Key Molecule in Inflammation-Related Depression Confirmed

Scientists have confirmed the role of an immune-activated enzyme in causing inflammation-related depression-like symptoms in mice. The work clarifies how the immune system can trigger depression and, more broadly, demonstrates the potential of this animal model for exploring the relationship between chronic inflammation—a common feature of diseases such as heart disease, cancer, and diabetes—and depression. LPC Continuing Education
Background

When an individual is infected with viruses or bacteria, cells of the immune system respond by secreting proteins called cytokines. These cytokines not only trigger inflammation and orchestrate the body's immune response against the infection, but they also cause changes in behavior, such as fatigue and withdrawal. Beyond these commonly experienced behavioral signs of illness, previous research has shown that cytokines can also cause depression in people with physical illnesses but who have no prior history of mental illness. For instance, around one-third of patients receiving the cytokine interferon-α for treatment of cancer or hepatitis C develop major depression. Clinical evidence has suggested that an enzyme (IDO) activated by these same cytokines might be a key player.

This Study

In this work, scientists used a weakened form of the tuberculosis relative, bacille Calmette-Guérin (BCG), to model chronic inflammation. This strain of bacteria is used outside the U.S. as a vaccine for tuberculosis. Infection of mice with high doses of BCG persistently activates the immune system; as a consequence, the mice develop depressive-like behavior after initial signs of illness have subsided. This study demonstrated that mice in which the gene for IDO is knocked out, or in which IDO is chemically blocked, do not exhibit depressive-like effects. The authors conclude that IDO is a necessary step in the development of this immunity-related depression.

Significance

The compound used in this work to block IDO may have potential as a treatment for depression in instances when immunotherapy such as interferon-α is used. In addition, chronic, low-grade inflammation is a feature not only of infectious diseases, but conditions like cancer, diabetes, obesity, and heart disease. Depression co-occurs frequently with these common diseases and is associated with poorer prospects for future health. Work in this animal model has the potential to provide insight into the role of chronic inflammation in precipitating depression that is often associated with these chronic conditions.

Scientists at the University of Illinois, Urbana-Champaign, led by Jason O'Connor, Robert Dantzer, and Keith Kelley, conducted this work with collaborators at the Centre National de la Recherche Scientifique, Bordeaux, France, and Miles Herkenham at the National Institute of Mental Health. The National Institute of Mental Health and the National Institute on Aging funded this research.

What's Next

The use of BCG in this mouse model offers a means to explore the molecular cascade induced by IDO that leads to inflammation-associated depression. The exact mechanism by which IDO causes these depressive behaviors is not yet clear; exploration of the downstream effects of IDO may provide additional avenues for developing approaches to blocking the development of immune-related depression.

Reference
O'Connor, J.C., Lawson, M.A., Andre, C., Briley, E.M., Szegedi, S.S., Lestage, J., Castanon, N., Herkenham, M., Dantzer, R., and Kelley, K.W. Induction of IDO by Bacille Calmette-Guerin Is Responsible for Development of Murine Depressive-Like Behavior. Journal of Immunology 2009 Mar 1;182(5):3202-12. PMID: 19234218

Combination Treatment for Psychotic Depression Holds Promise

A combination of an atypical antipsychotic medication and an antidepressant known as a selective serotonin reuptake inhibitor (SSRI) may be more effective in treating psychotic depression than an atypical antipsychotic alone, according to results from an NIMH-funded clinical study. Social Worker Continuing Education
Background
Psychotic depression is characterized by major depression accompanied by symptoms such as hallucinations, delusions, and breaks with reality. A person with psychotic depression may be unwilling or unable to care for him or herself and often is admitted to the hospital. Typically, psychotic depression is treated with electroconvulsive therapy (ECT), known to be effective but not always acceptable to patients and their families. It is less commonly treated with an antipsychotic or an antipsychotic plus an antidepressant.

Results of the Study
In a 12-week trial, all 259 participants were required to have psychotic depression with at least one delusion or irrational belief, although not all had hallucinations. Participants were randomly assigned to one of two treatments—the atypical antipsychotic olanzapine (Zyprexa) plus the SSRI sertraline (Zoloft) (combination therapy), or to olanzapine plus a placebo, or inactive, pill (monotherapy). Barnett S. Meyers, M.D., of Cornell University, and colleagues compared rates of remission and side effects among the participants. They also compared the responses of the 117 patients younger than 60 with the responses of the 142 patients older than 60 to determine if the two age groups responded differently.

