Thomas R. Insel, MD

[[{"type":"media","view_mode":"media_crop","fid":"43174","attributes":{"alt":"schizophrenia","class":"media-image","height":"167","id":"media_crop_3418870003478","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4790","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","title":"","typeof":"foaf:Image","width":"138"}}]]As with other chronic health conditions, there is no magic bullet for schizophrenia. At least as important as the search for magic bullets, however, is an increasing focus on early intervention and integrating existing treatments. This year, we’ve had encouraging news about integrated, comprehensive approaches for treating people with first episode psychosis, most recently from a major NIMH initiative, the Recovery After an Initial Schizophrenia Episode, or 

. RAISE looked at coordinated specialty care for first episode psychosis. With coordinated specialty care, the young person experiencing first episode psychosis works with a team of specialists to create a personal treatment plan, combining recovery-oriented psychotherapy, low-dose medication management, family education and support, case management, and work or education support. Coordinated specialty care emphasizes shared decision making, including family members, when possible.

RAISE began as two separate studies back in 2008. Each study looked at a different aspect of coordinated specialty care. One study, the RAISE Implementation and Evaluation Study, focused on the best way for clinics to start using the treatment program. The other project, the RAISE Early Treatment Program (

), studied whether or not the treatment worked better than care typically available in community settings. John M. Kane, MD, of the North Shore-Long Island Jewish Health System and the Zucker Hillside Hospital, led RAISE-ETP and . . . his team released the primary outcomes from this 

The RAISE-ETP research team spent five years testing their coordinated specialty care model, called NAVIGATE, at 34 real-world clinics across the country. They compared their treatment program to typical treatment and found that 223 clients who received the NAVIGATE coordinated specialty care program stayed in treatment longer; experienced greater improvement in their symptoms, interpersonal relationships, and quality of life; and were more involved in work or school compared with 181 clients at the typical-care sites. NAVIGATE clients who had a shorter duration of 

 (the time between the beginning of psychotic symptoms and the beginning of treatment) when they started the study showed greater improvements than those with longer duration of untreated psychosis.

Two other research teams have reported findings in recent months from trials of coordinated care for first episode psychosis. A team at Yale University collaborated with a center run by Connecticut’s mental health agency to test whether a comprehensive first episode psychosis service in the context of a public sector clinic could improve outcomes. After a year, those who received comprehensive care had fewer hospitalizations than those in standard care, were more likely to remain employed, and did better on overall measures of functioning.

 also reported that, in a trial of specialized, intensive treatment, patients receiving the intervention for two years had reduced psychotic and negative symptoms, were more satisfied and adherent with treatment, and were hospitalized less than patients receiving standard care.

 As a result of this study, the treatment has been implemented throughout Denmark.

The information coming from these trials shows that coordinated specialty care is an incremental but positive step in treating first episode psychosis. Coordinated specialty care-and ongoing testing of these approaches, with continuous incorporation of findings into practice-brings us closer to being able to intervene in a way that will enable young people with psychosis to avoid the long-term disability and vulnerability that too many experience. It is encouraging to note that more and more states-32 to date-are adopting coordinated specialty care programs to treat first episode psychosis. Their efforts have been supported by additional funding coming from the 

Community Mental Health Services Block Grant

 program administered by the Substance Abuse and Mental Health Services Administration . Based on the RAISE results, NIMH is launching the 

Early Psychosis Intervention Network (EPINET)

, aimed at creating a network of clinical sites offering evidence-based specialty care to persons experiencing signs of first episode psychosis. Using data sharing agreements, EPINET centers will gather participant-level data which can then drive improvements in clinical practice, a “learning health-care system.”

It should perhaps be no surprise that, given the complexity and variability of schizophrenia, outcomes will be better with treatment that is individualized, multi-faceted, and attuned to the preferences of each patient. While we have a long way to go, these recent reports suggest we’re headed in the right direction.

