Translational Research: Pathway to Improved Practice?

Every day, another science news story celebrates exciting research progress in understanding the brain, behavior and the roots of mental disorders. The recent growth in knowledge potentially relevant to psychiatry is striking. But how well are these scientific advances being translated into clinical care for the mentally ill? For many patients with severe and chronic disorders such as borderline personality disorder and schizophrenia, the answer is clear: not well enough. For example, a meta-analysis of 314 follow-up studies on "recovery" from schizophrenia between 1895 and 1992 revealed that during this period -- and even after the advent of two generations of antipsychotics -- fewer than half of all patients treated could be considered as recovered (Hegarty et al., 1994). We may be practicing state-of-the-art psychiatry, but the state of the art needs improvement. If, as many believe, research offers one important source for such improvement, what are the prospects for important, clinically relevant progress from scientific research?

Many psychiatric clinicians may be unaware that the National Institute of Mental Health has been the major supporter of basic behavioral research and neuroscience for the past 50 years. It is also not well-known that many basic research findings have moved out of the research laboratory and into the clinician's office. For example, exposure therapies, based explicitly on the work of J.B. Watson and other behaviorists of many decades ago, are still widely used to treat anxiety disorders and are the current treatment of choice for posttraumatic stress disorder (PTSD). Contingency management and social skills training interventions, based on principles drawn from Skinner's operant conditioning work (Skinner, 1938) and Bandura's social-learning theory (Bandura, 1986, 1977), have proven effective in the behavioral rehabilitation of the severely mentally ill. Behavioral techniques are also the recommended approach for managing autism. In mood disorders, cognitive therapies for depression, derived from basic research on attention and attention control, help patients to become aware of their characteristic focus on negative perceptions and experiences and to develop new ways of appraising situations.

Despite these advances, the growth of basic research knowledge has severely outpaced efforts to encourage its clinical application. For example, knowledge about fundamental aspects of cognitive operations has galloped ahead in recent years, spurred by better psychological models and new technologies (Figure). Indeed, during the past decade, the number of publications related to cognition and schizophrenia quintupled from 50 to more than 250. But there have been few attempts to apply new basic behavioral knowledge about cognition in clinical trials designed to remedy these deficits (Fenton, 2002). A recent NIMH report underscored the large gaps existing between basic behavioral research and its application to mental health clinical care (National Advisory Mental Health Council, 2000). It noted, as well, that the structure of academic research and its reward systems perpetuate these gaps. For example, basic behavioral and cognitive scientists are often situated in academic departments that value basic research more than applied research and that are far from psychiatry departments and their patients. Additional disincentives include narrow departmental boundaries and the typically slower publication rate of cross-disciplinary research. This problem is not confined to the mental health field or NIMH. It affects all research components of the National Institutes of Health (NIH), which have traditionally focused on sponsoring the finest biomedical science on the assumption that clinical practice would follow basic science breakthroughs. But because the public's interest in supporting basic biomedical science rests on its ultimate contribution to improved health, NIH has recently increased its sponsorship of translational research, which addresses how basic research on brain and behavior informs understanding of the etiology and treatment of mental disorders, and, conversely, how knowledge of mental illness contributes to an understanding of basic processes.

Issues for Mental Health Translational Research

During the past five years, NIMH has launched numerous new initiatives to enhance the clinical relevance of research in both neuroscience and behavioral science. It was clear that large knowledge gaps in the clinical care of severe mental disorders such as depression and schizophrenia might be addressed by reassessing basic behavioral and neuroscientific research knowledge and attempting to apply it more systematically to specific clinical issues. Some examples of actual and potential avenues for translational research follow. It is important to note that the translation process is a two-way street. Basic research findings can suggest new clinical applications, but problems and issues raised by astute clinicians can pose important new questions for basic research.

