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. Thompson is associate clinical professor of psychiatry in the Department of Psychiatry at the UCLA School of Medicine in Los Angeles.

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



Which patients suffering from anxiety respond to dynamic therapy and how does dynamic therapy effect change?  Dynamic therapy can be uniquely helpful to selected patients with anxiety disorders who are often inadequately treated with medication or time-limited treatments. Psychodynamic insight-oriented treatment conceptualizes anxiety not as an isolated symptom, but as a “signal” indicating deeper, more enduring maladaptive character traits and internalized interpersonal reactive patterns. Anxiety is examined concurrently as the patient’s dominant preoccupations, concerns, and relational patterns are identified.  Memories and emotions are explored, real versus fantasized dangers are clarified, and different interactive patterns offering more adaptive responses to current life challenges and opportunities are elaborated.



While Freud and other early psychoanalysts were fascinated by anxiety and other neurotic symptoms, the domain of the modern psychodynamic clinician is the study and treatment of personality. Today, insight is achieved not so much by the archeological search for deeply buried memories, but by attempts to understand personality. Personality, contributing to interpersonal relationships with aspects of desire, self-conceptions, views of others, and anticipations, is endlessly played out in interpersonal dramas of everyday life. These internal patterns of interaction, expectation, and defense typically only reinforce existing internal expectations and fears, often resulting in enduring anxiety.

The modern psychodynamic clinician recommends medication or time-limited cognitive-behavioral therapy for many types of anxiety. Yet, many anxious patients respond incompletely or not at all to medication or time-limited therapies. Numerous patients who are left with enduring anxiety inevitably find their way to psychodynamic therapy. There is no shortage of such patients, who come at personal expense, and apply hemselves to a treatment that requires time, commitment, and labor.


Psychodynamic Treatment

Clearly, not all patients will benefit from psychodynamic therapy. The challenge is identifying which ones will. Psychodynamic treatment has been woefully overprescribed in the past, and while a detailed description of patient selection for psychodynamic therapy is beyond the scope of this article, clinical experience and research would suggest that individuals with chronic maladaptive character traits and personality disorders can be greatly helped by psychodynamic therapy, whereas those with Axis I disorders cannot.

Systematic outcome studies of psychodynamic therapy have been difficult because of the complexity of variables inherent in psychodynamic therapy, the time and financial support necessary to conduct such studies, and a seeming lack of interest on the part of psychodynamic clinicians to develop and participate in such studies. In spite of these limitations, existing studies of psychodynamic therapy, comprehensively reviewed by Gabbard,1,2  suggest that it helps improve global functioning, decrease maladaptive character traits, and reduce the frequency of diagnosable personality disorders.3-8 Thus, insight-oriented therapy offers a viable treatment option when anxiety is interwoven with maladaptive personality traits and character patterns. Conversely, a patient who has no obvious personality difficulties, as evidenced by a healthy capacity to work, love, play, and interact, is likely to be more expediently treated with a time-limited treatment or medication.

How does the psychodynamically oriented clinician view anxiety? Anxiety is conceived of as the proverbial “tip of the iceberg.” Thus, anxiety is a barometer reflecting both temperamental and biologic vulnerabilities, but also complex, enduring inner struggles (eg, lack of inner harmony, anticipation of danger, evidence of deprivation, attachment struggles, or consequence of past trauma). Freud,9 who hypothesized that anxiety was the “signal affect,” posited that when a human being is faced with danger in the real world (eg, an enemy troop cresting the ridge), the individual has two options: flight (run with great urgency), or fight (reach for the nearest weapon).

Anxiety serves as a signal for inner, anticipated danger, which in turn activates an internal psychological response—the use of defenses or coping mechanisms.10-15 Once activated, defenses become the means to protect—a way to manage emotions, perceptions, impulses, desires, and, importantly, a way to deal with internal conflict surrounding significant objects in the individual’s internal world or current relationships.16 For instance, seeing one’s alcoholic mother realistically may be too painful; thus, the child subconsciously chooses not to see the mother’s brutality (denial). Should a friend ask the individual whether his mother has a problem with alcohol, the individual may transiently experience anxiety, which in turn activates a defense of denial. The individual shrugs off the question, minimizes the possibility suggested by the friend, and switches the topic to another subject. Any number of reflexive behaviors from simple to complex, whether changing the subject, leaving the room, having a drink, going for a jog, getting busy cleaning, or having an affair, can be defensive reactions.

How is anxiety addressed in the practice of psychodynamic therapy? First, anxiety must be examined in the context of the “company it keeps,” meaning anxiety does not occur in isolation and, thus, all of the patient’s words, concerns, and preoccupations must be considered in relation to how each might be related to the patient’s experience of anxiety. Freud’s notion of “psychic determinism” hypothesizes that every word, thought, and action has meaning. Free association, words, fantasies, thoughts, and particularly nonverbal communications, attitudes, anticipations, and desires, as expressed toward the therapist, are thought to tell a story. For example, the hopeful expectant look, the fearfully lowered eyes, or the angry sullen silence directed toward the therapist (transference) conveys information about the patient’s history. The story enacted in the transference relationship typically finds the same recurring conclusion. The sullen silence eventually arouses the therapist’s frustration and anger, yet at the same time, the patient’s internal narrative seeks a different ending. At some level, the patient hopes the therapist will not respond with anger and will care instead.

