PSYC 168 Fall Trimester

Joel Moody 21 November 2003

Annotated Bibliography: Identifying the Precursors of Schizophrenia

It may be disappointing to have a mother who is, let us say, an opera singer, and to find that that particular ability is not part of your genetic repertoire. However, when one has a mother who, rather than being an opera singer, is schizophrenic the emotional tenor of this line of questioning changes considerably. Suddenly it becomes very important to know if, in fact, such a psychotic condition is indeed part of your genetic repertoire. How does one know? What can be done if you find out that you are indeed likely to develop such life-altering symptoms?

Because the study of schizophrenia is still in its infancy (less than a century of real research) we are nowhere close to an understanding of its full etiology. The idea of preventing the onset of schizophrenia before it occurs, or treating its symptoms before they become irreversible, is an idea that has only recently begun to gather steam. However, there is a growing body of research, much of it in the area of genetics and brain imaging, which promises to provide direction for a therapeutic approach to the early identification and treatment of schizophrenia and related disorders.

If this were to become a reality one definitive benefit of such a therapeutic approach would be the promotion of much needed improvements in the effectiveness of our mental health care system by refocusing the treatment of schizophrenics on early treatment and prevention, rather than medicating and warehousing the psychotic.

I intend to explore the dominant viewpoints regarding the etiology of schizophrenia and the implications of those viewpoints on how we approach the treatment of the disease. I will look at the genetic point of view (various gene susceptibilities, etc.), the environmental point of view (obstetric complications, etc.), the combination of those two views, and also will consider clinical, neuropsychological, and physiological contributions to our understanding of this issue.

Basset, Anne S. (2001). Genetic Insights Into Schizophrenia [Electronic Version]. Canadian Journal of Psychiatry, 46(2): 131-137.

This article outlines new insights into the genetic etiology of schizophrenia. The author discusses several commonly held beliefs about the genetic issues regarding schizophrenia, including the idea that environmental factors may be causative factors in the development of schizophrenia, and concludes that research indicates that there are a certain number of chromosomal locations that appear to contain schizophrenia susceptibility genes and that the expression of those genes is the main causative factor of schizophrenia. The author acknowledges that no definitive causative mutations have been discovered. She also points out that environmental and other factors most likely affect gene expression, even though the genetic basis for schizophrenia is very clear.

Finally, the author points out that misconceptions about the implications of genetic research on our understanding of schizophrenia may hinder the clinical application of new genetic research (new treatments and interventions) unless such misapprehensions are addressed.

I found her treatment of the role and functioning of gene expression in schizophrenia to be quite helpful. To quote from the article:

These studies indicate that monozygotic twin discordance is due to non-expression of genetic susceptibility (incomplete penetrance), not purely environmentally caused phenocopies of schizophrenia as is commonly believed. Mechanisms other than external environmental factors therefore must be involved (Basset, 2001, p. 131).

Explanations such as this and her use of many examples from other disorders (deafness, Down’s syndrome, etc.) helped delineate the boundaries between gene expression and the influence of the environment.

She also did not commit the error of relegating all environmental influences to the waste bin and relying solely on genetics for her explanations. She writes:

These traditional genetic models may encourage the fallacy of genetic determinism--that all gene carriers will develop the (untreatable and unmodifiable) disease. They may also make it appear necessary to generate environmental explanations for the nonmendelian observations in schizophrenia genetics. While there is little evidence for environmental factors as the primary cause of schizophrenia, environmental factors are likely to be important modifying factors for age at onset and other manifestations over the course of illness (Bassett, 2001, p. 135).

This introduces the importance of considering gene expression when describing the causes of schizophrenia.

Wolkin, A., Rusinek, H. (2003). A Neuropathology of Psychosis [Electronic Version]? The Lancet, 361: 270.

This article is a commentary on previous studies on the subject of magnetic-resonance imaging in subjects at high risk for developing schizophrenia. The authors outline what they believe to be the most important considerations for further research:

Questions still largely unanswered concern the time course and pathophysiological basis of these abnormalities—at what point in neurodevelopment and in relation to nascent schizophrenic disease manifestation do central nervous system deviations emerge and what is the basis for the inter-individual variability in distribution of grey and white matter lesions (Wolkin & Rusinek, 2002, p. 270)?