Dr Insel is the former Director of the National Institute of Mental Health (NIMH). This article, originally published on October 20, 2015, is posted here courtesy of NIMH.

http://www.nimh.nih.gov/about/director/2015/new-hope-for-treating-psychosis.shtml

1 Kane JM, Robinson DG, Schooler NR, et al. Comprehensive Versus Usual Community Care for First Episode Psychosis: Two-Year Outcomes From the NIMH RAISE Early Treatment Program. 

doi: 10.1176/appi.ajp.2015.15050632. Epub 2015 Oct 20.
2 Srihari VH, Tek C, Kucukgoncu S, et al. First-Episode Services for Psychotic Disorders in the U.S. Public Sector: A Pragmatic Randomized Controlled Trial. 

 2015;66:705-712.
3 Nordentoft M, Melau M, Iversen T, et al. From research to practice: how OPUS treatment was accepted and implemented throughout Denmark. 

Articles

Results from a major study provide evidence that coordinated specialty care can improve outcomes for first episode psychosis. Dr Insel writes about the RAISE project and other recent studies of coordinated care.

New Hope for Treating Psychosis

The Medici effect encapsulates the benefits of cross-pollination and interaction between individuals and teams from different fields in the pursuit of innovation. It is named after the wealthy Medici family who helped catalyze the Renaissance by bringing together poets, philosophers, scientists, painters, and other artisans to Florence, Italy. We believe the modern Medici effect is convergence science, and it is set to revolutionize health and medicine in the 21st century given the interplays occurring among physical, computer, and life sciences.

Convergence science is defined as the merging of distinct technologies, industries, tools, disciplines, or devices into a unified whole to create new pathways and opportunities. Convergence relies on a new integrated approach to solving problems too complex for any single discipline. Sharp and Langer1 described convergence as the “third revolution” in biomedicine after the development of molecular and cellular biology (the first revolution) and genomics (the second revolution). Based on a study of scientific progress at the Massachusetts Institute of Technology, convergence science was recommended as a way to blend diverse scientific disciplines. More than an interdisciplinary science, convergence integrates distant paradigms, systems, theories, and disciplines with problem-oriented research that crosses boundaries of academic, public, and private spheres.


Oncology may be the current biomedical frontier for convergence science. Indeed, a new academic journal has just been launched: 

 The aim of the journal is to integrate physical science with cancer biology and clinical oncology to advance the understanding and treatment of cancer in patients. The National Cancer Institute’s Center for Strategic Scientific Initiatives supports convergent approaches to cancer innovation. Their mission is to “create and implement exploratory programs focused on the development and integration of advanced technologies, transdisciplinary approaches, infrastructures, and standards to accelerate the creation of publically available, broadly accessible, multidimensional data, knowledge, and tools to empower the entire cancer research continuum for patient benefits.”

This initiative has led to Cancer Nanotechnology Excellence and Integrative Cancer Biology Program Centers to be constructed to support convergent projects. Private companies (eg, IBM and NantHealth) are already developing data intensive systems to integrate, display, and analyze-via machine learning-data from all health providers, genomic and proteomic analyses, imaging, and other medical devices, with the actionable health information available at the point of care, anywhere.

Initiatives supporting convergence science approaches for psychiatry


If convergence is an approach to complexity, then what appears promising for oncology should be even more useful for psychiatry. Indeed, this approach has already been harnessed for neuroscience. A number of large-scale convergence neuroscience initiatives are underway globally, and these initiatives are essential to making progress in neuroscience. These projects bring together researchers from a multitude of disciplines to understand the basic functioning of the human brain, and the dysfunction that occurs during illness.

One such initiative is the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative funded by public agencies, private companies, and foundations.

 The express aim of this initiative is to develop new tools and technologies that will enable the research community to obtain a dynamic picture of the brain in action. With nearly 100 billion cells making 100 trillion connections, this is no small aim and will simply not be achievable with current tools and disciplinary approaches. One of the express themes of action for the BRAIN initiative is to “cross boundaries in interdisciplinary collaborations.” The BRAIN initiative consists of teams of engineers, nanotechnologists, computational scientists, materials scientists, and neuroscientists to create the next generation of imaging tools or probes for brain activity.

Will convergence become the future of psychiatry?


