Support Program Can Help Caregivers Cope with Relative’s Mental Illness

A free, nationally available program can significantly improve a family's ability to cope with an ill relative's mental disorder, according to an NIMH-funded study published June 2011 in Psychiatric Services, a journal of the American Psychiatric Association.

Background
The Family-to-Family (FTF) education and support program is a free, 12-week course offered by the National Alliance on Mental Illness (NAMI). FTF is offered throughout the United States, in two Canadian provinces and in three regions in Mexico. With more than 3,500 volunteer teachers, it is supported by local donations or municipal funds. Since 1991, 250,000 family members have participated in the program. It is the most widely available education and support program for family members of individuals with mental illnesses.

Two previous studies suggested that FTF reduces caregivers' stress and helps them gain a sense of empowerment over their situation. For this most recent evaluation of the program, Lisa Dixon, M.D., M.P.H., of the University of Maryland, and colleagues aimed to determine its effectiveness using a randomized controlled trial. Half of the 318 participants were assigned to the program immediately after enrolling in the study, while the other half were waitlisted for the program for at least three months (control condition). Those who were waitlisted were free to seek assistance from other sources.

Participants were interviewed at the beginning of the three-month program and again three months later. They were asked about their problem-solving and coping skills, their overall distress level and worries about their ill relative's situation. They were also asked about their sense of empowerment to manage challenges within the family, the mental health system, and the community. They were also tested regarding their factual knowledge about mental illness.

Results of the Study
Compared to the waitlisted control group, FTF participants showed significantly greater improvements in coping with their ill relative's condition by learning more about the illness and gaining a sense of empowerment in the family, service system and community. FTF participants also showed increased acceptance of their family member's illness as well as improved problem-solving skills, compared to those who were waitlisted. Results also suggested that FTF participants' overall sense of emotional distress eased.

Significance
The researchers concluded that FTF effectively enhances coping skills among families of people with mental illness. These results echo those found in the previous qualitative studies. The researchers suggest the program can positively influence how family members solve problems and "navigate emotional difficulties" surrounding their loved one's illness.

What's Next
Additional research is needed to conclusively determine if the positive effects of FTF can improve the outcomes of the individuals with mental illness for whom the family members were taking the class.

Citation
Dixon LB, Lucksted A, Medoff DR, Burland J, Stewart B, Lehman AF, Fang LJ, Sturm V, Brown C, Murray-Swank A. Outcomes of a randomized study of a peer-taught family-to-family education program for mental illness. Psychiatric Services. 2011 June. 62(6):591-597.

CEUs for Social Workers

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]

Stress-Defeating Effects of Exercise Traced to Emotional Brain Circuit

Evidence in both humans and animals points to emotional benefits from exercise, both physical and mental. Now, in recent experiments with mice, scientists have traced the stress-buffering effect of activity to a brain circuit known to be involved in emotional regulation as well as mood disorders and medication effects. The finding is a clue to understanding the neurological roots of resilience, key to developing new means of prevention and treatment for stress-related illness ceus for counselors

Background
In ongoing research, NIMH scientists have used a mouse model that mirrors particularly well the impact of social stress on mood in humans. Male mice are intensely aggressive when housed together; if these mice are placed in conditions that result in defeat by another mouse, they will behave in a way that mimics depression, much like a human might. Previous research demonstrated that mice housed in an environment with plenty of opportunities for exercise and exploration are relatively unfazed by bullying; they are resilient compared to mice housed in more spartan surroundings. The benefits from activity and stimulation depend on the growth of new neurons in the brain in mice (Novel Model of Depression from Social Defeat Shows Restorative Power of Exercise). A next step was to pinpoint where in the brain changes were taking place in response to exercise that resulted in stress resilience.

This Study
Before any mice were exposed to social defeat, all the mice in the study were housed for three weeks in either impoverished housing, with nothing but wood chip bedding; standard housing with a cardboard tube and place for a nest; or "enriched housing," with running wheels and tubes of various shapes and sizes to explore. After three weeks, half of the mice in each type of housing were then placed for two more weeks in close quarters with another mouse, but prevented from fighting by a barrier to prevent injury.

Mice that had been housed in the impoverished or standard housing, and that had been subject to social defeat, reacted to standard behavioral tests in a way that suggests depression; they were measurably passive and cautious, for example, avoiding light-filled spaces and preferring the safety of darkness. Bullied mice that had been housed in enriched environments behaved just like mice that had not experienced social defeat. As in earlier studies, the enriched environment seemed to protect them from the effects of social stress.

The NIMH investigators carrying out this study, Michael Lehmann and Miles Herkenham, then looked within the brain to see what exercise was changing to protect against stress. They focused on a functional circuit of brain centers known to be involved in emotional processing. In mice that had been housed in an enriched environment, levels of a protein that signals the activity level of neurons were increased in cells in the infralimbic cortex (ILC), a part of this circuit. Parts of the brain closely wired to and "downstream" from the ILC, that is, receiving activating signals from it, showed similar elevated activity. If the ILC was inactivated at the beginning of the experiment, environmental enrichment failed to have a positive effect. But if it was inactivated after the first three weeks of housing, environmental enrichment worked; the parts of the brain that receive signals from the ILC remained activated and the mice were stress resilient. The ILC was, in effect, a gateway for the positive activity in these "downstream" parts of the brain. Once these centers were activated by the ILC, it didn't matter if the ILC was still online.

