The Mental Health Social Worker

NIH Grantees Eye Neuroprotective Mechanism for Alzheimer’s

Scientists have discovered a compound that restores the capacity to form new memories in aging rats, likely by improving the survival of newborn neurons in the brain’s memory hub. The research, funded in part by the National Institutes of Health, has turned up clues to a neuroprotective mechanism that could lead to a treatment for Alzheimer’s disease.

“This neuroprotective compound, called P7C3, holds special promise because of its medication-friendly properties,” explained Steven McKnight, Ph.D., who co-led the research with Andrew Pieper, M.D., Ph.D., both of University of Texas Southwestern Medical Center, Dallas. “It can be taken orally, crosses the blood-brain barrier with long-lasting effects, and is safely tolerated by mice during many stages of development.”

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By Faith H. Robinson, CNN

(CNN) — Every Friday morning, students walk into an art class in Atlanta, Georgia. Some look dazed, uncertain in their environment, as if it’s vaguely familiar but they can’t fully recognize where they are — until they sit down and begin to draw.

The moment their brushes hit the paper, their faces light up. Using bright colors — yellows, oranges, greens, purples — they begin to transfer the images from their minds. Sometimes they paint what they want and sometimes they draw the highlighted centerpiece of the day. One week it’s vegetables, another week it’s hats. As their artworks progress, they look happy, smiling and glancing at their teachers for approval. They’re not the only ones who are pleased.

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By Elizabeth Landau
CNN.com Health Writer/Producer

Some guys sound tough – and according to a new study, that may a good way of predicting whether they really are.

Results  in the current Proceedings of the Royal Society B found that people can accurately evaluate the upper-body strength based on men’s voices from four different populations and language groups. The voice samples came from the Tsimane of Bolivia, Andean herder-horticulturalists from Argentina, and college students from the United States and Romania.

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Up to 14 percent of soldiers returning from Iraq suffer Post-Traumatic Stress Disorder (PTSD) or depression that is severe enough to disrupt their daily lives, new research finds. Between 8.5 percent and 14 percent of soldiers reported mental health issues that caused difficulties in work or private life, according to the report published in the Archives of General Psychiatry. After 12 months, there was a sharp increase among Guard members with self-reported depression and PTSD. Researchers speculate these men and women experience stress of going back to work and have less access to medical care. The regular Army soldiers may also suppress symptoms because they know they will be rotated back to duty. (HealthDay News, 6/07/10)

Older veterans with Post-Traumatic Stress Disorder (PTSD) are more likely to develop dementia than fellow vets who don’t have PTSD, new research finds. Researchers followed more than 180,000 veterans aged 55 and older for seven years. All were free from dementia at the study’s outset, while about 30 percent had PTSD. Nearly 11 percent of the vets with PTSD developed dementia during follow-up, compared to only about 7 percent of those who didn’t have PTSD. Once the researchers, whose findings are reported in the Archives of General Psychiatry, took into account factors such as other physical or mental health problems, they found that vets with PTSD were still nearly twice as likely to develop dementia. (Reuters, 6/07/10)

Secondhand smoke may place individuals at greater risk for mental health problems, new research asserts. In a study of 8,155 men and women in the Scottish Health survey, published in the Archives of General Psychiatry, researchers found non-smokers exposed to a lot of secondhand smoke were 50 percent more likely to suffer from psychological distress than those not exposed to other people’s smoke. Their risk of being admitted to a psychiatric hospital over the next six years nearly tripled. Previous studies had suggested a link between smoking and mood disorders, and nicotine exposure in animals is known to trigger depressive symptoms, stress, anxiety and a dampening of feelings of reward and satisfaction. (Reuters, 6/08/10)

Lack of quality long-term relationships related to poorer well-being.

Bad effects depend on certain personality traits; games can offer learning opportunities for others.

WASHINGTON – Playing violent video games can make some adolescents more hostile, particularly those who are less agreeable, less conscientious and easily angered. But for others, it may offer opportunities to learn new skills and improve social networking.

In a special issue of the journal Review of General Psychology, published in June by the American Psychological Association, researchers looked at several studies that examined the potential uses of video games as a way to improve visual/spatial skills, as a health aid to help manage diabetes or pain and as a tool to complement psychotherapy. One study examined the negative effects of violent video games on some people.

“Much of the attention to video game research has been negative, focusing on potential harm related to addiction, aggression and lowered school performance,” said Christopher J. Ferguson, PhD, of Texas A&M International University and guest editor of the issue. “Recent research has shown that as video games have become more popular, children in the United States and Europe are having fewer behavior problems, are less violent and score better on standardized tests. Violent video games have not created the generation of problem youth so often feared.”

