Category: Psychiatry

— Infants born prematurely are at risk for injuries to the white and gray matter of the brain that affect cortical development and neural connectivity. Certain forms of these injuries can be detected in the neonatal period using ultrasound, according to Columbia University Medical Center researchers.

Researchers who followed a group of premature infants until age 16 found that those with neonatal ultrasound abnormalities were at increased risk for specific psychiatric disorders, namely, attention deficit hyperactivity, tic disorders, obsessive compulsive disorder, and major depression―all of which are thought to arise from dysfunctions of the subcortical-cortical circuits. The findings were published in the July 2011 issue of the Archives of General Psychiatry.

Premature birth is a growing problem in the United States, adding to the significance of the findings. An increased appreciation of the relation between perinatal brain injuries and later psychiatric disorders could lead to earlier diagnosis and intervention by the pediatricians, psychiatrists, and neurologists who care for these children and adolescents. Future research may also explore the relation of perinatal brain injury to psychiatric disorders, such as schizophrenia, that more commonly come to clinical attention in adulthood

A research group at Columbia University Medical Center/New York State Psychiatric Institute led by Dr. Agnes Whitaker, MD, evaluated more than 400 nondisabled adolescents who had been born prematurely and had had abnormal brain ultrasounds taken at birth. When the researchers administered questionnaires and cognitive tests to the subjects and interviewed their parents, they found a relation between perinatal brain injuries and certain psychiatric disorders at adolescence that could not be explained by other medical or social factors.

Although scientists have speculated for decades that early brain injury can have long-term psychiatric effects, these results provide the first strong empirical evidence of such a relation. "The study," says Whitaker, a clinical professor of psychiatry in the Department of Psychiatry at Columbia University and research psychiatrist in the Division of Child and Adolescent Psychiatry at New York State Psychiatric Institute, "is a beautiful example of interdisciplinary work. The team included researchers from neonatology, pediatrics, psychiatry, and epidemiology. It couldn't have been done otherwise."

The study's authors are Agnes H. Whitaker (CUMC and NYSPI), Judith F. Feldman (CUMC and NYSPI), John M. Lorenz (CUMC), Fiona McNicholas (University Hospital Dublin), Prudence W. Fisher (CUMC and NYSPI), Sa Shen (CUMC and NYSPI), Jennifer Pinto-Martin (University of Pennsylvania), David Shaffer (CUMC and NYSPI), and Nigel Paneth (Michigan State University).

Compared to other common psychiatric disorders, the diagnostic reliability of alcohol dependence (AD) as determined by the Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition (DSM-IV) is relatively high. However, when members of the general public are asked to report on past experiences or lifetime history (LTH) of psychiatric or substance use disorders, associations are often unreliable and underestimated. A new study looking at the reliability of, as well as the influence of genetic and environmental influences on, DSM-IV LTH-AD in a population-based sample has found that a diagnosis based upon a single diagnostic interview is reasonably reliable.

Results will be published in the September 2011 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"People are inaccurate when interviewed about their history of psychiatric symptoms," observed Eivind Ystrom, a researcher at the Norwegian Institute of Public Health and corresponding author for the study. "The most obvious reason for this is that people just don't recall when prompted. Thus, by interviewing people several times about the same disorder it is possible to estimate to what extent people are inaccurate."

"This study is unique in that Ystrom and his colleagues report that certain variables, including a specific AD criterion, robustly predict the reliability of the diagnosis," said Alexis Edwards, a postdoctoral fellow at the Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University. "Obviously, all of the symptoms are, at some level, predictive of the disorder; but that some are more useful than others at identifying a reliable diagnosis is interesting."

The researchers examined a population-based sample of male twins in Virginia (n=4,203) who had been assessed for LTH-AD on two different occasions one year apart (i.e., each pair of twins was assessed twice, at about the same ages, one year apart). Logistic regression was used to identify clinical features that might predict a reliable diagnosis. Genetic and environmental influences were also examined.