In effect, how do you zero in on when schizophrenia begins in an individual and how do you account for the wide degree of variability in certain aspects of these brain dysfunctions, such as the above-mentioned lesions? The importance of these considerations is that such research lends itself to the improvement of the treatment and prevention of schizophrenia:

One obvious implication for these findings concerns evidence that early treatment of schizophrenia before the onset of symptoms may alter the course of the disease. The delineation by magnetic- resonance imaging of a structural profile present before the onset of psychosis could provide a more robust basis on which antipsychotic medication could be started with a reasonable risk- benefit ratio (Wolkin & Rusinek, 2002, p. 270).

This establishes that once the genetic basis of schizophrenia is accepted, one must turn to evaluative techniques such as brain imaging to understand the course of the disease as the genes express themselves. At this point the gene expression involved with this particular disease seems very complicated and merits much further research. Catching these symptoms early may mean that even with the genetic predisposition, gene expression and manifestation of symptoms may be minimized by early detection and treatment.

Tsuang, Ming T. (2002). Understanding Predisposition to Schizophrenia: Toward Intervention and Prevention [Electronic Version]. Canadian Journal of Psychiatry, 47(6): 518-527.

This article moves us into some more pragmatic territory. It is all well and good to understand that gene expression underlies the development and manifestation of schizophrenia, but how do you apply this knowledge in your approach to treatment and research? The author explains that his intention is to show us how the study of adult relatives of schizophrenia patients who carry the genetic predisposition, but do not develop schizophrenia, could aid us in understanding who develops the disorder and allow us to predict and prevent it.

This article diverges from my previous article because the author takes a slightly modified view of environmental factors into consideration:

Another variable related to the degree of risk for schizophrenia involves pregnancy and obstetric complications. Interestingly, documentation of fetal hypoxia predicted reduced gray matter and increased cerebral spinal fluid in patients and in their nonpsychotic relatives, but not in control subjects. These findings underscore the importance of environmental factors in producing not only schizophrenia but also the predisposition to schizophrenia (Tsuang, 2002, p. 520).

This approach does not deny the genetic basis of schizophrenia, in fact the research groups were chosen based on just such a genetic profile, but rather it also acknowledges the role of the environment in affecting the expression of those genes and the usefulness of such knowledge in predicting whether one will manifest schizophrenic symptoms. The author describes the results of a great deal of research that indicates a certain portfolio of symptoms that are common in the relatives of schizophrenia, which is called schizotaxia:

Taken together, these lines of evidence support the hypothesis that some relatives in schizophrenia families have a clinically meaningful, familiarly transmitted syndrome or set of traitsschizotaxia-that includes negative symptoms, psychophysiological abnormalities, neuroimaging-assessed brain abnormalities, neuropsychological deficits, and psychosocial impairments (Tsuang, 2002, p. 521).

The author proposes that all of this knowledge could be used to preselect preschizophrenic children for prevention protocols, using a very specific symptomology, and thus ensure that they never fully manifest schizophrenic symptoms. The usefulness of a concept such as schizotaxia is that it bridges the gap between a purely genetic model and a treatment approach (which are often more reliant on an understanding of environmental factors) in many ways:

As we proposed recently, the clinical symptoms required for a diagnosis emphasize the role of psychosis and may reflect a relatively nonspecific end state of the effects of schizotaxia plus psychosis. In contrast, many of the features of schizotaxia may be closer to the genetic and other adverse etiologic factors that produce the predisposition to schizophrenia. Consequently, symptoms of schizotaxia may come to represent particularly promising treatment targets for prevention protocols. These points do not detract from the major achievements and utility of the DSM and ICD systems in advancing psychiatric diagnosis, especially in reliability but also in validity. Rather, they suggest possible pathways for continued progress in confirming the reliability and validity of psychiatric classification (Tsuang, 2002, p. 523-524).

This part of the paper would allow me to describe who, in fact, is susceptible and what their characteristics are during childhood and early to mid-adulthood. This would make it much clearer who, according to research, is likely to have schizophrenia in their repertoire and who (despite having a relative with the disease) does not have such a susceptibility because they have manifested few or none of the other predictors of schizophrenia in their behavior. It would be nice to add in brain scans and other such diagnostic hardware, but a diagnosis is possible without all that.