How does change in anxiety occur? The therapist offers a benign, empathic, nonjudgmental, supportive relationship and models and encourages curiosity regarding the patient’s feelings and thoughts, without attempting to confront, “reality test” away (discourage or minimize the patient’s perception of reality), or behaviorally negate any of the patient’s perceptions or feelings. The initial goal of dynamic therapy is to find emotional “room” for the patient to allow for and contemplate inner experiences that he or she may otherwise feel is too shameful or guilt-producing to touch. Gradually, a process unfolds where cognitions, visceral reactions, and responses become more available for consideration. As the patient’s ideas, feelings, and perceptions are shared, they can be gradually clarified. The following physician comments may indicate that the patient’s dominant concerns are initially identified: “you seem to be talking about your kids;” “you seem to be sad;” “you seem to be talking about how heartless people can be;” or “you seem to be upset.” Repeatedly clarifying that the patient has a particular feeling or is thinking about a certain topic, allows both the patient and therapist to ponder further.

As the clarification process occurs, attitudes and reactions toward the therapist become more apparent, and the therapist concurrently becomes more aware of his or her attitudes and feelings toward the patient. Wants, expectations, and fears gradually become articulated and tested in the therapeutic relationship. Old internalized interpersonal schemas (eg, rebellious child, angry retaliating parent, needy child, or indifferent/contemptuous parent) are replayed, relived, and hopefully experienced in less painful, maladaptive, and traumatic ways than previously enacted. Fearful anticipations can be addressed and different interactive patterns can be experimented with.

Old experiences often become strikingly clear both in content and in terms of internal persistence and power. For example, one patient always seemed anxious and fearful, particularly in the moment when the therapist began to make a comment. The therapist stated that he “thought the patient felt as if the therapist was going to attack him.” The comment startled the patient, who found himself instantaneously raising his arms as if to protect his face in anticipation of being hit. The patient then immediately recalled how his mother would slap him as a child, often when he would enter the kitchen after coming home from school, and he began to cry.  With this incident, the patient saw with evident clarity how fearful he really was.17

Two broad elements of psychodynamic treatment contribute to change. First is the therapist’s interpretation of meaning, ideally in the context of felt experience like the above example (eg, you fear this, you anticipate this, you miss this, you want this). Second, is the noncondemning, empathic relationship, which vigorously attempts not to repeat past painful or traumatic interpersonal ways of relating. This is not easy, as the power of the patient’s expectations, the tendency to indirectly test, challenge, and ultimately sound out the therapist while always keenly anticipating and looking for the therapist to fulfill old frustrating and disappointing patterns, often perpetuates this cycle.

The focus of psychodynamic therapy is the stuff of life, the drama of interpersonal and familial experience, that always occurs in the context of temperament, biologic givens, and one’s own unique developmental experience. These are the concerns of life that are reflected in literature and art. This may be the deprivation of childhood that results in the bitterness and stinginess of Charles Dickens’ Ebenezer Scrooge.18 Or, for example, this may be the toddler’s traumatic life experience who, from a helpless position, witnesses his mother’s death by asphyxiation from tubercular hemoptysis, who is ever after left with a preoccupation with death, dying, and the living death. Thus was the life experience of the writer Edgar Allen Poe, as delineated by Terr,19 which apparently led to his adult preoccupation and repetitive expression in his creative works. 

The terrors and fears of human life become woven into the fabric of an individual’s psyche. The goal of psychodynamic therapy is to confront these fears in the light of the present, and in the context of an empathic, desensitizing, and understanding relationship.  Decreasing enduring anxiety typically requires time and patience. On occasion, an insight may offer immediate and sustained relief. For instance, an otherwise high-functioning professional woman who was normally mildly anxious, would become intensely anxious, to the point that she would be unable to sleep, when her husband was away on business trips. Through psychodynamic therapy, it became clear that being alone activated ill-defined fears that touched an old traumatic experience where, when alone in the middle of the night as a college student, the patient’s apartment was entered by a stranger and she was raped at knifepoint. As this old trauma was talked about and related to her current situation, her anxiety diminished and she was able to sleep in her husband’s absence. 

More typically, as illustrated in the following case, anxiety is not relieved so quickly and simply. A married, 35-year-old mother of two came to therapy complaining of an ill-defined sense of malaise and chronic anxiety.  After several months of therapy, she began to share a series of erotic fantasies about several male coworkers.  She deemed these fantasies as unacceptable, yet could not help thinking about how appealing these men were.  She became more and more anxious, worrying whether she could contain her desire, which made little sense to her as she thought she was in love with her husband, in spite of having been irritated with him recently for unclear reasons.

In the therapy sessions she also appeared increasingly anxious, but simultaneously seemed to flirt with her male therapist. She commented on his attractive style of dress, his tie, and wondering out loud how much fun he must be to be with. The clinician made a tentative comment that she seemed to find her therapist appealing but that at the same time she seemed anxious, and he wondered if this attraction and her anxiety were somehow related. At this remark, the patient appeared visibly more anxious and changed the subject. At the next visit, she reported several elements with little conscious awareness that they might be interrelated. She talked of recent anger with her husband after he approached her sexually and wondered why she felt so intensely about this interaction. She delineated a series of sexual inhibitions she had struggled with for many years—something she had not discussed previously. She then related a memory that she noted she had not thought of in 15 years. The memory was of her father, lying in her bed on a camping trip and fondling her genitals. The memory was evidently distressing to her as she relayed the incident.

While somewhat more dramatic than many memories that surface in the context of therapy, this sequence is fairly typical of interpersonal patterns, anxiety, and memories that become alive and more accessable in insight-oriented therapy. Latent feelings, desires, and fears are rekindled, in part by the proximity of the therapeutic relationship. Certain patterns are activated and addressed, resulting in reappearance of  old memories that enlighten the current dilemma. Yet, retrieval of memories alone is usually insufficient for change to occur. For this patient, retrieval of the old disturbing and traumatic memory was only the beginning. Previously, she had idealized her father, who had since come to a sudden and traumatic death.