In contrast, one study in the special issue shows that video game violence can increase aggression in some individuals, depending on their personalities.

In his research, Patrick Markey, PhD, determined that a certain combination of personality traits can help predict which young people will be more adversely affected by violent video games. “Previous research has shown us that personality traits like psychoticism and aggressiveness intensify the negative effects of violent video games and we wanted to find out why,” said Markey.

Markey used the most popular psychological model of personality traits, called the Five-Factor Model, to examine these effects. The model scientifically classifies five personality traits: neuroticism, extraversion, openness to experience, agreeableness and conscientiousness.

Analysis of the model showed a “perfect storm” of traits for children who are most likely to become hostile after playing violent video games, according to Markey. Those traits are: high neuroticism (e.g., easily upset, angry, depressed, emotional, etc.), low agreeableness (e.g., little concern for others, indifferent to others feelings, cold, etc.) and low conscientiousness (e.g., break rules, don’t keep promises, act without thinking, etc.).

Markey then created his own model, focusing on these three traits, and used it to help predict the effects of violent video games in a sample of 118 teenagers. Each participant played a violent or a non-violent video game and had his or her hostility levels assessed. The teenagers who were highly neurotic, less agreeable and less conscientious tended to be most adversely affected by violent video games, whereas participants who did not possess these personality characteristics were either unaffected or only slightly negatively affected by violent video games.

“These results suggest that it is the simultaneous combination of these personality traits which yield a more powerful predictor of violent video games,” said Markey. “Those who are negatively affected have pre-existing dispositions, which make them susceptible to such violent media.”

“Violent video games are like peanut butter,” said Ferguson. “They are harmless for the vast majority of kids but are harmful to a small minority with pre-existing personality or mental health problems.”

The special issue also features articles on the positives of video game play, including as a learning tool. For example:

• Video games serve a wide range of emotional, social and intellectual needs, according to a survey of 1,254 seventh and eighth graders. The study’s author, Cheryl Olson, PhD, also offers tips to parents on how to minimize potential harm from video games (i.e., supervised play, asking kids why they play certain games, playing video games with their children).
• Commercial video games have been shown to help engage and treat patients, especially children, in healthcare settings, according to a research review by Pamela Kato, PhD. For example, some specially tailored video games can help patients with pain management, diabetes treatment and prevention of asthma attacks.
• Video games in mental health care settings may help young patients become more cooperative and enthusiastic about psychotherapy. T. Atilla Ceranoglu, M.D., found in his research review that video games can complement the psychological assessment of youth by evaluating cognitive skills and help clarify conflicts during the therapy process.

Contact Dr. Christopher Ferguson by e-mail or by phone at (956) 326-2636 or (407) 384-8874 during June 1 – June 15.

Contact Dr. Patrick Markey by e-mail or by phone at (610) 519-4743.

Differences in brain growth patterns between preschool-aged boys with Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and their healthy peers suggest that the disorder may affect brain development both before and after birth, according to NIMH-funded researchers. In addition, their findings indicate ages 1-5 are an important window for better understanding the effects of FXS on brain development. The study was published May 18, 2010, in the Proceedings of the National Academy of Sciences.

Background

In addition to its association with intellectual disability, FXS is the most common known specific genetic risk factor for autism spectrum disorders (ASD). FXS results from mutations on a gene that creates a protein called FMRP. The mutations, in effect, turn off the gene. Relatively little is known about how these mutations affect brain development in early childhood.

Allan Reiss, M.D., of Stanford University, in collaboration with colleagues from Stanford and the University of North Carolina, used magnetic resonance imaging (MRI) to examine changes in brain volumes in 69 boys, first assessed at ages 1-3 and then again an average of two years later at ages 3-5. Of the participants, 41 had FXS, 21 had typical development, and seven had some form of developmental delay.

Results of the Study

The researchers found that some brain regions were similar between the boys with FXS and those without FXS at both times they underwent MRI. Other regions were abnormal among those with FXS at the first time point and remained that way at the second time point, suggesting that the gene mutations responsible for FXS begin to alter brain development early in life, possibly even before birth.

Furthermore, some brain regions were similar among all the participants at the start of the study but showed major differences by the second MRI at ages 3-5.

“This third category is the most interesting because it suggests that we have captured a critical development window of brain development that is significantly affected by fragile X,” said Reiss.

Significance

The same mutations that cause FXS are also strongly linked to ASD. Thus, FXS is considered a model condition for informing research on ASD.

This study provides greater insight into how FXS mutations affect early brain development, which may one day serve as targets for the development and evaluation of new interventions for FXS and related disorders.

What’s Next

The researchers note that their study provides only preliminary information and that it will be crucial to follow the study participants as they enter their school age years, a time when the greatest number and severity of ASD behaviors tend to appear.

