The NIMH research program in panic disorder: The present and future

Pergamon

THE NIMH RESEARCH PROGRAM IN PANIC DISORDER: THE PRESENT AND FUTURE LEWIS L. JU D D * Department of Psychiatry. University of California, San Diego, La Jolla. CA 92093.0603, U.S.A

DURING a decade of phenomenal advances in understanding and managing a number of mental disorders, none is more spectacular than our achievements regarding anxiety disorders in general, and panic disorders in particular. Thirty years ago, most of the field was unaware that panic disorder existed as a discrete mental disorder. Since that time, the field has developed reliable and valid diagnostic criteria for panic disorder, a growing idea of its genetics and pathophysiology, and a number of effective treatments. Much of this progress has occurred during the last 10 years. The next decade-which a Presidential Proclamation has designated as the “Decade of the Brain”-promises to be revolutionary, as the field gains even greater scientific momentum and the increasing power of the neurosciences is brought to bear on anxiety and other mental disorders. In the United States, the National Institute of Mental Health (NIMH) has played a fundamental role in this progress, funding grants to extramural researchers throughout the nation and abroad and conducting intramural research on the campus of the National Institutes of Health (NIH). This report presents a brief overview of the current NTMH research program in panic disorder and examines some exciting new directions for panic disorder research in the future. As shown in Table 1, NIMH total funding of anxiety disorders research has expanded dramatically from $6.9 million in 1980 to an estimated $40.5 million in 1990. (That almost seven-fold increase occurred while NIMH overall research increased by only two-and-ahalf times.) Of that $40.5 million, approximately one-third is for direct research on anxiety, and twothirds is for relevant neuroscience, behavioral, and neuropharmacology research. About 25% of the total NIMH anxiety research budget, or $10 million, is devoted to panic disorders alone. During the past decade, anxiety research has commanded an increasing

*Dr. Judd is currently Mary Gilman Marston Professor and Chairman of the Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0603, U.S.A. He was Director of the National lnstitutc of Mental Health, U.S. Department of Health and Human Services, when this paper was presented in Geneva on I9 June 1990. 221

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Anxiety research

FY FY FY FY FY FY I?Y PY

FY FY r-Y

1980: 1981: 19X2: 1983: 1984: 1985: 1986. 1987: 19xX: 1989: 1990:

$6.9 million X.0 9.0

I I.2

14.6

17.2 18.0 21.0 29.3 36.4 40.4 (est.)

Total rcscarch Sl61.8 million 162.1 156.5 168.0 188.5 211.3 221.4 265.9 29x.9 354.5 413.8 (est.)

NO/L,. *[Suurcc: NIMH Planning and Flnanci:tl M a n agement Branch].

share of the overall NIMH research budget. growing from 4 ?L in 1980 to approximately 10% in 1990. By devoting about 10% of its research budget to panic and anxiety disorders, NIMH now has a strong research investment in these disorders. A recent audit of current and recent past NIMH research efforts in panic and anxiety reveals that the program is very diversified, fully reflecting the scope and shape of the scientific field. Institute staff are constantly seeking balance between two important goals: giving priority to “hot,” promising areas that are moving very fast. and maintaining appropriate diversity. The program’s breadth is necessary because science moves cumulatively, and often seemingly unrelated data derived from diverse areas of science will combine to initiate the next breakthrough. In clinical research, NTMfi has supported--and to a degree still supports--research efforts to refine diagnostic criteria for panic disorder. (NIMH supported the originai field trials of DSM-III, which first oficially recognized panic disorder as a discrete diagnostic entity, and now supports field trials for DSM-IV.) Currently, a primary focus of the program concerns threshold issues for diagnosis. For example, more needs to be done to resolve issues such as precisely how many panic attacks over what time period should constitute the disorder. The criteria have changed from 6 attacks in 6 weeks (Research Diagnostic Criteria: RDC, Spitter, Endicott, & Robins, 1975) to 4 attacks in 4 weeks (,4PA, 1980) to 4 attacks in 4 weeks with I month of apprehension concerning the next attack (APA, 1987). The minimum number of associated symptoms in the RDC was three; in DSM-111 it was four. None of these changes has been based on definitive empirical data. Clearly, developing such a database is an important priority. Some NIMH-supported studies are attempting to clarify the relationship of panic to mood disorders. Various studies report that 4&80% of panic disorder patients have had at least one lifetime diagnosis of major depression. Current studies are attempting to determine whether there is a common central diathesis and/or what is the exact nature of the relationship between these disorders.

