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

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

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.

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

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

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).