In her relationships with men, she was often flirtatious, deferential, yet silently angry and self-defeating. She compulsively played out a pattern where she was subtly sexually provocative and would toy with the idea of an affair, yet never followed through, and ultimately felt guilty, anxious, and remained sexually inhibited. The memory described above marked a turning point for her, as her disappointment with her father and with men in general, began to crystallize, and her sexualized, yet self-demeaning pattern of interacting could now be examined openly.19 These patterns with her therapist were enacted with twists and variations as she both mourned the absence of a more supportive and nonabusive father, and experimented with different and more assertive ways of interacting in the context of therapy, with a concomitant decrease in her anxiety. In the process of therapy, the patient discovered feelings, memories, attitudes, and anticipation that heretofore she was only marginally aware of.



In dynamic therapy, the process of discovery occurs repeatedly before awareness of feelings, memories, and inner reactive patterns become fluid and can be accessed with ease. This repetitive process is the work of therapy, allowing for a gradual desensitization of old fears and concerns. Sorting out fantasized dangers from the real dangers of life and ultimately facing the true dangers is an important goal of psychodynamic therapy. An anxious patient may obsess about the risk of contracting acquired immunodeficiency syndrome, which may be a completely unrealistic danger for him. Yet, he may still need to face the true risk—that of being rejected and hurt, should he ask a woman out on a date. Life presents real risks that must be faced to handle adaptive living of life. Dealing with enduring psychological patterns and fears is a daunting task. Psychotherapy cannot undo all traumas and cannot always provide what has been neglected. Nevertheless, dynamic therapy can help in important ways to understand and offer patients a more benign laboratory for new experiences and opportunities to live life in less fearful and less maladaptive ways.  PP



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3. Bateman A, Fonagy P. Treatment of borderline personality disorder with psychoanalytically oriented partial hospitalization: An 18-month follow-up. Am J Psychiatry. 2001;158:36-42.
4. Kernberg OF, Burstein ED, Coyne L, Appelbaum A, Horwitz L, Woth H. Psychotherapy and psychoanalysis: Final report of the Menninger Foundation’s Psychotherapy Research Project. Bull Menninger Clin. 1972;36:87-275.
5.    Meares R, Stevenson J, Comerford A. Psychotherapy with borderline patients: I. A comparison between treated and untreated cohorts. Aust N Z J Psychiatry. 1999;33:467-472.
6. Monsen J, Odland T, Faugli A, Daae E, Eilersten DE. Personality disorders and psychosocial changes after intensive psychotherapy: A prospective follow-up study of an outpatient psychotherapy project, 5 years after end of treatment. Scand J Psychology. 1995a;36:256-268.
7. Monsen J, Odland T, Faugli A, Daae E, Eilersten DE. Personality disorders and psychosocial changes after intensive psychotherapy: Changes and stability after intensive psychotherapy focusing on affect consciousness. Psychotherapy Res. 1995;5:33-48.
8.     Stevenson J, Meares R. An outcome study of psychotherapy for patients with borderline personality disorder. Am J Psychiatry. 1992;149:358-362.
9.   Freud S. Inhibitions, Symptoms and Anxiety. Standard edition, vol. 20. London, England: Hogarth Press; 1926:77-178.
10. Freud S. Introductory Lectures on Psycho-analysis. Standard edition, vol. 15. London, England: Hogarth Press; 1933:13-80.
11. Freud S. The Ego and the Id. Standard edition, vol. 19. London, England: Hogarth Press; 1923:3-107.
12. Compton A. A study of psychoanalytic theory of anxiety. 1. The development of Freud’s theory of anxiety. J Am Psychoanalytic Assoc. 1972;20:3-44.
13. Compton A. A study of the psychoanalytic theory of anxiety: II. Developments in the theory of anxiety since 1926. J Am Psychoanalytic Assoc. 1972;20:341-394.
14. Compton A. A study of the psychoanalytic theory of anxiety: III. A preliminary formulation of the anxiety response. J Am Psychoanalytic Assoc. 1980;28:739-773.
15. Compton A. An investigation of anxious thought in patients with DSM-IV agoraphobia/panic disorder: rationale and design. J Am Psychoanalytic Assoc. 1998;46:691-721.
16. Vaillant GE, Vaillant LM. The role of ego mechanisms of defense in the diagnosis of personality disorders. In: Darron J, ed. Making Diagnosis Meaningful: Enhancing Evaluation and Treatment of Psychological Disorders. Washington, DC: American Psychological Association; 1999:139-158.
17. Dickens C. A Christmas Carol. New York, NY: Washington Square Press; 1962.
18. Terr L. Childhood trauma and the creative production. Psychoanalytic Study Child. 1987;42:545-572.
19. Thompson JM, Cotlove C. A Clinical Introduction to the Therapeutic Process.  Northvale, NJ: Jason Aronson Inc. Publishers. In press.

