Category: Disorders and Syndromes

— New research suggests that several commonly prescribed drugs for type 2 diabetes may not be as effective at preventing death and cardiovascular diseases, such as heart attacks and stroke, as the oral anti-diabetic drug, metformin.

Insulin secretagogues (ISs),* such as glimepiride, glibenclamide (known as glyburide in the USA and Canada), gliclazide and tolbutamide, have been used to treat type 2 diabetes since the 1950-1970s, Nevertheless, the long-term risk associated with these drugs has largely been unknown. Metformin is the first drug of choice in type 2 diabetes, but, until now, there have not been studies investigating the long-term risk of individual ISs compared with metformin.

A study published online April 6 in the European Heart Journal followed a large, unselected group of everyone living in Denmark, aged over 20, who had been treated with either an IS or metformin (monotherapy) between 1997 and 2006 — a total of 107,806 people. It found that, compared to metformin treatment, monotherapy with most ISs, including glimepiride, glibenclamide, glipizide and tolbutamide, was associated with a greater risk of death from any cause, and a greater risk of heart attacks, stroke or death from cardiovascular diseases. This was the case both for patients who had already suffered a heart attack and for patients who had not. Two other ISs, gliclazide and repaglinide, showed no significant difference to metformin in their effectiveness in patients with and without a history of heart attacks.

Compared to metformin, patients who had not suffered a heart attack had approximately a fifth to a third higher risk of death from any cause if they were taking glimepiride, glibenclamide, glipizide or tolbutamide. In patients with a history of heart attacks, the risk was approximately a third to a half higher.

The researchers, led by Dr Tina Ken Schramm, a senior resident doctor at the Heart Centre at the Rigshospitalet Copenhagen University Hospital (Copenhagen, Denmark), stress that the findings may not mean that these ISs actually cause harm, but only that they appear to be less effective than metformin.

"Previous studies have shown that ISs, in particular sulphonylureas, are associated with a reduction in long-term risk. Therefore, the increased risk from ISs shown in our study presumably has more to do with the beneficial effects of metformin, gliclazide and repaglinide, than the detrimental effect of the other ISs," explained Dr Schramm. "This is the first study to compare all ISs with metformin despite a wide debate on the possible cardiovascular risk associated with ISs for about three decades. Our findings emphasise how important it is to conduct long-term follow up studies of glucose-lowering medications."

In an accompanying editorial, Drs Odette Gore and Darren McGuire of the University of Texas Southwestern Medical Center (Dallas, Texas, USA), write that the study's findings are "among the most robust published," and continue: "It is of key importance to note that the observation of less benefit with most sulphonylureas [ISs] in the study compared with metformin should not be interpreted as causing harm."

Dr McGuire explained: "Patients taking metformin had the best outcomes, supporting prior evidence of metformin benefit and making it the first-line drug recommended for almost all patients with type 2 diabetes. Compared against this beneficial drug, most of the ISs were associated with worse outcomes, but they would almost certainly be similar to, or better, had the comparison been made against placebo treatment, with the added benefit on kidney, eye, and nerve disease of the glucose control they yield. So patients should not stop their medications based on this study, but certainly should discuss any concerns with their doctor."

He added: "It's important to remember that these are observational analyses and not randomised comparisons, so it is impossible to tease out what if any of the difference in outcomes is due to the drugs compared versus differences in the patients — those taking ISs might have an increased risk to begin with."

Dr Schramm and her colleagues say that the mechanisms underlying the effects of different ISs and metformin are not fully understood and require further research.

She concluded: "Our study supports previous studies demonstrating that metformin may be less hazardous or more beneficial than most ISs. This suggests that metformin should be the first drug of choice in type 2 diabetes in most patients. The study shows there are important differences in the risk associated with different ISs, suggesting that gliclazide and maybe repaglinide are preferable, although in patients who have had a previous heart attack the most beneficial agents are metformin and gliclazide. As a result of our findings it is important now that there should be randomised studies focusing on patients at low and high cardiovascular risk."

*ISs act by causing insulin to be released, thereby dealing with the problem of insufficient insulin production seen in type 2 diabetes. Metformin combats insulin resistance — one of the characteristics of diabetes — by increasing the action of insulin on insulin receptors, thereby reducing blood glucose in the liver, muscles and fat. During the period of the study, about 50-60% of those receiving glucose-lowering medications received monotherapy with metformin or ISs in Denmark. The initial treatment for diabetes patients is usually monotherapy with either metformin or ISs, and then later, when the diabetes becomes more advanced, insulin treatment or a combination of treatments becomes an option.

