” or “fire,” while processes characterized by growth, movement, or transformation, may be considered “wood” or “spring” properties. At first glance, the metaphoric language of Chinese medicine may appear archaic and nonscientific, deterring one from delving into the theory of Chinese medicine. However, once Chinese medicine theories are tested clinically and through research performed, a better appreciation of its effectiveness, complexity, and internal consistency will be developed.

The major components of the Chinese medical theory include: (1) the concept of interdependent and mutually-balancing components of the human body as represented by the yin and yang theory and the five element/phases theory; (2) the concept of the energy-matter communication network as represented by the meridian system, qi, and the vital substances theory; (3) the description of human anatomy as based in functional systems as represented by the zang fu organ network; and (4) the individualized description of the illness process and the body’s response to it as represented by the zheng pattern diagnosis.14 In modern terms, Chinese medicine has been said to embody a holistic, systemic view of the human body that emphasizes the inseparable nature of body/mind/spirit, the centrality of homeostatic balance and self-healing, and the importance of energetic flow. Akin to emerging trends within behavioral medicine, psychoneuroimmunology and psychosomatic disciplines, Chinese medicine has long recognized environmental, psychosocial and spiritual factors in health and disease (Figure).15


The Unity of Mind and Body

The dualistic view of soma and psyche dating back to the French philosopher, René Descartes, has shaped Western medicine’s division between physical and mental etiologies of illness. In contrast, the Chinese medicine framework considers soma, psyche, and spirit to be fundamentally intertwined in structure and function. The interaction is bidirectional and circular: cognitive and emotional factors affect physical aspects of the body just as much as the physical aspects affect mental and emotional expression. This dynamic relationship permeates Chinese medicine and can be exemplified by the relationships within the zang fu organ network and the vital substances theory.

The organ network is primarily composed of five interdependent systems: the heart, liver, spleen, kidney, and lung systems. Despite similarities in names and some functions, the organ network of Chinese medicine should not be equated with Western anatomical terms since each Chinese medicine organ network simultaneously encompasses a variety of physiological and mental/emotional characteristics. For example, the Chinese medicine liver network includes certain functional aspects of the hepatobiliary, musculoskeletal, genitourinary, hormonal, and nervous systems. Additionally, the liver network plays a role in distribution and movement of blood and overall emotional expression. Each organ is believed to have special affinity for a particular emotion or cognitive ability: liver—anger; heart—joy/happiness; spleen—pensiveness or over-thinking, kidney—fear/fright, and lung—sadness and grief.

The vital substances theory represents another level of mind-body integration within Chinese medicine. Jing, blood, fluids, qi, and shen are the main physiological substrates that form a spectrum from the more material (jing) to the more energetic/metaphysical (shen). Just like the organ network, the substances are mutually dependent and underscore the inseparable nature of somatic/biological and psychological/ energetic aspects of a person. Shen, often translated as the “spirit” has a special importance for mental-emotional disorders and has been described as the composite of all mental activities and characteristics, including thinking, consciousness, insight, intelligence, cognition, wisdom, formation of ideas, sleep, and memory.5 In Chinese medicine, the state of a person’s shen is a measure of their overall psychological well-being and vitality, and thus, most psychiatric disorders involve shen disturbance.

Emotions in Health and in Illness

In Chinese medicine, health results from adequate and optimal interaction between the somatic, psychological, and energetic aspects of the person. An appropriate and balanced flow of natural emotional states is necessary for health maintenance. Internal and external factors (stressors) challenge the body’s regulatory mechanisms and, if overwhelming, illness may result (ie, yin-yang and the organ network are out of balance). This view is analogous to the model of stress adaptation,16 in which various stressors may overstrain the homeostatic system and lead to illness. However, the way stressors are defined in Chinese medicine differs from in Western medicine. In Chinese medicine, excessive emotions are themselves considered the main internal stressors while extreme environmental, climate-related factors, infections, trauma, exertion, and lifestyle excesses are the main external stressors.

Within the organ network, prolonged and excessive expression of a particular emotion is thought to first affect (“injure”) its corresponding organ. However, due to interlinking of individual organs, any abnormal emotional expression can lead to imbalance in the entire system. Likewise, any of the external factors can lead to progressive dysfunction of the organ network that, once dysregulated, can produce abnormal emotional states.

The conceptual framework outlined above leads to a novel understanding of etiology and treatment strategies for both medical and psychiatric symptoms. In Chinese medicine, physical or psychological trauma, poor diet, exposure to extreme cold or heat, infections, and excessive or repressed emotions can lead to both physical and mental/emotional symptoms.

Diagnosis of Illness and Therapeutic Principles

The general Chinese medicine approach in any illness involves diagnosing and correcting the imbalance within the meridian system, the zang fu organ network, and the vital substances. The treatment methods usually include acupuncture, moxa, massage (tuina and acupressure), herbal medicine, and qigong exercises to restore flow and balance.

In making a zheng pattern diagnosis, Chinese medicine physicians pay close attention to the constellation of each patient’s emotional and somatic complaints, his or her preferences (dietary, climactic), constitution (genetic and postnatal contributions), and prevailing emotional expression and coping style. The history is supplemented with Chinese medicine pulse and tongue diagnosis.6 Although often called the “pattern” or “syndrome,” the zheng diagnosis is not merely a collection of symptoms, but reflects the location and stage of pathogenesis created by interaction between the stressor or pathogen and the body’s defense and regulatory systems. The diagnosis also aims to identify the global character of the conditions as either predominantly excessive or deficient within the overall yang (activating or upregulating) or yin (preserving and downregulating) processes.

The interaction of parasympathetic (yin) and sympathetic (yang) nervous systems can serve as a simplified example of yin-yang character in physiological processes. As a generalization, anxiety states can result from both excess of yang or deficiency of yin, but mixed excess-deficiency states are often observed. Since zheng pattern diagnosis reflects the individual characteristics of the patient as they influence illness manifestation and progression, patients with the same Western diagnosis may present with different zheng patterns. Likewise, patients with different Western diagnoses may present with the same zheng pattern.

Once a Chinese medicine practitioner makes a diagnosis, he or she will typically use acupuncture, massage, and herbal medicine together. As the treatment is applied, the practitioner monitors the changing manifestations of a zheng pattern to assess success of the treatment and to adjust the strategy if needed. Both herbal medicine and acupuncture are used according to a two-level treatment approach: (1) to relieve the acute physical and psychological symptoms (eg, insomnia, heart palpitations, acute anxiety, or gastrointestinal distress); and (2) to correct the patient’s unique underlying disharmony that has led to the somatic and psychological symptoms. In anxiety states, “shen calming” herbs such as semen zizyphy spinosae are commonly used, usually combined with other herbs to match the patient’s unique zheng pattern.

An acupuncture point found on the lower arm nei guan (pericardium 6) and a point located between the eyebrows, known as “yin tang,” are frequently used in anxiety states. Depending on each patient’s individual constellation of symptoms, other points are selected. Points on the external ear (auricular acupuncture) have also been used for psychological disorders. The acupuncture points can be stimulated by twisting the needle with low-current electricity, laser, or heat (moxa).2,11 Regional or localized massage (acupressure) can be done by the practitioner or taught to the patient as a self-help technique. Qigong (slow movements, breathing, and meditative exercises), which is thought to harmonize the spirit/mind/body unity, is frequently recommended to patients, especially if psychological distress is present.

Chinese Medicine and Psychiatric Disorders: Does It Work?

A paucity of research studies of Chinese medicine and psychiatric disorders exists. Furthermore, much of the available research studies in this area are published in Asian languages and/or have methodological problems limiting interpretation of their results. Among Chinese medicine modalities, acupuncture is by far the most studied. Two recent publications reviewed acupuncture trials for psychiatric conditions3,17 including depression, anxiety, schizophrenia, and substance abuse. One study investigated computer-controlled electroacupuncture in a mixed group of 104 patients with “neurotic depression,” generalized anxiety disorder, neurasthenia, and obsessive-compulsive disorder. Results indicated that computer-controlled electroacupuncture significantly reduced the total scores on the Hamilton Rating Scale for Depression and the Self-Rating Anxiety Scale.17 Another study compared electroacupuncture and amitriptyline in the treatment of depression. The authors reported similar significant improvement in depression scores in both treatment groups after 6 weeks, but superior improvement in clusters of anxiety, somatization, and cognitive disturbance with acupuncture.18 Supporting a common clinical observation, other research has shown that acupuncture has sedative effects19 and that auricular acupuncture can be used for anxiety.20, 21

In evaluating Chinese medicine research, it should be noted that most available studies have used Western diagnoses and standardized acupuncture protocols. However, Chinese medicine relies on designing an individualized treatment to address each patient’s unique imbalance and the omission of zheng pattern diagnosis (often diverse in patients with the same Western diagnosis) creates a sub-optimal model for testing Chinese medicine efficacy. In the future, attention to these factors when designing studies may yield more reliable results and provide new insights into diagnosis and treatment strategies.


Chinese medicine has a long history of use and represents a medical paradigm rooted in the philosophy of mind-body integration, a perspective that is also emerging through psychosomatic research and advances in neurobiology. The framework of Chinese medicine generates new ways to approach psychological and somatic distress, which may lead to novel ways of understanding etiology, prevention, and treatment of psychiatric illness. Some research studies have already implicated the ability of acupuncture to affect the central nervous system, and they suggest potential benefits from further research and clinical integration of conventional and Chinese medicine. The field of anxiety disorders with its long-standing recognition of interacting physiological and psychological states presents an opportunity for such exploration.  PP


1.    Hui K. Harmonizing traditional Chinese and modern Western medicine: a perspective from the US. Paper presented at: World Health Organization Regional Office for the Western Region workshop; November 1999; Beijing, China.
2.    Flaws B, Lake J. Chinese Medical Psychiatry: a Textbook & Clinical Manual Including Indications for Referral to Western Medical Services. 1st ed. Boulder, CO: Blue Poppy Press; 2001.
3.    Rainone F. Acupuncture for mental health. In: Muskin PR, ed. Complementary and Alternative Medicine and Psychiatry. Washington, DC: American Psychiatric Press; 2000:67-105.
4.    Hammer L. Dragon Rises, Red Bird Flies: Psychology, Energy, and Chinese Medicine. New York, NY: Station Hill Press; 1991.
5.    Maciocia G. The Practice of Chinese Medicine: the Treatment of Disease With Acupuncture and Chinese Herbs. Edinburgh, NY: Churchill Livingstone; 1994.
6.    Cassidy CM. Contemporary Chinese Medicine and Acupuncture. New York, NY: Churchill Livingstone; 2002.
7.    Hui K, Yu J, Zylowska L. The progress of Chinese medicine in the United States of America. In: Chan K, Lee H, eds. The Way Forward for Chinese Medicine. London, England: Taylor & Francis; 2002:345-377.
8.    Mayer D. Biological mechanisms of acupuncture. Progress in Brain Research. 2000;122:457-477.
9.    Birch S, Felt R. Understanding Acupuncture. Edinburgh, NY: Churchill Livingstone; 1999.
10.    White A, Ernst E. Acupuncture: a Scientific Appraisal. Boston, MA: Butterworth-Heinemann; 1999.
11.    Stux G, Hammerschlag R. Clinical Acupuncture: Scientific Basis. New York, NY: Springer; 2000.
12.    Middlekauff HR, Yu JL, Hui K. Acupuncture effects on reflex responses to mental stress in humans. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1462-1468.
13.    Hui K, Liu J, Makris N, et al. Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects. Human Brain Mapping. 2000;9:13-25.
14.    Maciocia G. The Foundation of Chinese Medicine. New York, NY: Churchill Livingstone; 1994.
15.    Hui K, Zylowska L, Hui E, Yu J, Li J. Introducing integrative East-West medicine to medical students and residents. J Altern Complement Med. 2002. In press.
16.    McEwen BS. The neurobiology of stress: from serendipity to clinical relevance. Brain Res. 2000;886:172-189.
17.    Meng F-Q, Luo H-C, Halbreich U. Concepts, techniques, and clinical applications of acupuncture. Psychiatric Ann. January 2002;32:45-49.
18.    Luo H, Jia YK, Meng F-Q, Zhao X. Clinical research on the therapeutic effect of the electro-acupuncture treatment in patients with depression. Psychiatry Clin Neurosci. 1988; 52(suppl):S338-S340.
19.    Lo CW, Chung QY. The sedative effect of acupuncture. Am J Chin Med. 1979;7:253-258.
20.    Wang SM, Peloquin C, Kain ZN. The use of auricular acupuncture to reduce preoperative anxiety. Anesth Analg. 2001;93:1178-1180.
21.    Wang SM, Kain ZN. Auricular acupuncture: a potential treatment for anxiety. Anesth Analg. 2001;92:548-553.

Dr. Zimand is director of children’s services and Dr. Anderson is director of clinical services at Virtually Better, Inc., in Atlanta.

Dr. Gershon is a psychology intern at the Boston Consortium in Boston.

Mr. Graap is president and CEO of Virtually Better, Inc., in Atlanta.

Dr. Hodges is professor and chair of computer science in the Department of Computer Science at the University of North Carolina in Charlotte.

Dr. Rothbaum is associate professor of psychiatry in the Department of Psychiatry at the Emory University School of Medicine in Atlanta.

Acknowledgments: Drs. Rothbaum and Hodges receive research funding and are entitled to sales royalty from Virtually Better, Inc., which is developing products related to the research described in this article.  In addition, they serve as consultants to, and own equity in, Virtually Better, Inc.  The terms of this arrangement have been reviewed and approved by Emory University and Georgia Institute of Technology in accordance with their conflict of interest policies.




How is virtual reality being used in the treatment of anxiety disorders? Virtual reality is a relatively new technology that combines visual, auditory, and kinesthetic experience in a computer-generated world. Current research indicates its efficacy as a powerful tool in the treatment of a number of anxiety disorders. Specifically, controlled studies of exposure therapy using virtual reality have demonstrated efficacy for specific phobias, including fear of flying, heights, and spiders. Virtual reality has also been used with other anxiety disorders such as panic disorder with agoraphobia, social phobia, and posttraumatic stress disorder in Vietnam veterans. Additionally, virtual reality has been used as a form of distraction among the pediatric population undergoing painful medical procedures. As the technology improves and the cost of equipment decreases, virtual reality will become more available to mental health practitioners. The benefits of virtual reality therapy include ease of use, increased confidentiality, public appeal, and greater control of the therapy. This article describes virtual reality technology, offers rationale for its use in mental health, reviews virtual reality treatment outcome studies, and examines future directions for the field.



To bridge clinical research and practice, professionals must evaluate the effectiveness of different treatment approaches and techniques. The fast pace of technological innovation underscores the need for systematic evaluation to identify promising treatments.  Whereas many of the applications of technology in mental health remain largely untested and unvalidated, virtual reality is an example of cutting-edge technology applied to mental health issues that has been examined within traditional research paradigms.  Although this technology is still emerging, a number of studies indicate that virtual reality exposure therapy can be efficacious in helping patients overcome and manage certain anxiety disorders. 


What Is Virtual Reality?

Virtual reality is a medium of human-computer interaction whereby an individual becomes an active participant within a three-dimensional virtual world. The user experiences multisensory stimuli (eg, visual, auditory, kinesthetic) that serve to immerse the individual into a computer-generated environment by wearing a helmetlike, head-mounted display consisting of display screens for each eye, earphones, and a head-tracking device. The head tracking provides orientation information to a computer, such that the images in the virtual world change in correspondence with the user’s movements. The environment changes in real time with the users’ movements, making the user feel like an active participant within the virtual world.

Theoretical Basis for Virtual Reality Use in Mental Health

The application of virtual reality to the treatment of anxiety disorders is based on cognitive/behavioral techniques and associated theories (eg, emotional-processing theory).1 In general, therapy for anxiety disorders is aimed at modifying a fear memory by first activating it through exposure and then pairing it with a new response or meaning (ie, relaxation, cognitive restructuring). With continued exposure to the feared stimuli in the absence of feared consequences, the process of habituation and extinction occur such that the previously feared stimuli no longer elicit the same anxiety response. Therefore, if virtual reality can activate the fear memory just as traditional exposure does, and if the exposure conducted in virtual reality generalizes to real-life situations, then this form of treatment should allow the individual to confront the feared situation in real life and manage the symptoms of anxiety.

Whereas the use of virtual reality exposure therapy for anxiety disorders capitalizes on immersing patients in a virtual world meant to recreate the real world, virtual reality for pain management benefits patients by distracting them from their real world. The basic theory behind distraction is that a patient’s attention is diverted away from a stimulus that produces anxiety or pain, and instead allows one to focus on a neutral or more pleasant stimulus.2 However, painful and noxious stimuli can be so overwhelming that passive forms of distraction (eg, watching videotapes, listening to audiotapes, or fantasy imagery) may not provide sufficient attentional demands to divert the patient’s attention away from the procedure. Virtual reality, on the other hand, engages multiple senses such that fewer attentional resources are available to focus on the less pleasant stimuli and should allow the patient to endure painful medical procedures with less distress.

Treatment of Specific Phobias

Initially, case studies were used to test the efficacy of virtual realitly in the treatment of specific phobias including claustrophobia, and fear of spiders, heights, and flying.3-7 In each of these reports, brief and focused treatment was deemed successful based on decreased self-report of anxiety and greater ease of confronting a previously fearful object or situation.  These positive results led researchers to further test virtual reality using larger-scale clinical trials.

The first published controlled study of virtual reality exposure therapy and phobia involved the treatment of acrophobia.8 Twenty individuals who met Diagnostic and Statistical Manual of Mental Disorders,9 Fourth Edition (DSM-IV) criteria for acrophobia were randomly assigned to virtual reality exposure or a wait-list control. The treatment group received seven weekly individual treatment sessions consisting of exposure to virtual footbridges, virtual balconies, and a virtual elevator presented according to each participant’s self-rated fear hierarchy. Participants were allowed to progress at their own pace, but were encouraged to spend as much time in each situation as needed for their anxiety to decrease. Results indicated significant decreases in anxiety, avoidance, and distress from pre- to posttreatment assessment for the virtual reality exposure group, but not for the control group. Furthermore, the virtual reality exposure group reported more positive attitudes toward heights than the control group. Without being instructed to do so, 7 of the 10 virtual reality exposure treatment completers faced real-life height situations by the end of treatment. This controlled study provided the first evidence that, not only could virtual reality exposure lead to decreased reported fear and avoidance, but it could also lead to changed behavior in the real world.

An independent replication compared virtual reality exposure with in vivo exposure therapy.10 Ten participants who met DSM-IV criteria for acrophobia received two sessions of virtual reality therapy followed by two sessions of in vivo exposure. Virtual reality exposure was found to be as effective as in vivo exposure in reducing anxiety and avoidance. In fact, following only two sessions of virtual reality exposure, participants were found to have approached a ceiling effect, having successfully overcome their fear and diminishing the potential effect of the in vivo exposure. These positive results support the previous research and suggest that brief exposure using virtual reality can be effective in overcoming a phobia. 

In summary, virtual reality exposure for fear of heights was effective in reducing self-reported anxiety and avoidance of heights, improving attitudes toward heights, and reducing the need for in vivo exposure. These studies show that fear could be experienced and overcome in the virtual world, and that this improvement generalizes to the real world.

Fear of flying is a significant problem, affecting approximately 10% to 25% of the population,11 and standard in vivo exposure therapy for fear of flying is inconvenient and cumbersome for therapists as well as extremely expensive for patients. Researchers thus developed and tested a virtual airplane to treat aerophobia. Forty-five fearful flyers were randomly assigned to one of three conditions: wait list, standard exposure therapy, and virtual reality exposure therapy.12 Treatment consisted of eight individual therapy sessions conducted over a 6-week study period. The first four sessions of both virtual reality exposure and standard exposure consisted of training in anxiety management using breathing retraining, cognitive restructuring for irrational beliefs, thought-stopping, and hyperventilation exposure. These were followed by four exposure sessions, either in virtual reality or to an actual airplane at the airport (standard exposure). Virtual reality exposure sessions were conducted twice weekly in the therapist’s office, using such stimuli as sitting in the virtual airplane, taxiing, taking off, landing, and flying in both calm and turbulent weather. For standard exposure sessions, patients were exposed to preflight stimuli (eg, ticketing, waiting area) and to a stationary airplane. Immediately following the treatment or wait-list period, all patients were asked to participate in a behavioral-avoidance test consisting of an actual commercial round-trip flight.  The therapist accompanied participants in a group on a flight that lasted about 1.5 hours each way.

Results indicated that both types of treatment were equally superior to the wait-list condition. Participants receiving virtual reality exposure or standard exposure showed substantial improvement, as measured by self-report questionnaires, willingness to participate in the graduation flight, self-report levels of anxiety on the flight, and self-ratings of improvement. There were no differences between the virtual reality exposure and standard exposure treatments on any measures of improvement. Wait list participants demonstrated no significant differences between pre- and posttreatment self-report measures of anxiety and avoidance, and only one of the 15 wait-list participants agreed to fly.

Follow-up data gathered 6 months posttreatment indicated that treated participants maintained their treatment gains and 93% had flown since completing treatment.12 Follow-up data collected 1 year following treatment indicated that patients maintained their gains.13 These data represent the first controlled study to compare the use of virtual reality in the treatment of a specific phobia to the current standard of care—standard exposure therapy. The findings suggest that virtual reality exposure is as efficacious as standard exposure.

