Cure Therapeutics and Strategic Prevention: Raising the Bar for Mental Health Research
T R Insel1 and E M Scolnick2
1NIMH, Bethesda, MD, USA
2 Broad Institute of Institute of MIT and Harvard, Cambridge, MA, USA
Mental disorders cause more disability than any other class of medical illness in Americans between ages 15 and 44 years. The suicide rate is higher than the annual mortality from homicide, AIDS, and most forms of cancer. In contrast to nearly all communicable and most non-communicable diseases, there is little evidence that the morbidity and mortality from mental disorders have changed in the past several decades. Mental health advocates, including psychiatric researchers, have pointed to stigma as one of the reasons for the lack of progress with mental illnesses relative to other medical illnesses. This review considers how the expectations and goals of the research community have contributed to this relative lack of progress. In contrast to researchers in cancer and heart disease who have sought cures and preventions, biological psychiatrists in both academia and industry have set their sights on incremental and marketable advances, such as drugs with fewer adverse effects. This essay argues for approaches that can lead to cures and strategies for prevention of schizophrenia and mood disorders.
Health care 100 years ago was dominated by acute, infectious diseases.1 Chronic infectious and non-infectious diseases, such as tuberculosis, syphilis, leprosy, and the mental illnesses were frequently confined to large public institutions where treatments were largely custodial. After 100 years in this country, most acute infectious illnesses are preventable or curable. In 2005, we find ourselves in the era of chronic illnesses.2 Many of the chronic illnesses of 1905, such as leprosy, syphilis, and (until recently) tuberculosis, have become so rare as to be unknown by young physicians. The conspicuous exception in this history of progress is mental illness. In spite of new medications and psychosocial treatments, mental illnesses, such as schizophrenia and mood disorders, are as much of a public health challenge now as they were a century ago. Mental illnesses are increasingly recognized to be chronic and disabling, belonging to a group of serious medical illnesses that includes heart disease, cancer, and diabetes. However, as we argue throughout this essay, researchers continue to approach mental illnesses as fundamentally different from these other medical diseases. While the goals of biomedical research for heart disease, diabetes, and cancer are generally cure and prevention, very little research for the mental illnesses has set the bar this high. Mental illness research has generally sought incremental advances. Here we ask: What would be a strategy for seeking a cure for a mental disorder? What are the impediments to raising the bar? How can we ensure that less than 100 years from now schizophrenia, mood disorders, and autism will join the ranks of leprosy, syphilis, and tuberculosis?
The public health challenge
As a starting point, it is important to recognize the challenge. Mental illnesses are common, chronic, and disabling. The recent National Comorbidity Survey-Replication (NCS-R) study used a population-based approach to estimate the prevalence of mood, anxiety, and substance use disorders in a household survey.3 Even leaving out schizophrenia, 6% of this household population was identified as having a 'serious' disorder, defined as a suicide attempt with serious lethal intent, work disability or substantial limitations, or being out of role for at least 30 days in the past year. As the NCS-R did not count some of the most severely disabled who are in hospitals, prisons, or homeless, the 6% estimate must be considerably lower than the rate of severe disability from mental illness in the general population. Indeed, schizophrenia affects roughly 1% of the population; most people with this disorder are unemployed, unmarried, and on public assistance.4 Autism spectrum disorder, also not counted in the NCS-R, has been estimated to affect between 0.3 and 0.6% of children, many with a lifelong absence of language and severe social deficits.5
In an attempt to quantify the public health burden of each of the major medical illnesses, the World Health Organization launched the Burden of Disease study. This study, which used the metric of 'disability-adjusted life years' to take into account the duration as well as the severity of the disability, identified mental illness as the number one source of disability from all non-communicable medical causes in developed nations.6 Relative to other major sources of morbidity and mortality, such as heart disease, cancer, and stroke, mental illnesses are chronic and they strike early in life. In the 15-44-year-age bracket, depression and substance abuse disorders account for more than 50% of the disability from all medical causes. Indeed, as shown in Table 1, all of the top five sources of medical disabilities are mental disorders in this age bracket in the US and Canada.
