Early Intervention and The Schizophrenia Prodrome

On May 7^th the Emory
University Graduate Students in Psychology and Neuroscience (GSPN)
hosted a colloquium talk given by Vijay
Mittal, assistant Professor of Psychology and Neuroscience at the
University of Colorado at Boulder. In the talk, titled “Translational
Clinical Science in the Psychosis Prodrome: From Biomarkers to Early
Identification and Intervention,” Dr. Mittal, who received his
Ph.D. from Emory, discussed some of his research on the prodrome for
schizophrenia.¹

Dr. Vijay Mittal

The prodrome for schizophrenia is a
collection of neurological and psychological symptoms that can
indicate risk for developing schizophrenia (as has been discussed previously on this
blog) prior to the development of clinically relevant symptoms.
Research on the prodrome
is gaining much attention and funding because it could lead to a
better understanding of how schizophrenia develops and better ways to
intervene prior to its onset.




Mittal began his talk with a background
on the schizophrenia prodrome. He explained that, though
schizophrenia usually manifests itself during late adolescence,
people who develop schizophrenia exhibit atypical characteristics
from a young age, during the premorbid and prodromal stages. In the
premorbid stage (which occurs during childhood) some minor cognitive
and social impairments are present, though they are hard to
differentiate from typical development. In the prodromal stage (which
starts during puberty) those traits worsen and new ones develop that
are similar to (though less frequent and severe than) the main
symptoms of schizophrenia (both the positive
and negative). Common symptoms of the prodrome include perceptual
aberration, paranoia, mild delusions (which can be distinguished from
reality²), depression, anhedonia, cognitive decline, and
social withdrawal.

The positive, negative, and cognitive symptoms of schizophrenia.

Via dasmaninstitute.org.

According to the current model of
schizophrenia development, Mittal explained, certain individuals
(through both inherited and environmental factors) have
neurological vulnerabilities that can lead to more severe neurological
damage, primarily effecting the dopamine system, as a result of the
normal physiological changes that occur during puberty (specifically
hormonal changes and synaptic
pruning). This explains why the prodrome occurs during puberty,
why schizophrenia develops after puberty, and why some symptoms are
even present from childhood.




Attention is being given to the
prodrome in schizophrenia research because it is the best predictor
of later psychosis (even more so than familial history). That said,
it is still not a very good one. Only a minority of the people who
exhibit prodromal traits go on to develop schizophrenia (Mittal gave
a range of 10% to 35%; the North American Prodrome
Longitudinal Study gives a range of between
20% and 50%). Because of this, Mittal explained, treatment with
antipsychotic medications is not usually prescribed for people with
prodromal traits, because it would be unethical to give expensive
medications with severe side effects to people who will most likely
not develop any pathology.




Mittal stressed the need for better
ways to predict schizophrenia, and he presented some of his research
on the topic. One method he described is testing for motor
abnormalities in addition to the more obvious psychological and
neurological symptoms. Some people with schizophrenia exhibit
excessive, involuntary movements (hyperkinesia) or have difficulty
moving (hypokinesia), and so do some during the prodromal phase. By taking such motor abnormalities into account (including
subclinical ones), Mittal
and colleagues were able to predict which prodromal patients who
would go on to develop schizophrenia with 72% accuracy. This study
was based on observing videotapes of patients, but clinical
handwriting analysis software, like that developed by NeuroScript
(currently used to test for movement disorders, injuries, and
medication side effects), could also be used to test for such motor
symptoms. Other diagnostic methods could be based on measuring
neurological biomarkers for schizophrenia risk, including reduced
putamen, thalamus, and hippocampus volume and decline in white
matter.




The importance of developing better diagnostic
techniques for susceptibility for schizophrenia is clear. It would lead to both a better understanding of the
causes and development of the disorder and have important
clinical applications. Such techniques could allow for better monitoring of high-risk
individuals and the ability to reassure low-risk prodromal patients that their
symptoms are not likely to become more severe. The fear and stigma of being classified as at risk for schizophrenia is often cited as one of the main ethical concerns of diagnosing people with the schizophrenia prodrome.³ Mittal is currently working on a paper in which he and his co-authors explore the ethical concerns of predicting schizophrenia, specifically how the decision to inform patients that they are at risk for schizophrenia involves balancing the benefits of potential early intervention with the stress and stigma that can come with such a diagnosis.⁴