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



1.    Foa EB, Kozak MJ. Emotional processing of fear: exposure to corrective information. Psychopharm Bull. 1986;99:20-35.
2.    McCaul KD, Malott JM. Distraction and coping with pain. Psychopharm Bull. 1984;95:516-533.
3.    Carlin AS, Hoffman HG, Weghorst S. Virtual reality and tactile augmentation in the treatment of spider phobia: a case report. Behav Res Ther. 1997;35:153-158.
4.    Botella C, Banos RM, Perpina C, Villa H, Alcaniz M, Rey A. Virtual reality treatment of claustrophobia: a case report. Behav Res Ther. 1998;36:239-246.
5.    Rothbaum BO, Hodges L, Kooper R, Opdyke D, Williford JS, North M. Virtual reality graded exposure in the treatment of acrophobia: a case report. Behav Ther. 1995;26:547-554.
6.    Rothbaum BO, Hodges L, Watson BA, Kessler GD, Opdyke D. Virtual reality exposure therapy in the treatment of fear of flying: a case report. Behav Res Ther. 1996;34:477-481.
7.    Smith SG, Rothbaum BO, Hodges L. Treatment of fear of flying using virtual reality exposure therapy: a single case study. Behav Ther. 1999;154-158.
8.    Rothbaum, BO, Hodges L, Kooper R, Opdyke D, Williford JS, North M. Effectiveness of computer-generated (virtual reality) graded exposure in the treatment of acrophobia. Am J of Psychiatry. 1995;152:626-628.
9.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
10. Emmelkamp PMG, Krijn M, Hulsbosch L, de Vries S, Schuemie MJ, van der Mast CAPG. Virtual reality treatment versus exposure in vivo: a comparative evaluation in acrophobia. Behav Res Ther. 2002;40:25-32.
11. Deran R. Whitaker K. Fear of Flying: Impact on the U.S. Air Travel Industry. Boeing Company Document #BCS-00009-RO/OM. 1980.
12. Rothbaum BO, Hodges L, Smith S, Lee JH, Price L. A controlled study of virtual reality exposure therapy for the fear of flying. JCCP. 2000;68:1020-1026.
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. 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.

Ms. Kohlmann is genetic counselor in the Division of Medical Genetics at the University of Michigan Medical Center in Ann Arbor.

Dr. Peterson is assistant professor in the Department of Behavioral Science at the University of Texas MD Anderson Cancer Center in Houston.

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



Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are the most common forms of hereditary colon cancer. Due to the increased cancer risks associated with these conditions, the need for intensive cancer screening and management programs, and disease implications for patients and families, both affected individuals and their family members have unique needs for medical information and psychosocial support. To address their medical and psychosocial needs, genetic counseling should be offered to persons who are concerned about a possible inherited risk for HNPCC or FAP, and who may be considering genetic testing for these conditions. The purpose of this article is to provide an overview of the HNPCC and FAP syndromes and relevant psychosocial issues. The need to address complex medical and psychosocial issues related to these syndromes also will be illustrated through the presentation of two genetic counseling case scenarios.



Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause of cancer-related deaths in the United States.1 Approximately 20% of CRC cases occur in individuals who have a family history of the disease. Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are the two most common forms of hereditary colon cancer as well as the most studied. Both conditions are associated with an increased lifetime risk for CRC and other cancers. At-risk individuals are advised to follow rigorous cancer screening and management regimens because of the increased likelihood that they may develop polyps or colon cancer at a younger age than the general population. Lack of information and poor adjustment to an HNPCC or FAP diagnosis may interfere with adherence to management recommendations and limit communication about these conditions amongst other at-risk family members.

It is important for healthcare providers in primary care settings to have an understanding of the medical, social, and psychological implications of hereditary colon cancer syndromes so that they can effectively and responsibly integrate this information into their current practice.

This article will provide an overview of HNPCC and FAP as well as psychological and behavioral issues associated with genetic counseling and testing for these hereditary cancer syndromes. Genetic counseling case studies are used to illustrate psychosocial issues experienced by individuals and families at risk for these syndromes, and how such issues may influence adjustment and cancer risk-management decisions.


Overview of Hereditary Nonpolyposis Colon Cancer and Familial Polyposis

Two well-characterized hereditary CRC syndromes account for 5% to 10% of all CRC cases: HNPCC, associated with germline mutations in mismatch repair genes (hMSH1, hMLH2, hMSH6, PMS1, PMS2) and FAP, caused by germline mutations in the APC gene.2 An inherited mutation in one of these genes is suspected in a family when CRC (or other syndrome-related cancers) is present in successive generations and at earlier ages compared with the general population, and when individuals have more than one primary cancer associated with these syndromes. Children of mutation carriers have a 50% chance of inheriting the mutation themselves, and both genders can inherit these conditions equally. A distinct feature of FAP is the development of multiple colorectal polyps, often beginning in puberty, and the disease can be diagnosed clinically on this basis.

HNPCC confers a 70% to 80% lifetime risk for developing colon cancer, with an average onset at 44 years of age.3-6 Women with HNPCC have a 40% to 60% lifetime risk for endometrial cancer and a 6% to 13% risk for ovarian cancer.7-10 HNPCC is also associated with an increased risk for biliary tract, small bowel, upper urinary tract, and gastric cancers.9,10

If polyps are not removed in persons with FAP, the lifetime risk of colon cancer approaches 100%, with an average onset of 42 years of age. FAP also is associated with benign features outside of the digestive system including epidermal cysts, osteomas, congenital hypertrophy of retinal pigmented epithelium (CHRPE), dental abnormalities, and desmoid tumors. FAP also confers an increased risk for upper gastrointestinal cancers, hepatoblastoma, brain tumors, and thyroid cancers. Some families have a milder expression of FAP with few polyps and later age of onset.11,12 Although this attenuated form of FAP is associated with increased cancer risks, its diagnosis may be missed due to the lack of classic presentation. It has been reported that 22% of FAP cases have no family history of the disease and result from a spontaneous APC gene mutation.13

When genetic testing is offered to a group of persons with family histories suggestive of HNPCC or FAP, it is optimal to begin testing in a person who has been diagnosed with a syndrome-associated cancer or who has a clinical diagnosis of FAP. Doing so increases the likelihood of finding a disease-predisposing mutation if one is present in the family. If a mutation is found in the index case, then genetic testing for the presence of this specific mutation can be offered to other at-risk family members. It is possible that a known deleterious mutation may not be detected in an index case with a family history suggestive of HNPCC, or in an index case with multiple polyps characteristic of FAP, because of limitations in current technology. When this occurs, families are still considered to be at high risk for a hereditary CRC syndrome and are recommended to follow high-risk screening and prevention recommendations. A negative test result is considered conclusive only if the deleterious mutation has been previously identified in an affected member.

