The schizophrenic brain is hobbled by three problems -- delusions, hallucinations and thinking difficulties.
And even though most people associate the disease with hearing voices and being afflicted with paranoid thoughts, many researchers believe the most important symptom to tackle is the cognitive challenges people with schizophrenia face.
Those with the disease have trouble remembering the steps they must take to carry out a task. They struggle with staying focused and speaking coherently. They have difficulty planning for the future. And many of those symptoms show up years before the patients start hearing voices or suffering from delusions.
Many people still believe that the hallucinations caused by the disease are the main cause of patients' disorganized thoughts, said Richard Keefe, a Duke University Medical Center psychiatry professor who spoke at a schizophrenia conference here last year.
"That's totally reasonable," he said, "and shockingly wrong."
The cognitive challenges people with schizophrenia face are the result of fundamental wiring and biochemical problems in their brains that scientists are still trying to unravel, and they are the biggest obstacle to being able to live a somewhat normal life, he said.
David Lewis, a noted schizophrenia researcher at the University of Pittsburgh, said that when he started in the field 25 years ago, "we didn't talk about cognitive impairments in schizophrenia. We thought of it as a disorder of hallucinations and delusions."
Scientists learned that the neurotransmitter dopamine -- sometimes known as the "reward" chemical in the brain -- was involved in the bizarre thoughts and voices that patients experienced, he said, because doctors knew that "amphetamines, which boost dopamine, could produce a psychotic state that resembles schizophrenia, and antipsychotic medications seemed to work by blocking dopamine receptors" in the brain.
Even today, though, these antipsychotic drugs are considered fairly blunt instruments. "Antipsychotic drugs are like using a sledgehammer" to reduce psychotic thinking, said Carol Tamminga, a psychiatrist at the University of Texas Southwestern Medical Center.
And they affect only the so-called positive symptoms of schizophrenia -- hallucinations and delusions -- but not the "negative symptoms," such as social withdrawal and depression.
"Whether you have hallucinations or not," Dr. Lewis said, "if you have impairments in motivation and low energy, it's tough to get up and go to work in the morning and stay on a job."
Parsing the cognitive deficit
There's a misconception that people with schizophrenia are brilliant, Dr. Lewis said. But the typical patient performs cognitively about 1 1/2 standard deviations below the population average. In IQ terms, that means the patient would have an IQ of about 80 -- 20 points below the mean.
And in some areas, like processing speed and visual memory, patients can score significantly lower and have special difficulty with those skills.
But what about brilliant schizophrenic scientists like John Nash, a Nobel Prize winner who is the subject of the book and movie, "A Beautiful Mind"?
The thing to remember about those rare cases, Dr. Lewis said, is that "if you start out with an IQ of 160 and you lose 1 1/2 standard deviations, you're down to 145, and you might still be pretty well-off in certain areas."
MYSTERIES OF THE MIND: SCHIZOPHRENIA
Second in a three-part series.
Schizophrenia involves hallucinations, delusions and cognitive deterioration. It can mean a lifetime of dependency for patients -- and in rare cases, it leads to frightening outbursts of violence.
Dr. Lewis and others are focusing on a set of inhibitory neurons in the brain's frontal cortex that don't function normally in people with schizophrenia. These neurons, known as fast-spiking basket cells, play a critical role in setting up a "thinking rhythm" in typical brains but don't do so efficiently in people with the disease.
When someone is learning new information or performing a mental task, excitatory neurons in the frontal cortex fire, which stimulates the basket cells, causing them to briefly suppress the excitatory neurons, so that the next time they fire, they act in concert, creating a back-and-forth rhythm that is critical for thinking, said Dr. Lewis and Vikaas Sohal, a researcher at the University of California at San Francisco.
In people with schizophrenia, Dr. Lewis said, the excitatory neurons seem to be underactive, so that the basket cells can never initiate that critical rhythm.
That may cause two kinds of thinking problems, Dr. Sohal said -- it could make it harder for patients to screen out distracting information and focus on a problem; it could also make it harder for different brain areas to communicate with each other.
Dr. Sohal has shown the importance of the basket cells by using bursts of light to control their activity in the brains of mice. By inserting light-reactive genes in mouse brains, he was able to excite the basket cells, which caused the mice's neurons to communicate more efficiently.
Dr. Lewis is exploring an experimental drug that is designed to boost the strength of the basket cells so they have a better chance of creating the proper rhythm. One early study showed the drug, MK-0777, improved patients' working memory, but "the drug is rather weak, so work is being done to take this molecule and substantially boost its potency."