In his talk, Mittal argued that
better diagnostic methods are important primarily because they will allow
early intervention with antipsychotic medications, which would
decrease the likelihood of high-risk patients developing
schizophrenia and decrease the severity of schizophrenia for those who
develop it. But antipsychotic use for prodromal patients is
controversial and there is no clear evidence that it can prevent
later schizophrenia³ (though the drugs are sometimes prescribed to treat the prodromal symptoms themselves). The evidence Mittal presented to
make his case was a study where low
doses of antipsychotics were given to a group of patients with prodromal symptoms and 18% of them developed schizophrenia, compared to 45% of the control group. Though he admitted that the results are not
statistically significant because of a high dropout rate due to the
side effects of the medication.



The diagnostic techniques that Mittal discussed have promise for improving the way that schizophrenia is diagnosed and treated. But how accurate would these technologies need to be before they can be ethically
integrated into the care of patients at risk for developing
schizophrenia? Care will need to be taken when
discussing the limitations and benefits of prodromal screening given
the potential for false positive and false negatives. Also, while these technologies would open the door for use of preventative treatments (particularly antipsychotics), it seems that stronger evidence of their efficacy is required before they are widely prescribed. 





References




1) Mittal, Vijay. “Translational Clinical Science in the Psychosis Prodrome: From Biomarkers to Early Identification and Intervention.” Emory University Graduate Students in Psychology and Neuroscience. Atlanta, GA. 7 May, 2014.




2) Rachel Aviv, "Which Way Madness Lies: Can psychosis be prevented?" Harper's, December 2010, 35-46.




3) 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 June 20, 2014, from http://www.theneuroethicsblog.com/2013/05/the-identification-of-risk-for-serious.html




4) V. Mittal (personal communication, July, 2, 2014)





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Queen, J. (2014). Early Intervention and The Schizophrenia Prodrome. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/07/early-intervention-and-schizophrenia.html

Response to “The Making of a Troubled Mind”

Prophylactic medicine is the new medicine. The primary ethical issue brought up by the paper revolves around the notion of diagnostic testing. Everyone wants to try and catch the disease early so that we can come up with treatment options and help them salvage whatever quality of life they have left. The problem arises because these tests are not perfect. They sometimes miss the targets, leading to false negatives. They also sometimes hit targets that aren’t actually targets, leading to false positives. In both cases, there could be catastrophic consequences. It’s usually one or the other though. So when the condition is more dangerous than the treatment, it’s important to minimize the false negatives, such as in the case of cancers. When the treatment is more dangerous than the condition, however, it’s important to minimize the false positives, such as for hypercoagulability. In the case of schizophrenia, it appears that the symptoms of the condition outweigh the commitment and side-effects of treatment.

Schizophrenia is a mental disorder that emerges primarily during adolescent years. The symptoms include the inability to distinguish between real and unreal experiences, irrational thinking, abnormal emotional responses, and abnormal social behavior. Initially, these symptoms present as irritability or tense feelings, difficulty sleeping and difficulty concentrating. As the disorder progresses, the person will begin to feel a lack of emotion, strongly held beliefs that are not based in reality, auditory or visual hallucinations, problems paying attention, dissociated thoughts, bizarre behaviors, and social isolation.¹ The hallucinations are the hallmarks of schizophrenia, and are also what can become dangerous to both the patient and the public.

Both genetics and environmental factors have been studied in their involvement in schizophrenia, and it appears to be a combination of both factors. Despite these studies, there is still very little known as to what actually causes schizophrenia, so the treatments mainly deal with the symptoms. Treatment options include medications, mainly antipsychotics, and also support programs and other behavioral interventions. There are adverse side-effects from the medications, including sleepiness, dizziness, weight gain, increased chance of diabetes and high cholesterol, feelings of restlessness or “jitters”, slowed movements, and tremor.¹ Side-effects of the behavioral interventions include boredom and feeling like your time is wasted.

So, given these options, what would the optimal test to pick? One that minimizes false negatives, or one that minimizes false positives? From my subjective point-of-view, the symptoms are much more serious than the side-effects of the treatments. In fact, the major problem with false positives might not even be the treatments – it might be the undue stress and anxiety associated with the knowledge of having schizophrenia. There are social stigmas associated with mental disorders, so the worst consequence might be the feeling of not belonging in society anymore, or just not feeling normal.