Treatment of Social Phobia

Early studies of virtual reality focused on environments with powerful physical cues (eg, depth perception, loud noises, and strong vibrations). Using virtual reality to treat individuals with social phobia who have prominent public-speaking fears requires a different set of stimuli. The hallmark of social phobia is a fear of negative evaluation, and it was not known whether or not virtual reality could elicit an interpersonal fear in order to be useful as an exposure environment. Two case studies are the only known research conducted to date using virtual reality exposure in the treatment of social phobia.14 Each participant met DSM-IV criteria for social phobia, nongeneralized subtype. As in previous studies, initial sessions focused on anxiety management techniques and video-camera exposure in which the participant was videotaped giving a talk and then watched the tape. The remaining sessions used virtual reality exposure which placed the patient in front of a small audience of five individuals around a conference table where the therapist could control the reaction of the audience (eg, listening intently, clapping, bored, sleeping, hostile). Following the course of treatment, both participants reported decreased anxiety while speaking in public, with levels comparable to typical public-speaking fears in the general population. In addition, both were willing to engage in a behavioral-avoidance test in which they reported mild levels of anxiety and adequate performance.  Although these results are only preliminary and are limited in their generalizability due to single-subject design, results suggest that further, large-scale investigation is warranted to further investigate the use of virtual reality exposure in the treatment of the fear of public speaking.  

Treatment of Posttraumatic Stress Disorder

Approximately 830,000 veterans suffer from chronic combat-related posttraumatic stress disorder (PTSD).15  Evidence suggests that behavioral therapies with an imaginal exposure component have been more effective than most other types of treatment,16 although the effects are not robust. Obviously, in vivo exposure to combat situations is impractical. Thus, a “virtual Vietnam” environment was created to explore the efficacy of virtual reality exposure with Vietnam combat veterans with PTSD.

The first use of virtual reality exposure for a Vietnam veteran with PTSD was reported in a recent case study17 of a 50-year-old, White male veteran meeting DSM-IV criteria for PTSD. He had served as a helicopter pilot in Vietnam approximately 26 years prior to the study. Treatment consisted of 14, 90-minute individual sessions conducted over a 7-week period. Results indicated posttreatment improvement on all measures of PTSD and maintenance of these gains at 6-month follow-up. 

This case study was followed by an open clinical trial of virtual reality exposure for Vietnam veterans.18 In this study, 16 male patients who met DSM-IV criteria for PTSD were enrolled, 10 of whom completed the study. These participants were exposed to two virtual environments—a virtual clearing surrounded by jungle and a virtual Huey helicopter, in which the therapist controlled various visual and auditory effects (eg, rockets, explosions, day/night, yelling). Patients were hierarchically exposed to their most traumatic Vietnam memories while immersed within the virtual environments. After an average of 13, 90-minute exposure therapy sessions delivered over 5–7 weeks, there was a significant reduction in PTSD and related symptoms. This preliminary evidence suggests that virtual reality exposure may be a promising component of a comprehensive treatment approach for veterans with combat-related PTSD. The relatively high drop-out rate suggests that more investigation is needed to understand which veterans are most likely to benefit from this type of treatment.

Distraction for Pediatric Pain Management

Virtual reality distraction for children undergoing painful medical procedures is another innovation in the field. Several case studies have demonstrated the benefit of virtual reality as a distracter. One research group found that virtual reality was somewhat successful in relieving children’s anxiety associated with chemotherapy.19 A second case study compared virtual reality distraction with a video game in three adolescent burn patients during wound-care procedures.20 All three patients reported that they experienced less pain using virtual reality distraction and that less pain medication was needed. The third case study involved a pediatric oncology patient followed over four consecutive appointments for medical procedures (J. Gershon, unpublished data, 2001). He reported less pain and lower anxiety ratings during virtual reality distraction, compared to no distraction or nonimmersive distraction, in which he could interact with the virtual environment displayed on a computer screen using a joystick. 

Although these case studies have limited generalizability, the positive results for virtual reality distraction led to a clinical trial in which children were randomly assigned to either no distraction (control group), nonvirtual reality distraction (on a computer screen) or virtual reality distraction.21 Overall, results suggested a benefit from distraction compared to the control group, with virtual reality distraction demonstrating more potency as indicated by reduced physiological arousal, fewer behavioral indices of distress, lower pain ratings by nurses, and lower anxiety ratings by parents and patients.


Outcome research conducted to date using virtual reality in behavioral treatment of anxiety disorders supports its effectiveness as a powerful research and clinical tool. In the area of specific phobias, data clearly indicate that specially designed virtual environments are effective tools for exposure therapy. Early indications of virtual reality exposure efficacy in social phobia and PTSD deserve further research in controlled clinical studies. Pain distraction applications may improve the quality of patients’ experiences during some medical procedures. Additional advantages for the use of virtual reality in treatment for anxiety disorders include greater control of situations, increased safety, less travel, and improved patient confidentiality.

Finally, there is some indication that patients prefer the virtual world when given the choice.13 People appear more willing to try things in virtual reality that they might avoid completely in the real world. As costs of equipment and programming are reduced, more specially designed environments can be created, which will allow for broader virtual reality usage in treatment and research.  PP



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13.    Rothbaum BO, Hodges L, Anderson P, Price L, Smith S. 12-month follow-up of virtual reality and standard exposure therapies for the fear of flying. JCCP. In press.
14. Anderson P, Rothbaum BO, Hodges L. Social phobia: virtual reality exposure in the treatment of fear of public speaking. Symposium chaired at: Annual meeting of the American Psychological Association; August 2000; Washington DC.
15.  Weiss DS, Marmar CR, Schlenger WE, et al. The prevalence of lifetime and partial post-traumatic stress disorder in Vietnam veterans. J Traumatic Stress. 1992;5:365-376.
16.   van Etten M, Taylor S. Comparative efficacy of treatments for posttraumatic stress disorder: a meta-analysis. Clin Psych Psychother. 1998;5:126-145.
17. Rothbaum BO, Hodges L, Alarcon R, et al. Virtual reality exposure therapy for PTSD Vietnam veterans: a case study. J Traumatic Stress. 1999;12:263-271.
18. Rothbaum BO, Hodges L, Ready D, Graap K, Alarcon RD. Virtual reality exposure therapy for Vietnam veterans with posttraumatic stress disorder. In press.
19. Schneider S, Workman M. Effects of virtual reality on symptom distress in children receiving chemotherapy. Cyberpsych Behav. 1999;2:125-134.
20. Hoffman HG, Doctor JN, Peterson DR, Carrougher GJ, Furness TA. Virtual reality as an adjunctive pain control during burn wound care in adolescent patients. Pain. 2000;85:305-309.
21.   Gershon J, Zimand E, Pickering M, Lemos R, Rothbaum BO, Hodges L. Virtual reality as a distraction during an invasive medical procedure for pediatric cancer patients. Poster presented at: Annual meeting of American Association of Behavior Therapy; November 2001; Philadelphia, PA.

Dr. Ward is associate professor of psychiatry in the Department of Psychiatry at the University of Florida in Gainesville.

Dr. Shapira is assistant professor of psychiatry in the Department of Psychiatry at the University of Florida.

Dr. Goodman is professor of psychiatry and chairman of the Department of Psychiatry at the University of Florida.

Acknowledgments: The authors would like to thank Mary Lessig for her editorial assistance in the preparation of this manuscript.



What alternative nonpharmacologic somatic treatment methods are available for patients with anxiety disorders? This article will review four such methods: ablative neurosurgery, deep-brain stimulation (DBS), vagus-nerve stimulation (VNS), and repetitive transcranial magnetic stimulation (rTMS). Major advances have been made in pharmacologic and psychological treatment of the anxiety disorders over the past 15 years. However, many patients remain refractory to all current treatments even after years of medication trials and cognitive-behavior therapy. For this group of severely ill, often debilitated patients, efforts are being made to offer anatomically based treatment. Modern stereotaxic procedures guided by high-resolution imaging have made ablative surgery (cingulotomy, capsulotomy, subcaudate tractotomy, limbic leucotomy) more precise and safe. “Functional ablation” is now possible using DBS, offering a reversible means of interrupting neurotransmission within circuits known to mediate anxiety and cognitions. VNS utilizes afferent input to cortical, limbic, and brainstem structures without craniotomy. rTMS provides a means of focal electrical stimulation of the surface of the brain. Mounting evidence for efficacy of rTMS in depression will hopefully lead to further development of this intervention in anxiety disorders.



Over the past 15 years, well-controlled clinical trials have documented the effectiveness of pharmacologic and psychological treatments for anxiety disorders such as panic disorder, generalized anxiety disorder, social phobia (social anxiety disorder), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Across these disorders, the majority of patients (60% to 80%) report clinically significant improvement with medication, cognitive-behavior therapy, or a combination of these interventions.1 However, for the treatment-refractory patient with anxiety, residual symptoms can be debilitating. Advances in neuroimaging and application of basic science models to clinical medicine are yielding more anatomically based treatment options for this group of severely ill patients. The anxiety disorder that has received the most investigation has been OCD. Of the 4–7 million people in the United States who suffer from OCD, approximately 20% are refractory to current pharmacotherapy and psychotherapy.2 This article will review four nonpharmacologic somatic treatments for refractory anxiety disorders: ablative neurosurgery, deep-brain stimulation (DBS), vagus-nerve stimulation (VNS), and repetitive transcranial magnetic stimulation (rTMS).


Neurobiology of Anxiety Disorders: Obsessive-Compulsive Disorder

Evidence from brain-imaging studies demonstrates that specific neural circuits may be responsible for OCD symptoms.3 Positron Emission Tomography (PET) scanning has shown hyperactivity in the orbitofrontal cortex and head of the caudate nucleus.4 Dysfunction in prefrontal basal-ganglia thalamic prefrontal circuits may be associated with information-processing deficits and intrusive symptoms in OCD.3,5 Anatomically based treatments share the strategy of interrupting neurotransmission within this circuit.


Ablative Neurosurgery

Ablative neurosurgery for psychiatric illness is performed in a few centers and reserved for the most seriously ill, treatment-refractory patients. Ablative neurosurgical techniques for OCD include cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy. Cingulotomy is the most common procedure in the US. Using magnetic resonance imaging (MRI)-guided stereotactic techniques, electrodes are inserted into the anterior cingulate gyrus, and lesions are created using radiofrequency thermocoagulation.3 For capsulotomy, lesions are created in the anterior limb of the internal capsule either by radiofrequency thermocoagulation or radiosurgically (γ-knife capsulotomy).3 The radiosurgical method avoids the need for craniotomy. Crossfiring beams of 60-Cobalt γ radiation from a stereotactic γ unit create lesions. Individual beams are not destructive to tissue except at their point of convergence.3,6 With subcaudate tractotomy, a lesion is created in the region of the substantia innominata just below the head of the caudate nucleus. Using MRI-guided stereotaxic techniques, lesions are made using β radioactive yttrium rods that have a half-life of approximately 60 hours and remain in the brain indefinitely.3,4 Typically, patients experience confusion in the first few weeks after the operation.3 Limbic leucotomy is a combination of subcaudate tractotomy and anterior cingulotomy.3 Lesions are created in the substantia innominata and the cingulate gyrus using thermocoagulation.

All of these surgical procedures have the common objective of severing interconnections between the frontal lobes and limbic and thalamic structures. Lesions in one region may affect the function of other brain areas. For example, lesions in the substantia innominata following subcaudate tractotomy cause neuronal degeneration of the internal capsule.7 Different surgical interventions with different targets for ablation may have similar effects on neurotransmission within the prefrontal basal-ganglia thalamic prefrontal circuits. Darin and colleagues8 recently reported on the long-term outcome of 44 patients who received cingulotomy for treatment-resistant OCD. Assessment measures, including the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised,9 the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Beck Depression Inventory, and the Sickness Impact Profile, were administered preoperatively and at follow-up. At 32 months postcingulotomy, 14 patients (32%) met criteria for treatment response and 6 others (14%) were partial responders.

Evaluation of efficacy for these different procedures for the treatment of OCD is inherently difficult.10 Severity of illness varies across studies and diagnostic criteria for OCD is inconsistent. In addition, some studies have been performed before effective pharmacologic intervention was available, and outcome measures vary across these studies. The optimal surgical procedure remains controversial, but response rates seem to vary from 35% to 65% for treatment-refractory OCD.11 The risk of neurosurgery for severe OCD is comparable to risk associated with stereotactic operations for nonpsychiatric illness.12 The risk of developing cognitive deficits after surgery has been evaluated in all four procedures described above, and no evidence of reduced intellectual function has been noted.13


Deep-Brain Stimulation

Bilateral DBS has been used successfully for essential tremor and Parkinson’s disease (PD) since about 1995, utilizing the Medtronic Activa Tremor Control System (Figure).14 Significant adverse events from the DBS procedure have included equipment failure or lead wire breakage, intracranial hemorrhage, infection, seizures, and paresis.


In 1999, a team of Swedish and Belgian physicians approached refractory OCD through DBS rather than bilateral capsulotomy.15 The selected stimulation targets for the chronic stimulation were identical to those aimed for in a capsulotomy. In four patients with severe treatment-resistant OCD, quadripolar electrodes were stereotactically bilaterally implanted in the anterior limbs of the internal capsule. Beneficial effects were seen in three patients. Of these, a 39-year-old woman suffering from severe OCD for more than 20 years reported feeling an almost instantaneous relief from anxiety and obsessive thinking when stimulation was activated. Her relief reportedly subsided with stimulation inactivation. She was continuously stimulated for 2 weeks during which her parents reporting that about 90% of her compulsive behavior and rituals had vanished. To further assess the effects of stimulation, the Profile of Mood States (POMS), was administered in a double-blind fashion by six independent raters. Ratings increased for social contact, communication, flow of ideas, assertiveness, and mobility during the stimulation period.15

These observations indicate that acute capsular stimulation can induce relevant beneficial effects in OCD and suggest that long-term stimulation may be useful in the management of treatment-resistant forms of OCD. The DBS-stimulating device operates at a level ≤100 Hz, which depolarizes the neurons, disrupting neurotransmission—essentially, functional ablation. It is hypothesized that bilateral electrical stimulation is effective because it targets the neuroanatomical substrate of OCD—ie, the limbs of the frontostriatal pallidal thalamic frontal loop—which passes through the anterior limb of the internal capsule.16


Vagus-Nerve Stimulation

The vagus nerve (10th cranial nerve) is best known for its efferent function with parasympathetic inervation to organs such as the heart and gut. However, approximately 80% of vagal-nerve fibers are afferent sensory fibers that relay information from the body to the brain.17 These afferent fibers project via the nucleus tractus solitarii to the locus ceruleus and parabracial nucleus. The locus ceruleus and parabracial nucleus project to all levels of the forebrain including the hypothalamus, orbital frontal cortex, amygdala, and bed nucleus of the stria terminalis.18 In theory, direct stimulation of the vagus afferent fibers could affect sensory input to limbic, brain stem, and cortical areas known to be involved in mood and anxiety disorders.

The US Food and Drug Administration approved VNS in 1997 for treatment-resistant partial-onset seizures in epilepsy. The device, VNS™ NeuroCybernetic Prosthesis (NCP) System, is manufactured by Cyberonics, Inc., in Houston, Tex, and has been implanted in over 12,000 patients worldwide. Implantation of VNS™ is similar to implantation of a pacemaker. The pulse generator is about the size of a pocket watch and is implanted subcutaneously in the left chest wall. The vagus nerve is exposed through a separate incision near the carotid artery. A tunnel is made under the skin up to the neck for connection of bipolar leads to the vagus nerve. Generator settings are checked and adjusted telemetrically by holding a wand connected to a laptop computer, over the pulse generator. Patients are given a magnet that when held over the generator, turns it off. Stimulation cycles are typically 30 seconds of stimulation every 5 minutes. Current output, pulse width, and frequency can also be adjusted using the telemetric wand and laptop.

VNS has had an excellent safety record in seizure patients.19 The most common adverse event related to implantation is mild pain at the incision site that typically resolves over the 2 weeks following surgery. Stimulation-related side effects include hoarseness, throat/neck pain, and shortness of breath while the stimulator is on. These are typically mild and can be minimized by adjustments in stimulator settings.

Among psychiatric disorders, VNS has been best studied in depression. Rush and colleagues20 conducted a multicenter open trial of VNS in 30 adult outpatients with nonpsychotic, treatment-resistant major depression, bipolar I or II (depressed phase). Positive findings have led to a pivotal trial of VNS in major depression that has been completed and is awaiting analysis of the data.

A multicenter pilot study of VNS in treatment-resistant anxiety disorders is now under way. There are currently seven patients with OCD, two patients with PTSD, and one panic disorder patient implanted with the device. Acute and long-term data is not yet available on these patients.


Repetitive Transcranial Magnetic Stimulation

Transcranial magnetic stimulation was introduced by Barker and colleagues21 in 1985 as a noninvasive means of stimulating the cerebral cortex. It involves placing an electromagnetic coil on the scalp and passing a rapidly-alternating high-intensity current through the coil. This sets up a magnetic field, which passes through the cranium and induces local electrical changes on the surface of the cortex.22 Initially, TMS was used to study nerve conduction by stimulating an area of the motor cortex and measuring contralateral muscular-evoked potentials.23 Therapeutically, rTMS has received the most attention with treatment-resistant depression.24-28

Studies of patients with anxiety disorder has been much more limited. For example, Greenberg and colleagues29 treated 12 patients with OCD and found that a single session of right prefrontal rTMS decreased compulsive urges for 8 hours, but there was no effect on obsessions. In addition, Alonso and colleagues30 randomly assigned 18 patients with OCD to real or sham rTMS. Five patients were unmedicated and eight were receiving therapeutic doses of fluoxetine or a combination of clomipramine and fluvoxamine. All patients received 18 20-minute sessions of stimulation at 1 Hz. Intensity was 110% of motor threshold for real rTMS and 20% of motor threshold for sham condition. The Y-BOCS and the Hamilton Rating Scale for Depression were used for assessment. No significant changes in OCD symptoms were detected in either group after treatment. In another study, McCann and colleagues31 treated two PTSD patients openly with right frontal 1-Hz rTMS at 80% of motor threshold. Each session was 20 minutes. One patient received 17 sessions and the other patient received 30 sessions. Both patients reported symptom improvement. However, in both cases, symptoms returned to pretreatment levels by 1 month after rTMS discontinuation. Finally, Grisaru and colleagues32 treated 10 PTSD patients openly using a single session of TMS at slow frequency over the motor cortex. Improvement in core symptoms of avoidance, anxiety, and somatization were noted, but the effect was short lived with return to baseline symptoms by day.28


Currently, only patients with chronic, severe, disabling illness refractory to all reasonable conventional therapies, are considered for ablative surgery. For OCD, this usually means a 5-year treatment period with therapeutic trials (at least 10 weeks) of clomipramine, all selective serotonin reuptake inhibitors, and a monoamine oxidase inhibitor. Augmentation strategies must be attempted. Additionally, an extended trial of cognitive-behavior therapy (exposure with response prevention) must be documented. The same criteria must be met for DBS in treatment-refractory OCD. However, it should be noted that disruption in neural transmission with DBS is reversible. VNS avoids craniotomy and stimulates brainstem, limbic, and cortical pathways via vagal stimulation in the neck. In anxiety disorders, VNS is just in the pilot stage of investigation. Least invasive, rTMS delivers localized electrical stimulation on the surface of the cortex. It has shown considerable promise in depression, but findings have been mixed in anxiety disorders. It should be noted that DBS, VNS, and rTMS remain investigational at this point and are only available through research protocols.    PP



