52.3 Understanding Schizophrenia

Schizophrenia is a dreaded psychological disorder. It is also one of the most heavily researched. Most studies now link it with abnormal brain tissue and genetic predispositions. Schizophrenia is a disease of the brain manifested in symptoms of the mind.

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Brain Abnormalities

52-3 What brain abnormalities are associated with schizophrenia?

Might chemical imbalances in the brain underlie schizophrenia? Scientists have long known that strange behavior can have strange chemical causes. The saying “mad as a hatter” refers to the psychological deterioration of British hatmakers whose brains, it was later discovered, were slowly poisoned as they moistened the brims of mercury-laden felt hats with their tongue and lips (Smith, 1983). Could schizophrenia symptoms have a similar biochemical key? Scientists continue to track the mechanisms by which chemicals produce hallucinations and other symptoms.

Dopamine OveractivityOne possible answer emerged when researchers examined schizophrenia patients’ brains after death. They found an excess of receptors for dopamine—a sixfold excess for the dopamine receptor D4 (Seeman et al., 1993; Wong et al., 1986). Such a hyper-responsive dopamine system may intensify brain signals in schizophrenia, creating positive symptoms such as hallucinations and paranoia (Grace, 2010). Drugs that block dopamine receptors often lessen these symptoms. Drugs that increase dopamine levels, such as amphetamines and cocaine, sometimes intensify them (Seeman, 2007; Swerdlow & Koob, 1987).

Most people with schizophrenia smoke, often heavily. Nicotine apparently stimulates certain brain receptors, which helps focus attention (Diaz et al., 2008; Javitt & Coyle, 2004).

Abnormal Brain Activity and AnatomyBrain scans show that abnormal activity accompanies schizophrenia. Some people diagnosed with schizophrenia have abnormally low brain activity in the frontal lobes, areas that help us reason, plan, and solve problems (Morey et al., 2005; Pettegrew et al., 1993; Resnick, 1992). Brain scans also show a noticeable decline in the brain waves that reflect synchronized neural firing in the frontal lobes (Spencer et al., 2004; Symond et al., 2005). Out-of-sync neurons may disrupt the integrated functioning of neural networks, possibly contributing to schizophrenia symptoms.

One study took PET scans of brain activity while people were hallucinating (Sil-bersweig et al., 1995). When participants heard a voice or saw something, their brain became vigorously active in several core regions. One was the thalamus, the structure that filters incoming sensory signals and transmits them to the brain’s cortex. Another PET scan study of people with paranoia found increased activity in the amygdala, a fear-processing center (Epstein et al., 1998).

Many studies have found enlarged, fluid-filled areas and a corresponding shrinkage and thinning of cerebral tissue in people with schizophrenia (Goldman et al., 2009; Wright et al., 2000). People often inherit these brain differences. If one affected identical twin shows brain abnormalities, the odds are at least 1 in 2 that the other twin will have them (van Haren et al., 2012). Even people who will later develop the disorder may show these symptoms (Karlsgodt et al., 2010). The greater the brain shrinkage, the more severe the thought disorder (Collinson et al., 2003; Nelson et al., 1998; Shenton, 1992).

Two smaller-than-normal areas are the cortex and the corpus callosum connecting the brain’s two hemispheres (Arnone et al., 2008). Another is the thalamus, which may explain why people with schizophrenia have difficulty filtering sensory input and focusing attention (Andreasen et al., 1994; Ellison-Wright et al., 2008). The bottom line is that schizophrenia involves not one isolated brain abnormality but problems with several brain regions and their interconnections (Andreasen, 1997, 2001).

Prenatal Environment and Risk

52-4 What prenatal events are associated with increased risk of developing schizophrenia?

What causes brain abnormalities in people with schizophrenia? Some scientists point to mishaps during prenatal development or delivery (Fatemi & Folsom, 2009; Walker et al., 2010). Risk factors for schizophrenia include low birth weight, maternal diabetes, older paternal age, and oxygen deprivation during delivery (King et al., 2010). Famine may also increase risks. People conceived during the peak of World War II’s Dutch wartime famine later developed schizophrenia at twice the normal rate. Those conceived during the famine of 1959 to 1961 in eastern China also displayed this doubled rate (St. Clair et al., 2005; Susser et al., 1996).