---

Journal References:

1. Tina Ken Schramm et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. European Heart Journal, 2011 DOI: 10.1093/eurheartj/ehr077
2. Odette Gore and Darren McGuire. Resolving drug effects from class effects among drugs for type 2 diabetes mellitus: more support for cardiovascular outcome assessments. European Heart Journal, 2011 DOI: 10.1093/eurheartj/ehr019

An international team of scientists lead by researchers from Duke University and Johns Hopkins University have discovered a key "switch" in the brain that allows neurons to stop dividing so that these cells can migrate toward their final destinations in the brain.

The finding may be relevant to making early identification of people who go on to develop schizophrenia and other brain disorders.

"This work sheds light on what has been a big black box in neuroscience," said Nicholas Katsanis, Ph.D., co-senior author of the work and Jean and George Brumley Jr., MD, Professor of Developmental Biology, Professor of Pediatrics and Cell Biology. "It helps answer the question of what happens when neurons stop dividing and start moving along to populate the brain."

The study was published by Nature journal on April 6 in its advance online publication.

Katsanis predicts that, for perhaps 10 percent of psychiatric illness, the illness is primarily driven by defects in this switch system. "So we now have ways to interpret variation in humans, in a context that is relevant to their particular cases, to their physiology — that is where medicine will move next," Katsanis said.

Katsanis, who directs the Duke Center for Human Disease Modeling, and Akira Sawa, M.D., Ph.D., a Professor in the Department of Psychiatry at Johns Hopkins, were introduced to each other by a clinical colleague who thought that Bardet-Biedl syndrome (BBS) proteins that are involved in transport duties within cells might have a role in schizophrenia. Katsanis is an expert in using BBS genetic mutations and proteins to learn more about other diseases. BBS is a complex genetic disease with autism-like symptoms, cognitive defects and depression. Sawa is an expert on DISC1, the protein named Disrupted in Schizophrenia 1, known to be a major susceptibility factor for schizophrenia and related disorders.

Together, they discovered that these proteins are involved in a key switch for neurons that is necessary for brain development. When DISC1 gains a phosphate group at a specific site, it recruits BBS1. When BBS1 is missing in this system, the team could observe defective neuron migration, while a model with no DISC1 at all leads to defects in both cell proliferation and migration.

We can now appreciate that some fraction of schizophrenia is truly developmentally regulated, Katsanis said.

"Even though the disease manifests itself after pubescence, scientists have suspected that the underpinnings are prenatal," he said. "We can greet this news with sadness or see it as an opportunity: we may have 20 years to help before a person starts experiencing symptoms, if we can develop techniques to use early enough."

The study also provides another example of how BBS proteins fit into neuroscience and provide another instance in which understanding of a rare phenotype (BBS) informs complex traits, like schizophrenia, profoundly, Katsanis said. "The trend in recent years has been to focus heavily on common disorders and to disregard disorders that might impact fewer people. Yet rare disorders continue to provide such important insights both into basic biological processes and complex disease."

"With these findings, we have tools for interpretation in some schizophrenia cases," Katsanis said. About one in 100 children born go on to develop schizophrenia in early adulthood.

Now the scientists are engaged in medical re-sequencing of patients with psychiatric illness with a specific focus on the groups of proteins involved in the switch process. "We will be able to ask focused questions about the amount of variation that this particular system contributes to the complex landscape of genetic disease," Katsanis said.

Other authors include Edwin C. Oh and John F Robinson of the Center for Human Disease Modeling and Departments of Cell Biology and Pediatrics at Duke; and researchers from the Departments of Psychiatry and Behavioral Sciences and Neuroscience at Johns Hopkins University in Baltimore; the Departments of Physiology and Anatomy at Keio University School of Medicine in Tokyo; and the Molecular Pharmacology Group, Institute of Neuroscience and Psychology at the University of Glasgow.

The study was supported by U.S. Public Health Service grants, from the Silvio O. Conte Center; grants from Stanley and RUSK foundations and from Maryland Stem Cell Research Fund; grants from NARSAD and S-R foundations; grants from the Macular Vision Research Foundation and the Foundation for Fighting Blindness; the Distinguished George W. Brumley Professorship; a grant from Health Labor Sciences; grants from Strategic Research Program for Brain; the Fight for Sight Postdoctoral Fellowship; and a grant from the Medical Research Council, UK.