1.    Ballenger JC. Current treatments of the anxiety disorders in adults. Biol Psychiatry. 1999;46:1579-1594.
2.    Rasmussen SA, Eisen JL. The epidemiology and clinical features of OCD. Psychiatr Clin North Am. 1992;15:743-758.
3.    Binder DK, Iskander BJ. Modern neurosurgery for psychiatric disorders. Neurosurgery. 2000;47:9-23.
4.    Baxter LR, Ackermann RF, Swerdlow NR, et al. Specific brain system mediation of obsessive-compulsive disorder responsive to either medication or behavior therapy. In: Obsessive Compulsive Disorder: Contemporary Issues in Treatment. Goodman Wk, Rudorfer MV, Maser JD, eds. Mahwah, NJ: Lawrence Earlbaum Associates; 2000:573-609.
5.    Mindus P, Rasmussen SA, Lindquist C. Neurosurgical treatment for refractory obsessive compulsive disorder: implications for understanding frontal lobe function.
J Neuropsychiatry. 1994;6:467-477.
6.    Mindus P, Bergstrom K, Levander SE, et al. Magnetic resonance images related to clinical outcome after psychosurgical intervention in severe anxiety disorder. J Neurol, Neurosurg, Psychiatry. 1987;50:1288.
7.    Corsellis J, Jack, AB. Neuropathological observations on yttrium implants and on undercutting in the orbito-frontal areas of the brain. In: Laitinen LV, Livingston KE, eds. Surgical Approaches in Psychiatry. Baltimore, MD: University Park Press; 1973:60.
8.    Darin DD, Baer L, Cosgrove GR, et al. Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am J Psychiatry. 2002;159:269-275.
9.    Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington DC: American Psychiatric Association; 1987.
10.    Jenike MA. Neurosurgical treatment of obsessive-compulsive disorder. In: Goodman WK, Rudorfer MV, Maser JD, eds. Obsessive-Compulsive Disorder, Contemporary Issues in Treatment. London, England: Lawrence Erlbaum Associates; 2000:457-482.
11.    Cosgrove GR. Surgery for psychiatric disorders. CNS Spectrums. 2000;5:43-52.
12.    Blaauw C, Braakman R. Pitfalls in diagnostic stereotactic brain surgery. Acta Neurosurgery. 1988;42(suppl):161.
13.    Sweet WH, Meyerson BA. Neurosurgical aspects of primary affective disorders. In: Youmans JR, ed. Neurological Surgery. Philadelphia, PA: Saunders; 1990.
14.    Medtronic Inc. Submission of premarked approval application (PMA) P960009 Supplement 7 for the Medtronic Activa Parkinson’s Control System. Presented at: 13th Neurological Devices Advisory Panel Meeting of the Food and Drug Administration; March 31, 2000; Rockville, Md.
15.    Nuttin B, Cosyns P, Demeulemeester H, et al. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet. 1999;354:1526.
16.    Irle E, Exner C, Thielen K, et al. Obsessive-compulsive disorder and ventromedial frontal lesions: clinical and neuropsychological findings. Am J Psychiatry. 1998;155:255-263.
17.    Foley JO, DuBois F. Quantitative studies of the vagus nerve in the cat, I: the ratio of sensory and motor studies. J Comp Neurol. 1937;67:49-67.
18.    Van Bockstaele EJ, Peoples J, Valentino RJ. Anatomic basis for differential regulation of the rostrolateral peri-locus coeruleus region by limbic afferents. Biol Psychiatry. 1999;46:1352-1363.
19.    Fisher RS, Handforth A. Reassessment: Vagus nerve stimulation for epilepsy: A report of he Therapeutics and Technology Assessment Subcommittee for the American Academy of Neurology. Neurology. 1999;53:666-669.
20. Rush JA, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: A multicenter study. Biol Psychiatry. 2000;47:276-286.
21. Barker AT, Jalinous R, Freeston IL. Non-invasive stimulation of the human motor cortex. Lancet. 1985;1:1106-1107.
22.    Barker AT. An introduction to the basic principles of magnetic nerve stimulation. J Clin Physiol. 1991;8:26-37.
23. Hallet M, Cohen LG. Magnetism: A new method for stimulation of nerve and brain. JAMA 1989;262:538-541.
24.    George MS, Wasserman EM, Kibrell TA, et al. Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry. 1997;154:1752-1756.
25.    Klein E, Kreinin I, Chistyakov A, et al. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch Gen Psychiatry. 1999;56:315-320.
26.    Triggs WSJ, McCoy KJ, Greer R, et al. Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold. Biol Psychiatry. 1999;45:1440-1446.
27.    Berman, RM, Narasimhan M, Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry. 2000;47:332-337.
28.    Grunhaus L, Dannon PN, Schreiber S, et al. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of non-delusional major depressive disorder: an open study. Biol Psychiatry. 2000;47:314-324.
29.    Greenberg BD, George MS, Dearing J, et al. Effect of prefrontal repetitive transcranial magnetic stimulation (rTMS) in obsessive-compulsive disorder: a preliminary study. Am J Psychiatry. 1997;154:867-869.
30.    Alonso P, Pujol J, Cardoner N, et al. Right prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: A double-blind, placebo-controlled study. Am J Psychiatry. 2001;158:1143-1145.
31.    Mc Cann UD, Kimbrell TA, Morgan CM, et al. Repetitive transcranial magnetic stimulation for posttraumatic stress disorder. Arch Gen Psychiatry. 1998;55:276-278.
32.    Grisaru N, Amir M, Cohen H, Kaplan Z. Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study. Biol Psychiatry. 1998;44:52-55.

Dr. Rapgay is assistant clinical professor of psychiatry in the Department of Psychiatry at the Neuropsychiatric Institute, UCLA School of Medicine in Los Angeles, and director of the university’s Behavioral Medicine Program.

Acknowledgments: The author would like to thank Lidia Zylowska, MD, for her editorial assistance.



Among the Eastern medical traditions, Tibetan medicine is considered to have the most comprehensive definition, classification, diagnostics, and treatment of mental disorders. The system includes herbal, physical, nutritional, behavioral, psychological, and spiritual interventions to treat mental illnesses (such as anxiety disorders) known as “heart energy disorders” (sNing rLung in Tibetan). Although there is no evidence yet of the clinical efficacy of these treatment modalities, the Tibetan system provides an alternative model of defining anxiety disorders and of treating them from a mind-body perspective.



Tibetan medicine is gradually becoming known in the Western world, particularly for the way it defines, categorizes, and treats mental illnesses. The origin of Tibetan medicine began when Indian Ayurvedic medicine came to Tibet in the fourth century. The Tibetan kings, particularly during the seventh and eighth centuries, began to encourage the development of an integrated system of medicine by inviting Indian, Chinese, Persian, Greek, Nepalese, and Kashmiri physicians to Tibet.1 During the 11th century, the best known Tibetan physician, Yuthok Yonten Gonpo, combined the various systems of medicine into one integrated system. He presented the new system known as Sowa Ripga (science of healing) in his compilation of The Four Tantras, which serves as the core text taught to students of Tibetan medicine.2

Tibet had many medical schools before the country was invaded by the Chinese. The two most prominent schools in Lhasa, the country’s capital city, included one that specialized in monastics and another for lay trainees. Each district and monastery in Tibet would select two or more of their best students to train at these schools for 7 years. When the students graduated, they were assigned to practice in their local districts or monasteries.

In exile, the main site of Tibetan medical learning and training is in Dharamsala, India, the headquarters of the Dalai Lama. Today, Tibetan medicine is widely practiced in Tibet, India, China, Southeast Asia, Bhutan, Nepal, Mongolia, and Russia. Although Tibetan medicine is fairly new to the West, there are a number of Tibetan practitioners in Europe and the United States.3

Overall, there is very little research in the area of Tibetan medicine. The existing pilot studies on Tibetan medicine are primarily in the treatment of medical disorders,4 and no such studies address the treatment of mental illnesses. However, there is widespread recognition that among all the traditional systems of medicine, Tibetan medicine stands out in terms of its conceptualization and treatment of mental illnesses.


The Theory of Tibetan Medicine

The Tibetan medical theory is based on the three psychophysiological systems (Nepa Sum in Tibetan). The psychophysiological systems are sometimes referred to as the three basic energies or constitutions. Each system is related to different elements—air, fire, water, earth, and space—which denote unique physiological characteristics. In Tibetan language, the three systems are known as rLung, Tkripa, and Badkan. rLung, also known as the wind system, involves the activities of the air and space elements and relates to the central and secondary nervous systems. rLung  is thought to include all psychological states and functions. Tkripa, also known as the bile system, involves the function of the fire and air elements and refers to function of the endocrine and vascular systems of the body. Badkan, also known as the phlegm system, involves the activities of earth and water elements and relates to the functions and activities of the lymphatic and digestive systems in the body.5

Based on Buddhist theories, Tibetan medicine identifies three driving principles that influence the three psychophysiological systems. These three principles are the instinctual forces: drives of attachment, aggression, and ignorance.5 According to Buddhist concept, the innate state of ignorance, which refers to a state of not knowing, creates tension and anxiety in the organism. Such tension leads to attempts to relieve the tension by seeking to search for stimuli and conditions that relieve the tension. The organism becomes attached to such tension-relieving stimuli.

However, such attachment to tension-relieving stimuli, can create new anxious feelings of loss, threat, etc. When the source of tension relief is threatened, the organism often responds with aggression. However, aggression then creates new forms of psychological and physiological tensions. These psychological states predispose the organism to disturbances of the three psychophysiological systems. However, additional causative factors and triggers need to be present for pathology to manifest.6

Causative and triggering factors such as imbalance in diet, nutrition, toxicity, infection, injury, and emotional and spiritual distress result in excesses, deficiencies, or disturbances in individual or multiple psychophysiological systems. When the causative factors are not treated, the psychophysiological systems exacerbate beyond their usual homeostatic functions. Consequently, other homeostatic functions are disrupted, resulting in signs and symptoms indicative of a particular disease.7

The Tibetan physician uses observation, palpation, and questioning to determine diagnosis. Observation involves urine analysis and tongue examination while palpation involves pulse examination. Questioning refers to clinical interview and history-taking. Based on the above assessment, treatment is planned. Treatment consists of  behavior therapy, nutrition therapy, herbal therapy, five detoxifying treatments (nasal cleansing, enemas, purgatives, emetics, blood vessel cleansing with oral herbals), and invasive therapies.

Etiology, Diagnosis and Treatment of Anxiety Disorders in Tibetan Psychiatry

Among the ancient traditions of medicine, Tibetan medicine is widely regarded as possessing the oldest written system of psychiatry medicine that is currently practiced. The Tibetan medical texts identify two broad categories of mental illnesses—the neurotic and psychotic types.8 The neurotic types are broadly classified as “heart energy disorder” (sNing rLung in Tibetan) equivalent to general anxiety disorders, and “life-sustaining wind disorders” (Sog rLung in Tibetan) or general depression.  There are four broad categories of psychotic disorders, two of which are schizophrenia and manic depression.9 In neurotic disorders, the imbalances of the rLung system do not interfere with other psychophysiological systems.  However, in the case of psychotic disorders, there is wide-spread interference of other systems which, in turn, further disrupts the rLung homeostatic functions.

Etiology of Heart Energy Disorders

In Tibetan medicine, anxiety disorders (Ning–rLung in Tibetan, which means “heart energy”) are either mild or severe. Heart energy refers to the dysregulation of the autonomic nervous functions responsible for many of the anxiety symptoms. Mild heart energy disorders refer to general anxiety disorders; severe heart energy disorders refer to anxiety-related psychoses.10

Heart energy disorders are caused by distal and immediate factors. Distal causes are the primodal causes of the disorder, while immediate conditions refer to the triggers that activate the symptoms and signs of the disorder. Distal causes are the primal driving principles of attachment, aggression, and ignorance. At a primal level, heart energy disorders are predominantly caused by attachment issues. The contributory conditions that turn these disruptions into pathological entities are: (1) rLung-producing nutrition; (2) rLung-producing behavior; (3) rLung-producing emotional and psychological factors; and (4) rLung-producing toxicity, injury, etc.11

According to the Tibetan medical text The Four Tantras, heart energy disorders are marked by autonomic nervous system dysregulation, particularly in association with activity of the heart.12 The rLung system is characterized by its various functions, such as lightness, roughness, mobility. These functions manifest themselves respectively as dizziness, dry or itchy skin, and a shifting nature of symptoms such as pain.  

Tibetan medicine appears to identify most of the common causes and conditions, as well as signs and symptoms, of anxiety disorders. The following conditions are thought to cause general and severe anxiety disorders: psychological and physical trauma, worrying, agitation, excessive anger, rumination,  insomnia, work-related stress, excessive bleeding, excessive physical and verbal exertion, loss, poor nutrition, medical illness, and toxicity.

Pathogenesis of Heart Energy Disorder

Tibetan tradition presents a different model of looking at the pathogenesis of psychiatric disorders, and, in particular, understanding  the comorbidity of anxiety and depression.

Causative factors such as psychological factors—ie, fear of  specific objects, worrying—create disturbances in the rLung homeostatic functions. Failure to control the dysregulation results in further exacerbation of the central and secondary nervous systems, as well as psychological functions.13 At this phase of the pathogenesis, signs and symptoms of heart energy disorders occur. When the homeostatic dysregulation of the rLung system does not interfere with other systems, mild and moderate heart energy disorders occur. However, when other systems are disrupted, severe heart energy disorders result. For instance, when the pathological process of the rLung system interferes with the Badkan system, interference with the phlegm homeostatic functions results in a comorbidity of depression. Symptoms and signs of phlegm imbalances, such as loss of interest, or mental and physical stagnation, manifests in the patient.14

Diagnostic Procedure for General and Severe Anxiety Disorder

While the Tibetan diagnostic procedures are very different from those used in modern medicine, the procedures involve intimate human contact that might contribute towards fostering the doctor-patient relationship as well as the healing process.

The initial part of the physician examination involves analysis of the urine and the tongue. A sample of urine is collected in the early morning and the patient is required to avoid foods and behavior the night before that may impact the quality and quantity of urine. The Tibetan physician examines the urine by looking for nine characteristics of the urine, such as the size of the bubbles on stirring, rate at which they disappear, color of urine, sedimentation, presence of albumin, and rate of discoloration. For example, in heart energy disorder, the urine appears to be clear, like water, with huge bubbles that form rapidly on stirring and disappear instantly once stirring is stopped. There is minimal odor, vapor, and albumin in the urine. In the case of severe heart energy disorders with bile complications, the urine may crackle when it begins to disappear, be darker in color, and have a strong odor and albumin. In the case of phlegm complications, the urine has stagnant, small, congestive bubbles which increase on stirring, minimal odor, and a whitish hue.

Palpation, which is the next diagnostic procedure, involves palpating the right and left radial arteries of the patient with the physician’s right and left middle fingers of each hand respectively. Each of the fingertips of the physician represents and reads a specific organ of the patient. The medical texts identify specific pulse features and characteristics for each disorder. Heart energy disorder involves a rapid, fluctuating, surface pulse beat which stops completely when pressure is applied. In particular, the pulse under the physician’s index fingers, which represents the physiological functions of the area around the heart, tends to be fast and fluctuating. In the case of severe anxiety disorders, with bile or agitation complications, the pulse tends to be fast, thin, and to cease on pressure. In the case of the phlegm complications, the pulse is slow and weak, but stop under pressure.

Specific acupressure points on the body are sensitive to pressure with more sensitivity in the case of severe heart energy disorders. The main points are on the sternum between the two nipples, and the 1st, 6th, and 7th thoracic vertebrae.15

Treatment of General and Severe Anxiety Disorders

Tibetan medicine presents a very different, alternative approach to the treatment of anxiety disorders, sequentially matching levels of treatment with the severity of the disorder. After physical and clinical evaluation, treatment is planned on the basis of severity and comorbidity of the heart energy disorder. The treatment for heart energy disorders involves four stages of treatment.

Stage I: Behavioral Therapy

The treatment of choice for mild heart energy disorders involve naturopathic and nonpharmacological methods. The two main naturopathic treatments are behavior and nutrition. Tibetan medicine, unlike Indian Ayurveda, recommends behavior over nutrition as the initial therapy, since behavior involves spiritual, psychological, health, and social-related interventions.

There are three types of behavioral therapy: daily behavior, seasonal, and occasional. Daily behavior refers to daily psychological, physical, and spiritual behavior. Psychological and social behavior recommendations involve guidelines about interpersonal relationships and unhealthy behavior patterns. Spiritual behavior involves following guidelines for leading a moral and religious life. Seasonal behavior deals with adapting behavior such as conduct, exercise, activity, and dress according to seasonal changes. Occasional behavior involves regulating bodily and natural urges such as not suppressing hunger, thirst, sneezing, yawning, breathing, and sleep.

For heart energy disorders, engaging in spiritual practices that are soothing and relaxing, such as counting the breath meditation, equanimity, and visualization-based meditation, are recommended. Patients are encouraged to participate in social services and perform acts of generosity. Interventions such as cognitive restructuring, diaphragmatic breathing, and spiritual practices are recommended for adaptation to stressful and traumatic situations and conflicts, and reduction of worrying and rumination. Seasonal behavior refers to avoiding behaviors  such as excessive exercising during summer, exposure to cold during winter, and eating the wrong seasonal foods.

Stage II: Nutrition Therapy

The nutrition stage involves recommendations of appropriate quantity of food to eat, nutrition for heart energy disorders, and nutrition for each of the seasons. Appropriate quantity of food for heart energy disorders involves eating three meals a day. The diet includes protein in the form of meat as well as other sources of protein, while sugar, caffeine, raw light-green vegetables and raw night-shade vegetables, should be avoided. During winter, the meals should be well cooked and herbal medicated wine is highly recommended. In the summer, high protein intake should be reduced—for instance, from red meat to white.16

Stage III: Herbal Therapy

When naturopathic approaches fail or are not adequate to treat disorders, the physician resorts to herbal therapy. Herbal therapy can be administered in nine different formulations, including syrups, powdered remedies, decoctions, and nutritional supplements. Single herbs are regarded as generally toxic and, therefore, are rarely used in traditional medicine. The use of single herbs in the US is more a Western phenomena. Tibetan pharmacopoeia consists of more than 400 formulas, with each herbal formula consisting of anywhere from 3 to 90 herbal and other ingredients.

Stage IV: External Treatment

When patients do not respond to herbal therapy, stage IV, which is external treatment, is recommended. This stage is composed of three subphases of external treatments: (1) five-detoxification treatment; (2) medicated massage, fomentation, and moxabustion with or without acupuncture; and (3) surgery. The five-detoxification treatment involves a preliminary treatment with oleation (application of medicated oil on the body) and herbal steaming, followed by the actual detoxification therapy using enemas, purgatives, emetics, nasal therapy, and blood detoxification. For instance, in the case of severe heart energy disorder, after strengthening the patient with nutritional supplements, a series of herbal enemas are administered over a period of several days or more to eliminate excessive rLung.

When the five detoxifying treatments are not effective, the second subphase of the treatment is recommended. This involves three types of treatment: massage and acupressure with herbal medicated oils, fomentation, and moxabustion with or without acupuncture. When these fail, the third subphase of treatment involving various forms of minor surgery is recommended. The medical texts depict various major surgical procedures for cataracts, rhinoplasty, and removal of any anal fistulas. However, such interventions were discontinued many centuries ago when a queen died from brain surgery.17

Depending on the needs of the patient, psychological and spiritual interventions are administered during any or all of the four stages of treatment. The psychospiritual interventions involve using the five stages of meditation. The first is sensory meditation such as basic breathing-based meditation—eg, counting the breath, focusing on inhalation and exhalation, and diaphragmatic breathing. Yantra yoga, involving specific movements regulated with breathing and concentration on the breath, may be prescribed. The second stage, cognitive meditation, involves labeling all thoughts, sensations, and emotions that arise as the patients attempt to focus on the breath.   Once the patients are mindful of their own cognitive and emotional states, the third stage, analytical meditation, is recommended. This involves analyzing automatic thoughts and basic assumptions. The goal, as in cognitive therapy, is to come up with a more appropriate cognition of the situation. Once the patients have acquired the appropriate cognition of the event, they are taught the fourth stage, affective meditation, to recognize and generate the appropriate emotions. When the patients generate the appropriate cognition and emotions, they are taught the final meditation stage, visualizations, to dynamically integrate the sensory, cognitive, and affective processes.18


The Tibetan system provides an alternative model of diagnosing and treating anxiety disorders that integrates medical, behavioral, psychological, and spiritual approaches of managing anxiety disorders. The system seeks to include patients in their diagnosis and treatment by acknowledging the patient’s complaints, incorporating them with the physician’s medical diagnosis, and clarifying treatment options for both. This method provides a new way of conceptualizing the role of mind-body medicine in anxiety disorders and creates a framework for assessment and treatment of anxiety disorders to faciliate the doctor-patient relationship beyond the medical model.  PP


1.    Tsarong TJ. Fundamentals of Tibetan Medicine. Dharamsala, India: Tibetan Medical Centre; 1988.
2    Dhonden Y, Tsering G. What is Tibetan Medicine? New Delhi, India: Tibetan Reviews Publications; 1978.
3.    Badmajew P, Badmajew V. Healing Herbs, the Heart of Tibetan Medicine. Berkeley, Calif: Red Lotus Press; 1988.
4.    Dhonden Y. Ambrosia Tantra. Dharamsala, India: Library of Tibetan Works and Archives; 1977.
5.    Rapgay L. The Tibetan Book of Healing. Salt Lake City, UT: Passage Press; 1996.
6.    Clifford T. Tibetan Buddhist Medicine and Psychiatry. Yorke Beach, ME: Samual Weiser, Inc; 1984.
7.    Rinpoche R. Tibetan Medicine. Berkeley, Calif: University of California Press; 1976.
8.    Burang T. Tibetan Medicine. London, England: Robinson and Watkins Books; 1987.
9.    Clark B. The Quintessence Tantras of Tibetan Medicine. Ithaca, NY: Snow Lion Publications; 1995.
10.   Rapgay L. Mind and Mental Health in Tibetan Medicine. New York, NY: Potola Publications; 1988.
11.  Finckh E. Studies in Tibetan Medicine. Ithaca, NY: Snow Lion Publications; 1988.
12.  Rapgay L. Tibetan Art of Urinalysis.  Dharamsala, India: Tibetan Medical Series; 1988.
13. Kangkar LD. Lectures on Tibetan Medicine. Dharamsala, India: Library of Tibetan Works and Archives; 1986.
14.  Dash B. Formulary of Tibetan medicine. Delhi, India: Classics India Publications; 1988.
15. Clifford T. Tibetan Buddhist Medicine and Psychiatry. Yorke Beach, ME: Samuel Weiser, Inc; 1984.
16. Dhonden Y. Ambrosia Tantra. Dharamsala, India: Library of Tibetan Works and Archives; 1977.
17. Rinpoche R. Tibetan Medicine. Berkeley, Calif: University of California Press; 1976.
18. Clifford T. Tibetan Buddhist Medicine and Psychiatry. Yorke Beach, ME: Samuel Weiser, Inc.; 1984.