It is also clear that these illnesses account for considerable mortality. There are approximately 30 000 suicides in the US each year, with 90% related to a mental disorder.7 This is greater than the number of deaths from homicide (18 000), AIDS (20 000), and all but three forms of cancer (lung, breast, and colon). While suicide is usually associated with depression, the relative risk of death from suicide is increased nearly 10-fold in schizophrenia and 50-fold in anorexia nervosa.8, 9
What is perhaps most surprising in looking at morbidity and mortality data is that we have made so little progress on some of the most serious mental disorders. While we are seeing recent reductions in deaths from cardiac disease, AIDS, certain cancers, and even homicide, the mortality rate as measured by the number of suicides has changed little in the past century.7 Are we reducing morbidity? The epidemiological data on prevalence and severity are not encouraging. Clearly, more people are receiving treatment over the past decade, but there is little evidence thus far that this has led to reductions in disability.10
Progress: the glass half full
This sober accounting of the state of mental health care neglects substantial progress in many areas. For the most common major illnesses, we now have medical and psychosocial interventions of proven efficacy in randomized, controlled trials. Exceptions include anorexia nervosa and autism where we still lack large-scale, controlled trials. However, even for a chronic, disabling illness like schizophrenia, we have medications that predictably reduce most of the positive symptoms, allowing patients to leave hospitals. Many patients with mood disorders will respond to treatment and some will recover completely.
How does this availability of effective treatments square with the persistent morbidity and mortality of these disorders? The traditional answer is that we fail at service delivery, that is, too few patients receive evidence-based interventions. There are good data to support this argument. The PORT study demonstrated the low rate of use of several evidence-based treatments for schizophrenia.11 A recent meta-analysis of 28 studies demonstrates that family psycho-education can reduce relapse in schizophrenia by 50%, but only 31% of patients receive this relatively cost-effective intervention.12, 13 The NCS-R study reports that only 50% of those with depression receive any treatment and approximately 20% receive minimally adequate care.10 Cognitive behavioral treatment has been demonstrated to be an effective psychotherapy for mood and anxiety disorder, but a recent survey documents that the majority of psychotherapy training programs in the US do not provide adequate training in this or any other evidence-based treatment (Weissman, 2005, personal communication).
Limitations: the glass half empty
While there can be little doubt that we have not fully utilized the available treatments, it is important to recognize that the available treatments are insufficient. To repeat an oft-used metaphor from the history of polio, while we can continue to make more and better iron lungs available, we also need to go after the vaccine. All current medical treatments for mental illnesses are palliative, none are even proposed as cures. Yes, too few people receive evidence-based palliative care. However, to stretch the polio metaphor, we have not yet gone after the vaccine. Indeed, while the recent President's New Freedom Commission on Mental Health Care proclaimed 'recovery' as the goal of mental health care, few research studies have aimed for 'recovery' as an outcome.14
In fairness, researchers may avoid the term 'recovery' because it is difficult to quantify. Remission has been a more widely accepted term, with several attempts to provide consensus definitions of remission in mood disorders and schizophrenia.15, 16, 17 Resnick et al.18 have recently described two definitions of recovery: recovery as an outcome (which might be defined as remission over an extensive duration) and recovery as an orientation (defined as life satisfaction, hope and optimism, knowledge about mental illness and services, and empowerment). While the latter definition of recovery may be more achievable with the provision of current services as envisioned by the President's New Freedom Commission, we suspect this goal would fall far short of what most researchers in cancer or heart disease would accept as success. We suggest that in mental illnesses as in other medical illnesses, we need to aim for a goal of recovery defined by a complete and permanent remission. In other areas of medicine, this approach has been called 'cure therapeutics' (URL: www.jdrf.org).
