Gene Combinations Help Predict Treatment Success for Alcoholism Medication

NIH-funded study says five-marker genotype panel can guide ondansetron use

An experimental treatment for alcohol dependence works better in individuals who possess specific combinations of genes that regulate the function and binding of serotonin, a brain chemical affected by the treatment, according to a study supported by the National Institutes of Health.  A report of the finding appears online in the American Journal of Psychiatry.

“This study is another important step toward personalized treatments for alcohol dependence,” says Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which funded the study.  “A personalized approach based on a person’s genetic makeup is increasingly being investigated for delivering optimum treatment to the ‘right’ patient.”

Ondansetron is a medication currently used to treat nausea and vomiting, often following chemotherapy.  It works by blocking serotonin-3 receptors, and has shown potential as a treatment for defined subpopulations with alcohol dependence.

In previous studies, Professor Bankole Johnson, D.Sc., M.D., and his team at the University of Virginia, Charlottesville, have shown that variations in genes that encode the serotonin transporter, a protein that regulates the concentration of serotonin between nerve cells, can significantly influence drinking intensity.  They have also shown that the effectiveness of ondansetron therapy among people with alcohol dependence is influenced by variations of the serotonin transporter gene.

In the current study, Professor Johnson and his colleagues extended their prior work by analyzing variants of serotonin receptor genes, collectively designated as HTR3, among nearly 300 alcohol-dependent individuals who were participating in a clinical trial of ondansetron.  They found that three HTR3 variants were significantly associated with the effectiveness of ondansetron treatment for alcohol dependence.

“Taken together, these studies implicate a collective effect of serotonin receptor and transporter gene combinations, defined by a five-marker genotype panel, on the response to treatment with ondansetron for a genetically defined subpopulation of individuals with alcohol dependence,” says Professor Johnson.  “Multi-site, larger studies are about to begin to progress this work.”


About the National Institute on Alcohol Abuse and Alcoholism (NIAAA):

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at

About the National Insututes of Health (NIH):

NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit


Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT3 antagonist ondansetron. Johnson, BA, et al. American Journal of Psychiatry. 2013 July 30. [Epub ahead of print]

Recovery After an Initial Schizophrenia Episode (RAISE): A Research Project of the NIMH

RAISE logoRecovery After an Initial Schizophrenia Episode (RAISE) is an NIMH research project that seeks to fundamentally change the trajectory and prognosis of schizophrenia through coordinated and aggressive treatment in the earliest stages of illness. RAISE is designed to reduce the likelihood of long-term disability that people with schizophrenia often experience. It aims to help people with the disorder lead productive, independent lives. At the same time, it aims to reduce the financial impact on the public systems often tapped to pay for the care of people with schizophrenia.

NIMH has awarded separate contracts to two independent research teams to develop interventions that can be tested in real-world treatment settings and be readily adopted and quickly put into practice should they prove successful. The contract awards, bolstered by funds from the American Recovery and Reinvestment Act of 2009, have been awarded to: the Feinstein Institute for Medical Research (Principal Investigator, John M. Kane, M.D.) in Manhasset, NY, and to the Research Foundation for Mental Hygiene at Columbia University (Principal Investigator, Lisa Dixon M.D.) in New York City.

The team led by Dr. Kane has developed the RAISE Early Treatment Program, a research study which will be conducted in community clinics across the United States. The team led by Dr. Dixon has developed the RAISE Connection Program, a research study which will be conducted at community clinics in partnership with the Maryland and New York state mental health systems.

Treatment models being tested focus on intervening as soon as possible after the first episode of schizophrenia. Each model integrates medication, psychosocial therapies, family involvement, rehabilitation services, and supported employment, all aimed at promoting symptom reduction and improving life functioning.

While the studies have similar goals and will each be conducted in diverse, real-world health care settings, they differ in research methodology, the nature and location of clinical sites, the organization of intervention teams, specific services being offered, and how services will be reimbursed or paid for. Taken together, the results of these complementary studies will inform the most effective strategies for improving the recovery of functioning and quality of life for people affected with schizophrenia.

–National Institute of Mental Health (NIMH)

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Schizophrenia, Bipolar Disorder Share the Most Common Genetic Variation

The largest genome-wide study of its kind has determined how much five major mental illnesses are traceable to the same common inherited genetic variations. Researchers funded in part by the National Institutes of Health found that the overlap was highest between schizophrenia and bipolar disorder; moderate for bipolar disorder and depression and for ADHD and depression; and low between schizophrenia and autism. Overall, common genetic variation accounted for 17-28 percent of risk for the illnesses.