In any case, that consequence is paled in comparison to the possibility of spiraling into a state of extreme paranoia and hallucinations. The NAPLS recognizes this need, and provides the test to address this need. They’ve created prediction algorithms that have an increased rate of being accurate with their positive calls, 74%-81% as compared to the 35% of the original diagnostic techniques.² This increased positive predictive power (PPP) suggests a decrease in false positives. However, we want to minimizes false negatives, not false positives. The study also says that new predictive algorithms had lower sensitivity, which is the ability to actually detect afflicted individuals, than the original diagnostics, going from 29%-80% for the original to 8%-67% for the new algorithms.² This is just the trade-off. They managed to lower false positives (but still enough for critics to be satisfied), but they raised the likelihood of false negatives. In this case, because of the greater severity of the condition than the treatment, the diagnostic needs more work in the opposite direction, in my opinion.

--James Zhang

Neuroscience Graduate Program

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Zhang, J. (2011). Response to “The Making of a Troubled Mind”. The Neuroethics Blog. Retrieved on
, from http://www.theneuroethicsblog.com/2011/12/response-to-making-of-troubled-mind.html




Resources cited:

1. “Schizophrenia.” A.D.A.M. Medical Encyclopedia. PubMed Health. 2010. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001925/

2. Cannon, T.D., et al. 2008. “Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America”. Arch Gen Psychiatry. 65(1):28-37.

“The Making of a Troubled Mind”

David Dobbs describes new developments in schizophrenia research, prodromal schizophrenia, and potential new treatments for the disorder in “The Making of a Troubled Mind”. He cites several recent advancements in researchers’ understanding of the disease and indicates that targeting GABA receptors is a promising pharmacological therapy. Like many psychiatric and medical diseases, schizophrenia presents itself in various subtle ways before it may be clinically recognized and diagnosable. This is because the mechanisms behind the disease—dysfunctional pyramidal and chandelier cell structure and activity, at least in part—are present throughout a person’s life but only start causing significant, noticeable problems in adolescence. Pre-clinical signs of schizophrenia may include paranoia, cognitive impairments, hallucinations or “peculiar” thoughts.

Dobbs mentions a survey to assess a young person’s risk of developing schizophrenia—the Structured Interview for Prodromal Syndrome. It has shown up to an 80% accuracy rate for predicting which young people will go on to have a psychotic episode over the next two-and-a-half years. Diagnosing someone with prodromal schizophrenia could provide the opportunity for them to begin an antipsychotic regimen early, as well as “psychotherapy, cognitive training [and] family therapy”. It seems perfectly benign on the surface, but herein lays the question of ethics: how beneficial is it to administer this survey to adolescents?

Til Wykes presents the argument that “false positives”—that is, classifying someone as “high risk” of developing schizophrenia when they are not going to develop the disorder—in fact outweighs the “good” that true early diagnoses might accomplish. Falsely diagnosing someone with prodromal schizophrenia will, in many cases, cause family members, friends, and the person himself to view a patient differently. A diagnosis of schizophrenia may cause anxiety. These psychological stressors may turn into a self-fulfilling prophecy: they could “generate just the thing [i.e., schizophrenia] that you’re trying to protect against.” Wykes claims that these false-positive patients are “not really” at risk of developing schizophrenia.




This is a claim with which I whole-heartedly disagree. I posit that these people are at the same exact high risk of developing schizophrenia as are the individuals who do actually experience psychoses within the following two years. They are merely the “lucky ones” whose particular gene-environment interaction was not substantially conducive to develop psychosis. Perhaps they are just somehow more resilient, or perhaps they have not yet experienced psychosis. Maybe they will in the next five years. As Dobbs’ graph indicates, schizophrenia does not only target adolescents or 20-somethings. 

Wykes does not cite any research substantiating her claims that anxiety regarding a diagnosis of prodromal syndrome could independently lead to psychosis. A quick PubMed search did not turn up any evidence showing this exactly; however a few studies indicate that a patient’s home life and family relationships may predict the onset of his first psychotic episode.

In any case, the thoughts and behaviors measured by the Structured Interview for Prodromal Syndrome are indicative of some abnormality. Hallucinating “whisperings”, experiencing paranoia, and having fragmented thoughts are not hallmarks of normal adolescent development. Perhaps they are not certain signs of schizophrenia, but they are certainly symptoms which should be addressed clinically.