Arguably, if the brain is so complex as to require a convergent approach, then the study of psychiatry (mind, brain, and behavior) is complexity on a whole different level. Although the challenge is evident, our approaches have been remarkably singular, focusing on the mind, the brain, or behavior in isolation, with too little integration across disciplines and even less assistance from the vast areas of science that are now poised to alter other areas of medicine.

What would a convergence science of mental illness look like?


A convergent approach to mental illness could begin with software engineers, informatics experts, behavioral scientists, and clinicians designing a new generation of devices to provide objective measures to augment patients’ reports of their symptoms. Imagine devices developed to provide continuous assessment of mental state, similar to the glucose or heart rate monitors available today. Passive data such as voice analytics, facial expression monitoring, actigraphy, and engagement of social networks could indicate the onset of depression or mania. Closed loop brain stimulation could detect and correct abnormal neural circuit activity, as is used today for managing epilepsy.

Implanted devices for the management of hallucinations and obsessive thoughts may seem like science fiction, but with the engineering of wireless, miniaturized electrodes, a new era is emerging for interventional neurology as well as psychiatry.

 Envisage creating social prosthetics for children with autism, similar to the cochlear implants used routinely for nerve deafness. While today’s tools such as Google Glass and Siri may not be up to the task, rapid progress in facial processing and computer engineering suggests that software could allow children with “social blindness” to read facial emotions in real time.

The application of convergence to psychiatry can be much more than smart software and social prosthetics. Convergence may include combining the current tools for diagnosis. The neurobiological mechanisms of psychiatric disorders are complex and often involve the interplay of changes in brain structure, function, neurochemistry, and neuropathology. Clark and colleagues5 have outlined the added value of multiple diagnostic modalities used in predicting the risk of transition into first episode psychosis. Karalunas and colleagues

 were able to refine subtyping of childhood ADHD by using biologically based behavioral dimensions (ie, temperament), a novel classification algorithm (ie, community detection analysis), and multiple external validators (ie, resting-state functional magnetic resonance imaging and cardiac measures of respiratory sinus arrhythmia and pre-ejection period). Diniz and colleagues

 have shown how plasma biosignatures and brain pathology relate to resistant cognitive impairment in late-life depression. They utilized comprehensive analysis of blood-based immune proteins, magnetic resonance imaging, and positron emission tomography with machine learning data analytics. While all of these examples draw from multiple data sources, the ultimate promise of convergence is the integration of biological, psychological, sociocultural, and environmental data into a more comprehensive, individualized portrayal of diagnosis (ie, precision medicine).

Early examples of convergence science for psychiatric disorders


Convergence science approaches could also aid in the development of novel treatment strategies for psychiatric disorders allowing interventions to be proactive as well as reactive. There is an increasing interest in electronic mental health interventions given enhanced computing power and the widespread availability and use of smartphones.

 Psychosocial treatments delivered via mobile health (mHealth)-the practice of medicine supported by mobile devices-have the benefit of reach, scalability, affordability, convenience, flexibility, and facilitation by a non-professional workforce. Concerns remain about acceptability to consumers, quality of interaction, and the potential for unsupervised and counterproductive therapy.

Massive open online interventions for mental health is a concept recently defined by Munoz and colleagues

 and describes mental health and substance abuse interventions, scientifically validated and available online to unlimited numbers of consumers. These researchers showed how a free, multifactorial smoking cessation program in English and Spanish could be used by 7607 participants worldwide. Their findings indicate a 50.3% quit rate over 12 months.

The field of socially assistive robotics in mental health, whereby robots assist patients through social interactions (eg, companionship, as therapeutic partner and/or coach), is receiving greater attention, particularly as computing power grows and artificial intelligence systems become more sophisticated, ubiquitous, and useful. A recent review by Rabbitt and colleagues

 has outlined potential benefits of socially assistive robotics (eg, providing therapy and monitoring where there are few mental health providers and reinforcing human-led therapy), as well as potential downsides (eg, poor quality user interface leading to frustration and cost considerations). Even in the near term, the development of monitors for the fidelity of psychosocial interventions could improve the quality of care.