Dr. Ackerman is associate research epidemiologist at the UCLA School of Public Health in Los Angeles.

Dr. Cameron is assistant clinical professor of psychiatry at the UCLA Neuropsychiatric Institute.

Acknowledgments: The authors report no financial, academic, or other support of this work.



Why do people from different cultural backgrounds seek energy-based methods for stress relief? Energy healing is the fastest-growing alternative therapy for relaxation and stress reduction. The energy-based therapies include the self-help methods—eg, meditation, yoga, and other movement therapies—and the touch therapies—eg, therapeutic touch, external qigong, Reiki, and pranic therapy—in which there is believed to be a transfer of energy between the practitioner and the patient. The results from anecdotal reports, case reports, nonrandomized or uncontrolled studies, and a few controlled studies suggest that energy therapies appear to have beneficial effects. Experts offer various explanations for the observed benefits, based upon different functional levels of organization: mind-body interactions, chemical reactions, and electromagnetic energy. Devotees of energy therapies believe they normalize the universal life force, qi, which consists of neurochemicals or electrical impulses. Skeptics believe the effects are placebo effects. Most agree that these therapies need to be studied, particularly because millions of Americans are using them.



A recent survey of trends in the use of alternative therapies found that energy healing is the fastest-growing alternative therapy for chronic health problems, relaxation, and stress reduction.1 The energy-based therapies include the self-help methods—eg, meditation, yoga, internal qigong, and other movement therapies—and the touch therapies—eg, therapeutic touch, external qigong, Reiki, and pranic therapy—in which there is believed to be a transfer of energy between the practitioner and the patient. Throughout most of the accumulating medical literature in which these treatments have been evaluated on convenience samples or self-selected patients, improvements have been seen in quality of life, reduced anxiety, lower blood pressure, and improved tolerance of pain. All are changes consistent with the relaxation response, which Benson2 described after studying practitioners of transcendental meditation (TM).

The energy-based therapies are founded on the paradigm of a universal life force, or energy field, that coexists with and interpenetrates the physical body. In the West, the philosophical roots of the various self-help methods may be downplayed with an emphasis instead on harmonizing mind-body connections. Nevertheless, restoring the life force is the ultimate goal in restoring overall health and well-being to the individual. Depending on the tradition, this force is referred to as qi or chi (in Chinese medicine), ki (in Japanese), prana (in Ayur vedic medicine), and “the will to live.” Uncontrolled and suppressed emotions and habitual stress, worry, anger, and frustration are said to result in qi depletion.


Self-Help Methods

Meditation is one of the more common self-help stress-reduction methods. There are two basic forms of meditation: concentration and mindfulness. Concentration requires focusing the mind on one thing—eg, breath, an image, a sound—and holding that focus for a period of time. All other mental activity is considered a distraction. Mindfulness meditation requires paying attention to a detail of momentary reality, such as the breath or a sensation, while the field of awareness is allowed to expand to other sensations or objects in the environment. This practice interrupts automatic stress reactions.


Transcendental Meditation

Transcendental meditation, popularized in the 1960s by the Maharishi Mahesh Yogi, involves concentrating on a mantra or sound and holding that concentration for 20 minutes or more, twice a day. Jevning and colleagues3 reviewed the literature describing physiologic changes observed among practitioners of TM. These changes are consistent with subjective reports of relaxed alertness. The authors consider these changes to reflect a hypometabolic state, with decreased oxygen consumption and carbon-dioxide elimination, decreased respiration, decreased adrenal-corticol activity, enhanced recovery from stressful stimulation, increased electroencephalogram coherence, and evoked potential changes (shorter latencies and larger amplitude of response) and sensory and motor responses consistent with increased alertness.

Mindfulness-Based Stress Reduction

Mindfulness-based stress reduction (MBSR) is an 8-week group program in which subjects learn, practice, and apply “mindfulness meditation” as a self-regulatory approach to stress reduction and emotion management. This type of meditation uses the method of focusing on breath as a way to learn moment-to-moment awareness. The awareness thus developed enables individuals to view their experiences more realistically: thoughts are just thoughts, sensations are just sensations. This approach has been widely used within medical settings in the last 20 years, and many claims have been made regarding its effectiveness. Jon Kabat-Zinn developed the program in 1979 at the Stress Reduction Clinic at the University of Massachusetts Medical Center in Worcester.

The 8-week program consists of weekly 2-hour classes that include meditation instruction in a variety of mindfulness meditation techniques, silent and guided meditations, simple hatha yoga exercises and stretching, and group discussion. Practice assignments and audio cassettes are given for between-class work with meditations on breath, bodily sensations, and the senses. In a series of uncontrolled studies, Kabat-Zinn and colleagues4-8 have demonstrated that mindfulness meditation reduced symptoms of anxiety and panic and helped maintain these reductions in patients with generalized anxiety disorder, panic disorder, or panic disorder with agoraphobia.

Several controlled studies have demonstrated favorable results. Williams and colleagues9 compared an 8-week mindfulness program with educational materials and encouragement to use existing community resources for stress management. Fifty-nine self-selected community residents in the intervention group learned, practiced, and applied mindfulness meditation 20 minutes a day. The 44 controls received educational materials and were encouraged to use community resources for stress management. The intervention group reported significant decreases in daily hassles (24%), psychological distress (44%), and medical symptoms (46%). These changes were maintained at the 3-month follow-up.

Reibel and colleagues10 assessed 136 medical outpatients, before and after the 8-week program, using the Short-Form Health Survey, Medical Symptom Checklist, and Revised Symptom Checklist. They looked for changes in vitality, pain, role limitations caused by physical health, and social functioning. Subjects showed a reduction in psychological distress and alleviation of physical symptoms. Improvement on many measures was maintained after the 1-year follow-up.

Mindfulness-based cognitive therapy (MBCT) integrates aspects of group cognitive behavioral therapy for depression11 with components of MBSR (without yoga exercises). Teasdale and colleagues12 compared an 8-week MBCT program with treatment-as-usual for 145 patients newly recovered from recurring depression. Patients were stratified on time since recovery (<1 year versus 1–2 years) and number of previous episodes (2 versus >2).  Relapse/recurrence was assessed for 60 weeks. The relapse rate was twice as high in the treatment-as-usual group as in the MBCT group, and a positive linear relationship between number of episodes and risk of relapse was found in the treatment-as-usual group but not in the MBCT group. The relapse rate was lowest among 112 patients who had three or more previous episodes. The authors surmised that MBCT interferes with reactivation of “depressogenic” thinking patterns at times of potential relapse/recurrence.

Touch Therapies

External qigong involves the transfer of qi from a qigong master to another person. The master may touch areas on the person’s body or simply pass his hands over the body. Internal qigong, a distillation of meditation, yoga, and breathing exercises, is practiced by individuals to promote self-healing. Sancier13,14 briefly summarized research conducted in the past 30 years (mostly in China) that showed benefits of qigong for hypertension and heart disease, respiratory disease, cancer, and drug addiction.

Therapeutic Touch

Therapeutic touch was developed by Delores Krieger and Dora Kunz in 1972. In therapeutic touch, the most studied of the “touch” therapies, the therapist moves his or her hands above the body to “repattern” the body’s energy. Two review articles15,16 identified more than 38 research articles that reported on the use of therapeutic touch for a wide variety of medical problems in a wide variety of subjects. Decreased pain and anxiety were the most often observed effects, though most of the studies were uncontrolled. 

A few randomized controlled trials have been conducted that compared therapeutic touch with no treatment, treatment as usual, or a sham therapeutic touch procedure. Turner and colleagues17 observed reduced anxiety, pain, and T-lymphocyte concentrations among burn patients who received therapeutic touch compared with sham therapy. Lafreniere and colleagues18 reported reduced anxiety and tension and increased vigor in healthy volunteers who received therapeutic touch over 3 months compared to no treatment. Giasson and Bouchard19 compared therapeutic touch with rest in terminally ill cancer patients and found enhanced well-being in the treatment group. Samarel and colleagues20 compared therapeutic touch with rest and dialogue in two groups of women before and immediately after surgery for breast cancer. They found that the experimental group had lower preoperative state anxiety than the control group. Gagne and Toye21 compared therapeutic touch with sham therapy and guided relaxation therapy among psychiatric inpatients. Both therapeutic touch and relaxation produced similar reductions in subjective anxiety compared with the control.

Healing Touch

Healing touch is similar to therapeutic touch. Developed by Janet Mentgen,22 healing touch emphasizes practitioner self-care and the patient-practitioner relationship, and sometimes includes physical touch. One recent crossover study found that a majority of subjects had increased immunoglobulin A (IgA) concentrations, lower self-reported stress, and enhanced pain tolerance after healing touch treatment.23


Reiki (pronounced RAY-kee), developed in Japan in the late 1800s by Mikao Usui, is a technique similar to healing touch involving light touch and the use of 13 specific hand positions. The Reiki practitioner must first be “attuned” by a Reiki master. Reiki was introduced to the Western world in the mid-1970s. A recent uncontrolled study24 of the effects of Reiki on healthy subjects compared state anxiety, salivary IgA, cortisol, blood pressure, galvanic skin response, muscle tension, and skin temperature before and after Reiki treatment. The after-treatment change in all physiological measurements was consistent with greater relaxation (and with regression to the mean).

Theoretical Considerations

Various explanations for the observed benefits of energy-based healing mind-body interactions, electromagnetic energy, and placebo effects, have been offered. Brody25,26 summarized the work of Pert and others that has shown mental states can modulate the immune system and trigger the release of endorphins and other neuropeptides that influence mood, behavior, and immune function. Pert and colleagues27 hypothesized that the nervous, endocrine, and immune systems are functionally integrated. Emotions trigger the secretion of peptides throughout the body and are thereby the link between mind and body, psyche and soma, soul and matter. Mobile immune cells transport peptides between the brain and the body along pathways that correspond with qi pathways, or meridians. Stimulating points along these pathways, through methods such as acupuncture, may start the flow of endorphins and immune-system cells.

The mind-body relationship offers an explanation for self-regulatory therapies like biofeedback, meditation, yoga, self-hypnosis, etc. But how do energy healers influence the flow of energy in their patients even when there is no physical contact? The challenge has been to devise more sensitive methods to measure the body’s energy field. Do healers emanate their own energy that triggers changes in the recipient?

At present, the detection and direct measurement of qi has eluded Western-based investigations. In the early 1960s, Kirlian photography was promoted as a way of visualizing the human energy field. Discovered by Semyon Davidovich Kirlian, a Russian electrician, the photographic phenomenon occurs when an electrically grounded object discharges sparks between itself and an electrode generating the electrical field. However, the technique and its interpretation remain controversial.

In a controversial study to determine whether practitioners of therapeutic touch can actually perceive a human energy field, 21 practitioners were correct in identifying which of their hands was closest to the investigator’s hand in 123 (44%) of 280 trials.28 The study was subsequently criticized on grounds that the detection of human energy field was taken out of context of the actual therapeutic environment, which may require a genuinely ill patient and a practitioner whose intention is to heal.

Oschman29 summarized the vast literature on bioenergetics. Extremely low frequency (ELF) energy is produced by the human body and creates a biomagnetic field. Externally applied electromagnetic fields in the ELF range accelerate the healing of soft-tissue injuries and bone fractures. Healers produce strong biomagnetic fields in the ELF range. During noncontact therapeutic touch and related methods, the biomagnetic field of the therapist may penetrate into the body of the patient.


The results from anecdotal and case reports, as well as nonrandomized, uncontrolled, and a few controlled studies, suggest that energy therapies appear to have beneficial effects. Some Western doctors credit the beneficial effects of the energy therapies to placebo effects. However, investigations have shown that belief is capable of affecting matter. Placebo analgesia is mediated by the endogenous opiate system.30-32 Similarly, in Parkinson’s disease, placebo effects appear to be mediated by dopaminergic pathways.33

A major shift in the Western paradigm of medicine has been necessitated by the evidence that brain function is modulated by neuropeptides. In his recent book The Psychobiology of Mind-Body Healing, Ernest Rossi34 suggests that neuropeptides may be the basis of many hypnotherapeutic, psychosocial, and placebo responses. Thus, the neuropeptide system may be the psychobiological basis of folk, shamanistic, and spiritual forms of healing currently in vogue. Perhaps cognitive therapies have the same effect by modifying thoughts that lead to physiological and neurochemical changes in the brain.35

In February 2001, Newsweek reported that 27 hospital-sponsored clinics provide a mixture of alternative medical treatments (including qigong, acupuncture, and meditation) combined with standard primary care.36 Devotees of energy therapies believe that qi consists of neurochemicals or electrical impulses. Skeptics believe the effects are placebo effects. Most agree that these therapies need to be studied, if only because millions of Americans are using them.  PP


1.    Eisenberg DM, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-1575.
2.    Benson H. The Relaxation Response. New York, NY: Avon Books; 1975.
3.    Jevning R, Wallace RK, and Beidebach M. The physiology of meditation: a review. A wakeful hypometabolic integrated response. Neurosci Biobehav Rev. 1992;16:415-424.
4.    Kabat-Zinn J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychiatry. 1982;4:33-47.
5.    Kabat-Zinn J, Lipworth L, and Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8:163-190.
6.    Kabat-Zinn J, Massion AO, Kristeller J, et al. Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry. 1992;149:936-943.
7.    Kabat-Zinn J, Wheeler E, Light T, et al. Influence of a mindfulness meditation-based stress reduction intervention on rates of skin clearing in patients with moderate to severe psoriasis undergoing phototherapy (UVB) and photochemotherapy (PUVA). Psychosom Med. 1998;60:625-632.
8.    Miller JJ, Fletcher K, Kabat-Zinn J. Three-year follow-up and clinical implications of a mindfulness meditation-based stress reduction intervention in the treatment of anxiety disorders. Gen Hosp Psychiatry. 1995;17:192-200.
9.    Williams KA, Kolar MM, Reger BE, Pearson JC. Evaluation of a Wellness-Based Mindfulness Stress Reduction intervention: a controlled trial. Am J Health Promot. 2001;15:422-432.
10. Reibel DK, Greeson JM, Brainard GC, Rosenzweig S. Mindfulness-based stress reduction and health-related quality of life in a heterogeneous patient population. Gen Hosp Psychiatry. 2001;23:183-192.
11.   Beck AT, Rush AG, Shaw BF, Emery G. Cognitive Therapy of Depression. New York, NY: Guilford Press; 1979.
12.   Teasdale JD, Segal ZV, Williams JM, Ridgeway VA, Sovlsby JM, Lau MA. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol. 2000;68:615-623.
13.  Sancier KM, Medical applications of qigong. Altern Ther Health Med. 1996;2:40-46.
14.  Sancier KM. Therapeutic benefits of qigong exercises in combination with drugs. J Altern Complement Med. 1999;5:383-389.
15.  Spence JE, Olson MA. Quantitative research on therapeutic touch. An integrative review of the literature 1985-1995. Scand J Caring Sci. 1997;11:183-190.
16. Winstead-Fry P, Kijek J. An integrative review and meta-analysis of therapeutic touch research. Altern Ther Health Med. 1999;5:58-67.
17. Turner JG, Clark AJ, Gauthier DK, Williams M. The effect of therapeutic touch on pain and anxiety in burn patients. J Adv Nurs. 1998;28:10-20.
18. Lafreniere KD, Mutus B, Cameron S, et al. Effects of therapeutic touch on biochemical and mood indicators in women. J Altern Complement Med. 1999;5:367-370.
19.  Giasson M, Bouchard L. Effect of therapeutic touch on the well-being of persons with terminal cancer. J Holist Nurs. 1999;16:383-398.
20.  Samarel N, Fawcett J, Davis MM, Ryan FM. Effects of dialogue and therapeutic touch on preoperative and postoperative experiences of breast cancer surgery: an exploratory study. Oncol Nurs Forum. 1998;25:1369-1376.
21.  Gagne D, Toye RC. The effects of therapeutic touch and relaxation therapy in reducing anxiety. Arch Psychiatr Nurs. 1994;8:184-189.
22.  Mentgen J. Healing touch certificate program. Beginnings. 1999;19:6.
23.  Wilkinson DS, Knox PL, Chatman JE, et al. The clinical effectiveness of healing touch. J Altern Complement Med. 2002;8:33-47.
24.  Wardell DW, Engebretson J. Biological correlates of Reiki Touch(sm) healing. J Adv Nurs. 2001;33:439-445.
25.   Brody HB, Brody D. Placebo and health-II. Three perspectives on the placebo response: expectancy, conditioning, and meaning. Adv Mind Body Med. 2000;16:216-232.
26.   Brody H. The placebo response. Recent research and implications for family medicine. J Fam Pract. 2000;49:649-654.
27.   Pert CB, Dreher HE, Ruff MF. The psychosomatic network: foundations of mind-body medicine. Altern Ther Health Med. 1998;4:30-41.
28.    Rosa L, Rosa E, Sarner L, Barrett S. A close look at therapeutic touch. JAMA. 1998;279:1005-1010.
29.    Oschman J. Energy Medicine: The Scientific Basis. Edinburgh, UK: Churchill Livingstone; 2000.
30.    Benedetti F, Amanzio M. The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol. 1997;52:109-125.
31.   Wall PD. Pain and the placebo response. Ciba Found Symp. 1993;174:187-211. Discussion, no. 212-216.
32.    Weiner F. Psychoneuroimmunology: the biological basis of the placebo phenomenon? J Manipulative Physiol Ther. 1997;20:224.
33.   de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science. 2001;293:1164-1166.
34.   Rossi EL. Psychobiology of Mind-Body Healing: New Concepts of Therapeutic Hypnosis. New York, NY: Norton; 1993.
35.   Baxter LR, Jr, Saxena S, Brody AL, et al. Brain mediation of obsessive-compulsive disorder symptoms: evidence from functional brain imaging studies in the human and nonhuman primate. Semin Clin Neuropsychiatry. 1996;1:32-47.
36.   Meadows S. Kinder, gentler clinics. Newsweek. February 26, 2001:52.

Dr. Ankenman is director of special services at Madison County Hospital in London, OH.

Acknowledgments: The author reports no financial, academic, or other support of this work. 



Are disorders distinct from attention-deficit/hyperactivity disorder (ADHD) prevalent in the overactive patient population? Giddy disinhibition disorder (GDD), a newly described syndrome of impulsive behavior, is distinctive in that the patient shows disinhibited, euphoric reactions to life events. GDD is often coexistent with other behavioral syndromes such as ADHD and obsessive-compulsive disorder, but has several unique symptoms, such as an almost constant giddiness, inability to demonstrate a serious response to consequences, and pain-seeking behavior. GDD is also unique in its response to therapy with naltrexone, which is an oral narcotic antagonist—an opioid receptor blocker. Naltrexone doses for GDD are up to three times higher than the 50 mg/day dose used for treating drug dependency. GDD is most often seen in developmentally disabled (DD) patients. In the author’s outpatient clinic for DD patients, approximately 10% receive naltrexone therapy. Some patients without developmental disability have been diagnosed with GDD?and treated. One such individual’s personal description of his experience illustrates some of the unique features of this disorder.



The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition1 (DSM-IV), does not include many of the behavioral situations seen in psychiatry, particularly in the developmental disabled (DD) population, where functional immaturity often contributes to psychiatric symptomology. Thus, in treating the DD population, physicians are likely to encounter syndromes not identified among the standard population. Since 1991, the Madison County Hospital Special Psychiatric Service in London, Ohio, has diagnosed certain DD individuals as having a disorder not previously defined and has treated them accordingly. The treating physicians have termed that condition “Giddy Disinhibition Disorder” (GDD), due to the increased level of giddy behavior observed in these patients during their social interactions. GDD patients demonstrate extreme tendencies to seek continuous pleasure-producing stimulation. They do not respond well to typical psychotropic medication regimens, but many of them demonstrate improved behavior when treated with the opioid receptor blocker naltrexone. This article describes the clinical features, prevalence, and results of therapy for this proposed disorder.

Due to the prevalence of comorbid conditions in the DD population, patients with GDD were rarely treated with naltrexone monotherapy in the Madison County Hospital clinic. However, there were enough cases of outstanding changes in behavior when naltrexone was added to the medication regime that it seems legitimate to propose GDD as a distinct disorder with a distinct treatment, and to expect that other clinicians will start to recognize it in the future.


Identification and Treatment Of Giddy Disinhibition Disorder

Individuals with GDD are often mistaken for having ADHD. They especially have many of the behaviors in the ADHD hyperactivity/impulsivity criteria, such as fidgeting, inability to stay seated, inability to play quietly, and being “on the go.” However, the GDD patient exhibits several distinct differences:

(1) The patient is continuously giddy, demonstrating excessive, inappropriate enjoyment of repetitive maladaptive acts (eg, the first patient treated would turn over the living room table again and again, laughing each time).
(2) The patient does not alter his/her behavior in response to negative reinforcement. Verbal and even physical confrontation generally brings on more giddy reactivity and laughing.
(3) The patient may not exhibit any defensive reaction against attempts at physical control. If one grabs the patient’s arm in an effort to redirect him/her, the arm may remain nonresponsive and “flabby.”
(4) The patient often seems immune to physical pain and will even seek it at times (eg, several individuals would seek to slam a finger into the hinge side of a closing door or stick a finger into electrical outlets to get shocked).
(5) In addition to the other four symptoms, the patient does not gain significant, lasting benefits from treatment with psychostimulants.

