Novel Model of Depression from Social Defeat Shows Restorative Power of Exercise

New Neurons Pinpointed as Central to Exercise Benefit

In a study in a mouse model that mimics the contribution of social stress to human depression, an environment that promotes exercise and exploration alleviated depressive behavior in the mice. The beneficial effect of activity depended on the growth of new neurons in the adult brain Continuing Education for Counselors

Background
In the 1990s scientists established that new neurons grow in the adult as well as the immature brain. The functions of neurogenesis, or new neuronal growth, are still being explored, but it is known that stress slows this growth in the hippocampus―a brain center involved in the formation of new memories―and that antidepressant treatment promotes it.

Previous research in animal models has also demonstrated that environmental enrichment―the addition of features in an animal's cage that provide opportunities for exercise and investigation―fosters resilience to stress and can alleviate the depression-like behavior that results from uncontrollable stress. Environmental enrichment has also been shown to promote hippocampal neurogenesis in animals.

This Study
This work, by Michael Lehmann and Robert Schloesser and colleagues in NIMH's intramural research program, focused on the ability of environmental enrichment to reverse depressive behaviors caused by social defeat, a situation paralleling the social stresses that can trigger human depression. Past work in animal models has often used physical stressors such as electric shock, restraint, or forced exercise to create depressive behaviors. In addition, the scientists inserted a gene in mice that made it possible to selectively interrupt the growth of new neurons at a specific time and in a specific population of cells in the hippocampus, avoiding any spillover effects to other tissues.

More on Mouse Behavior
Although "dominant and aggressive" may not sound like descriptors that apply to mice, male mice in the wild live apart from other males and they are intensely aggressive if housed together. In this study, male mice were allowed to interact directly for no more than five minutes at a time and were supervised to make sure one mouse did not injure or kill the other.
Mice naturally cover territory in the wild; if furnished with running wheels in a cage, they will, on their own, run the equivalent of as much as 6 to 10 kilometers in one day.
Stress―in this case social defeat stress―has unmistakable effects on the behavior of mice. Researchers use a variety of tests to describe changes in behavioral tendencies, including observing how boldly the mice explore an unfamiliar cage; how much time they will choose to spend in a dark (safe) vs. light (risky) compartment; and the extent to which they'll indulge their taste for something pleasant like sweetened water. Mice who have been the losers of repeated social defeats are visibly cautious and subdued, even in the judgment of observers who do not know whether they were winners or losers in a conflict.
Test mice in this study were housed across a partition in the home cage of a dominant, aggressor mouse. For 5 minutes per day, the partition was removed, allowing the "intruder" and dominant mouse to interact directly. After 2 weeks, the test mice consistently behaved submissively. The test mice were then divided and placed in either a spare environment, or one enriched with running wheels, and tubes of various shapes and sizes. Some of the mice assigned to either environment were a standard laboratory strain. Others had an inserted gene targeted to a population of hippocampal cells that give rise to new neurons; in mice with this transgene, the antibiotic valganciclovir is toxic to dividing cells so neurogenesis is prevented when the drug was added to the animals' feed.

The nontransgenic test mice in the enriched environment, but not those in the more spartan cages, recovered from the submissive behavior seen after social defeat. The transgenic mice, in which neurogenesis was stopped, remained submissive, resembling the mice housed in the impoverished environment.

In tests to probe affect, or mood, the transgenic mice housed in the enriched environment also resembled mice housed in the impoverished environment in that they showed the same reduced inclination to explore, greater anxiety, and a less than normal interest in sweet solutions which mice usually prefer. Interruption of neurogenesis had no effects on the baseline health and behavior of the animals, so the lack of new neurons did not cause depression, but interfered with recovery.

Significance
This study demonstrates that psychosocial stress in mice can cause behavior resembling human depression, which environmental enrichment can ameliorate as long as neurogenesis is intact.

Key elements of this study included its use of a social stressor, more analogous to the social experiences that can contribute to human depression than the physical stressors often used in research. In addition, the use of the transgene in test animals enabled the scientists to control the interruption of neurogenesis with precision with respect to both timing and location and with no effects on neighboring cells.

According to author Michael Lehmann, "There are multiple avenues through which environmental enrichment can have a positive impact on depression. In this model we use a natural psychosocial stressor with relevance to social stress in humans, to induce depressive-like behaviors. We show that environmental enrichment can facilitate the recovery from social stress, and that adult neurogenesis is a requirement for the rehabilitating effects of enrichment."