Just as a glucose monitor in a contact lens provides continuous feedback for optimizing diabetes control; engineers, computer scientists, and psychiatrists can develop simple devices to assess the quality of psychiatric treatment as a path to improving outcomes. Examples in psychiatry include software and hardware for smartphones and wearable devices to monitor physical activity, sleep, social interactivity, calorimetry, and emotional tone of voice.

Implications of convergence science for psychiatry


If convergence science principles are part of the future of psychiatry, it may not be too soon to introduce this approach in the teaching of psychiatry. Additional skills may include an enhanced understanding of neuroscience, the “omics” (eg, genomics, proteomics, metabolomics), big data analytics, mHealth, economics, and policy. Yager

 suggests psychiatry training and careers are likely to undergo substantial change in the future to complement projected health burdens and innovations, postulating the development of additional psychiatric specializations in information technology and executive management (ie, combining clinical practice, administration, entrepreneurialism, and health services management).

The training of psychiatrists as clinical neuroscientists has recently been outlined, and indeed there are signs to suggest a resurgent interest in psychiatric neuroscience among medical students given the need for new discoveries and the promise of new research techniques.

 Interesting educational curricula to model include the National Institute of Mental Health (NIMH)-led, 4-day Brain Camp offered in the US to MD-PhD students; the National Neuroscience Curriculum Initiative; and the NIMH-funded, 5-day Summary Research Institute in Geriatric Mental Health.


The Medici effect is upon us in biomedicine, and it’s called convergence science. We believe convergence science and its greater application to psychiatry is important to address the integration of mind, body, and behavior; the urgent need for improved quality and access to clinical care; the high burden of disease; and the promise of new technologies. As the Medici family catalyzed the Renaissance by bringing together poets, philosophers, scientists, and painters and other artisans, we believe a renaissance in psychiatry can be delivered by facilitating interactions, research, and innovations between clinical neuroscientists, molecular biologists, big data scientists, roboticists, imagers, public health experts, economists, and user interface and gamification experts.

Dr Eyre is a PhD student within the discipline of psychiatry at the University of Adelaide in Adelaide, Australia; Dr Lavretsky is Professor in Residence in the department of psychiatry at the Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA; Dr Insel is Director of the National Institute of Mental Health, Bethesda, MD. The authors report no conflicts concerning the subject matter of this article.

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 Karalunas SL, Fair D, Musser ED, et al. Subtyping attention-deficit/hyperactivity disorder using temperament dimensions: toward biologically based nosologic criteria. 

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. 2015. http://cpx.sagepub.com/content/early/2015/05/11/2167702615583840.abstract. Accessed September 29, 2015.


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 Bartels SJ, Lebowitz BD, Reynolds CF III, et al. Programs for developing the pipeline of early-career geriatric mental health researchers: outcomes and implications for other fields. 

The Medici effect is upon us in biomedicine, and it’s called convergence science. 

Convergence Science: Shaping 21st Century Psychiatry

, the main character says, “There’s an old joke. Two elderly women are at a Catskill restaurant. One of them says, ‘Boy, the food at this place is just terrible.’ The other one says, ‘Yeah, I know. And such small portions.’”

Over the past decade, nearly all of the national conversation about mental health care has focused on the small portions. Parity for insurance coverage, increasing psychiatric beds to reduce incarceration, expanding the workforce-all of these essential efforts were about access, increasing the quantity of care. In a nation in which 55% of counties have no mental health provider, increasing quantity is important.

 In a nation where severe mental illness affects 15% to 24% of prison inmates, there can be little question that we need more beds.

 When a psychiatrist from Boston tells me that it is easier to get into Harvard Medical School than to find a public bed for a psychotic patient in Massachusetts, I understand the need to focus on quantity.

But we need to be thinking about quality as well. There are effective, evidence-based treatments for nearly every mental illness. For those lucky enough to have access to care, what are the odds of receiving evidence-based treatment? A new Institute of Medicine report looks at a part of this question. The report, 

Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards

 looks specifically at psychosocial treatments, such as psychotherapies. The research is unambiguous: rigorous clinical trials have demonstrated the value of many effective psychotherapies for specific mental disorders across diverse settings. But the pathway from research to practice is strikingly different for psychotherapies compared with medications.