Phillips, Prashant. (2002). Soft Drug, Hard Facts [Electronic Version]. Mental Health Practice, 5(7): 25.

This article is a short treatment of misunderstandings surrounding the role of drug use on the development of psychotic symptoms. The author makes a clear statement dispelling most misunderstandings:

When considering persistent psychotic illness, current evidence suggests it is extremely unlikely that cannabis use can independently cause a persistent chronic psychotic illness such as schizophrenia; but its role as a risk factor in the onset of schizophrenia remains unclear and controversial. The temporal relationship between cannabis and schizophrenia remains hotly disputed (Prashant, 2002, p. 25).

The author’s conclusion is that using cannabis will not cause long term psychosis. The purpose of using this article is that while I am dealing with the diagnostic symptomology of preschizophrenic behavior (relying largely on the previous article by M. Tsuang) I would make a short aside to deal with fears about the influence of casual drug use on one’s chances of developing a psychosis, in order to allay fears that even if one does not have a schizophrenic relative, and even if one does not exhibit schizotaxic symptomology, one may be one of the unlucky few to become schizophrenic just because they tried hash one time.

Rust, J., Golombok, S., Abram, M. (1988). Creativity and Schizotypal Thinking [Electronic Version]. Journal of Genetic Psychology, 15o(2): 225-227.

This article discusses studies regarding the supposed link between creativity and a predisposition to schizophrenia. No relationship was found, however, there may be some relationship between creativity and borderline personality disorder.

This article would be included to dispel worries about an increased susceptibility to developing schizophrenia simply because one has artistic leanings or exhibits a lot of creative thinking.

Harrison, Paul J., Owen, Michael J. (2003). Genes for schizophrenia? Recent findings and their pathophysiological implications [Electronic Version]. The Lancet, 361: 417-419.

In this article the authors discuss various genetic findings that increase our scientific understanding of schizophrenia. They draw parallels between current genetic research on schizophrenia and earlier research on Alzheimer’s disease:

Alzheimer’s disease also illustrates how a genetic breakthrough can lead rapidly to treatment approaches aimed at pathogenesis rather than at symptoms (Harrison & Owen, 2003, p. 419).

Their conclusion is that it is likely that we will find similar treatments for schizophrenia. At this point in the paper I would like to draw attention to the idea of treating the origins of the disease and the importance of genetic research, but without close attention to the symptoms how will we know whom we should treat with these new therapies? We aren’t going to genetically screen everyone and then treat them. The people who will be treated because someone recognized their symptomology or because they are at risk because they are related to someone who exhibits symptoms.

The power of genetic research is that it may bypass many of those symptoms to treat the disease at its very root. I point this out to underscore the approach outlined in the article on schizotaxia. Such an approach would bring more people into treatment and it would bring them into treatment sooner, so that they can take advantage of the marvelous treatment promised us by our genetic researchers.

Bower, B. (2002). Psychotic Biology: Genes Yield Clues to Schizophrenia’s Roots [Electronic Version]. Science News, 162: 195-196.

This article discusses genetic research on schizophrenia and the activity of NMDA receptors. The author discusses the research and some of their findings and then gives this cautionary statement:

If the findings hold up, people who inherit either or both of the critical gene versions still aren’t doomed to develop schizophrenia, Cohen cautions. Further research is needed to identify other genes, as well as environmental factors, that influence the same NMDA-receptor pathway, he says (Bower, 2002, p. 195).

He concludes with the need for further study. I would include this quote to illustrate that even with a description of schizophrenia on a molecular level and genetic certainty (which we don’t have) we would still need to take into account other factors that would affect how an individual manifest their genetic makeup. In fact, we wouldn’t know if they would be schizophrenic until they began exhibiting symptoms, even if we had extensive genetic information on them. Apart from the development of new treatments targeted at genes and molecular pathways, the genetic understanding of the disease has limited diagnostic utility. We still must rely on symptoms for our understanding of how, in whom, and when schizophrenia may manifest. We must simply pinpoint traits that are closer in origin to the genetic underpinnings of the disease, so we can catch it sooner and with more certainty.

