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Order From Chaos: Making Sense of Schizophrenia Research

The tyranny of choice also appears to affect research into schizophrenia: The sheer volume of data can make teasing out what's important from what's trivial an obstacle to better understanding the disease.

Researchers zeroing in on the origins of schizophrenia and the mechanisms that cause its debilitating delusions, hallucinations and disordered thinking agree it is an extraordinarily complex disease, with multiple contributing causes.

As they explore genetic and neurotransmitter networks (and the possibility of more effective drug treatments), the deluge of new data can sometimes make it hard for to see the forest for the trees.

Among the latest findings:

  • Researchers at the National Institute of Mental Health identified in schizophrenia sufferers a mutated form of a gene for potassium ion channels in nerve cell membranes that has been linked to dysfunction in the hippocampus, the brain's memory center. Healthy people carrying the gene showed subtle schizophrenia-like symptoms, the study found.
  • A growing number of genes have been implicated. They interact in complicated ways, with some genes being over-expressed or under-expressed. Duke University researchers meanwhile found that schizophrenia sufferers may have distinctive forms of the DNA structural changes known as copy number variants.
  • Some schizophrenia symptoms, like impaired working memory, result from dysfunction of the dorsolateral prefrontal cortex. This may be due to genetic changes that reduce levels of a key neurotransmitter called gamma-aminobutyric acid (GABA), which in turn seems to disrupt the rhythmic firing of neurons needed for normal functioning.

"One of the problems with many theories is they pick and choose the facts they want to account for," says Angus McDonald III, a University of Minnesota researcher who thought the array of findings from different disciplines was creating more confusion than coherence.

Genetic studies alone have implicated many different DNA regions. Where it once seemed scientists would discover the key genes that caused schizophrenia symptoms, "We've got more and more candidates," he says. "There has been an increasing implication of different neurotransmitter systems."

Together with colleague S. Charles Schulz, McDonald sought to restore some order, publishing "What We Know: Findings That Every Theory of Schizophrenia Should Explain," in a special section they edited for the May 2009 issue of Schizophrenia Bulletin. The pair set forth 22 facts about schizophrenia that they hoped would help focus future research efforts.

They started with six "basic" facts: schizophrenia presents in many different forms; it afflicts about 0.7 percent of the world's population; it is more prevalent among young men at first but equally distributed between men and women by late middle age; peak onset is in young adulthood, and it is rare in childhood or after middle age; it is highly heritable (about 81 percent genetic) and current anti-psychotic drugs block dopamine receptors in the brain but do not alleviate all schizophrenia symptoms.

They added three known facts about the causes of the disease. First, studies find potential schizophrenia-causing genes on at least 11 different chromosomes. Also, the brains of people with genetic liability to schizophrenia are physically different, and these people experience diminished cognitive and brain function. Finally, there are certain environmental risks, such as being an immigrant, having an older father, prenatal exposure to toxoplasmosis (a microbe carried by cats), prenatal famine, lifetime marijuana use, obstetric complications, having been raised in a city and being born in the winter or spring.

Patients respond differently to antipsychotic medications, McDonald and Schultz noted, but the longer the disease is untreated, the worse the outcome. (Patients have a much higher risk of suicide than the rest of the population.) Exposure to drugs like amphetamine, PCP and ketamine can trigger schizophrenia-like symptoms in some people, they found. Meanwhile, the brains of schizophrenics are abnormal on both structural and microscopic levels.

Many genes have been tied to schizophrenia, but they tend to have small individual effects. "We're having trouble finding many genes that do a lot," McDonald says. That suggests multiple genes must be acting in concert.

As for neurotransmitters and schizophrenia, the oldest theory focused on abnormal dopamine levels after scientists noticed that existing antipsychotic drugs block the brain's D2 dopamine receptors to reduce "positive" symptoms like hallucination, and that amphetamines can induce psychosis by raising dopamine levels.

But the dopamine theory doesn't account for the so-called "negative" symptoms of schizophrenia, like flattened emotional response and impaired working memory. Lately, research has focused on other neurotransmitters, like GABA and glutamate, McDonald says.

At the University of Pittsburgh, Dr. David A. Lewis and his team noticed schizophrenics had lower levels of an enzyme that makes GABA neurons in the dorsolateral prefrontal cortex, the seat of "working memory" — the ability to keep track of what we are thinking about from moment to moment. Antipsychotic medications don't treat this problem, which causes disorganized thinking characteristic of schizophrenia, Lewis says.

But in a double blind, placebo-controlled trial involving 16 schizophrenic men, Lewis administered a benzodiazepine-like drug that bound to the GABA receptors. The patients' cognitive functioning improved, as did their gamma band brain wave oscillations. A larger drug trial will start soon. "We're trying to use a rational pharmaceutical strategy based on an understanding of the disease process," Lewis says.

Other schizophrenia researchers have looked at neural dysconnectivity — abnormal integration among different regions of the brain. German scientist Klaas E. Stephan and his colleagues suggest this arises from impaired N-methyl-D-aspartate receptors, or NMDARs.

Their paper, "Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring," also published in the Schizophrenia Bulletin special section, traces a pathway from these impaired NMDARs to the hallucinations and delusions typical of schizophrenia.

Schizophrenics often have trouble distinguishing between self-generated and externally generated actions. A breakdown of self-monitoring "may prevent frontal areas generating thoughts (inner speech) from informing auditory areas that this inner-speech is self generated," the scientists write. "This could lead to a misattribution of inner speech to external sources and thus produce auditory hallucinations."

Why are humans prone to develop schizophrenia? One theory is that it is a byproduct of the rapid evolutionary change that gave rise to human intelligence.

In a recent paper, Philipp Khaitovich led a post-mortem study of the brains of chimpanzees, rhesus monkeys and human schizophrenia sufferers, comparing genes that have changed in the course of recent human evolution.

"We find a disproportionately large overlap between processes that have changed during human evolution and biological processes affected in schizophrenia," they wrote in their paper, "Metabolic changes in schizophrenia and human brain evolution," published in Genome Biology. "Genes relating to energy metabolism are particularly implicated for both the evolution and maintenance of human-specific cognitive abilities."

According Khaitovich, a researcher at the Max Planck Institute For Evolutionary Anthropology in Germany, human brains have much higher energy needs than those of chimpanzees, our closest relatives. But those demands may put this highly complex system at greater risk of spinning out of control.

"If you have such a rapid evolutionary event, you don't have enough time for a biological system to stabilize," Khaitovich says.

Meanwhile, for Angus McDonald, the abundance of creative research creates a classic bad news/good news scenario.

"It does feel like we've got a lot of different balls in the air," McDonald says. "At some points it's frustratingly confusing, and on the other hand, there's lots of loose strings to pull on, which might yield better insights."

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