When research shows that a medication is effective, there is a clear regulatory path for approval and consumers can be confident that the pill they receive is identical to the medicine tested in a clinical trial and approved by the FDA. The pathway for psychotherapies is not so clear. There is no FDA equivalent to set standards, and consumers cannot be certain that the therapy offered is identical or even vaguely similar to what was tested in a clinical trial.

As the new report notes, since 1982 there have been calls for a regulatory agency for psychosocial treatments, but there has been little progress in even defining a common language with which to frame guidelines. The Institute of Medicine report states, “. . . the result has been sets of guidelines that often are at odds with one another, and clinicians, consumers, providers, educators, and health care organizations seeking information are given little direction as to which reviews are accurate and which guidelines should be employed.”

Of course, rigorous training can ensure that therapists are delivering something close to the treatment developed in careful trials. Nearly 10 years ago, 

 studied training in evidence-based psychotherapies for each of the major mental health care disciplines. The 2 disciplines with the largest number of students-professional clinical psychology (PsyD) and social work-had the largest percentage of programs (67.3% and 61.7%, respectively) not requiring coursework and clinical supervision in any evidence-based treatment. The new report makes it clear that little has changed in the past decade. Not only are new therapists not trained in the very treatments that have been shown to work, therapists in practice continue to operate as they were taught decades earlier. And there are few if any “metrics” for measuring the quality of psychosocial treatment. Is there any other area of health care that would tolerate this low level of quality or quality control?

 of a “quality chasm” in this field have identified the need for specific standards, similar to the standards of care found in other areas of medicine.

 The Institute of Medicine report is helpful in pointing out that those standards should include structural measures (training and credentialing), process measures (eg, monitoring homework for cognitive behavior therapy or home visits for assertive community treatment), and outcome measures (especially patient-reported outcomes). Programs in the UK, such as 

Improving Access to Psychological Therapies

 Veterans Health Administration psychotherapy project

, have demonstrated that high-quality psychotherapy can be trained and delivered at scale. And, most important, attention to quality improves outcomes.

While we don’t know everything that’s needed to completely fix the “quality chasm,” we do know enough to start taking immediate action. The time is right to use evidence-based interventions informed by research and implementation strategies to address the quality chasm for mental health care. We don’t need additional research to know that mental health providers should be trained in evidence-based psychotherapies and that mastery of these treatments can become part of credentialing standards. Likewise, while the assessment of quality is complex, we don’t need more research to know that measuring outcomes should be a part of treatment. Of course, we need to make sure we have an efficient strategy for implementing evidence-based therapies and an effective process for improving quality.

A new initiative from NIMH is a step in that direction. It will support the development and testing of tools and strategies for measuring the quality of psychotherapy delivered in real-world practice settings. But even with what we know today, much can be done to improve the quality of mental health care, just as we have done previously for diabetes and heart disease. To reduce suicide, ensure recovery, and improve real-world outcomes, quality will be just as important as quantity. We need to improve both.

Dr Insel is Director of the National Institute of Mental Health (NIMH) in Bethesda, MD.

: This article, originally published on July 14, 2015, 

(http://www.nimh.nih.gov/about/director/2015/quality-counts.shtml

) is reprinted here courtesy of NIMH, with minor editorial changes.

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http://www.nap.edu/catalog/19013/psychosocial-interventions-for-mental-and-substance-use-disorders-a-framework

 Weissman MM, Verdeli H, Gameroff MJ, et al. National survey of psychotherapy training in psychiatry, psychology, and social work. 

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 Clark DM. Implementing NICE guidelines for the psychological treatment of depression and anxiety disorders: the IAPT experience. 

 Karlin BD, Cross G. From the laboratory to the therapy room: national dissemination and implementation of evidence-based psychotherapies in the US Department of Veterans Affairs Health Care System.

"The time is right to use research-informed interventions and implementation strategies to address the quality chasm for mental health care," says to NIMH Director Insel.