Improving Cognition in Schizophrenia

Cognitive symptoms, such as deficits in attention and working memory, abound in schizophrenia and are associated with poorer social problem-solving, work performance and community adaptation (Green, 1996). Yet, most current psychosocial rehabilitation approaches, as well as antipsychotic medications, have a relatively limited impact in this area of functioning. Preliminary research evidence suggests, however, that targeted psychological and physiological interventions might ameliorate circumscribed cognitive deficits. For example, several clinical investigators have used the operant technique of shaping to increase sustained attention in patients with schizophrenia hospitalized in state facilities. Improved attention following shaping interventions has been related to greater participation in social skills training classes (Silverstein et al., 1999), successful completion of academic class assignments (Menditto et al., 1991) and continuous performance at work tasks (Spaulding et al., 1986).

Another promising avenue in cognitive rehabilitation emphasizes environmental strategies to offset enduring deficits in patients' attention, memory and problem-solving abilities (Heinssen, 1996). In essence, this approach saturates the patient's natural milieu with cues, instructions and feedback mechanisms that combine to create pathways for adaptive behavior. The impact of environmental engineering methods on the functioning of cognitively impaired individuals is illustrated in case study reports (Heinssen, 2002; Velligan and Bow-Thomas, 2000) and has been validated in a randomized, controlled study (Velligan et al., 2000).

Complementing behavioral approaches are studies searching for ways to enhance memory and attention through pharmacological modulation of neurobiological processes thought to subsume these cognitive functions. For example, more than a decade of neuroscience research on the cellular basis of visual working memory in animal models has clarified the fundamental role of dopaminergic input and D1 (dopamine) receptor function in the prefrontal cortex, an area strongly implicated in cognitive deficits seen in schizophrenia (Lezcano et al., 2000). Other important research has indicated that particular attentional impairments of schizophrenia are associated with genetically based dysfunction of α7 nicotinic receptors in the hippocampus of patients with schizophrenia (Freedman et al., 1997). The research challenge will be to use these insights into the cellular basis of memory and attention to identify new or existing compounds that enhance cognition in patients with deficits in these functions. If successful, this should lead to the availability of new medications to remedy the cognitive impairments responsible for disability in this disorder.

Preventing the Development of PTSD

The events of Sept. 11, 2001, have increased both public and professional awareness of PTSD and the widespread need for effective prevention and treatment of the aftereffects of trauma. A considerable body of basic research on the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic/adrenal response to stress is clarifying the physiological mechanisms underlying PTSD. Preclinical studies have shown that memory formation is facilitated by the rise in norepinephrine following stressful events (McGaugh, 1989), leading to the hypothesis that PTSD may result from excessive noradrenergic stimulation following trauma (Pitman, 1989). Consistent with this, recent findings indicate that the HPA axis is dysregulated in PTSD, resulting in low cortisol levels. Because cortisol normally buffers elevated adrenergic inputs in response to stress, a current prominent theory holds that the abnormal memory formation in PTSD results from low cortisol levels (perhaps resulting from prior traumatic events), which fail to contain the noradrenergic surge (Bremner et al., 1997; Heim et al., 2001; Yehuda et al., 1998). Taken together, these findings suggested that early treatment with behavioral treatments/psychotherapy or with ß-blockers may prevent the development of PTSD (Pitman et al., 2002).

Enhancing Treatment Adherence

Today's psychiatrists have a powerful array of medications to offer patients, but drug treatments are only as powerful as patient adherence permits. In a treatment environment dominated by outpatient care, finding ways to encourage adherence is clearly critical. The NIMH is now stimulating such research, and there are interesting behavioral models to guide these efforts (e.g., the Theory of Reasoned Action [Ajzen and Fishbein, 1980; Fishbein and Ajzen, 1975] and the Health Belief Model [Bebbington, 1995; Becker and Maiman, 1975]). These and other behavioral science theories have successfully informed behavior-change interventions in areas as diverse as AIDS prevention and advertising, and they offer promise for mental health applications. As a very recent case study illustrated (Heinssen 2002), adherence is affected by "the complex interplay of illness features, personal values, interpersonal supports, and environmental conditions," and successful interventions must address these issues in their behavioral complexity.