Much of the giddy behavior seen in DD psychiatric patients is attributable to their emotional immaturity. The Madison County Hospital clinic derived the new designation “GDD” for those patients who had such extreme giddy reactivity that it was the dominating problem of their clinical presentation. Standard medication regimens for treating impulsivity were minimally helpful, but, in some cases, the symptoms improved markedly with the administration of the opioid receptor blocker, naltrexone. The use of this medication was attempted because these individuals demonstrated not only indifference to physical pain, but also indifference to the social pressure of authority. This indifference to authority seemed similar to that of some narcotic addicts when they are “high.” It was hypothesized that individuals with GDD might have excessive endorphin activity and might respond to a narcotic-blocking medication.


Use of an Opioid Receptor Blocker

Use of opioid receptor blockers in the DD population has been occasionally mentioned in the literature, particularly for treating self-abusive behavior. Two important understandings were gleaned from these reports.

(A) Some individuals responded instantly, even responding transiently to the short-acting medication naloxone.2 This suggested the existence of an intrinsically high endorphin function that could be counteracted immediately; (B) There was a commonly stated effective dosage of 1–2 mg/kg/day.

Our clinic had seen successful treatment of self-abusive behavior with naltrexone in less than 20% of those administered the drug. A much higher percentage of GDD patients responded to naltrexone, and the response was surprisingly rapid. The first patient treated had decreased “pesky” behavior and “obnoxious” compulsions within 2 days. One child with fetal alcohol syndrome demonstrated increased verbalizations/responses to questions and a decrease in giddiness after 3 weeks of treatment. Individuals who had been in a constant state of disinhibition became more responsive to caregiver direction. However, they could still develop giddy arousal. In general, most individuals were about 50% less giddy. The efficacy of naltrexone was convincingly demonstrated in some patients who were given a low dose in the morning. Their behavior would be controlled until mid-afternoon and then become disinhibited. This responded to the addition of a second dose.

Over 100 patients in the Madison County Hospital clinic have been given a trial of naltrexone for symptoms suggesting GDD. In certain individuals, symptoms of the disorder dominated their entire presenting behavior and persisted for years, suggesting that they had a distinct pathological syndrome. However, in others who responded to naltrexone therapy, GDD symptoms were relatively minor and seemed to resolve over time. There is therefore a question of whether the disrupted physiology involved in GDD represents a true pathology, or an exaggeration of immaturity.  Approximately 50% of responders demonstrated considerable improvement with naltrexone therapy. The others showed modest but sufficient benefit to warrant continued use.

Of the 484 DD patients currently treated by the outpatient service, 46 are presently receiving naltrexone. Most of the recipients are young: 55% are 10–20 years of age and 44% are 20–30 years of age; one patient is over 30 years old. The dosage range is 50–200 mg/day (0.5–3.0 mg/kg/day). Sixty-four percent of current patients receive 1.4–2.4 mg/kg, and the mean is 1.7 mg/kg—a higher average than anticipated. Giving very high doses of naltrexone has rarely produced improved results. Generally, discontinuation trials with the drug have been safe. Those individuals whose behavior worsened when the naltrexone was lowered almost always re-established their previous improvement when the higher dose was reinstated.


Successful Treatment of Giddy Disinhibition Disorder: Case Study

The concept of GDD has remained unreported for a number of years. Although it seems to be a distinct clinical diagnosis with a specific treatment for some individuals, other DD patients presenting with symptoms suggesting GDD did not respond to naltrexone. Furthermore, the patients themselves could not give feedback about the effects of treatment.

In November 1997, a 17-year-old male without developmental disabilities was treated successfully with naltrexone for symptoms that were identified with GDD. The patient was in constant trouble for impulsive acts throughout high school (eg, he once sprayed a fellow students with a spray bottle containing urine). His behavioral problems began in middle school, and seemed to improve when he was treated with methylphenidate. However, at age 14 years, the patient’s symptoms of impulsive, socially disruptive activities returned, and he was given the diagnosis of bipolar disorder. He was then prescribed various stimulants, as well as clonidine, imipramine, valproate, verapamil, and olanzapine, without any success. When first seen by the author, the patient was taking lithium and risperidone. He was briefly treated for obsessive-compulsive disorder, but the behavioral patterns suggesting giddy disinhibition quickly became obvious.

The patient’s inability to respond to adult authority was notable. He also had recently sustained a significant cut to his arm without noticing it. Naltrexone 50 mg QAM was too sedating, but he tolerated 25 mg BID. The patient developed nearly instant control over his inappropriate social reactivity. Once the patient began treatment with naltrexone, both he and his parents rated his social improvement near 100%. His weight was about 75 kg, thus he responded to a much lower dosage of naltrexone (0.66 mg/kg) than used in most DD patients. He remained on lithium and risperidone because there was still a question of his having bipolar disorder.

The patient wrote the following statement about the effect of naltrexone on his behavior:

Before I was on naltrexone, I did not feel out of control even though I was. When I would do something wrong, I would not think it was wrong and I would just laugh about it. When teachers or parents or anyone else would try to correct me, I would just laugh in their faces—not because I wanted to make them mad, but just because I could not help it. I would also laugh in other situations and at other things that were inappropriate. Before I was on any medication at all, I often felt invincible—like I could conquer the world—and would often stay awake for days at a time. When we started fooling around with medicines, it did not do any good. We went through many, many different medications and combinations of medications and they either made me worse and more active, or sedated me to the point where I could hardly function and had many bad side effects. When I went on naltrexone, I noticed improvements immediately. I did not feel the need to laugh at everyone and everything. I have more of a concept of right and wrong and what their consequences are. I do not feel sedated, but I am not out of control for the first time in my life. I feel balanced and I enjoy life very much.

Since 1997, a few other patients without DD have been seen with symptoms suggesting GDD as part of their psychiatric history. These patients identified another symptom—that of disinhibited response to catastrophe. For example, in one patient’s history, it was noted that when a schoolmate cracked his head in a fall on concrete, the sound was so peculiar that he could not help laughing loudly in spite of the serious nature of the injury. As in the DD population, not all individuals who presented with the symptoms have benefited from naltrexone therapy.


Considerations About the Use of Naltrexone

Naltrexone has two Food and Drug Administration-approved indications—the treatment of narcotic addiction and alcohol dependency. Its use in self-abusive behavior is documented in more than a dozen references.3 There have been reports in the literature of benefits using narcotic antagonists in clinical states as diverse as Tourette’s disorder,4 “narrative” hallucinatory experiences,5 and chronic obstructive pulmonary disease.6 Various theories exist concerning the nature of endorphin dysregulation in these conditions. In cases where there is an immediate therapeutic response, it is generally theorized that the “endorphin high” originates from innately elevated endorphin activity rather than being related to a learned behavior. Currently, naltrexone is the only oral narcotic antagonist available, although others are being investigated.7



GDD is presented here as a previously unrecognized symptom cluster seen predominately, but not exclusively, in the DD population. Symptoms of GDD include giddiness, laughing, and pain-seeking behaviors—symptoms which are not included in the DSM-IV criteria for ADHD or the impulse-control disorders. There are extreme cases in which the entire behavioral pattern is dominated by GDD symptoms. A larger percentage of patients demonstrate various GDD symptoms as one of several comorbid states. Both types of patients can demonstrate rapid improvement when treated with an opioid receptor blocker like naltrexone, but some individuals with typical GDD symptoms do not respond to this treatment. Since a number of treated individuals do seem to demonstrate increasing control over their giddy disinhibited behavior over time, there remains the question of whether these symptoms represent a true psychiatric disease state or whether they represent an extreme case of immaturity. Other clinicians will need to determine if GDD is a valid diagnostic entity. Because its symptomology and pharmacologic treatment suggest an endorphin dysfunction, recognition of this syndrome may open the way to definitive research into the role of the endorphin system in psychiatric diseases other than the substance abuse disorders.   PP



1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2.    Sandman CA, Datta PC, Barron-Quinn J, Hoehler FJ, Williams C, Swanson JM. Naloxone attenuates self-abusive behavior in developmentally disabled client. Appl Res Ment Retard. 1983;4:5-11.
3.    Barret RP, Feinstein C, Hole WT. Effects of Naloxone and Naltrexone on self-injury: a double-blind, placebo-controlled analysis. Am J Ment Retard. 1989;93:644-651.
4.    McConville BJ, Normal AB, Fogelson MH, Erenberg G. Sequential use of Opioid Antagonists and Agonists in Tourette’s Syndrome. Lancet. 1994;343:601.
5.    Watson SJ, et al. Effects of Naloxone in schizophrenia: reduction in hallucinations in a subpopulation of subjects. Science. 1978;193:1242-1263.
6.    Reents SB, Beck CA Jr. Naloxone and Naltrexone in COPD. Chest. 1988;92:217-219.
7.    Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB. Nalmefene for Alcohol Dependence. Arch Gen Psychiatry. 1999;56:719-724.

Dr. Apter is medical director at Global Medical Institutes LLC and in the Department of Psychology at Princeton University in New Jersey.

Dr. Allen is assistant professor of psychiatry in the Department of Psychiatry at Robert Wood Johnson Medical School at the University of Medicine and Dentistry of New Jersey in Piscataway, New Jersey.

Drs. Woolfok and Comer are professors of psychology in the Department of Psychology at Princeton University in New Jersey.

Acknowledgments: The authors report no financial, academic, or other support of this work. 



How can we improve our therapeutic armamentarium in psychiatry? The last decade has witnessed an evolution of a new generation of psychopharmacologic agents. As a whole, these new compounds act on more specific receptors and are associated with fewer adverse effects than medications of earlier generations. This article reviews recently approved medications and novel therapeutic mechanisms under investigation in five areas: major depression, anxiety disorders, bipolar disorder, psychotic disorders, and Alzheimer’s disease. Evolving medications available outside the United States or currently under investigation in American clinical trials are discussed.



The central nervous system drug pipeline is rich, and newer mechanisms of drug action are currently being researched. As novel medications emerge for hypertension and diabetes, so too are they evolving for use in the major disorders treated by psychiatrists. Each therapeutic area under study has developed so that safer and newer drugs are available for depression, anxiety, bipolar, psychotic disorder, and Alzheimer’s disease (AD).

According to a new study1 from Tufts University in Boston, MA, it has been estimated that it now takes an average of 10–15 years of research and development and a cost of $802 million to market a new drug successfully in the United States (US). Relating to such economic realities, and strict Food and Drug Administration (FDA) standards for demonstrating drug safety and efficacy, physicians and scientists have grown accustomed to waiting years for effective medications already available abroad, to be granted FDA approval. On occasion, scant time remaining on patents has prevented drugs from ever becoming available in the US. However, this situation is changing. 

The National Institute of Mental Health, through establishment of its Psychotherapeutic Medication Development Program in 1990, has taken initiatives to stimulate drug discovery, preclinical and clinical drug research, and clinical testing in areas where more effective agents are needed. These areas include disseminating information, providing in vitro testing, and identifying corporate developers. A resulting larger armamentarium of psychopharmacologic agents will certainly require greater efforts for clinicians to remain fully informed and up-to-date, but it will offer new hope for those suffering from psychiatric disorders.


Major Depression

Although the efficacy of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) is well documented, the many side effects and potential for lethality in overdose associated with these drugs have been a discouragement for patients and physicians. MAOIs, when combined with tyramine-containing foods or certain medications (ie, demerol, epinephrine, decongestants), have been linked with hypertensive crises. TCAs have been shown to have a high incidence of anticholinergic effects and cardiotoxicity. Because of the drawbacks of MAOIs and TCAs, investigators have developed new antidepressant agents that minimize adverse events.2 Table 1 lists the new antidepressants currently marketed in the US. Research suggests that each of these agents reduces depressive symptomology more effectively than placebo.2-4 Unlike TCAs and MAOIs, most of these agents selectively act on one neurotransmitter system. Venlafaxine and mirtazapine are the exceptions in that they have dual mechanisms of action.


Reversible inhibitors of monoamine oxidase A (RIMAs) are a class of antidepressants with an alternative mechanism of action. Unlike MAOIs, which inhibit both monoamine oxidase (MAO)-A and MAO-B activity, RIMAs inhibit only MAO-A activity. By allowing MAO-B to remain active (and deaminate tyramine), RIMAs are thought to act on the isoenzyme (MAO-A, which deaminates noradrenaline, adrenaline, and serotonin) responsible for the antidepressant effect of MAOIs without bringing on hypertensive crises. None of the RIMAs are currently available in the US. However, moclobemide is widely prescribed in Europe. Most clinical trials have shown moclobemide to be as effective as TCAs and more effective than placebo in the treatment of depression.5 Also, moclobemide appears to have a more favorable side-effect profile than do TCAs; it has few anticholinergic effects, minimal sedation effects, and no cardiotoxicity.6

Selective noradrenaline reuptake inhibitors (NRIs) represent another pharmacologic approach to the treatment of depression. Unlike the noradrenaline TCAs, NRIs act preferentially at noradrenergic sites. Reboxetine is an NRI that inhibits presynaptic uptake of norepinephrine. It has not been approved for use in the US, but is marketed in Europe. Reboxetine has been shown to be as beneficial as imipramine6 and fluoxetine7 in reducing depression in adults. Some investigators have found that reboxetine enhances the social functioning of severely depressed adults more effectively than fluoxetine.7 The incidence of adverse events experienced by patients taking reboxetine appears to be lower than that of patients taking imipramine and comparable to that of patients taking fluoxetine.8 Duloxetine is a specific serotonin and norepinephrine (NE) reuptake inhibitor similar in action to venlafaxine, with a dual and balanced reuptake inhibition of serotonin and NE. The agent causes minimal raised blood pressure and has less titration than venlafaxine. Duloxetine also appears to have an excellent efficacy and safety profile.

Hypericum perforatum (St. John’s wort) is an herbal remedy with few side effects, used in the treatment of depression. Studies9 suggest that it is equally effective as TCAs and more effective than placebo in treating mild to moderate depression. Various mechanisms for hypericum perforatum’s mechanism of action have been proposed, including serotonin reuptake inhibition, decreased serotonin receptor expression, inhibition of benzodiazepine binding, and inhibition of MAO. In Germany, hypericum perforatum is used widely. In the US, concerns have been raised regarding the standardization and quality control of commercial preparations of the drug. Also, the long-term efficacy of hypericum perforatum has not yet been examined adequately. Currently, large-scale trials of the drug are being conducted—a recent study from the National Institute of Mental Health showed no efficacy.

Another new approach to the treatment of depression involves neuropeptides. Substance P, an undecapeptide, appears to be distributed throughout the limbic system and has been associated with monoamine-containing circuits. Substance P, along with neurokinin (NK) A and NK B have been found to bind preferentially to NK1, NK2 and NK3 receptors. Recent evidence suggests that NK1 antagonists may have antidepressant actions,10 and two positive studies have been presented at the American College of Neuropsychopharmacology from Merck Pharmaceuticals.11

The newest class of antidepressants under investigation are the selective serotonin reuptake inhibitor (SSRI) enantiomers. Fluoxetine is a racemic mixture of the enantiomers R-fluoxetine and S-fluoxetine. In theory, R-fluoxetine may have a more rapid onset of action and produce fewer side effects than racemic fluoxetine. Also, escitalopram, the s-enantiomer of citalopram that is currently under investigation, has been submitted for FDA approval. Escitalopram may have a faster onset of action and fewer side effects than the racemic citalopram. Other novel therapeutic approaches involve corticotropin-releasing factor  (CRF) antagonists, especially CRF1, vagal nerve stimulation, and even mifepristone, in psychotic depression.

In summary, the last decade of the 20th century witnessed substantial progress in the pharmacologic treatment of depression. New medications effectively reduce symptoms of depression and coincide with fewer adverse events than the TCAs and MAOIs. Ongoing research aims to develop antidepressant agents that benefit a greater proportion of patients and coincide with fewer side effects than the current agents.


Anxiety Disorders

Various classes of medications have proven effective in the treatment of anxiety disorders. Prior to the introduction of SSRIs, benzodiazepines and TCAs were the first-line agents for panic disorder, obsessive-compulsive disorder (OCD), and generalized anxiety disorder (GAD). Activating the benzodiazepine γ-aminobuyric acid (GABA) receptor complex, benzodiazepines have been considered by many to be the treatment of choice because of their rapid onset of action. The disadvantages of benzodiazepines include the potential for drowsiness, cognitive impairment, and physical dependency. TCAs have demonstrated efficacy in treating anxiety, yet their numerous side effects and delayed onset of action limit their appeal. Within the last decade, SSRIs have replaced the older generation medications in treatment of many anxiety disorders. The favorable side-effect profile and nonaddictive nature of SSRIs allow for their long-term use, which is essential for many patients suffering from anxiety disorders. Another advantage of SSRIs is their efficacy with both anxious and depressive symptomology since many patients experience both sets of symptoms simultaneously.

The pharmacologic treatment of social phobia has recently received considerable attention. Although only paroxetine has received FDA approval for this indication,12 the other SSRIs (ie, fluvoxamine, sertraline, fluoxetine, and citalopram) have appeared efficacious in treating social phobia.13-15 Two other new psychotropics appear to be effective for, and well tolerated by, socially phobic patients. They are moclobemide, the RIMA presented earlier,16 and gabapentin, a new anticonvulsant described in the section on bipolar disorder.17

The past 10 years of research has supported the use of many new pharmacologic agents for the anxiety disorders. Promising anxiolytics in the pipeline include long-acting or patch formulations of 5-HT1A agonists, glutamate agonists, GABA modulators (such as pagaclone and pregabalin), drugs acting at the benzodiazepine site without dependency potential, substance P antagonists, and the SSRI enantiomers. Finally, a recent meta-analysis suggests that kava extract, piper methysticum, may be an effective anxiolytic.18


Bipolar Disorder

Although lithium is considered the drug of choice for bipolar disorder, in the past 17 years, research has found that many bipolar patients find it unsatisfactory.19 Only 40% to 50% of bipolar patients respond to lithium. Nonresponders include patients with rapid-cycling or mixed episodes as well as those who are unable to tolerate lithium’s adverse events. Unfortunately, lithium’s therapeutic range falls very close to its toxic range.

Over the past 10 years, numerous new treatments for bipolar disorder have been developed. Each of these treatments was initially designed and/or approved for epilepsy. Valproate and carbamazepine were the first two anticonvulsants to be used for bipolar disorder. Valproate has FDA approval for the treatment of acute mania and is widely used in treating these patients. Controlled clinical trials have shown that valproate more effectively reduces manic symptoms than placebo.20 The drug appears to be as effective as lithium for manic episodes and possibly more effective than lithium for mixed episodes. Carbamazepine has also been proven to reduce manic symptoms more effectively than placebo and about as effectively as lithium in controlled clinical trials.20 Notwithstanding the promising results from controlled trials, a large percentage of patients are inadequately responsive to either valproate or carbamazepine.

The two newest anticonvulsants that have shown initial promise in the treatment of bipolar disorder are lamotrigine and gabapentin. Lamotrigine appears to act by inhibiting the release of excitatory amino acids and by blocking sodium channels. Gabapentin’s mechanism of action, although unknown, may be related to its effect on GABA. Research on the mood-stabilizing effects of lamotrigine is quickly emerging from studies on bipolar depression.21,22 Additional trials are currently being conducted to examine the drug’s efficacy with rapid-cycling bipolar patients. Positive studies23,24 have been presented in bipolar depression and prevention of relapse in bipolar disorder. Gabapentin’s mood-stabilizing properties have been examined only in uncontrolled studies.22 As a whole, the preliminary evidence on both of these agents, when used alone or in combination with other agents, suggests they may benefit bipolar patients. Gabapentin’s low rate of side effects and interactions with other medications are especially encouraging.

Future treatments for bipolar disorder are likely to include newer anticonvulsants and atypical antipsychotics. Pregabalin, a gabapentin analogue, and topiramate, a sulfamate-substituted monosaccharide, are two of the newest agents currently under investigation in the treatment of both neurologic and psychiatric disorders. The atypical antipsychotic, olanzapine, has recently received FDA approval for the treatment of bipolar disorder. Other antipsychotics, such as risperidone, ziprasidone, and quetiapine, are currently under investigation for treating this disorder as well.


Psychotic Disorders

Schizophrenia is associated with hallucinations and delusions (positive symptoms) and apathy, anhedonia, and lack of motivation (negative symptoms). In treating the positive symptoms of acute schizophrenia, conventional antipsychotic agents have had unquestionable success. The negative symptoms of schizophrenia have been less responsive to these agents. Conventional antipsychotics show inefficacy, negative symptoms, and many side effects; this may explain the high incidence of treatment noncompliance and, thus, high relapse rate associated with this class of drugs.

A new era of antipsychotic treatment began with the release of the first atypical antipsychotic, clozapine, in 1990. Clozapine was demonstrated to be more effective than standard antipsychotics, especially with treatment-resistant schizophrenics, without causing tardive dyskinesia.25,26 The risk of agranulocytosis that is associated with clozapine prohibits its use as a first-line treatment. Nevertheless, a number of other second-generation antipsychotics that do not pose a risk of agranulocytosis, have received FDA approval since 1990 (Table 2). Controlled clinical trials suggest that these second-generation antipsychotics have two advantages over the earlier medications. First, atypical antipsychotics produce significantly fewer extrapyramidal adverse events than conventional neuroleptics.27-31 Second, the new agents seem to ameliorate the negative as well as the positive symptoms of schizophrenia.27-31 The primary clinical differences among these new agents are listed in Table 2.