The researchers conducted assessments at the beginning of the trial, weekly for the first six weeks, and then every other week until week 12. They found that 42 percent of those on combination therapy remitted compared to 24 percent of those on the monotherapy, with no significant differences in remission rates between age groups. Combination therapy's superiority became most evident between weeks eight and 12 of the trial.

Overall, the two age groups experienced comparable side effects. Both groups experienced significant increases in cholesterol and triglyceride levels, and both gained weight. However, the younger age group gained twice as much on average—about 14 pounds—compared to the older group, which gained an average of 7 pounds. This finding is consistent with other reports that have found older adults tend to gain less weight with atypical antipsychotics, specifically olanzapine, the researchers said. However, older participants also tended to be on lower doses of the antipsychotic than the younger adults, which may partially explain the disparity in weight gain, according to the researchers.

Unexpectedly, older participants had no more difficulty tolerating the medications than younger participants, nor were they any more likely to experience falls, sedation or have greater movement disorder symptoms than younger participants.

Overall, about 45 percent of participants dropped out of the study, although the drop-out rate was lower in the combination treatment group (37 percent) compared to the monotherapy group (53 percent).

Significance
Because the drop-out rate was relatively high and no follow-up data on those who discontinued were collected, the authors caution against applying the study's results to clinical practice prematurely. Still, the authors suggest that combination therapy holds promise as an alternative therapy to ECT. "Psychotic depression is difficult to treat," said NIMH Director Thomas R. Insel, M.D. "This study provides insight into one approach to treatment that may be a valid alternative for many patients who cannot or will not undergo ECT."

What's Next
Longer-term studies are needed to evaluate side effects. "Future research must weigh the benefits of continuing atypical antipsychotic medication beyond 12 weeks against the risks of associated metabolic side effects," lead author Meyers concluded.

Reference
Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley-Miklus C, Papademetriou E, Leon AC, Heo M for the STOP-PD study group. A double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression—The Study of Pharmacotherapy of Psychotic Depression (STOP-PD). Archives of General Psychiatry. 2009;66(3):838-847.

Air Force Suicide Prevention Program Reduces Suicide Rate

U.S. Air Force Photo/ Staff Sgt. Angelita M. LawrenceA U.S. Air Force suicide prevention program is associated with reduced suicide rates among Air Force personnel during times in which the program was rigorously implemented and monitored, according to an NIMH-funded study published online ahead of print May 13, 2010, in the American Journal of Public Health. LCSW CEUs
Background
The Air Force Suicide Prevention Program (AFSPP) was implemented in 1997. Based on the premise that individuals at risk for suicide exhibit early warning signs, AFSPP emphasizes leadership and community involvement in reducing suicide by encouraging Air Force leaders to actively support and get involved with suicide prevention efforts. It trains commanders in how and when to seek out mental health services for their troops, provides training to all military and civilian personnel in suicide prevention, and incorporates other community-based components.

Kerry Knox, Ph.D., of the University of Rochester Medical Center, and colleagues studied the impact of AFSPP in reducing suicide among Air Force personnel from 1997 until 2008. They examined suicide rates from 1981 to 2008 to provide historical context during three military conflicts, and a downsizing of the Air Force that occurred in the 1990s.

Results of the Study
The researchers found that suicide rates were significantly lower after the program was launched than before—an average of two suicides per 100,000 per quarter occurred during the intervention period compared to three suicides per 100,000 per quarter prior to the intervention rollout. During the third quarter of 2004, however, suicide rates increased. Knox and colleagues suggest that the upward spike may have been the result of a diminished implementation of ASFPP due to increased demands from the two ongoing wars in Iraq and Afghanistan. In response, Air Force leadership took steps to strengthen implementation of the program and ensure compliance of its components, according to the authors.

Significance
The results suggest that the program is effective but its success is contingent on continuous implementation efforts and ongoing monitoring. The program cannot be maintained by "inherent momentum," the authors concluded.

