Archive for category Schizophrenia

How Drugs for Schizophrenia Sow Seeds of Resistance


How Drugs for Schizophrenia Sow Seeds of ResistanceA new study has identified why certain drugs have mixed success in treating schizophrenia; effective at first, but with chronic administration becoming less and less so.

In the study, reported online in the journal Nature Neuroscience, scientists investigated the external genetic reasons (called epigenetic factors) that cause treatment-resistance to atypical antipsychotic drugs.

Use of antipsychotic drugs is the standard of care for schizophrenia. Researchers at Mount Sinai School of Medicine report that 30 percent of individuals with schizophrenia do not respond to currently available treatments.

Researchers discovered that, over time, an enzyme in the brains of schizophrenic patients, analyzed at autopsy, begins to compensate for the prolonged chemical changes caused by antipsychotics, resulting in reduced efficacy of the drugs.

“These results are groundbreaking because they show that drug resistance may be caused by the very medications prescribed to treat schizophrenia, when administered chronically,” said Javier Gonzalez-Maeso, Ph.D., lead investigator on the study.

Researchers found that an enzyme called HDAC2 was highly expressed in the brain of mice chronically treated with antipsychotic drugs, resulting in lower expression of the receptor called mGlu2 and a recurrence of psychotic symptoms. A similar finding was observed in the postmortem brains of schizophrenic patients.

In response, the research team administered a chemical called suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs. This treatment prevented the detrimental effect of the antipsychotic called clozapine on mGlu2 expression, and also improved the therapeutic effects of atypical antipsychotics in mouse models.

Previous research conducted by the team showed that chronic treatment with the antipsychotic clozapine causes repression of mGlu2 expression in the frontal cortex of mice, a brain area key to cognition and perception.

The researchers hypothesized that this effect of clozapine on mGlu2 may play a crucial role in restraining the therapeutic effects of antipsychotic drugs.

“We had previously found that chronic antipsychotic drug administration causes biochemical changes in the brain that may limit the therapeutic effects of these drugs,”said Gonzalez-Maeso. “We wanted to identify the molecular mechanism responsible for this biochemical change, and explore it as a new target for new drugs that enhance the therapeutic efficacy of antipsychotic drugs.”

Mitsumasa Kurita, Ph.D., a postdoctoral fellow at Mount Sinai and the lead author of the study, said, “We found that atypical antipsychotic drugs trigger an increase of HDAC2 in the frontal cortex of individuals with schizophrenia, which then reduces the presence of mGlu2, and thereby limits the efficacy of these drugs.”

As a result of these findings, Gonzalez-Maeso’s team is now developing compounds that specifically inhibit HDAC2 as adjunctive treatments to antipsychotics.

Source:The Mount Sinai Hospital/Mount Sinai School of Medicine

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Gene Related to Autism Behavior ID’d in Mice Study


Gene Related to Autism Behavior ID'd in Mice StudyIn a new mouse study, University of California, Davis, researchers have found that a defective gene is responsible for brain changes that lead to the disrupted social behavior that accompanies autism.

Investigators believe the discovery could lead to the development of medications to treat the condition.

Prior research had determined that the gene is defective in children with autism, but its effect on neurons in the brain was not known.

The new studies in mice show that abnormal action of just this one gene disrupted energy use in neurons. The harmful changes were coupled with antisocial and prolonged repetitive behavior — traits found in autism.

The research is published in the scientific journal PLoS ONE.

“A number of genes and environmental factors have been shown to be involved in autism, but this study points to a mechanism — how one gene defect may trigger this type of neurological behavior,” said study senior author Cecilia Giulivi, Ph.D.

“Once you understand the mechanism, that opens the way for developing drugs to treat the condition,” she said.

The defective gene appears to disrupt neurons’ use of energy, Giulivi said, the critical process that relies on the cell’s molecular energy factories called mitochondria.

In the research, a gene called pten was modififed in the mice so that neurons lacked the normal amount of pten’s protein. The scientists detected malfunctioning mitochondria in the mice as early as 4 to 6 weeks after birth.