Wykes’ assertion that the risk of making errors of false-positive diagnoses in up to 20% of adolescents outweighs the potential benefits for diagnosing other teens early is also a fallacy. Dobbs cites the statistic that screening for cardiovascular disease has a similar accuracy rate, and mild cognitive impairment (a prodromal stage of dementia) predicts conversion to clinical dementia with an accuracy of about 60%. Anxiety also has exacerbating effects to these two clinical disorders; it would be ridiculous to suggest that we not identify those who are at risk for heart disease or Alzheimer’s disease because it might cause unnecessary worry. Early treatment for each of these disorders, including schizophrenia, may result in an improved prognosis, or at least a delay or lessened severity in the clinical onset of the disorder. 

Schizophrenia, though a serious and scary disorder, there are many misconceptions surrounding the diagnosis. For those who are fearful of unnecessary anxiety regarding a false diagnosis of prodromal schizophrenia, efforts should be made to lessen this anxiety. First of all, it should be possible to make this screening completely voluntary. Patients and their families should be given ample resources and information should be made available to them in an attempt to lessen the potential misconceptions and anxiety, even before administering a screening. Family and cognitive therapy should also be a part of these adolescents’ early intervention regimen.

While there are no sure-fire treatments or preventions for schizophrenia currently, Dobbs alludes to the fact that promising therapies are being researched. Several studies have shown that current therapies (some pharmacological, some psychotherapy-based) may slow the progression of or improve the outcome of early-stage schizophrenia. Furthermore, with improved understanding of and treatments for schizophrenia, it is likely that early-intervention outcomes (as well as screening measures) will improve.

--Amy Luce

Neuroscience Graduate Program

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Luce, A. (2011). “The Making of a Troubled Mind”. The Neuroethics Blog. Retrieved on
, fromhttp://www.theneuroethicsblog.com/2011/12/neuroethics-blogpost.html





Sources

(2003). Early intervention for people with psychosis. Retrieved from National Institute for Mental Health in England website: http://www.p3-info.es/PDF/NIMHE.pdf

Coentre, et al. (2010). Early intervention in psychosis: Prepsychotic period. Acta Med. Port., 23 (6). 1083-90.

Dobbs, D. (2010). The making of a troubled mind. Nature, 468. 154-156.

Marshall, M. & Rathbone, J. (2011). Early intervention for psychosis. Cochrane Database Syst. Rev., 6.

Onwumere, J. et al. (2011). Family interventions in early psychosis: Specificity and effectiveness Epidemiol Psychiatr Sci, 20, (2). 113-119.

“Dans le doute, mon cher… abstiens-toi”1?

If science has one defining tenet, it would be the pursuit of knowledge. By pushing boundaries and expanding the horizon of the possible, science itself seems antithetical to the old adage "Where ignorance is bliss, 'tis folly to be wise."² But the philosophy of truth and the reality of its application are two very different things. As clinicians’ ability to diagnose conditions earlier and earlier improves, a complex ethical issue arises. Where exactly does one draw the line between the bliss of ignorance and the benefits of knowledge? Such a debate hinges on two questions: What are the inherent ramifications of that knowledge, and what benefits does it grant. The first question is the more complex, as it begs at the very ontology of disease, when knowledge is but an echo of future sorrow, whose ears wish for such a burden. Yet by knowing the future, you can prepare. Thus knowledge, in itself, of a future disease or disorder is a double edged blade. It cuts through the wilds of uncertainty, but not without drawing the blood of its wielder. The second question is less metaphysical. As the science of bio-markers improves and genetic screenings become commonplace, disease may become as predictable as the weather. If this prediction permits valuable treatment that could turn the tide of fate, then aren’t all the difficulties of knowing, suddenly so much less damning? Healthcare as we know it could be transformed. People will no longer get disorders, they will get antidotes. When knowledge offers a way out of doom, only the fool would cover his ears.

