Cardiometabolic Risks Begin Early in Schizophrenic Spectrum Disorders

Christoph U. Correll, MD Professor of Psychiatry and Molecular Medicine Hofstra North Shore LIJ School of Medicine Medical Director, Recognition and Prevention (RAP) Program The Zucker Hillside Hospital Investigator Feinstein Institute for Medical Research North Shore Long Island Jewish Health Interview with:
Christoph U. Correll, MD
Professor of Psychiatry and Molecular Medicine
Hofstra North Shore LIJ School of Medicine
Medical Director, Recognition and Prevention (RAP) Program
The Zucker Hillside Hospital Investigator
Feinstein Institute for Medical Research
North Shore Long Island Jewish Health System

Medical Research: What are the main findings of the study?

Dr. Correll: The main findings of the study of 398 patients with first-episode schizophrenia-spectrum disorders who were on average in their mid twenties are that:

  • 1) despite their young age, an average of only 47 days lifetime antipsychotic exposure and overweight/obesity figures that were comparable to similarly aged US population members, there was a clear pattern of increased smoking and several metabolic risk parameters compared to similarly aged persons in the general US population;
  • 2) dyslipidemia, a constellation of at least one relevant abnormal blood fat value, was as frequent as in a 15-20 years older general US population;
  • 3) body composition related risk markers were significantly associated with longer total psychiatric illness duration, whereas metabolic risk markers were significantly associated with the overall very short mean lifetime antipsychotic treatment duration; and
  • 4) relevant for treatment choice and recommendations for patients, significantly higher continuous metabolic risk factor values were associated with olanzapine treatment and, less so, with quetiapine treatment.
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Obsessive-Compulsive Disorder Increases Risk Of Schizophrenia Interview with:
Sandra M. Meier, PhD
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH,
National Centre for Register-Based Research
Aarhus University, Aarhus, Denmark

Medical Research: What are the main findings of the study?

Dr. Meier: People with an obsessive-compulsive disorder are at a 6 to 7 times higher risk of developing schizophrenia than people without an obsessive-compulsive disorder. If the parents are diagnosed with an obsessive-compulsive disorder, their offspring experience a 3 to 4 times higher chance to develop schizophrenia.
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Sleep Deprivation Can Induce Symptoms Resembling Schizophrenia

Prof. Dr. Ulrich Ettinger Departments of Psychology University of Bonn Bonn, Interview with:
Prof. Dr. Ulrich Ettinger
Departments of Psychology
University of Bonn
Bonn, Germany

Medical Research: What are the main findings of the study?

Prof. Ettinger: We found that 24-hour sleep deprivation induced subjective cognitive, perceptual and emotional alterations resembling the symptoms of schizophrenia. We also observed that sleep deprivation led to a deficit in a sensorimotor filter mechanism called prepulse inhibition (PPI), similar to the disturbance seen in schizophrenia.
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Single Gene Mutation May Predispose to ADHD

Dr. Anders Nykjaer MD, PhD Mayo Clinic in Florida and Aarhus University in Interview with:
Dr. Anders Nykjaer MD, PhD
Mayo Clinic in Florida and
Aarhus University in Denmark

MedicalResearch: What are the main findings of the study?

Dr. Nykjaer: It is well known that ADHD is a complex condition caused by a number of factors including genetic and environment. However, approximately 75% etiology is considered to be genetic and a large body of investigations suggests that it is multiple genes each with a moderate effect that is responsible for conferring susceptibility to ADHD. We have here found one single gene the dysfunction of which is sufficient to trigger the disease.  The gene encodes a receptor, SorCS2, which ensures correct wiring our reward system during embryonic development. Malfunction of the receptor causes ADHD-like symptoms in mice. It is well accepted that ADHD predisposes to psychiatric disorders and genetic reports have linked variations in the SorCS2 gene with schizophrenia. Studies are currently ongoing to evaluate if mutations disrupting the function of SorCS2 may also result in schizophrenia. If this is the case we have come closer to an explanation for the link between ADHD and psychiatric disorders. In the future when prenatal genetic screening becomes established, non-sense mutations in the SorCS2 gene can be used to predict that the child will develop ADHD with 100% certainty.   Continue reading

