Category: Schizophrenia

Two new research studies published in Biological Psychiatry point to progressive abnormalities in brain development that emerge as vulnerable individuals develop schizophrenia.

The first of these papers studied individuals with a deletion of a small section of chromosome 22. This genetic deletion often results in the development of abnormalities in the structure of the heart and of the face, a condition called velocardiofacial syndrome (VCFS; also known as 22q11.2 deletion syndrome). Up to 32% of people with VCFS develop psychotic disorders including schizophrenia, which occurs in 1% of the general population.

Using magnetic resonance imaging (MRI), Dr. Wendy Kates and her colleagues showed that during adolescence, progressive deficits in the volume of the temporal cortex gray matter were predictive of developing psychosis.

"Our findings suggest that in VCFS, brain changes during mid-adolescence, particularly in the temporal lobe, predict early signs of psychosis," said Dr. Kates. "This suggests that it may be possible, eventually, to develop a screening tool that would identify those VCFS-affected youth who are at the highest risk for schizophrenia."

In another paper, Dr. Andrew McIntosh and colleagues report a similar pattern among adolescents and young adults who were followed over a 10 year period. All of the young people were well at the beginning of the study, but some were at high genetic risk of developing schizophrenia due to having family members with schizophrenia.

"The participants were examined repeatedly by a psychiatrist and with structural brain scans to see if there were changes in brain structure in people who later became unwell," explained Dr. McIntosh. "At the end of the study, we found that there were accelerated reductions in the volume of particular brain structures in the people at high risk, and additional reductions in the volume of the frontal lobes in those people who later developed schizophrenia."

These two studies highlight the existence of progressive changes in brain structure related to the emergence of symptoms among individuals at risk for developing schizophrenia.

"These studies cannot define the specific changes at the cellular level and thus, we are limited in our capacity to make precise predictions based on these MRI data," commented Dr. John Krystal, Editor of Biological Psychiatry. "However, the findings suggest that schizophrenia is not simply a 'scar' but rather an ongoing brain process that might need to reach an as yet unclear stage where symptoms emerge. That being the case, there is hope that someday one might develop treatments that block this 'disease process' as we have been able to do for some other heritable brain diseases."

---

Journal References:

1. Wendy R. Kates, Kevin M. Antshel, Stephen V. Faraone, Wanda P. Fremont, Anne Marie Higgins, Robert J. Shprintzen, Jo-Anna Botti, Lauren Kelchner, Christopher McCarthy. Neuroanatomic Predictors to Prodromal Psychosis in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome): A Longitudinal Study. Biological Psychiatry, 2010; DOI: 10.1016/j.biopsych.2010.10.027
2. Andrew M. McIntosh, David C. Owens, William J. Moorhead, Heather C. Whalley, Andrew C. Stanfield, Jeremy Hall, Eve C. Johnstone, Stephen M. Lawrie. Longitudinal Volume Reductions in People at High Genetic Risk of Schizophrenia as They Develop Psychosis. Biological Psychiatry, 2011; 69 (10): 953 DOI: 10.1016/j.biopsych.2010.11.003

Computer networks that can't forget fast enough can show symptoms of a kind of virtual schizophrenia, giving researchers further clues to the inner workings of schizophrenic brains, researchers at The University of Texas at Austin and Yale University have found.

The researchers used a virtual computer model, or "neural network," to simulate the excessive release of dopamine in the brain. They found that the network recalled memories in a distinctly schizophrenic-like fashion.

Their results were published in April in Biological Psychiatry.

"The hypothesis is that dopamine encodes the importance-the salience-of experience," says Uli Grasemann, a graduate student in the Department of Computer Science at The University of Texas at Austin. "When there's too much dopamine, it leads to exaggerated salience, and the brain ends up learning from things that it shouldn't be learning from."

The results bolster a hypothesis known in schizophrenia circles as the hyperlearning hypothesis, which posits that people suffering from schizophrenia have brains that lose the ability to forget or ignore as much as they normally would. Without forgetting, they lose the ability to extract what's meaningful out of the immensity of stimuli the brain encounters. They start making connections that aren't real, or drowning in a sea of so many connections they lose the ability to stitch together any kind of coherent story.