"The first key finding was that men who are diagnosed with LTH-AD using a clinical interview tend to have many symptoms of AD, they have at some point in their life sought treatment for their AD, their period of life with AD lasted a long time, or they spent much time on obtaining alcohol or recovering from alcohol use," said Ystrom. "The second key finding was that, after taking into account that people are inaccurate when reporting psychiatric symptoms, the heritability of LTH-AD was estimated to be 71 percent. Or, put another way, 71 percent of the causes as to why some people in the general population become AD, while others do not, were genetic."

"This higher heritability of the LTH-AD phenotype, a bit higher than we might have expected, confirms the importance of genetic influences," added Edwards. "Furthermore, while the reliability of the diagnosis itself is moderate, results show that we can potentially increase our confidence in the diagnosis by taking into account a few specific variables."

"Since the study identifies which characteristics are associated with a reliable diagnosis," said Ystrom, "these characteristics can be used to enhance the reliability of single measures of LTH-AD. In addition, although psychometric theory states that the heritability should go up as the diagnostic reliability goes up, this study describes the phenomenon empirically. Finally, by estimating the heritability of LTH-AD to 71 percent, the study moves AD into a class of disorders that are highly dependent on genes, such as schizophrenia or bipolar disorder."

Both Ystrom and Edwards see practical implications from these findings for various audiences.

"Researchers often want to know what characterizes people with a disorder," said Ystrom. "If the diagnoses of the cases in their sample are inaccurate, they will be less able to correctly describe the characteristics of the people with the disorder."

"Clearly clinicians would be interested in reliable diagnoses because of their goal of providing appropriate treatment for patients," said Edwards. "Clinicians need to be confident that a patient truly has a disorder before embarking on a treatment program, whether that involves counseling, pharmaceutical treatment, or something else."

"However, the finding that LTH-AD is a disorder which is to a great extent dependent on genes, is also important to the public," said Ystrom. "Some people might view AD purely as a matter of will. Since most people in the western world use alcohol regularly, but only a few become dependent on it, it is significant to know that much of the reason why this happens to people is because of individual genetic vulnerability. Genetic vulnerability is not a demerit." Edwards concurs. "Most people know someone who has struggled with alcohol problems, and this report underscores the fact that the disorder is very complicated, and is a function of both biology and the environment. While some of the nuances of the report might be too technical to be relevant to someone not involved in this research, the general findings are still of broad interest simply because AD affects so many people, directly or indirectly."

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Journal Reference:

1. Eivind Ystrom, Ted Reichborn-Kjennerud, Steven H. Aggen, Kenneth S. Kendler. Alcohol Dependence in Men: Reliability and Heritability. Alcoholism: Clinical and Experimental Research, 2011; DOI: 10.1111/j.1530-0277.2011.01518.x

— Johns Hopkins Children's Center scientists have found that having a regular outpatient mental health provider may not be enough to prevent children and teens with behavioral problems from repeatedly ending up in the emergency room.

The study is published in the June 1 issue of the journal Psychiatric Services.

Analyzing more than 2,900 records of pediatric patients, ages 3 to 17, treated at the Hopkins Children's ER for mental health crises over eight years, the investigators found that 338 of them (12 percent) returned to the ER within six months of their initial visit. The majority of the ER visits stemmed from behavioral problems or minor psychiatric crises, such as disruptive classroom behavior, verbal altercations and running away, the researchers said. Only a few involved severe psychotic episodes (3 percent of the visits) or suicide attempts (10 percent). Most importantly, the researchers found, two-thirds of patients (220) reported having an outpatient mental health provider at both visits, and 288 (85 percent) reported at the second visit that they have a regular mental health provider.

The findings are concerning, the researchers said, because they may signal that patients are not actually getting the care they need on an outpatient basis.

Mental health experts have traditionally emphasized the importance of outpatient care in managing non-emergency cases and have urged connecting such patients to outpatient mental health programs. Most ERs are neither designed nor staffed to deliver effective, coordinated mental health care, the investigators said.

"We think of the ER as a 'front door to care,' but our findings suggest otherwise as a significant number of patients repeatedly seek care in the ER despite being connected to an outpatient provider," said lead author Emily Frosch, M.D., a pediatric psychiatrist at Hopkins Children's.

The findings, Frosch said, raise more questions than they answer, and researchers have only begun to untangle the complex reasons behind recurrent ER visits for non-emergency psychiatric problems.

