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Ann Marie T. Sullivan, M.D., Acting Commissioner
Governor Andrew M. Cuomo

2005-2009 Statewide Comprehensive Plan for Mental Health Service Services
Chapter 4: Basic and Clinical Research

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Numerous reports document extraordinary gains recently made in mental health care, some of them based on advances in our understanding of the human brain and some based on a better understanding of how to deliver care to those who suffer from mental disorders. Since 1999, the U.S. Surgeon General has released two broad-ranging reports on mental health, one general,1 and one focused on ethnic, cultural, and racial issues.2 In 2001, the World Health Organization (WHO) released a comprehensive report on the state of global mental health.3 In 2003, a White House Commission released its final report on the U.S. mental health care delivery system.4

Collectively, these reports demonstrate an increasing societal awareness of mental illness, and reflect the unambiguous emergence of mental health research as a key priority in the U.S. and internationally. However, the reports also point to substantial gaps in basic and clinical scientific knowledge related to the treatment and prevention of mental diseases, as well as gaps in mental health services research to translate state-of-the-art treatments and incorporate them into mainstream practice. As a result, the disease burden of mental illness remains very high, perhaps higher than that of any other single category of disease, and the costs for treating mental illness are higher than those of other chronic diseases.5

Disease Burden of Mental Illness

Recent WHO estimates suggest that at any one time, 450 million persons worldwide suffer from neuropsychiatric disorders, including depression and/or mania, schizophrenia, dementias, and anxiety disorders.6 In New York State, a majority of the more than 600,000 adults and children who receive services in the public mental health system each year are diagnosed with serious mental illness—a mental disorder where symptoms have led to serious impairment of day-to-day functioning.

The WHO uses disability-adjusted life years (DALYs), a measure that combines estimates of disease morbidity (relative incidence) and mortality to estimate how many productive years of life are lost due to the impact of disease. Mental disease ranks second only to cardiovascular disorders in the number of years lost (Table 4.1). Specifically, 1991 data collected by WHO , Harvard University, and others indicate that 15.4% of the total disease burden in industrialized countries can be directly attributed to mental disorders.7 By comparison, only cardiovascular diseases rank higher, at 18.6%. Cancer is a close third, at 15%, while respiratory diseases (6.2%) and alcohol-related morbidity (4.7%) are fourth and fifth, respectively.1,8

Table 4.1
Disease Burden by Selected Illness Categories in Established Market Economies, 1990
Illness Category Percent of Total Years Lost
All cardiovascular conditions 18.6
All mental illness5 15.4
All malignant diseases (cancer) 15.0
All respiratory conditions 4.8
All alcohol use 4.7
All infectious and parasitic diseases 2.8
All drug use 1.5
Source: DHHS, 1999

Comorbidity, which signifies the simultaneous occurrence of two or more disorders in a person is also important to understanding the disease burden of mental illness. Comorbid mental disorders are often under-recognized and not always effectively treated; they result in lower adherence to medical treatment, an increase in disability and mortality, and higher health costs. According to WHO (2003), research shows that a number of mental disorders (e.g., depression, anxiety, and substance abuse) occur in people suffering from other diseases more often than would be expected by chance. In addition, people suffering from chronic physical conditions have a greater probability of developing mental disorders such as depression (Figure 4.1), and rates of suicide are higher among people with physical disorders than among other people. These relationships between mental and medical illnesses further emphasize the need for continued mental health research.

Figure 4.1 Prevalance of major depression in patients with physical illnesses

High costs of mental disorders compared to other major chronic conditions

In addition to the severe disease burden of mental disorders, research shows that the costs for treating these disorders are high compared to the costs for treating other major chronic conditions. A recent study 9 considers different diseases in terms of the average cost per patient, and as shown in Figure 4.2, Alzheimer's disease and schizophrenia are the two most costly, their average cost per patient being higher than that for cancer and stroke.

Figure 4.2 Yearly Cost Per Patient of Selected Medical Conditions: United States US$/Patient/Year

Given the high disease burden and treatment costs for mental illness, the WHO , U.S. Surgeon General, and President's New Freedom Commission on Mental Health have concluded that we must continue to invest in research at all levels to gain needed advances in treatment, and ultimately to prevent mental illness. Just as research offers great hope for cancer, heart disease, and diabetes, research is essential to reducing the burden of mental illness by improving access to effective care and achieving urgently needed knowledge about the brain, mind, and behavior.

Table 4.2
Mission and Goals of OMH Research

Mission
The mission of OMH Research is to develop better methods of prevention and treatment of mental illness.

Goals

  • Learn more about the causes of mental disabilities
  • Contribute to the development of new treatments.
  • Evaluate the effectiveness of existing and emerging treatment methods.
  • Determine new and better models of service delivery which are planned with input from consumers and are culturally relevant.
  • Quickly and effectively disseminate the results of research findings to State and local clinicians, providers, recipients, families, and other stakeholders.
  • Make the expertise of research scientists available to practitioners in the OMH system through continuous education and consultation.
  • Delineate the magnitude of social cost and burden of mental disorders in order to prioritize utilization of resources.

