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The identification of risk for serious mental illnesses: Clinical and ethical challenges

By Elaine Walker, Ph.D., Sandy Goulding, MPH, MA., Arthur Ryan, MA., Carrie Holtzman, MA., Allison MacDonald, MA.

Elaine Walker is Samuel Candler Dobbs Professor of Psychology and Neuroscience in the Department of Psychology at Emory University.  She leads a research laboratory that is funded by the National Institute of Mental Health  to study risk factors for major mental illness.  Her research is focused on child and adolescent development and the brain changes that are associated with adolescence.

The identification of risk factors for illness is receiving increased attention in all fields of medicine, especially cardiology, oncology, neurology and psychiatry.  There are three potential benefits to identifying risk factors. The first is to reduce morbidity by reducing risk exposure. The second is to enhance opportunities for targeting preventive treatment toward those who are most likely to benefit. Finally, the identification of risk factors can shed light on pathological mechanisms.

There are, of course, costs as well as benefits involved in this endeavor.  The benefits, in terms of reducing morbidity and mortality, are noncontroversial.  The costs, however, can be very controversial and they have generated discussion among ethicists. Foremost among the costs is the potential discomfort and distress that results from the identification of an individual as being at statistical risk for future illness.  There are also significant concerns about whether treatment should be initiated prior to the manifestation of symptoms that reach clinical threshold.  These concerns are especially salient in the field of psychiatry. In this post, we discuss current efforts to identify risk factors for serious mental illness and the ethical considerations they raise.

Among researchers and practitioners in the field, the term “serious” mental illness is typically used to refer to psychotic and chronic mood disorders.  Such disorders include schizophrenia, schizoaffective disorder, bipolar disorder, and major depression.  By definition, schizophrenia and schizoaffective disorders always entail psychotic symptoms; hallucinations, delusions and/or thought disorder.  Bipolar disorder and depression can occur with or without psychotic symptoms. Currently, the general consensus in the field is that these disorders stem from brain dysfunction that is caused by both biological and environmental factors. These illnesses also have substantial adverse social and personal consequences. In fact, this is particularly true of schizophrenia and other psychotic disorders, as they affect 1-2% of the population, typically begin in late adolescence/early adulthood, and are often chronic.

Consistent with other fields of medicine, research aimed at identifying risk factors for serious mental illnesses has burgeoned in the past few decades.  The first ‘generation’ of these investigations, referred to as “genetic” high-risk research, focused on the biological offspring of parents who suffered from serious mental illnesses such as schizophrenia. While this work yielded some useful findings, it was limited by the fact that the psychosis risk-rate for children of parents with schizophrenia is about 12% to 15%. In other words, the overwhelming majority do not develop the illness.  Further, the majority of schizophrenia patients do not have a biological relative with the illness, meaning that this approach failed to include a substantial portion of individuals with schizophrenia.

As a result of these limitations, researchers shifted their attention to individuals who manifest clinical signs of risk. This line of investigation draws on the results of prospective and retrospective studies of the behavioral signs that precede the onset of clinical psychosis. These signs include, but are not limited to, mood disturbances, unusual ideations and perceptual experiences, and declines in occupational, academic and social functioning.  The period when these signs emerge can vary from months to years, and is referred to as the “prodrome”.

Assessment instruments have been developed to measure prodromal signs, and criteria have been established to designate those at greatest statistical risk. Most of those who meet these criteria are in subjective distress and have previously sought or received mental health services.  In the context of research, the term “clinical high risk” is typically used to refer to these help-seeking individuals.   Further, based on the results of prospective studies, it is estimated that the risk rate for subsequent psychosis ranges from 25% to 40% – – – far higher than the risk rate for individuals with an affected family member.  The other 60% to 75% manifest a range of outcomes, with some remaining stably symptomatic and others showing a decline in symptoms and no subsequent psychiatric disorder.

There are numerous ongoing research projects in many countries that are aimed at enhancing our ability to predict psychosis risk beyond the 25-40% level.  Our research group is pursuing this goal as part of a multi-site project funded by the NIMH.  This project, the North American Prodrome Longitudinal study (NAPLS), is also concerned with elucidating the neural mechanisms that are associated with the development of psychotic disorders. We are now in the 5th year of this project, and just beginning the stage of data-analysis that will test alternative prediction algorithms.

In the interim, clinical researchers are confronted with questions concerning the potential stigma and psychological distress associated with psychosis-risk identification, as well as the provision of treatment for these individuals. The issues of stigma and subjective distress have some unique aspects when it comes to disorders of brain function, as opposed to disorders involving other organ systems. The brain is generally assumed to be the organ that subserves our mind and personal identity, and the behavioral problems that can result from its dysfunction are sometimes viewed as being under volitional control.  The latter view is one source of the stigma associated with mental disorders: patients are assumed to be responsible for their symptoms.  At the same time, there is a tendency for many to view individuals with mental illnesses as being dangerous because they are unable to control their behavior.   Together, these factors reduce sympathy for individuals with mental illness.  They also place additional burdens on those who are already experiencing the mood, perceptual and ideational abnormalities that are associated with the prodrome to psychosis.