If cure therapeutics is the goal, how insufficient are today's treatments for mental illnesses? For some disorders such as autism and anorexia nervosa, we simply lack biomedical treatments for the core symptoms. For others, such as schizophrenia, current treatments target only select symptoms. Neuroleptics, both conventional and atypical antipsychotics, reduce psychotic symptoms but may not treat the cognitive deficits or negative symptoms of schizophrenia.19 While five decades of research have shown that antipsychotics have greater efficacy than placebo for reducing hallucinations and delusions in schizophrenia, the effectiveness of these drugs remains disappointing. The recent Clinical Antipsychotic Treatment Intervention Effectiveness (CATIE) trial demonstrated that only about one in four patients with chronic schizophrenia continued either a first or second generation antipsychotic throughout an 18-month trial.20 An analysis of the 1490 patients who began this trial revealed that less than 10% met cross-sectional criteria for symptomatic and functional remission at the 18-month end point (S Scott, personal communication). Of course the patients in CATIE were chronically ill and partially treatment resistant, so a low rate of recovery should not be surprising. However, even in a 5-year follow-up of 118 schizophrenic patients after their first episode of psychosis, only 13.7% met criteria for full remission lasting 2 years or more.21 Schizophrenia remains a chronic, disabling disorder, just as it was a century ago. We know that psychosocial interventions, such as supported employment and family psychoeducation, reduce relapse and may help patients to achieve a life in the community. Surprisingly, we do not know how many or which patients with schizophrenia will recover with the optimal combined application of current medical and psychosocial interventions. And our expectations continue to be limited. For instance, the recent consensus definition of remission for schizophrenia developed by an American Psychiatric Association working group does not even include a requirement of improved functioning, which many patients and families view as the essence of recovery.17
Are treatments for mood disorders much better? Antidepressants, the third most commonly prescribed class of medications in the US, have been shown to reduce the symptoms of major depressive disorder, but these drugs are generally better than placebo only after 6 weeks of administration and in most studies, patients on medication continue to have substantial depressive symptoms.22 A consensus definition of remission published in 1991 has helped the field to measure remission as a target in the treatment of major depressive disorder. How often do SSRIs result in remission? In a large-scale effectiveness study of the SSRI citalopram less than a third of patients met criteria for remission (defined as a 17 item Hamilton Rating Score 23 Placebo was not used as a comparison for this trial, so it is not clear how many of these patients would have recovered without active medication. However, even accepting that roughly one-third meet criteria for remission, is the treatment sufficient? In an illness characterized by intense emotional suffering, hopelessness, and suicidal ideation, should we be satisfied with treatments that require several weeks to be effective and will not lead to remission in the majority of patients? Would our colleagues in medicine be satisfied with these outcomes for an illness characterized by intense pain, high morbidity, and a 4% mortality rate?
In considering the shortcomings of current treatments, one can hardly ignore the absence of progress in developing medications with new mechanisms. While scores of new antipsychotics and antidepressants have been introduced over the past three decades to reduce side effects or improve efficacy, virtually all of these 'new' medication are simply variations on old themes. In contrast to other areas of medicine, there have been few medications with new mechanisms of action developed in the past three decades for schizophrenia and depression (Figure 1). In fact, after more than three decades, we do not truly know the mechanisms or targets for the first generation medications, so one can hardly be certain if newer atypical antipsychotics or SSRIs represent compounds with different mechanisms of action or simply chemical analogues with fewer or different side effects.24
A different approach
Whether one focuses on the glass as half full or half empty, there can be little doubt that we need a different approach for medication development for mental disorders. For the past five decades, the biological study of mental illness has been dominated by the study of the action of the available drugs. In retrospect, this might have been productive if the drugs targeted the core pathophysiology of the disorders. Certainly, the study of insulin action has been useful for developing new approaches to diabetes and research on adrenergic pharmacology has been helpful for cardiovascular medicine. However, as we have just reviewed, the available medications in psychiatry are insufficient for treating the disorders. Indeed, after five decades, we need to recognize that we may never get from neuropharmacology to the pathophysiology of mental disorders.
The canonical approach to treatment development in psychiatry is essentially a recipe for developing 'me-too' compounds, as the entire process is based on developing drugs modeled on an existing, insufficient drug (Figure 2). In other areas of medicine, from heart disease to cancer, treatment development begins by defining pathophysiology (Figure 2). Through cell biology (identifying the tyrosine kinase for myeloid cell division) or epidemiology (recognizing the role of cholesterol in heart disease), the process begins with target identification.
How will we identify new targets for mental disorders? This will happen just as it is happening in the rest of medicine, through research on the core mechanism of these diseases. There are three key steps in this process. First, comprehensive studies of people with these disorders, using genomics, transcriptomics, and proteomics, should identify cellular pathways that are affected. This will undoubtedly be more difficult than in other areas of medicine, but genetics is already providing some hints. The study of the serotonin transporter promoter demonstrates that the short allele is associated with an increase in the vulnerability to depression.25, 26 This allele also is associated with a reduction in the volume of Area 25 in the ventromedial prefrontal cortex, a region with one of the most intense serotonergic innervations in the forebrain.27 Along with reduced volume of this brain region, the short allele is associated with a functional dissociation of this region from the amygdala during the processing of negative affect.27 Understanding how this allele alters development of Area 25 and affects functional connectivity in the forebrain could serve as a starting point for defining targets for major depressive disorder.