Quality Counts

The recent tragedy with the Germanwings crash in the Alps has started a worldwide discussion about mental illness and suicide. We don’t yet know what happened on this flight and we certainly don’t have access to the medical history of the copilot who is now the focus of the investigation, but this heartbreaking news from France, and the debate that it has spawned, illustrates the difficulties of understanding suicidal behavior, much less predicting it.

While much attention has focused on this tragedy, it is important to remember that 41,000 people in America died by suicide in 2013.

 Suicide is the tenth leading cause of death in our country. Most of the other top-ten causes of mortality, such as heart disease, cancer, stroke, Alzheimer disease, and diabetes are rightly the targets of visible and productive research efforts. For cause number four, accidents (which include automobile crashes), research has led to measures (both devices and law enforcement) that have substantially reduced mortality. Effective vaccines have been developed for the eighth leading cause of death, influenza and pneumonia.

If research on these conditions has shown anything, it is that research investments can, eventually, make a large and life-saving difference, even for issues that at first seem intractable. The 

National Action Alliance for Suicide Prevention

, a public-private partnership, is determined to champion suicide prevention as a national priority; catalyzing efforts to implement high priority objectives of the 

, and cultivating the resources needed to sustain progress. Last month, the Action Alliance’s 

 released a comprehensive look at suicide research underway in the United States: 

U.S. National Suicide Prevention Research Efforts: 2008-2013 Portfolio Analyses

. The report finds that “public and private investments in research are meager, given that suicide is the 10th leading cause of death in the US”

Unlike many of the leading causes of death, the suicide rate has shown no appreciable decline over the last 50 years; indeed, the rate among middle-aged Americans is increasing, and for young people ages 15-34, it is not the tenth, but the second leading cause of death. Because of this significant burden, suicide is among the top conditions for DALYs-disability-adjusted life years (an aggregate of the number of years lost to premature mortality and years lost to disability). A few weeks ago I released a 

 on NIMH funding showing how mental disorder and suicide DALYs stack up compared to other NIH investments. Indeed, in terms of dollars invested/death, the suicide research number was roughly 1000, many fold less than the comparable investments in heart disease, cancer, or AIDS.

 for suicide prevention identified six broad areas of research, with short- and long-term objectives for each. As important as identifying what we don’t know, the agenda also made clear what we do know, and how we could build on current knowledge to make the quickest inroads into reducing suicide rates. The report pointed out, for example, that 51% of suicide deaths in the US were by firearms. Research has already demonstrated that reducing access to lethal means (including gun locks and barriers on bridges) can reduce death rates. It is not correct to assume that everyone who attempts suicide but survives will continue to attempt suicide until they succeed.

Research with multiple psychotherapies has shown that adult suicide attempters can be prevented from reattempting. This point was reinforced in a report from Denmark just published; over 5000 people who attempted suicide were treated with a psychosocial intervention and followed for 20 years. Relative to 17,000 attempters who did not receive psychotherapy, the treated population had fewer subsequent acts of self-harm, fewer suicides, and fewer deaths from any cause. The results were stunning: in this population, it appeared that psychosocial therapy prevented 153 deaths, including 30 suicides.

Perhaps the most important point brought home by the efforts of the Action Alliance and the 

 is that suicidal behavior must be a target of research in and of itself. While it is true that suicide often occurs in the context of mental illness, studying depression and schizophrenia, for example, is not enough; there are many types of individuals at risk for suicide. More empirically based tools are needed to apply early upstream prevention (e.g., community-based interventions), as well as acute and follow-up care approaches for those at highest risk. To develop the most effective and efficient interventions, risk stratification and personalized treatments will benefit from research that can be used to identify those at greatest risk and match interventions to the specific factors that are related to the genesis and maintenance of suicidal thoughts and behaviors for a given individual.

Soon, the crash of the Germanwings airliner in France will begin to fade from the headlines and our own consciousness. When will we change our national habit of paying brief attention to suicide when circumstances make it newsworthy and start viewing it as the major public health problem it is: one to be addressed by marshalling-and sustaining-research, as we have for other health issues, with the clear goal of saving lives?

