Excess body fat increases the risk of depression

A new study from Aarhus University and Aarhus University Hospital, Denmark, shows that ten kilograms of extra body fat increases the risk of depression by seventeen percent.

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Carrying ten kilograms of excess body fat increases the risk of depression by seventeen per cent. The more fat, the greater the probability of developing depression. This is the main conclusion of a new study carried out by researchers from Aarhus University and Aarhus University Hospital, Denmark.

"Our study also indicated that the location of the fat on the body makes no difference to the risk of depression. This suggests that it is the psychological consequences of being overweight or obese which lead to the increased risk of depression, and not the direct biological effect of the fat. If the opposite was true we would have seen that fat located centrally on the body increased the risk the most, as it has the most damaging effect in biological terms," says the study's last author Dr. Søren Dinesen Østergaard. 

He is professor at the Department of Clinical Medicine at Aarhus University and affiliated with the Department of Affective Disorders at Aarhus University Hospital. 

Prior studies in the field have predominantly used Body Mass Index (BMI) to measure obesity. BMI is calculated solely on the basis of body weight and height and is therefore a fairly crude measure, that does not, for example, take build and muscle mass into account.

"BMI is an inaccurate way of measuring overweight and obesity. Many elite athletes with a large muscle mass and a low body fat mass will have a BMI above 25, which is classified as overweight according to the common definition. This obviously doesn't make much sense. Therefore, one of the strengths of our study is that we've been able to zoom in and look at the specific relationship between the amount of body fat and the risk of depression," explains Dr. Østergaard.

In the study, which has been published in the journal Translational Psychiatry, the researchers have analysed data from two large genetic data sets: the UK Biobank, which contains data on the correlation between genetic variants and physical measurements (including body fat mass distributed around parts of the body); and the Psychiatric Genomics Consortium, which contains information on the correlation between genetic variants and depression.

Dr. Østergaard also highlights his research group's choice of the 'Mendelian randomization' method as the main reason why the study was successful. He also emphasises that the findings are particularly significant in light of the fact that almost 40 per cent of the world's adult population is overweight. 

"In addition to the known physical consequences of obesity such as diabetes and cardiovascular disease, there is also a significant and now well-documented psychological component, which needs to be dealt with as well. This is yet another argument for resolving the obesity epidemic," he says, before emphasising that it is important to have a balanced approach to the issue: 

"As it appears to be the psychological consequences of obesity, such as a negative body image and low self-esteem that is the main driving force behind the increased risk of depression, society's efforts to combat obesity must not stigmatise, as this will probably increase the risk of depression even further. It is important to bear this in mind so we can avoid doing more harm than good in the effort to curb the obesity epidemic," says Dr. Østergaard. 

FACTS ABOUT MENDELIAN RANDOMIZATION:

Mendelian randomization (named after the Austrian monk Gregor Mendel, who was the father of modern genetics) is a method which in recent years has helped researchers to overcome a major challenge associated with observational studies - namely that of making causal inference. In observational studies researchers often find correlations between two conditions - e.g. between obesity and depression - where it is difficult, or rather impossible, to determine whether there is indeed a causal effect going from obesity to depression - or vice versa. Mendelian randomization may solve this challenge.

Mendelian randomization can be described as nature's version of the randomised controlled trials that are carried out when testing whether a new drug has the desired (causal) effect in the treatment of a disease. In the clinical trials of drugs, lots are drawn to determine whether individual participants will receive the active drug or a placebo, without them knowing which treatment they have been assigned to. Instead, Mendelian randomization takes advantage of the fact that a completely natural randomization takes place during the formation of the sex cells (egg cells and sperm cells), which represent the origin of all human beings. When sex cells are formed, the parents' genetic variants - including those that give rise to increased body fat- are randomly distributed. Therefore, some individuals will have received many of these variants and others less. In the study in question, the researchers have utilised this natural and random source of variation to determine whether people who have received many genetic variants for increased body fat have an increased risk of suffering depression.

THE RESEARCH RESULT - MORE INFORMATION

Genetic epidemiological study utilising data from the UK Biobank (with information on the association between genetic variants and fat mass based on a study of 330,000 people) and the Psychiatric Genomics Consortium (with information on the association between genetic variants and depression based on a study of 135,000 people with depression and 345,000 control subjects).

The research group comprises Maria S. Speed, Oskar H. Jefsen, Anders D. Børglum, Doug Speed and Søren D. Østergaard - all from Aarhus University.

