Biology 202
2003 First Web Paper
On Serendip

Imagine being functional your entire childhood and teenage life. You attend class, study, work, and juggle a myriad of activities. You may have friends with whom you socialize in your free time. You are becoming more independent and learning to care for yourself. Suppose the newscaster on television starts talking directly to you or that someone calling with the wrong number is really a government spy or that you were going out to lunch with the president? You lose control of your life, as you can no longer discern reality from wildly absurd fantasy. Available medical treatment is imperfect and it is difficult to engage your compliance. Friends and family watch your behavior deteriorate, heartbroken, and know not how to react. Such is the tragic web that schizophrenia weaves into the lives of its victims.

When thinking about the concept of the relationship of brain to behavior, what more dramatic condition comes to mind than schizophrenia. One percent of the population, or 2 million Americans alone, are affected by schizophrenia. Imagine living in a town with a population of 10,000 people. It is likely that ten of your neighbors and community members would suffer from schizophrenia. The tragic illness is not limited to one race or culture. It is found all over the world. It affects slightly more men than women, with first signs of schizophrenia appearing between 16 and 25 years of age, although it had been observed among children as well. (1) Sufferers experience psychosis or psychotic episodes when they are unable to distinguish between what is real and what is not. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), for a person to be diagnosed schizophrenic they must exhibit two or more of the following symptoms in the active phase of the disorder: delusions; auditory, visual, olfactory, and/or tactile hallucinations; disorganized thinking and/or speech; negative symptoms (absence of normal behavior); and catatonia. Of those diagnosed, there are three types of schizophrenic patients: disorganized (characterized by lack of emotion and disorganized speech), catatonic (characterized by reduced movement, rigid posture, or sometimes too much movement), and paranoid (strong delusions or hallucinations). (2)

Interested in the relation of brain and behavior, I must ask: What causes schizophrenia? Maybe not one single cause can be named as separate causes contribute to create a syndrome, or a complex of signs and symptoms presenting a clinical picture of a disease or disorder. This question has not yet been clearly answered but research has suggested that genetics and biochemical abnormalities combined with environmental factors are to blame. Genetic studies of twins have shown that the tendency for both monozygotic (identical) twins to develop schizophrenia is between 30-50%, while that of dizygotic (fraternal) twins is 15%, which is close to that of siblings who are not twins. (2) The greater tendency for monozygotic twins to have the illness shows that genetics plays a role but because the tendency is not 100%, genetics are not the sole factor. Considering that only 1% of the population is affected by schizophrenia, the elevated risk of relatives—8% for non-twin siblings, 12% for child whose parent has schizophrenia, 12% for fraternal twin, 40% for child who had two affected parents, and about 47% for identical twins—further supports the influence of genetics. A 2000 issue of Science identified a small region on chromosome 1 (1q21-q22) to be genetically involved in schizophrenia but little more about it is currently understood. (3)

In physiological studies, MRI brain scans of twins, one with schizophrenia and one without, have shown that people with schizophrenia have larger than normal lateral ventricles. (2) Does this mean that all people with larger lateral ventricles have schizophrenia? Do all schizophrenic patients have large lateral ventricles? Currently, testing has suggested only that large lateral ventricles are characteristic of schizophrenic patients. Reduced size of the hippocampus, increased size of basal ganglia, and abnormalities of the prefrontal cortex have also been associated but are not necessarily indicative of schizophrenia. (2)

Biochemical research performed by Richard C. Deth, a professor of Pharmaceutical Science at Northeastern University, suggests that elements from four popular theories centering around the dysfunction of the neurotransmitter systems in the brain that are responsible for normal cognition and attention may play a role in schizophrenia: the Dopamine Hypothesis, the NMDA Receptor Hypothesis, the Single-carbon Hypothesis, and the Membrane Hypothesis. The Dopamine Hypothesis theorizes that overactive dopamine neurotransmitter in the cortical and limbic areas of the brain, particularly the D4 dopamine receptor, is a possible culprit and is most strongly supported by the fact that dopamine blocking drugs, such as clozapine or olanzapine, reduce schizophrenic symptoms. (4) The NMDA Receptor Hypothesis suggests that NMDA receptor dysfunction may cause schizophrenia based on the fact that drugs affecting NMDA receptors (such as ketamine or PCP) can cause schizophrenia-like hallucinations and neuroleptic drugs (like clozapine) can inhibit them. Studies showing that methionine metabolism is impaired in most schizophrenics support the Single-Carbon Hypothesis which suggests that disturbances of the single-carbon folate metabolic pathway, which provides carbon groups for a variety of biochemical reactions including the synthesis of purine and pyrimidine nucleotides and the methyl-donating amino acid methionine, may lead to schizophrenia. The Membrane Hypothesis theorizes that disturbances of phospholipid membrane structure where highly unsaturated fatty acids levels are low leads to an impairment in the transmission of neuron signals across cell membranes that leads to schizophrenia. (4) Deth's research shows that dopamine can stimulate the methylation of membrane phospholipids through activation of the D4 dopamine receptor and, in summary, suggests that schizophrenia may result from impairment in the ability of D4 dopamine receptors to modulate NMDA receptors at nerve synapses via phospholipids methylations.