By 20 to 29 weeks, DNA damage in the mitochondria and disruption of their function had increased dramatically.

At this time, the mice began to avoid contact with their litter mates and engage in repetitive grooming behavior. Mice without the single gene change exhibited neither the mitochondria malfunctions nor the behavioral problems.

The antisocial behavior was most pronounced in the mice at an age comparable in humans to the early teenage years – a period in which schizophrenia and other behavioral disorders become most apparent, Giulivi said.

The research showed that, when defective, pten’s protein interacts with the protein of a second gene known as p53 to dampen energy production in neurons.

The interaction causes severe stress that leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus — brain regions critical for social behavior and cognition.

Investigators report that pten mutations previously have been linked to Alzheimer’s disease as well as a spectrum of autism disorders.

The new research shows that when pten protein was insufficient, its interaction with p53 triggered deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism.

Source: University of California – Davis Health System

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Face in the Mirror More Distorted in Schizophrenia


Face in the Mirror More Distorted in SchizophreniaIndividuals with schizophrenia experience more intense perceptual illusions while gazing into a mirror than do healthy people, according to a new study.

The new research also showed that patients with schizophrenia were more likely to believe the illusions they see in the mirror were real.

The research highlights the underlying ego dysfunction and body dysmorphic disorder found in schizophrenia.

According to the researchers, gazing at one’s own reflected face under low light can lead to ghostly experiences called “strange-face in the mirror” illusions. No study has previously focused on mirror gazing in schizophrenic patients, who already experience delirium, hallucination and self mis-attribution.

Stefano Zago of the University of Milan conducted the study to compare strange-face apparitions in response to mirror gazing in 16 patients with schizophrenia and 21 mentally healthy controls.

Subjects took a 7-minute mirror-gazing test, after which they filled out a specially designed questionnaire asking them to describe their strange-face perceptions.

The results show a number of differences between patients with schizophrenia and mentally healthy controls.  Patients on average reported a greater total number of strange faces than controls, at 2.8 versus 1.5.

The types of strange faces also differed between patients and controls. Hugely deformed features were seen by all schizophrenia patients and 71% of controls, archetypal faces by 50% of patients and 19% of controls, and monstrous faces by 88% of patients and 29% of controls. Patients’ archetypical and monster faces were typically described as satanic beings.

Furthermore, patients tended to report greater intensity in the strange faces and were more likely to say that they felt real than controls.

Of note, mentally healthy participants felt dissociative experiences during the strange-face illusions and never identified with them.

Overall, the research suggests that strange-face illusions in schizophrenia can be caused by ego dysfunction, body dysmorphic disorder, or by misattribution of self-agency, said Zago.

The research is published in Schizophrenia Research.

Source:  Schizophrenia Research

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Why We Can’t Live in the Moment


Why We Can't Live in the MomentThe sought-after ideal of “living in the moment” may be impossible, according to research conducted at the University of Pittsburgh, which pinpoints an area of the brain responsible for using past decisions and outcomes to guide future behavior.

The study analyzes signals associated with metacognition, which is a person’s ability to monitor and control cognition — a term described by the researchers as “thinking about thinking.”

“The brain has to keep track of decisions and the outcomes they produce,” said Marc Sommer, Ph.D., who did his research for the study as a University of Pittsburgh neuroscience faculty member and is now on the faculty at Duke University. “You need that continuity of thought. We are constantly keeping decisions in mind as we move through life, thinking about other things.”

Sommer said the researchers “guessed it was analogous to working memory,” which led them to predict that neuronal correlates of metacognition resided in the same brain areas responsible for cognition, including the frontal cortex, a part of the brain linked with personality expression, decision making, and social behavior.

The research team studied single neurons in three frontal cortical regions of the brain: The frontal eye field, associated with visual attention and eye movements; the dorsolateral prefrontal cortex, which is responsible for motor planning, organization, and regulation; and the supplementary eye field (SEF), which is involved in the planning and control of saccadic eye movements, which are the extremely fast movements of the eye that allow it to continually refocus on an object.