“Since our study only looked at common gene variants, the total genetic overlap between the disorders is likely higher,” explained Naomi Wray, Ph.D., University of Queensland, Brisbane, Australia, who co-led the multi-site study by the Cross Disorders Group of the Psychiatric Genomics Consortium (PGC), which is supported by the NIH’s National Institute of Mental Health (NIMH). “Shared variants with smaller effects, rare variants, mutations, duplications, deletions, and gene-environment interactions also contribute to these illnesses.”

Dr. Wray, Kenneth Kendler, M.D., of Virginia Commonwealth University, Richmond, Jordan Smoller, M.D., of Massachusetts General Hospital, Boston, and other members of the PGC group report on their findings August 11, 2013, in the journal Nature Genetics.

“Such evidence quantifying shared genetic risk factors among traditional psychiatric diagnoses will help us move toward classification that will be more faithful to nature,” said Bruce Cuthbert, Ph.D., director of the NIMH Division of Adult Translational Research and Treatment Development and coordinator of the Institute’s Research Domain Criteria (RDoC) project, which is developing a mental disorders classification system for research based more on underlying causes.

Earlier this year, PGC researchers – more than 300 scientists at 80 research centers in 20 countries – reported the first evidence of overlap between all five disorders. People with the disorders were more likely to have suspect variation at the same four chromosomal sites. But the extent of the overlap remained unclear. In the new study, they used the same genome-wide information and the largest data sets currently available to estimate the risk for the illnesses attributable to any of hundreds of thousands of sites of common variability in the genetic code across chromosomes. They looked for similarities in such genetic variation among several thousand people with each illness and compared them to controls – calculating the extent to which pairs of disorders are linked to the same genetic variants.

The overlap in heritability attributable to common genetic variation was about 15 percent between schizophrenia and bipolar disorder, about 10 percent between bipolar disorder and depression, about 9 percent between schizophrenia and depression, and about 3 percent between schizophrenia and autism.

The newfound molecular genetic evidence linking schizophrenia and depression, if replicated, could have important implications for diagnostics and research, say the researchers. They expected to see more overlap between ADHD and autism, but the modest schizophrenia-autism connection is consistent with other emerging evidence.

The study results also attach numbers to molecular evidence documenting the importance of heritability traceable to common genetic variation in causing these five major mental illnesses. Yet this still leaves much of the likely inherited genetic contribution to the disorders unexplained – not to mention non-inherited genetic factors. For example, common genetic variation accounted for 23 percent of schizophrenia, but evidence from twin and family studies estimate its total heritability at 81 percent. Similarly, the gaps are 25 percent vs. 75 percent for bipolar disorder, 28 percent vs. 75 percent for ADHD, 14 percent vs. 80 percent for autism, and 21 percent vs. 37 percent for depression.

Among other types of genetic inheritance known to affect risk and not detected in this study are contributions from rare variants not associated with common sites of genetic variation. However, the researchers say that their results show clearly that more illness-linked common variants with small effects will be discovered with the greater statistical power that comes with larger sample sizes.

“It is encouraging that the estimates of genetic contributions to mental disorders trace those from more traditional family and twin studies. The study points to a future of active gene discovery for mental disorders” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funds the project.

SNP-based Coheritibilities

Common inherited genetic variation (single nucleotide polymorphisms, or SNPs) accounted for up to about 28 percent of the risk for some disorders, such as ADHD (dark green). Among pairs of disorders (light green), schizophrenia and bipolar disorder (SCZ-BPD) shared about 16 percent of the same common genetic variation (coheritabilities).
Source: Cross-Disorder Group of the Psychiatric Genomics Consortium


Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics, August 11, 2013


R01MH065562, R01MH43518, R01MH065554, R01MH65707,
R01MH065571, R01MH65588, R01MH65578, R01MH65558


The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Aug. 28-30th: Ask Dr. Vikaas Sohal about the Brain in Schizophrenia

Understanding Dopamine’s Role in Schizophrenia

Psychosis can be a singularly terrifying and bewildering experience. Doctors have known for decades that blocking dopamine receptors is an effective pharmaceutical means to remedy psychosis, but the question remains open—why? How is dopamine involved in schizophrenia?

One scientist beginning to find answers is the dynamic Dr. Vikaas Sohal, IMHRO Assistant Professor of Psychiatry at UCSF. For instance, his recent discoveries suggest that too much dopamine input to a specific type of neuron in the prefrontal cortex may overgenerate specific patterns of electrical activity and thus may contribute to schizophrenia’s disorganized behavior.

Dr. Sohal is an ace at explaining the brain, and loves to do so. Watch his new Brain Waves interview, and then, you can log in and ask him questions of your own. He will respond to questions from Wednesday, August 28 through Friday, August 30, 2013.