Genetic testing for hereditary cancers can identify persons who would benefit from increased screening and surveillance because they carry a disease-predisposing mutation. Conversely, genetic testing can identify persons who are not genetically at high risk for developing cancer, and as such are recommended to follow screening guidelines for the general population. Recommended screening and prevention options for HNPCC and FAP are presented in the accompanying table.14-16 Recent evidence indicates that chemopreventive agents may play a role in the management of FAP. However, at this time these medications are not a replacement for screening and prophylactic surgery.17


Genetic testing for adult-onset disorders such as HNPCC is discouraged for persons under 18 years of age, because the medical and psychosocial benefits of testing are not realized until adulthood. Ethical concerns about testing children include the inability of minors to give informed consent, as well as the possibilities that children found to be carriers may be stigmatized, may be given fewer opportunities, and may not receive appropriate counseling about their results.18 On the other hand, genetic testing is offered to families with children at risk of FAP, generally beginning at 10 years of age, because surveillance for this condition is warranted at an early age.19


Genetic Counseling for Hereditary Colon Cancer

Professional organizations have issued statements to guide the implementation of genetic counseling and testing for hereditary cancers in clinical and research settings to assure that individuals seeking these services receive sufficient information to make an informed decision about testing, screening, and prevention options.20-22 Genetic counseling should be conducted with persons who are concerned about a possible inherited risk for cancer and/or who may be considering cancer genetic testing, because the interpretation of genetic test results is complex.22 A study of persons undergoing commercial genetic testing for FAP found that less than 20% of them were offered genetic counseling prior to testing.23 Only 17% of persons in that study gave written informed consent prior to testing and results were misinterpreted by the physician in 32% of cases.23

The process of genetic counseling is ideally carried out in a manner that combines education about genetic concepts with counseling techniques.24 Genetic counselors gather detailed information about individuals’ personal and family history of cancer in order to accurately assess their inherited cancer risk, and to educate them about options for early detection and prevention, which may include genetic testing. An initial genetic counseling visit may include discussion of the family history, providing information about personal and familial cancer risks, and the option of genetic testing, assessment of the client’s motives, coping strategies, and family strategies.

Although there are potential medical and psychological benefits to defining one’s inherited cancer risk through genetic testing, there also are significant risks and limitations to the process. Genetic counselors generally discuss the option of genetic testing in a nondirective manner, and encourage individuals to make a decision about testing based on the risks and benefits relevant to their personal and family situation. The importance of adhering to age- and risk-appropriate screening guidelines is emphasized to all individuals regardless of their eligibility or decision regarding genetic testing.

If a client decides to pursue genetic testing, results are given during a follow-up genetic counseling session. Clients at risk for hereditary CRC may benefit from ongoing interactions with a genetic counselor to reassess changes in the family history and to stay informed about new early detection and prevention developments. Continued support also may help assure that information about the diagnosis is shared with other at-risk relatives, and can help families cope with medical and psychosocial issues that may develop over time (eg, a new cancer diagnosis in the family, reproductive considerations, screening for children).


Psychosocial Impact of Genetic Testing for Hereditary Colon Cancer

Studies that have evaluated interest and participation in hereditary CRC genetic testing have found that individuals are motivated by recommendations from their doctor or genetic counselor, beliefs in the benefits of testing, and a desire to gain information that may reduce uncertainty about their condition, help their children, reduce the need for frequent screening, and facilitate lifestyle or health-habit decisions.25-28 Few studies have evaluated psychological or behavioral outcomes of testing for HNPCC or FAP. Based on validated distress measures, the limited evidence suggests that undergoing genetic counseling and testing for other hereditary cancers does not cause significant psychological morbidity for most individuals.29-32

Notification that one does not carry a hereditary cancer mutation has been associated with a reduction in distress from the pre- to post-test time periods, suggesting that receipt of true negative test results confers a psychological benefit.31,32 However, subgroups of individuals may be at higher risk for experiencing adverse emotional outcomes from testing, and may benefit from increased support. Individuals who have higher levels of distress, lower quality of life and social support, and concerns about their ability to cope with their mutation carrier status prior to testing may be at greatest risk for experiencing distress after disclosure of positive genetic test results.33-35 Carriers of cancer-predisposing mutations reported higher levels of psychological distress compared with noncarriers,31,32,36 and one study37 suggested that mutation carriers who did not expect to receive positive genetic test results experienced higher distress after disclosure. Additional research is needed to evaluate the impact of carrier status notification on psychological adjustment as well as adherence to screening and surveillance recommendations.

Psychological adjustment to the genetic counseling and testing process may be influenced by family members’ experiences as well. A study of children who had undergone FAP genetic testing found that mutation carriers and noncarriers scored within normal ranges on measures of distress and behavioral problems. However, children with an FAP-affected mother were more distressed compared with children of unaffected mothers.38 Persons seem generally willing to share test results with other family members and follow through in doing so,28,39 although cancer patients have expressed concern about having the responsibility of passing on this information to others in their family.39 A limitation of studies to date is that they have focused on outcomes of the genetic counseling and testing process, and have not evaluated the impact of hereditary cancers on persons who have not come forward for counseling and testing. Future research should attempt to close this gap and further assess the impact of hereditary cancer on the family as well as the individual level.


Case Studies in Genetic Counseling for Hereditary Colon Cancer

The following cases illustrate psychosocial issues and counseling decisions faced by families with HNPCC and FAP. These cases represent two families who have participated in research studies for HNPCC and FAP. Pedigrees were modified to maintain confidentiality.


