CAUSAL FACTORS IN SCHIZOPHRENIA

The causal factors in schizophrenia remain unclear, with biological, psychosocial, and
sociocultural factors being the primary attributions. These factors are not mutually exclusive, and
each may be involved in some cases. Biological factors are discussed in greater detail due to
their prominence in contemporary thinking

Biological Factors in Schizophrenia

Research on biological factors contributing to schizophrenia has primarily focused on genetics,

biochemical, neuro-physiological, and neuroanatomical processes, with each focus being
discussed in the following section.

Genetic influence

● Genetic Influences It has been known for many decades that disorders of the
schizophrenic type tend to "run in fami-lies," giving rise to the notion of "tainted" genes as
an impor-tant-causal factor.
● In fact, the evidence for higher-than-expected rates of schizophrenia among biological
relatives of "index" cases (that is, the diagnosed group of people who provide the starting
point for inquiry, also called "probands") is overwhelming, Moreover, that evidence
includes a strong correlation between closeness of the blood relationship (i.e. level of
gene-sharing or consanguinity) and degree of concordance for the diagnosis,
● Of course, and as we have repeatedly emphasized, the interpretation of such familial
concordance patterns is never completely straightforward, in part because of the strong
relationship between the sharing of genes and the sharing of the environments in which
those genes express themselves.
● While some investigators continue to hold the view that the genetic influence in
schizophrenia is confined to one or at most a very few genes, the evidence points strongly
toward polygenic involvement.
● It will be helpful for the student to bear in mind these continuing uncertainties as we
review below the available data on twin and adoption studies of schizophrenia.

Twin studies
 ● schizophrenia concordance rates for identical twins are routinely, and over very many
studies, found to be significantly higher than those for fraternal twins or ordinary siblings.
● Noting in particular overall pairwise concordance rates of 28 and 6 percent in MZ versus
DZ twin-ships, respectively, we mày conclude that a reduction in shared genes from 100
percent to 50 percent reduces the risk of schizophrenia nearly 80 percent.
● If schizophrenia were exclusively a genetic disorder, the concordance rate for identical
twins would, of course, be 100 percent.
● These potentially disruptive conditions, when they occur, are more likely to be shared by
MZ than by DZ twins.
● The higher concordance rate for schizophrenia in MZ than in DZ twins might be a
consequence, at least in part, of a higher rate of shared pathogenic factorsother than
tainted genes-for example, an inadequate maternal blood supply, which would affect MZ
embryos more similarly than DZ ones.
● The nonschizophrenic co-twins of discordant pairs, while less neurologically impaired than
their disordered siblings, were more impaired than a set of control MZ twins where both
members of the twinship were considered psychiatrically normal. •
● These results would seem to establish beyond reasonable doubt that genetically identical
individuals can manifest widespread biological differences, particularly in neurological
integrity, that are associated with relative THE CAUSAL FACTORS IN SCHIZOPHRENIA 481
risk for the development of schizophrenia.

Adoption studies

● Several studies have attempted to overcome the shortcomings of the twin method in
achieving a true separation of hereditary from environmental influences by using what is
called the adoption strategy.
● Here concordance rates for schizophrenia are compared for the biological and the
adoptive relatives of persons who have been adopted out of their biological families at an
early age (preferably at birth) and have subsequently become schizophrenic.
● A follow-up study of 47 people who had been born to schizophrenic mothers in a state
mental hospital and placed with relatives or in foster homes shortly after birth found that
16.6 percent of these subjects were later ding-nosed as schizophrenic.
● In addition to the greater probability of being diagnosed schizophrenic, the offspring of
schizophrenic mothers were more likely to be diagnosed as mentally retarded, neurotic,
and psychopathic (that is, antisocial).
● Using a national sample of schizophrenic adoptees and their biological and adoptive
relatives (together with suitable control cases), the data show a preponderance of
schizophrenia and "schizophrenia spectrum" (which includes schizo-typal and paranoid
personality disorder) problems in the biological relatives of schizophrenic adoptees.
● Unfortu-nately, we cannot be certain that the emergence of odd or psychotic behavior in
adoptees did not precede and cause, in whole or in part, the disorganization of their
adoptive families.
● Everything considered, the Finnish Adoption Study (as it is called) has provided strong
confirmation of the diathesis-stress model as it applies to the origins of schizophrenia.
Studies of High-Risk Children

● The prospective re-search strategy of long-term monitoring of children known to be at

high risk for schizophrenia by virtue of having been born to a schizophrenic parent) is
basically intended to identify the environmental factors that cause breakdown (or
resistance to it) in predisposed people.
● Although the available results of high-risk studies have generally proved difficult to
interpret, they have supported the observation that having a schizophrenic parent is a
good predictor of psychological disorder, including schizophrenia (e.g., Erlenmeyer-
Kimling et al, 1997).
● Summing up, the question of genetic transmissibility of a predisposition to schizophrenia
is not as easily answered as it may appear to be when first posed.
● In-deed, most people who develop schizophrenia have no close relatives who are also
known to have had the disor-der—although, as we shall see, some of these normal
relatives may share biological anomalies statistically associated with a schizophrenia
diagnosis.