Enrichment had the opposite effect on a part of the brain that is an important trigger for the body's stress response system. So enrichment seemed to enhance positive behavior, while at the same time, dampened activity in an area linked with an increased stress response.

Significance
A central target of research is understanding how stress contributes to mood disorders and why some animals and people seem resilient to the same stresses that can make others ill. Much recent research is aimed at investigating mental processes and disorders in terms of neural circuits. Abnormalities in how the brain deals with fear memories, for example, are thought to play a role in both anxiety disorders and depression. In rats that have been conditioned to fear a particular sound, stimulation of the ILC can dampen the fear reaction. In the study reported here, experience in the environment had the effect of inoculating the mice against a stressor, through changes in this same circuit in the brain.

The areas of the brain examined in this study are analogous to brain regions with altered function in people with disorders like depression and post traumatic stress disorder. Knowledge of the physiological basis of emotional resilience is crucial to developing strategies to help prevent mood disorders; it can also offer targets for the development of new medications for which there remains a pressing need.

Reference
Lehmann, M.I., and Herkenham, M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. Journal of Neuroscience 31:6159-6173, 2011.

Autism Blurs Distinctions Between Brain Regions

Erodes Molecular Identities in Cortex – NIH-funded Study
Autism blurs the molecular differences that normally distinguish different brain regions, a new study suggests. Among more than 500 genes that are normally expressed at significantly different levels in the front versus the lower middle part of the brain's outer mantle, or cortex, only 8 showed such differences in brains of people with autism, say researchers funded in part by the National Institutes of Health continuing education for social workers

"Such blurring of normally differentiated brain tissue suggests strikingly less specialization across these brain areas in people with autism," explained Daniel Geschwind, M.D., Ph.D., of the University of California, Los Angeles, a grantee of the NIH's National Institute of Mental Health. "It likely reflects a defect in the pattern of early brain development."

He and his colleagues published their study online May 26, 2011 in the journal Nature. The research was based on post mortem comparisons of brains of people with the disorder and healthy controls.

In fetal development, different mixes of genes turn on in different parts of the brain to create distinct tissues that perform specialized functions. The new study suggests that the pattern regulating this gene expression goes awry in the cortex in autism, impairing key brain functions.

"This study provides the first evidence of a common signature for the seemingly disparate molecular abnormalities seen in autism," said NIMH director Thomas R. Insel, M.D. "It also points to a pathway-based framework for understanding causes of other brain disorders stemming from similar molecular roots, such as schizophrenia and ADHD."

In an earlier study, the researchers showed that genes that turn on and off together at the same time hold clues to the brain's molecular instructions. These modules of co-expressed genes can reveal genetic co-conspirators in human illness, through what Geschwind and colleagues call "guilt by association." A gene is suspect if its expression waxes and wanes in sync with others in an illness-linked module.

Using this strategy, the researchers first looked for gene expression abnormalities in brain areas implicated in autism — genes expressed at levels different than in brains of healthy people. They found 444 such differently expressed genes in the cortexes of postmortem brains of people with autism.

Most of the same genes turned out to be abnormally expressed in the frontal cortex as in the temporal cortex (lower middle) of autistic brains. Of these, genes involved in synapses, the connections between neurons, tended to be under-expressed when compared with healthy brains. Genes involved in immune and inflammatory responses tended to be over-expressed. Significantly, the same pattern held in a separate sample of autistic and control brains examined as part of the study.

Autistic and healthy control brains were similarly organized –– modules of co-expressed genes correlated with specific cell types and biological functions.

Yet normal differences in gene expression levels between the frontal and temporal cortex were missing in the modules of autistic brains. This suggests that the normal molecular distinctions — the tissue differences — between these regions are nearly erased in autism, likely affecting how the brain works. Strikingly, among 174 genes expressed at different levels between the two regions in two healthy control brains, none were expressed at different levels in brains of people with autism.

An analysis of gene networks revealed two key modules of co-expressed genes highly correlated with autism.

One module was made up of genes in a brain pathway involved in neuron and synapse development, which were under-expressed in autism. Many of these genes were also implicated in autism in previous, genome-wide studies. So, several different lines of evidence now converge, pointing to genes in this M12 module (see picture below) as genetic causes of autism.

A second module of co-expressed genes, involved in development of other types of brain cells, was over-expressed in autism. These were determined not to be genetic causes of the illness, but likely gene expression changes related to secondary inflammatory, immune, or possible environmental factors involved in autism.

This newfound ability to see genes in the context of their positions in these modules, or pathways, provides hints about how they might work to produce illness, according to Geschwind and colleagues. For example, from its prominent position in the M12 module, the researchers traced a potential role in creating defective synapses to a gene previously implicated in autism.

Follow-up studies should explore whether the observed abnormalities in the patterning of gene expression might also extend to other parts of the brain in autism, say the researchers.