"We need to understand why families who are already connected to outpatient providers continue to seek ER care, why providers send patients to the ER and what role, if any, ERs may play in the continuum of care for non-psychotic, non-suicidal patients," Frosch said. "It is possible that ERs fulfill an important function in that continuum for some patients."

The researchers said one possible explanation is that patient families face barriers to routine outpatient psychiatric care, including limited office hours. Families who have had a positive experience in the ER in the past may be simply choosing to return there for subsequent problems, the researchers say. Also, some families may also find ER care less stigmatizing than outpatient mental health services. Frosch added that ER visits may be driven by some outpatient providers who may not have sufficient resources for optimal care and instead send patients to the ER.

The Hopkins team said future studies should explore more specifically the link between outpatient care and ER visits.

"Perhaps the most critical questions to ask are 'When was the child's latest outpatient visit?' and 'What exactly transpired between that visit and their subsequent trip to the ER?'" Frosch said.

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Journal Reference:

1. Emily Frosch, Susan dosReis, and Kate Maloney. Connections to Outpatient Mental Health Care of Youths With Repeat Emergency Department Visits for Psychiatric Crises. Psychiatric Services, 2011; 62: 646-649 DOI: 10.1176/appi.ps.62.6.646

Analysis of data from two long-term studies of the impact of attention-deficit hyperactivity disorder (ADHD) on the development of psychiatric disorders in young adults confirms that ADHD alone significantly increases the risk of cigarette smoking and substance abuse in both boys and girls.

The report from a team of Massachusetts General Hospital (MGH) investigators will appear in the Journal of the American Academy of Child & Adolescent Psychiatry and has been released online.

"Our study, which is one of the largest set of longitudinal studies of this issue to date, supports the association between ADHD and substance abuse found in several earlier studies and shows that the increased risk cannot be accounted for by co-existing factors such as other psychiatric disorders or family history of substance abuse," says Timothy Wilens, MD, of the MGH Pediatric Psychopharmacology Unit, who led the study. "Overall, study participants diagnosed with ADHD had a one and a half times greater risk of developing substance abuse than did control participants."

While previous studies from investigators at MGH and elsewhere found an increased risk of substance abuse in adolescents and young adults with ADHD, questions have been raised about whether specific aspects of ADHD such as impulsive behavior, cognitive problems, school problems, accompanying conditions such as bipolar disorder or conduct disorder, or family factors were actually responsible for the risk. To get a clearer picture of the factors behind the increased risk, the researchers examined data from two previous studies — one of boys, one of girls — that analyzed the prevalence of a broad range of psychiatric and behavioral disorders in participants diagnosed with ADHD as children.

From those two studies, a decade of more of follow-up information was available for a total of 268 participants with ADHD and 220 control participants, both groups equally divided by gender. Among the ADHD participants, 32 percent developed some type of substance abuse, including cigarette smoking, during the follow-up period, while only 25 percent of control participants had substance abuse problems. Factors such as gender, cognitive difficulties, mood disorders, school problems or family history of substance abuse did not impact the risk. The only additional diagnosis that had an effect was conduct disorder, which tripled the risk when combined with ADHD.

"Anyone with ADHD needs to be counseled about the risk for substance abuse, particularly if they have any delinquency," explains Wilens. "We still need to understand why some kids with ADHD develop substance abuse and others don't, whether particular treatment approaches can prevent substance problems and how best to treat young adults that have both ADHD and substance abuse." Wilens is an associate professor of Psychiatry at Harvard Medical School.

Additional authors of the JAACAP report are MaryKate Martelon, MPH; Gagan Joshi, MD; Clancey Bateman; Ronna Fried, EdD; Carter Petty, MA, and Joseph Biederman, MD, all of the MGH Pediatric Psychopharmacology Unit. The study was supported by grants from the National Institutes of Health, the Eli Lilly and Company Foundation and the MGH Pediatric Psychopharmacology Philanthropy Fund.