OMH Research
As a national and international leader in mental health research, New York State is committed to reducing the burden of mental illness and improving access to effective care. OMH research is conducted by the Research Division and also by Evaluation Research (ER) staff from of the Center for Information Technology and Evaluation Research (CITER). The Research Division performs basic, clinical and services research primarily at two locations: the Nathan S. Kline Institute for Psychiatric Research (NKI) in Orangeburg New York, and the New York State Psychiatric Institute (NYSPI) in New York City.10 Evaluation research focusing on service system improvement is conducted by staff from CITER-ER at OMH Central Office in Albany, and some research activities are also carried out at other OMH facilities, including Bronx Psychiatric, Bronx Children's, Buffalo, Creedmoor, Hutchings, Manhattan, Pilgrim, Rochester, Rockland, and Sagamore Children's Psychiatric Centers. New York State's investment in research is augmented by many grants from Federal and other sources through the Research Foundation for Mental Hygiene (RFMH), Inc. This Chapter provides highlights of the exemplary basic and clinical research that is taking place in the Research Division. Chapter 5 provides an overview of OMH evaluation activities that focus on service system improvement.

OMH 's interdisciplinary teams of clinical and services researchers include physicians, epidemiologists, psychologists, neuroscientists, and sociologists who perform a broad range of basic, clinical and services research (Table 4.3). All institute clinical research must first receive approval from the facility Institutional Review Board (IRB), which is in turn overseen by the Director of the Research Division with the assistance of staff from RFMH . All OMH Central Offices research must first receive approval from either the Central Office or Forensic IRB (depending on the population under study), which is in turn overseen by the Senior Deputy Commissioner and Chief Information Officer of CITER , with the assistance of RFMH .

Table 4.3
OMH Research Areas of Study

  • Alzheimer's Disease and Other Memory Disorders
  • Personality Disorders
  • Assessment and Prevention of Violence
  • Post-traumatic Stress and Other Anxiety Disorders
  • Child and Adolescent Psychiatry
  • Psychiatric Epidemiology
  • Genetics
  • Psychoanalytic Research
  • Geriatrics and Gerontology
  • Psychopharmacology and Other Therapeutics
  • Homelessness and Mental Illness
  • Schizophrenia and Bipolar Disorder Research
  • Social and Community Psychiatry
  • Neurochemistry
  • Statistical Sciences and Research Methods
  • Neuroimaging
  • Substance Abuse and Mental Illness
  • Neurophysiology

As they contribute to the science knowledge base for mental illness prevention, treatment, and service delivery, OMH researchers are actively involved in national and international research communities. Each research institute has a strong collaboration with an academic partner—NKI with New York University, and NYSPI with Columbia University. Research is also performed collaboratively with institutions including Alzheimer's Disease International, the Institute of Psychiatry in London, the Louis de la Parte Florida Mental Health Institute, the National Association of State Mental Health Program Directors Research Institute, and the World Health Organization. Additional academic collaborations take place with universities including the State University of New York (SUNY) at Albany, SUNY Buffalo, SUNY Upstate, SUNY Downstate, Brown, Harvard, the University of Pennsylvania, the University of Rochester, Texas A&M, and Yale.

Research in public mental health is also supported through public psychiatry fellowships designed to train psychiatrists who plan to devote their careers to working with high-risk populations in the public sector and conducting research. Fellows are trained to use evaluation strategies, clinical techniques, and management skills within established institutions serving these populations.

Improving Care through Basic and Clinical Research

OMH 's Research Division makes important contributions toward improving care through basic and clinical research. Described here are contributions in two critical areas: schizophrenia and dementia.

Schizophrenia Research

Burden of Care

Schizophrenia is among the costliest of diseases. It affects about two million people in the United States and is more prevalent than epilepsy or multiple sclerosis.11 Nationwide, individuals with schizophrenia account for approximately 20% of all social security disability days and 25% of hospital bed days are devoted to individuals with schizophrenia.12 In New York, approximately 23% (96,000) of adults aged 18-64 who receive care in the public mental health system have a primary diagnosis of schizophrenia or a related disorder. Ten percent of individuals with schizophrenia take their own lives. 13

According to 1996 figures, schizophrenia costs the U.S. health care system $17.3 billion per year with an additional $15.2 billion per year in indirect costs.14 Much of the burden of caring for individuals with schizophrenia is borne at state, county and local levels as the first onset of schizophrenia, which can be longstanding, is usually in the teens and twenties.

OMH researchers were the first to show that symptoms can be grouped into five categories: positive symptoms including delusions and hallucinations; negative symptoms such as loss of interest in the environment and emotional withdrawal; autistic preoccupation symptoms such as preoccupation, poor attention and cognitive deficits; activation symptoms such as hostility, excitement, and poor impulse control; and dysphoric mood symptoms, such as anxiety, guilt, and depression.15 Prior to the introduction of the second generation antipsychotics in the 1990s, positive symptoms were considered the only symptoms of schizophrenia amenable to medication treatment. Now, thanks to research initiated in OMH facilities, new medications are becoming available that target not only positive but also negative, activation, dysphoric mood, and autistic preoccupation symptoms.

The precise causes of schizophrenia, at present, are unknown. We do, however, know that schizophrenia is associated with both genetic and environmental factors. Children of individuals with schizophrenia have about a 15% chance of developing the illness, and if one member of an identical twin pair has schizophrenia, then there is a 50% likelihood that the other twin will have schizophrenia, too. These rates are similar to other complex conditions such as diabetes or obesity, but much lower than those that are single gene.