Future studies should include larger control samples, track development from an earlier age, and follow participants for a longer period of time. Studies comparing FXS population with those affected by other specific genetic risk factors, such as those occurring in Williams syndrome, may be useful as well.

Reference

Hoeft F, Carter JC, Lightbody AA, Cody Hazlett H, Piven J, Reiss AL. Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome. Proc Natl Acad Sci U S A. 2010 2010 May 18;107(20):9335-9. Epub 2010 May 3. PubMed PMID: 20439717.

An early response to second-course treatment is associated with greater likelihood of remission among teens with hard-to-treat depression, according to recent data from an NIMH-funded study published online ahead of print May 17, 2010, in the American Journal of Psychiatry.

“These results suggest that early treatment decisions are probably the most crucial to the recovery of teens with hard-to-treat depression,” said NIMH Director Thomas R. Insel, M.D.

In the Treatment of Resistant Depression in Adolescents (TORDIA) study, teens whose depression had not improved after an initial course of selective serotonin reuptake inhibitor (SSRI) antidepressant treatment were randomly assigned to one of four interventions for 12 weeks:

• Switch to another SSRI-paroxetine (Paxil), citalopram (Celexa) or fluoxetine (Prozac)
• Switch to a different SSRI plus cognitive behavioral therapy (CBT), a type of psychotherapy that emphasizes problem-solving and behavior change
• Switch to venlafaxine (Effexor), another type of antidepressant called a serotonin and norepinephrine reuptake inhibitor (SNRI)
• Switch to venlafaxine plus CBT

As reported in February 2008, after 12 weeks, about 55 percent of those who switched to either type of medication and added CBT responded, while 41 percent of those who switched to another medication alone responded.

For the most recent findings, Graham Emslie, M.D., of the University of Texas Southwestern Medical Center at Dallas, and colleagues measured the teens’ rate of remission after 24 weeks of treatment. Among the 334 TORDIA participants, 78 percent completed the 24-week assessment. The researchers found that nearly 40 percent of those who completed 24 weeks of treatment achieved remission, regardless of which treatment to which they had initially been assigned. However, those who achieved remission were more likely to have responded to treatment early—during the first 12 weeks.

Those who had very severe depression at baseline, a sense of hopelessness, anxiety and family conflict were less likely to achieve remission. Those who were taking an additional mood stabilizing medication, such as an antipsychotic or anti-anxiety medication, or who were receiving CBT, were more likely to achieve remission, but ONLY if the teens received these additional treatments in the first 12 weeks.

Moreover, those who achieved remission tended to have responded to treatment by six weeks into treatment compared to those who had not achieved remission by 24 weeks, underscoring the importance of early treatment decisions.

The authors suggest that the current clinical guidelines, which recommend staying with a treatment for at least eight to twelve weeks before trying another, may need to be revisited. More research is needed to clarify when is the optimal time to change a treatment strategy among treatment-resistant teens with depression, they concluded.

Reference

Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD,Asarnow JR, Spirito A, Birmaher B, Ryan N, Kennard B, DeBar L, McCracken J, Strober M, Onorato M, Zalazny J, Keller M, Iyengar S, Brent D. Treatment of resistant depression in adolescents (TORDIA): week 24 outcomes. American Journal of Psychiatry. Online ahead of print May 17, 2010.

A coordinated, multi-component treatment approach was more effective in treating anxiety disorders than usual care found in primary care settings, according to an NIMH-funded study published May 19, 2010, in a special issue of the Journal of the American Medical Association devoted to mental health.

Background

Research has found that a collaborative care approach, in which one care manager coordinates a team of treatment providers, is effective in treating depression. However, research is limited on whether the same type of approach could work to treat anxiety disorders, which are commonly treated in primary care settings.

In response, Peter Roy-Byrne, M.D., of the University of Washington Seattle, and colleagues designed a flexible collaborative treatment model for anxiety disorders—Coordinated Anxiety Learning and Management (CALM)—and compared it to usual care. CALM included cognitive behavioral therapy (CBT) that was tailored to any one of four anxiety disorders—panic disorder, generalized anxiety disorder, social anxiety disorder or post traumatic stress disorder. It also included strategies to improve medication delivery and adherence. Of the 1,004 participants recruited from 17 primary care clinics in four U.S. cities, half were randomized to CALM and were allowed to choose whether they received CBT, medication, or both. The other participants were referred to usual care which could include medication, brief counseling with a physician, or referral to a mental health specialist. All participants were diagnosed with at least one of the four anxiety disorders addressed in the CBT program.

CALM participants received their initial treatment for 10 to 12 weeks. Those who still had symptoms after 12 weeks could receive additional CBT or medication, or both. They then received monthly follow-up phone calls to reinforce CBT skills or medication management advice for up to a year.