However, the search for genomic variations associated with mental illness is really just beginning. With the recent completion of the human haplotype map and the advent of rapid genotyping capacity, we should finally make rapid progress identifying some of the vulnerability genes and thus critical pathways for the pathophysiology of the major mental illnesses.28 In other complex genetic diseases, such as age-related macular degeneration, this strategy is already revealing new targets that would not have been suspected based on decades of descriptive research.29
A second step, the use of in vitro screening, will be critical for identifying new compounds. What we have learned elsewhere in medicine is that target identification is a long and high-risk process with many false leads. It is also the easy part, in that cellular pathways frequently have specific pressure points for modifying function and these may be implicated in many diseases. The second step, developing small molecules that affect these pressure points, may prove more difficult. Indeed, this step has historically been ceded to the pharmaceutical industry. The recent creation of a molecular library screening centers network (MLSCN) in universities and the NIH has, for the first time, encouraged academic investigators to engage in the early phase of identifying small molecules for influencing specific cellular pathways.30 The MLSCN uses a library of small molecules, an array of assays recommended by the field, and high throughput screening centers to identify 'hits' for any given target. Of course, there will be a vast amount of medicinal chemistry necessary to translate a 'hit' in a small molecule screen into a drug, but this network promises to increase the number and the range of targets that can be interrogated. One might expect that early years of this project will largely be focused on cancer and metabolic targets, but the advent of targets for mental disorders should allow rapid development of new compounds for cell biology, some of which may graduate to medications with novel mechanisms of action.
Once new compounds are available from in vitro screening, they can be tested in whole animals. Whereas 'animal models' in psychiatry have largely been developed to simulate psychopathology and validated by their response to existing medications, drug discovery models are created based on a pathologic mechanism and used to search for new targets and ultimately new compounds. For instance, the identification of the role of specific genes in Alzheimer's disease has led to the creation of flies, fish, and mice with homologous alleles, a similar phenotype, and a model system for testing new interventions.31 While similar progress has been reported in a number of neurodevelopmental disorders recently, including Fragile X and Rett syndrome, we have not yet seen the first 'animal model' of a psychiatric disorder in which various genetic lesions are used to develop the phenotype.32, 33
Finally, new compounds can be tested in clinical trials. Trials may increasingly be public rather than private. The NIH Roadmap as part of its effort to re-engineer clinical research has proposed the development of a national network of clinical trialists who can move quickly to test the efficacy and the effectiveness of new treatments. Networks have already been developed in pediatric cancer and cystic fibrosis, such that nearly every patient becomes a participant. The NIMH effectiveness trials, such as CATIE, STAR-D, and STEP-BD may represent the beginning of such a network for mental illness.
Our discussion to this point has focused on the development of new medications that could be cures. The approach described above has proven effective for acute myeloid leukemia. The discovery of a single tyrosine kinase, BCR-ABL, with effects on myeloid transformation led to a small molecule, imitiab, that has already revolutionized treatment of leukemia and other blood disorders.34 This spectacular success is notable because it lays out a pathway of discovery that could lead to cures of many illnesses based on an understanding of pathophysiology, identifying targets for intervention, and developing effective small molecules. It is also notable because it is relatively rare in medicine.
The great public health success stories of the past century are largely stories of prevention. From sanitation to vaccines to smoking cessation to the use of statins, we have proven much more successful at pre-empting disease than curing it. What do we need to pre-empt or prevent mental disorders? As with sanitation, there are undoubtedly public health interventions that will change social norms and improve functioning. For instance, a nurse visitation program for new mothers reduces antisocial behavior in their offspring even 15 years after the intervention.35 This is an important contribution but there is no evidence that such public health interventions reduce morbidity and mortality of schizophrenia, mood disorders, or autism. Psychiatry will need to develop strategies for prevention for each of these disorders.