The neural network used by Grasemann and his adviser, Professor Risto Miikkulainen, is called DISCERN. Designed by Miikkulainen, DISCERN is able to learn natural language. In this study it was used to simulate what happens to language as the result of eight different types of neurological dysfunction. The results of the simulations were compared by Ralph Hoffman, professor of psychiatry at the Yale School of Medicine, to what he saw when studying human schizophrenics.

In order to model the process, Grasemann and Miikkulainen began by teaching a series of simple stories to DISCERN. The stories were assimilated into DISCERN's memory in much the way the human brain stores information-not as distinct units, but as statistical relationships of words, sentences, scripts and stories.

"With neural networks, you basically train them by showing them examples, over and over and over again," says Grasemann. "Every time you show it an example, you say, if this is the input, then this should be your output, and if this is the input, then that should be your output. You do it again and again thousands of times, and every time it adjusts a little bit more towards doing what you want. In the end, if you do it enough, the network has learned."

In order to model hyperlearning, Grasemann and Miikkulainen ran the system through its paces again, but with one key parameter altered. They simulated an excessive release of dopamine by increasing the system's learning rate-essentially telling it to stop forgetting so much.

"It's an important mechanism to be able to ignore things," says Grasemann. "What we found is that if you crank up the learning rate in DISCERN high enough, it produces language abnormalities that suggest schizophrenia."

After being re-trained with the elevated learning rate, DISCERN began putting itself at the center of fantastical, delusional stories that incorporated elements from other stories it had been told to recall. In one answer, for instance, DISCERN claimed responsibility for a terrorist bombing.

In another instance, DISCERN began showing evidence of "derailment"-replying to requests for a specific memory with a jumble of dissociated sentences, abrupt digressions and constant leaps from the first- to the third-person and back again.

"Information processing in neural networks tends to be like information processing in the human brain in many ways," says Grasemann. "So the hope was that it would also break down in similar ways. And it did."

The parallel between their modified neural network and human schizophrenia isn't absolute proof the hyperlearning hypothesis is correct, says Grasemann. It is, however, support for the hypothesis, and also evidence of how useful neural networks can be in understanding the human brain.

"We have so much more control over neural networks than we could ever have over human subjects," he says. "The hope is that this kind of modeling will help clinical research."

---

Journal Reference:

1. Ralph E. Hoffman, Uli Grasemann, Ralitza Gueorguieva, Donald Quinlan, Douglas Lane, Risto Miikkulainen. Using Computational Patients to Evaluate Illness Mechanisms in Schizophrenia. Biological Psychiatry, 2011; DOI: 10.1016/j.biopsych.2010.12.036

Schizophrenia is a serious mental disorder that currently affects about one in every 200 people. Most patients find some relief from their symptoms by treatment with antipsychotics, however they may still suffer from cognitive and negative symptoms. These include poor concentration and memory, apathy, or a reduced ability to cope in social situations. Preliminary research published in BioMed Central's open access journal BMC Medicine shows that patients who received L-lysine alongside their normal medication found some reduction in the severity of their symptoms.

In a cross-over study, ten patients with schizophrenia were given either 6g of L-Lysine or a placebo every day for four weeks. Each of the patients had been on a stable dose of medication for the past three months and had been free from psychotic episodes for the two months before the study began. They were tested for blood levels of lysine as well as the severity of their symptoms (PANSS) and functional ability (including the Wisconsin Card Sorting and Trail Making tests) at the start, after four, and after eight weeks.

Eight of the patients responded to L-lysine treatment, as shown by an increase in blood lysine levels. For these eight there was a general trend, over most of the symptomatic and cognitive tests, for improvement due to treatment with lysine. Three of the patients reported that they themselves felt some improvement. However there was a tendency for any intervention, L-lysine or placebo, to improve PANSS scores, and familiarity with the tests improved scores for the memory and mental functioning tests. So improvement was seen using both L-lysine and placebo. Results were probably also confounded by the beneficial effect of L-lysine continuing even after treatment stopped and consequently affecting scores of patients who received placebo after lysine.

