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ScienceWeek
MEDICAL BIOLOGY: ON PSYCHIATRY AS CLINICAL NEUROSCIENCE
The following points are made by T.R. Insel and R. Quirion (J. Am. Med. Assoc. 2005 294:2221):
1) Genomics and neuroscience, two areas of science fundamental to psychiatry, have undergone revolutionary changes in the past 20 years. Yet methods of diagnosis and treatment for patients with mental disorders have remained relatively unchanged. Indeed, during the same time, the public health burden of mental disorders has grown alarmingly. Mental disorders are now among the largest sources of medical disability worldwide[1] and, like AIDS and cancer, they are urgent and deadly.[2,3]
2) The authors argue that psychiatry's impact on public health will require that mental disorders be understood and treated as brain disorders. In the past, mental disorders were defined by the absence of a so-called organic lesion. Mental disorders became neurological disorders at the moment a lesion was found. With the advent of functional neuroimaging, patterns of regional brain activity associated with normal and pathological mental experience can be visualized, including detection of abnormal activity in brain circuits in the absence of an identifiable structural lesion. If mental disorders are brain disorders, then the basic sciences of psychiatry must include neuroscience and genomics and the training of psychiatrists in the future needs to be profoundly different from what it has been in the past.[4]
3) Mental disorders are considered genetically complex, similar to hypertension, diabetes, and cancer. This means they are not the result of a single causative mutation as in cystic fibrosis; rather, several common genetic variations likely contribute to risk.[5] Scores of genes will likely be involved in risk for schizophrenia, autism, bipolar disorder, and even the vulnerability to addiction, but, as we have seen in hypertension and certain types of cancer, their function may aggregate around key intracellular pathways. In the past few months, the map of human haplotypes has been added to the map of the human genome (http://www.hapmap.org/). This new map provides a guide to individual variation, a critical tool for identifying the vulnerability genes for genetically complex disorders. Defining the risk architecture of the major psychiatric disorders appears now limited only by being able to identify the phenotypes and endophenotypes of the illnesses, having access to DNA from enough patients and their relatives, and learning to detect critical gene-environment interactions.
4) It is also important to recognize the limitations of genetics for complex illnesses, such as schizophrenia. Although identifying the alleles associated with psychopathology may indicate risk, it is not clear that genetics research will yield a binary diagnostic test for most of the psychiatric disorders. Nevertheless, identifying genetic variations associated with disease should provide a gateway into pathophysiology, revealing new targets for treatment. Genomics should also yield an approach to understanding risk and thus possible strategies for preventive interventions.
References (abridged):
1. The World Health Report 2002 Reducing Risks, Promoting Health Life. Geneva, Switzerland: World Health Organization; 2002
2. Kessler RC, Berglund P, Borges G, Nock M, Wang PS. Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990-1992 to 2001-2003. JAMA. 2005;293:2487-2495
3. Cole TB, Glass RM. Mental illness and violent death: major issues for public health. JAMA. 2005;294:623-624
4. Kandel ER. A new intellectual framework for psychiatry. Am J Psychiatry. 1998;155:457-469
5. Cowan WM, Kopnisky KL, Hyman SE. The human genome project and its impact on psychiatry. Annu Rev Neurosci. 2002;25:1-50
J. Am. Med. Assoc. http://www.jama.com
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NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA AND COGNITIVE IMPAIRMENT
The following points are made by C.G. Lyketsos et al (J. Am. Med. Assoc. 2002 288:1475):
1) Dementia is a serious public health problem with an increasing prevalence because of the aging of the population.(1) Dementia is characterized by global cognitive decline sufficient to affect functioning.(2) It is a chronic illness with seriously disabling effects for patients, their families, and society.(2) Mild cognitive impairment (MCI) describes cognitive impairment in elderly persons not of sufficient severity to qualify for a diagnosis of dementia.(3) Individuals with MCI have complaints of impairment in memory or other areas of cognitive functioning usually noticeable to those around them. In addition, their performance on memory and cognitive tests is below that expected for their age and education. However, their day-to-day functioning is generally preserved. Several operational definitions for MCI have been proposed.(3,4) Mild cognitive impairment is a chronic condition and may be a precursor to Alzheimer-type dementia.(4) Mild cognitive impairment is often worrisome to patients and families, and is increasingly a presenting complaint for care.
2) Neuropsychiatric symptoms are a common accompaniment of dementia.(5) These include agitation, depression, apathy, delusions, hallucinations, and sleep impairment. In some cases, they cluster into syndromes, leading to the proposal of operational criteria for specific dementia-associated psychotic or mood disturbances. These symptoms have serious adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, more rapid cognitive decline, worse quality of life, earlier institutionalization, and greater care-giver depression. Thus, the neuropsychiatric accompaniments of dementia are serious conditions that are increasingly becoming a focus of attention.