---

Journal Reference:

1. Koko Ishizuka, Atsushi Kamiya, Edwin C. Oh, Hiroaki Kanki, Saurav Seshadri, Jon F. Robinson, Hannah Murdoch, Allan J. Dunlop, Ken-ichiro Kubo, Keiko Furukori, Beverly Huang, Mariela Zeledon, Akiko Hayashi-Takagi, Hideyuki Okano, Kazunori Nakajima, Miles D. Houslay, Nicholas Katsanis, Akira Sawa. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature, 2011; DOI: 10.1038/nature09859

Scientists have shed new light on how older people may lose their memory. The development could aid research into treatments for age-related memory disorders.

Stress and memory

Many believe that stress is bad for our brains especially as we get older. Now University researchers have shown how two receptors in older brains react to a stress hormone called cortisol. This has been linked to increasing forgetfulness as we age.

"While we know that stress hormones affect memory, this research explains how the receptors they engage with can switch good memory to poorly-functioning memory in old age," according to Dr Joyce Yau of the University's Centre of Cardiovascular Science.

Stress hormone receptors

The study, by the University of Edinburgh, found that one receptor was activated by low levels of cortisol, which helped memory. However, once levels of this stress hormone were too high they spilled over onto a second receptor. This activates brain processes that contribute to memory impairment.

The study found that high levels of the stress hormone in aged mice made them less able to remember how to navigate a maze. The memory recall problem was reversed when the receptor linked to poor memory was blocked.

The research helps explain why too much stress over a prolonged period interferes with the normal processes in storing everyday memories.

This is despite the fact that a little bit of stress can help us better remember emotional memories.

Dr Joyce Yau said: "We now know that lowering the levels of these stress hormones will prevent them from activating a receptor in the brain that is bad for memory. Understanding the mechanisms in the brain, which affect memory as we age, will help us to find ways to combat conditions linked to memory loss."

Potential drug treatment

The researchers are currently investigating a new chemical compound which blocks an enzyme — 11beta-HSD1 — that is involved in producing stress hormones within cells.

They hope this could be used to develop a drug treatment to slow the normal decline in memory associated with aging or even improve memory in the already very old.

The study was funded by the Medical Research Council. This research is also supported by a Seeding Drug Discovery Award from the Wellcome Trust.

---

Journal Reference:

1. J. L. W. Yau, J. Noble, J. R. Seckl. 11 -Hydroxysteroid Dehydrogenase Type 1 Deficiency Prevents Memory Deficits with Aging by Switching from Glucocorticoid Receptor to Mineralocorticoid Receptor-Mediated Cognitive Control. Journal of Neuroscience, 2011; 31 (11): 4188 DOI: 10.1523/JNEUROSCI.6145-10.2011

Drugs like marijuana act on naturally occurring receptors in the brain called cannabinoid receptors. However, the mechanisms by which these drugs produce their sensory and mood altering effects within the brain are largely unknown. Research led by Steven Laviolette at The University of Western Ontario has now identified a critical brain pathway responsible for the effects of cannabinoid drugs on how the brain processes emotional information.

The findings, published in The Journal of Neuroscience, also help to explain the possible link between marijuana use and schizophrenia.

Laviolette and his team at the Schulich School of Medicine & Dentistry discovered that activating cannabinoid receptors directly in a region of the brain called the amygdala, can strongly influence the significance of emotional information and memory processes. It also dramatically increased the activity patterns of neurons in a connected region of the brain called the prefrontal cortex, controlling both how the brain perceived the emotional significance of incoming sensory information, and the strength of memories associated with these emotional experiences.

"These findings are of great clinical relevance given recent evidence suggesting that exposure to marijuana during adolescence can increase the likelihood of developing schizophrenia later in life," says Laviolette, an associate professor in the Department of Anatomy and Cell Biology. "We know there are abnormalities in both the amygdala and prefrontal cortex in patients who have schizophrenia, and we now know these same brain areas are critical to the effects of marijuana and other cannabinoid drugs on emotional processing."