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There is growing interest in mixed states-subthreshold symptoms of anxiety combined with subthreshold symptoms of depression. Despite the lack of a formal diagnostic category, these symptoms often combine in individual patients to create considerable disability. However, very few studies are as yet exploring the clinical epidemiology of mixed states, except in primary care settings. The relationship between post-traumatic stress disorder, other anxiety disorders, and depression is also receiving some attention. NIMH continues to support epidemiological studies related to anxiety disorders and panic disorders. A prospective study is being conducted in a relatively large cohort of adolescents because many clinicians believe that the peak age of onset is during adolescence. NIMH studies have also examined the prevalence of anxiety and panic disorders in primary care settings, emergency rooms, and cardiac clinics. In an analysis of ECA data, Weissman, Klerman, Markowitz and Ouelette (1989) added a new dimension to public and professional understanding of panic disorder. As shown in Table 2, they confirmed that panic disorder, far from being a “trivial” mental disorder, was a significant risk factor for suicide attempts, but not for completed suicides. Table 2 Comparison of Suicide Ar~empt Rates: General P o p u l a t i o n , O t h e r Psychiatrrc lkorders. PWIK Artacks, & Panic Disorder*

General population: Other psychiatric disorder: Panic attacks: Panic disorder: Note. *[Source: Weissman et al.,

I% 6% 12% 20%

19891.

These data on the elevated suicide risk among panic disorder patients do a great service to the field and to national policy, because they provide solid grounding for combating the general tendency, among health professionals and the general public alike, to trivialize these disorders. Some studies, but too few, are examining the disability, morbidity, and mortality associated with these disorders. More research on the disability from panic disorder is very much needed. In etiology and pathophysiology, the Institute is beginning to fund some molecular genetic studies to identify large, multiplex families for linkage analysis. In addition, a number of family studies are developing data that can aid in defining the relationship between anxiety, mood disorders, and mixed states, and in finding familial and possibly genetic patterns of transmission. New studies are also looking at comorbidity with substance abuse disorders, with an eye toward causality. Consistent with the 40-year NIMH tradition of research in experimental psychopathology and phenomenology, the Institute is supporting studies on the experimental manipulation of arousal and anxiety levels that compare anxiety disorder patients with other patient and nonpatient groups. NIMH also supports research in classical psychophysiology, such as studies of how panic disorder patients physiologically respond to various cxpcrimcntal challenges. In addition, many clinical studies have been conducted in patient populations by using

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a variety of pharmacological probes in treatment and/or challenge designs, and correlating this with a wide variety of biological markers, such as neurotransmitters and metabolites in various body fluids. Such studies have revealed that several neurotransmitter systems (e.g.. norepinephrine, serotonin, etc.) appear to be implicated in anxiety and panic. A large amount of clinical research is examining the character and mechanisms of panic attacks that are provoked by various challenge agents. These agents include lactate, CO,, yohimbine, caffeine, isoproterenol, meta-chlorophenylpiperazine (mCPP). and soon the inverse benzodiazcpine agonist ROI 5- 1788. Surprisingly. to date there have been only a few neuroimaging studies of panic disorder using positron emission tomography (PET), cerebral blood flow (CBF), and single photon emission computed tomography (SPECT). Clearly more studies are needed, both to identify pathophysiology and to clarify treatment response. Finally, NIMH is supporting a relatively large number of studies in the treatment of anxiety disorders, especially panic disorder. Among thcsc have been assessments of the effectiveness of psychosocial psychotherapies involving individuals, couples and groups. Studies of specific brief, targeted behavioral treatments, such as cognitive/behavioral therapies, imagery therapy and various forms of relaxation. arc being studied in controlled designs. NIMH also supports pharmacological treatment studies in controlled comparison designs. In addition, integrated or combined treatment studies fin which medications are combined with proven psychosocial treatments designed specifically for panic disorder appear to be very promising. Previous studies have provided intriguing hints that somatic and psychosocial treatment effects may be additive. NIMH is now sponsoring the first large (N = 600) multiccnter controlled study of combined somatic and psychosocial treatments for panic disorder. The large size of this population should be sufficient to yield definitive answers concerning the relative efficacy of imipramine (IMI) alone, a special form of psychosocial treatment (cognitive/behavioral panic control: CPC) alone, and their combination. The study uses five treatment tracks: IMI + medical management; placebo + medical management; CPC + IMI; CPC + placebo: CPC alone. Combined treatment research in panic disorder as well as other disorders (e.g.. mood disorder) will increase in the future. Turning now to basic research. the NIMH basic research portfolio has undergone phenomenal growth and technical advances as the neurosciences have become the basic sciences of mental illness. Progress in anxiety and panic disorder research has already been excellent: it may even bc revolutionary in the next decade. NIMH supports a number of behavioral pharmacology studies and encourages the development of new animal models of anxiety to add to the existing roster. That roster includes the Maudsley and Roman strains of rats. the mouse open-field models. and others. A wide variety of pharmacological probes are being tested and studied in these animal models. For example, the learned helplessness model (which was originally created by exposing the animal to inescapable shock). although traditionally viewed as a depression analogy. appears to be a model for anxiety as well. Beta-carboline derivatives induce learned helplessness, while pretreatment with benzodiazepines prevents it. Further research is