3) The authors report a population-based study to estimate the prevalence of neuropsychiatric symptoms in dementia and MCI. A total of 3608 participants were cognitively evaluated using data collected longitudinally over 10 years and additional data collected in 1999-2000 in 4 US counties. Dementia and MCI were classified using clinical criteria and adjudicated by committee review by expert neurologists and psychiatrists. A total of 824 individuals completed the Neuropsychiatric Inventory (NPI); 362 were classified as having dementia, 320 as having MCI; and 142 did not meet criteria for MCI or dementia. From their results, the authors conclude: Neuropsychiatric symptoms occur in the majority of persons with dementia over the course of the disease. These are the first population-based estimates for neuropsychiatric symptoms in MCI, indicating a high prevalence associated with this condition as well. The authors suggest these symptoms have serious adverse consequences and should be inquired about and treated as necessary.
References (abridged):
1. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337-1342.
2. Rabins PV, Lyketsos CG, Steele C. Practical Dementia Care. New York, NY: Oxford University Press; 1999.
3. Petersen RC, Stevens JC, Ganguli M, et al. Practice parameter: Early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology. 2001;56:1133-1142.
4. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58:397-405.
5. Finkel SI, Costa e Silva J, Cohen G, et al. Behavioral and psychological signs and symptoms of dementia. Int Psychogeriatr. 1996;8(suppl 3):497-500.
J. Am. Med. Assoc. http://www.jama.com
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NEUROPSYCHIATRY: THE DEVELOPMENT OF CHLORPROMAZINE
The following points are made by Samuel H. Barondes (citation below):
1) The existence of drugs that can effectively relieve persistent and disabling forms of mental distress can be traced back to a series of surprising discoveries that began around 1950. Until then, psychiatrists had very little interest in drugs. The only drugs that they regularly prescribed were sedatives, mainly barbiturates.
2) Of these the most widely used was phenobarbital (Luminal). Introduced in 1912 by Bayer, the company that had made its name by creating aspirin, it was especially popular with doctors in general practice, who prescribed it in small doses as an all-purpose psychiatric drug -- an aspirin for the mind. It was also used extensively by psychiatrists in mental hospitals, who gave large doses to agitated or unruly patients to put them to sleep, sometimes for several days.
3) But despite the extensive use of phenobarbital, there was keen awareness of its limitations. At best it provides only transient relief of mental distress, which often returns in full force when the drug wears off. Furthermore, repeated use gradually produces adaptive changes in the brain, so that progressively higher doses are needed to get the beneficial effect. To make matters worse, some people who are treated with phenobarbital become addicted to it and begin to use it compulsively. Little wonder, then, that psychiatrists were not enthusiastic about phenobarbital or the other sedative drugs of that period, all of which had similar shortcomings.
4) Their attitude changed in the i950s with the discovery of a completely different type of medication. Unlike phenobarbital, this new drug improves the mental functioning of certain patients, rather than simply sedating them. Unlike phenobarbital, the gradual changes in the brain that follow from its repeated use makes it progressively more effective rather than less effective. Unlike phenobarbital, it is not addictive. As psychiatrists became convinced of the great value of this new drug, and the other drugs that soon followed, they started dusting off their prescription pads. The discovery of this remarkable medication depended on a series of lucky breaks. They were set in motion in the late 1940s by Henri Laborit, a surgeon in the French navy, when he became interested in the sleep-inducing properties of an antihistamine called promethazine (Phenergan). Although sedation is not a desirable property of a remedy for colds or allergies -- which accounts for the current popularity of nonsedating antihistamines such as Claritin --Laborit decided to turn it to his advantage by utilizing promethazine as an aid in anesthesia. In 1949 he reported this off-label use of promethazine in a Belgian surgical journal.
5) Aware of Laborit's research, Pierre Koetschet, assistant scientific director at Rhone-Poulenc, the French pharmaceutical company responsible for promethazine, initiated a hunt for derivatives with stronger sedative effects. On October 3, 1950, he circulated a memo in which he recommended "chemical work... that will provide substances with maximal activity... [in] prolonging the action of general anesthetics." Koetschet's goal was to find a better promethazine that would be widely used by surgeons and anesthesiologists.
6) Based on Koetschet's suggestion, Paul Charpentier, the chemist who had created promethazine a decade earlier from a smelly tar derived from coal, began tinkering with its structure. In December 1950 he made a novel compound, 4650RP, which he submitted for testing in rats. Having had no reason to believe that there would be anything special about 4650RP, Charpentier was excited to learn that the animal tests showed that it is indeed more sedating than promethazine -- just what Koetschet had hoped for. Furthermore, the drug seemed sufficiently safe to justify its use in humans. In April 1951 Rhone-Poulenc made it available to doctors for testing under its new name, chlorpromazine.
7) Rhone-Poulenc's luck did not end with the discovery of the sedating properties of chlorpromazine. The company also had the good fortune to give test samples to psychiatrists. In retrospect this seems like an obvious thing to have done. But in 1951 most psychiatrists were mainly concerned with the psychological aspects of mental illness and turned to medications only as a last resort. It was Laborit's enthusiasm about the many potential uses of the calming effects of chlorpromazine that encouraged a few psychiatrists to try it. It was they who made the astonishing finding that chlorpromazine is much more than a strongly sedating antihistamine.
Adapted from: Samuel H. Barondes: Better than Prozac: Creating the Next Generation of Psychiatric Drugs. Oxford University Press 2003, p.17.
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