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Let’s consider another possible culprit. Might a midpregnancy viral infection impair fetal brain development (Brown & Patterson, 2011)? Can you imagine some ways to test this fetal-virus idea? Scientists have asked the following:

These converging lines of evidence suggest that fetal-virus infections contribute to the development of schizophrenia. They also strengthen the U.S. government recommendation that “pregnant women need a flu shot” (CDC, 2014).

Why might a second-trimester maternal flu bout put a fetus at risk? Is the virus itself the culprit? The mother’s immune response to it? Medications taken (Wyatt et al., 2001)? Does the infection weaken the brain’s supportive glial cells, leading to reduced synaptic connections (Moises et al., 2002)? In time, answers may become available.

Genetic Factors

52-5 Do genes influence schizophrenia? What factors may be early warning signs of schizophrenia in children?

Fetal-virus infections may increase the odds that a child will develop schizophrenia. But many women get the flu during their second trimester of pregnancy, and only 2 percent of them bear children who develop schizophrenia. Why are only some children at risk? Might some people be more vulnerable because they inherit a predisposition to this disorder? Some people with no family history of schizophrenia develop the disorder (Xu et al., 2011). But the evidence strongly suggests that, Yes, some may inherit a predisposition to schizophrenia. The nearly 1-in-100 odds of any person’s being diagnosed with schizophrenia become about 1 in 10 among those who have a sibling or parent with the disorder. If the affected sibling is an identical twin, the odds increase to nearly 5 in 10 (FIGURE 52.1). Those odds remain the same even when the twins are raised apart (Plomin et al., 1997). (Only about a dozen such cases are on record.)

Figure 52.1
Risk of developing schizophrenia The lifetime risk of developing schizophrenia varies with one’s genetic relatedness to someone having this disorder. Across countries, barely more than 1 in 10 fraternal twins, but some 5 in 10 identical twins, share a schizophrenia diagnosis. (Data from Gottesman, 2001.)

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Remember, though, that identical twins share more than their genes. They also share a prenatal environment. About two-thirds share a placenta and the blood it supplies; the other one-third have separate placentas. Shared placentas matter. If the co-twin of an identical twin with schizophrenia shared the placenta, the chances of developing the disorder are 6 in 10. If the identical twins had separate placentas (as do fraternal twins), the co-twin’s chances of developing schizophrenia drop to 1 in 10 (Davis et al., 1995a,b; Phelps et al., 1997). Twins who share a placenta are more likely to share the same prenatal viruses. So perhaps shared germs as well as shared genes produce identical twin similarities.

Adoption studies help untangle genetic and environmental influences. Children adopted by someone who develops schizophrenia seldom “catch” the disorder. Rather, adopted children have an elevated risk if a biological parent is diagnosed with schizophrenia (Gottesman, 1991).

Schizophrenia in identical twins When twins differ, only the one afflicted with schizophrenia typically has enlarged, fluid-filled cranial cavities (right) (Suddath et al., 1990). The difference between the twins implies some nongenetic factor, such as a virus, is also at work.

The search is on for specific genes that, in some combination, predispose schizophrenia-inducing brain abnormalities (Levinson et al., 2011; Mitchell & Porteous, 2011; Ripke et al., 2011; Vacic et al., 2011). (It is not our genes but our brains that directly control our behavior.) Some of these genes influence the effects of dopamine and other neurotransmitters in the brain. Others affect the production of myelin, a fatty substance that coats the axons of nerve cells and lets impulses travel at high speed through neural networks.