This bright future is not yet upon us though. So we must balance the state of preventative medicine with the risk of false diagnosis, because as anyone who has been caught unprepared by a mid day rain shower knows, predictions are only predictions, and even the most reliable forecasts can be very wrong. When the predictions are about your health and the forecasts prescribe intense treatment, the costs of error suddenly become much greater. For most disorders, adequate early treatment does not yet exist, so all the risks and all the sorrow of impending fate seem without reconcile. But knowledge begets knowledge, and as science pushes forward the benefits granted by early diagnosis will only improve. And if we do not begin with early diagnosis, scientists will be unable to properly track how diseases and disorders develop over time. Early diagnosis also offers a pool of subjects for clinical trials. Finding the at-risk population is the first step towards treating them. The science of medicine is inexact, but for it to improve, sometimes difficult steps must be taken. When knowledge of doom is only that, it seems better not to know. But herein lays the role of science: doubt need not leave us frozen in inaction. From doubt, science can weave truths. Only by embracing the scattered pieces of knowledge, can those pieces be formed into more coherent wholes. For the time being, it can only be voluntary that people should submit themselves for early diagnostic screening. And by doing so they may not help themselves, but they will likely be invaluable in helping the future.

--Dan Curry

Neuroscience Graduate Program

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Curry, D. (2011). “Dans le doute, mon cher… abstiens-toi”? The Neuroethics Blog. Retrieved on
, from http://www.theneuroethicsblog.com/2011/12/dans-le-doute-mon-cher-abstiens-toi.html

Sources

1 Leo Tolstoy, War and Peace, 1869.

2 Thomas Gray, Ode on a Distant Prospect of Eton College, 1742.

Ethical Implications of Diagnosing High-risk for Schizophrenia

In the last decade, there has been a push to develop and characterize a diagnosis for adolescents at high-risk for schizophrenia, called prodromal risk syndrome.¹ The Personal Assessment and Crisis Evaluation (PACE) clinic in Melbourne, Australia, was first to develop a classification of prodromal syndromes.² The disease of schizophrenia is most typically diagnosed in early adulthood, when most schizophrenics experience their first psychotic break, therefore, early intervention tactics are aimed at adolescents. This is one of the reasons that the PACE clinic is located in a shopping mall.³

On the other side of the globe, the North American Prodrome Longitudinal Study (NAPLS) has been developing and improving methods to reliably diagnose individuals in the prodrome stage. Once identified, they offer these individuals psychotherapy, family therapy, drugs, or cognitive training to hopefully lessen the progression of symptoms. Their method of assessment scores symptoms including family history of psychosis, unusual or fragmented thoughts, school or social troubles, as well as peculiar emotions, behaviors, and thinking, such as; paranoia. After following the individuals for two years, they developed an algorithm that successfully predicts progression to schizophrenia with an accuracy rate of 80%.¹ While this is an impressive rate of accuracy, many ethical implications are raised by both the existence of false positives and true positives. 

Regarding the false positives, individuals deemed high-risk who are actually not at risk of developing schizophrenia, one of the first issues deals with the effects of diagnosis and treatment. Anti-psychotic drugs can have side effects that may include excessive weight gain, galactorrhea, sedation, sexual side effects, and mild dystonia.^4,5 Some side effects of diagnosis, however, might be more hidden. The stigma involved may affect the patient's and family's expectations for the future, altering their choices in terms of employment, schooling, and life goals.⁶ This is a high price for an individual to pay if they otherwise would not have seen many consequences in their life. 

For those individuals who are true positives, there are also sacrifices made in the interest of early intervention. For many individuals who develop schizophrenia, their pre-symptomatic years are a period of time during which they have the best likelihood of living a life of normalcy. The potential of effective treatment needs to be weighed with the effect of tainting this pre-symptomatic period with knowledge of an impending lifelong struggle with mental illness. This cost increases with any shift towards earlier diagnosis or diagnosis in a less symptomatic population. If encouraging results from prodromal research are found, then many parties, including researchers and drug companies, will inevitably push for earlier and earlier diagnosis.⁶

Finally, for anyone receiving a prodomal diagnosis, there are many risks involving third parties such as insurance agencies, schools, employers, and peers.¹ Families need to be informed of the possible effects of disclosing medical information such as this, but patients and families may not always foresee the consequences involved.

One area in which the cost and benefit balance may be addressed is in who is targeted for screening. Most of the research done to this point has been on help-seeking families who have noticed something wrong and are looking for answers and treatment. This population's current quality of life may already be affected, they may be more symptomatic, and they may be more likely to view the early diagnosis as a cause for hope as opposed to a reason for despair.⁶ There will always be pressure, however, from competing interests that would rather expand the patient base through earlier and more widely applied screening. It is therefore imperative that we address these issues involving the interests of the patients before those with other financial incentives are permitted to steer the direction of the field.