The mechanism of action of atypical antipsychotics also differs from that of conventional antipsychotics. The new agents selectively block dopamine receptors and serotonin receptors with minimal effect on muscarinic or cholinergic receptors. Specifically, these agents tend to have high 5-HT2 and D2 receptor affinity ratios. In addition, they bind to a range of receptors, including 5- HT1A, D1, and D4 with varying degrees of intensity.

Other new antipsychotics with diverse mechanisms of action are in developmental stages. Aripiprazole is a presynaptic dopamine agonist and a postsynaptic D2 antagonist. Iloperidone and perospirone are serotonin-dopamine antagonists. Amisulpride is a selective D2/D3 receptor antagonist. Lastly, metabotropic glutamate receptor agonists are under investigation for treating psychosis.

The turn of the century marks an exciting era in the treatment of schizophrenia, with changes that parallel that of SSRI use in the treatment of depression. It is likely that some of these atypical antipsychotics will become first-line treatments because of their efficacy for both positive and negative symptoms of schizophrenia. Also, their superior side-effect profile, as compared with the side-effect profiles of conventional agents, may facilitate patient compliance, and thus, reduce relapse rates. Research has yet to confirm whether any of the new compounds will achieve the efficacy of clozapine in refractory patients. However, studies are under way to examine this.


Alzheimer’s Disease

AD is a prevalent progressive illness affecting memory and cognitive functioning. The incidence of senile dementia of the Alzheimer’s type (SDAT) is expected to reach 20 million by the year 2050. Currently, approximately 4 million Americans are diagnosed with SDAT. The cost of SDAT to society is approximately $90 billion annually, a figure that includes average nursing home rates ($36,000 per year) and average in-home costs ($18,000 per year) for these patients.

AD pathology is characterized by β-amyloid plaques and neurofibrillary tangles. Also, AD has been associated with a substantial decrease in cholinergic function. Evidence of acetylcholine (ACh) deficiency has been supported by various lines of research. Postmortem samples of AD patients have shown shortages of the cholinergic enzyme, choline acetyltransferase, and acetylcholinesterase.32 Drugs that block ACh have been shown to cause memory deficits in elderly patients.33 In addition, improvement in cognitive functioning has been observed with the use of cholinergic drugs and via stimulation of muscarinic and nicotinic cholinergic receptors.

Acetylcholinesterase inhibitors, the first agents developed for treating SDAT, have been studied extensively. These agents delay degradation of acetylcholine and, thus, potentiate cholinergic neurotransmission. Although cholinergic treatment probably does not alter the progression of neurodegeneration, it improves symptomatology, delays institutionalization, and reduces the costs of SDAT.34 Tacrine35 was the first inhibitor approved by the FDA in 1993. Initial enthusiasm for tacrine, the first cholinesterase inhibitor approved by the FDA in 1993,35 quickly waned because of the drug’s hepatotoxic effects and need for QID dosing. In 1996, donepezil gained FDA approval and became the drug of choice for SDAT. Donepezil’s favorable side-effect profile and once-per-day dosing appeal to both patients and physicians.36

A number of other cholinesterase inhibitors have been studied extensively. Rivastigmine, recently approved by the FDA, appears to be highly effective and lacks drug-drug interactions—perhaps because it does not interact with P456.37 Galanthamine has received FDA approval for marketing in the US.38 Metrifonate and eptastigmine, although extensively studied, have been withdrawn from consideration by the FDA because of reported adverse effects.

Other approaches to slowing degeneration of cholinergic cells in AD patients include the use of muscarinic agents, nicotinic agents, and nerve-growth factor. Muscarinic agonists, such as xanomeline, may delay cognitive deterioration.39 The neuroprotective properties of nicotine have been considered after a study found that smoking was inversely correlated with SDAT.40 Also, nerve-growth factor and other neurotrophins are currently being developed in hopes that they may retard the loss of cholinergic cells. Nerve-growth factor has been shown to increase acetylcholine and prevent cholinergic cell loss and atrophy.41

Evidence suggesting the presence of oxidative damage in AD has prompted research on the use of antioxidants with this population. It has been hypothesized that the increase in MAO-B activity (that is characteristic of AD) may cause an increase in oxidative deamination of monoamines. In turn, hydrogen peroxide and other free radicals may be formed and damage cells. Selegiline, an MAOI-B with antioxidant properties, and α-tocopherol (vitamin E) appear to benefit some AD patients.42 Ongoing research is examining the efficacy of other antioxidants in delaying the progression of SDAT.

Some researchers are examining the relationship between AD and inflammatory processes. Individuals taking nonsteroidal anti-inflammatory drugs (NSAIDs) have fewer cerebral microglia and are less likely to develop SDAT than are individuals who do not take NSAIDs.43,44 Agents with anti-inflammatory properties, including the new COX-2 inhibitors, are being examined for their ability to alter this abnormal inflammatory process. For example, estrogen has received attention for its anti-inflammatory, antioxidant, and antiapoptic effects.45 Despite its initial promise, a recent multisite trial found no evidence that estrogen slows the progression of SDAT.46 Another putative antioxidant and anti-inflammatory agent, ginkgo biloba, has been associated with small improvements in cognitive functioning in AD patients.47

Two of the newest treatment approaches are targeting the amyloid plaques that characterize the brains of AD patients. β- and γ-secretase inhibitors are currently in phase II-A trials with the hope that they will inhibit amyloid plaque formation. Also, a vaccine consisting of AN-1792, a synthetic form of the primary component of amyloid plaques, is now in phase I trials. Immunization with this vaccine may remove existing amyloid plaques and prevent the formation of new plaques.

Another direction for the treatment of SDAT involves N-methyl-D-aspartate (NMDA) antagonists. Preliminary data suggests that NMDA antagonists, such as memantine, may slow cognitive deterioration in AD patients.48

Other potentially important neurotransmitters involved in SDAT include CRF1, somatostatin, NE, 5-HT, dopamine, and GABA. The relationship between these neurotransmitters and the cognitive deficits observed in AD patients has not yet been fully described. Catecholamine abnormalities may contribute to the behavioral disturbances observed in AD patients. A broad range of psychotropic medications (including SSRIs, benzodiazepines, antipsychotics, and anticonvulsants) has been used in the treatment of behavioral disturbances (eg, depression, agitation, aggression, insomnia, psychosis) that may accompany cognitive deficits.

At present, there are two different approaches to the treatment of SDAT under investigation. The use of cholinesterase inhibitors, muscarinic agonists, SSRIs, benzodiazepines, and antipsychotics is directed at symptomatic relief. Structural changes aimed to delay disease progression are being attempted with agents such as antioxidants, NSAIDs, NMDA antagonists, and secretase inhibitors. Future investigators are likely to examine the efficacy of combining these agents to achieve symptomatic and structural benefits.



Buoyed by the discovery of better psychotropic drugs, the search to maximize desired effects and minimize side effects in new compounds is in high gear. Appreciation of both the multiple subtypes of receptors and the complicating effects of active metabolites is leading to more sophisticated and specific approaches to drug design and preclinical testing. The last decade of drug development in psychiatry has been very productive for new drug approvals and the next decade will likely offer equal or even greater breakthroughs. The areas discussed (major depression, anxiety disorders, bipolar disorder, psychotic disorders, and AD) give the clinician a glimpse of the potential of newer drugs still in development.   PP



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34.    Tune LE, Sunderland T. New cholinergic therapies: treatment tools for the psychiatrist. J Clin Psychiatry. 1998;59(suppl 13):31-35.
35.    Conway EL. A review of the randomized controlled trials of tacrine in the treatment of Alzheimer’s disease: methodologic considerations. Clinical Neuropharmacol. 1998;21:8-17.
36.    Doody RS. Clinical profile of donepezil in the treatment of Alzheimer’s disease. Gerontology. 1999;45(suppl 1):23-32.
37.    Forette F, Anand R, Gharabawi G. A phase II study in patients with Alzheimer’s disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon). European J Neurology. 1999;6:423-429.
38.    Rainer, M. Galanthamine in Alzheimer’s disease: A new alternative to tacrine? CNS Drugs. 1997;7:89-97.
39.    Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord. 1997;11(suppl 4):S16-S22.
40.    Ulrich J, Johannson-Locher G, Weiler WO, Stahelin HB. Does smoking protect from Alzheimer’s disease? Alzheimer-type changes in 301 unselected brains from patients with known smoking history. Acta Neuropathol (Berl). 1997;94:450-454.
41.    Holtzman DM, Li Y, Chen K, Gage FH, Epstein CJ, Mobley WC. Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration. Neurology. 1993;43:2668-2673.
42.    Sano M, Ernesto C, Thomas RC, et al. A controlled trial of selegeline, alpha-tocopherol or both as treatment of Alzheimer’s disease. N Engl J Med. 1997;336:1216-1222.
43.    Mackenzie IR, Munoz DG. Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology. 1998;50:986-990.
44.    Breitner JCS, Welsh KA, Helms MJ, Gaskell PC, et al. Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995;16:523-530.
45.    Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998;4:447-451.
46.    Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54:295-301.
47.    Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol. 1998;55:1409-1415.
48.    Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999;14:135-146.

Mr. Voelz is a PhD candidate in the Department of Psychology at Florida State University in Tallahassee.

Dr. Joiner is the Bright-Burton Professor of Psychology and director of the University Psychology Clinic in the Department of Psychology at Florida State University.

For information on measures which assess negative and positive affectivity (ie, Positive and Negative Affect Schedule), and physiological hyperarousal (ie, Beck Anxiety Inventory), contact Thomas Joiner (joiner@psy.fsu.edu).

Acknowledgments: The authors report no financial, academic, or other support of this work.



With sound theory and demonstrated validity, the Tripartite Model of Anxiety and Depression has been shown to enhance conceptualization of anxious and depressive symptomatology, leading to more reliable assessment and diagnosis of depressive disorders among adolescents and adults in clinical, community, and college samples. It is suggested that the attendant measurement techniques of negative and positive affectivity (ie, Positive and Negative Affect Schedule) and physiological hyperarousal (ie, Beck Anxiety Inventory) be incorporated into standard assessment protocol as quick, convenient, and reliable methods of screening patients for anxiety, depression, and comorbid anxiety and depression.  Improved identification and conceptualization of presenting depressive and anxious symptomatology will lead to more accurate patient diagnoses which, in turn, will lead to implementation of the most appropriate and effective treatment for a given disorder.



Mood disorders are the most common mental disorders treated by psychiatrists, comprising 28% of overall psychiatric visits.1 This standing is unlikely to change, as the incidence of depression in the general population appears to be steadily increasing.2  Prevalence rates for major depressive disorder have been estimated at 20% to 25% for women and 9% to 12% for men, with women experiencing major depression twice as often as men.3 Notably, these prevalence rates and gender differences appear to persist across the adult life span. As the risk for depression continues to grow, researchers have also found the age of onset to be steadily decreasing,4 thus directing attention toward an increasingly vulnerable and potentially undertreated population—adolescents. As is true with adults, the occurrence of depressive disorders among adolescents is common (lifetime incidence is 20% or greater), costly (for both patients and healthcare providers), persistent (the average episode length is 8 months), recurrent (single episodes are very rare, if they exist at all), and relapsing (75% to 80% of patients will relapse prior to complete symptom remission). It is thus crucial that mental health providers be competent in their ability to clearly identify presenting depressive symptomology, make reliable clinical diagnoses, and implement the most appropriate and effective treatment for any given depressive disorder among both adults and adolescents.


The Tripartite Model

Logically, effective treatment of depression depends largely upon the accurate identification and conceptualization of presenting symptomology, which then leads to a treatment-directing clinical diagnosis. It is thus assumed that more accurate conceptualizations of symptoms will ultimately lead to more effective treatment. The Tripartite Model of Anxiety and Depression5 may serve such a purpose. Developed by Clark and Watson, the model proposes that anxiety and depressive disorders have shared and specific components. More explicitly, it suggests that pure anxiety and depression overlap considerably through a general, nonspecific factor called negative affectivity (NA), which reflects the level of averse feelings within an individual. For example, low NA corresponds to a state of calmness and serenity, whereas high NA includes mood states such as anger, contempt, disgust, fear, and nervousness.6 However, there are areas of differentiation between anxiety and depression. The remaining two factors of this model are positive affectivity (PA), which, when low, is relatively specific to depression and represents the level of pleasant feelings within an individual—eg, interest, enthusiasm, delight, and excitement,—and physiological hyperarousal (PH)—eg, heart pounding, shortness of breath, trembling or shaking hands, dizziness, dry mouth, and lightheadedness—which is relatively specific to anxiety.

To sum up, the Tripartite Model of Anxiety and Depression proposes the following:

(1) Anxiety is characterized by high NA and high PH;
(2) Depression is characterized by high NA and low PA (feelings of anhedonia); and
(3) Comorbid anxiety and depression is characterized by high NA, low PA, and high PH.

In support of this model, a large body of research has validated these three factors in child, adolescent, and adult samples.7-11

How has the conceptualization of these three factors been integrated with, and useful to, existing research on depression? Importantly, the conceptualization of depressive symptomology based on the tripartite model has shed light on the long-asserted existence of gender differences among depressed adolescents. A consistent finding over the past few decades is that approximately twice as many adolescent girls are depressed as adolescent boys,12 a finding that parallels the gender differences found in depressed adults.13

What might account for the gender difference observed in clinical depression? While some have suggested that the gender difference results from greater recurrence of depression among girls,14 others have suggested that girls simply experience twice the number of new depressive cases when compared to boys.12 However, Joiner, and colleagues15 applied the conceptualization of the tripartite model (ie, measuring levels of NA, PA, and PH) to a sample of depressed adolescent inpatients, and produced intriguing preliminary results that may elucidate prior questions and inconsistencies regarding the debate over gender differences. They found that previously asserted gender differences do not exist among adolescents with pure depression (high NA, low PA). Rather, they found that girls with depressive symptoms were far more likely to have comorbid anxious symptoms (+high PH) than boys with depressive symptoms. Thus, prior research examining potential gender differences may not have differentiated between pure forms and comorbid forms of depressive and anxious psychopathology. The findings of Joiner and colleagues support the emerging view that generalized negative affect and PH (the two tripartite components that represent pure anxiety when elevated) are important in understanding gender differences in depression (for similar findings among adult samples, see Joiner and Blalock,16 Ochoa and colleagues,17 and Romanoski and colleagues18).

Not only have the components of the tripartite model (ie, NA, PA, and PH) been shown to be associated with self-report measures of anxiety and depression, they have also been shown to be closely related to physiological measures in recent research examining differential brain activity in anxious and depressed individuals. For example, in 1995, Heller and colleagues19 found that individuals with high levels of anxiety exhibited increased right parietotemporal activity compared to individuals with low levels of anxiety. In contrast, individuals with high levels of depression exhibited reduced right parietotemporal activity compared to individuals with low levels of depression (for similar findings, see Keller and colleagues20). Recently, Voelz and colleagues21 extended these findings by providing evidence for a longitudinal relationship between patterns of right posterior brain activity and the components of the tripartite model. Accordingly, they found that the level of right posterior brain activity successfully predicted future levels of PH (anxiety) and PA (depression) such that increased right posterior activity was associated with increased anxiety (including the specific component of PH) while decreased right posterior activity was associated with decreased PA.

Recent studies have also demonstrated that PA appears to be related to the left frontal region of the brain.  More specifically, while increased left frontal activity is associated with increased PA (hence, less depressive symptomology22,23), decreased left frontal activity is associated with decreased PA (hence, increased depressive symptomology24,25). Davidson and colleagues26 recently replicated the reported association between PA and left frontal brain activity and further reported that decreased activity in the left frontal region (and thus low PA) appears to also be related to decreased immunological functioning in humans. This finding is consistent with prior investigations that have found levels of PA and NA to be associated with quality of self-reported health. More specifically, high levels of NA and low levels of PA, appear to be independently related to poorer health conditions.27-30 In summation, research has invaluably strengthened the external validity of the tripartite model while concurrently expanding our knowledge of depressive phenomena through its own application, by uncovering intriguing relationships between NA, PA, PH, regional brain activation, and personal health.


Improved Assessment and Treatment of Depression

With sound theory and demonstrated validity, the tripartite model has been shown to enhance our conceptualization of anxious and depressive symptomology, leading to more reliable assessment and diagnosis of depressive disorder among adolescents and adults in clinical, community, and college samples. To further explain, let us revisit the findings of past research that has found that twice as many females experience depression as males. Most of these studies involved clinical populations that were diagnosed using standard screening and assessment procedures within hospitals and other public mental health facilities.

With this in mind, recall the recent findings of Joiner and colleagues,11 which, using the tripartite factors of NA, PA, and PH to assess adolescent patients, found that there were no gender differences among pure depressives. In fact, the 2:1 gender difference held only when patients with comorbid anxiety and depression were included in the sample (not just pure depressives), in which case there were many more females. The alarming aspect of this observation is that thousands of individuals (twice as many females as males) had passed through “standard” assessment procedures within community hospitals and mental health facilities without being identified as comorbid for depression and anxiety. Why is this so alarming? Research has shown that outcome effects and long-term prognosis are affected by the presence of more than one disorder.31,32 Likewise, comorbidity often serves as a moderator of treatments for which evidence continues to emerge.33

Whether pharmacologic or psychosocial in nature, mental health treatment varies as a function of pure depression, pure anxiety, and comorbid depressive-anxiety conditions. Failing to identify the comorbid status of depressed patients makes it unlikely that they will receive the most appropriate and effective treatment for their true condition. Administering less than optimal treatment because of this unfortunate oversight can lead to increased persistence of depressive episodes, increased recurrence, increased rates of relapse, and higher overall costs of health care. Clearly, the oversight of comorbid diagnostic status, particularly those concerning comorbid depression and anxiety, may result in negative consequences that are self-defeating to healthcare providers and consumers. With this in mind, it is enlightening that utilization of the tripartite model within our assessment protocol can help in identifying pure and comorbid forms of depression and anxiety.

How is the tripartite model easily incorporated into a clinical setting, and how are its three factors measured? Instrumentation and norms for the assessment of PA and NA are in place, and are available from current research literature. The quickest, simplest, and most widely researched assessment measure is the Positive and Negative Affect Schedule (PANAS), by Watson, Clark, and Tellegen.34 While other measures exist which appraise PA and NA, the PANAS is perhaps the only such scale that has demonstrated discriminant validity with comorbid anxiety and mood disorders among adolescents and adults. The scale was originally developed in connection with basic research on the nature and structure of human emotion.