Biochemical Factors

● The idea that serious mental disorders are due to "chemical imbalances" in the brain is
now commonplace.
● We cannot effectively address the general question of possible biochemically based
contributions to the onset or maintenance of schizophrenic behaviors in the absence of
clues that tell us where to look and what to look for.
● At present, as in the case of the severe mood disor-ders, the search is governed largely by
attempts to discover the site and nature of central nervous system effects induced by
drugs that diminish the behavioral expression of the disorder.
● According to the dopamine hypothesis, then, schizophrenia is the product of an excess of
dopamine activity at certain synaptic sites.

Neurophysiological Factors

● Much recent research has focused on the role of neurophysiological disturbances in

schizophrenia, such as an imbalance in various neurophysiologic processes (e.g., those
involved in eye movement control—see below) and inappropriate autonomic arousal.
● Such disordered physiology would disrupt normal attentional and information-processing
ca-pabilities, and there seems to be a growing consensus that disturbances of this type
underlie the cognitive and perceptual distortions characteristic of schizophrenia.
● A substantial proportion of schizophrenic persons are found to be deficient in their ability
to track a moving target vi-sually, a skill referred to as smooth pursuit eye movement
(SPEM) (Holzman et al.,
● The deficiency is sometimes attributed to a disorder of nonvoluntary attention, one likely
 ●
related to an impaired ability to detect the velocity of moving visual stimuli.

Neuroanatomical Factors

● Abnormal neurophysiological processes in schizophrenia could be genetic in ori-gin, but

some at least could also be the product of biological deviations caused by other factors,
as suggested in the discordant MZ twin data reviewed earlier.
● servations have led to a resurgence of interest in an old question—that of the anatomical
intactness of the schizophrenic brain—to which we now turn.
● Research on the structural properties of the brain in living subjects was largely
unproductive until the development of modern computer-dependent technologies, such as
computerized axial tomography (CAT), positron emission tomography (PET), and magnetic
resonance imaging (MRI).
● The use of these techniques in the study of schizophrenic people's brains has developed
at an accelerating pace in recent years, with important results.

Brain Mass Anomalies

● Much evidence now indicates that in a minority of cases of schizophrenia, particularly

among those of chronic, negative-symptom course, there is an abnormal enlargement of
the brain's ventricles-the hollow areas filled with cerebrospinal fluid lying deep within the
core (Andreasen et al.,
● Several other associated anatomical anomalies, such as enlarged sulci (the fissures in the
surface of the cerebral cor-tex), are often reported as well.
● These rather consistent findings relate to an ongoing controversy as to whether the
supposed anatomical substrates of schizophrenia are best considered due to a
neurodegenerative or to a neurodevelopmental process (Buchanan, Stevens, & Carpenter,
1997; sernansky & Bardgett, 1998).
● The findings of a particular brain anomaly associated with some cases is of enormous
potential significance for at least the types of schizophrenia primarily implicated.

Deficit Localization

● Concerning the frontal and prefrontal regions, many studies have demonstrated
abnormally low frontal lobe acti-vation-called hypofrontality among schizophrenic persons
when they engage in tasks supposedly requiring substantial frontal lobe involvement, such
as the Wisconsin Card Sorting Test (WCST).
● It should be cautioned, however, that the levels of hy-pofrontality observed among
schizophrenic persons are often only marginally, albeit statistically significantly, different
from levels observed in normal control subjects, with much overlap between the groups
(e.g., Buchsbaum et al.,
● Dysfunctional frontal lobes are believed to be especially important in accounting for
negative signs and symptoms, and perhaps also attentional-cognitive deficits (Cannon et
al.,
Neurodevelopmental Issues

● Given all these find- ings, noted schizophrenia researcher Timothy Crow (1997) has
recently voiced a persistent question that has quietly frustrated many of his colleagues
around the world: "Where is the primary lesion in schizophrenia and what is its nature?"
● The nature of this new thinking is by no means completely developed or uniformly
expressed, but its essential kernel involves the idea that what we call schizophrenia is due
to a probably variable aberration in the basic cir-cuitry, the basic wiring, of the brain itself.
● Most forms of the idea include the notion of an early, even prenatal, insult to the brain, one
that may have detectable neurological effects in early childhood but will not necessarily
result in the later development of schizophrenia.

RELATIONSHIP BETWEEN INCREASING DAMAGE TO NEURONAL CIRCUITS AND CLINICAL

PHENOMENOLOGY

● This peculiar observation, which itself is now beyond dispute, has given rise to a variety of
hypotheses involving what has come to be called the "season of birth effect" in the
development of schizophrenia.
● Some of these relate directly to the question of compromised brain integrity in
schizophrenia, as was suggested early on by Bradbury and Miller (1985).
● Seemingly important and possibly related findings, reported by Torrey and colleagues
(1993), establish a strong correlation between the occurrence of stillbirths and the live
births of persons who become schizophrenic, both being elevated in winter months.
● The investigators suggest that there appears to be a common factor for both stillbirths
and schizophrenia risk, presumably some infectious agent; in the one case, according to
this hypothesis, it leads to death of the fetus, while in the other to brain changes that
enhance vulnerability to schizophrenia.
● It is a reasonable hypothesis, therefore, that these preschizophrenic children as a group
suffered from subtle neurological impairment of unknown origin.