What's Next
The authors suggest that the program, if maintained and monitored for compliance, can continue to keep suicide rates low in the Air Force. They also suggest that the program could be implemented in other communities and organizations to prevent suicide and reduce the stigma associated with the mental and psychosocial problems that often precipitate suicide attempts.

Reference
Knox K, Pflanz S, Talcott GW, Campise RL, Lavigne JE, Bajorska A, Tu X, Caine ED. The US Air Force Suicide Prevention Program: Implications for Public Health Policy. American Journal of Public Health. Online ahead of print May 13, 2010.

Study Identifies Three Effective Treatments for Childhood Anxiety Disorders

Treatment that combines a certain type of psychotherapy with an antidepressant medication is most likely to help children with anxiety disorders, but each of the treatments alone is also effective, according to a new study funded by the National Institutes of Health’s National Institute of Mental Health (NIMH). The study was published online Oct. 30, 2008, in the New England Journal of Medicine. MFT Continuing Education


“Anxiety disorders are among the most common mental disorders affecting children and adolescents. Untreated anxiety can undermine a child’s success in school, jeopardize his or her relationships with family, and inhibit social functioning,” said NIMH Director Thomas R. Insel, M.D. “This study provides strong evidence and reassurance to parents that a well-designed, two-pronged treatment approach is the gold standard, while a single line of treatment is still effective.”

The Child/Adolescent Anxiety Multimodal Study (CAMS) randomly assigned 488 children ages 7 years to 17 years to one of four treatment options for a 12-week period:

Cognitive behavioral therapy (CBT), a specific type of therapy that, for this study, taught children about anxiety and helped them face and master their fears by guiding them through structured tasks;
The antidepressant sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI);
CBT combined with sertraline;
pill placebo (sugar pill).
The children, recruited from six regionally dispersed sites throughout the United States, all had moderate to severe separation anxiety disorder, generalized anxiety disorder or social phobia. Many also had coexisting disorders, including other anxiety disorders, attention deficit hyperactivity disorder, and behavior problems.

John Walkup, M.D., of Johns Hopkins Medical Institutions, and colleagues found that among those in combination treatment, 81 percent improved. Sixty percent in the CBT-only group improved, and 55 percent in the sertraline-only group improved. Among those on placebo, 24 percent improved. A second phase of the study will monitor the children for an additional six months.

“CAMS clearly showed that combination treatment is the most effective for these children. But sertraline alone or CBT alone showed a good response rate as well. This suggests that clinicians and families have three good options to consider for young people with anxiety disorders, depending on treatment availability and costs,” said Walkup.

Results also showed that the treatments were safe. Children taking sertraline alone showed no more side effects than the children taking the placebo and few children discontinued the trial due to side effects. In addition, no child attempted suicide, a rare side effect sometimes associated with antidepressant medications in children.

CAMS findings echo previous studies in which sertraline and other SSRIs were found to be effective in treating childhood anxiety disorder. The study’s results also add more evidence that high-quality CBT, with or without medication, can effectively treat anxiety disorders in children, according to the researchers.

“Further analyses of the CAMS data may help us predict who is most likely to respond to which treatment, and develop more personalized treatment approaches for children with anxiety disorders,” concluded Philip C. Kendall, Ph.D., of Temple University, a senior investigator of the study. “But in the meantime, we can be assured that we already have good treatments at our disposal.”

The six CAMS sites were Duke University; New York State Psychiatric Institute/Columbia University Medical Center; Johns Hopkins University; Temple University/University of Pennsylvania; University of California, Los Angeles; and the Western Psychiatric Institute and Clinic/University of Pittsburgh Medical Center.



Reference
Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill J, Ginsburg GS, Rynn MA, McCracken J, Waslick B, Iyengar S, March JS, Kendall PC. Cognitive-behavioral therapy, sertraline and their combination for children and adolescents with anxiety disorders: acute phase efficacy and safety. New England Journal of Medicine. Online ahead of print 30 Oct 2008.

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.