--Kevin Watkins

Neuroscience Graduate Program

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Watkins, K. (2011). Ethical Implications of Diagnosing High-risk for Schizophrenia. The Neuroethics Blog. Retrieved on
, from http://www.theneuroethicsblog.com/2011/12/ethical-implications-of-diagnosing-high.html

References

1. Dobbs, D. Nature 468, 154-156 (2010).

2. McGorry, PD, Yung, A., & Phillips, L. Schizophr Res. 51, 17-29 (2001).

3. Yung, A.R. et al. Schizphr Bull. 22, 283–303 (1996).

4. Correll, C.U. et al. Biol Psychiatry 55, 147S (2004).

5. Tsuang, M.T. et al. Biol Psychiatry 45, 1412-1418 (1999).

6. Corcoran, C., Malaspina, D., & Hercher, L. Schizophr Res. 73, 173–184 (2005).

The Risks of Schizophrenia: Is Early Intervention Always Beneficial?

John Forbes Nash Jr. was a brilliant mathematician at Massachusetts Institute of Technology when in 1959 he began to exhibit extreme paranoia and erratic behavior. Later that year, he would check into a mental hospital where he would be diagnosed with schizophrenia. Although over 50 years have passed since that time, schizophrenia has no cure, no well-defined cause, and no means of prevention.

Schizophrenia is debilitating and extremely costly, not only to patients and their families, but also to society at large. Approximately 1% of the world's population will be diagnosed with schizophrenia within their lifetime. Recent research has focused on identifying individuals at the highest risk before the full onset of psychosis, but these efforts have proven highly controversial due to ethical concerns.

The North American Prodrome Longitudinal Study (NAPLS) has championed efforts to characterize the schizophrenia prodrome, which is defined as early symptoms of the disease that may be used to identify schizophrenia patients prior to the onset of full psychosis.^1-2 The participants in these studies are already seeking medical help due to psychological symptoms or behaviors that the patients or their families find alarming. Often, these symptoms are already interfering with the patients' daily lives. In order to be classified as prodromal, the patient must fit one of three criteria: 1) exhibition of attenuated positive symptoms (such as hallucinations or delusions) associated with schizophrenia, 2) brief periods of fully psychotic positive symptoms, or 3) a recent deterioration in function and a family history of psychosis.³ We must be careful to distinguish these high risk patients from schizophrenia patients: having a high risk of contracting a disease is not equivalent to having the disease itself.

Prodromal patients often receive antipsychotic or antidepressant medications as well as cognitive and behavioral therapy.⁴ These treatments may help delay the onset of full psychosis and lessen the severity of disease symptoms once they occur. Indeed, this claim has received some support from recent research, and future research aims to increase the efficacy of these treatments.^{5, 6} The potential benefits of this research are undeniable, but what are the costs?

The social stigma attached to schizophrenia is deeply rooted in our society. People unfamiliar with prodrome research might incorrectly assume that the prodrome patient has schizophrenia, therefore prodrome patients may be subject to the same stigma. Although researchers and clinicians maintain patient confidentiality, they cannot prevent patients or their parents from sharing information with their friends and extended family. From there, the information may reach neighbors, teachers, and employers. The potential consequences of association with a prodromal study are numerous and can be detrimental for the patients involved.⁵

 

As prodrome research undergoes refinement, researchers become better equipped to identify patients destined for schizophrenia. Yet inevitably some prodromal patients prove to be false positives: they will never develop schizophrenia. According to some estimates, false positives account for 50-85% of prodromal patients, but this figure may be misleading.^1,2,5 Because prodromal patients often undergo preventative treatment, some of these patients may be "false" false positives: intervention halted disease progression but without that treatment they would have descended into full psychosis.⁵ However, many false positives truly represent individuals who never would have developed schizophrenia, even in the absence of medical intervention. These individuals probably have little to gain from preventative treatments yet suffer from unnecessary social stigmas and medication side effects. Future research should aim not only to minimize the number of people within this category, but also the risk of unintentional harm inflicted upon them as a result of their participation in prodromal studies.