The authors suggest that neurogenesis may be central to the ability of an animal to update emotional information upon exposure to a novel environment. With neurogenesis impaired, they may be unable to integrate information on the features of a new, changed environment. The resulting cognitive distortions may trigger symptoms of major depression.

Research suggests that one important consequence of environmental enrichment is its impact on the function of the body's stress response system. Animals in these enriched environments show positive effects on the physiology of stress resilience. In humans, successful antidepressant treatment is reflected in similar beneficial changes. Prior research has also linked neurogenesis with positive changes in the stress response system.

The authors also point out that in humans, physical exercise and positive psychosocial activity have beneficial effects on depression and stress resilience. Forms of entertainment that encourage mental activity, according to Lehmann, such as reading, video games, exercise and outdoor recreation could have longer lasting changes for many suffering from mild depressive symptoms than pharmacologic treatment, without the accompanying side effects.

Reference
Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., and Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate recovery from psychosocial stress. Molecular Psychiatry 2010 Dec;15(12):1152-1163. Epub 2010 March 23.

Combination Antidepressant Therapy May Not Improve Odds of Remission Among Chronically Depressed

A combination of two antidepressants may not be any more effective in treating chronic major depression than a single antidepressant, according to an NIMH-funded study published online ahead of print May 2, 2011, in the American Journal of Psychiatry CEUs for Counselora

Background
When treating depression, doctors sometimes prescribe a second antidepressant medication if a patient does not improve after several weeks. Because some antidepressants work for some people and not others, the hope is that adding another one will increase the odds of remission. However, treatment guidelines generally do not recommend adding another medication until it is evident the first one is not working.

Madhukar H. Trivedi, M.D., at the University of Texas Southwestern, and colleagues aimed to determine if combination antidepressant therapy as a first treatment step might produce a higher remission rate among people with chronic major depression. In the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, 665 adult participants from several sites around the country were randomly assigned to one of three antidepressant combinations:

Escitalopram plus placebo
Bupropion sustained release plus escitalopram
Venlafaxine plus mirtazapine
Although participants did not know which treatments they were receiving, clinicians were aware of their patients' treatment assignments so that they could adjust doses as necessary to manage symptoms and side effects. The measurement of primary outcome was based on a self-reporting scale called the Quick Inventory of Depressive Symptoms.

Results of the Study
After three months, remission rates among the three groups all were around 38 percent. After seven months, remission rates continued to be similar among the three treatment groups and averaged around 45 percent. However, the venlafaxine plus mirtazapine combination was associated with a higher risk for side effects and serious adverse events compared to the other treatment options.

Significance
Despite other research suggesting combination antidepressant treatment may work better than a single medication, neither of the combination therapies in this trial appeared to be more effective than the single medication plus placebo. The researchers suggest that the chronic nature of participants' major depression may be associated with lower remission rates. They also noted that dosage differences may account for the difference in outcomes compared to other studies.

What's Next
Further evaluation is needed to determine if other drug combinations may affect remission rates differently. Results also highlight the need to evaluate biological markers as a means of personalizing treatment and possibly improving remission rates in major depression.

Reference
Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, Warden D, Morris DW, Luther JF, Husain MM, Cook IA, Shelton RC, Lesser IM, Kornstein SG, Wisniewski SR. Combining medications to enhance depression outcomes (CO-MED): Acute and long-term outcomes: a single-blind randomized study. Journal of American Psychiatry. online ahead of print May 2, 2011.

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Study Reveals New Clues to How Depression May Develop

Activating neurons in a brain structure linked to disappointment increased depression-like behaviors in rats, while suppressing the neurons' activity reduced the behaviors, according to an NIMH-funded study. The findings help to explain previous research linking this brain structure to depression in humans and highlight a cellular process that hadn't been previously explored in mood disorders research. The study was published in the February 24, 2011, issue of Nature.

Background
Depression is one of the most studied mental disorders, with research honing in on brain structures, circuits, and biochemical processes critical to the development of the disorder. Yet many questions remain about how changes in the brain result in the observable symptoms and behaviors associated with depression. Counselor continuing education
To advance the science in this area, Bo Li, Ph.D., of Cold Spring Harbor Laboratory in New York, and colleagues, explored the role and connectivity of neurons in the lateral habenula (LHb) in rats that showed learned helplessness, a set of behaviors similar to symptoms of depression in people. The LHb is associated with how humans and animals experience disappointment or anticipate negative outcomes.