Study participants were asked to perform a visual decision-making task that involved random flashing lights and a dominant light on a cardboard square. They were asked to remember and pinpoint where the dominant light appeared, guessing whether they were correct. The researchers found that while neural activity correlated with decisions and guesses in all three brain areas, the metacognitive activity that linked decisions to bets resided exclusively in the SEF.

“The SEF is a complex area linked with motivational aspects of behavior,” said Sommer. “If we think we’re going to receive something good, neuronal activity tends to be high in SEF. People want good things in life, and to keep getting those good things, they have to compare what’s going on now versus the decisions made in the past.”

Sommer said he sees his research as one step in a systematic process of working toward a better understanding of consciousness. By studying metacognition, he says, he reduces the big problem of studying a “train of thought” into a simpler component: Examining how one cognitive process influences another.

“Why aren’t our thoughts independent of each other? Why don’t we just live in the moment? For a healthy person, it’s impossible to live in the moment. It’s a nice thing to say in terms of seizing the day and enjoying life, but our inner lives and experiences are much richer than that.”

The scientist said that patients with mental disorders have not been tested on these tasks, but added he is interested to see how SEF and other brain areas might be disrupted in people with these disorders.

“With schizophrenia and Alzheimer’s disease, there is a fracturing of the thought process,” he said. “It is constantly disrupted, and despite trying to keep a thought going, one is distracted very easily. Patients with these disorders have trouble sustaining a memory of past decisions to guide later behavior, suggesting a problem with metacognition.”

The study was published in the  journal Neuron.

Source: University of Pittsburgh

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Brain Abnormalities in Schizophrenia Due to Disease, Not Genetics


Brain Abnormalities in Schizophrenia Due to Disease, Not GeneticsThe brain differences found in people with schizophrenia are mainly the result of the disease itself or its treatment, as opposed to being caused by genetic factors, according to a Dutch study.

Schizophrenia is a mental disorder that significantly affects cognition and usually contributes to chronic problems with behavior and emotion. Along with a breakdown of thought processes, the disorder is also characterized by poor emotional responsiveness, paranoia, auditory hallucinations and delusions.

People with schizophrenia are likely to have additional conditions, including major depression and anxiety.

The strong familial link of schizophrenia is thought to be as high as 81 percent, and researchers have suggested that schizophrenia-related brain abnormalities may be present in unaffected relatives, a notion that has been supported by several studies.

For the current study, Heleen Boos and a team from University Medical Center Utrecht performed structural magnetic resonance imaging (MRI) whole-brain scans on 155 patients with schizophrenia, 186 of their non-psychotic siblings, and 122 healthy controls (including 25 sibling pairs).

Researchers used the images to measure volume, cortical thickness and to map the brain anatomy in order to evaluate group differences.

Compared with healthy controls, participants with schizophrenia had strong reductions in total brain, gray matter, and white matter volumes, and significant increases in lateral and third ventricle volumes after taking into account age, gender, intracranial volume, and left or right handedness.

However, there were no significant differences in brain volume between unaffected siblings and healthy controls.

Schizophrenia patients also showed cortical thinning compared with healthy controls, and had decreased gray matter density. Again, this was not found in unaffected siblings and healthy controls.

“Our study did not find structural brain abnormalities in nonpsychotic siblings of patients with schizophrenia compared with healthy control subjects, using multiple imaging methods,” the team says.

“This suggests that the structural brain abnormalities found in patients are most likely related to the illness itself.”

Source:  University Medical Center Utrecht 

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First Marijuana Use Linked to Psychosis in Vulnerable People


Among individuals with psychosis who are also heavy marijuana users, the age they first used marijuana is strongly linked to the age of their first bout of psychosis, according to a study of 57 patients.