Current Treatments for Schizophrenia

All current medications for schizophrenia, including both typical and newer atypical antipsychotics, function by blocking the actions of dopamine, a neurotransmitter that carries signals between nerve cells in the brain. Because of various improvements, the newer atypical antipsychotics produce fewer neurological side effects, such as motor disturbances, than did older medications, and are also better tolerated by many individuals. Nevertheless, many of the newer atypical medications have turned out to have unexpected side effects, such as propensity to cause weight gain and precipitate diabetes, complicating clinical care.

Most importantly, only about 20% of individuals with schizophrenia show full resolution of symptoms despite treatment with the best available agents.16 Although persistent positive symptoms contribute to poor outcomes, many individuals can learn to function despite hallucinations or even delusions. More debilitating are negative symptoms such as severe apathy, loss of drive, social withdrawal, and cognitive deficits, such as impaired memory and problem solving ability. These core symptoms of schizophrenia remain largely unaffected by current medications, suggesting that new treatment approaches are required.

Research Programs

OMH conducts schizophrenia research with the overarching goal of developing new treatment approaches for this disease. Over the past five years, OMH researchers have been awarded numerous grants from both the Federal government and independent research foundations to support their research, and have also published hundreds of articles and chapters on topics relevant to schizophrenia. This section highlights how OMH is facilitating the translation of new research approaches into practical new treatments for schizophrenia in three key areas: basic research, studies of neurocognition, and medication treatment studies.

Basic research studies

To develop better treatments, investigators need to understand how schizophrenia arises. Many brain regions and systems operate abnormally in schizophrenia. Although imbalances in the neurotransmitter dopamine were once thought to be the prime cause of schizophrenia, new findings suggest that impoverished signaling by the more pervasive neurotransmitter glutamate—or, more specifically, by one of glutamate's key targets on neurons (the NMDA receptor)- better explains the wide range of symptoms in this disorder.

These new findings are guided by the "phencyclidine model of schizophrenia." The model is based on the observation that phencyclidine causes symptoms similar to those seen in schizophrenia by blocking the NMDA receptors, which are widely distributed in the brain and participate in processes such as learning, memory, attention, and "signal amplification." The ability of phencyclidine and related drugs to induce symptoms of schizophrenia by blocking NMDA receptors has led to the theory that dysfunction of NMDA receptors may cause symptoms of schizophrenia. This model was first proposed by OMH research scientists in a 1991 journal article,17 which has since been cited over 700 times, and was the second most widely cited schizophrenia paper during the 1990s.

Studies conducted over the past several years have investigated effects of phencyclidine, with the goal of developing new targets for treatment. One issue addressed by these studies is the relationship between NMDA disturbances and dopamine functioning in individuals with schizophrenia. With a goal of better understanding the possible causes of schizophrenia and developing more effective treatments, these studies investigated first, the ability of phencyclidine to induce abnormalities of the dopamine system similar to those seen in schizophrenia, and second, the ability of amino acids, such as glycine, to reverse the effects. Study results suggest that glycine counteracts the effects of phencyclidine. This pattern is similar to what has been observed symptomatically in individuals with schizophrenia receiving glycine. A limitation of glycine treatment is that high doses must be given to obtain significant therapeutic effect.

This analysis, and others like it that have been developed by OMH research scientists, permit testing of newer medications that may be shown to treat schizophrenia more effectively. To date, several novel medications, including a class of drugs termed "glycine transport inhibitors," have been shown to produce effects quite similar to those produced by glycine. Several such compounds are currently under clinical development and are expected to begin clinical testing within the next few years. Other newer approaches are currently under development in the Research Division, providing a multifaceted attack on the problem. These studies were funded from grants received from both the National Institutes of Health (NIH) and the Stanley Medical Research Institute. Study results have been published in several high profile journals, including Biological Psychiatry and Neuropsychopharmacology.

Studies of neurocognition

OMH studies of neurocognition are providing a better understanding of the cognitive deficits associated with schizophrenia. Average IQ in the normal adult population is set at 100, and a value of 70 is considered the cutoff for "borderline" intellectual function. Approximately 80% of individuals with schizophrenia are below their expected IQ , based on those of their parents and siblings.18 On average, adolescents with schizophrenia have a mean IQ of 85 and 30% of these adolescents have IQ s of 70 or below.19 This is because their mean IQ is reduced by about five points during childhood, and they then experience another ten to 15 point drop in the six-month to two-year period prior to the onset of the illness. This drop in IQ is illustrative of the "dementia" aspect of schizophrenia that robs individuals of the coping skills they need to deal effectively with their symptoms.

The pattern of cognitive deficit in schizophrenia, however, is different from the pattern observed in other dementing illnesses such as Alzheimer's disease. Further, the degree of brain degeneration is much less, suggesting that the deficits might be reversible (or at least preventable) if underlying causes are known. Thus, OMH studies of neurocognition have the overall goals of providing information to allow early identification of individuals predisposed to schizophrenia, and early intervention to prevent cognitive decline, as important next steps in the management of the disease.