Schizophrenia Treatment Maintenance: Comparison of Long Acting Injectable Medications

Scott Stroup, MD, MPH Professor of Psychiatry Director, Program for Intervention Effectiveness Research, Associate Director for Adult Services, Division of Mental Health Services and Policy Research,  New York State Psychiatric Institute Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New Interview with:
Scott Stroup, MD, MPH
Professor of Psychiatry
Director, Program for Intervention Effectiveness Research,
Associate Director for Adult Services, Division of Mental Health Services and Policy Research,  New York State Psychiatric Institute
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York

MedicalResearch: What are the main findings of the study?

Dr. Stroup: We conducted a study sponsored by the National Institute of Mental Health that compared long-acting injectable antipsychotics for people with schizophrenia. Long-acting injectable antipsychotics, also known as depot antipsychotics, are used to promote treatment adherence.  We compared a newer injectable antipsychotic, paliperidone palmitate, to an older one, haloperidol decanoate.  We did not find an advantage for the newer drug in overall effectiveness.  The drugs performed very similarly, and were tolerated about the same.
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Schizophrenia: Impact of Estradiol on Psychosis Symptoms Interview with:
Professor Jayashri Kulkarni MBBS, MPM, FRANZCP, PhD
Monash University What are the main findings of the study?

Professor Kulkarni: Persistent schizophrenia is difficult and unfortunately common, despite advances over the past years in antipsychotic drug development. New treatment approaches are urgently needed. Also, a specific focus for women with schizophrenia is still somewhat lacking and there is a need to consider the special issues facing women with schizophrenia.

Over many years, we have been conducting clinical trials to develop the role of adjunctive estradiol use to treat symptoms of schizophrenia. This study is the largest clinical trial in the world of this type and we found that in an 8 week, three arm, double blind, placebo-controlled, adjunctive trial of transdermal estradiol (200mcg v 100mcg v placebo) in 183 women with schizophrenia, that the women who received either 200mcg or 100mcg transdermal estradiol made a better recovery. The women who received 200mcg transdermal estradiol made a slightly better recovery than women receiving 100mcg transdermal estradiol. Both estradiol groups were significantly better than the group who received adjunctive transdermal placebo.

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Using biomarkers to identify and treat schizophrenia

In the current online issue of PLoS ONE, researchers at the University of California, San Diego School of Medicine say they have identified a set of laboratory-based biomarkers that can be useful for understanding brain-based abnormalities in schizophrenia. The measurements, known as endophenotypes, could ultimately be a boon to clinicians who sometimes struggle to recognize and treat the complex and confounding mental disorder.

“A major problem in psychiatry is that there are currently no laboratory tests that aid in diagnosis, guide treatment decisions or help predict treatment response or outcomes,” said Gregory A. Light, PhD, associate professor of psychiatry and the study’s first author. “Diagnoses are currently based on a clinician’s ability to make inferences about patients’ inner experiences.”

Diagnosing and treating schizophrenia is a particularly troubling challenge. The disorder, which affects about 1 percent of the U.S. population or roughly 3 million people, is characterized by a breakdown of normal thought processes and erratic, sometimes dangerous or harmful, behaviors.

“Schizophrenia is among the most severe and disabling conditions across all categories of medicine,” said Light, who also directs the Mental Illness, Research, Education and Clinical Center at the San Diego VA Healthcare System.

The precise cause or causes of schizophrenia are not known, though there is a clear genetic component, with the disorder more common in some families.

Clinicians typically diagnose schizophrenia based upon inferences drawn from the patient’s inner experiences. That is, their ability to describe what’s happening inside their minds.

“But even the best clinicians struggle with diagnostic complexities based on sometimes fuzzy clinical phenomenology,” said Light. The clinical challenge is compounded by the fact that “many schizophrenia patients have cognitive and functional impairments,” said Light. They may not be able to reasonably explain how or what they think.