CALM relied on a computerized program to help train care managers in CBT techniques and ensure consistency of care. The computer program employed CBT principles common to all anxiety disorders, but included specific techniques designed to address the four anxiety disorders in the study, thus allowing for personalized treatment.

Care managers also encouraged participants to stay in treatment and monitored their reactions to medication, relaying any observations and suggestions for changes to the primary care provider. CALM tracked participants’ progress and outcomes through a web-based monitoring system as well.

Results of the Study

Participants in the CALM group showed significantly greater symptom improvement than those receiving usual care. After 12 months, about 63.6 percent receiving CALM had responded to treatment compared to 44.7 percent in usual care, and 51.5 percent receiving CALM had remitted compared to 33 percent in usual care.

CBT appeared to be the most popular treatment choice among those in the CALM group—57 percent chose CBT and medication combination treatment, and 34 percent chose CBT-only treatment, while 9 percent chose medication-only treatment. This preference is consistent with research that finds those with anxiety disorders tend to favor psychosocial treatment approaches over medication to treat their illness, said the researchers.

Significance

Because CALM included flexible treatment options, targeted multiple anxiety disorders, and was effective across a range of patients and clinics, it is broadly applicable in primary care settings. It could serve as a model for developing effective collaborative care of people with anxiety disorders as well as those with coexisting psychiatric disorders like depression, a situation commonly found in clinical settings.

What’s Next

Research is needed to determine how the strategy could best be implemented in primary care settings. In addition, a cost analysis of CALM is needed to determine whether it is a financially feasible option for payers and clinical settings.

Reference

Roy-Byrne P, Craske MG, Sullivan G, Rose RD, Edlund MJ, Lang AJ, Bystritsky A, Welch SS, Chavira DA, Golinelli D, Campbell-Sills, L, Sherbourne CD, Stein MB. Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial. Journal of the American Medical Association. 19 May 2010. 303(19).

A comprehensive behavioral therapy is more effective than basic supportive therapy and education in helping children with Tourette syndrome manage their tics, according to a study funded by the National Institute of Mental Health (NIMH). The study was published May 19, 2010, in a special issue of the Journal of the American Medication Association dedicated to mental health.

“People with Tourette syndrome experience considerable impairment and social isolation, and effective treatments are limited,” said NIMH Director Thomas R. Insel, M.D. “This study makes a strong case for a specialized behavioral therapy, either as a stand-alone treatment or as an adjunct to medication.”

Tourette syndrome is a chronic neurological disorder that is associated with motor or vocal tics that can be embarrassing and disruptive. It is commonly treated with antipsychotic medication such as haloperidol or risperidone. But these medications often are unable to eliminate tics entirely. They also are associated with troubling side effects such as weight gain and sedation. Few studies have examined the effectiveness of behavioral interventions.

John Piacentini, Ph.D., of the University of California Los Angeles, and colleagues tested the effectiveness of a Comprehensive Behavioral Intervention for Tics (CBIT), a therapy based on habit reversal training that includes two concepts—tic-awareness and competing-response training. Tic-awareness training teaches the child how to self-monitor for early signs that a tic is about to occur. Competing-response training teaches the child how to engage in a voluntary behavior designed to be physically incompatible with the impending tic, thereby disrupting the cycle and decreasing the tic. For example, a child with vocal tics who blurts out words or sounds inappropriately may be taught slow rhythmic breathing techniques to manage the urge to vocalize.

CBIT includes parent training as well. Parents in the study were taught how to manage their own reactions to their children’s tics, and how to best encourage and praise their children for practicing the behavioral intervention techniques they were learning.

“CBIT emphasizes the development of skills that foster autonomy and empowerment, allowing for patients and their families to take an active role in treatment,” said Dr. Piacentini.

The researchers randomized 126 children ages 9-17 at several sites to either CBIT or a control treatment that included supportive therapy and basic education about the condition. Each group received eight sessions over a 10-week period. Those who responded to therapy received monthly booster sessions for three months, and were assessed three months and six months after the 10-week acute treatment ended.

About 52.5 percent of the children who received CBIT showed significant symptom improvement compared to 18.5 percent receiving the control treatment. The benefits of CBIT also appeared to endure over time—87 percent of CBIT responders who were reassessed six months after the end of the 10-week trial continued to benefit.

“The response to CBIT is comparable to results of trials with antipsychotic medications for Tourette syndrome,” said Dr. Piacentini.

In addition, few children dropped out of the study, suggesting that the intervention was well-received and tolerated by both the children and parents. Moreover, the researchers note that 38 percent of children in the study were already taking medication for their disorder when they entered the study and were allowed to remain on the medication. Many also had co-existing disorders. Both these conditions mimic real-world situations, making the results more relevant to clinical populations.