Problem of poor connections
If different parts of schizophrenia patients' brains are not communicating well with each other, another possible explanation is poor cable connections between them.
Joseph Buxbaum and Patrick Hof of the Icahn School of Medicine at Mount Sinai in New York have found evidence of that.
A review of more than 30 brain imaging studies has shown that the fibers connecting brain regions are more disorganized in people with schizophrenia than in people without the disease, even at the earliest stages of the illness, Dr. Buxbaum said.
Those connections are known as white-matter tracts because of the fatty layer of myelin that sheaths the fibers, and his studies have shown that people with schizophrenia have fewer genes that govern brain cells known as oligodendrocytes, which create the myelin covering.
Dr. Hof, who studies autopsy samples of brains of people with the disorder, said that patients' brains had 30 percent fewer oligodendrocytes than typical brains did, and that they were not clustered together in the way they were in normal brains.
People with schizophrenia also have memory problems, and that has been the focus of the University of Texas' Dr. Tamminga.
In normal people, neurons in the hippocampus, a small structure near the bottom of the brain, are excited when a person is learning new information, and that activity helps create memories of a face, a new skill or a factoid.
In people with schizophrenia, she has found, the hippocampus cells are constantly more excited than normal, and so they have a harder time categorizing memories accurately. One result of that is that when patients have delusions -- that the C.I.A. is listening in on their phone calls, for instance -- their memories of that are just as vivid or even stronger than for other information.
On the other hand, there is now evidence that every time we recall an event in our lives, we reshape our memory of it anew, and that might offer a therapy target for people with the disease. "From my point of view," she said, "that's the way psychosis eventually will repair itself. Every time you call up a memory, you get a chance to change it."
What causes hallucinations?
About 75 percent of people with the disease hear voices, said Judith Ford, a psychiatric researcher at the University of California at San Francisco. They can also experience visual hallucinations, she said, but they seem to be less common.
In fact, when the movie "A Beautiful Mind" showed Dr. Nash talking to imaginary companions, those visual hallucinations were the creation of the filmmaker, said Frederick Frese, a psychologist with schizophrenia who knows the Nash family.
In trying to understand how auditory hallucinations occur, Dr. Ford said it is important to distinguish between people's inner speech -- "don't forget to mail the rent check" -- and other kinds of thoughts.
Most people with schizophrenia will say they can differentiate their inner speech from their hallucinations, which come to them out of the blue as distinct voices from other people or entities, she said. The problem is that there is some flaw in their brains that causes them to perceive certain internal thoughts as coming from outside voices.
"If you're sitting idly on the shuttle," she said, "and your mind wanders, you may hear your mom's voice on the answering machine, and yet you don't think, 'It's my mother speaking to me.' "
Her team found that people with schizophrenia have a disruption in the "corollary discharge network."
That is the brain system that allows us to know which actions or thoughts are being generated by our own movement or thinking.
It doesn't take a mental illness for that system to be thrown out of kilter. Some stroke patients, for instance, no longer believe one of their limbs belongs to them because they can't sense it.
In the same way, a schizophrenia patient may no longer believe that his thoughts belong to him, because he can't sense them in the way the rest of us can.
A noisy 'default network'
Some research suggests that people with the disease have a particular network in their brains that is too noisy.
Known as the default network, these brain areas normally are active when we're daydreaming or not attending to a task. But in most people, the minute they start to concentrate on a mental challenge, the default network becomes quieter and areas in the frontal cortex become more active.
Alan Anticevic, a research scientist at Yale University, said that the better people can suppress their default network, the more they can focus on a demanding task.
While even some people without mental illness have trouble accomplishing this switch, those with schizophrenia seem to have a particularly difficult time, he said.
The bottom line, Dr. Anticevic said, is that people with schizophrenia are constantly distracted when they try to grapple with mental demands.
Some scientists believe this background noise also may contribute to patients' delusions.
John Gabrieli, a neuroscientist at the Massachusetts Institute of Technology, said if the brain network involved in introspective thoughts never quiets down, "then you might imagine that a lot of the world is about you. If you hear noise in the next room while you're working, you and I might screen it out, but [schizophrenic patients] might think someone's talking about them or thinking about them."
What's the source?
Most scientists believe that people with the disorder are born with some sort of genetic vulnerability, and that stresses in adolescence or young adulthood create a tipping point that shoves them into the disease.
But finding the genetic culprits has been extremely difficult.
