The Roots of Schizophrenia
What leads to these symptoms? Like the other causes of disorders we have discussed, the causes of schizophrenia are complex, involving genetic, prenatal, neural, social, and psychological factors.
It has long been known that schizophrenia runs in families (Figure 16.23). For example, if a person has a sibling with schizophrenia, the likelihood that he has (or will get) the disease himself is four times greater than the likelihood of schizophre-nia in the general population—8%, compared with 1 or 2% in the broad population (Andreasen & Black, 1996; D. Rosenthal, 1970). But this fact, by itself, does not prove a genetic contribution. (After all, the increased risk among siblings might reflect a factor in the home or family environment.) Better evidence comes from concordance rates between twins, which are between 41 and 65% if twins are identical, and between 0 and 28% if they are fraternal (Cardno & Gottesman, 2000).
Separate evidence comes from adoption studies. Consider a child who is born to a mother with schizophrenia and placed in a foster home (with foster parents who are not schizophrenic) within a week or so after birth. The odds are about 8% that this child will develop schizophrenia, the same percentage as for children who remain with a biological parent who has the disease (Kendler & Gruenberg, 1984; Kety, 1988; Tsuang, Gilbertson, & Faraone, 1991).
All of these findings suggest that there is some genetic contribution to the develop-ment of schizophrenia (Sullivan, Kendler, & Neale, 2003), and, in fact, scientists may be closing in on the specific genes that are responsible. For example, two separate stud-ies have found that people with two specific DNA deletions are substantially more likely than people without these deletions to develop schizophrenia (International Schizophrenia Consortium, 2008; Stefansson et al., 2008).
However, if genes were the whole story for schizophrenia, the concordance rate would be 100% for identical twins, and of course it is not. In addition, if genes were all that mattered, we would expect that genetically identical individuals who develop schizophrenia will have identical symptom profiles. This is not the case. For example, the genetically identical Genain quadruplets (see Figure 16.24) all have schizophrenia, but two of the sisters have a more serious symptom profile than the others. These observations lead us to ask what other (nongenetic) factors play a role. In recent years, attention has focused on factors associated with birth—both prenatal factors and factors during delivery.
One line of evidence suggests that the mother’s exposure to an infectious agent dur-ing pregnancy may increase the likelihood that her child will develop schizophrenia. The influenza virus has attracted special attention based on the finding that when mothers are in the second trimester of pregnancy during an influenza epidemic, their children are more likely to develop schizophrenia (Brown, Cohen, Harkavy-Friedman, & Babulas, 2001; Mednick, Huttunen, & Macho’n, 1994; Sham et al., 1992). These find-ings are supported by epidemiological studies that show that children who develop schizophrenia are disproportionately likely to have been born during the winter (January to March in the Northern Hemisphere, July to September in the Southern
Hemisphere), the season during which people stay inside more and thus share more viral infections. In geographic areas where there are no seasons—that is, in areas near the equator—there is no link between schizophrenia and birth month (Battle, Martin, Dorfman, & Miller, 1999; McGrath, Welham, & Pemberton, 1995; Parker, Mehendran, Koh, & Machin, 2000).
Infections, however, are likely not the whole story. Another line of evidence suggests that maternal malnutrition during pregnancy also increases the risk that the child will later develop schizophrenia (Figure 16.25). Thus, children born just after a major crop failure in China in the early 1960s were twice as likely as Chinese children born earlier or later to develop schizophrenia (St. Clair et al., 2005).
Evidence further suggests that a diverse set of birth complications is associated with schizophrenia, and what these complications have in common seems to be a period of diminished oxygen supply to the newborn. This oxygen deprivation by itself is not enough to produce the disease, but it may interfere with the newborn’s brain develop-ment in a way that increases the likelihood that a genetic predisposition will eventually be expressed as schizophrenia (T. D. Cannon et al., 2000; Zorilla & Cannon, 1995).