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needed to demonstrate the value of learned helplessness as an animal model for both depression and anxiety. A relatively large number of NIMH-supported studies are further characterizing the benzodiazepine-GABA-chloride ionophore complex (Bdz/GABA). This supramolecular complex is made up of an oligomeric protein that gates and controls the flow of chloride ions in the neuronal ion channel, which in turn alters the level of neuronal activity. The characterization of this receptor complex has served as a model for research in other ligandgated ion channel receptors (e.g., glutamate, acetylcholine) in the CNS. Furthermore, the concentration of the Bdz/GABA receptor in the hippocampal/amygdaloid areas and in the septum has provided an important lead in understanding the pathophysiology of panic disorder. Progress continues in the characterization of GABA receptors, benzodiazepine receptors operating through GABA, benzodiazepine antagonists, and inverse agonist sites as well as other high-affinity binding sites on this receptor complex. It is now axiomatic that where there are receptors there are naturally occurring endogenous ligands that have affinity for those receptors. The search for those ligands continues at NIMH and at other centers throughout the world. For example, in a collaboration between the NIMH Intramural Research Program (Paul, S.) and the University of Texas at San Antonio, Purdy and colleagues (Morrow, Pace, Purdy, & Paul, 1990) have identified specific endogenous steroids that attach near the barbiturate binding site. These agents have proven to act as hypnotics and potential anxiolytics in various animal models of anxiety. In another line of study, Costa and co-workers at the Georgetown University Medical School are investigating endogenous anxiogenic agents such as diazepam binding inhibitor (DBI) and other neuropeptides (Barbaccia et al., 1985). As the preceding remarks indicate, research advances in the past decade have contributed to enormous progress in understanding and controlling anxiety disorders and panic. These advances include: (1) Providing a scientific foundation for new appreciation of the prevalence and potential severity of anxiety disorders; (2) Identifying panic disorder as a discrete anxiety disorder and establishing for it clear diagnostic criteria; (3) Making significant inroads into understanding the involved basic brain mechanisms at gross neuroanatomical, cellular, and molecular levels; Confirming a strong familial-and probably genetic-role in the etiology of panic (4) disorder; (5) Developing and testing many drug and behavioral treatments, which have contributed to the wide array of effective treatments now available for this once daunting disorder; and (6) Establishing mechanisms for disseminating relevant research advances to clinicians and the general public to encourage help-seeking and improve clinical care. Even more exciting developments are expected in the next decade. We at NIMH believe that the groundwork has now been laid for a significant advance in our understanding of anxiety disorders in general and panic disorder in particular. The Institute is especially encouraging studies in the following research areas, which are viewed as particularly promising:

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1. Neuroimuging studies yf‘punic disorder. Brain imaging has enormous potential for revealing more precisely the brain areas and systems involved in panic attacks, the effects of medications, and the extent to which abnormal function is state or trait related. The potential value of studies of this type is demonstrated by the reports of Reiman, Raichle, Butler, Herscovitch and Robins (1984) and Nordahl et al. (1990) both describing abnormal cerebral bloodflow patterns in the parahippocampal and hippocampal regions of the brain in panic disorder patients. NIMH particularly encourages further imaging studies in panic disorder, including those involving more specifically designed radioactive ligands to study the CNS receptor distribution of the Bdz/GABA receptor complex and its specific role in panic disorder. 2. Genetic linkage und moleculur genetics studies. Increasing opportunities are arising to extend observations of familial transmission to possible genetic transmission and to identify more precisely the specific sites on the genome that transmit the vulnerability to develop panic disorders. Human and animal molecular genetics studies are highly promising in clarifying the role of genetic factors in panic disorder. In humans, two scientific strategies require further elaboration. First. NIMH is considering adding panic disorder to its Molecular Genetics of Mental Illness Network. Second, it is clear that expanded effort is needed to search for large multiplex families from which to work up individuals and develop cell lines so necessary for linkage studies. In animals, behavioral genetics studies using selective mating in various animal models are promising, especially when combined with linkage and molecular genetic studies. One potential avenue for study should be to follow up the observations of Gray, Whatley and Snape (1990) of the potential presence of a different or abnormal protein in the hippocampus of selectively bred Maudsley rats as compared to control rodents. 3. Further c’fluruc’trrizution of’ the GA BA jBd= rewptor complex und studies of encloy~nous ligands. There is much more to be learned about the molecular pathophysiology of anxiety.