In recent years, significant strides have been made in developing tests that distinguish individuals with schizophrenia from those without the disease. A goal over the next several years is application of these tests to individuals showing what may be early signs of schizophrenia to identify those who require early intervention. OMH researchers use a combination of high-density electrophysiology, which analyzes the minute electrical waves given off by the brain during cognitive activity using electrodes placed on the scalp, and functional brain imaging, which analyzes blood flow in key brain regions using magnetic resonance imaging. Together these techniques can trace the flow of information in the brain, and determine the locations and hopefully, the causes of abnormal brain functions.

One area of particular interest is in the early stages of information processing. Most schizophrenia studies focus on dysfunction of complex brain regions, and while there are deficits associated with those regions in schizophrenia, even much simpler processes appear to be impaired which involve how individuals "decode" the world around them. For example, it has often been assumed that individuals with schizophrenia hear and see information normally, but just interpret it incorrectly. OMH research has shown that this is not the case. For example, individuals with schizophrenia have much more difficulty than others in detecting simple changes in musical pitch. As a result, they are less sensitive than other individuals to detecting emotion based upon other people's vocal intonations. Individuals with schizophrenia also have difficulty in decoding complex images, such as partially obscured pictures, or even facial expressions. This also leads to difficulty in understanding other people's emotions. These same deficits also give rise to difficulty in reading books or magazines, another overlooked deficit in schizophrenia.

These deficits in basic sensory processes contribute to the difficulty that individuals with schizophrenia may have in what for most people are simple day-to-day interactions-decoding a person's emotions by looking at their face or listening to the tone of their voice, expressing their own emotions, or distinguishing frightening from non-frightening objects. These basic deficits are not affected by the types of medication available to date, and whether or not they respond to newer medications remains to be established. Recent OMH studies of cognitive dysfunction point up new avenues for cognitive remediation. For example, when individuals with schizophrenia are helped to read, their comprehension is often relatively normal. These findings provide new avenues for designing remediation programs to address the core disturbances in schizophrenia, and hope for ultimate rehabilitation.

Medication treatment studies

OMH research scientists conduct medication trials in order to hasten the use of behavioral science and neuroscience advances in clinical care. The research institutes have been test sites for several promising compounds, including glycine and other compounds that stimulate NMDA receptors.

Clinical trials are conducted collaboratively across several centers. For example, an OMH research institute participated recently in the National Institute for Mental Health (NIMH) CONSIST trial for treatment of cognitive and negative symptoms, and will be one of only six sites nationwide that will be evaluating new medications to treat neurocognition as part of the newly awarded, NIMH -funded TURNS consortium. Some of the compounds entering clinical trials, such as D-serine, are compounds conceived or developed within OMH research institute laboratories. Others have been developed based upon complementary theories elsewhere.

Dementia Research

Burden of Care

Dementia describes a syndrome associated with a range of diseases that progressively impair brain functions and rob the afflicted of their ability to learn, reason, make judgments, communicate and carry out daily activities. Dementia knows no social, economic, ethnic or geographical boundaries, and the full extent of its impact has only begun to be appreciated. Alzheimer's disease, the leading cause of dementia, accounts for 50-60% of all cases. Other common causes of dementia include vascular dementia, Parkinson's disease, and Lewy Body disease.20 Alzheimer's disease or other forms of dementia frequently coexist with psychiatric conditions. In older psychiatric patients with even mild dementia, disruptive behaviors are more common and persistent, and increase the utilization of psychiatric services, including hospitalization. Studies of psychiatric inpatient populations show that the presence of dementia is under-recognized by clinicians, which may complicate the treatment outcomes of these individuals.

Increasing age is the greatest risk factor for Alzheimer's disease. The likelihood of developing Alzheimer's approximately doubles every five years after age 65.21,22 By age 85, the risk reaches nearly 50%.23,24 An estimated 4.5 million Americans have Alzheimer's disease 25,26 and, based on a 1992 Gallup survey that indicated 1 in 10 persons had a family member with Alzheimer's disease, in 2000 an estimated 19 million Americans 21 years of age or older had a family member with the disease.27,28 These numbers have more than doubled since 1980 as the percentage of elderly in the population has risen. In New York State, the number of people with dementia, currently estimated to be 300,000, will grow to approximately 500,000 in just five years.29 Without a preventative therapy, the burden of care for this growing population will fall to a smaller, younger generation.

The impact of Alzheimer's and related disorders on individuals, families, and our health care system makes dementia one of society's greatest medical, social and fiscal challenges. Alzheimer's disease advances at widely different rates, and consequently, the duration of the illness can vary from three to 20 years. Because of its disabling rather than fatal nature, dementia not only deprives individuals of many years of healthy life, but also consigns family members to long years of care giving associated with substantial psychological and financial strain.