Dr Insel is Director of the National Institute of Mental Health (NIMH).

Note: This article, originally published on April 2, 2015, is posted here courtesy of NIMH.


http://www.nimh.nih.gov/about/director/2015/targeting-suicide.shtml

1. National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. Web-based Injury Statistics Query and Reporting System, Fatal Injury Reports, National and Regional, 1999-2013. 

http://webappa.cdc.gov/sasweb/ncipc/mortrate10_us.html

. Accessed April 9, 2015.
2. Erlangsen A, Lind BD, Stuart EA, et al. Short-term and long-term effects of psychosocial therapy for people after deliberate self-harm: a register-based, nationwide multicentre study using propensity score matching. 

http://dx.doi.org/10.1016/S2215-0366(14)00083-2

The recent tragedy with the Germanwings crash in the Alps has started a worldwide discussion about mental illness and suicide. NIMH Director Thomas Insel reflects on the larger issues we continue to face.

Targeting Suicide

Precision medicine seems to be the new hot topic in the research world. President Obama spoke about precision medicine in his 

 on January 20, his budget released today requests $215M for precision medicine, and NIH just announced plans for a study of a million or more volunteers to explore precision medicine. What precisely is it? The 

 has a useful definition: getting the right treatment at the right time to the right person. The President, in an event devoted to precision medicine in the East Room last Friday [January 30, see video, below], told the story of ivacaftor, a drug that effectively treats the underlying cause-not the symptoms-of cystic fibrosis, but works in only 4% of patients who have a specific mutation in the gene causing this disease.

Most of the conversation about precision medicine focuses on cancer. Because cancer is a disease of genetic mutations leading to unregulated cell division, defining the precise mutations in the affected tissue have already led to breakthrough treatments for both blood and solid tissue cancers. In fact, the same mutation can occur in different parts of the body, so cancer is increasingly diagnosed in terms of its genetic and molecular signature rather than the tissue of origin. Part of the proposed precision medicine plan will involve scaling up efforts at the National Cancer Institute to find these mutations and to develop drugs or biologics as treatments.

What does precision medicine mean for mental health? Our version is the 

, which aims to develop more precise diagnostic categories based on biological, psychological, and socio-cultural variables. It is certainly possible that we may find specific mutations in relevant brain circuits that explain some cases of schizophrenia, bipolar disorder, or autism, just as mutations in the tumor explain cancer. NIMH has supported research on inherited genetic risk for several years; a new initiative on another class of mutations, somatic mosaicism (the term for mutations that develop after fertilization), will launch this year. But more likely, precision medicine for mental disorders will not come from a single genomic glitch. Rather, like many other areas of medicine, many genes each contribute only a small amount of vulnerability as part of an overall risk profile that includes life experiences, neurodevelopment, and social and cultural factors. RDoC assumes that we will need many kinds of data to reach precision, more like triangulating to find your position on a map. These data will draw from many sources, including symptoms, genotype, physiology, cognitive assessment, family dynamics, environmental exposures, and cultural background.

I know that RDoC sounds more complex than the cancer version of precision medicine, but that is the nature of the problem. For now, we need to embrace the complexity to identify the simpler, actionable categories that can be used in the clinic. The rationale for this approach is no different from what the President talked about for cancer or cystic fibrosis-getting the right treatment at the right time to the right person.

Dr Insel is Director of the National Institute of Mental Health (NIMH).

Note: This article, originally published on February 2, 2015, is posted here courtesy of NIMH. 

http://www.nimh.nih.gov/about/director/2015/precision-medicine-for-mental-disorders.shtml

Precision medicine seems to be the new hot topic in the research world. What precisely is it? 

Precision Medicine for Mental Disorders

“What caused this to happen?” is usually one of the first questions asked by patients and their families following a psychotic episode, suicide attempt, or manifestation of any serious mental illness. In earlier times, the explanations ranged from an imbalance of the “humours” to demonic possession. More recently, there have been “schizophrenogenic” or “refrigerator” mothers and “abusive” or “toxic” fathers. Modern scientists and clinicians point to a mix of genetic and environmental factors but these explanations are rarely satisfying and do little to stem the tide of guilt, shame, and blame that surrounds mental illness as much today as during the witch hunts of centuries past.