Drug Boosts Growth Factor to Jumpstart Rapid Antidepressant Response

Little-known Enzyme Pivotal, Mouse Study Reveals
A study in mice has pinpointed a pivotal new player in triggering the rapid antidepressant response produced by ketamine. By deactivating a little-known enzyme, the drug takes the brakes off rapid synthesis of a key growth factor thought to lift depression, say NIMH-funded researchers LPCC Continuing Education

"Other agents that work through this pathway and block the enzyme may also similarly induce anti-depressant-like effects and hold promise for development of new treatments," said Lisa Monteggia, Ph.D., of the University of Texas Southwestern Medical Center, Dallas.

Monteggia, Ege Kavalali, Ph.D., and colleagues reported their findings online June 15, 2011 in the journal Nature.

Unlike currently available antidepressants that take weeks to work, ketamine can lift mood within hours. Yet adverse side effects preclude it from becoming a practical treatment. So, researchers have been studying its mechanism of action, in hopes of developing safer alternatives that work the same way.

Earlier studies had shown that the growth factor, called brain-derived neurotrophic factor (BDNF), produces antidepressant-like effects. To find out if BDNF is involved in ketamine's action, the researchers gave the drug to mice genetically engineered to lack BDNF. Unlike in control mice, ketamine failed to produce a fast-acting antidepressant-like response in such BDNF knockout mice exposed to experimental situations that trigger depression-like behaviors. This and other tests confirmed that ketamine's rapid antidepressant effects depend on rapid synthesis of BDNF in the brain's memory center, or hippocampus.

The researchers determined that this happens so quickly — within 30 minutes — because it only requires the translation of BDNF mRNA into protein, rather than transcription, which involves new gene expression and takes much longer.

Ketamine achieves this boost in BDNF levels by first blocking a protein on neurons (brain cells) called the NMDA receptor. The Texas team discovered that this blockade, in turn, deactivates an enzyme called eukaryotic elongation factor 2 (eEF2) kinase, that restrains BDNF synthesis. So, ketamine (and presumably other agents that similarly turn off the enzyme) effectively takes the brakes off of this antidepressant mechanism.

"Selectively inhibiting the eEF2 kinase was sufficient to trigger a rapidly acting antidepressant response in control mice but not in mice lacking BDNF," explained Monteggia.

The researchers discovered that the boost in BDNF occurs while neurons are in their default mode — not doing anything in particular. But the cells continue communicating via a low level of background chatter, spontaneously releasing chemical messengers that bind to receptors. So, when ketamine blocks NMDA receptors, it prevents their naturally-occurring messenger chemical, glutamate, from binding to them.

"Interference with such spontaneous neurotransmission to trigger production of a protein represents a novel mode of drug action," Monteggia noted. "It may also hold clues to what goes awry in the brain in disorders like depression."

Although BDNF levels fall off sharply following the transient increase triggered by ketamine, she says evidence may also support a role for BDNF in the drug's longer-term antidepressant effects. The exact role of another enzyme implicated in ketamine's antidepressant action remains to be determined, in light of the new findings. Yale researchers reported last Fall that the drug triggered increased connections between neurons via effects on the enzyme, called mTOR.

"This discovery of a novel pathway involved in mediating fast-acting antidepressant action holds hope for development of new rapid-acting medications," said Monteggia.

When in their default state, neurons that mediate ketamine's action engage in the brain's equivalent of background chatter. They spontaneously spray out (orange) the chemical messenger glutamate (green circles), which binds to NMDA receptors (black ovals) on adjoining neurons. This activates the enzyme eEF2 kinase, which suppresses synthesis of BDNF, a growth factor that has antidepressant effects. Treatment with ketamine blocks the binding of the neurotransmitter to the receptors (blue dots on black ovals), which inactivates the enzyme, taking the brakes off translation of BDNF into protein. This jumpstarts a fast-acting antidepressant effect.

Source: Lisa Monteggia, Ph.D., University of Texas Southwestern Medical Center

Reference
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. Nature. 2011 Jun 15. doi: 10.1038/nature10130. [Epub ahead of print] PMID:21677641

Focusing on School Attendance Reduces HIV Risk Among Orphaned Teens

Source: iStock
A comprehensive school support program effectively reduced risk factors associated with infection with HIV among teens who had lost one or both parents, according to early results from a pilot study funded by NIMH. The paper was published online ahead of print on February 17, 2011, in the Journal of Adolescent Health LPCC Continuing Education

Background
Current statistics estimate there are more than 11 million children living in sub-Saharan Africa who have lost one or both parents to HIV/AIDS. These children are at increased risk of dropping out of school, which in turn increases their risk for unprotected sexual behavior. Some research suggests that interventions that aim to change a person's living conditions, such as methods designed to help them stay in school, may be effective in reducing or preventing HIV infection among these at-risk children.