Dr Wass said, "This study is a starting place for further research into the beneficial effects of L-lysine as part of the treatment of patients with schizophrenia. It was an extremely low dose, and a small sized trial, which limited the conclusions we could draw. Nevertheless this study suggests that L-lysine may be of benefit to patients in alleviating some of the negative and cognitive effects of schizophrenia."

---

Journal Reference:

1. Caroline Wass, Daniel Klamer, Evangelos Katsarogiannis, Erik Pålsson, Lennart Svensson, Kim Fejgin, Inga-Britt Bogren, Jörgen A Engel and Birgitta Rembeck. L-lysine as adjunctive treatment in patients with schizophrenia: a single-blinded, randomized, cross-over pilot study. BMC Medicine, 

Toxoplasma gondii infects approximately 25 percent of the human population. The protozoan parasite is noted for altering the behavior of infected hosts. Jianchun Xiao and colleagues of the Johns Hopkins School of Medicine find clear differences in the manipulation of host gene expression among the three clonal lineages that predominate in Europe and North America, "despite the high level of genetic similarity among them," says Xiao. Type I infection largely affects genes related to the central nervous system, while type III mostly alters genes that modulate nucleotide metabolism. Type II infection does not alter expression of a clearly defined set of genes.

The research is published in the March 2011 issue of the journal Infection and Immunity.

Indeed, T. gondii can play its infected rodent hosts like a piano, converting rats' and mice's natural aversion to feline odors into an attraction, presumably to enable the parasite's sexual cycle. T. gondii can reproduce sexually only in cats. Investigations of effects on humans have found an increased risk of traffic accidents, and other reckless behavior, as well as links to hallucinations.

"Toxoplasma infections, at least for mice, are so variable in their severity and heavily dependent on which strain is doing the infecting," says Xiao. "Understanding the differential effects caused by these strains could enable predicting the outcome of infection and point out directions to be explored in future studies to eliminate transmissions or cure disease. If Toxoplasma is linked to schizophrenia, this could lead to new treatments of that disease as well."

"It is noteworthy that we found vasoactive intestinal peptide receptor 2 (VIPR2) was upregulated by all three Toxoplasma strains," says Xiao. VIPR2 "is linked to schizophrenia in some recent publications. Since the tropism of Toxoplasma for brain has been linked with specific behavioral changes and psychosis in humans, this finding will have some fundamental significance for understanding the correlation between Toxoplasma and psychosis."

Type II strains cause 70-80 percent of human cases reported in North America and Europe.

---

Journal Reference:

1. J. Xiao, L. Jones-Brando, C. C. Talbot, R. H. Yolken. Differential Effects of Three Canonical Toxoplasma Strains on Gene Expression in Human Neuroepithelial Cells. Infection and Immunity, 2010; 79 (3): 1363 DOI: 10.1128/IAI.00947-10

A warning issued by the Food and Drug Administration regarding the use of atypical antipsychotics for the treatment of dementia was associated with a significant decline in the use of these medications for treating dementia symptoms in elderly patients, according to a report in the February issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

"In 2001, more than 70 percent of U.S. atypical antipsychotic prescriptions were written for off-label indications such as dementia, and atypical antipsychotics accounted for 82 percent of antipsychotic prescriptions written for older patients in Canada in 2002," according to background information in the article. "In 2005, the Food and Drug Administration (FDA) issued a black box warning that stated, 'Treatment of behavioral disorders in elderly patients with dementia with atypical antipsychotic medications is associated with increased mortality. '" Black box warnings are the strongest warnings the FDA issues.

To examine changes in the use of atypical (second generation antipsychotic drugs) and conventional (first generation or "typical" antipsychotics) antipsychotic medications for treatment in patients with dementia, Helen C. Kales, M.D., of the University of Michigan, Ann Arbor, and colleagues reviewed data from more than 250,000 patients with dementia. Data were collected from the national Veterans Affairs (VA) registries maintained by the Serious Mental Illness Treatment, Research and Evaluation Center in Ann Arbor, Mich., for veterans age 65 or older who received a dementia diagnosis between April 1999 and September 2007. The overall study period was divided into three sections: no warning (1999-2003), early warning (2003-2005) and black box warning (2005-2007).