Of course, genetics and environment are important. But their effects are probabilistic. With the exception of a few rare mutations that appear causal for autism, genetics confers a tendency for height, personality, and risk for mental illness through the aggregate effects of hundreds of common variations in the genome. This information may be useful in populations, but it is of little help in explaining cause for any individual.

[[{"type":"media","view_mode":"media_crop","fid":"31025","attributes":{"alt":"severe mental illness","class":"media-image","id":"media_crop_1997330928874","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3277","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","title":" ","typeof":"foaf:Image"}}]]Environment or, more accurately, experience is undeniably a factor for PTSD, but for most other forms of mental illness the link is difficult to prove. We use terms like “adversity,” “toxic stress,” or “trauma,” recognizing that our assays of these experiences are woefully imprecise and knowing that subjective experience, especially memories of childhood experience, may trump any objective measure of the event. None of these factors have prevented patients and clinicians from assuming that “trauma” is the cause of most mental illness, perpetuating a culture of blame that has permeated mental health care for a century.

The scientific answer to the question of “what caused this to happen?” is to cite a mixture of genetic and environmental factors, often expressed as a gene-environment interaction. The honest answer to the question of cause is that we don’t know. Gene-environment interaction is a multi-syllabic way of saying “we don’t know.” Our minds seek explanations to reduce the mystery and pain of mental illness, but in truth, we are early in our search for understanding how, when, and where these disorders develop.

I found myself thinking about all of this after reading a recent paper on cancer. In last week’s Science, 

 describe a very simple approach to the cause of cancer.1 We have known for a century that some tissues (skin and colon) have more cancers than others (bone and brain). Tissues differ in the rate at which cells reproduce normally. Skin and gut cells, for instance, are constantly self-renewing at a high rate whereas cells in bone and brain show little replication. Because cancer happens when cell replication goes berserk, perhaps we should not be surprised that the lifetime risk of cancer in any particular tissue can be predicted by the normal rate of cell replication in that tissue. Replication is imperfect with mutations happening “by chance” all of the time. Cancers develop when mutations hit genes that regulate the cell cycle and this is statistically more likely in tissues with high rates of normal cell replication.

 is the strength of this prediction. I can’t do better than their summary:

These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.

There are exceptions-lung cancer and smoking, skin cancer and sun exposure-but for most forms of cancer, the data suggest the “cause” is “bad luck.”

What does this have to do with mental illness? Outside of a few areas of the brain, adult neurons don’t divide and exuberant cell replication is unlikely to be the cause of schizophrenia or depression. The link starts much earlier. In fact, between weeks 4 and 24 of gestation, the human brain is generating 100,000 cell divisions every minute-arguably a 

 than any other organ at any other time in the lifespan.2 Curiously, cancer is not an outcome except in rare cases, presumably because mutations hitting cell cycle genes are quickly suppressed. But could other mutations that influence excitability or connectivity or even survival be affected, leading to changes in brain architecture that years later emerge as psychopathology? A new 

 will investigate this question as a potential cause of mental illness.

President Lincoln’s famous line that “a tendency to melancholy is a misfortune not a fault” comes to mind. We need explanations. “Bad luck” is not particularly satisfying as an explanation of cause, but that does not make it wrong. Of course, genetics and environment influence brain development during gestation. And we don’t know that this new explanation, which seems so attractive for cancer etiology, has any relevance at all to autism or schizophrenia. But this new report for cancer serves as a useful reminder that we really know too little about “what caused this to happen” when someone we care about develops a mental illness. And the real cause may be something that is, unfortunately, out of our control.

Dr Insel is Director of the National Institute of Mental Health (NIMH).
Note: This article, 

1 Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 2015;347:78-81.
2 Insel TR. Brain somatic mutations: the dark matter of psychiatric genetics? Mol Psychiatry. 2014;19:156-158.

This is usually one of the first questions asked by patients and their families following a psychotic episode, suicide attempt, or manifestation of any serious mental illness. More from the Director of NIMH.