Furthermore, the findings by Laviolette's laboratory identify a novel new brain pathway by which drugs acting on the cannabinoid system can distort the emotional relevance of incoming sensory information which in turn may lead to psychotic side-effects, such as paranoia, associated with heavy marijuana use. Developing pharmacological compounds, and there already are some, that block or modify this pathway could help control psychotic episodes. It could also be used to help patients with Post Traumatic Stress Disorder who have difficulty controlling the resurgence of highly emotional events into their memory.

Laviolette's research was funded by the Ontario Mental Health Foundation and the Natural Sciences and Engineering Research Council of Canada (NSERC).

Lithium is an element used in batteries and also for medication, as an established and common treatment for bipolar disorder. Swedish researchers have now found that women in four mountain villages in Argentinean Andes Mountains ingest so much lithium via the groundwater that this could affect thyroid function, causing so-called hypothyroidism. This is a metabolic disorder which gives rise to weight gain, fatigue, depression, sensitivity to cold and memory loss.

That the thyroid can be affected and that the kidneys in rare cases can be damaged are known side-effects of medication with lithium. Female patients who become pregnant are also advised against taking medicine containing lithium, as the substance can affect the fetus.

"The amounts of lithium that the Latin American women are ingesting via their drinking water are perhaps a tenth of what a patient would take daily for bipolar disorder. But, on the other hand, they are absorbing this lithium all their lives, even from before birth," says occupational and environmental physician Karin Broberg from Lund University in Sweden.

"What this implies for their health, we don't really know in practice. That is why we are planning a new study which will compare the health of two groups of mothers and children: respectively, the ones with the highest and lowest levels of lithium in their blood."

The Andes Mountains are rich in elements, to which the large copper mines in Chile and Peru, among others, bear witness. In several countries, lithium is also extracted, and Bolivia has enormous lithium reserves in its large salt desert, Salar de Uyuni. However the elements in the ground are not just a resource but also an environmental risk. In an earlier study in which Karin Broberg took part, involving the same mountain villages in the Salta province in Northwest Argentina, high levels of arsenic, lithium, cesium, rubidium and boron were found in the drinking water and in the urine of the women studied.

"Lifelong ingestion of arsenic and lithium brings a clear health risk. What the ingestion of the other substances implies is not known, because there is very little research on their role in ordinary drinking water," she says.

The researchers have carried out their studies with a technique called mass spectrometry. With older techniques it has only been possible to analyse one substance at a time in a water sample for example, but through refinement of mass spectrometry scientists are now able to measure the content of a long list of substances at the same time. That is why Karin Broberg thinks the technique should be widely used to analyse people's drinking water.

"Groundwater has in many places been considered better to drink than the often polluted water from lakes and rivers. But in Bangladesh this has caused enormous health problems, when it turned out that the water from drilled wells contained arsenic. Very little is known about the concentration of lithium and other potentially dangerous substances in the groundwater around the world, so this should also be measured," she believes.

---

Journal Reference:

1. Karin Broberg, Gabriela Concha, Karin Engstrom, Magnus Lindvall, Margaretha Grandér, Marie Vahter. Lithium in Drinking Water and Thyroid Function. Environmental Health Perspectives, 2011; DOI: 10.1289/ehp.1002678

Scientists in Finland have revealed metabolic abnormalities that are associated with schizophrenia. This may be an important step towards development of a clinical test of the disease.

Schizophrenia is a chronic and severe psychotic disorder that affects around 1% of the population. Currently, there is no clinical test for diagnosing schizophrenia, and therefore the condition is usually recognized and treated on the basis of patient symptoms.

A new study performed by Matej Orešič and colleagues from VTT Technical Research Centre of Finland in collaboration with Jaana Suvisaari from the Finnish National Institute for Health and Welfare reveals metabolic abnormalities that are associated specifically with schizophrenia, as opposed to other psychotic disorders. These findings, which were published in Genome Medicine in March 2011, might be an important step towards the development of a clinical diagnostic test for schizophrenia.

The team used metabolomics, a high-throughput method for detecting small metabolites, to produce profiles of the serum metabolites associated with schizophrenia, other nonaffective psychosis (ONAP) or affective psychosis. Their analysis indicates that schizophrenia is associated with elevated serum levels of specific triglycerides, indicative of hyperinsulinemia, and also upregulation of the serum amino acid proline. Orešič et al. then combined these metabolic profiles to create a diagnostic model with the potential to discriminate schizophrenia from other psychoses.

