PSYC 168 Joel Moody

Fall Trimester 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 traits-
schizotaxia-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.