Results of the Study
The researchers found that LHb neurons receive input from many different brain regions involved in responding to stress. LHb neurons also connect out to many brain regions, such as the ventral tegmental area (VTA). The VTA helps to control reward-seeking behavior and may have a role in depression and other mood disorders.

LHb neurons in helpless rats were more responsive, such that communication signals to the VTA were more likely to be transmitted in the helpless rats than in control rats. In an attempt to moderate this phenomenon, the researchers tested the effects of deep brain stimulation (DBS), a surgical procedure currently being tested in humans for treatment-resistant depression. Applying continuous electrical stimulation directly to the LHb resulted in greatly reduced transmission to the VTA and a marked reduction in helpless behavior. The effects on transmission lasted only as long as the stimulation lasted. More intense stimulation resulted in stronger behavioral effects.

Significance
Although LHb activity was previously unstudied in the context of mood disorders, these findings suggest that this brain structure may actually play a central role in the development of depression.

What's Next
Further studies focusing on the molecular processes and signals underlying LHb activity in depression may reveal new targets for treatment development, according to the researchers. Such new treatments also may be able to reverse some forms of depressive disorders.

This study was supported in part by a Biobehavioral Research Award for Innovative New Scientists (BRAINS) from NIMH. Dr. Li was one of 12 researchers to receive this award in 2010.

Manic Phase of Bipolar Disorder Benefits from Breast Cancer Medication

The medication tamoxifen, best known as a treatment for breast cancer, dramatically reduces symptoms of the manic phase of bipolar disorder more quickly than many standard medications for the mental illness, a new study shows. Researchers at the National Institutes of Health's National Institute of Mental Health (NIMH) who conducted the study also explained how: Tamoxifen blocks an enzyme called protein kinase C (PKC) that regulates activities in brain cells. The enzyme is thought to be over-active during the manic phase of bipolar disorder. Professional Counselor Continuing Education.

By pointing to PKC as a target for new medications, the study raises the possibility of developing faster-acting treatments for the manic phase of the illness. Current medications for the manic phase generally take more than a week to begin working, and not everyone responds to them. Tamoxifen itself might not become a treatment of choice, though, because it also blocks estrogen — the property that makes it useful as a treatment for breast cancer — and because it may cause endometrial cancer if taken over long periods of time. Currently, tamoxifen is approved by the Food and Drug Administration for treatment of some kinds of cancer and infertility, for example. It was used experimentally in this study because it both blocks PKC and is able to enter the brain.

Results of the study were published online in the September issue of Bipolar Disorders by Husseini K. Manji, MD, Carlos A. Zarate Jr., MD, and colleagues.

Almost 6 million American adults have bipolar disorder, whose symptoms can be disabling. They include profound mood swings, from depression to vastly overblown excitement, energy, and elation, often accompanied by severe irritability. Children also can develop the illness.

During the manic phase of bipolar disorder, patients are in "overdrive" and may throw themselves intensely into harmful behaviors they might not otherwise engage in. They might indulge in risky pleasure-seeking behaviors with potentially serious health consequences, for example, or lavish spending sprees they can't afford. The symptoms sometimes are severe enough to require hospitalization.

"People think of the depressive phase of this brain disorder as the time of risk, but the manic phase has its own dangers," said NIMH Director Thomas R. Insel, MD. "Being able to treat the manic phase more quickly would be a great asset to patients, not just for restoring balance in mood, but also because it could help stop harmful behaviors before they start or get out of control."

The three-week study included eight patients who were given tamoxifen and eight who were given a placebo (a sugar pill); all were adults and all were having a manic episode at the time of the study. Neither the patients nor the researchers knew which of the substances the patients were getting.

By the end of the study, 63 percent of the patients taking tamoxifen had reduced manic symptoms, compared with only 13 percent of those taking a placebo. Patients taking tamoxifen responded by the fifth day — which corresponds with the amount of time needed to build up enough tamoxifen in the brain to dampen PKC activity.

The researchers decided to test tamoxifen's effects on the manic phase of bipolar disorder because standard medications used to treat this phase, specifically, are known to lower PKC activity — but they do it through a roundabout biochemical route that takes time. Tamoxifen is known instead to block PKC directly. As the researchers suspected would happen, tamoxifen's direct actions on PKC resulted in much faster relief of manic symptoms, compared with some of the standard medications available today.

"We now have proof of principle. Our results show that targeting PKC directly, rather than through the trickle-down mechanisms of current medications, is a feasible strategy for developing faster-acting medications for mania," said Manji. "This is a major step toward developing new kinds of medications."