The authors note that although CBIT helped many children, not all children in the study benefited from the treatment. They suggest that future analyses may provide guidance on who is most likely to respond to the therapy, allowing for more personalization of treatment. “We’ve shown that it works about as well as the standard medications for tics but without the negative side effects,” concluded Dr. Piacentini. “Knowing that CBIT is effective for many patients with Tourette syndrome adds to the available treatment options for this disorder.”

Dr. John Piacentini of UCLA talks about CBIT, a new therapy that treats tics associated with Tourette Syndrome

Read transcript.

Reference

Piacentini J, Woods DW, Scahill L, Wilhelm S, Peterson AL, Chang S, Ginsburg G, Deckersbach T, Dziura J, Levi-Pearl S, Walkup JT. Randomized trial of a behavioral intervention for children with Tourette’s Disorder. Journal of the American Medical Association. 19 May 2010. 303(19).

Targeting Gene Regulator in Brain Reward Circuit Eyed as Treatment

Scientists have discovered a mechanism that helps to explain resilience to stress, vulnerability to depression and how antidepressants work. The new findings, in the reward circuit of mouse and human brains, have spurred a high tech dragnet for compounds that boost the action of a key gene regulator there, called deltaFosB.

A molecular main power switch – called a transcription factor – inside neurons, deltaFosB turns multiple genes on and off, triggering the production of proteins that perform a cell’s activities.

“We found that triggering deltaFosB in the reward circuit’s hub is both necessary and sufficient for resilience; it protects mice from developing a depression-like syndrome following chronic social stress,” explained Eric Nestler, M.D., of the Mount Sinai School of Medicine, who led the research team, which was funded by the National Institute of Health’s National Institute of Mental Health (NIMH).

“Antidepressants can reverse this social withdrawal syndrome by boosting deltaFosB. Moreover, deltaFosB is conspicuously depleted in brains of people who suffered from depression. Thus, induction of this protein is a positive adaptation that helps us cope with stress, so we’re hoping to find ways to tweak it pharmacologically,” added Nestler, who also directs the ongoing compound screening project.

Nestler and colleagues report the findings that inspired the hunt online May 16 2010 in the journal Nature Neuroscience.

“This search for small molecules that augment the actions of deltaFosB holds promise for development of a new class of resilience-boosting treatments for depression,” said NIMH director Thomas R. Insel. “The project, funded under the American Recovery and Reinvestment Act of 2009, is a stunning example of how leads from rodent experiments can be quickly followed up and translated into potential clinical applications.”

DeltaFosB is more active in the reward hub, called the nucleus accumbens (see diagram below), than in any other part of the brain. Chronic use of drugs of abuse – or even natural rewards like excess food, sex or exercise – can gradually induce increasing levels of this transcription factor in the reward hub. Nestler and colleagues have shown that this increase in deltaFosB can eventually lead to lasting changes in cells that increase rewarding responses to such stimuli, hijacking an individual’s reward circuitry – addiction.

The new study in mice and human post-mortem brains confirms that the same reward circuitry is similarly corrupted (though to a lesser degree than with drugs of abuse) in depression via effects of stress on deltaFosB.

Depressed patients often lack motivation and the ability to experience reward or pleasure — and depression and addiction often go together. Indeed, mice susceptible to the depression-like syndrome show enhanced responses to drugs of abuse, the researchers have found.

But the similarity ends there. For, while an uptick in deltaFosB promotes addiction, the researchers have determined that it also protects against depression-inducing stress. It turns out that stress triggers the transcription factor in a different mix of nucleus accumbens cell types — working through different receptor types — than do drugs and natural rewards, likely accounting for the opposite effects.

The researchers explored the workings of deltaFosB in a mouse model of depression. Much as depressed patients characteristically withdraw from social contact, mice exposed to aggression by a different dominant mouse daily for 10 days often become socially defeated; they vigorously avoid other mice, even weeks later.

Among key findings in the brain’s reward hub:

• The amount of deltaFosB induced by the stress determined susceptibility or resilience to developing the depression-like behaviors. It counteracted the strong tendency to learn an association, or generalize the aversive experience to all mice.
• Induction of deltaFosB was required for the antidepressant fluoxetine (Prozac) to reverse the stress-induced depression-like syndrome.
• Prolonged isolation from environmental stimuli reduced levels of deltaFosB, increasing vulnerability to depression-like behaviors.
• Among numerous target genes regulated by deltaFosB, a gene that makes a protein called the AMPA receptor is critical for resilience — or protecting mice from the depression-like syndrome. The AMPA receptor is a protein on neurons that boosts the cell’s activity when it binds to the chemical messenger glutamate.
• Increased activity of neurons triggered by heightened sensitivity of AMPA receptors to glutamate increased susceptibility to stress-induced depression-like behavior.
• Induction of deltaFosB calmed the neurons and protected against depression by suppressing AMPA receptors’ sensitivity to glutamate.
• Post-mortem brain tissue of depressed patients contained only about half as much deltaFosB as that of controls, suggesting that poor response to antidepressant treatment may be traceable, in part, to weak induction of the transcription factor.