Greater refinement in prodrome research also promises to identify prodromal patients earlier in their lives, perhaps even before the onset of obvious symptoms. This early identification could further improve the outcome for schizophrenia patients but also threatens the period of relative normalcy that patients enjoy before disease sets in.⁵ We might think of this as a time of blissful ignorance when patients can enjoy life without the anxiety of impending disease. If researchers can identify patients during this time, do they have a responsibility to do so, or should they let these patients enjoy this time uninterrupted by psychiatric exams and medications, especially when they cannot offer a cure?

After his psychotic episode in 1959, John Nash would go on to win the 1994 Nobel Prize in Economics for work done while he was a graduate student in his mid-twenties. In 2001, his story as depicted on the silver screen in A Beautiful Mind would astound audiences worldwide. But what if Nash had lost the period of relative normalcy he enjoyed prior to 1959 when he was doing his greatest work? If current knowledge of the schizophrenia prodrome had been available to Nash's parents in the 1940s, perhaps they would have found some aspect of their teenage son's behavior cause for concern. After clinicians identified their son as prodromal, they might have placed him on antipsychotics and into therapy. They, as well as his teachers, might have dissuaded him from pursuing his dreams of mathematical greatness and encouraged him to pursue a career "more appropriate" for someone with his condition. His medications might have interfered with his outstanding cognitive abilities. Would a teenage Nash resist these limitations, or would he feel so anxious about his own condition that he would admit defeat in the face of impending disease? Perhaps medical intervention would have lessened the severity of John Nash's symptoms, but we cannot easily predict the consequences this intervention would have had on his life.

--Kristen Thomas

Neuroscience Graduate Program



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Thomas, K. (2011). The Risks of Schizophrenia: Is Early Intervention Always Beneficial? The Neuroethics Blog. Retrieved on
, from http://www.theneuroethicsblog.com/2011/12/risks-of-schizophrenia-is-early.html

References

1. Dobbs, D. Nature 468, 154-156 (2010).

2. Chuma, J. & Mahadun, P. BJP 199, 361-366 (2011).

3. Woods, S.W. et al. Schizophrenia Bulletin 35, 894-908 (2009).

4. Tandon, R, Nasrallah, H.A. & Keshavan, M.S. Schizophr Res 122, 1-23 (2010).

5. Corcoran, C., Malaspina, D. & Hercher, L. Schizophr Res 73, 173-184 (2005).

6. Perkins, D.O. et al. Am J Psychiatry 162, 1785-1804 (2005).

The Prodrome: The Evaluation of Risk for Schizophrenia

How has research on schizophrenia recently changed?

In the past twenty years, schizophrenia research has turned its attention to the symptomatic period preceding a transition to the first episode of psychosis¹. In an attempt to prevent or at least dampen the cognitive, social, and psychological deterioration associated with the development of schizophrenia, research has identified a host of symptoms now described as “prodromal symptoms” to schizophrenia². The prodrome is the period of subclinical symptoms that develop prior to the onset of an illness, such as visual aura leading up to the onset of a migraine. With schizophrenia, these symptoms have a diverse range of manifestations from depression to grandiosity (an unrealistic sense of superiority), have no definite linear progression, and can only be retrospectively identified as prodromal schizophrenia once a transition has occurred. Until the patient develops full onset schizophrenia, symptoms can only be accurately described as putatively prodromal³. 

"Kaleidoscope Cats": Paintings of cats by artist Louis Wain reflecting the development of his schizophrenia over a period of time. Images from the Bethlem Royal Hospital Archive and Schizophrenia.org

Can clinicians predict a future onset of schizophrenia?

Putatively prodromal symptoms of schizophrenia are disturbing experiential changes that create a great deal of distress. Research on the schizophrenia prodrome aims to provide relief and care for symptomatic individuals and to identify high risk for a transition to psychosis⁴. By refining diagnostic criteria, researcher hope to quantify risk in order to predict a possibility of conversion; however, a diagnosis of prodromal schizophrenia is never possible, as the development of schizophrenia is not caused by any concrete factors. The manifestation of putatively prodromal symptoms is in no way an indication of an inevitable conversion to psychosis⁵.

What is the potential benefit or harm in evaluating risk for schizophrenia?