Findings from another recent NIMH study strengthen the results. This previous study showed that the risk of developing bipolar disorder is influenced by a variation in a gene called DGKH. The gene makes a PKC-regulating protein known to be active in the biochemical pathway through which standard medications for bipolar disorder exert their effects - another sign that PKC is a promising direct target at which to aim new medications for the illness.

"Mania isn't just your average mood swing, where any of us might feel upbeat in response to something that happens. It's part of a brain disorder whose behavioral manifestations can severely undermine people's jobs, relationships, and health," said Zarate. "The sooner we can help patients get back on an even keel, the more we can help them avoid major disruptions to their lives and the lives of people around them."



Reference
Zarate Jr. CA, Singh JB, Carlson PJ, Quiroz J, Jolkovsky L, Luckenbaugh DA, Manji HK. Efficiency of a Protein Kinase C Inhibitor (Tamoxifen) in the Treatment of Acute Mania: A Pilot Study. Bipolar Disorders, online ahead of print, September 2007.
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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

International Impact of Bipolar Disorder Highlights Need for Recognition and Better Treatment Availability

The severity and impact of bipolar disorder and bipolar-like symptoms are similar across international boundaries, according to a study partially funded by NIMH. The results were published in the March 2011 issue of the Archives of General Psychiatry. Marriage and Family Therapist Continuing Education

Background
Although several studies report prevalence rates of mental disorders on an international level, the numbers have varied because each study tends to use different methodology and definitions. To remedy this, the World Health Organization’s World Mental Health (WMH) survey initiative used consistent data collection methods in 11 countries in the Americas, Europe, Asia, the Middle East and New Zealand. The survey also applied common diagnostic definitions for mental disorders found in the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV).

NIMH researcher Kathleen Merikangas, Ph.D., and colleagues used WMH data to track prevalence rates of three subtypes of bipolar spectrum disorder—bipolar I, bipolar II and bipolar disorder not otherwise specified (BD-NOS). Bipolar I disorder is considered the classic form of the illness, in which a person experiences recurrent episodes of mania and depression. People with bipolar II disorder experience a milder form of mania called hypomania that alternates with depressive episodes. People with BD-NOS, sometimes called subthreshold bipolar disorder, have manic and depressive symptoms as well, but they do not meet strict criteria for any specific type of bipolar disorder noted in the DSM-IV. Yet, BD-NOS can significantly impair those who have it.

Results of the Study
The prevalence rates of bipolar I, bipolar II and BD-NOS were 0.6 percent, 0.4 percent, and 1.4 percent, respectively, with an overall bipolar spectrum rate of 2.4 percent. The United States had the highest prevalence rate of bipolar spectrum (4.4 percent), while India had the lowest rate (0.1 percent). More than half of those with bipolar disorder in adulthood note that their illness began in their adolescent years.

Across all countries studied, 75 percent of those who had bipolar symptoms met criteria for having at least one other disorder. Anxiety disorders, especially panic disorder, were the most common coexisting disorders, followed by behavior disorders and substance use disorders. Patterns of coexisting conditions were similar across countries.

Less than half of those with bipolar symptoms received mental health treatment. In low income countries, only 25 percent reported having contact with a mental health professional.

Significance
This study provides the first international prevalence data on bipolar disorder using reliable, standardized methodology. It highlights the international impact of bipolar disorder and the need for better recognition and treatment availability. The findings also support the notion that, given its multi-dimensional nature, bipolar disorder may be better characterized as a spectrum disorder.

In addition, because so many people note that their illness began in adolescence — a critical time of life for educational, occupational and social development — early detection, intervention, and possibly prevention of subsequent coexisting disorders and complications should be emphasized.

What’s Next
More research is needed to better define the thresholds and boundaries of bipolar symptoms. In addition, further research is needed to better understand why and how the disorder tends to originate in adolescence and persist into adulthood, and how it intersects with coexisting mental disorders.

Reference
Merikangas KR, Jin R, He J, Kessler RC, Lee S, Sampson NA, Viana MC, Andrade LH, Hu C, Karam EG, Mora MEM, Browne MO, Ono Y, Posada-Villa J, Sagar R, Zarkov Z. Prevalence and correlates of bipolar spectrum disorder in the World Mental Health Survey Initiative. Archives of General Psychiatry. March 2011. 68(3):241-251.