Case 1

Anna was diagnosed with CRC at age 35 years, and underwent HNPCC genetic counseling and testing as part of a research study. During a genetic counseling session to disclose results indicating that she was a mutation carrier, the genetic counselor began by reviewing the family history (Figure 1). Anna reported that the family had no contact with her sister, Nancy, and that she had “heard through the grapevine” that Nancy had been diagnosed with CRC. This information cued the genetic counselor to further explore issues about family communication during the session. Anna indicated that she planned to share the test results with her brothers and her mother, but not with Nancy. She stated that since Nancy had excluded herself from the family it would be Nancy’s own responsibility to seek out information about her cancer risk.


The genetic counselor further explored implications of Anna’s estrangement from her sister by role-playing scenarios focusing on possible outcomes from sharing or not sharing her test results with Nancy. Through this exercise, Anna expressed concern about her at-risk niece, Erica, regardless of her feelings about her relationship with Nancy. Anna stated that knowledge of her own test results could benefit Erica, who was approaching the age when high-risk screening options would be recommended. Although Anna still did not feel comfortable contacting her sister, a plan was developed to have her brother, who still had some contact with Nancy, share the information from genetic testing with her.

This case illustrates the important issue that Anna’s genetic test results also had medical implications for her family. In cases such as this the genetic counselor is faced with the issue of one’s duty to warn other at-risk family members. This matter has been addressed through case law, which has indicated that the clinician does have a duty to inform patients of familial risks.40 However, whether solely warning the patient fulfills this duty or whether and how family members can be notified without breaking patient confidentiality has not been clarified. Thus, genetic counselors and other healthcare providers face challenges regarding their roles and boundaries in disseminating genetic information to at-risk family members.

In families who express communication barriers due to estrangement, distance, or other reasons, simply informing the client about genetic risks for family members may not assure that the information is conveyed. Dissemination of genetic information in families may be limited, even in the absence of identified communication barriers, because of concerns about arousing relatives’ anxiety or other reasons.41 As a result, family members may not convey hereditary cancer risk information in a manner that emphasizes the importance of this information for one’s health or that prompts action among relatives. Any discomfort with communicating genetic information may be magnified when there are other problems with family relationships. Genetic counseling strategies that may facilitate the dissemination of risk information within families include role-playing to increase clients’ comfort in explaining information, providing written information to share with other relatives, identifying relatives who can help communicate the information, and preparing clients to cope with possible reactions from family members.

This case also illustrates the potential risk to Anna’s own emotional well-being if she chooses not to share genetic information with her sister because of their prior conflicts. One goal of genetic counseling is to help clients cope with immediate issues resulting from a genetic diagnosis and to help them anticipate feelings that they may experience in the future as a result of the genetic condition in their family, including the potential impact on future generations.42 Anna was disturbed by the thought of her niece developing cancer. Through genetic counseling, Anna better understood the possible decisional outcomes if she withheld or shared her test results with her sister and identified factors important to that decision.


Case 2

Lisa was diagnosed with FAP when she was 18 years of age. She underwent prophylactic colectomy at 25 years of age and subsequently developed a desmoid tumor, which required several additional surgeries and chemotherapy (Figure 2). Lisa requested genetic counseling to discuss the option of genetic testing for her children, and canceled several counseling appointments before she was finally seen. During the session, she appeared very apprehensive about having genetic testing for her daughters when they reached 10 years of age, and the genetic counselor explored reasons for her reluctance. The counselor discussed common concerns expressed by parents with FAP, including feelings of guilt about passing on a genetic condition, worries about the impact of testing on their relationship with their children, and worries about children’s ability to cope with an FAP diagnosis. Lisa acknowledged her fear that an FAP diagnosis might negatively affect her relationship with her daughters. The counselor asked Lisa to describe her feelings toward her mother, Maria, for passing this condition on to her. Lisa indicated that she understood that her mother could not control the path of inheritance. However, she stated that she had blamed Maria for her health problems when she was a child and young adult, and did not think that she could cope with her daughters having similar feelings towards her. Lisa suggested that having more information about the cause of her disease and talking with other teenagers who had FAP may have helped her cope better with her condition. Lisa and the counselor discussed how such strategies could be implemented for her children as they undergo screening and genetic testing.


In addition to her worries about her children, it became clear during the session that Lisa was having difficulties coping with her own disease. Her desmoid tumor was not responding well to treatment and Lisa expressed bitterness because she was the only person in the family to have developed this FAP-related complication. She and the counselor discussed reestablishing her relationship with her mother as another source of support as her daughters approached ages when genetic testing is recommended. Through counseling, Lisa identified how her difficulties in coping with her own disease may affect how she would be able to cope with the additional stress of learning her children were positive. This issue was important to explore because the early onset of FAP requires that parents take an active role in their children’s care.

An educational approach in genetic counseling can convey information, but it may not truly facilitate understanding of the personal implications of a genetic diagnosis.21 In addition to educating Lisa about her children’s risk of inheriting an FAP-predisposing mutation, it was important for the genetic counselor to address her feelings of guilt, anger, and fear related to her own experience with this condition as well as the experiences she anticipated for her children. Parents may avoid having their children evaluated at an appropriate age because of an underlying fear that their children might blame them for having passed on a genetic condition. Indeed, Lisa’s worries about her children’s reaction may have been part of the reason she missed several genetic counseling appointments prior to being seen by the counselor.

This case also illustrates the importance of evaluating clients’ personal experiences with genetic conditions as part of the genetic counseling process. Both FAP and HNPCC can exhibit different phenotypes among family members who carry the same disease-predisposing mutation, which in turn may carry different psychosocial implications for those affected. Lisa’s other mutation-positive family members underwent colectomy for FAP and had no further complications, in contrast to her own experience with desmoid tumors and additional treatment. Perception of one’s own disease also may be affected by whether other affected family members survived their cancers or whether they had a caregiver role for an affected family member.

