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Translational Research: Pathway to Improved Practice?

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.

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