Caffeine No Substitute for a Nap to Enhance Memory: Equivalent of 2-3 Cups of Coffee Worsens Motor Learning and Word Recall

Hoping to improve your tennis serve? It's probably better to catch a few winks than load up on java after a lesson, results of a NIMH-supported study suggest. Caffeine impaired such motor learning and verbal memory, while an afternoon nap benefited all three types of learning tested by Sara Mednick, Ph.D., and colleagues at the University of California, San Diego. The researchers report on their findings in the November issue of Behavioural Brain Research. CEUs for MFTs
Background

Ninety percent of Americans use caffeine daily, some substituting it for sleep. While the stimulant enhances alertness and concentration, it's been unclear whether it also helps learning and memory. By contrast, daytime naps, like nighttime sleep, benefit both alertness and memory, Mednick and colleagues have shown in a series of studies.

In this first head-to-head day-time comparison, 61 participants trained in the morning on verbal memory, motor, and perceptual learning tasks. After lunch, one group napped (60-90 min), while two other groups listened to a book on tape and received a pill containing either the caffeine equivalent of a little less than a Tall Starbucks brewed coffee (200mg) or a placebo. Later in the afternoon, the three groups were tested to see how well they had learned the tasks.

Findings of This Study

The nap group performed significantly better on a finger tapping motor task and in recalling words, than the caffeine group. The nap group also trumped the other groups on a texture discrimination task of perceptual learning. The placebo group performed better than the caffeine group on all three tasks. Curiously, just thinking that the pill might contain caffeine — the placebo effect — helped as much as a nap on the motor task.

Significance

Evidence suggests that caffeine interferes with tasks that require processing explicit, as opposed to implicit, information - like recalling a specific word, versus remembering how to type or ride a bike. Studies show that consolidation of such explicit verbal memory during sleep depends on lowered levels of the chemical messenger acetylcholine in the brain's memory hub. Yet, by blocking activity of a natural sedative chemical, caffeine boosts acetylcholine in this hub.

"This increase in acetylcholine by caffeine may impair the consolidation process by blocking replay of new memories," proposes Mednick. "Consistent with this, we found that the greater the explicit component of each task, the worse the caffeine group performed."

What's Next?

"Such an impairment of performance runs counter to society's assumption that caffeine typically benefits cognitive performance," she notes. "Apparent improvements with caffeine might actually reflect a relief from withdrawal symptoms. Just as no medicinal alternative to a good night's rest has been discovered, so too caffeine, the most common pharmacological intervention for sleepiness, may not be an adequate substitute for the memory enhancements of daytime sleep, either."

Mednick and colleagues are using new pharmacological agents found to selectively enhance particular stages of nighttime sleep to see if they can enhance memory consolidation during daytime naps. Brain imaging will pinpoint effects on neural circuits. These studies of pharmacologically enhanced naps could lead to improved treatments for memory impairment in mental disorders, based on manipulations of sleep, say the researchers.

Reference
Mednick SC, Cai DJ, Kanady J, Drummond SP. Comparing the benefits of caffeine, naps and placebo on verbal, motor and perceptual memory. Behav Brain Res. 2008 Nov 3;193(1):79-86. Epub 2008 May 8. PMID: 18554731

Autism Intervention for Toddlers Improves Developmental Outcomes

Children with autism who receive a high intensity developmental behavioral intervention starting by age 18-30 months show major improvements in IQ, language, adaptive behavior, and severity of their diagnosis, according to an NIMH-funded study. Continuing Education for Counselors

Background
Current guidelines by the American Academy of Pediatrics recommend screening children for autism spectrum disorder (ASD) by age 18 months. However, no randomized clinical trials of intensive interventions for this age group had been conducted.

To address this gap, Geraldine Dawson, Ph.D., who was at the University of Washington at the time of the study, and colleagues randomly assigned 48 children, ages 18-30 months, to one of two intervention groups:

Early Start Denver Model (ESDM), a comprehensive, developmental behavioral intervention designed for toddlers with ASD as young as 12 months old. ESDM combines aspects of applied behavioral analysis (ABA) with developmental and relationship-based approaches.
Assess and Monitor (A/M), the comparison group intervention in which parents received recommendations on ASD interventions for their children, as well as referrals to local community providers of the interventions. A/M represents typical community-based care.
Children in the ESDM group were provided 20 hours per week of therapy from study clinicians, while their parents received related training to use ESDM strategies for at least five additional hours per week during their daily activities. Parents of all study participants were also free to receive other community services they thought appropriate.