We still need to ask, though, what these various factors do to produce the illness we call schizophrenia. What are the effects of the infection, or the oxygen deprivation, or the genetic pattern associated with this illness? According to many investigators, the answer lies in the fact that schizophrenia is, at its heart, a neurodevelopmentaldisorder (Sawa & Snyder, 2002; Waddington, Torrey, Crow, & Hirsch, 1991). In otherwords, the various factors we have mentioned cause the child’s brain (in both its structure and its chemistry) not to develop as it should from a fairly early age. By this logic, though schizophrenia may not be diagnosed until adolescence, it reflects developmental problems that occurred years earlier.
Consistent with this notion, evidence suggests that many individuals who are even-tually diagnosed with this illness are, in fact, unusual in early childhood. For example, close examination of home movies of children who, years later, were diagnosed with schizophrenia reveals that the “preschizophrenic children” showed less positive emotion in their facial expressions and more negative facial emotion, compared with siblings who did not later develop schizophrenia (Walker, Grimes, Davis, & Smith, 1993; Walker, Kestler, Bollini, & Hochman, 2004; Walker, Savoie, & Davis, 1994). The preschizo-phrenic children also showed unusual motor patterns, including odd hand movements. In some cases, these differences were visible at a very early age—as young as 2 years old—which strongly suggests that the disease starts influencing the person in early childhood, even if the full disruption it causes is not detected for years (Figure 16.26).
Clearly, genetic factors and environmental factors before and during birth contribute to schizophrenia and seem to throw brain develop-ment somehow off-course. But off-course how? Can we pinpoint the biological changes that these various factors produce, which then lead to the illness?
According to the dopamine hypothesis, schizophrenia is associated with an abnormally high level of activity in the brain circuits sensitive to the neurotransmitter dopamine. The strongest line of evidence for this hypothesis comes from the effects of a number of medications known as classical antipsychotics, medications that include the drugs Thorazineand Haldol. These drugs block receptors for dopamine (Figure 16.27), and, as the dopamine hypothesis predicts, they relieve many of the symp-toms associated with schizophrenia. In addition, some antipsychotics are more effective than others in blocking dopamine receptors, and the stronger the blockade, the more therapeutic the drug.
Other evidence comes from people who do not have schizophrenia but who have taken overdoses of amphetamines. Amphetamines are stimulants whose effects include the enhancement of dopamine activity and, when taken in large enough doses, produce a temporary psychosis similar to schizophrenia. As the dopamine hypothesis would predict, medications that block dopamine activity at the synapse also reduce the psychotic symptoms that follow amphetamine abuse.
The dopamine hypothesis has much to recommend it, but in recent years investigators have realized that it is incomplete (Carlsson et al., 1995). One clue is that many of the newer antipsychotic medications—which are at least as effective as older antipsychotics but generally have fewer side effects—do not appear to be strong dopamine antagonists (Burris et al., 2002). Researchers now believe that people with schizophrenia may suffer both from excessive dopamine stimulation in some brain circuits (Laruelle, Kegeles, & Abi-Darham, 2003) and from insufficient dopamine stimulation elsewhere (e.g., in the prefontal cortex; Koh, Bergson, Undie, Goldman-Rakic, & Lidow, 2003).
Other neurotransmitter systems also seem to be implicated in schizophrenia. For example, people with schizophrenia may have a dysfunction in glutamate transmis-sion in their brains, either because they have insufficient glutamate or because they are relatively insensitive to it. Several pieces of evidence point in this direction, includ-ing the fact that the illicit drug phencyclidine (more commonly known as PCP or angel dust) blocks glutamate receptors and induces symptoms similar to those seen in schizophrenia (Gorelick & Balster, 1995). In addition, drugs that increase glutamate activity alleviate both positive and negative symptoms of schizophrenia (Goff & Coyle, 2001).
We probably should not think of the dopamine and glutamate proposals as competi-tors; both might capture part of the truth. Indeed, this reflects one of the messages emerging from recent research on schizophrenia: Multiple neurotransmitters seem to be involved, affecting multiple brain areas, under the control of multiple genes (cf. Javitt & Coyle, 2004; Sawa & Snyder, 2002).