This exciting study demonstrates how metabolomics can be a powerful tool for dissecting disease-related metabolic pathways and for identifying candidate diagnostic and prognostic markers in psychiatric research.

---

Journal Reference:

1. Matej Oresic, Jing Tang, Tuulikki Seppanen-Laakso, Ismo Mattila, Suoma E Saarni, Samuli I Saarni, Jouko Lonnqvist, Marko Sysi-Aho, Tuulia Hyotylainen, Jonna Perala, Jaana Suvisaari. Metabolome in schizophrenia and other psychotic disorders: a general population-based study. Genome Medicine, 2011; 3 (3): 19 DOI: 10.1186/gm233

ccording to research presented at the School of Medicine and the University of Navarra Hospital by Dr. Roberto Muñoz, a physician of the Neurology Service of the Hospital Complex of Navarra, those persons with serious cases of sleep apnea have 2.5 times more the possibility of suffering an ischemic stroke.

This was confirmed in an study undertaken for his doctoral dissertation among 394 subjects aged 70 or more. "After studying the quality of their sleep, we tracked the volunteers over the course of six years. After which, 20 of the study subjects had suffered a stroke," explained this native Pamplonan. Furthermore, he confirmed that in addition to the fact that sleep apnea affects above all persons of middle and advanced age — it is estimated that 5% of all adults suffer from it — this prevalence may significantly increase with age.

In addition, the new Ph.D. in Medicine noted that apnea "can appear in childhood, although with different causes and characteristics." Among the predisposing factors for suffering this disorder, the expert emphasized obesity: "Therefore, one of the measures for avoiding the problem is losing weight. In fact, there are patients who have been able to make their sleep apnea disappear simply by reducing their weight."

"It is also a good idea to avoid sleeping face-upwards — since this position aids in the appearance of snoring — as well as quitting tobacco use and the excessive consumption of alcohol," adds Muñoz. In the most serious cases, the treatment includes the nightly use of a pressurized air mask, although he emphasized that each patient should receive the treatment most appropriate for his or her case.

Sequelae and disability

In the opinion of Roberto Muñoz, even though the incidence of death by stroke is important, "in recent years it has gone down significantly, both in Spain as well as in Navarra, thanks, above all, to the stroke units of hospitals and programs for immediate attention."

Nonetheless, an elevated percentage of those affected presented sequelae, and in addition, some disability: "We are, therefore, faced with a serious problem of public health, not only due to the deaths that it causes, but because it is one of the principal causes of disability in our society."

With regards to the problems associated with sleep apnea, Roberto Muñoz indicated that the problem — which is basically characterized by intense snoring accompanied by prolonged pauses in breathing (more than ten seconds) — also provokes tiredness and poorer intellectual performance, since sleep is of lower quality. "Over the long term, in addition, the alterations in respiration can result in hypertension, cardiovascular problems, and finally in stroke; hence the importance of preventing it and treating it from its outset," concluded the expert.

— In order to develop new medications for alcoholism, researchers need to understand how alcohol acts on the brain's reward system. A previously unknown mechanism has been shown to block the rewarding effects of alcohol on the brain, reveals a thesis from the University of Gothenburg, Sweden.

Research has shown that the glycine receptor in the brain's reward system plays a role in the development of alcoholism. This receptor normally acts as a brake on the brain's communication, and has previously been shown to be heavily implicated in the transmission of pain and in epilepsy. However, this thesis and previous results from the research group at the Department of Psychiatry and Neurochemistry have shown that the glycine receptor also plays a major role in alcoholism.

Acamprosate is found in an existing medicine for reducing relapses in alcoholics. Unfortunately, this type of medicine works for some patients only and there is a real need for new, more effective medication.

"We've chosen to clarify the role of acamprosate in the process and to find out whether this can help us understand how alcohol functions in the brain's reward system," says researcher PeiPei Chau from the Sahlgrenska Academy's Department of Psychiatry and Neurochemistry.

In animal trials with rats, the researchers have seen that acamprosate activates the glycine receptors, so inhibiting the rewarding effects of alcohol, and that it is through this mechanism that acamprosate reduces alcohol consumption.

"We've identified a brand new mode of action in an existing medicine, and this helps us to understand better why alcohol dependency can arise in the brain," says Chau. "Our results also consolidate the group's previous results which showed that glycine receptors can play a major role in the development of new medicines to treat alcohol dependency."