Most Teens with Eating Disorders Go Without Treatment

About 3 percent of U.S. adolescents are affected by an eating disorder, but most do not receive treatment for their specific eating condition, according to an NIMH-funded study published online ahead of print March 7, 2011, in the Archives of General Psychiatry. Social Worker Continuing Education
Background
Kathleen Merikangas, Ph.D., of NIMH and colleagues analyzed data from the National Comorbidity Study-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey of more than 10,000 teens ages 13 to 18. Previously published results found that about 20 percent of youth are affected by a severe mental disorder, and a substantial proportion of these youth do not receive mental health care.

In this new study, the authors tracked the prevalence of eating disorders and the proportion of those youth who received treatment for these disorders.

Results of the Study
According to the data, 0.3 percent of youth have been affected by anorexia, 0.9 percent by bulimia, and 1.6 percent by binge-eating disorder. The researchers also tracked the rate of some forms of eating disorders not otherwise specified (ED-NOS), a catch-all category of symptoms that do not meet full criteria for specific disorders but still impact a person’s life. ED-NOS is the most common eating disorder diagnosis. Overall, another 0.8 percent had subthreshold anorexia, and another 2.5 percent had symptoms of subthreshold binge-eating disorder.

In addition,

Hispanics reported the highest rates of bulimia, while Whites reported the highest rates of anorexia.
The majority who had an eating disorder also met criteria for at least one other psychiatric disorder such as depression.
Each eating disorder was associated with higher levels of suicidal thinking compared to those without an eating disorder.
Significance
The prevalence of these disorders and their association with coexisting disorders, role impairment, and suicidal thinking suggest that eating disorders represent a major public health concern. In addition, the significant rates of subthreshold eating conditions support the notion that eating disorders tend to exist along a spectrum and may be better recognized by doctors if they included a broader range of symptoms. In addition, the findings clearly underscore the need for better access to treatment specifically for eating disorders.

Reference
Swanson SA, Crow SJ, LeGrange D, Swendsen J, Merikangas KR. Prevalence and correlates of eating disorders in adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. Archives of General Psychiatry. Online ahead of print March 7, 2011.

New study shows that most substance abuse treatment programs accept private health insurance

Study indicates that most will be ready to adapt to greater health care coverage provided by the Affordable Care Act and Mental Health Parity and Addiction Equity Act
A new nationwide survey of substance abuse treatment facilities reveals that in 2008 nearly two thirds (65 percent) accepted some private health insurance payment. The survey conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA) also indicated that there were significant differences in the level of private insurance payment acceptance among different types of substance abuse treatment facilities. Professional Counselor Continuing Education
For example, private insurance payment was accepted by 85 percent of facilities with a primary focus on mental health services, 82 percent of facilities offering general health care, and 78 percent of facilities offering a mix of mental health and substance abuse treatment services. On the other hand, private insurance payment was accepted by only 56 percent of facilities primarily focused on substance abuse treatment services and 37 percent of facilities focused on other services (e.g., providing shelter for people experiencing homelessness).

"The ability to bill third party payers including private insurers and Medicaid is critical to the survival of treatment facilities," said SAMHSA Administrator Pamela S. Hyde, J.D. "The dramatic increase in numbers of people covered with health insurance that includes coverage for mental and substance use disorders will revolutionize the behavioral health field. Treatment facilities need to be preparing now and SAMHSA has technical assistance resources available to help."

The study noted that substance abuse treatment facilities that accepted private insurance payments were far more likely than those that did not to accept payment from other sources such as Medicaid (68 percent versus 31 percent), state-financed health insurance (53 percent versus 14 percent) and Medicare (48 percent versus 12 percent).

This capacity of substance abuse programs to bill Medicaid may become more critical as Medicaid’s coverage of substance abuse services becomes more comparable to its coverage of mental health services.

Other significant differences between treatment programs that accepted private insurance payment and those that did not include the use of cognitive-behavioral therapy services at their facilities (70 percent versus 58 percent). Facilities accepting private insurance were more likely than others to accept adolescents into their programs (58 percent versus 33 percent).

The study also showed that treatment facilities located in more central large urban areas were less likely than rurally situated facilities to accept private insurance payment (54 percent versus 78 percent). In general the further away facilities were from central city areas, the more likely they were to accept private insurance payment.

The study, Acceptance of Private Health Insurance in Substance Abuse Treatment Facilities is based on data from SAMHSA’s Treatment Episode Data Set (TEDS) -- a reporting system involving treatment facilities from across the country. The study was developed as part of SAMHSA’s strategic initiative on data, outcomes, and quality -- an effort to inform policy makers and service providers on the nature and scope of behavioral health issues