One difficult to define factor associated with schizophrenia is that of environment. In an article in April 2001 Proceedings of the National Academy of Sciences, U.S. and German scientists found that 1/3 of newly diagnosed schizophrenics contained genetic material from HERV-W retroviruses in their cerebrospinal fluid as opposed to only 5% of chronic sufferers and 0% of healthy people. Although the origin of the virus is unknown, it seems to trigger the onset of schizophrenia. (5) Patricia S. Goldman-Rakic, professor of neuroscience at Yale University School of Medicine, claims to have found the beginnings of evidence to suggest that another environmental stress, fetal brain damage, leads to schizophrenia after hormonal changes during and after puberty in humans based on studies with rhesus monkeys. (3) According to a study in the British Journal of Psychiatry lack of DHA (docosahexaenoic acid), a fatty acid in breast milk, during infancy increases risk of schizophrenia in adults. (6) Stress in the family, poor social interactions, or trauma at an early age also seem to relate to the onset of schizophrenia. (7) Is schizophrenia the result of one factor, all of the factors, or a select few? Although the specific combination is unknown, schizophrenia is most likely a result of many of the factors listed above, however, current studies support that genetic, physiological and biochemical influences outweigh the influence of the environment alone.

How well do current medications treat schizophrenia? Although the illness is yet incurable, antipsycotics or neuroleptics (such as clozapine, risperidone, quetiapine, and olanzapine) have been shown to effectively control symptoms in most patients. (8) After ten years of treatment, a study concluded that ¼ of the patients recovered completely while treated with antipsycotics, ¼ greatly improved, ¼ minimally improved, 15% showed no improvement, and 10% died of suicide or an accident. (7) Most of these medications have negative side effects, such as agranulocytosis which is a loss of white blood cells, so continued development of more effective drugs with fewer side effects is important. If in fact schizophrenia is not completely triggered by genetics, physiology, and/or biochemistry further study of environmental stimuli may be the key to developing lifestyle changes and effective counseling approaches that will alter that environment of an at-risk or affected person. Continued research of biological causes and effective medications to treat those causes is also critical.

How frightening it must be for an individual to ponder the likelihood of succumbing to the illness themselves when struggling to accommodate an affected family member. What I really want to know from future research is if someone is predisposed to the disorder to the extent that they have a schizophrenic family member, what can they do, if anything, to prevent it from afflicting them? According to a list compiled by family members of affected patients affiliated with the World Fellowship for Schizophrenia, social withdrawal is the most common warning sign indicating onset of the illness with excessive fatigue, deterioration of social relationships, inability to concentrate or cope with minor problems, apparent indifference to even highly important situations, decline in academic and athletic performance, deterioration of personal hygiene, frequent aimless moves or trips, drug or alcohol abuse, bizarre behavior, inappropriate laughter, low tolerance to irritation, and forgetfulness also noted. (9) If in fact brain equals behavior and their brain and environment dictate that they will be exhibit schizophrenic behavior, then they cannot will themselves into preventing it even with the onset of early warning signs; conceivably only a change in actual genetics, brain physiology, biochemistry and/or environment could prevent someone who is predisposed either to schizophrenia from becoming ill. Regarding the retrovirus hypothesis, could a change from a normal brain to an abnormal brain caused by an environmental stimulus like a viral infection cause schizophrenia in someone who is not already genetically predisposed? Is it necessary for all components—physiology, genetics and environment—to be responsible or can cause of schizophrenia vary from patient to patient? At this time my questions must remain unanswered but with the fast pace of research, I soon may have my answers.

References

1) NIH
2) Schizophrenia
3) National Institute of Mental Health, Genetic Link
4) Scientific American
5) Scientific American Link to Viruses
6) Schizophrenia home page
7) Yale Bulletin
8) Schizophrenia at the National Institute of Mental Health
9) World Fellowship for Schizophrenia


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