Two recent approaches offer promise. Most people with schizophrenia have symptoms of this illness for more than 18 months before they become overtly psychotic.36 Studies of the prodrome have reported a strategy to identify those who will go on to have a psychotic break with 86% sensitivity and 91% specificity.37 Analogous to identifying those at risk for myocardial infarction, one can imagine that early intervention could pre-empt the psychotic break and prevent the long-term disability of this illness. In cardiology, biomarkers (plasma lipids), family history, and functional imaging are all critical for identifying risk, and statins, exercise, and even surgical interventions are essential for prevention. In schizophrenia, we lack biomarkers and imaging has not yet been developed for clinical use. Also, we do not know if either medication or psychosocial interventions will pre-empt a psychotic break. Nevertheless, we have an opportunity to develop a strategy for pre-emption that could have an impact as great as or even greater than a new, effective class of drugs.
In many ways, PTSD is a disorder defined by a failure of recovery. Following trauma, an acute emotional response is expected and potentially adaptive. Whereas, most individuals recover from trauma, a small percentage subsequently develop PTSD, the actual percentage resulting from a complex mix of individual vulnerability and the nature of the trauma. Identifying who is at risk for PTSD could focus intervention efforts, much as we do now in cardiovascular disease. Shalev and co-workers have tested a transcriptional approach to identify a fingerprint for susceptibility; others have recommended specific clinical features of the early stress response that indicate a high likelihood for subsequent PTSD.38, 39 We do not yet have the equivalent of cholesterol or Thallium imaging for PTSD, but the model clearly has promise as there are several behavioral and medical interventions that might pre-empt the development of PTSD.40, 41
Note that both of these examples require a better understanding of the pathophysiology of mental disorders, not for developing interventions but for identifying risk. As in the rest of medicine, genomics will be essential, but we will need epidemiology and developmental neuroscience to understand how these illnesses develop if we are to pre-empt them.
Mental illnesses are among the most disabling of medical illnesses. Currently evidence-based medical and psychosocial treatments are not delivered to the majority of patients who would benefit. These palliative treatments are necessary but not sufficient. Even with optimal care, many patients with mental illness will not recover, where recovery is defined as permanent remission. Patients need rapid, effective treatments that target the core pathophysiology of these illnesses. And they need tools for early detection and preventive interventions. Psychiatric research can develop new diagnostic markers and treatments, but this will require defining the pathophysiology of these illnesses. We now have the research tools necessary. Now is the time for research to set an ambitious goal of finding cures and preventive interventions for these disabling illnesses.
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- The President's New Freedom Commission on Mental Health. Achieving the Promise: transforming mental health care in America, Final Report, July 2003.
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- Trivedi M, Rush J, Wisniewski S, Nierenberg A, Warden D, Ritz L et al. Outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical research and practice. Am J Psychiatr, in press.
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Drug development in the past 50 years
While pharmacologic research in cardiovascular medicine and other areas of medicine has developed medications with new mechanisms of action, psychiatry has enjoyed less innovation in terms of drug development. Over the past 50 years, new medications for schizophrenia and depression have been almost exclusively based on existing medications without developing compounds that have either new clinical targets (eg. the cognitive deficits in schizophrenia or suicidal behavior in depression) or new molecular mechanisms (beyond dopamine receptor blockade for schizophrenia or monoamine transporter or enzyme blockers for depression).
Pathways for drug development
The traditional pathway for medication development in psychiatry has begun with a serendipitous clinical observation of efficacy followed by intensive study of the drug's actions. Based on neuropharmacology, new drugs have been developed with greater specificity or potency and these, in turn, are tested in animal studies and clinical trials. This is a recipe for developing new drugs that will mimic existing drugs. The modern approach to drug development begins with identifying a molecular or cellular target based on pathophysiology, then uses high throughput screening of small molecule libraries to detect potential hits that can be refined by medicinal chemistry into drugs for testing in animals and ultimately adapted for clinical trials.
Defining the Public Health Burden at the Beginning of the 21st Century
Causes of Disability by Illness Category (all ages)
|Alcohol and Drug Use||11.5|
|Sense Organ Diseases||6.4|
Causes of Disability by Specific Illness (ages 15-44)
|Hearing Loss (adult onset)||2.4|
Values represent percent of disability due to either class or specific illness. Disability defined by WHO as years lost due to disability for all medical illnesses (excluding communicable diseases). Reference: WHO Report 2002 - http://www.who.int/healthinfo/bodestimates/en/ .