Lisa’s distress regarding her disease and her children was not resolved through genetic counseling alone, and further psychological counseling was recommended. Follow-up genetic counseling visits were recommended to reassess Lisa’s feelings about having her children evaluated, and to establish a medical management plan to assure that her children receive the care they need.



Families affected by HNPCC and FAP face a challenging array of medical, psychological, and social issues. It is important for primary healthcare providers to be aware of these issues and to integrate knowledge about hereditary cancer syndromes into their current practice and care of families who may potentially be at risk for HNPCC or FAP. In addition to assuring that at-risk individuals receive appropriate referrals for genetic counseling and medical care related to the management of these conditions, primary care providers also could provide encouragement for adherence to screening recommendations and support for medical decisions that may impact both patients and their families.

This article emphasizes the importance of utilizing genetic counselors and other genetics professionals to educate families about their hereditary CRC risks and risk management options. As illustrated by the cases presented here, it is crucial to address the psychosocial issues that may arise during these discussions to facilitate ability in both individuals and families to effectively cope with and successfully manage their disease. Ongoing support from genetic counselors and other healthcare providers can be instrumental in helping persons adjust to new developments that may affect their own or their family members’ risks.   PP



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Dr. Wellisch is professor-in-residence in the Department of Psychiatry at the UCLA School of Medicine in California.

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



Most woman who have experienced breast cancer in a beloved first-degree relative (eg, mother, sister) are profoundly impacted by the experience. This article attempts to deal with three basic questions regarding the family experience of the woman at high risk for breast cancer. These include: 1) What are the known predictors of increased difficulties in adaptation/coping in this population? 2) What are some important clinical manifestations of problems in this population? and 3) What are reasonable interventions to be considered and attempted in this population? Although homogenous in their experience of having a first-degree family member with breast cancer, this is also a heterogeneous population in important issues such as the age of the woman at the time of the family member’s breast cancer diagnosis, the survival or death of the family member(s), the number of afflicted relatives, and the pre-cancer coping, support, and communication capacities of the family system, all of which serve to differentiate and subdivide this population.



The women on whom this article is based can be daughters, sisters, nieces, granddaughters, or even mothers of women with breast cancer. They bear a genetic legacy of trauma, past visions of suffering, and some degree of resolution of grief over their past family experiences with breast cancer. These women must learn to live with the conflict of loving, empathizing with, and/or missing the one who confers upon them increased risk in regard to their own physical vulnerability. This population must also learn to live with a vulnerability for which there is currently no 100% definitive medical intervention to eradicate their increased risk. Further complicating their family legacy is the reality that this threat/risk will never end and, in fact, increases and becomes co-mingled with age, forming a composite risk factor for breast cancer.

Since 1993, a multidisciplinary group has formed a working team/clinic at the Revlon-Breast Center at the University of California at Los Angeles (UCLA) School of Medicine. This is the High Risk Clinic of the Revlon-UCLA Breast Center. Since its inception, we have seen approximately 1,200 high-risk women, and are actively following and studying a matrix of 600 such women at the present time. A more complete description of the High Risk Clinic has been previously published.1


Predictors of Problems Stemming From the Family Experience

To date, somewhat limited data and clues exist on how to predict which women are likely to experience increased difficulty with adaptation and coping in adulthood as a result of their family experiences with cancer.

The data that exists suggest that the following factors can predict poorer adjustment. A constellation of factors from the family experience predict poorer (adult) adjustment in daughters of breast cancer patients. These include being an adolescent at the time of mother’s diagnosis (versus being preadolescent or an adult), and having a mother die from breast cancer (versus surviving).2 This developmental stage issue was confirmed by another group who showed that adolescent girls whose mothers had breast cancer displayed more symptoms of anxiety and depression than either preadolescents or young adult women in the same circumstance.3

A second constellation of factors also predicts poorer adult adjustment in the daughters. These include: poorer prognosis in the patient (eg, mother with breast cancer), poorer adjustment to the cancer (by the patient with cancer), and more severe surgery (mastectomy versus lumpectomy).4

A third constellation of factors correlates with women above the cutting score of 16 on the Center for Epidemiologic Studies Depression Scale (CES-D) in our clinic, having the increased likelihood of clinical depression. Some variables that significantly correlated with CES-D scores above 16 included: having had significantly more relatives with breast cancer (P=.04), having been significantly younger at the diagnosis time of the relatives (P=.05), and never having viewed the site of the relatives’ breast surgery (P=.03).5


Current Clinical Manifestation of Issues Stemming From Earlier Family Experiences:

Several clinical symptom patterns have been presented to us by this population which reflect current coping/adjustment problems, appear to reflect past and unresolved family issues, and appear to embody mandates for interventions. Six such patterns1 will be described, including:

(1) The woman who either cannot speak about the family experience of breast cancer at all, or cannot speak about the experience without overt painful, tearful grief. For the staff of the High Risk Clinic, this is a major clue that grief remains largely or totally unresolved. In clinic experience this is more often true for women whose mothers had breast cancer (and died from it) in the 1950’s and early 1960’s when families often lived in silence about the experience of cancer. However, we also see women who are younger and have more recently been confronted with familial breast cancer who sometimes are hard pressed to talk about the experience. Interestingly, and to our surprise, some of these women are even engaged in ongoing psychotherapy when visiting our clinic and report never discussing their familial experience of breast cancer in psychotherapy.