The PANAS includes two 10-item scales, one for PA (items include interested, active, excited, attentive) and one for NA (items include nervous, irritable, distressed, jittery). Each item is rated on a scale of 1–5 (1=very slightly or not at all; 5=extremely); patients rate items based on how self-descriptive they are. Scores are derived by tallying item ratings separately for the NA and PA items. Thus, scores for PA and NA can each range from 10–50. The completion of the scale, as well as its scoring and interpretation, are quite brief—the entire process takes approximately 5 minutes. The scale is self-explanatory, and thus can easily be administered by anyone in the medical office (eg, clerical staff, nursing staff). Measurement techniques for the third component of the tripartite model—PH—are less well developed. The best available strategy is to use a current scale, such as the Beck Anxiety Inventory (BAI)3—a 21-item self-report inventory that assesses general symptoms of anxiety. For the purpose of measuring the tripartite component of PH specifically, particular emphasis would be placed on the somatic or physiological items of the BAI.35



The Tripartite Model of Anxiety and Depression5 has allowed mental health professionals to more accurately conceptualize the development and presentation of depressive symptomology and its relationship to anxiety among adolescents and adults. As illustrated above, utilization of the tripartite conceptualization (ie, examining factors of NA, PA, and PH) within current depression research has led to new insight regarding the nature of current depressive phenomenology (eg, gender differences, regional patterns of brain activation, and personal health). It is further suggested that the attendant measurement techniques of NA (ie, PANAS), PA (ie, PANAS), and PH (ie, BAI) be incorporated into standard assessment protocol as quick, convenient, and more reliable methods of screening patients for pure anxiety, pure depression, and comorbid anxiety and depression.  Improved identification and conceptualization of presenting depressive and anxious symptomology may lead to more accurate patient diagnoses which, in turn, will lead to implementation of the most appropriate and effective treatment for a given disorder.   PP



1.    Maxmen JS, Ward NG. Essential Psychopathology and Its Treatment. 2nd ed. New York, NY: WW Norton & Company; 1995:206-243.
2.    Lewinsohn PM, Rohde P, Seeley JR, Fischer SA. Age-cohort changes in the lifetime occurrence of depression and other mental disorders. J Abnorm Psychol. 1993;102:110-120.
3.    Antonuccio DO, Danton WG, DeNelsky GY, Greenberg RP, Gordon JS. Raising questions about antidepressants. Psychother Psychosom. 1999;68:3-14.
4.    Weissman MM, Bruce ML, Leaf PJ, Florio LP, Holzer C. Affective disorders. In: Robins LN, Regier DS, eds. Psychiatric Disorders of America:  The Epidemiologic Catchment Area of Study. New York, NY: Free Press; 1991:53-80.
5.    Clark LA, Watson D. Tripartite model of anxiety and depression: psychometric evidence and taxonomic implications. J Abnorm Psychol. 1991;100:316-336.
6.    Watson D, Clark LA, Carey G. Positive and negative affectivity and their relation to anxiety and depressive disorders. J Abnorm Psychol. 1988;97:346-353.
7.    Brown TA, Chorpita BF, Barlow DH. Structural relationships among dimensions of the DSM-IV anxiety and mood disorders and dimensions of negative affect, positive affect, and autonomic arousal. J Abnorm Psychol. 1998;107:179-192.
8.    Chorpita BF, Albano AM, Barlow, DH. The structure of negative emotions in a clinical sample of children and adolescents. J Abnorm Psychol. 1998;107:74-85.
9.    Joiner Jr TE. A confirmatory factor-analytic investigation of the tripartite model of depression and anxiety in college students. Cognit Ther Res. 1996;20:521-539.
10. Joiner Jr TE, Catanzaro SJ, Laurent J. The tripartite structure of positive and negative affect, depression, and anxiety in child and adolescent psychiatric inpatients. J Abnorm Psychol. 1996;105:401-409.
11.    Joiner Jr TE, Steer RA, Beck AT, Schmidt NB, Rudd MD, Cantanzaro SJ. Physiological hyperarousal: construct validity of a central aspect of the tripartite model of depression and anxiety. J Abnorm Psychol. 1999;108:290-298.
12.   Hankin BL, Abramson LY, Moffitt TE, Silva PA, McGee R, Angell KE. Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study. J Abnorm Psychol. 1998;107:128-140.
13.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:317-391.
14.    Amenson CS, Lewinsohn PM. An investigation into the observed sex differences in prevalence of unipolar depression. J Abnorm Psychol. 1981;90:1-13.
15.    Joiner Jr TE, Blalock JA, Wagner KD. Preliminary examination of gender differences in depressive symptoms among adolescent psychiatric inpatients: The role of anxious symptoms and generalized negative affect. J Clin Child Psychol. 1999;28:211-219.
16.    Joiner TE Jr, Blalock JA. Gender differences in depression: the role of anxiety and generalized negative affect. Sex Roles. 1995;33:91-108.
17.    Ochoa L, Beck AT, Steer RA. Gender differences in comorbid anxiety and mood disorders. Am J Psychiatry. 1992;149:1409-1410.
18.    Romanoski AJ, Folstein MF, Nestadt G, et al. The epidemiology of psychiatrist-ascertained depression and DSM-III depressive disorders. Results from the Eastern Baltimore Mental Health Survey Clinical Reappraisal. Psychol Med. 1992;22:629-655.
19.    Heller W, Etienne MA, Miller GA. Patterns of perceptual asymmetry in depression and anxiety: implications for neuropsychological models of emotion and psychopathology. J Abnorm Psychol. 1995;104:327-333.
20.    Keller J, Nitschke JB, Bhargava T, et al. Neuropsychological differentiation of depression and anxiety. J Abnorm Psychol. 2000;109:3-10.
21.    Voelz ZR, Gencoz F, Gencoz T, Pettit JW, Perez M, Joiner TE Jr. Patterns of hemispheric perceptual asymmetries: left-hemispatial biases predict changes in anxiety and positive affect among undergraduate women. Emotion. 2000;1:339-347.
22.    Jacobs GD, Snyder D. Frontal brain asymmetry predicts affective style in men. Behav Neurosci. 1996;110:3-6.
23.    Tomarken AJ, Davidson RJ. Frontal brain activation in repressors and nonrepressors. J Abnorm Psychol. 1994;103:339-349.
24.    Allen JJ, Iacono WG, Depue RA, Arbisi P. Regional electroencephalographic asymmetries in bipolar seasonal affective disorder before and after exposure to bright light. Biol Psychiatry. 1993;33:642-656.
25.    Henriques JB, Davidson RJ. Regional brain electrical asymmetries discriminate between previously depressed and healthy control subjects. J Abnorm Psychol. 1990;99:22-33.
26.    Davidson RJ, Coe CC, Dolski I, Donzella B. Individual differences in prefrontal activation asymmetry predict natural killer cell activity at rest and in response to challenge. Brain Behav Immun. 1999;13:93-108.
27.    Costa Jr PT, McCrae RR. Hypochondriasis, neuroticism, and aging: when are somatic complaints unfounded? Am Psychol. 1985;40:19-28.
28.    Costa Jr PT, McCrae RR. Neuroticism, somatic complaints, and disease: is the bark worse than the bite? J Pers. 1987;55:299-316.
29.    Dua JK. Comparative predictive value of attributional style, negative affect, and positive affect in predicting self-reported physical health and psychological health. J Psychosom Res. 1994;38:669-680.
30.    Watson D, Pennebaker JW. Health complaints, stress, and distress: exploring the central role of negative affectivity. Psychol Rev. 1989;96:234-254.
31.    Harrington R, Fudge H, Rutter M, Pickles A, Hill J. Adult outcomes of childhood and adolescent depression. II: links with antisocial disorders. J Am Acad Child Psychiatry. 1991;30:434-439.
32.    Kazdin AE, Crowley M. Moderators of treatment outcome in cognitively based treatment of antisocial children. Cognit Ther Res. 1997;21:185-207.
33.    Kazdin AE, Weisz JR. Identifying and developing empirically supported child and adolescent treatments. J Consult Clin Psychol. 1998;66:19-36.
34.    Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS Scales. J Pers Soc Psychol. 1988;54:1063-1070.
35.    Beck AT, Epstein N, Brown G, Steer R. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56:893-897.

Dr. Blaine is assistant professor in the Department of Family and Community Medicine at the University of Toronto in Canada and researcher at the Mount Sinai Hospital Family Medicine Genetics Program in Toronto. He is also a family physician in Stratford, Canada.

Dr. Carroll is associate professor and Sydney G. Frankfort Chair in Family Medicine in the Department of Family and Community Medicine at the University of Toronto, and researcher at the Mount Sinai Hospital Family Medicine Genetics Program.

Dr. Esplen is a scientist at the National Cancer Institute of Canada (NCIC). She is also head of the program of psychosocial and psychotherapy research in cancer genetics in the Department of Psychiatry at Mount Sinai Hospital in Toronto, Canada, and assistant professor in the Departments of Psychiatry and Nursing at the University of Toronto.

Acknowledgments: Drs. Blaine and Carrol have received financial support from the Imperial Oil Charitable Foundation. Dr. Esplen received support from career scientest award granted to her from the NCIC. 



What is the role of the primary care physician (PCP) in managing patients at risk for familial cancer? The current interest, knowledge, and attitudes of both patients and physicians relating to genetics serve to highlight the importance of a key role for PCPs managing patients who may be genetically susceptible to cancer. Unfortunately, the knowledge and confidence to actively engage in genetic counseling and discussions of the psychosocial issues relating to predictive genetic testing are often lacking in primary care. The PCP’s role in cancer genetics is an extension of his/her previously established screening, risk assessment, and supportive counseling skills. Both innovative and traditional models may be applied to enable the physician’s role in the provision of primary care genetic services.


Introduction: The Challenge

The pace of discovery resulting from the Human Genome Project has accelerated our understanding of the genetic contributions to health and disease. While many hope that unraveling the inherited predispositions to disease may promote evidence-based individualized treatment and prevention strategies, others suggest that we retain a healthy skepticism regarding the promise of these new technologies.1 Some are even concerned that the results of predictive genetic testing may lead to fatalism and a sense that some diseases are uncontrollable, thus adversely affecting motivation to change.2

Regardless of the ultimate impact of genetics on medicine, primary care physicians (PCPs) will serve an increasingly important role in managing patients and families at increased genetic risk for these common diseases.3 The question is whether or not PCPs are prepared for this responsibility.4 This article will explore the challenges of integrating cancer genetics into primary care, highlight issues facing both patients and providers, and review the role of the PCP in this area with special emphasis on psychosocial issues.

Patient Interest, Knowledge, and Attitudes Regarding Genetics

A recent survey conducted by the American Medical Association (AMA) found that among Americans, if a known genetic disorder were present in the immediate family, 71% would most likely consult their PCP to learn about the possibility of inheriting the condition.5 In two surveys of women in the general population, 82% to 90% expressed interest in testing to detect a genetic susceptibility to breast cancer.6,7 In another study, only 43% of family members with BRCA1-linked hereditary breast/ovarian cancer requested results when offered genetic testing.8 More interest is expressed in genetic tests for which a proven intervention is available to either prevent or treat the disease.9 Motivations for testing include desire to reduce uncertainty about risk, participate in research, learn about risk for offspring, learn about other associated risks, explore further surveillance options, and make child-bearing and marital decisions.10

The public has a variable and in some cases extremely limited understanding of genetics. One public survey in the United Kingdom (UK) revealed that one in five people were unable to say what the terms “genetics” or “genetic information” meant to them.11 Studies have shown that patients dislike the uncertainty inherent in the probabilistic risk information associated with predictive testing and find challenges in comprehending risk information.12 There appears to be a complex interplay among the variables of perceived risk, anxiety, and surveillance behaviors. For example, women with just one first-degree relative with breast cancer may overestimate their own risk of cancer. Studies have shown that this overestimation is profound and difficult to modify and that psychological factors (eg, anxiety, feelings of loss) may impede risk comprehension and surveillance behaviors.13-16

A major public consultation11 on the future use of personal genetic information in the UK revealed broad support for the responsible use of human genetic information, especially with regard to improving diagnosis of disease, determining who is at risk of inheriting common diseases, and developing treatment for genetic disorders. However, some felt that human genetics research amounted to unethical tampering with nature. A recent survey of the Canadian public revealed that 91% felt it was acceptable to use genetic testing to determine the risk of transmitting disease to one’s children.17

In the United States, the Secretary’s Advisory Committee on Genetic Testing was chartered to advise on the medical, scientific, ethical, legal, and social issues raised by the development and use of genetic tests. Many public comments expressed concern about the potential use of genetic test results to discriminate against people in such areas as employment and health insurance. Education and counseling resources to facilitate informed decision-making regarding genetic testing were recommended.9


Knowledge and Attitudes of PCPs Regarding Genetics

Several studies have highlighted the limited knowledge of PCPs in the provision of genetic services in clinical practice.3,18-20 Most physicians agree that they have a role to play in genetic susceptibility screening, but also have concerns including the cost of testing, testing for diseases for which there is no effective treatment, the use of genetic tests by insurance companies, and the challenge of communicating risk to patients.21 Physicians have expressed a reluctance to adopt genetic tests because of questionable clinical validity and utility, and perceive a more practical importance of these tests in the future rather than in the present.22 They are concerned about alarming their patients, the majority of whom will see no health gain from genetic testing.23


Psychosocial Issues Associated With Having a Family History of Cancer

Individuals with a family history of cancer frequently believe that they are at high risk for the disease, even when that may not be the case. Elevated risk perceptions are often associated with high levels of psychosocial distress or anxiety.13-15 Individuals who experience elevated risk perceptions feel vulnerable to cancer and often suffer intrusive thoughts about the disease threat.13,15 They may not be reassured by the provision of a negative test result or with accurate risk information. These individuals often require psychosocial interventions to address associated psychological factors, such as previous losses or caregiving experiences around a family member’s cancer.14,16

The interplay between perceived risk and anxiety is important in considering disease-screening behaviors. Studies on surveillance indicate that a minimum level of distress and anxiety is necessary for attendance to a screening program, but if anxiety exceeds a certain level it can have a negative influence on surveillance adherence.13,15 Some individuals feeling a threat of disease may adopt a denial coping strategy, resulting in noncompliance or delay.24,25 Similarly, levels of anxiety and concern influence the adoption of lifestyle changes and other health behaviors. Hypervigilance in the form of seeking out additional health information to alleviate concerns about risk is a common response to elevated risk perception.26 Factors in the literature that have been identified to be associated with an overestimation of risk and distress include having a family history of disease, beliefs about the disease and risks, lower educational level (specifically being uninformed about genetics and disease), prior loss of a family member to cancer, identification with a family member, and media attention surrounding cancer risk.13,14,16,27-29

Risk information contains probabilities and doubts that may lead to confusion. In addition, genetic information can be an existential threat to the individual and his/her family members. Risk information can not only arouse fears about developing the disease, but feelings of anger towards those who transmitted the disease and guilt about the potential transmission of the genes to offspring.24 Such reactions have potential for influencing the person’s well-being and relationships with family members, which in turn can interfere with the process of notification of a genetic mutation to family members who may be at risk.30

Individuals pursuing genetic testing in cancer are often confronted with additional difficult decisions. Any test result that brings forward serious and difficult decisional options can pose additional psychological burden. Examples include decision-making around current prevention and treatment options (eg, increased surveillance, prophylactic surgery, chemoprevention), test result notification to extended family members and offspring, and relationship decisions (eg, marriage, childbearing).25

Relationships among siblings, parents, offspring, and partners can be complicated by the pursuit of genetic testing and results. For example, some individuals found not to carry a known gene mutation in the family may experience “survivor guilt” and feelings of rejection by their families when they find that they no longer have a key bond that previously tied them together.24,25 Sometimes families attempt to protect a family member through nondisclosure of familial cancer information, which can pose difficult and challenging ethical dilemmas for a PCP managing the health care of different family members.

The literature is beginning to pinpoint factors that may be helpful in identifying the group of individuals who may have more difficulty in the genetic and risk counseling process. These include previous familial experience of the disease, the amount of loss in the family, perceived current threat to the individual, proximity in age to the time of diagnosis of a relative who previously dealt with the disease, the expectation of receiving an unfavorable result, the amount of social support and coping style (anxious preoccupied style), and a premorbid psychological history.13,25,29,31,32

Recent studies indicate that 20% to 25% of individuals eligible for genetic testing experience distress in the clinical ranges for depression and anxiety.33-35 Baseline distress is highly predictive of post-test adjustment,33-35 suggesting the need for psychosocial screening at the time of pretest.


The Evolving Role of PCPs in Cancer Genetics

Media hype and direct marketing of genetic tests will likely increase awareness of the significance of a family history of cancer among the public. PCPs will therefore have a vital role in educating their patients about the genetic risk of cancer, often to reassure those at low risk for whom genetic testing is not warranted. Such counseling can readily be provided within the existing framework of primary care and need not require specialized skills.36 The problem is that only 5% to 10% of all breast, ovarian, and colorectal cancers are considered inheritable, with little evidence for risk-reduction strategies. Genetic risk information has yet to change behavior any more than nongenetic information.37 For these reasons, some have argued that routine family history screening of symptom-free patients to document cancer does not meet the criteria for a screening test.38

PCPs cannot be expected to take on the expert role of a clinical geneticist, but rather they should incorporate key elements of genetics into everyday primary care practice.36 Greater awareness of the potential impact of genetics in primary care may allow PCPs to more consistently recognize clues to a genetic condition, use the family history to perform a genetic risk assessment, identify those at increased psychosocial risk related to their genetic history, provide or refer the patient for psychosocial support, and ultimately facilitate informed choice regarding subsequent health decisions (Table).


Taking a Family History

PCPs have many opportunities to ask about family history: new patient encounters, periodic health examinations, and even during episodic visits for those who rarely frequent the clinic. A recent study using direct observation of patient visits found that family physicians discussed family history during only half of new patient visits.39 PCPs should be aware of the potential limitations of family history information as reported by patients, such as use of incorrect or lay terminology, uncertainty regarding the type of primary cancer affecting a relative, and age at diagnosis.

Although a three-generation family history or pedigree may be ideal, simple tools may assist clinicians in capturing important elements of a cancer family history. Computerized patient-administered family history-taking tools have been developed; they are currently being evaluated and may facilitate the task of systematically organizing this information.40,41

Genetic Risk Assessment

Once a family history of cancer has been identified, risk assessment tools and/or guidelines may be used to identify patients at increased risk for the disease. For some of these cases, genetic testing will distinguish between the family members truly at high risk (carriers, positive for a known family mutation) who may benefit from increased surveillance or prevention strategies versus those family members at low risk (negative for a known family mutation), who may revert to population-based screening recommendations despite their alarming family history.42 PCPs need to recognize the patients who may benefit from specialized genetics services43 as well as those patients whom they feel can manage themselves. The more common role for the PCP will likely be to provide reassurance, counseling, and support to patients with low-risk cancer family histories—situations where referral and testing are not indicated.

Counseling About Genetic Testing

In some situations, counseling may only entail the provision of basic genetics information to help with informed decision-making.43 In other situations, these discussions may be followed by referral to genetics clinics44 and/or involve psychosocial counseling to address any psychological concerns and symptoms. Benefits of genetic testing include reassurance for those found to be negative for a cancer susceptibility gene mutation or, if testing is positive, the opportunity for increased surveillance or prophylactic treatment or surgery.

Risks of knowing genetic information, particularly a positive genetic test for cancer susceptibility, are numerous. Concerns have been raised about privacy and discrimination issues related to employment and insurance. A recent systematic review31 of the psychological consequences of predictive genetic testing reported that the majority of both carriers and noncarriers showed decreased distress after testing. However, a significant number of individuals do experience difficulty in adjusting to their test results. Pretest emotional state was predictive of subsequent distress, suggesting that individuals at psychological risk undergoing genetic testing be identified beforehand so that post-test supportive care can be targeted at those in need.31

Not all carriers will develop cancer, but if they do, the age of onset is unknown. This uncertainty may lead to fear or anxiety. Some family members may not want to know about their risk and this can pose challenges to family dynamics. Carriers may feel guilty for passing on a genetic mutation to children, which ultimately may impact on family relationships. When such psychological factors are identified, psychosocial counseling or a mental health referral may be required. Those who test negative for the family’s mutation may experience “survivor guilt.”44

Offering Genetics Referral

Patients assessed as being at high risk for hereditary cancer by their PCP should be offered referral to a genetics center or familial cancer clinic for further counseling and consideration of genetic testing. Patients must understand that a genetics referral does not necessarily imply that genetic testing will be offered after further details of the family history are obtained. Some patients may not meet high-risk referral criteria and yet still have a cancer family history that is clearly not low risk. Although perhaps not eligible for genetic testing, such moderate risk patients may still be offered referral to a genetics center for further information and/or to a mental health specialist for counseling depending on the nature and severity of their distress. PCPs may help prepare referred patients by explaining the genetics consultation process and the role that specific psychological issues may play in decisions for themselves and their families.

Treatment and Surveillance

At present, recommendations for the treatment and surveillance of carriers of cancer susceptibility genes are based mainly on expert opinion. PCPs, with the help of genetic specialist colleagues, will need to discuss treatment and management options with these patients. They can assist patients in making informed choices based on available information, family concerns, and psychosocial health. This is a most challenging task given the variability of evidence for surveillance recommendations, chemoprevention, and prophylactic surgery. Uncertainty and potential costs and side effects associated with preventive options can result in added psychological burden. For example, while women at high risk for breast and ovarian cancer are strongly motivated to take action to reduce their risk and may consider prophylactic surgery, they must weigh these decisions against the consequences of surgery, such as premature menopause. These can be challenging decisions for women who are currently healthy.

Long-Term Care

PCPs often provide continuity of care to patients and families for a comprehensive range of health services over many years. Patients and their families found to be at high risk for familial cancer may return to consult the same provider long after a genetic risk was first identified. Whether or not these individuals underwent genetic testing or even received informative test results, they will no doubt require ongoing routine medical care, with special attention drawn to the psychosocial impact of their known familial cancer susceptibility. In addition, challenges can occur around family dynamics (eg, disclosure). Individuals sometimes try to protect others in the family from worrying about a cancer risk through nondisclosure. They also grapple with the question of when and how to tell offspring about risk.45 These patients will require counseling regarding newly discovered clinically-relevant predictive, diagnostic, and/or therapeutic technologies that may impact upon their previously assigned genetic predisposition. PCPs can be supportive in assisting other family members to consider testing, by providing disclosure plans, and treatment options.

Meeting the Challenge

Will PCPs be able to fill the following roles: taking a comprehensive family history, genetic risk assessment, provision of genetics information, appropriate genetics referral, genetic testing, assessing and managing psychosocial issues, and formulating and coordinating individualized management plans? Some have expressed concern that PCPs may be too directive in their counseling21,46 and may lack the knowledge and skills required.43,47 Others cite time, money, and legal and ethical concerns as barriers to primary care involvement in genetics.47 However, direct marketing pressures and media hype may make PCPs the initial point of contact for many patients seeking information about genetic testing and inherited cancers.48 Some argue that PCPs are ideally suited to guide their patients through the decision-making process of genetic assessment and testing44 while at the same time addressing psychological and social issues. Such a role is indeed an extension of the well-established experience of PCPs in screening and risk assessment in primary care.36

Enabling a Role for PCPs in Cancer Genetics

Awareness of the potential scope and limitations of genetic technologies is necessary if PCPs are to become more involved in the delivery of genetic services. Several groups have developed comprehensive core competencies of genetics education for health professionals.49 These guidelines may assist health disciplines in modifying genetics curricula and create providers competent in genetics service delivery at the primary care level.