Reduced deltaFosB in the reward hub likely helps to account for the impaired motivation and reward behavior seen in depression, said Nestler. Boosting it appears to enable an individual to pursue goal-directed behavior despite stress.

The high-tech screening for molecules that boost DeltaFosB, supported by the Recovery Act grant, could lead to development of medications that would help people cope with chronic stress. The molecules could also potentially be used as telltale tracers in brain imaging to chart depressed patients’ treatment progress by reflecting changes in deltaFosB, said Nestler.

Few youths with early-onset schizophrenia who are treated with antipsychotic medications for up to a year appear to benefit from their initial treatment choice over the long term, according to results from an NIMH-funded study. The study was published online ahead of print May 4, 2010, in the Journal of the American Academy of Child and Adolescent Psychiatry.

Background

The NIMH Treatment of Early Onset Schizophrenia Study (TEOSS) included 116 youth between 8 and 19 years old, diagnosed with early onset schizophrenia spectrum disorder (EOSS). The TEOSS team randomly assigned the children to eight weeks of either olanzapine (Zyprexa) or risperidone (Risperdal)—both new generation atypical antipsychotics—or to the older conventional antipsychotic molindone (Moban). Response rates after eight weeks of treatment were comparable among the three medications. The results were reported in September 2008.

After the initial 8-week trial, 54 of the 116 participants entered the maintenance treatment phase in which they continued their initial medication and were monitored for up to 44 more weeks of treatment. Only 14 participants completed the additional 44 weeks of treatment.

Results of the Study

Robert Findling, M.D., of Case Western Reserve University in Cleveland, and the TEOSS team reported that the participants’ treatment response tended to plateau during the follow-up, maintenance therapy period, such that most of the children did not improve beyond what they had already achieved during the initial eight weeks of treatment. In addition, most discontinued treatment during the maintenance phase, most commonly due to side effects such as weight gain, anxiety, increases in cholesterol levels, and other metabolic changes, regardless of which treatment they were receiving. None of the three medications appeared to be more effective than the others.

Significance

The findings suggest that few youths with EOSS continue treatment on the same antipsychotic medication over the long-term, with lack of effectiveness and adverse effects cited as the most common reasons for discontinuation. Most of those who initially responded to medication were able to at least maintain their initial improvements, but very few participants stayed on the medication through the 12-month study most frequently because of intolerable side effects.

What’s Next

The authors conclude that more effective and safer treatments need to be developed to treat children with EOSS.

Reference

Findling R. Johnson JL, McClellan J, Frazier JA, Vitiello B, Hamer RM, Lieberman JA, Ritz L, McNamara NK, Lingler J, Hlastala S, Pierson L, Puglia M, Maloney AE, Kaufman EM, Noyes N, Sikich L. Double-blind maintenance safety and effectiveness findings from the TEOSS. Journal of the American Academy of Child and Adolescent Psychiatry. Available online May 4, 2010.

Confirming results from earlier research, a clinical trial of treatment for major depression showed that the medication scopolamine, commonly used for motion sickness and as a sedative, could lift symptoms of depression within days, far faster than current antidepressants. Though the study was small, the magnitude of scopolamine’s effects in comparison with placebo suggests that this class of medications has potential for rapid treatment of depression.

Background

Currently available antidepressants typically require 3 to 4 weeks to take effect. In addition, despite a range of existing medications for depression, it’s estimated that 30 to 40 percent of patients do not respond at all to antidepressants. Developing new medications that act with alternative mechanisms to those already available—and more quickly—is an important goal of current research.

The most commonly used antidepressant medications affect signaling by serotonin, a neurotransmitter known to play a role in mood. Scopolamine interacts with cell receptors for another neurotransmitter, acetylcholine. Scopolamine is one of a class of compounds that block a specific type of receptor for acetylcholine (muscarinic receptors). Although various lines of research have suggested that acetylcholine-related activity plays a role in depression, to date, other neurotransmitter systems have been thought to be more central in the development of depression.

This Study

This study sought to replicate an earlier trial that demonstrated the ability of scopolamine to relieve symptoms of depression quickly in a group of patients with major depressive disorder or bipolar disorder. The current study focused on people with major depressive disorder. Like the earlier study, this one compared scopolamine with placebo, and was double-blind in that neither patients nor clinicians administering medication knew whether patients were receiving placebo or scopolamine (both were given intravenously).