Due to the harmful psychological effect of putatively prodromal symptoms and the potential of delaying or preventing a transition to psychosis, research will continue to explore the possibilities of identifying and treating prepsychotic symptoms. However, clinicians must proceed with extreme caution as “diagnosing” a patient with prodromal schizophrenia, or even associating the symptoms with schizophrenia or psychosis, could exacerbate distress. For example, the stigma of schizophrenia could be detrimental to the putatively prodromal patient. I posit that a connection of current symptoms to schizophrenia, a psychotic illness with visual and auditory hallucinations, could damage the patient’s sense of reality. This association could provoke the already fragile patient, exacerbating symptoms and encouraging a progression towards psychosis. With this being said, the upcoming Diagnostic and Statistical Manual of Mental Disorder, DSM-V, will likely include criteria for “Attenuated Psychosis Syndrome” in order to facilitate patients’ access to medical coverage from insurance providers^6,7.

What about preventative treatment?

As for possible treatment for subthreshold symptoms, a viable pharmaceutical approach has yet to be thoroughly researched. Therapeutic treatment remains expensive and often difficult to acquire due to the complexity of insurance stipulations. Atypical antipsychotics are being tested and clinically prescribed for putatively prodromal symptoms, though their use for full onset schizophrenia is still relatively new⁸. Some studies suggest that the discontinuation of antipsychotic medications can encourage a transition to full onset psychosis⁹.

What are some ethical implications of risk evaluation and preventative care?

The early detection of psychosis presents a host of neuroethical dilemmas. How do you identify a risk of psychosis and does that identification consequently turn risk into a disorder? Is the prepsychotic period the last possible chance for patient consent and autonomy? Schizophrenia typically develops in late adolescence or early adulthood¹⁰. Does the approach to a risk of psychosis change if the patient is a minor or in the midst of a major life transition, such as entering college? Antipsychotics can have destructive effect but might be the key in preventing the development of schizophrenia. When is the right time to start medication, if the progression to psychosis is gradual and indeterminate? What therapeutic approaches should be the first line of treatment and how might this affect the patient’s progression? Finally, how should individual clinicians respond until there is a directive for symptom assessment and treatment, and how might this future directive in turn affect the medical industry and society as a whole?




--Sabrina Bernstein

Neuroethics Program Intern






Want to cite this post?


Bernstein, S. (2011). The Prodrome: The Evaluation of Risk for Schizophrenia. The Neuroethics Blog. Retrieved on
, from http://www.theneuroethicsblog.com/2011/10/evaluation-of-risk-for-schizophrenia.html

Sources and Additional Reading

¹ Haroun, N., Dunn, L., Haroun, A., & Cadenhead, K. S. (2006). Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophr Bull, 32(1), 166-178.

² Bota, R. G., Sagduyu, K., Filin, E. E., Bota, D. A., & Munro, S. (2008). Toward a better identification and treatment of schizophrenia prodrome. Bulletin of the Menninger Clinic, 72(3), 210-227.

³ Häfner, H., & Mauer, K. (2006). Early detection of schizophrenia: current evidence and future perspectives. World Psychiatry, 5(3), 130-138.

⁴ Corcoran, C., Malaspina, D., & Hercher, L. (2005). Prodromal interventions for schizophrenia vulnerability: the risks of being "at risk". Schizophrenia Research, 73(2-3), 173-184.

^5,8 McGlashan, T. H., Addington, J., Cannon, T., Heinimaa, M., McGorry, P., O'Brien, M., et al. (2007). Recruitment and Treatment Practices for Help-Seeking “Prodromal” Patients. Schizophrenia Bulletin, 33(3), 715-726.

⁶ Addington J, Cadenhead KS, Cannon TD, Cornblatt B, McGlashan TH, Perkins DO, Seidman LJ, Tsuang M, Walker EF, Woods SW, Heinssen R; “The NAPLS group”. (2007). North American Prodrome Longitudinal Study: A Collaborative Multisite Approach to Prodromal Schizophrenia Research. Schizophrenia Bulletin. 33(3): 665-672.

⁷ American Psychiatric Association (2010). Attenuated Psychosis Syndrome. APA DSM-5 Proposed Revisions.

^{9, 10} Larson, M. K., Walker, E. F., & Compton, M. T. (2010). Early signs, diagnosis and therapeutics of the prodromal phase of schizophrenia and related psychotic disorders. Expert Review of Neurotherapeutics, 10(8), 1347-1359.