NIMH is encouraging further. more detailed charactcrixation of this receptor-gated ion channel. which we believe may be fundamentally important in the pathophysiology of anxiety at the cellular and molecular levels. NIMH also will strongly encourage the continuing pursuit of potential anxiolytic and anxiogenic endogenous ligands for this complex (Barbaccia et al., 1985). 4. Treutnwnt reseurcf~ on .somutic’ and c~o~niti~~clheflur~ioruf upproucfws and their wmhinution. The design and development of new psychotherapies specific to panic and anxiety is particularly important, especially those designed for maintenance treatment and designed for combined use with medications. The next generation of treatment research studies for panic disorder will emphasize the individual, and particularly the combined, effects of psychosocial and somatic treatments, both in treating acute episodes ofpanic and especially in sustaining or maintarnmg treatment gains. NIMH is also encouraging the search for new medications, and is initiating a medication development program that will identify and test new anxiolytics as well as other psychotropic medications. The growing recognition that panic disorder can be a life-long disease is shifting treatment goals from treating acute

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episodes to a more long-term perspective. Thus, NIMH will encourage more focus on maintenance treatment aimed at keeping patients symptom-free throughout their lives. In addition to its role in supporting research, the NIMH is concerned with finding ways to translate research advances in understanding and treating panic disorder into improved clinical practice. The recognition that there are 1.5 million adults in the U.S. with panic disorders, of whom only one in three receive treatment, has led the Institute to sponsor two important new public health educational efforts aimed at improving recognition and treatment of this often severe disorder. On 13 November 199 1, at a news conference at the National Press Club, Washington, DC, NIMH launched the Panic Disorder Prevention and Public Education Program (PDEP), a national public and professional education program focused on panic disorder. It is based on the NIMH Depression Awareness, Recognition, and Treatment (D/ART) Program (which, in turn, was modeled after a hypertension education program developed by the Heart, Lung, and Blood Institute of NIH). Like the D/ART program, PDEP is science based, and is guided by a panel of experts in panic disorder research and treatment. The professional education component, addressed to primary care practitioners as well as mental health clinicians, has been developed and implemented in conjunction with various relevant professional and consumer organizations. The public education component includes media public service announcements, advertisements, and literature for lay audiences distributed through physicians. Another important, national public health event, aimed at increasing awareness, and improving treatment access and quality for panic disorder, was held 25-27 September 199 1, in Bethesda, Maryland. Here the NIMH in collaboration with the Office of Medical Applications Research, NIH, collaborated in convening a Consensus Development Conference on the Treatment of Panic Disorder. The recommendations and conclusions of the Consensus Development Consensus are as follows: 1. Panic disorder is a distinct condition with a specific presentation, course, and positive family history for which there are effective pharmacologic and cognitive-behavioral treatments. 2. Treatment that fails to produce an effect within 8 weeks should be reassessed. 3. Panic disorder patients often have one or more comorbid conditions that require careful assessment and treatment. 4. The most critical research needs are: (i) The development of reliable and valid measures of assessment. (ii) The identification of optimal choices and structuring of treatments designed to meet the varying individual needs of patients. (iii) The implementation of basic research to define the nature of the disorder. 5. Barriers to treatment are availability, accessibility and affordability. 6. An aggressive educational campaign to increase awareness of these issues should be mounted for clinicians, patients and their families, the media, and the general public. As in previous conferences of this type, both the broad dissemination of conference results and the high credibility of the sponsoring organizations are likely to serve as a catalyst for improved clinical practice. In conclusion, it was very gratifying to NIMH to learn that the conclusions and rec-

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