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Journal Reference:

1. Timothy E. Wilens, MaryKate Martelon, Gagan Joshi, Clancey Bateman, Ronna Fried, Carter Petty, Joseph Biederman. Does ADHD Predict Substance-Use Disorders? A 10-Year Follow-up Study of Young Adults With ADHD. Journal of the American Academy of Child & Adolescent Psychiatry, 2011; DOI: 10.1016/j.jaac.2011.01.021

Researchers at the University of Pittsburgh School of Medicine have developed a mouse model of major depressive disorder (MDD) that is based on a rare genetic mutation that appears to cause MDD in the majority of people who inherit it. The findings, which were published online May 19 in the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics EarlyView, could help to clarify the brain events that lead to MDD, and contribute to the development of new and better means of treatment and prevention. This report also illustrates an advance in the design of recombinant mouse models that should be applicable to many human diseases.

"Major depressive disorder is a leading cause of suffering, disability and premature death from all causes including suicide. While the cause currently is unknown, twin and adoption studies indicate that genetic factors account for 40 to 70 percent of the risk for developing this common disorder," explained lead author George Zubenko, M.D., Ph.D., professor of psychiatry, Pitt School of Medicine.

"In this report, we describe how we constructed a laboratory mouse strain that mimics the brain mechanism that leads to major depression in humans, rather than symptoms," he said. "Nonetheless, in our initial characterization, the mutant mice exhibited several features that were reminiscent of the human disorder, including alterations of brain anatomy, gene expression, behavior, as well as increased infant mortality."

"These findings support the role of the genetic variant in the development of MDD, and affirm the mutant mouse strain as a model of MDD worthy of further study," Dr. Zubenko said. Hugh B. Hughes, III, M.S., served as the co-author of this report.

Previous studies of families with a severe and strongly familial form of MDD revealed a mutation in the control region of CREB1, a gene that orchestrates the expression of many other genes that play important roles in normal brain functioning. Mice have a CREB1 gene that is very similar to the human version and, with the aid of genetic engineering techniques, the researchers were able to establish a mutant mouse strain that bore the same genetic error. Since the control regions of corresponding human and mouse genes often have regions of high similarity, the methods described in this report may be useful in creating mouse models of other human diseases.

"Treatments that are the most effective and produce the fewest side effects typically address the root causes of the disease," Dr. Zubenko noted. "Animal models that recapitulate those root causes should better inform us about the brain mechanisms that lead to MDD, and have the best chance of leading to advances in treatment and prevention."

This work was supported by grants from the National Institute of Mental Health; and the Provost's Fund for Research Development and the Shane Richard Brown Fund, both of the University of Pittsburgh. MRI data were collected at the Pittsburgh NMR Center for Biomedical Research at Carnegie Mellon University and were analyzed with support from the Office of the Senior Vice Chancellor for the Health Sciences, University of Pittsburgh, and the National Center for Research Resources, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research.

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Journal Reference:

1. George S. Zubenko, Hugh B. Hughes. Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2011; DOI: 10.1002/ajmg.b.31197

 Anorexia nervosa is more common among people born in the spring, a new study led by Oxford University scientists has found.

The researchers writing in the British Journal of Psychiatry say their study — which is the largest to date — provides 'clear evidence' of a season-of-birth effect in anorexia.

The research team, led by Dr Lahiru Handunnetthi of the Wellcome Trust Centre for Human Genetics at Oxford University, compared the birth dates of 1,293 patients with anorexia to those of the general population.

They found an excess of anorexia births between March and June, and a deficit from September to October.

Although some previous studies have suggested a link between season of birth and eating disorders, these involved much smaller numbers of patients and did not reach statistical significance.

'We meta-analysed four cohorts of anorexia nervosa patients from the UK, making this the largest ever study to assess the presence of a season-of-birth effect in anorexia,' said Dr Handunnetthi. 'We found that susceptibility to anorexia nervosa is significantly influenced by a person's season of birth, being higher in those people born in the spring and lower in those born in the autumn.'

Dr Handunnetthi added: 'A number of previous studies have found that mental illnesses such as schizophrenia, bipolar disorder and major depression are more common among those born in the spring — so this finding in anorexia is perhaps not surprising.

'However, our study only provides evidence of an association. Now we need more research to identify which factors are putting people at particular risk.'