A review of empirical and clinical findings on medication compliance in schizophrenia (Fenton et al., 1997) suggested that a modified version of the Health Belief Model may be used to guide differential diagnosis of noncompliance and the development of individualized plans to improve adherence. As noted by Fenton et al. (1997), this model posits:

Health behavior is a product of an implicit and subjective assessment of the relative costs and benefits of compliance in relation to personal goals and the constraints of everyday life. Elements of this model include (1) individual goals and priorities; (2) an evaluation of the perceived adverse effects of illness and the personal risk of suffering these effects; (3) the individual's perception of the advocated health behavior's likely effectiveness and feasibility (the patient's subjective assessment of benefits weighed against the costs of treatment, including physical, psychological, and practical disadvantages and barriers to action); and (4) the availability of internal or external cues to action that trigger health behavior.

The model suggested a multidimensional perspective that can aid in evaluating and managing medication noncompliance in patients with schizophrenia. It emphasized achieving patients' cooperation through a combined approach: a) understanding the attitudes and behaviors underlying their nonadherence; b) applying individualized behavior-change strategies; and c) using collaborative pharmacotherapy planning that emphasizes how the medications will aid in reaching patients' personal goals. Heinssen's very recent case study (2002) illustrated how a combination of collaborative treatment contracts, analysis of adherence behaviors, and techniques for boosting medication cues and reinforcers transformed a chronically noncompliant middle-aged patient with paranoid schizophrenia and numerous hospitalizations into an adherent outpatient who obtained work and remained adherent throughout a four-year follow-up. Such reports suggest the potential power of this line of study. However, much more research is needed to explore systematically these promising options.

Challenges for Translational Research

The potential payoff from translational research for psychiatric clinical care is enormous. But it requires intensive and sustained nurturing to overcome many existing barriers. First, translational research in mental health, an enterprise typically integrating diverse areas such as neuroscience, emotion, cognition and social processes, requires researchers with broad perspectives and skills who are willing to collaborate across disciplinary, departmental and even institutional boundaries. As academic departments are now structured, these collaborations are difficult and often not encouraged. Second, it requires researchers who understand the real needs of patients and those who work with them. But many basic behavioral researchers lack strong clinical training and skills, and many strong clinicians lack research training and acumen. In particular, the need for psychiatrist researchers is particularly acute, but a drought of new psychiatrists has contributed to a dwindling pool. Between 1992 and 2001, there were steep declines in the number of M.D. and M.D./Ph.D. programs in psychiatry (from 143 to 104), and in the number of M.D. and M.D./Ph.D. graduates of these programs (from 342 to 210) (Kupfer, 2002).

The NIMH is addressing both of these issues through new incentives intended to stimulate translational research. For example, a newly issued NIMH program announcement, "Building Translational Research in Behavioral Science," is specifically targeted to support translational mental health research linking behavioral science and clinical science. The NIMH is also sponsoring a number of initiatives designed to bring basic research knowledge to bear on specific aspects of mental disorders. Parallel with efforts to give new impetus to research on cognition in schizophrenia, NIMH is promoting behavioral and clinical research on emotion, emotional regulation and mood in depression. In addition, an upcoming multidisciplinary scientific meeting on borderline personality disorder will focus on behavioral components of the disorder as a basis for developing fresh approaches to diagnosis and treatment. New approaches to fostering treatment adherence in the mental health arena are receiving increased attention through a relatively new NIMH behavioral research program that also sponsors research exploring novel ways to reduce mental illness stigma. New efforts to stimulate clinical research training in psychiatry include a loan repayment program based on research participation, as well as a forthcoming mental health education grant program that offers multiple ways to increase the number of M.D. researchers (e.g., through establishing clinical research residency training programs).

It is still too soon to tell how successful these efforts will be, and how well-established translational research can become within the current structure of academic medicine. However, to date, the research community has responded enthusiastically to these new research directions. And both clinicians and mental health care advocates generally support this new emphasis on making federally sponsored mental health research more relevant to those in the front lines of clinical care.

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