Innovative educational strategies must target PCPs currently in active practice as well as those in training programs. In the US, Genetics in Primary Care (GPC): A Faculty Development Initiative targets family medicine, general internal medicine, and general pediatrics to plan, implement, and evaluate outcomes of primary care training programs in genetics.50 Both traditional and creative models may help to translate relevant genetic knowledge into practical applications for primary care. Efficient, organized, clear, and simple protocols to obtain, evaluate, and act on family history information will need to be developed to take advantage of this powerful clinical tool.39 Linking PCPs with clinical genetics nurse specialists may facilitate the screening of genetic problems in primary care settings.51 Collaborative practice-based research networks may be used to foster PCP involvement in clinical research on genetic tests, perhaps even serving as an educational outlet for some of these clinicians.22 Even simple interventions, such as providing general practitioners with a written information pack on inherited cancer, have been shown to significantly improve referral decisions regarding patients with a positive family history.52 The development of psychological screening tools to assist PCPs in identifying those at psychological risk may be helpful. In addition, linkages and communication with mental health resources to promote further integration of supportive care may be required. Innovative models such as “Shared Care,”53 which involves a consultation-liaison kind of partnership between PCPs and psychiatrists/psychologists, may be helpful to provide consultation and support to PCPs. Regardless of the model, the need for effective partnership between genetics experts and the general public is critical if improved education, information transfer, and community building is to flourish.54


PCPs play an important and evolving role in the management and psychosocial support of patients with a family history of cancer. They must be prepared to engage patients in discussions of predictive genetic testing for cancer susceptibility. This includes taking a comprehensive family history, genetic risk assessment, provision of genetics information, appropriate referral for genetics consultation or genetic testing, and formulating and coordinating individualized management plans. PCPs possess much of the necessary knowledge, skills, and attitudes needed to manage and support patients at increased genetic risk for cancer. Both traditional and innovative strategies may further establish the integration of genetics into primary care practice.   PP


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16.    Esplen MJ, Toner B, Hunter J, et al. A supportive-expressive group intervention for women with a family history of breast cancer: results of a phase II study. Psychooncology. 2000;9:243-252.
17.    Martin S. Most Canadians welcome genetic testing. CMAJ. 2000;163:200.
18.    Julian-Reynier C, Eisinger F, Moatti JP, Sobol H. French physicians’ knowledge about hereditary breast/ovarian cancer: the need for continuing vocational training in genetics. Community Genet. 1999;2:165-172.
19.    Escher M, Sappino AP. Primary care physicians knowledge and attitudes towards genetic testing for breast-ovarian cancer predisposition. Ann Oncol. 2000;11:1131-1135.
20.    Mouchawar J, Klein CE, Mullineaux L. Colorado family physicians knowledge of hereditary breast cancer and related practice. J Cancer Educ. 2001;16:33-37.
21.    Geller G, Holtzman NA. A qualitative assessment of primary care physicians’ perceptions about the ethical and social implications of offering genetic testing. Qual Health Res. 1995;5:97-116.
22.    Mountcastle-Shah E, Holtzman NA. Primary care physicians’ perceptions of barriers to genetic testing and their willingness to participate in research. Am J Med Genet. 2000;94:409-416.
23.    De Bock GH, Vliet Vlieland TP, Hageman GC, Oosterwijk JC, Springer MP, Kievit J. The assessment of genetic risk of breast cancer: a set of GP guidelines. Fam Pract. 1999;16:71-77.
24.    Codori A. Psychological opportunities and hazards in predictive genetic testing for cancer risk. Gastroenterol Clin North Am. 1997;26:19-39.
25.    Stiefel F, Lehmann A, Guex P. Genetic detection: The need for psychosocial support in modern cancer prevention. Support Care Cancer. 1997;5:461-465.
26.    Shaw C, Abrams K, Marteau T. Psychological impact of predicting individuals’ risks of illness: a systematic review. Soc Sci Med. 1999;8:361-367.
27.    Decruyenaere M, Evers-Kiebooms G, Denayer L, et al. Predictive testing for hereditary breast and ovarian cancer: a psychological framework for pre-test counselling. Eur J Hum Genet. 2000;8:130-136.
28.    Phillips KA, Glendon G, Knight JA. Putting the risk of breast cancer in perspective. N Engl J Med. 1999;340:141-144.
29.    Wellisch DK, Gritz ER, Schain W, Wang HJ, Siau J. Psychological functioning of daughters of breast cancer patients. Part II: Characterizing the distressed daughter of the breast cancer patient. Psychosomatics. 1992;33:171-179.
30.    Lerman C, Peshkin B, Hughes C, Isaacs C. Family disclosure in genetic testing for cancer susceptibility: determinants and consequences. J Healthcare Law Policy. 1998;1:352-371.
31.    Broadstock M, Michie S, Marteau T. Psychological consequences of predictive genetic testing: a systematic review. Eur J Hum Genet. 2000;8:731-738.
32.    Meiser B, Gleeson MA, Tucker KM. Psychological impact of genetic testing for adult-onset disorders. An update for clinicians. Med J Aust. 2000;172:126-129.
33.    Gilbar O. Women with high risk for breast cancer: psychological symptoms. Psychol Rep. 1997;80:800-802.
34.    Zakowski SG, Valdimarsdottir HB, Bovbjerg DH, et al. Predictors of intrusive thoughts and avoidance in women with family histories of breast cancer. Ann Behav Med. 1997;19:362-369.
35.    Wellisch DK, Lindberg NM. A psychological profile of depressed and nondepressed women at high risk for breast cancer. Psychosomatics. 2001;42:330-336.
36.    Kumar S, Gantley M. Tensions between policy makers and general practitioners in implementing new genetics: grounded theory interview study. BMJ. 1999;319:1410-1413.
37.    Marteau TM, Lerman C. Genetic risk and behavioural change. BMJ. 2001;322:1056-1059.
38.    Emery J, Lucassen A, Murphy M. Common hereditary cancers and implications for primary care. Lancet. 2001;358:56-63.
39.    Acheson LS, Wiesner GL, Zyzanski SJ, Goodwin MA, Stange KC. Family history-taking in community family practice: implications for genetic screening. Genet Med. 2000;2:180-185.
40.    Acheson LS, Wiesner GL, Zyzanski SJ, Stange KC (North American Primary Care Research Group [NAPCRG]). A new tool for automating family history collection. Abstract presented at: NAPCRG conference; October 2001; Halifax, Canada.
41.    Emery J, Walton R, Coulson A, Glasspool D, Ziebland S, Fox J. Computer support for recording and interpreting family histories of breast and ovarian cancer in primary care (RAGs): qualitative evaluation with simulated patients. BMJ. 1999;319:32-36.
42.    Warner E, Heisey RE, Goel V, Carroll JC, McCready DR. Hereditary breast cancer. Risk assessment of patients with a family history of breast cancer. Can Fam Physician. 1999;45:104-112.
43.    Emery J, Hayflick S. The challenge of integrating genetic medicine into primary care. BMJ. 2001;322:1027-1030.
44.    Carroll JC, Heisey RE, Warner E, Goel V, McCready DR. Hereditary breast cancer. Psychosocial issues and family physicians’ role. Can Fam Physician. 1999;45:126-132.
45.    Esplen MJ, Hunter J, Narod S, et al. Supportive-expressive group intervention for women who test positive for BRCA1/2. Psychooncology. 2000;9:S25.
46.    Geller G, Tambor ES, Chase GA, Hofman KJ, Faden RR, Holtzman NA. Incorporation of genetics in primary care practice. Will physicians do the counseling and will they be directive? Arch Fam Med. 1993;2:1119-1125.
47.    Watson EK, Shickle D, Qureshi N, Emery J, Austoker J. The ‘new genetics’ and primary care: GPs views on their role and their educational needs. Fam Pract. 1999;16:420-425.
48.    Caulfield TA. The informed gatekeeper? A commentary on genetic tests, marketing pressure and the role of primary care physicians. Health Law Rev. 2001;9:14-18.
49.    National Coalition for Health Professional Education in Genetics. Available at: http://www.nchpeg.org. Accessed January 20, 2002.
50.    Health Professions Maternal & Child Health. Genetics in Primary Care (GPC): a Faculty Development Initiative. Available at: bhpr.hrsa.gov/medicine-dentistry/genpc.html. Accessed January 20, 2002.
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Dr. Hughes is assistant professor of psychiatry in the Department of Psychiatry and director of the Community and Minority Cancer Prevention and Control Initiative at the University of Pennsylvania in Philadelphia.

Acknowledgments: This work was supported by Department of Defense Grant #DAMD17-00-1-0262.



What role does culture play in cancer genetics research? Genetic counseling and testing for BRCA1 and BRCA2 mutations is increasingly being integrated into the clinical management of individuals who have a family history of cancer that is suggestive of inherited breast-ovarian cancer. While several studies have been conducted to understand the psychological, clinical, and familial impact of genetic testing, relatively little attention has been given to the role of cultural influences on the process of providing genetic counseling and testing services. Cultural factors such as beliefs and values and ethnic background are likely to play an important role in genetic risk profiles, decisions about participation in genetic risk assessment and testing, and responses to genetic risk information. This article reviews emerging literature on the role of cultural factors in cancer genetics research.



A substantial amount of research has been conducted to understand the clinical, psychological, and familial impact of genetic testing for inherited breast cancer risk. For example, women who are found to carry a cancer predisposing BRCA1 or BRCA2 (BRCA1/2) mutation have an estimated 55% to 85% increased risk of developing breast cancer and a 15% to 60% increased risk of developing ovarian cancer.1-3 Men who have a risk conferring the BRCA1/2 mutation are also at increased risk for developing prostate cancer.1 Several studies have also shown that rates of communicating BRCA1/2 test results to family members are high4-6. However, genetic testing may have an adverse effect on family and personal relationships.

In a recent study, approximately one third of BRCA1/2 mutation carriers reported that their family or personal relationships had been affected by genetic testing, and of these, 50% reported that these relationships were more emotionally strained after genetic testing.7 Data on the psychological impact of genetic counseling and testing continue to emerge, and recent studies have demonstrated that receiving BRCA1/2 test results may generate specific emotional reactions, such as anxiety or sadness, rather than have an adverse effect on overall psychological functioning.8-14 Compared to women who did not carry a deleterious BRCA1/2 mutation, BRCA1/2 mutation carriers reported significantly greater levels of genetic testing-specific distress in a recent study.15

While there is an abundance of data on the clinical, psychological, and familial impact of genetic counseling and testing for inherited breast cancer risk, culture is increasingly being recognized as an important factor in cancer genetics research. Culture is defined as a framework of beliefs and values that shape behavior and influence the way in which information about illness is interpreted and used to make healthcare decisions.16 Recent reviews have recommended increased consideration of cultural characteristics in cancer prevention and control research,16,17 and several studies have explored how cultural factors influence outcomes within cancer genetics studies (ie, genetic testing decisions, responses to genetic risk information).

While there is an increasing emphasis on distinguishing the contributions of underlying beliefs and values that are derived from one’s cultural worldview (racial or ethnic differences in cancer prevention and control behaviors)18 data are limited on the influence of specific cultural beliefs and values on genetic counseling and testing outcomes. For this reason, this review focuses on empirical research that has addressed how cultural factors such as ethnic background influence (A) the prevalence of genetic risk factors; (B) interest in genetic testing; and (C) responses to education and counseling about hereditary breast cancer and genetic testing. A review of how ethnic background has influenced these outcomes is informative for identifying areas that should be addressed in future cancer genetics research.

Research is now being conducted to identify susceptibility genes that confer an increased risk of developing other forms of cancer (eg, prostate cancer susceptibility genes)19,20 and investigators are now exploring interest in genetic testing21-24 for these forms of hereditary cancer.

This review is designed to identify underlying themes and issues related to cultural influences in cancer genetics research. Because increased attention is being directed towards reducing or eliminating racial and ethnic disparities in cancer morbidity and mortality,25,26 articles that address ethnic group differences among African-American and White women are the focus of this article.


Ethnic Differences in Cancer Risk

A substantial amount of research has demonstrated that ethnic background is an important factor in breast cancer risk and survival. For example, while breast cancer incidence rates are greater among White women than among women from other racial and ethnic groups (ie, African American, Hispanic, Asian), African-American women are at increased risk for developing early onset disease, have higher rates of advanced-stage breast cancer, and show reduced rates of breast cancer survival.27-30

Recent work suggests that ethnic differences in breast cancer risk may also be due to variations in genetic risk factors.31 For example, although BRCA1/2 mutations account for only about 5% to 10% of all breast cancer cases,32,33 the prevalence of three founder BRCA1/2 mutations (185delAG, 5382insC in BRCA1 and 617delT in BRCA2) is about 2.5% among women of Ashkenazi Jewish background.1,34 Specific BRCA1/2 mutations have also been identified among other ethnic groups, including Icelanders (999del5 in BRCA2), Norwegians (1136insA in BRCA1), and African Americans (M1775R, 1832del5, and 5296del4 in BRCA1).31 Furthermore, data from recent epidemiological studies suggest that the prevalence of deleterious BRCA1/2 mutations ranges between 12% to 21% among clinic-based samples of African-American women who have a personal and family history of breast and/or ovarian cancer.35 While our understanding of BRCA1/2 mutations among African Americans is increasing, efforts to further understand the penetrance of BRCA1/2 mutations among this population may be limited because of reduced participation in cancer genetics research.


Interest in Genetic Risk Assessment and Testing

Several studies have shown that women in the general population and those who have a family history of breast cancer report a high level of interest in genetic testing for inherited breast cancer risk.36-38 However, these studies were conducted before predictive testing was available, and findings from these studies were based on data collected from samples of women who had a low or moderate risk of having a BRCA1/2 gene alteration. However, one of the first studies to report actual rates of test acceptance found that only 43% of high-risk individuals identified from a hereditary breast cancer registry received BRCA1/2 test results.14 While this study suggested that rates of genetic test acceptance may be lower than anticipated among high-risk individuals, a recent study found that 82% of high-risk probands (ie, the first index case affected with breast and/or ovarian cancer to have genetic testing) ascertained from breast cancer clinics utilized genetic testing and received BRCA1/2 test results.39 However, a limitation of these studies is that the findings are based on samples that were ethnically homogenous. A study by Schwartz and colleagues39 found that rates of genetic test acceptance did not differ among African-American and White women; however, African-American women made up only 5% of the study sample.

Previous research has shown that African-American women are significantly less likely to participate in an education session about hereditary breast cancer and genetic testing compared to White women.40 Even though African-American women reported significantly greater expectations about the positive outcomes of genetic testing than White women,41 only 49% of African-American women participated in a pretest education session about hereditary breast cancer and genetic testing compared to 68% of white women.40

While greater levels of cancer-specific distress may be a barrier to participating in education and counseling programs designed to provide information about hereditary cancer and genetic testing among African-American women,40 it is possible that reduced participation in education programs that were conducted before actual testing was available may underestimate interest in testing among African Americans at high risk for having a BRCA1/2 gene alteration.

A recent study found that 82% of African Americans at high risk for having a BRCA1/2 gene alteration reported that they would definitely have genetic testing.42 However, our preliminary findings suggest that rates of participation in genetic risk assessment and testing may be lower among high-risk African-American women. Only about 60% of African-American women who had a family history of breast and/or ovarian cancer that was suggestive of inherited breast cancer susceptibility participated in genetic risk assessment and received BRCA1/2 test results.43 The small number of studies that have focused on genetic counseling and testing specifically among African Americans is a significant limitation in our ability to understand the psychological and behavioral impact of genetic counseling and testing for inherited breast cancer risk among this population. However, we can anticipate these potential effects based on data from studies that have evaluated responses to breast cancer risk counseling and education.


Responses to Risk Education and Counseling

Previous research has shown that African-American women may have different needs and preferences for information about inherited cancer risk. For example, when compared to White women, African-American women were less knowledgeable about breast cancer genetics (ie, transmission of inherited cancer susceptibility).41,44 Although there were no differences among African-American and White women in terms of overall perceptions of the limitations and risks of testing in one study,4 more recent work has demonstrated that African-American women have greater concerns about the limitations and risks of genetic testing.44 However, African-American women were significantly more concerned about their ability to handle the emotional impact of genetic testing results compared to White women in both studies.41,44

Only a few studies have evaluated ethnic differences in the impact of education about hereditary breast cancer and genetic testing. For example, African-American women who participated in an education program about hereditary breast cancer and genetic testing reported significantly greater genetic testing intentions and were more likely to provide a blood sample for storage and possible future testing following an education and counseling intervention about hereditary breast cancer compared to African-American women who received an education-only intervention.40

Although this study was conducted before predictive testing for BRCA1/2 mutations was available and participants were women who had a low-to-moderate risk of having a BRCA1/2 gene alteration, the effects of the education and counseling intervention were only observed among African-American women. There were no differences in genetic testing intentions or provision of a blood sample among white women who received the education and counseling intervention compared to white women who received the education-only intervention.40 However, printed educational materials that were designed to provide information about hereditary breast cancer, BRCA1/2 genes in the Ashkenazi Jewish population, and information about the benefits, limitations, and risks of genetic testing, led to greater perceptions of the limitations and risks of genetic testing, increased levels of knowledge about breast cancer genetics, and decreased genetic testing intentions among Ashkenazi Jewish women at low risk for having a BRCA1/2 gene alteration.45

While the specific mechanisms that contribute to differences in responses to education about hereditary breast cancer and genetic testing among African-American women and Ashkenazi Jewish women are unclear, it is possible that education and counseling provide in-person increased motivations to have genetic testing among African-Americans because they had a high level of trust in the nurse educator who delivered the intervention.40 The education and counseling sessions for the majority of the African-American participants were completed by an African American nurse educator.46 Emphasis on interpersonal relationships is a key component of African-American culture, and it is possible that women were able to identify more strongly with the African-American nurse during the education session. This process may have contributed to increased genetic testing motivations.

Previous research has shown that ethnic identity or the level of affiliation with one’s ethnic or racial group is associated with responses to breast cancer risk education and counseling. Improvements in risk comprehension and reductions in cancer-related distress were associated with higher levels of African-American ethnic identity among women who participated in a breast cancer risk education program that was delivered in a group format.47 The process of identifying with women who are of the same ethnic background may be one mechanism through which African-American women comprehend cancer risk information. However, it is also likely that the specific beliefs and values related to interpersonal relationships, temporal orientation, and religion and spirituality that are highly endorsed within one’s cultural worldview also have a direct influence on responses to risk information and counseling provided within genetic counseling and testing settings.48


Cultural Considerations in Genetic Counseling for BRCA1/2 Mutations

In most clinical research settings, predictive genetic testing for BRCA1/2 mutations is offered to individuals who have a minimum 10% to 20% prior probability of having a deleterious BRCA1/2 mutation.49 It is standard practice to provide pretest education about hereditary breast cancer, the probability of having a BRCA1/2 gene alteration, and information about the benefits, limitations, and risk of genetic testing in order to facilitate informed decision-making about genetic testing.49,50 Post-test counseling is also provided to improve adjustment to BRCA1/2 test results and enhance informed decisions about cancer prevention, surveillance, and treatment.49,50

While provision of risk information is one of the key aspects of genetic assessment and counseling, temporal orientation may influence the salience of risk information. Temporal orientation is described as the level of cognitive involvement within past, present, and future dimensions, and greater levels of future temporal orientation have been associated with improved psychological functioning following traumatic events.51 It is possible that cancer risk estimates may be more meaningful among individuals with a future temporal orientation because they increase perceptions of control. However, among individuals with a present or past temporal orientation, estimates of genetic probability and disease risk may be less meaningful because there is little focus on the immediate situation.48

Previous research conducted among African Americans and Whites affected with hypertension has shown that individuals who had a present temporal orientation reported lower perceptions of the efficacy of disease prevention and control, as well as lower perceptions of susceptibility to the consequences of uncontrolled hypertension.52 In this study, as well as in studies conducted among individuals from the general population, African Americans were significantly more likely than Whites to have a present temporal orientation.52,53

Previous studies have shown that greater levels of spiritual faith were associated with lower rates of test acceptance in a prior study by Schwartz and colleagues.39 However, religious and spiritual beliefs may play a significant role in coping with genetic risk information among African-American women. Spirituality and religion are critical aspects of African-American culture,46 and previous research has shown that African-American women affected with breast cancer were more likely than white women to use religious coping strategies and resources to adjust to their breast cancer diagnosis and treatment.54 Religious coping strategies may also be used by African-American women to cope with genetic risk information. However, the psychological impact of genetic testing for BRCA1/2 mutations among African-American women and the effectiveness of religious coping strategies has not been evaluated among high-risk African-American women who have received BRCA1/2 test results.



Genetic counseling and testing for BRCA1/2 mutations is increasingly being integrated into the clinical management of individuals who have a family history of disease that is suggestive of inherited cancer susceptibility. A substantial amount of research has been conducted to understand the clinical, psychological, and familial impact of genetic testing for BRCA1/2 mutations. While few studies have addressed these outcomes among ethnically diverse populations, our knowledge about the prevalence of BRCA1/2 genes among these populations is increasing. For example, recent studies have shown that the prevalence of BRCA1/2 susceptibility genes is 12% to 21% among African-American hereditary breast cancer families. This finding provides support for the need for future studies designed to clarify the penetrance of BRCA1/2 mutations among this population. However, this review has demonstrated that reduced participation of African Americans in cancer genetics research is consistent. This is likely to be a significant limitation of future cancer genetics research, and increased culturally sensitive community outreach efforts may be needed to educate lay audiences about the availability of genetic counseling and testing or to recruit African Americans into cancer genetics research protocols.

This review has also demonstrated that ethnic background influences responses to information about hereditary breast cancer and genetic testing. However, the mechanisms that contribute to ethnic differences in responses to education about hereditary breast cancer are not clear. Additional research is needed to evaluate the influence of specific cultural beliefs and values on psychological and behavioral responses to genetic counseling and testing.   PP



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