Cannon, Tyrone D. (1997). On the nature and mechanisms of obstetric influences in schizophrenia: a review and synthesis of epidemiologic studies [Electronic Version]. International Review of Psychiatry, 9: 387-397.

This article looks at whether obstetric complications “covary with, depend on, or are independent of the disorder’s genetic basis.” His findings suggest that having the genes that predispose you to schizophrenia also makes you more susceptible to “the neurotoxic consequences of oxygen deprivation” during development or birth, rather than oxygen deprivation causing schizophrenia. He writes:

If obstetric risk factors are correlated with the disorder’s genetic basis (gene-environment covariation model), then their influences are confounded, and precision of linkage statistics may be lost if OCs have other than an inconsequential association with schizophrenia. If an obstetric influence depends on the presence of genetic predisposition (gene-environment interaction model), then elucidating the nature of this influence should provide important clues as to the genes involved, since such genes would then be expected to confer a heightened susceptibility to the mechanism by which the particular complication increases risk for schizophrenia.

This article would be included in order to elucidate the chicken- and-egg situation we find ourselves in when considering environmental and genetic factors and their contribution to schizophrenia. It is difficult to distinguish how exactly environmental influences interact with a genetic predisposition to cause an overt phenotypic manifestation of schizophrenia. This is a question that deserves a great amount of careful

study. To me it shows that the best understanding of schizophrenia is where we find the most seamless linking between genetic, environmental, and symptomatic features of the disease. This again, is where an understanding of the syndrome of schizotaxia seems to tie things together.

Fitzgerald, P. B. (2001). The role of early warning symptoms in the detection and prevention of relapse in schizophrenia [Electronic Version]. Australian and New Zealand Journal of Psychiatry, 35: 758–764.

In this article the author reviews various programs for the early detections of schizophrenia and concludes that, with the proper approach, it is indeed possible to detect schizophrenia early and prevent relapses in those who are already schizophrenic. He writes:

The studies reviewed suggest the best approach required the utilisation of clinical judgement, non-specific and specific symptoms, frequent assessments and the involvement of patients, clinicians and carers (Fitzgerald, 2001, p. 761).

I would include this article in order to outline more clearly the approach that would be needed in order to implement early intervention and prevention protocols that would use the schizotaxic model as a way of predicting future schizophrenic behavior and targeting those people with schizotaxia for treatment.

Davidson, M., Reichenburg, A., Rabinowitz, J., et al. (1999). Behavioral and Intellectual Markers for Schizophrenia in Apparently Healthy Male Adolescents. American Journal of Psychiatry, 156: 1328-1335.

This article would be used to show a successful example of a study that linked low test scores (derived from draft records in Israel) with later hospitalization for schizophrenia. Such screenings (the draft tests measure intelligence, social functioning, organizational ability, interest in physical activity, and individual autonomy) could be used to identify individuals who might receive a preventative evaluation by a doctor or clinician. The conclusion of the article says that “the strongest predictors for schizophrenia were deficits in social functioning, organizational ability and intellectual functioning (Davidson, et al.).”

In conclusion, when considering if one has a predisposition to schizophrenia it is important to take into account more that just having a schizophrenic relative, or even (if one were in possession of such knowledge) the genetic markers that are characteristic of schizophrenia, but also environmental and developmental influences, and, most importantly whether one exhibits the complex of behaviors that characterize the syndrome schizotaxia (defined broadly in the study by Tsuang as abnormalities in affect, cognition, and social functioning). In addition, if one receives treatment early enough it may be possible to avoid the most deleterious effects of such gene expression. Therefore, just as it is clearly possible to have a highly talented parent with less than talented offspring, it is equally possible for a schizophrenic parent to have a normal functioning child. It is important that we do not ape the misunderstandings of genetic determinism unthinkingly.

We must, for the sake of schizophrenic people and their families, endeavor to paint a much clearer picture of schizophrenia and schizotaxic behavior so that risk factors are better understood and treatment and prevention may happen with greater speed and certainty. This is why research in schizophrenia must continue in all fields—not just with a focus on genetics—so that a more comprehensive perspective, inclusive of improved treatment for schizophrenics can be developed, by identifying them before their condition deteriorates too far. I believe the syndrome of schizotaxia and an understanding of the symptoms it describes will be very important to this effort.