The researchers believe that environmental factors around the time of conception or when the baby is developing in the womb may be responsible.

Dr Handunnetthi explained: 'Seasonal changes in temperature, sunlight exposure and vitamin D levels, maternal nutrition and exposure to infections are all possible risk factors. Identifying these risk factors is important in helping us understand and maybe even prevent illness in future.'

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Journal Reference:

1. G. Disanto, A. E. Handel, A. E. Para, S. V. Ramagopalan, L. Handunnetthi. Season of birth and anorexia nervosa. The British Journal of Psychiatry, 2011; DOI: 10.1192/bjp.bp.110.085944

The evidence base for the prescribing of aripiprazole in maintenance treatment of bipolar disorder is limited to a single trial, sponsored by the manufacturer of aripiprazole, according to a rigorous appraisal of the evidence for its use led jointly by Alexander Tsai of Harvard University, Boston USA, and Nicholas Rosenlicht of the University of California San Francisco, USA. In the paper, published in PLoS Medicine, the authors describe key limitations of the trial, which were not identified in most subsequent review articles and guidelines for the treatment of bipolar disorder in which the trial was cited.

Bipolar disorder (also known as manic depression) is a common and serious psychiatric illness. Individuals with bipolar disorder experience mood swings with manic episodes (where they may feel euphoric, restless, and behave impulsively), along with depressive episodes where they may feel low, worthless, and suicidal. Aripiprazole is a second-generation antipsychotic medication and the newest of such drugs to have received approval by the US Food and Drug Administration (FDA) for use both in treatment of acute episodes and, more recently, for maintenance therapy.

Drs. Tsai and Rosenlicht and their colleagues conducted a systematic search to find all published and unpublished studies relating to use of aripiprazole for maintenance therapy of bipolar disorder, including a request to the FDA under Freedom of Information Act legislation. They critically appraised this evidence and then used citation searches to examine how the primary evidence was subsequently referenced in the medical literature. The authors found only a single trial describing the use of aripiprazole during the maintenance phase of bipolar disorder. Further, they found significant limitations of this trial that constrain its interpretation as supporting the use of aripiprazole for this indication. First, the trial duration was too short to show that the drug was truly helpful in maintaining initial benefit or preventing mood swings over the long term. Second, very few participants in the trial completed the entire study. Third, the trial was based on a select minority of subjects who had shown an initial response to the drug, making it difficult to extrapolate these findings to patients with bipolar disorder more widely. Fourth, the trial had a design whereby patients assigned to placebo were abruptly taken off aripiprazole treatment given to them during a previous "run-in" phase and reassigned to placebo; differences in risk of relapse seen between trial arms may thus also reflect the potentially harmful effects of rapid drug withdrawal in patients given placebo.

Despite these shortcomings, the authors found that this single trial was subsequently cited by 104 review articles and treatment guidelines, with very few mentioning the study's limitations.

The authors comment that "…alternative modifications or study designs may improve the probability of generating more useful data from studies in this vulnerable patient population to inform the treatment of similar patients in the future."

Patients (or their family members) who may learn of this study's findings are urged to contact their physician if concerned about what these findings may mean for their treatment. Specifically, the findings do not mean patients should cease their medication; despite the limitations of the evidence described here, this drug may be helpful to them. In addition, the study did not assess the evidence for the use of aripiprazole in acute treatment of bipolar disorder.

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Journal Reference:

1. Alexander C. Tsai, Nicholas Z. Rosenlicht, Jon N. Jureidini, Peter I. Parry, Glen I. Spielmans, David Healy. Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature. PLoS Medicine, 2011; 8 (5): e1000434 DOI: 10.1371/journal.pmed.1000434

Taking two medications for depression does not hasten recovery from the condition that affects 19 million Americans each year, researchers at UT Southwestern Medical Center have found in a national study.

"Clinicians should not rush to prescribe combinations of antidepressant medications as first-line treatment for patients with major depressive disorder," said Dr. Madhukar H. Trivedi, professor of psychiatry and chief of the division of mood disorders at UT Southwestern and principal investigator of the study, which is available online May 2 and is scheduled for publication in an upcoming issue of the American Journal of Psychiatry.