After an initial treatment session in which all 22 patients in the trial received placebo once, half then received scopolamine three times, each treatment 3 to 5 days apart, and then placebo three more times, 3 to 5 days apart. The other half, after the initial placebo dose, received placebo three more times, then scopolamine three times. Patients receiving scopolamine first reported positive effects by the time they returned for a second dose 3 to 5 days later; many even reported improvement by the morning following treatment. After three treatments, their scores on a test for depression symptoms declined by 32 percent compared with 6.5 percent for placebo. These improved scores persisted until the end of the trial. Those receiving scopolamine after placebo had a 53 percent reduction in depression scores by the end of the clinical trial. Eleven of those in the trial experienced complete remission (one of those while on placebo).

Side-effects of scopolamine included drowsiness, dry mouth, light headedness, and blurred vision, but they were transient, resolving within hours.

Significance

Depression is a costly disease for both society and individuals. It is a leading cause of disability worldwide. For individuals and their family members, major depression is painful and frightening; depression is the predominant risk factor for suicide, the 11th leading cause of death in the U.S. The need for effective, rapid treatment alternatives is an urgent one.

While this is a small study, the difference between the response to scopolamine and placebo was statistically significant. By the end of the study 14 of the 22, or 64 percent of subjects, had achieved at least a 50 percent reduction in symptoms.

Subjects in the study reported short-term sedation but not euphoria with scopolamine. The antidepressant effects persisted weeks after the medication was no longer in the bloodstream. It is possible, according to the authors, that scopolamine’s antidepressant effects escaped notice earlier because it is usually used in smaller doses (such as for motion sickness) than in this study. The authors note the importance of replicating this work in larger groups of patients and developing more practical means of administering scopolamine. Further research will also provide information on the exact mechanism of action of the drug, a guide to development of additional new medications.

Dr. Maura Furey talks about her research with Scopolamine.

Read transcript.

References

Drevets, W.C. and Furey, M.L. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biological Psychiatry 67:432-8, 2010.

Furey, M.L. and Drevets, W.C. Antidepressant efficacy of the antimuscarinic drug scopolamine. Archives of General Psychiatry 63:1121-1129, 2006.

Trial of Non-Invasive Treatment Used New, Convincing Sham Control

Some depressed patients who don’t respond to or tolerate antidepressant medications may benefit from a non-invasive treatment that stimulates the brain with a pulsing electromagnet, a study suggests. This first industry-independent, multi-site, randomized, tightly controlled trial of repetitive transcranial magnetic stimulation (rTMS) found that it produced significant antidepressant effects in a subgroup of patients, with few side effects.

Active rTMS treatment accounted for remissions in 14 percent of antidepressant-resistant patients actively treated, compared to about 5 percent for a simulated treatment.

“Although rTMS treatment has not yet lived up to early hopes that it might replace more invasive therapies, this study suggests that the treatment may be effective in at least some treatment-resistant patients,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health, which funded the study.

Mark George, M.D., of the Medical University of South Carolina, Charleston; Harold Sackeim, Ph.D., and Sarah Lisanby, M.D., of Columbia University, New York City; David Avery, M.D., of the University of Washington, Seattle; William McDonald, M.D., of Emory University, Atlanta; and colleagues, report on their findings in the May 2010 issue of the Archives of General Psychiatry.

“This study should help settle the debate about whether rTMS works for depression,” said George, who led the research team. “We can now follow up clues suggesting ways to improve its effectiveness, and hopefully further develop a potential new class of stimulation treatments for other brain disorders.”

The treatment aims to jump-start underactive mood-regulating circuitry by targeting the top left front part of the brain with an electromagnetic coil that emits 3,000 pulses over a 37-minute session. It can be safely administered in a doctor’s office with few side effects — unlike more invasive brain stimulation treatments, such as electroconvulsive therapy (ECT) (See Background below).

Following a decade and a half of studies yielding mixed results, the FDA cleared an rTMS device for treatment of mildly treatment resistant depression in 2008, based on data submitted by the manufacturer. The field has been awaiting the results of the NIMH-funded multi-site trial to provide more definitive evidence of efficacy.

Lack of a convincing simulation control treatment that mimics transient tapping and twitching sensations produced by the magnet weakened confidence in findings of some previous rTMS studies. To address these concerns, the new study sought to blind patients, treaters and raters with a simulation control treatment that produced the same head-tapping sensation and scalp twitching as the active treatment. A metal insert below the magnet blocked the magnetic field from entering the brain, while electrodes touching the scalp delivered the tapping sensation. This simulation was so convincing that even the treaters could not confidently guess the randomization above chance level, according to the researchers.