At the beginning of the study, 17.7 percent of patients with dementia were using atypical or conventional antipsychotics. Overall antipsychotic use began to decline during the no warning period. However, use of atypical antipsychotics increased during the no-warning period, began to decline during the early-warning stage and more sharply declined during the black box warning period.

By 2007, overall use of antipsychotics for treatment leveled off at 12 percent of all patients with dementia. The percentage of VA patients with dementia using psychotropics (antipsychotics plus antidepressants, anxiolytics and anticonvulsants) remained consistent at 40 percent during the study and the number of patients not receiving these medications also remained constant around 60 percent. Therefore, the authors conclude that VA patients with dementia continued receiving medication after the black box warning and were not taken off medication completely.

"In this national VA sample, we found that use of both conventional and atypical antipsychotics for patients with dementia began to decline significantly well before implementation of the black box warning," the authors write. "In conclusion, use of atypical antipsychotics for patients with dementia began to decline significantly in 2003, and the FDA advisory was temporally associated with a significant acceleration in the decline."

---

Journal Reference:

1. H. C. Kales, K. Zivin, H. M. Kim, M. Valenstein, C. Chiang, R. Ignacio, D. Ganoczy, F. Cunningham, L. S. Schneider, F. C. Blow. Trends in Antipsychotic Use in Dementia 1999-2007. Archives of General Psychiatry, 2011; 68 (2): 190 DOI: 10.1001/archgenpsychiatry.2010.200

When elderly drivers get behind the wheel, they often confront the harrowing reality that they cannot easily see other cars, pedestrians, or cyclists moving around them. This frightening effect of aging, it turns out, is not necessarily a result of a reduced ability to perceive moving objects, as one might suspect, but a heightened awareness of the backdrop against which these objects move.

A team of scientists led by University of Rochester Assistant Professor Duje Tadin has isolated the cause of this phenomenon, and the surprising results could not only help train elderly people to be better drivers, but they could also help psychiatrists better understand abnormal brain processes in psychological conditions like depression and schizophrenia. Their research, conducted at the Berenson-Allen Center for Noninvasive Brain Stimulation at the Harvard Medical School, will be published in the Journal of Neuroscience on January 25.

In a healthy, young person, a brain region called the middle temporal visual area, or MT, actively suppresses often irrelevant background motion so that he or she can concentrate on the more important motions of smaller objects in the foreground. Previous studies have found that elderly people, as well as those with psychological conditions such as schizophrenia and depression, are better at perceiving motion in the background. But this above average motion perception is not something to look forward to as we age. Because the brain is spending its limited resources constantly paying attention to the unimportant motions of background objects, it has a harder time noticing the motions of smaller objects.

"The amount of visual information around us is huge, and we don't have the brain power to process it all," Tadin said. "Evolutionarily speaking, moving objects are the most important visual features to detect quickly, because they could be your lunch or they could want to eat you for lunch. It just makes sense that our vision prioritizes processing them."

Tadin and his colleagues discovered that the MT was responsible for this effect by using a technique called Transcranial Magnetic Stimulation (TMS). By precisely placing magnetic coils on the back of a subject's head, the scientists stimulated the MT with electrical signals for 15 minutes to temporarily inhibit its functioning. Then, while the MT was less active, they tested how well subjects identified motions of smaller and larger objects on a computer screen. They found that when the MT was inhibited, subjects had an easier time identifying the motion of large, background-like objects. These results indicate that an improperly functioning MT may be the cause behind better than normal perception of background motion in older adults.

In the future, this knowledge could be useful to psychiatrists trying to better diagnose schizophrenia and depression, Tadin says. Current diagnostic techniques for these conditions can involve subjective and qualitative information like a history of hallucinations or feelings of apathy. But if a person also exhibits better than normal detection of background motion, it could be a quantitative confirmation that he or she has one of these conditions.

---

Journal Reference:

1. D. Tadin, J. Silvanto, A. Pascual-Leone, L. Battelli. Improved Motion Perception and Impaired Spatial Suppression following Disruption of Cortical Area MT/V5. Journal of Neuroscience, 2011; 31 (4): 1279 DOI: 10.1523/JNEUROSCI.4121-10.2011

One of the first studies published from the University of Missouri Brain Imaging Center (BIC) gives researchers insight into the brain and memory and may provide researchers clues to treating a variety of debilitating disorders.