To further explore this idea, Hyunsan Cho, Ph.D., of the Pacific Institute for Research and Evaluation in Chapel Hill, N.C., and colleagues recruited 105 students, ages 12-14, from a rural area in Kenya with high HIV prevalence who had lost one or both parents to any cause. All participants received supportive household supplies (e.g., mosquito nets, blankets, food supplements) every two weeks. Participants randomly assigned to the test group also received school uniforms and money to pay school fees. A local woman, designated as a "community visitor," was assigned for every 10 teens in the test group to visit their homes at least monthly. She also visited the teens' schools weekly to monitor their school attendance and address problems that may lead to absenteeism.

Results
After one year, teens in the test group were less likely to have:

Dropped out of school (4 percent vs 12 percent of the control group)
Begun having sex (19 percent vs 33 percent control)
Reported attitudes supporting initiation of sexual relationships at a young age
Teens in the test group were also more likely to perceive that adults in the family liked or cared about them, and were generally less likely to endorse attitudes accepting of husbands beating their wives.

Significance
According to the researchers, these findings support previous research suggesting that comprehensive, community-based school support can help reduce multiple HIV risk factors among orphaned teens. The researchers also found evidence that school support enhances social bonding and positive attitudes toward gender equity.

What's Next
Given that these findings resulted from an experimental pilot study, the researchers emphasized that future studies should include more participants and focus on methods for generalizing this approach to broader populations.

Reference
Cho H, Hallfors DD, Mbai II, Itindi J, Milimo BW, Halpern CT, Iritani BJ. Keeping Adolescent Orphans in School to Prevent Human Immunodeficiency Virus Infection : Evidence From a Randomized Controlled Trial in Kenya. J Adolesc Health. 2011 Feb 17. [online ahead of print]

Behavioral Training Improves Connectivity and Function in the Brain

Children with poor reading skills who underwent an intensive, six-month training program to improve their reading ability showed increased connectivity in a particular brain region, in addition to making significant gains in reading, according to a study funded in part by the National Institute of Mental Health (NIMH). The study was published in the Dec. 10, 2009, issue of Neuron. LPCC Continuing Education
"We have known that behavioral training can enhance brain function." said NIMH Director Thomas R. Insel, M.D. "The exciting breakthrough here is detecting changes in brain connectivity with behavioral treatment. This finding with reading deficits suggests an exciting new approach to be tested in the treatment of mental disorders, which increasingly appear to be due to problems in specific brain circuits."

For the study, Timothy Keller, Ph.D., and Marcel Just, Ph.D., both of Carnegie Mellon University, randomly assigned 35 poor readers ages 8-12, to an intensive, remedial reading program, and 12 to a control group that received normal classroom instruction. For comparison, the researchers also included 25 children of similar age who were rated as average or above-average readers by their teachers. The average readers also received only normal classroom instruction.

Four remedial reading programs were offered, but few differences in reading improvements were seen among them. As such, results for participants in these programs were evaluated as a group. All of the programs were given over a six month schooling period, for five days a week in 50-minute sessions (100 hours total), with three students per teacher. The focus of these programs was improving readers' ability to decode unfamiliar words.

Using a technology called diffusion tensor imaging (DTI), the researchers were able to measure structural properties of the children's white matter, the insulation-clad fibers that provide efficient communication in the central nervous system. Specifically, DTI shows the movement of water molecules through white matter, reflecting the quality of white matter connections. The better the connection, the more the water molecules move in the same direction, providing a higher "bandwidth" for information transfer between brain regions.

At the outset of the study, poor readers showed lower quality white matter than average readers in a brain region called the anterior left centrum semiovale. Six months later, at the completion of the intensive training, the poor readers showed significant increases in the quality of this region. Children who did not receive the training did not show this increase, suggesting that the changes seen in the remedial training group were not due to natural maturation of the brain.

In an effort to further pinpoint the mechanism underlying this change, the researchers deduced that a process called myelination may be key. Myelin is akin to electrical insulation, allowing for more rapid and efficient communication between nerve cells in the brain. However, the directional association between brain changes and reading improvements remains unclear—whether intensive training brings about increased myelination that results in improved word decoding skills, or whether improved word decoding skills leads to changes in reading habits that result in greater myelination.

"Our findings support not only the positive effects of remediation and rehabilitation for reading disabilities, but may also lead to improved treatments for a range of developmental conditions related to brain connectivity, such as autism," noted Just.


Source: Timothy Keller, Ph.D.; Marcel Just, Ph.D.

Left brain image shows the area of lower quality white matter (blue area) among poor readers relative to good readers at the beginning of the study.

Center brain image shows the area where the white matter quality increased (red/yellow area) among poor readers who received the remedial reading instruction.

Right brain image shows that following the instruction, there were no differences between the poor and average readers with respect to the quality of their white matter.

Reference
Keller TA, Just MA. Altering cortical connectivity: Remediation-induced changes in the white matter of poor readers.