More than 70% of people with Alzheimer's disease live at home, where nearly 75% of their care is provided by family and friends. The remaining care 30 is provided by professional caregivers at an average cost of $12,500 per year, which is paid mostly out-of-pocket by families. Dementia is the greatest single contributor to the cost of residential aged care, which often exceeds $60,000 per year per consumer. Nationally, direct and indirect annual costs of caring for individuals with Alzheimer's disease alone are at least $100 billion a year.31 These include $61 billion in costs to American businesses for Alzheimer health care and expenses related to caregivers of individuals with Alzheimer's, which include lost productivity, absenteeism, and worker replacement.32

The promise of Dementia Prevention

In the absence of a cure for Alzheimer's, interventions that produce even a modest delay in the onset of dementia will have a major positive public health impact. It has been estimated that a preventative treatment in 2005 that delays the onset of Alzheimer's by just five months could reduce new cases by 5% each year. A preventative treatment that delayed onset by five years could reduce new cases annually by 50%, and halve the burden of total cases by 2040. The savings in terms of human suffering are immeasurable. Given the impending epidemic of dementia, there is an urgent need to maintain the commitment to research to reduce the human toll of dementia and its expanding economic burdens.

Research Programs

A wealth of accumulating evidence indicates that with a sustained research effort, the goal of delaying dementia is within reach. Over the last 15 years, remarkable progress has been made toward understanding dementia and improving its management as a result of advances in neuroscience, genetics, medical technology, and clinical care. OMH researchers have been on the forefront of these developments, contributing to both the understanding of the causes of dementia and the use of this knowledge to develop the newest generation of therapies aimed at preventing or delaying its onset. Complementary clinical programs have continued to make advances in the treatment and management of individuals who already have dementia and are in the community, residential homes, and State hospitals.

For their work in dementia, OMH researchers have received the highest awards bestowed by the National Institute of Health (NIH), the national Alzheimer's Association and other organizations. Their research has been published in highly regarded scientific journals, including Nature, Science, and Neuron. More importantly, as illustrated below, OMH research in dementia and affiliated clinical programs has made tangible progress toward translating research findings into practical clinical treatments for the prevention, treatment and management of dementia, and disseminating this knowledge to individuals with dementia and their caregivers.

Progress toward dementia prevention is accelerating

Alzheimer's disease is a devastating disorder of the brain's nerve cells and not a normal part of aging. By the time symptoms emerge, nerve cells that process, store and retrieve information have already begun to degenerate and die. The areas of the brain that control memory and thinking skills are affected first, but as the disease progresses, cells die in other regions of the brain. Alzheimer's disease has no known single cause, but in less than two decades, scientists have learned a great deal about factors that play a role. Two abnormal microscopic structures that appear in the brain, called "plaques" and "tangles," are considered Alzheimer hallmarks. Plaques contain clumps of amyloid protein that accumulate outside the brain's nerve cells. Tangles are twisted strands of another protein that form inside cells. Although it has not been fully resolved whether or not plaques or tangles cause Alzheimer's, therapies that lower amounts of these abnormal proteins have been a key objective of many researchers trying to develop new therapies to prevent or treat the disorder.

OMH researchers have advanced this goal by identifying novel processes that can cause nerve cells to overproduce amyloid, thereby revealing new possibilities for blocking amyloid accumulation. In international collaborative studies, OMH research scientists recently discovered that amyloid in the blood outside the brain may contribute to its accumulation in the brain. This research is being viewed as a scientific basis for novel medications that act outside the brain to prevent amyloid accumulation, including the Alzheimer's vaccine currently in clinical trials. OMH research scientists were also instrumental in a milestone study that first demonstrated memory-enhancing effects of an amyloid vaccine, and are well recognized for their models of Alzheimer's which are being used worldwide by pharmaceutical companies and scientists to screen potential therapeutic agents for both Alzheimer's and Parkinson's disease. In addition, new models of Alzheimer tangle pathology recently patented by OMH researchers are already being used in drug discovery programs.

It has become clear that whatever triggers Alzheimer's disease begins to damage the brain years before symptoms appear. OMH research scientists have shown that, even before this damage or amyloid appears, critical changes in nerve cell function are detectable up to a decade or more before the person develops symptoms of Alzheimer's. These Alzheimer's-specific changes, the earliest known sentinels of the disease detected so far, involve defects in the way brain cells bring in and metabolize nutrients, and provide insights into why and how brain cells eventually die in the disease. These findings, which were the principal basis for a 1999 $7 million NIH grant award for OMH Alzheimer's research, are revealing novel strategies for early diagnosis and a rationale for new prevention approaches, some of which have already reached the stage of clinical testing. That disease-specific changes precede the symptoms of Alzheimer's by many years, or even its earliest nerve cell damage, has enormous implications. The time that exists between the first tell-tale biochemical sign of disease and the first memory symptoms provides a valuable opportunity to intervene before brain cells are ever lost.

Achieving earlier diagnoses and preventative treatments by capitalizing on this knowledge is a major thrust of current OMH dementia research. For example, OMH researchers have utilized advanced brain imaging to detect abnormal brain function, possibly heralding the future onset of Alzheimer's, in symptom-free elderly individuals who are at higher genetic risk to develop the disease. Other new imaging techniques are now being applied with the goal of widening the window of prevention opportunity even further.

It has been estimated that a preventative treatment in 2005 that delays the onset of Alzheimer's by just five months could reduce new cases by 5% each year. A preventative treatment that delayed onset by five years could reduce new cases annually by 50%, and halve the burden of total cases by 2040.