Watch Interview and Ask Questions

When Philosophy Meets Psychiatry

Dr. Jacqueline Owen said that the talk offered a new way to think about a problem she often encountered in her work. “I’m on a ward with teenagers — boys and girls — who complain of hearing voices,” she said. “So how do I discriminate between the ones who are really having hallucinations and those who are just listening to their own thoughts? Perhaps what we need to do is step back and think about what they are experiencing in the first place. Philosophy can provide a way into that — something that isn’t a gene, or a drug, but that can still be useful.”

“Psychiatry crosses domains,” Dr. Gareth Owen said. “So it is important that the people who do it can cross domains as well. Our aim with the seminar is to provide a kind of third space — outside academic psychiatry or clinical practice or academic philosophy.”

“It gives the philosophers a chance to get out into the world a bit,” he continued. “And I’ve found it helps me both in my research and in my clinical practice. It’s a way of reminding myself to keep the whole patient in mind.”

By D. D. Guttenplan, The New York Times

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Psychotic Symptoms, Not Antipsychotic Medication, Linked to Institutionalization, Death in Alzheimer’s Patients

It is the presence of psychiatric symptoms, including psychosis and agitation, not the use of antipsychotic medications that appears to raise the risk for institutionalization or death among patients with Alzheimer’s disease (AD), according to a new study published in AJP in Advance.

….A higher proportion of patients exposed to antipsychotic medications, especially conventional antipsychotics, were admitted to a nursing home or died compared with those who never took these medications, but the association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with nursing home admission and time to death, but neither conventional nor atypical antipsychotics were associated with time to death.

–Psychiatric News Alert

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After Newtown: The Existing Federal Mental-Health Agency Actually Opposes Efforts to Treat Mental Illness

In January 2011, Jared Loughner killed six and injured 13, including Representative Gabrielle Giffords, in Tucson. In July 2012, James Holmes killed twelve and injured 70 in Aurora, Colo. And in December 2012, Adam Lanza killed 27 in Newtown, Conn. All of these tragedies were carried out by perpetrators who had an untreated severe mental illness, and President Obama and the nation in general now seem to realize that America has a major problem with untreated severe mental illness. Following Newtown, Obama promised to make “access to mental health care as easy as access to guns.”

Obama’s first step was to set up a task force under Vice President Biden to make recommendations. Biden, in turn, asked the lead government agency on mental-health services for direction. That agency, the Substance Abuse and Mental Health Services Administration (SAMHSA), is a $3.1 billion component of the Department of Health and Human Services. SAMHSA’s official mission is to reduce “the impact of substance abuse and mental illness on America’s communities.” The only problem is that SAMHSA knows nothing about severe mental illness and, indeed, is not even certain that it believes such illnesses exist.

By E. Fuller Torrey and D.J. Jaffe, National Review

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Brain Ultrasound Can Elevate Mood

Ultrasound waves sent to specific brain regions can alter a person’s mood, according to a new study published in the journal Brain Stimulation. The research, conducted by University of Arizona researchers, has led to further investigations with the hope that this procedure could one day be used to treat mental disorders such as depression and anxiety.

….Hameroff wanted to try ultrasound treatment for mood in human brains.

“I said to my anesthesiology colleagues, ‘we should try this on chronic pain patient volunteers’,” he said.

His colleagues respectfully suggested he try it on himself first. Hameroff agreed.

He placed an ultrasound transducer against his head for 15 seconds and felt no effect.

“I put it down and said, ‘well, that’s not going to work.’ And then about a minute later I started to feel like I’d had a martini,” he said.

–Magpie Media

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Research Participants Needed: Tardive Dyskinesia and Schizophrenia/Schizoaffective

Kinect 2 Study

Kinect2Study logoTardive dyskinesia – or TD – is a neurological disorder resulting in involuntary, repetitive body movements. It can be the result of long-term or high-dose use of certain medications. These involuntary movements can include grimacing, tongue protrusion, lip smacking, and rapid eye blinking. Involuntary movements of the limbs, torso, fingers, and toes may also occur.

Whether or not you’ve been formally diagnosed with TD, we invite you to learn more about the Kinect 2 Study.

We invite those 18 to 85 years old who are experiencing involuntary movements in their face or other parts of their body – and suffer from schizophrenia or schizoaffective disorder – to see if they may qualify for the Kinect 2 Study. The purpose of this clinical research study is to determine the safety and effectiveness of an investigational oral medication for tardive dyskinesia.

Each individual will be evaluated to determine his or her eligibility. Those who qualify will receive study medication, study-related medical exams, and lab tests at no charge. Compensation for time and travel may also be available.

Upon enrollment in the study, participants will be required to complete a screening period prior to receiving their first dose of study medication and a study treatment period of up to 6 weeks (which includes three in-office visits and a follow-up appointment two weeks after completing treatment). Throughout the study, participants will continue to receive regular general health check-ups and monitoring of TD symptoms.

Learn More