A sample of 190 patients who had previously failed to respond to antidepressant medications received at least three weeks of randomized, controlled magnetic stimulations on weekdays for three weeks, with the rTMS magnet aimed at their brain’s left prefrontal cortex. Those who showed improvement received up to an additional three weeks of such blinded treatment.

Thirteen (14 percent) of 92 patients who received the active treatment achieved remission, compared to 5 (about 5 percent) of 98 patients who received the simulation treatment. Patients who received active rTMS were significantly more likely to reach remission, particularly if they had been moderately, rather than severely, treatment resistant. The remission rate climbed to nearly 30 percent in an open-label phase of this study in which there was no simulation control. George said this is comparable to rates seen in the STAR*D medication studies. However, the researchers note that “the overall number of remitters and responders was less than one would like with a treatment that requires daily intervention for three weeks or more, even with a benign side effect profile.”

Patients who responded to active treatment received up to three weeks of additional blinded, controlled rTMS until they achieved remission or stopped showing a meaningful response – so the number of responders did not differ significantly from the number of remitters. These patients who remitted then received a combination of medications intended to help maintain the treatment effect. Despite failing to respond to medications in the past, most remained in remission for several months.

Study participants who failed to improve during the blinded phase entered a course of open-label rTMS. Among those who had been in the active rTMS group, 30 percent achieved remission during this second phase. This suggests that some patients might require as many as 5-6 weeks of daily rTMS treatment, according to George. Most patients who remitted required 3-5 weeks of treatment.

“For treatment resistant-patients, we found that rTMS is at least as good as current medications or anything else we have available, except ECT,” said George. “Our current antidepressants do not work for many people.”

Since the rTMS treatment did not trigger any seizures or notable side effects, the researchers propose that higher levels of magnetic stimulation be used in future studies, as evidence suggests antidepressant effects of such stimulation are dose-dependent. Higher remission rates might also be attainable if rTMS were combined with medications, they suggest.

Using magnetic resonance imaging (MRI) scans of patients’ brains showing exactly where the magnetic coil was positioned, the researchers hope to confirm earlier findings suggesting that a more forward and to-the-side placement produces a larger therapeutic effect. They plan to report the results of the MRI analysis at the American Psychiatric Association meeting in late May.

Background

George, and colleagues, had earlier pioneered magnetic stimulation as a treatment for depression while at the NIMH intramural research program, beginning in the early l990s. They adapted a technology that NIH colleagues had developed for basic science studies to experimentally probe the brain. The prevailing brain stimulation therapy for treatment-resistant depression, ECT, involved a much more invasive, seizure-inducing procedure requiring general anesthesia in a surgical suite, with risk of memory loss. By contrast, rTMS could be administered to an awake, alert patient in an office setting, without a seizure or side effects — if it could be shown to work. Some skeptics argued, for example, that a seizure might be essential for a robust antidepressant effect.

In rTMS, a pulsing electromagnetic coil aimed at the brain area to be stimulated generates a magnetic field that passes readily through the skull, inducing an electrical current in the immediately adjacent brain tissue. By contrast, ECT requires a current sufficient to penetrate the skull’s resistance to electricity.

Since brain imaging studies by George and colleagues found that the brain’s left prefrontal cortex is under-activated in depression, their pilot rTMS studies targeted the magnet at this area, theorizing that the stimulation would likely be telegraphed to other mood-regulating areas via neural circuitry.

Following a course of such daily treatments over several weeks, some patients’ mood lifted while others did not change. In the years following these early studies, dozens of small, weakly controlled studies testing rTMS for depression have continued to report varied results, so skepticism continued.

Meanwhile, neuroscience advances have led to a proliferation of clinical trials testing rTMS as a potential treatment for a variety of other conditions — from tinnitus to schizophrenia. New, invasive brain stimulation treatments for depression have also appeared — including deep brain stimulation, vagus nerve stimulation and magnetic seizure therapy. Magnetic seizure therapy is a more robust version of TMS which produces a seizure on purpose and thus requires anesthesia and a similar setting as ECT. Sobering assessments of the current crop of antidepressants’ real-world effectiveness have also emerged from large-scale studies, such as STAR*D. These coincided with growing public demand for more effective, side effect-free treatments, sparking continued interest in rTMS.

Against this backdrop, the 2008 FDA clearance, or reclassification, allowed the marketing of an rTMS device for treatment of depression in mildly treatment-resistant patients, rather than for use in treatment of depression generally.

Reference

Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PD, Schwartz T, Sackeim HA. Arch Gen Psychiatry. 2010 May.

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.

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.

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 online ahead of print, March 23, 2010, doi:10.1038/mp.2010.34.