Although marijuana use by itself is neither sufficient nor needed to trigger schizophrenia, “if cannabis use precipitates the onset of psychosis, efforts should be focused on designing interventions to discourage cannabis use in vulnerable individuals,” Dr. Juan A. Galvez-Buccollini and his associates said.

This caution pertains to someone with a first-degree relative with psychosis, which is “the highest risk factor for schizophrenia,” said Dr. Lynn E. Delisi, senior investigator for the study, a psychiatrist at the Boston VA Medical Center in Brockton, Mass., and professor of psychiatry at Harvard Medical School, Boston.

If someone had a first-degree relative, “I would caution them about the consequences of cannabis use and the association with schizophrenia,” she said.

Findings from previous research has shown that marijuana use is associated with an earlier age of psychosis onset in people abusing multiple substances, but studies have not looked at a possible link between the onset of cannabis use itself and resulting psychosis.

Because of this, Dr. Galvez-Buccollini, a psychiatry researcher at VA Boston Healthcare System and Harvard, and his colleagues interviewed 57 patients with a current diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, or psychosis not otherwise specified, who also had a history of heavy cannabis use before the onset of psychosis. They defined heavy cannabis use as 50 or more uses during a one year period.

Average age of the subjects was 25 years with a range of 18-39 years. Of the total, 83 percent were men, and 88 percent were not married. The average age of psychosis onset was 22 years, and the average age for first psychosis-related hospitalization was 23.

Schizophrenia was the most common psychosis (42 percent), followed by schizoaffective disorder (32 percent). The average age of first marijuana use was 15, preceding psychosis onset by an average of 7 years.

During the study period, the prevalence of daily cannabis was 59 percent with another 30 percent reporting use 2-5 days per week, and the remaining 11 percent reporting weekly use. Alcohol abuse was 16 percent and alcohol dependence was 8 percent.

The researchers found a statistically significant link between the age when cannabis use first started and the age when psychosis was first diagnosed. This association was consistent after researchers excluded patients with any diagnosis of alcohol abuse or dependency during their lifetime.

The analysis also showed a strong link between the time a patient first smoked marijuana and their age of first psychosis hospitalization.

Marijuana affects dopamine receptors and can have other neurochemical effects.

“There are two components of cannabis, one that potentiates and another that antagonizes psychotic symptoms,” said Delisi. The balance between these two effects can differ among various strains of cannabis, she added.

Source: Schizophrenia Research

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Genetic Link Found to Rapid Weight Gain from Antipsychotic Meds


Genetic Link Found to Rapid Weight Gain from Antipsychotic MedsScientists have discovered two genetic variants associated with substantial, rapid weight gain occurring in nearly half of patients treated with antipsychotic medications.

The results from two studies from the Centre for Addiction and Mental Health in Canada could eventually be used to identify which patients have the variations, enabling doctors to choose strategies to prevent this serious side effect and offer more personalized treatment, the researchers note.

“Weight gain occurs in up to 40 percent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,” said Dr. James Kennedy, senior author of the study.

The weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span, he noted.

“Identifying genetic risks leading to these side effects will help us prescribe more effectively,” said Kennedy. Currently, the center screens for two other genetic variations that affect patients’ responses to psychiatric medications.

Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.

In the latest study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics.

The study had four patient groups: Two from the U.S., one in Germany, and one from a larger European study. Three of the four groups had never taken atypical antipsychotics.

Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed, the researchers said. Weight and other metabolic-related measures were taken at the start and during treatment.

“The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behavior or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,” noted researcher Dr. Daniel Müller.

“The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.”

The gene’s role in antipsychotic-induced weight gain was identified in a study published earlier this year in The Pharmacogenomics Journal. Researchers
found a different variation on MC4R that was linked to the side effect.

For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene — known as single nucleotide polymorphisms (SNPs) — related to the drug-induced weight gain side effect.

The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. “We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,” said Müller. “We need further studies to validate this result and eventually turn this into a clinical application.”

The recent study is published online in the Archives of General Psychiatry.

Source: The Centre for Addiction and Mental Health (CAMH)

DNA photo by shutterstock.

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