Although genes matter, the genetic formula is not as straightforward as the inheritance of eye color. Genome studies of thousands of individuals with and without schizophrenia indicate that schizophrenia is influenced by many genes, each with very small effects (International Schizophrenia Consortium, 2009; Xu et al., 2012). And, as we have so often seen, nature and nurture interact. Epigenetic (literally “in addition to genetic”) factors influence whether or not genes will be expressed. Like hot water activating a tea bag, environmental factors such as viral infections, nutritional deprivation, and maternal stress can “turn on” the genes that put some of us at higher risk for schizophrenia. Identical twins’ differing histories in the womb and beyond explain why only one of them may show differing gene expressions (Dempster et al., 2013; Walker et al., 2010). Our heredity and our life experiences work together. Neither hand claps alone.

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Consider how researchers have studied these issues with LaunchPad’s How Would You Know If Schizophrenia is Inherited?

Thanks to our expanding understanding of genetic and brain influences on maladies such as schizophrenia, the general public more and more attributes psychiatric disorders to biological factors (Pescosolido et al., 2010). In 2007, one privately funded new research center announced its ambitious aim: “To unambiguously diagnose patients with psychiatric disorders based on their DNA sequence in 10 years’ time” (Holden, 2007). In 2010, $120 million in start-up funding launched a bold new effort to study the neuroscience and genetics of schizophrenia and other psychiatric disorders (Kaiser, 2010). So, can scientists develop genetic tests that reveal who is at risk? If so, will people in the future subject their embryos to genetic testing (and gene repair or abortion) if they are at risk for this or some other psychological or physical malady? Might they take their egg and sperm to a genetics lab for screening before combining them to produce an embryo? Or will children be tested for genetic risks and given appropriate preventive treatments? In this brave new twenty-first-century world, such questions await answers.

Environmental Triggers for Schizophrenia

If prenatal viruses and genetic predispositions do not, by themselves, cause schizophrenia, neither do family or social factors alone. It remains true, as Susan Nicol and Irving Gottesman (1983) noted over three decades ago, that “no environmental causes have been discovered that will invariably, or even with moderate probability, produce schizophrenia in persons who are not related to” a person with schizophrenia.

Hoping to identify environmental triggers of schizophrenia, researchers have compared the experiences of high-risk children (for example, those with relatives with schizophrenia) and low-risk children. In one 2.5-year study that followed 163 teens and early-twenties adults who had two relatives with schizophrenia, the 20 percent of participants who developed schizophrenia showed social withdrawal or other abnormal behavior before the onset of the disorder (Johnstone et al., 2005). Researchers (Abel et al., 2010; Freedman et al., 1998; Schiffman et al., 2001; Susser, 1999; Welham et al., 2009) identified these other possible early warning signs:

Few of us can relate to the strange thoughts, perceptions, and behaviors of schizophrenia. Sometimes our thoughts jump around, but we rarely talk nonsensically. Occasionally we feel unjustly suspicious of someone, but we do not fear that the world is plotting against us. Often our perceptions err, but rarely do we see or hear things that are not there. We feel regret after laughing at someone’s misfortune, but we rarely giggle in response to bad news. At times we just want to be alone, but we do not live in social isolation. However, millions of people around the world do talk strangely, suffer delusions, hear nonexistent voices, see things that are not there, laugh or cry at inappropriate times, or withdraw into private imaginary worlds. The quest to solve the cruel puzzle of schizophrenia continues, more vigorously than ever.

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For an 8-minute description of how clinicians define and treat schizophrenia, visit LaunchPad’s Video: Schizophrenia–New Definitions, New Therapies.

RETRIEVAL PRACTICE

  • A person with schizophrenia who has __________ (positive/negative) symptoms may have an expressionless face and toneless voice. These symptoms are most common with __________ (chronic /acute) schizophrenia and are not likely to respond to drug therapy. Those with __________ (positive/negative) symptoms are likely to experience delusions and to be diagnosed with __________ (chronic /acute) schizophrenia, which is much more likely to respond to drug therapy.

negative; chronic; positive; acute

  • What factors contribute to the onset and development of schizophrenia?

Biological factors include abnormalities in brain structure and function, prenatal exposure to a maternal virus, and a genetic predisposition to the disorder. However, a high-risk environment, with many environmental triggers, can increase the odds of developing schizophrenia.