Obsessive-compulsive disorder is often diagnosed too late in children and adolescents. In the current issue of Deutsches Ärzteblatt International, Susanne Walitza and her colleagues point out that appropriate early recognition and treatment can positively affect the course of the disease.

Compulsive washing, the most common obsessive-compulsive manifestation among children and adolescents, is present in up to 87% of all patients; other common types are compulsive repetitive behavior and checking, and obsessive thoughts of an aggressive type. Comorbidities such as attention deficit/hyperactivity disorder are present in more than 70% of patients. Obsessive-compulsive disorder presenting in childhood or adolescence often becomes chronic and impairs mental health onward into adulthood.

The specific manifestations of obsessive-compulsive disorder can be diagnosed early with psychodiagnostic techniques. Treatment is often highly time-consuming. Behavioral therapeutic methods have been found effective and are accordingly considered first-line treatment. In behavioral therapy, the patient is confronted with the situation that precipitates the obsessive-compulsive manifestations, but the manifestations are suppressed. Second-line treatment consists of behavioral therapeutic intervention combined with the administration of a serotonin reuptake inhibitor. The authors state that, even after a course of intensive treatment has been completed, patients still need psychotherapy or combination therapy to prevent a later recurrence.

The etiology and pathogenesis of obsessive-compulsive disorder are multifactorial, with psychological, neurobiological, and genetic factors all playing a role.

---

Journal Reference:

1. Walitza S, Melfsen S, Jans T, Zellmann H, Wewetzer C, Warnke A. Obsessive-compulsive disorder in children and adolescents. Dtsch Arztebl Int, 2011; 108(11): 173%u20139 DOI: 10.3238/arztebl.2011.0173

Brain scans of aggressive and antisocial teenage boys with conduct disorder (CD) have revealed differences in the structure of the developing brain that could link to their behaviour problems.

The study reveals that the brain differences were present regardless of the age of onset of the disorder, challenging the view that adolescence-onset CD is merely a consequence of imitating badly behaved peers.

CD is a psychiatric condition characterised by increased aggressive and antisocial behaviour. It can develop in childhood or in adolescence and affects around five out of every 100 teenagers in the UK. Those affected are at greater risk of developing further mental and physical health problems in adulthood.

Neuroscientists at the University of Cambridge and the MRC Cognition and Brain Sciences Unit used magnetic resonance imaging to measure the size of particular regions in the brains of 65 teenage boys with CD compared with 27 teenage boys who did not display symptoms of behavioural disorder.

Their findings revealed that the amygdala and insula — regions of the brain that contribute to emotion perception, empathy and recognising when other people are in distress — were strikingly smaller in teenagers with antisocial behaviour. The changes were present in childhood-onset CD and in adolescence-onset CD, and the greater the severity of the behaviour problems, the greater the reduction in the volume of the insula.

Smaller volume of structures in the brain involved in emotional behaviour has been linked to childhood-onset CD, in which behavioural problems manifest early in life. However, adolescence-onset CD was previously thought to be caused solely by the imitation of badly behaved peers. The current findings cast doubt on this view and suggest a potential neurological basis for these serious and challenging conditions, whether they emerge in childhood or adolescence.

Ian Goodyer, Professor of Child and Adolescent Psychiatry at the University of Cambridge, and Dr Graeme Fairchild, now based at the University of Southampton, led the research. Dr Fairchild explained: "Changes in grey matter volume in these areas of the brain could explain why teenagers with conduct disorder have difficulties in recognising emotions in others. Further studies are now needed to investigate whether these changes in brain structure are a cause or a consequence of the disorder."

Professor Goodyer added: 'We hope that our results will contribute to existing psychosocial strategies for detecting children at high risk for developing antisocial behaviour."

Dr Andy Calder from the MRC Cognition and Brain Sciences Unit, who co-led the research, commented: "Studies such as this are tremendously important in understanding the causes of conduct disorder. Only when we are confident that we understand why the disorder develops can we apply this knowledge to the further development and evaluation of treatments. The disorder has a devastating impact on families and communities, and at the moment, we have few effective treatments."

The group have previously shown that individuals with both forms of conduct disorder display abnormal patterns of brain activity, but this new work marks an important advance in understanding the biology of aggression and violence by showing that differences in brain structure are linked to the disorder.

The study was funded jointly by the Wellcome Trust and the Medical Research Council,

The study will appear online March 31 in the American Journal of Psychiatry.