Interpreting the Biological Evidence: Diathesis/ Stress

● The role of biological factors in the etiology of schizophrenia has been established.
● In summary, then, biologically oriented research, particularly in recent years, has given us
a wealth of new insights regarding the nature of schizophrenia and some of the sources of
vulnerability to it.
● We turn now to an examination of the evidence relating to psychosocial influences in
schizophrenia,

Psychosocial Factors in Schizophrenia

● It is unfortunate and counterproductive that biological and psychosocial research are often
 ●
conceived as mutually antagonistic and that they rarely make contact with one another
(Carson & Sanis-low, 1993).
● Notwithstanding its potential importance, research on psychosocial factors in the
development of schizophrenia has been exceedingly sparse in recent years, especially as
compared with the research investment in biological correlates.
● As a result, much of the available psychosocially oriented research in schizophrenia is
seriously dated.

Damaging Parent-Child and Family Interactions

● Studies of interactions in families having schizophrenic offspring have focused on such

factors as (1) schizo-phrenogenic (schizophrenia-causing) parents; (2) destructive
parental interactions; and (3) faulty communi-cation.
● The focus of research has shifted in recent years from parent-child to total family
interactions.
● For example, studies by Mishler and Waxler (1968) and Liem (1974) both found that
parents' attempts to deal with the disturbed behavior of schizophrenic sons and daughters
had pathological effects on their own behavior and communication pat-terns.
● Gregory Bateson, a pioneer in schizophrenic families, identified the confusing and
conflicting nature of communication, a phenomenon he termed double-bind
communication.

The Role of Excessive Life Stress and Expressed Emotion

● A marked increase in the severity of life stress has been found during the ten-week period
prior to a person's schizophrenic breakdown (Brown, 1972).
● We also note that life stressors, like schizophrenia itself, have a higher co-occurrence rate
in twins than in ordinary siblings (Kendler et al.,
● Whether or not poor relations with parents and tam-ily members is a cause of
schizophrenia, we do know that relapse into schizophrenia following remission is
associated with a certain type of negative communication, called expressed emotion (EE),
directed at the patient by family members (Butzlaff & Hooley, 1998; Hooley & Hiller, 1998;
Linszen et al.,
● Some research shows EE to predict schizophrenia before its initial onset (Goldstein, 1985),
and strongly suggests that its role in relapse is a directly causal one (Nuechterlein, Snyder,
& Mintz, 1992), Also, attempts to reduce EE and associated behaviors in family members
have been very impressive in terms of relapse prevention (Falloon et al.,
● Familial Expressed Emotion has thus turned out to be a quite potent variable in the
precipitation of schizophrenic episodes.

Sociocultural Factors in Schizophrenia

● As was noted earlier, prevalence rates for schizophrenia appear to vary substantially
 ●
around the world, Granting the already acknowledged hazards of such cross-cultural
comparisons, there is at least a twofold to threefold-and possibly considerably greater
variation in occurrence of the disorder in the various social groupings and geographic
regions for which epidemiologic data are available (Gottesman, 1991; Stevens & Hallick,
1992) No satisfactory biological explanation for this variation has been identified (Kirch,
1993), and the possibility that the differences reflect intercultural social factors (e.g.,
religious beliefs and practices, family organization and val-ues) that modify the
schizophrenia risk cannot be ruled out (Torrey, 1987).
● If there are cultural factors that both enhance and diminish the risk for schizophrenia, it
would obviously be of great value to understand how these operate.
● Systematic differences in the content and form of schizophrenia between cultures and
even subcultures have been documented by various investigators over many years.
● Focusing on sociocultural factors within the United States, there is now a huge body of
evidence going back to the 1930s indicating that the lower the socioeconomic status, the
higher the prevalence of schizophrenia.
● Proportionally far more blacks than whites in the United States receive a diagnosis of
schizophrenia.

TREATMENTS AND OUTCOMES

● Before the 1950s the prognosis for schizophrenia was generally considered extremely
unfavorable, even hope-less.
● As often as not, perhaps after a brief trial at one or more of the inadequate "therapies"
offered, the patient was simply left to adjust to an institution he or she was never expected
to leave (Deutsch, 1948).
● Thus, complying with the self-fulfilling prophecies of their dismal prognoses, most
admitted patients, in fact, did not ever leave.

The Effects of Antipsychotic Medication

● Pharmacotherapy (treatment by drugs) with these potent compounds transformed the

environment of mental hospitals practically "overnight" by virtually eliminating the ever-
present threat of wild, dangerous, or otherwise anxiety-produc-ing patient behaviors.
● Newer and better (mostly in the sense of reduced problematic side effects) antipsychotic
drugs did in fact make their appearance in the interim, and they continue today to be
introduced at a high rate (see Chapter 16).
● Unfortunately, the rate of readmission remains extremely high, and many schizophrenic
patients experience repeated discharges and readmissions in what is commonly referred
to as the "revolving door" pattern.