In addition to the neurochemical disruptions in schizophrenia, research indicates that patients with this disorder also suffer from structural abnormalities in their brains. MRI scans show that a certain proportion of people with schizophrenia—males, especially—have an enlargement of the ventricles, the fluid-filled cavities in the brain. Simply put, the ventricles become enlarged because there is not enough brain to fill the
skull (Figure 16.28). This finding indicates that in many cases of schizophrenia, there is either a dramatic loss of brain tissue or a defi-ciency that existed from the start (Andreasen et al., 1986; Chua & McKenna, 1995; Lawrie & Abukmeil, 1998; Nopoulos, Flaum, & Andreasen, 1997).
Abnormalities associated with schizophrenia have also been reported in other areas of the brain (Heckers, 1997; L. K. Jacobsen et al., 1997), but the most persuasive findings involve the frontal and temporal lobes (Black & Andreasen, 1994; Martin & Albers, 1995). Studies of brain structure have documented a loss of gray matter in prefrontal regions that support working memory, and the degree of tis-sue loss seems to be correlated with symptom severity (Cannon et al., 2002). When these areas are examined during autopsy, individuals with schizophrenia also show various irregularities, including missing or abnormally sized neurons. These neuronal defects—not surprisingly—affect overall brain function: neuroimag-ing studies of patients with schizophrenia indicate atypical functioning in the areas where neuronal defects are common (Barch et al., 2001; Tan et al., 2006).
Almost a century ago, epidemiological studies revealed a link between schizophrenia and socioeconomic status, or SES (Faris & Dunham, 1939). In fact, one study suggested that low-SES individuals are nine times more likely to develop schizophrenia than are high-SES individuals (Hollingshead & Redlich, 1958). The same point can be made geographically, since the prevalence of schizophrenia is highest in the poorest and most dilapidated areas of a city and diminishes as one moves toward higher-income regions (Figure 16.29; M. L. Kohn, 1968).
What produces this relationship? Part of the answer is, sadly, daily stress—poverty, inferior status, and low occupational rank are all stressful, and so can help trigger schiz-ophrenia in someone who is (for biological reasons) already vulnerable (Goldberg & Morrison, 1963). But there is another reason why schizophrenia is associated with poverty: Someone who suffers from schizophrenia is less likely to do well in school and less likely to get or hold a good job. As a result, people with schizophrenia suffer from downward drift. Their disease pro-duces problems that, in turn, put them into a lower social class (Dohrenwend et al., 1992; Jones et al., 1993). Notice, then, that cause and effect run in both directions here: Poverty is a risk factor for schizophrenia, making the disease more likely, but schizophre-nia is itself a risk factor that makes poverty more likely.
What about someone’s immediate environment—for example, her family? Some investigators have looked to the per-sonality of a person’s parents as a potential source of schizophrenia. Others have focused on communication patterns in the family (Bateson, 1959, 1960). There is little evidence, however, in favor of either of these claims. In fam-ilies that include someone with schizophrenia disturbances may be common, but this is likely to be a consequence of the disease rather than its cause. After all, having a fam-ily member who suffers from schizophrenia can be tragic for the family. Parents often blame themselves for their child’s illness and are likely to become frustrated and despondent in their attempts to reach their child (Mishler & Waxler, 1968; Torrey, 1983).
Children with schizophrenia may have difficult parents for another reason. Given the link between schizophrenia and genetics, a child with schizophrenia is likely to have at least one parent with the same pathological genes as the child’s. Thus, the parents may have a muted (or perhaps just an undiagnosed) version of the disease, contribut-ing to the family’s problems (Holtzman et al., 1988; Reveley, Reveley, & Clifford, 1982; Tsuang et al., 1991).
In short, there is no reason to believe that poor familial relations cause the disorder. But the family context surely matters in other ways, including how well a person with schizophrenia copes with the disorder. This is reflected in the fact that patients, once treated and released from a hospital, are rehospitalized more often if their parents are hostile and critical toward them (Hooley, 2004). Such negative reactions from family members are likely to impede the patient’s adjustment to his disorder and may create such distress that another hospital stay becomes necessary.
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