"The clinical implications are very clear — the extra cost and burden of two medications is not worthwhile as a first treatment step," he said.

In the Combining Medication to Enhance Depression Outcomes, or CO-MED, study, researchers at 15 sites across the country studied 665 patients ages 18 to 75 with major depressive disorder. Three treatment groups were formed and prescribed antidepressant medications already approved by the Food and Drug Administration. One group received escitalopram (a selective serotonin reuptake inhibitor, or SSRI) and a placebo; the second group received the same SSRI paired with bupropion (a non-tricyclic antidepressant); and a third group took different antidepressants: venlafaxine (a tetracyclic antidepressant) and mirtazapine (a serotonin norepinephrine reuptake inhibitor). The study was conducted from March 2008 through February 2009.

After 12 weeks of treatment, remission and response rates were similar across the three groups: 39 percent, 39 percent and 38 percent, respectively, for remission, and about 52 percent in all three groups for response. After seven months of treatment, remission and response rates across the three groups remained similar, but side effects were more frequent in the third group.

Only about 33 percent of depressed patients go into remission in the first 12 weeks of treatment with antidepressant medication, as Dr. Trivedi and colleagues previously reported from the Sequenced Treatment Alternatives to Relieve Depression, or STAR*D, study. STAR*D was the largest study ever undertaken on the treatment of major depressive disorder and is considered a benchmark in the field of depression research. That six-year, $33 million study initially included more than 4,000 patients from sites across the country. Dr. Trivedi was a co-principal investigator of STAR*D.

The next step, Dr. Trivedi said, is to study biological markers of depression to see if researchers can predict response to antidepressant medication and, thus, improve overall outcomes.

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Journal Reference:

1. A. John Rush, Madhukar H. Trivedi, Jonathan W. Stewart, Andrew A. Nierenberg, Maurizio Fava, Benji T. Kurian, Diane Warden, David W. Morris, James F. Luther, Mustafa M. Husain, Ian A. Cook, Richard C. Shelton, Ira M. Lesser, Susan G. Kornstein, and Stephen R. Wisniewski. Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-Term Outcomes of a Single-Blind Randomized Study. Am J Psychiatry, May 2, 2011 DOI: 10.1176/appi.ajp.2011.10111645

Researchers at the Center for Translational Social Neuroscience (CTSN) at Emory University are focusing on prairie voles as a new model to screen the effectiveness of drugs to treat autism.

They are starting with D-cycloserine, a drug Emory researchers have shown enhances behavioral therapy for phobias and also promotes pair bonding among prairie voles. Giving female voles D-cycloserine, which is thought to facilitate learning and memory, can encourage them to bond with a new male more quickly than usual.

The results are published online and will appear in a future issue of Biological Psychiatry.

"The prairie vole model has enabled us to learn about complex neural pathways in social areas of the brain," says senior author Larry Young, PhD. We believe these insights will be useful in identifying drugs that enhance social cognition and learning. Drugs with these properties, particularly when combined with behavioral therapies, may be beneficial in the treatment of autism spectrum disorders."

Young is division chief of Behavioral Neuroscience and Psychiatric Disorders at the Yerkes National Primate Research Center, William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine and director of the Emory CTSN (www.ctsn.emory.edu).

He and his colleagues have been studying the prairie vole for more than 15 years as a model to explore the neurobiology of prosocial behaviors, including cooperation, compassion, bonding and social reciprocity. Now, they are hoping to identify drugs that can enhance social learning in individuals with autism spectrum disorders, and they think the process of pair bonding in the prairie vole may be a useful tool for identifying new therapies.

The prairie vole is one of the few species in nature that is monogamous and that creates deep social bonds while mating, Young says. The basic mechanisms of voles' and humans' social learning are similar enough that the learning that occurs during voles' pair bonding can model complex human social interactions, he says. Young and his colleagues have used voles to show the importance for social interactions of hormones such as oxytocin, which has also been proposed as a treatment for autism spectrum disorders.

The first author of the paper is Emory graduate student Meera Modi. She showed that D-cycloserine promotes pair bonding in prairie voles when it is injected peripherally. By infusing the drug directly into specific regions of the brain, she also showed the importance of two regions linked to social learning and reward, the nucleus accumbens and amygdala.