Promising recent advances in the treatment and prevention of Alzheimer's

Among the most promising recent advances in the treatment and prevention of Alzheimer's are new studies revealing factors, beyond age and rare genetic causes, that increase the risk of dementia. These studies have raised hopes that dementia onset may be delayed or prevented by modifying these factors. Of particular importance is the discovery that vascular disease plays a large role not only in vascular dementia, but also in Alzheimer's disease, most likely by decreasing blood flow to the brain. The benefits from this research in terms of Alzheimer's prevention may be coming soon since moderately effective measures that can prevent stroke and disease of the blood vessels in the brain already show promise.

People with heart disease are at higher risk of developing dementia while those with Alzheimer's disease pathology decline faster if they also have vascular-related brain damage. Research in this area was catalyzed by the findings of an OMH research scientist, who identified the first gene causing a form of dementia that is related to Alzheimer's but affects primarily the blood vessels. Subsequently, these scientists have developed unique laboratory models of the disease for drug screening and understanding further this important interaction of blood vessel disease with Alzheimer's disease. In current clinical trials of the amyloid vaccine and other amyloid-lowering therapies, the impact on blood vessels has assumed critical importance and research by OMH scientists is having a crucial influence on the design of these promising therapeutic strategies.

Strengthening the link between heart and brain in Alzheimer's disease even further are new observations that a host of risk factors for vascular disease (including high blood pressure, cholesterol and homocysteine, diabetes, smoking, and obesity) increase risk for dementia and hasten memory decline. Emerging evidence suggests that controlling these risk factors and promoting general healthy aging reduce Alzheimer risk.

Observations that dementia may develop at different rates in individuals from the same ethnic population living in different parts of the world has suggested that lifestyle factors, many of which are modifiable, may potentially forestall the onset of dementia. Diet is one of these lifestyle factors. Foods or supplements containing antioxidants or omega-3 fatty acids have been found to be protective whereas foods high in total and saturated fat and cholesterol increase risk. Seminal work by several OMH researchers showing that dietary reductions of cholesterol lowered amyloid accumulation in the brain led to the first demonstration that cholesterol-lowering drugs, called statins, have similar but even more potent effects. These and other findings have provided the impetus for current clinical trials of statins nationwide in people with Alzheimer's disease, the first of which has recently reported very encouraging results.

Based on these rapidly emerging findings and the precedent that population-based strategies to reduce heart disease (general screening, dietary interventions, education, and pharmacotherapy) reduce mortality and cardiovascular risk, and are cost effective, the Alzheimer community and the national Alzheimer's Association urge the adoption of healthy lifestyles such as regular exercise to delay the onset of dementia, which would have enormous benefits to citizens around the nation and in New York State.33

Even after neurodegenerative processes have begun, the symptoms of dementia are treatable. Of the four medications available to treat Alzheimer's, three act by raising levels of a chemical messenger (acetylcholine) that is depleted when cells die, while the fourth (memantine) belongs to a new generation of drugs aimed at preventing brain cells from dying.

In addition to its history of conducting trials on acetylcholine-enhancing drugs as they were developed, OMH research institutes served as a clinical site in the first U.S. study showing the efficacy of memantine in moderate Alzheimer's. The study found that memantine showed beneficial effects on thinking, behavior, and overall functioning (as compared to a placebo). Moreover, the medication was found to be quite safe and not significantly different from placebo in terms of reported side effects. As a result, memantine received FDA approval and was made available in 2004 for the treatment of "moderately to severely impaired" individuals with Alzheimer's. Individuals who were in the group receiving the study medication were able to receive this medication when they were in the earlier, rather than later stages of the disorder, and three or four years prior to the time it became available to others commercially.

Managing Dementia: Raising Standards of Care

An important mission of OMH Alzheimer's research has been to optimize the management of both memory and behavioral symptoms of people with dementia. Besides trials of new memory-enhancing medications, these efforts have included research into effective treatments for agitation, the most common symptom leading to hospitalization and residential nursing care of demented individuals, as well as investigations on the adverse effects of commonly used medicines for dementia. Such studies are crucial to the development of best practice standards for dementia care.

OMH clinicians and scientists are also working in concert with residential care groups, local clinicians, and Alzheimer's Association chapters to inform them about the latest advances in dementia therapy and management. The need is great. A recent OMH public information event for Alzheimer's disease attracted an audience of more than 400. Although there is now greater awareness of dementia, there is much less understanding of the nature of these disorders, their progression, and the potential for prevention. Increasing public awareness and understanding on an ongoing basis sends a strong public health message that individuals may be able to reduce their risk of dementia and that support for care-givers, evidence-based care interventions, and medications can reduce the impact of the condition.

Future Directions for Schizophrenia and Dementia Research

While OMH research programs continue to be highly effective in determining causes and new treatment approaches for schizophrenia and dementia, much work still remains. In schizophrenia research, new imaging approaches have been developed over recent years that permit detailed assessment of structural brain abnormalities in schizophrenia, to complement functional neuroimaging studies. Highly significant relationships have been observed between these brain structural deficits and both symptoms and neurocognitive dysfunction that need further study. There is also a clear need to start translating current treatment approaches into younger populations to prevent the deterioration that often occurs in the early years of the illness, and to determine whether schizophrenia can be prevented rather than just treated.