Nelson Cowan, director of the BIC and Curator's Professor in the Department of Psychological Sciences, used the BIC's magnetic resonance imaging (MRI) to produce graphics that depict the structure and function of the brain during various mental tasks in an effort to understand abstract working memory. People use their abstract working memories to assign meaning when trying to recall facts — for example, when someone dials a set of phone numbers, their abstract memory brings forth an image of the person they are calling.

Previous studies identified an area of the brain responsible for holding abstract working memory, although it was assumed by some researchers to hold only visual information. At the BIC, Cowan found that this same part of the brain can hold auditory information as well. For example, when people hear "Jingle Bells" they relate it to the Christmas season and retain the meaning of the song temporarily.

"This research has given us better understanding of an area of the brain that may be affected in people with various learning disabilities, autism and schizophrenia," said Cowan. "For example, recent research has shown that people with schizophrenia simply hold fewer items in their working memories, rather having an inability to disregard unimportant items, as previously thought. Thus, discovering more about working memory will enable scientists to better target schizophrenia, among other disorders."

Cowan's research will be published in the Journal of Cognitive Neuroscience, and his related research on the childhood development of working memory has been funded by the National Institutes of Health since 1985. The study is one of many research projects that are currently underway at the BIC.

For example, researchers from the Department of Nutrition and Exercise Physiology in the College of Human Environmental Sciences are studying the neurological effects of eating breakfast on obese people. That research team is also studying the effects of eating breakfast on working memory. Cowan said psychiatry researchers are studying the effects of medications on the brain, and researching addictive behaviors is enhanced by the BIC.

"The center enables us to conduct interdisciplinary research that can advance the field of psychology," Cowan said. "Brain imaging makes our behavioral research more powerful because we can better understand the brain and how it functions during different activities and conditions."

In addition, Nelson says the ability to do brain imaging makes grant proposals stronger. He says the facility attracts new faculty members and makes for better research.

---

Journal Reference:

1. Nelson Cowan, Dawei Li, Amanda Moffitt, Theresa M. Becker, Elizabeth A. Martin, J. Scott Saults, Shawn E. Christ. A Neural Region of Abstract Working Memory. Journal of Cognitive Neuroscience, 2011; : 1 DOI: 10.1162/jocn.2011.21625

Smoking is a common problem for patients with schizophrenia. The increased tendency of patients diagnosed with this disorder is to not only smoke, but to do so more heavily than the general public. This raises the possibility that nicotine may be acting as a treatment for some symptoms of schizophrenia.

Nicotine acts through two general classes of brain receptors, those with high and low affinity for nicotine. The low affinity class of nicotinic receptors contains the alpha-7 subunit, which is present in reduced numbers in people with schizophrenia.

Two papers published in the January 1^st issue of Biological Psychiatry suggest that drugs that stimulate these alpha-7 subunit-containing nicotinic receptors might enhance cortical function and treat cognitive impairments associated with schizophrenia.

In their study of healthy monkeys, Graham Williams and colleagues at Yale University and AstraZeneca found that very low doses of AZD0328, a novel drug that acts as an alpha-7 agonist, produced both acute and persistent improvements in their performance on a spatial working memory task.

"Our work demonstrates that that the neuronal nicotinic alpha-7 receptor plays a critical role in the core cognitive function of working memory, which is a key indicator of outcome in patients with schizophrenia," explained Dr. Williams. "The function of the alpha-7 receptor may account for the ability of a partial agonist to induce long-term beneficial changes for high-order cognition at such low doses."

This influence on cortical function has been exemplified by the work of Jason Tregellas and colleagues. These researchers examined the effects of DMXB-A, a novel alpha-7 partial agonist, on the brain's 'default network' in people with schizophrenia. Function of the default network, which is likely a major contributor to the intrinsic neuronal activity that accounts for 60-80% of the brain's energy use, is different in people with schizophrenia.

Dr. Tregellas summarized their findings: "We found that DMXB-A altered default network activity in people with schizophrenia in a pattern consistent with improved function of the network. We also found that these neuronal differences were related to the genotype of the alpha-7 nicotinic receptor and to drug-related improvements in symptoms."