Light and colleagues investigated whether a select battery of neurophysiological and neurocognitive biomarkers could provide clinicians with reliable, accurate, long-term indicators of brain dysfunction, even when overt symptoms of the disorder were not apparent. These markers ranged from tests of attention and memory to physiological assessments of basic perceptual processes using scalp sensors to measure brain responses to simple sounds.

The researchers measured the biomarkers in 550 schizophrenia patients, and then re-tested 200 of the patients one year later. They found that most of the markers were significantly abnormal in schizophrenia patients, were relatively stable between the assessments and were not affected by modest fluctuations in clinical status of the patient.

Light said further research is required, including whether the endophenotypes can differentiate other psychiatric disorders, be used to anticipate patient response to different kinds of drugs or non-pharmacological interventions or even be used to predict which subjects are at high risk of developing a psychotic illness.

“We believe this paper is an important step towards validating laboratory-based biomarkers for use in future genomic and clinical treatment studies of schizophrenia,” Light said.


Co-authors are Neal R. Swerdlow, Anthony J. Rissling and Marlena Pela, Department of Psychiatry, UCSD; Allen Radant, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; Catherine A. Sugar, Departments of Psychiatry and Biostatistics, UCLA; Joyce Sprock, Mark A. Geyer and David L. Braff, Mental Illness, Research, Education and Clinical Center, San Diego VA Healthcare System and Department of Psychiatry, UCSD.

Source: Eurekalert July 11 2012

Study finds genetic ‘overlap’ between schizophrenia, bipolar disorder

Knowledge about the biological origin of diseases like schizophrenia, bipolar disorder and other psychiatric conditions is critical to improving diagnosis and treatment.

In an effort to push the field forward, three UCLA researchers, along with scientists from more than 20 countries, have been taking part in one of the largest collaborative efforts in psychiatry — a genome-wide study involving more than 50,000 study participants aimed at identifying which genetic variants make people susceptible to psychiatric disease.

This collaborative, the Psychiatric Genome-Wide Association Study Consortium (PGC), now reports in the current online edition of the journal Nature Genetics that it has discovered that common genetic variants contribute to a person’s risk of schizophrenia and bipolar disorder.

The PGC’s studies provide new molecular evidence that 11 regions on the genome are strongly associated with these diseases, including six regions not previously observed. The researchers also found that several of these DNA variations contribute to both diseases.

The findings, the researchers say, represent a significant advance in understanding the causes of these chronic, severe and debilitating disorders.

The UCLA researchers who contributed to the schizophrenia study are Roel A. Ophoff, a professor of psychiatry and human genetics and one of the founding principal investigators of the schizophrenia portion of the study; Dr. Nelson Freimer, a professor of psychiatry and director of the Center for Neurobehavioral Genetics at the Semel Institute for Neuroscience and Human Behavior at UCLA; and Rita Cantor, a professor of psychiatry and human genetics.

Schizophrenia and bipolar disorder are common and often devastating brain disorders. Some of the most prominent symptoms of schizophrenia are persistent delusions, hallucinations and cognitive problems. Bipolar disorder is characterized by severe, episodic mood swings. Both affect about 1 percent of the world’s population and usually strike in late adolescence or early adulthood.

Despite the availability of treatments, these illnesses are usually chronic, and patients’ response to treatment is often incomplete, leading to prolonged disability and personal suffering. Family history, which reflects genetic inheritance, is a strong risk factor for both schizophrenia and bipolar disorder, and it has generally been assumed that dozens of genes, along with environmental factors, contribute to disease risk.

In the schizophrenia study, a total of seven locations on the genome were implicated in the disease, five of which had not been identified before. When similar data from the bipolar disorder study, which ran concurrently, were combined with results from the schizophrenia study, three gene locations were identified that proved to be involved in both disorders, suggesting a “genetic overlap” between schizophrenia and bipolar disorder.