(2) The woman who presents the relatively common theme of “I have decided not to have children.” We often feel such decisions can be based on traumatic memories of their experiences as children of breast cancer patients and fears of perpetuating such genetic legacies on future generations. Sometimes embedded and coexisting with this is a lack of participating in any meaningful or intimate relationship with a man. This leads us to explore the woman’s memories of her father’s participation, or lack thereof, in the familial breast cancer experience. We have found instances of unresolved disappointment and rage at these fathers for their behavior and the position their behavior has put their daughters in during their mother’s illness. Sometimes these daughters are so angry and disappointed in their fathers, especially if the mother died and their fathers further mismanaged the father-daughter relationship, that their relationships with men are paralyzed and foreclosed without intervention.

(3) The woman who acknowledges sexual conflicts secondary to a fear of breast cancer, potential loss of breasts, or generalized dysphoria or more major depression. Of the first 161 patients in the High Risk Clinic, 36 (22%) were above the cutting score of 16 on the CES-D, indicating a probable presence of a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition6 diagnosis of depression. In this context, we are often presented with the notion “Why should I get pleasure from something (ie, my breasts) which I will almost certainly lose?” This is a complex, multilayered area, with guilt over sexual pleasure in the context of a depressed, traumatized mother who lost her ability to have sexual pleasure in the wake of breast cancer and treatments therein. In addition, the daughter who was an adolescent when her mother was diagnosed may have been developing breasts simultaneously to her mother losing hers. Thus, developmental issues resurface in this area of symptomatology.

(4) The woman who cannot touch her breasts, much less perform breast self-examination (BSE). This is not an unusual problem in this population. In a study of BSEs among high-risk women, only 27% performed a monthly BSE.7 Those who performed a BSE less than monthly, or never, were found to be significantly more anxious than those who performed a monthly BSE (P<.007).7 Thus, we view such women as having anxiety that has a somatic component and wonder about these women identifying with an ill relative who was phobically anxious about BSE and was also unable to deal with breast cancer as a life challenge.

(5) The woman who, by description, has identified with the mother’s maladaptive style of coping with her breast cancer. Two prominent styles we hear about in the mothers and see in the daughters is that of the anxious one in denial and that of the angry isolate, respectively. The issue of disentangling the daughter’s anxious identification with her mother is psychodynamically complex in that her agency of self and femininity are also wrapped up in this process.8

(6) The woman who presents as (chronically) dysphoric. The question we ask is whether this is unresolved (now internalized) anger in the daughter about her forced participation in the mother’s (or other relative’s) illness, or how much this is a pre-cancer aspect of the woman’s personality structure unrelated to the family experience of illness.


Reasonable Interventions Based on Earlier Family Experiences

Almost no data exists in the literature regarding interventions specifically for the population of women at high risk for breast cancer. The limited published data suggests that group therapy of a combined supportive/educative nature with this population can be successfully conducted, may lower symptoms of anxiety and depression, and may lead to increased knowledge about breast cancer and decreased personal risk perceptions.9,10 Given this reality, interventions will be described that fit the symptom patterns described previously based on the assumption that data does exist to link interventions with such symptom patterns.

(1) For the woman who cannot speak about the experience of familial breast cancer at all or with fresh and obviously unresolved grief, we tend to recommend supportive individual therapy which can be of a relatively brief duration. Just the experience of speaking about the occurence the context of our brief clinic interviews is cathartic to such women. We always recommend that women who have not spoken about familial breast cancer during ongoing psychotherapy should redouble their efforts to do so.

(2) For the woman who has decided not to have children, we start with intensive education from our clinical geneticist about the vulnerability to breast cancer. For those who also lack any intimacy with men (or women who are gay), we recommend more intensive, dynamic therapy. Anger and disappointment at fathers is often, or usually, entangled in this web of conflicts. We have seen women who are even further into such conflicts who have not really been able to begin living adult lives because they are preoccupied with the idea they will die when they reach the age their mothers were diagnosed or died. Often these women come to our clinic at an age that is shortly before the anniversary of their mother’s illness or death.

(3) For the woman who acknowledges sexual conflicts/phobic fears about her breasts, we carefully assess underlying etiology of an anxiety disorder and/or depressive disorder with vegetative symptoms such as anhedonia. We then try to facilitate psychopharmacologic intervention and supportive psychotherapy.

(4) For the woman who cannot examine or touch her breasts, we have her begin intensive work with our clinic nurse practitioner in systematic desensitization around breast touching and examining. The first step is with a breast model, the second is with the woman’s own breasts. We realize this can take many clinic visits and are willing to have the nurse do the breast exams for a series of visits while this desensitization process unfolds. The nurse is a highly skilled listener and often-repressed anxiety and memories emerge during this most sensitive process.

(5) For the woman who is trapped in a complex, fearful, and unproductive identification with her mother, we suggest dynamic individual therapy and group therapy where she can identify with other, different styles of coping.

(6) For the woman who is chronically dysphoric, often angry, and often at odds with our clinic staff, we try to first create a safe “holding” environment in our clinic itself. We try to deal with the potential for staff splitting and pitting created by such a patient. Slowly, we explore the possibilities for referral to a therapy that will be psychodynamic, ventilative, and/or grief resolving, and offer the possibility of adjunctive use of medications such as antidepressants. We do not feel rejected or disillusioned when such patients refuse these referrals. They have been dysphoric and angry as a way of life, and we have learned to view change in them as a gradual process.



Women at high risk for breast cancer are a psychologically heterogeneous population with a similar background of a familial history experience with breast cancer. Interventions are in the process of being developed and tested for this population and modest data exists to suggest or guide these interventions. Styles of problems in these women may stem from identifications with family members who struggled maladaptively to cope with breast cancer or from unresolved grief or anger about such familial experiences.   PP



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