"We think D-cycloserine interacts with the brain's social information processing circuits to enhance the natural learning processes that occur there," Modi says.

With voles, the "partner preference paradigm" works like this: sexually naïve females are placed with sexually experienced males for six hours of cohabitation. The females are not ovulating and no mating occurs. Normally, pair-bonding requires more time — 24 hours — and mating is necessary.

Later, the females are given a choice between spending time with the newly familiar male and a stranger; researchers then measure how much time they spend with each male over the next three hours. When a low dose of the drug D-cycloserine is injected at the start of cohabitation, the female prefers the familiar male by a factor of at least four. Without the drug, the female doesn't markedly prefer either male.

Emory researchers have shown D-cycloserine can be used to treat psychiatric diseases such as phobias and social anxiety. It is now in clinical trials for treatment of post-traumatic stress disorder. D-cycloserine is thought to enhance learning by acting on receptors for the neurotransmitter glutamate.

Autism spectrum disorders affect one in 110 children in the United States, according to the Centers for Disease Control and Prevention. Currently there are no drugs that specifically target social deficits found in individuals with autism, Young notes. Most drugs now prescribed for individuals with autism were originally developed for other disorders such as depression or schizophrenia.

The research was supported by a fellowship from Autism Speaks and by the National Institutes of Health.

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Journal Reference:

1. Meera E. Modi, Larry J. Young. D-Cycloserine Facilitates Socially Reinforced Learning in an Animal Model Relevant to Autism Spectrum Disorders. Biological Psychiatry, 2011; DOI: 10.1016/j.biopsych.2011.01.026

A new study reveals a novel gene associated with major depression. The research, published in the April 28 issue of the journal Neuron, suggests a previously unrecognized mechanism for major depression and may guide future therapeutic strategies for this debilitating mood disorder.

Major depression is a psychiatric disorder that is responsible for a substantial loss in work productivity and can even lead to suicide in some individuals. "Current treatments for major depression are indispensible but their clinical efficacy is still unsatisfactory, as reflected by high rates of treatment resistance and side effects," explains study author Dr. Martin A. Kohli from the Max Planck Institute of Psychiatry in Munich, Germany. "Identification of mechanisms causing depression is pertinent for discovery of better antidepressants."

While is likely that a combination of genetic and environmental risk factors contribute to major depression, identification of risk-conferring genes has been challenging due to the complexity of the genetics and the considerable environmental factors associated with the disease. Dr. Kohli and colleagues performed a stringent genome-wide association study of patients diagnosed with major depression and matched control subjects with no history of psychiatric illness. They identified SLC6A15, a gene that codes for a neuronal amino acid transporter protein, as a novel susceptibility gene for major depression. The finding was confirmed in an expanded study examining over 15,000 individuals.

The researchers examined the functional relevance of the genetic association between SLC6A15 and major depression. Already nondepressed subjects carrying the risk-conferring genetic variants showed lower expression of SLC6A15 in the hippocampus, a brain region implicated in major depression. Moreover, using human brain imaging, risk variant carriers with a positive life history of major depression showed smaller hippocampi. Finally, in a mouse model, lower hippocampal SLC6A15 expression was linked to the effects of chronic social stress, a proven risk factor for depression.

The authors suggest that reduced SLC6A15 expression might lead to perturbation of neuronal circuits related to susceptibility for major depression. "Our results support the notion that lower SLC6A15 expression, especially in the hippocampus, could increase an individual's stress susceptibility by altering neuronal integrity and excitatory neurotransmission in this key brain region," says senior author Dr. Elisabeth B. Binder. "Because SLC6A15 appears amenable to drug targeting, our results may incite the discovery of a novel class of antidepressant drugs."

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Journal Reference:

1. Martin A. Kohli, Susanne Lucae, Philipp G. Saemann, Mathias V. Schmidt, Ayse Demirkan, Karin Hek, Darina Czamara, Michael Alexander, Daria Salyakina, Stephan Ripke et al. The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression. Neuron, Volume 70, Issue 2, 252-265, 28 April 2011 DOI: 10.1016/j.neuron.2011.04.005