With regard to the stigma associated with clinical risk for psychosis, the issues vary among individuals.   Among those who participate in our collaborative NIMH project clinical risk, some self-identify as being “at-risk”, through statements such as “I am afraid something is wrong with my mind,” or “I feel like I am going crazy.”  In contrast, others report nonspecific concerns with recurring, distressing ideas, and are seeking help to reduce their distress.   Finally, some individuals who are manifesting signs of risk for psychosis do not perceive a problem. This is especially likely to be true of adolescents whose behavior raises concerns in parents and teachers, although the child views him or herself as being “misunderstood.”

At the present time, there is no standard practice for informing individuals about risk signs for psychosis, and the principle of doing no harm guides practitioners and clinical researchers. Furthermore, clinical researchers emphasize that we cannot predict the onset or course of any illness with precision, and that many who manifest risk signs, especially during adolescence, subsequently experience remission and show no signs by the time they enter young adulthood.

There are also challenging issues when it comes to the provision of treatment for those manifesting signs of psychosis risk.  While there is a consensus that psychotherapy/counseling should be available to any individual in significant distress, the issue of medication for individuals at clinical risk for psychosis is controversial.  At the present time there is no cure for psychotic disorders, and the antipsychotic medications that are used to treat psychosis only partially reduce symptoms, and they are ineffective for a substantial proportion of patients.   These medications also have a variety of side effects (e g., metabolic, neurological) and can be highly sedating.  Finally, there is no consistent evidence that antipsychotic medications can prevent psychosis, although some studies suggest that they reduce the severity of preclinical symptoms.

Based on the currently available data, most researchers in the field of psychosis risk do not advocate the preventive use of antipsychotic medication.  Yet, many individuals who manifest preclinical signs of risk for psychosis do receive antipsychotics from mental health practitioners.  There are several reasons for this, including the practitioner’s desire to reduce the severity of the subclinical symptoms, the broad marketing of antipsychotics (e g., Abilify) to the general public for the treatment of depression, and the desire of patients and their families to intervene in any way possible to prevent the a first episode of psychosis.  The latter concern is especially salient for families who already have an adult child affected by a psychotic illness.

In summary, it is clear that we have a long way to go before we are able to predict serious mental illness at a level of positive predictive power that would justify targeted preventive intervention, especially with agents that can have adverse side effects.  Moreover, we do not yet have consistent evidence of any effective preventive treatment.  But, as indicated in the references listed below, clinical studies are underway around the world. Findings from these studies are yielding important information about prediction, as well as the brain changes that accompany the emergence of psychosis.   As we await more scientific progress in these key areas, we should also continue to carefully consider the ethical issues that surround the identification of individuals who are at risk for serious illnesses.  This is especially the case for illnesses that entail brain dysfunction.


Addington, J., Cadenhead, K. S., Cornblatt, B. A., Mathalon, D. H., McGlashan, T. H., Perkins, D. O., Walker, E. F. & Cannon, T. D. (2012). North American Prodrome Longitudinal Study (NAPLS 2): Overview and recruitment. Schizophrenia research.

Addington, J., Cornblatt, B. A., Cadenhead, K. S., Cannon, T. D., McGlashan, T. H., Perkins, D. O., … & Heinssen, R. (2011). At clinical high risk for psychosis: outcome for nonconverters. The American journal of psychiatry, 168(8), 800.

Cornblatt, B. A., Carrión, R. E., Addington, J., Seidman, L., Walker, E. F., Cannon, T. D., … & Lencz, T. (2012). Risk factors for psychosis: impaired social and role functioning. Schizophrenia bulletin, 38(6), 1247-1257.

Walker, E. F., Trotman, H. D., Pearce, B. D., Addington, J., Cadenhead, K. S., Cornblatt, B. A., … & Woods, S. W. (2013). Cortisol Levels and Risk for Psychosis: Initial Findings from the North American Prodrome Longitudinal Study. Biological psychiatry.

Weiser, M. (2011). Early intervention for schizophrenia: the risk-benefit ratio of antipsychotic treatment in the prodromal phase. American Journal of Psychiatry, 168(8), 761-763.

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Walker, E., Goulding, S., Ryan, A., Holtzman, C., MacDonald, A. (2013). The identification of risk for serious mental illnesses: Clinical and ethical challenges. The Neuroethics Blog. Retrieved on , from


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