Dennis Vitkup, a computational biologist at Columbia University, said there may be 500 to 1,000 genes that contribute to schizophrenia, but it's unlikely that each gene codes for a different biological effect, "so they are probably related to certain pathways."
His work shows there may be 20 to 30 gene networks that contribute to schizophrenia.
He also has found there are several gene clusters that are similar in autism and schizophrenia, even though the behaviors in the two disorders are quite different. One of those clusters involves genes that control the growth of dendritic spines, the tree-like branches in neurons that promote communication among brain cells.
In schizophrenia, there appear to be fewer genes than normal controlling dendritic spines, which could help explain the connectivity problems seen in patients.
It may also be a clue to why schizophrenia usually doesn't show up until the teen years. That is when the brain is pruning many of its connections, he said, which could spell trouble for those with a genetic risk for having too few of them.
Vaibhav Diwadkar, a neuroscientist at Wayne State University, is trying to see if there are ways to detect who's at greatest risk for the disease so doctors can intervene early, before symptoms strike.
To do that, he is studying the children of parents who have schizophrenia. While the risk in the general population of getting the disease is 1-2 percent, children of parents with the disease have a 30-50 percent risk of getting a major psychiatric illness during their lifetimes.
Using brain imaging, Dr. Diwadkar looked at how these children reacted to pictures of happy faces vs. angry or sad faces. Compared to a matched group of typical young people, the children of schizophrenic parents reacted less strongly to the positive faces, and showed more signs of trying to suppress their reactions to the negative faces.
Those findings fit with symptoms of the disease, in which patients often have trouble enjoying life and perceive threats in the world around them.
The children will need to be tracked to see which of them develop schizophrenia symptoms in later years, but ultimately, Dr. Diwadkar would like to develop tests that might allow early treatment.
One reason for the interest in prevention is that drug researchers have not been able to find any antipsychotic medication that effectively controls all the symptoms of the disease.
Leslie Citrome, a drug development consultant who spoke to the American Psychiatric Nurses Association meeting here last year, said one new drug that has shown some promise is bitopertin, which acts on a different set of brain receptors than most antipsychotics do.
In one preliminary trial, the drug, which is being developed by Hoffman-La Roche, showed an advantage over a placebo in reducing the depressed mood and lack of energy in schizophrenia patients, but he said much more work remains.
The research shows just how complex schizophrenia and other major mental illnesses are.
"It's much easier to look back and say how far we've come than to be confident about how far we have to go," said Pitt's Dr. Lewis. "We're talking about an illness that affects the most complex biological organism in the known universe and in that organ affects the most complex aspects of it, so this is a really tough problem."
About this series
Every day, we are reminded of a mental disorder that affects our society.
Yet another mass shooting rips lives apart, and often the gunman has a history of mental illness. News reports document another athlete whose life has crumbled after repeated blows to the head.
A new statistical study raises the odds of a child being born with autism, or television commercials show depressed people barely able to get out of bed. And each month, there seems to be a new type of phobia to report.
They all have one thing in common: deep-rooted defects in the function of the brain that scientists are just beginning to understand.
Over the next year, the Pittsburgh Post-Gazette will explore five of these brain disorders: schizophrenia; chronic traumatic encephalopathy -- a form of brain deterioration affecting athletes and soldiers; autism; depression and phobias.
Number of people affected: 3.1 million in the United States, 1 percent of the population.
Onset: Late teens or early 20s for men; mid-20s for women.
Symptoms: Delusions (false beliefs); hallucinations (hearing voices); social withdrawal; poor thinking skills.
Derivation of term: From the Greek for "split mind," schizophrenia actually does not involve multiple personalities or other forms of split identities.
Where to get help: If you are concerned that you are experiencing symptoms of mental illness or have family members who are, you can contact these places: Western Psychiatric Institute and Clinic of UPMC has a call center for general inquiries and for scheduling outpatient appointments at 412-624-2000. The clinic, in partnership with Allegheny County, also offers the re:solve Crisis Network, which provides telephone, mobile, walk-in and residential behavioral health crisis services around the clock to any resident of the county at 1-888-7-YOU-CAN (1-888-796-8226). Help can be found at the West Penn Allegheny Health System by contacting www.wpahs.org/specialties/psychiatry, or calling 412-330-4000. Mercy Behavioral Health, part of the Pittsburgh Mercy Health System, has an around-the-clock toll free number, 1-877-637-2924, and also operates an around-the-clock crisis center at 264 South 9th St., South Side. More information available at www.mercybehavioral.org
Mark Roth: firstname.lastname@example.org or 412-263-1130.