In dementia research, more needs to be done to establish safe therapies that prevent or delay the onset of the many forms of dementia. We are beginning to identify some of the factors that increase or reduce the risk for Alzheimer's disease, but it is also critical to know how these factors influence specific aspects of the disease process in the brain in order to maximize the effectiveness and safety of potential therapies. The most successful preventative and treatment approaches will require that interventions begin during the period between the first brain changes and the appearance of the first memory symptoms of Alzheimer's. Such interventions can happen only if this crucial window of time can be recognized reliably in a diverse and aged population. No such early diagnostic test currently exists but momentum toward this goal is building. Biomarkers, which are factors measurable in blood or other fluids that provide information about the presence of disease, are being investigated in people with Alzheimer's disease. More research in this area is needed if caregivers are to begin treatments early enough in the disease to make the greatest difference.

OMH Research Benefits Many New Yorkers

As has been also described above, research conducted at OMH 's research institutes benefits an increasingly large proportion of New York State's population and many millions of people nationally and internationally. Table 4.4 presents examples of how a broader population benefits from OMH research. In addition to the examples provided below, Chapter 8 presents an extensive review of OMH 's suicide prevention initiative, which represents a significant research effort applicable to a broader audience.

Table 4.4.
Examples of OMH Research Benefiting a Broader Population

Psychological Risk Factors for Heart Disease
This research explores a psychophysiological model of coronary disease that identifies the autonomic nervous system as the link between psychological factors and atherosclerosis. Specifically, the model suggests that by enhancing parasympathetic control of the heart, already known by cardiologists to promote survival following myocardial infarction, potentially pathogenic oscillations in blood pressure can be buffered. This model is the basis of several ongoing investigations funded by NIMH and the National Heart, Lung, and Blood Institute to explore factors that alter cardiac autonomic control: aerobic conditioning, cognitive-behavioral reduction of hostility, and surgical denervation. Additional research studies the relationship of depression to the development of cardiac disease and to mortality and morbidity in heart attack, unstable angina, and coronary artery bypass patients.

Seasonal Affective Disorder
Within the past two decades, seasonal affective disorder (SAD) has been increasingly diagnosed and treated. OMH researchers are comparing three distinct treatments for seasonal affective disorder: post-awakening bright light therapy, dawn simulation, and high-intensity negative air ionization (the latter two administered during sleep). Interim results demonstrate superiority of all three active treatments relative to a low-density negative ion placebo control. OMH researchers have also published a novel on-line instrument (http://www.cet.org/en/index.html Leaving OMH site ) by which people can estimate their circadian rhythm phase and determine the optimum time for antidepressant light exposure. The instrument is being used in a new research study to chart chronotype (e.g., the set of circadian factors that determine whether someone is a morning or an evening person) globally and across the seasons.

Conclusion

New York State has a tradition of commitment to engaging in basic and clinical mental health research that has brought hope to many thousands of individuals with mental illness and their families.

Individuals with mental illness and their care providers are entitled to the same high quality of research-based information upon which to make treatment and service decisions as persons with heart disease, cancer, or other general medical conditions. Today, researchers, mental health care providers, general health care personnel, service systems administrators, policymakers, and most critically, individuals with mental illnesses and their families recognize that research is essential to generate information that, properly used, will better enable people with mental illnesses to receive optimal care. Mental health research must be sustained to guarantee improving the health and quality of life of individuals with mental illness, their families and our communities across New York State.