Together, "these two studies provide additional support for a novel pharmacologic approach to treat cognitive impairments in schizophrenia," observed Dr. John Krystal, Editor of Biological Psychiatry.

---

Journal References:

1. Stacy A. Castner et al. Immediate and Sustained Improvements in Working Memory After Selective Stimulation of α7 Nicotinic Acetylcholine Receptors. Biological Psychiatry, (in press)
2. Jason R. Tregellas, Jody Tanabe, Donald C. Rojas, Shireen Shatti, Ann Olincy, Lynn Johnson, Laura F. Martin, Ferenc Soti, William R. Kem, Sherry Leonard. Effects of an Alpha 7-Nicotinic Agonist on Default Network Activity in Schizophrenia. Biological Psychiatry, 2011; 69 (1): 7 DOI: 10.1016/j.biopsych.2010.07.004

Many prescriptions for the top-selling class of drugs, known as atypical antipsychotic medications, lack strong evidence that the drugs will actually help, a study by researchers at the Stanford University School of Medicine and University of Chicago has found. Yet, drugs in this class may cause such serious effects as weight gain, diabetes and heart disease, and cost Americans billions of dollars.

"Because these drugs have safety issues, physicians should prescribe them only when they are sure patients will get substantial benefits," said Randall Stafford, MD, PhD, associate professor of medicine at the Stanford Prevention Research Center, who is senior author of the study to be published online Jan. 7 in Pharmacoepidemiology and Drug Safety. "These are commonly used and very expensive drugs."

Prescriptions for these drugs have risen steadily since they first came on the U.S. market in 1989, largely replacing the first generation of antipsychotics, which were mainly used to treat schizophrenia. The U.S. government's original stamp of approval for the new drugs was for treating schizophrenia, but they're used more today for other conditions, including other psychoses, autism, bipolar disorder, delirium, dementia, depression and personality disorders. And while some of these uses have recently been approved by the U.S. Food and Drug Administration, many have not.

For example, the FDA has approved quetiapine (brand name, Seroquel), the antipsychotic with the biggest U.S. sales, for treating schizophrenia and some aspects of bipolar disorder and depression, but the drug is also often used for anxiety and dementia, among other conditions.

These new drugs accounted for more than $10 billion in retail pharmacy U.S. prescription drug costs in 2008, representing the largest expenditure for any single drug class — nearly 5 percent of all drug spending, surpassing even blockbusters like statin cholesterol medications. According to a 2004 study, a quarter of all residents of U.S. nursing homes had taken them. Among the drugs are quetiapine, aripoprazole (brand name, Abilify), olanzapine (Zyprexa) and risperidone (Risperdal), each with annual U.S. sales exceeding $1 billion.

Stafford's new study adds to concerns about the drugs, which have been the focus of thousands of lawsuits, and as a class make up the single largest target of litigation filed under the federal False Claims Act. All major companies selling new-generation antipsychotics have either recently settled cases for hundreds of millions of dollars or are currently under investigation for skewing results or using questionable marketing tactics.

In 2005, the FDA issued its strongest type of caution, the "black box" warning, for use of new-generation antipsychotics, because of increased risk of death for dementia patients.

"Most people think, 'If my doctor prescribed this, the FDA must have evaluated whether this drug was safe and effective for this use.' That's not true," said Stafford. When doctors prescribe drugs for purposes other than those approved by the FDA, it's called "off-label" use. Though it's riskier for patients, there's nothing illegal about it, and can make sense medically in some instances, Stafford said, especially if there are no approved treatments or if a patient has not responded to approved drugs.

Previous studies had shown that antipsychotic drug use is ballooning. Stafford's new study not only corroborated and updated these findings but also identified the fraction of off-label use that is based on uncertain evidence.

The researchers' first step was to analyze the results of a physicians' survey conducted by health-care information company IMS Health. The IMS Health National Disease and Therapeutic Index survey gives a snapshot of the conditions doctors treated and drugs they prescribed. About 1,800 physicians participate each calendar quarter and each is randomly assigned two days per quarter to provide data.