“Genetic factors play an important role in the susceptibility to develop schizophrenia,” Ophoff said, “but identifying these genetic factors has been very difficult. We know that schizophrenia is not caused by a single gene that explains everything but an interplay of many genetic and non-genetic factors.”

At the same time, he said, the disease itself is not uniform but manifests itself in different ways; currently, there is no objective biological marker or “sign” that can be used for diagnosis.

“This so-called heterogeneity at the genetic and clinical level is the biggest challenge for genetic studies of neuropsychiatric disorders,” Ophoff said. “One way to deal with these difficulties is to increase the size of the study so there is sufficient ‘power’ to detect genetic effects, even amidst this clinical and genetic diversity.”

The fact that even this large study resulted in a limited number of schizophrenia and bipolar genes demonstrates once again, he said, the complex nature of the disease.

The research was funded by numerous European, American and Australian funding bodies. Funds for coordination of the consortium were provided by the National Institute of Mental Health in the U.S.


Sporadic Mutations cause more than half the cases of Schizophrenia

Columbia University Medical Center researchers have shown that new, or “de novo,” protein-altering mutations—genetic errors that are present in patients but not in their parents—play a role in more than 50 percent of “sporadic” —i.e., not hereditary—cases of schizophrenia. The findings will be published online on August 7, 2011, in Nature Genetics.

A group led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD, PhD, examined the genomes of patients with schizophrenia and their families, as well as healthy control groups. All were from the genetically isolated, European-descent Afrikaner population of South Africa.

These findings build on earlier studies by Karayiorgou, professor of psychiatry at Columbia University Medical Center. More than 15 years ago, Karayiorgou and her colleagues described a rare de novo mutation that accounts for 1-2 percent of sporadic cases of schizophrenia. With advances in technology, three years ago the Columbia team was able to search the entire genome for similar lesions that insert or remove small chunks of DNA. The mutations found accounted for about 10 percent of sporadic cases.

Encouraged by their progress, they wondered whether other, previously undetectable, de novo mutations accounted for an even greater percentage of sporadic cases. Using state-of-the-art “deep sequencing,” they examined the nucleotide bases of almost all the genes in the human genome. This time they found 40 mutations, all from different genes and most of them protein-altering. The results point the way to finding more, perhaps even hundreds, of mutations that contribute to the genetics of schizophrenia—a necessary step toward understanding how the disease develops.

“Identification of these damaging de novo mutations has fundamentally transformed our understanding of the genetic basis of schizophrenia,” says Bin Xu, PhD, assistant professor of clinical neurobiology at Columbia University Medical Center and first author of the study.

“The fact that the mutations are all from different genes,” says Karayiorgou, “is particularly fascinating. It suggests that many more mutations than we suspected may contribute to schizophrenia. This is probably because of the complexity of the neural circuits that are affected by the disease; many genes are needed for their development and function.” Karayiorgou and her team will now search for recurring mutations, which may provide definitive evidence that any specific mutation contributes to schizophrenia.

The potentially large number of mutations makes a gene-therapy approach to treating schizophrenia unlikely. Researchers suspect, however, that all of the mutations affect the same neural circuitry mechanisms. “Using innovative neuroscience methods,” says co-author Dr. Joseph Gogos, MD, PhD, and associate professor of physiology and neuroscience at Columbia University Medical Center, “we hope to identify those neural circuit dysfunctions, so we can target them for drug development.”

The study’s results also help to explain two puzzles: the persistence of schizophrenia, despite the fact that those with the disease do not tend to pass down their mutations through children; and the high global incidence of the disease, despite large environmental variations.


The study’s authors are Bin Xu (CUMC), J. Louw Roos (University of Pretoria), Phillip Dexheimer (HudsonAlpha Institute), Braden Boone (HudsonAlpha Institute), Brooks Plummer (HudsonAlpha Institute), Shawn Levy (HudsonAlpha Institute), Joseph A. Gogos (CUMC), and Maria Karayiorgou (CUMC).

The study was supported by NIMH, the Lieber Center for Schizophrenia Research at Columbia University, and NARSAD.

The authors declare no financial conflict of interest.