Notes

  1. United States Department of Health and Human Services. (1999). Mental health: A report of the surgeon general. Rockville, MD : U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Mental Health Services, National Institutes of Health, National Institute of Mental Health.
  2. United States Department of Health and Human Services. (2001). Mental health: Culture, race and ethnicity. A supplement to Mental health: A report of the surgeon general. Rockville, MD : U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Mental Health Services, National Institutes of Health, National Institute of Mental Health.
  3. World Health Organization. (2001). The World Health Report 2001. Mental health: New understanding, new hope. Geneva: WHO .
  4. New Freedom Commission on Mental Health, Achieving the Promise: Transforming Mental Health Care in America. Final Report. DHHS Pub. No. SMA-03-3832. Rockville, MD : 2003. Retrieved November 1, 2004 from http://www.mentalhealthcommission.gov/reports/FinalReport/toc.html Leaving OMH site
  5. Disease burden associated with "mental illness" includes suicide. In these rankings, mental illness ranks first if one includes the burden of substance abuse in addition to suicide.
  6. World Health Organization. (2003). Investing in mental health. Geneva: WHO .
  7. Mental disorders include unipolar major depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and self-inflicted injuries (e.g., suicide). Excluded are substance-abuse disorders that include alcohol addiction.
  8. Murray, C. J., & Lopez, A. D. (1996). Evidence-based health policy-lessons from the global burden of disease study. Science, 274(5288), 740-743.
  9. Berto, P., D'Ilario, D., Ruffo, P., Di Virgilio, R., & Rizzo, F. (2000). Depression: Cost-of-illness studies in the international literature: A review. The Journal of Mental Health Policy and Economics, 3(1), 3-10.
  10. More information about the institutes can be found at their respective Web sites: http://nyspi.org/Kolb/index.htm Leaving OMH site and http://www.rfmh.org/nki/ Leaving OMH site .
  11. Hafner, H., & an der Heiden, W. (1997). Epidemiology of schizophrenia. Canadian Journal of Psychiatry, 42, 139-51.
  12. Management Decision and Research Center. (October, 2002). Effective treatment for schizophrenia. Practice Matters, 7(1): 1-6.
  13. National Institute of Mental Health. (2000, May). Schizophrenia research fact sheet. Bethesda, MD : NIMH Office of Communications and Public Liaison. Retrieved December 15, 2004, at http://www.nimh.nih.gov/health/publications/schizophrenia-easy-to-read/schizophrenia-easy-to-read.shtml Leaving OMH site
  14. Knapp, M., Mangalore, R., & Simon, J. (2004). The global costs of schizophrenia. Schizophrenia Bulletin, 30(2):279-293.
  15. White, L., Harvey, P.D., Opler, L.A., & Lindenmayer, J.P. (1997). Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. The PANSS Study Group. Psychopathology, 30(5):263-274.
  16. Robinson, D.G., Woerner, M.G., McMeniman, M., Mendelowitz, A., & Bilder, M. (2004). Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry, 161(3):473-479.
  17. Javitt, D. C., & Zukin, S. R. (1991). Recent Advances in the Phencyclidine Model of Schizophrenia. American Journal of Psychiatry, 148(10), 1301-1308.
  18. Goldberg, T.E., Torrey, E.F., Gold, J.M., Bigelow, L.B., Ragland, R.D., Taylor, E., Weinberger DR. (1995). Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder. Schizophrenia Research, 17(1):77-84.
  19. Hollis, C. (2002). Adolescent schizophrenia. Advances in Psychiatric Treatment, 6, 83-92.
  20. Lewy Body disease, the second most frequent cause of dementia in elderly adults, is a neurodegenerative disorder associated with abnormal structures (Lewy bodies) found in certain areas of the brain. Because these structures and many of the symptoms of dementia with Lewy bodies are associated with Parkinson's and Alzheimer's diseases, researchers do not yet understand whether dementia with Lewy bodies is a distinct clinical entity or perhaps a variant of Alzheimer's or Parkinson's disease.
  21. Brookmeyer, R., Gray, S., & Kawas, C. (1998). Projections of Alzheimer's Disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health, 88(9): 1337-1342.
  22. National Institute of Aging. (2004). 2003 Progress report on Alzheimer's disease: Research advances at NIH . U.S. Department of Health and Human Services, National Institutes of Health, Publication No. 04-5570.
  23. Evans, D.A., Funkenstein, H.H., Albert, M.S., et al. (1989). Prevalence of Alzheimer's Disease in a community population of older persons: higher than previously reported. JAMA, 262(18): 2551-2556.
  24. National Institute of Aging. (2000). 2000 Progress report on Alzheimer's disease: Taking the next steps. U.S. Department of Health and Human Services, National Institutes of Health, Publication No. 00-4859.
  25. Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A., & Evans, D.A. (2003). Alzheimer disease in the U.S. population: Prevalence estimates using the 2000 Census. Archives of Neurology, 60(8): 1119-1122.
  26. National Institute of Aging. (2004). 2003 Progress report on Alzheimer's disease: Research advances at NIH . U.S. Department of Health and Human Services, National Institutes of Health, Publication No. 04-5570.
  27. Alzheimer's Association. (1993). Gallup survey commissioned by the Alzheimer's Association. Chicago: Alzheimer's Association Green-Field Library.
  28. U.S. Census Bureau. (2000). QT-01. Profile of general demographic characteristics: 2000. Data Set: Census 2000 supplementary survey summary. Tables. Accessed online December 15, 2004, at
    http://www.census.gov/mp/www/cat/decennial_census_2000/census_2000_profiles_of_general_demographic_characteristics_national_summary_special_packages.html Leaving OMH site .
  29. New York State Department of Health. (2004). Chronic disease teaching tools - New York State dementia registry: Quick facts about the registry and dementia in New York State. Albany, NY : Author. Retrieved December 15, 2004, at http://www.health.state.ny.us/nysdoh/chronic/nysdr.htm Leaving OMH site .
  30. The bulk of this care is custodial care/supervision (e.g., help with activities of daily living, preventing wandering, etc.) and may include skilled or unskilled nursing care.
  31. Medicare and Medicaid Costs for People with Alzheimer's Disease. Washington, D.C. ; April 2001: The Lewin Group; p.1. Retrieved December 16, 2004 at http://www.alz.org/national/documents/alzreport.pdf Leaving OMH site  (PDF)
  32. Alzheimer's disease: The costs to U.S. businesses in 2002. Chicago: Alzheimer's Association. Retrieved December 15, 2004, at: http://www.alz.org/national/documents/report_alzcosttobusiness.pdf Leaving OMH site  (PDF)
  33. Alzheimer's Association. (2004, July 20). Alzheimer's, cardiovascular disease share risk factors: Cholesterol levels, diabetes and hypertension - known risk factors for strokes and heart attacks - can contribute to risk of cognitive decline and dementia later in life [news release]. Chicago: Author. Retrieved December 15, 2004, at http://www.alz.org/national/documents/report_alzfactsfigures2009.pdf Leaving OMH site  (PDF)

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