After identifying which antipsychotics were being used, and for what, the researchers assessed the strength of the evidence supporting those that lacked FDA approval, using efficacy ratings from the widely used drug compendium, Drugdex.

Lead author Caleb Alexander, MD, assistant professor of medicine at the University of Chicago, and colleagues conducted the analysis. Stafford supervised the project and with Alexander interpreted the data. Stanford clinical assistant professor of psychiatry Anthony Mascola, MD, provided expertise on the treatment of psychiatric conditions.

Among their findings:

• Antipsychotic treatment prescribed during the surveyed doctors' visits nearly tripled from 6.2 million in 1995 to 16.7 million in 2008, the most recent year for which they had data. During this period, prescriptions for first-generation antipsychotics decreased from 5.2 million to 1 million.
• Antipsychotic use for indications that lacked FDA approval by the end of 2008 increased from 4.4 million prescriptions during surveyed doctors' visits in 1995 to 9 million in 2008.
• In 2008, more than half — 54 percent — of the surveyed prescriptions for the new-generation antipsychotics had uncertain evidence.
• An estimated $6 billion was spent in 2008 on off-label use of antipsychotic medication nationwide, of which $5.4 billion was for uses with uncertain evidence.
• Prescriptions for antipsychotics began dropping slightly in 2006, shortly after the FDA issued a warning about their safety.

Stafford suggests the upswing in prescriptions for antipsychotics despite the absence of good evidence for their value in many instances is the result of marketing — whether legal or illegal — and ingrained cultural tendencies. "Physicians want to prescribe and use the latest therapies — and even when those latest therapies doesn't necessarily offer a big advantage, there's still a tendency to think that the newest drugs must be better," he said.

Physicians could benefit from more feedback on what percentage of their prescriptions is for off-label uses, said Stafford. "In many cases, physicians don't realize they're prescribing off-label," he said.

In fact, in a previous survey of physicians, Alexander found that the average respondent accurately identified the FDA-approval status of drugs for a given condition just over half the time.

The research was funded by the federal Agency for Healthcare Research and Quality, the Robert Wood Johnson Foundation and the National Heart, Lung and Blood Institute. The data were obtained under licensed agreement with IMS Health.

Alexander is a consultant for IMS Health. Stafford has served as a consultant to a company that produces generic drugs, including first-generation antipsychotics.

Normally, cortical nerve cells or neurons reside in the brain's gray matter with only a few scattered neurons in the white matter, but some people with schizophrenia have a higher number of neurons in the white matter. Neuronal migration errors may arise in schizophrenia as a consequence of both genetic and environmental factors.

The phenomenon of aberrant cellular localization has now been studied in detail in a paper by Yang and colleagues, published in the current issue of Biological Psychiatry.

Using a specialized technique that involves staining cells, the researchers were able to determine the distribution of nerve cells in brain tissue from people who had been diagnosed with schizophrenia in comparison to tissue from people who did not carry this diagnosis prior to their death.

Their results linked two main findings emerging from analyses of brain tissue in schizophrenia: abnormalities in the inhibitory neurons within the cortex and increases in neurons in white matter below the cortex.

"Our observations challenge the long held theory that increased neurons in the white matter might be remaining from a transient layer of cells," explained Prof. Cyndi Shannon Weickert and Dr. Samantha Fung. "We suggest that, in schizophrenia, inhibitory neurons that were travelling to the cortex might actually be stuck at some stage in their development."

This study's findings highlight the importance of brain development for the emergence of symptoms associated with schizophrenia. As noted by Dr. John Krystal, Editor of Biological Psychiatry, "this study highlights the importance for schizophrenia of better understanding the molecular switches that control the migration of nerve cells and the development of the connections between nerve cells."

If scientists understood the molecular factors that prevented the neurons from migrating into the cortex, they might be able to develop treatments that prevented the inhibitory neurons from getting "stuck" in the white matter.

---

Journal Reference:

1. Yang Yang, Samantha J. Fung, Alice Rothwell, Si Tianmei, Cynthia Shannon Weickert. Increased Interstitial White Matter Neuron Density in the Dorsolateral Prefrontal Cortex of People with Schizophrenia. Biological Psychiatry, 2011; 69 (1): 63 DOI: 10.1016/j.biopsych.2010.08.020