All children in the study had been diagnosed with autism or a milder form of ASD called pervasive developmental disorder not otherwise specified (PDD-NOS). They were assessed yearly for two years or until the child turned four years old, whichever was longer.

Results of the Study
By the first- year assessment, children in the ESDM group gained 15.4 IQ points on average, while children in the A/M group gained an average of 4.4 points.

Over the two-year study period, children in the ESDM group consistently improved on measures of communication skills. They also showed improvements in motor skills, daily living skills, and other adaptive behaviors.

While children in the ESDM group were significantly delayed in their adaptive behaviors compared to typically developing children, they showed similar rates of improvement. In contrast, children in the A/M group fell further and further behind over time.

By the end of the study, more children who had received ESDM received improved diagnoses than children in the A/M group—seven children initially diagnosed with autistic disorder had their diagnosis change to PDD-NOS after receiving ESDM (30 percent), compared to only one child in the A/M group (5 percent).

Significance
According to the researchers, this is the first randomized controlled trial to study a potentially useful intensive intervention for very young children with ASD.

The study's findings suggest that ESDM can help children with ASD achieve better outcomes in terms of IQ, language, and behavioral skills, and in severity of their ASD diagnosis, than if they receive community-based care. Compared to research on other, similar interventions, this study showed greater differences between groups, suggesting that ESDM, delivered at a very young age, may be more effective than other approaches. The researchers noted that parents' use of ESDM strategies at home may have been key to this intervention's effectiveness.

What's Next
The University of Washington research team has been funded through the NIH Autism Centers of Excellence (ACE) program to follow this study's participants to determine whether the effects of ESDM can be sustained over time. In addition, Dr. Sally Rogers, Ph.D., a co-author on the study and co-developer with Dr. Dawson of the ESDM model, is leading a multi-site, randomized clinical trial of ESDM, also funded through the NIH ACE program. With a larger sample size, the investigators hope to better understand factors that predict level of response to the ESDM intervention.

Reference
Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J. Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model. Pediatrics. 2009 Nov 30. [Epub ahead of print] PubMed PMID: 19948568.

Brain Emotion Circuit Sparks as Teen Girls Size Up Peers

What is going on in teenagers' brains as their drive for peer approval begins to eclipse their family affiliations? Brain scans of teens sizing each other up reveal an emotion circuit activating more in girls as they grow older, but not in boys. The study by Daniel Pine, M.D., of the National Institute of Mental Health (NIMH), part of National Institutes of Health, and colleagues, shows how emotion circuitry diverges in the male and female brain during a developmental stage in which girls are at increased risk for developing mood and anxiety disorders. LCSW CEUs
"During this time of heightened sensitivity to interpersonal stress and peers' perceptions, girls are becoming increasingly preoccupied with how individual peers view them, while boys tend to become more focused on their status within group pecking orders," explained Pine. "However, in the study, the prospect of interacting with peers activated brain circuitry involved in approaching others, rather than circuitry responsible for withdrawal and fear, which is associated with anxiety and depression."

Pine, Amanda Guyer, Ph.D., Eric Nelson, Ph.D., and colleagues at NIMH and Georgia State University, report on one of the first studies to reveal the workings of the teen brain in a simulated real-world social interaction, in the July, 2009 issue of the Journal Child Development.

Thirty-four psychiatrically healthy males and females, aged 9 to 17, were ostensibly participating in a study of teenagers' communications via Internet chat rooms. They were told that after an fMRI (functional magnetic resonance imaging) scan, which visualizes brain activity, they would chat online with another teen from a collaborating study site. Each participant was asked to rate his or her interest in communicating with each of 40 teens presented on a computer screen, so they could be matched with a high interest participant.

Two weeks later, the teens viewed the same faces while in an fMRI scanner. But this time they were asked to instead rate how interested they surmised each of the other prospective chatters would be in interacting with them.

Only after they exited the scanner did they learn that, in fact, the faces were of actors, not study participants, and that there would be no Internet chat. The scenario was intended to keep the teens engaged –– maintain a high level of anticipation/motivation –– during the tasks. This helped to ensure that the scanner would detect contrasts in brain circuit responses to high interest versus low interest peers.

Although the faces were selected by the researchers for their happy expressions, their attractiveness was random, so that they appeared to be a mix of typical peers encountered by teens.

As expected, the teen participants deemed the same faces they initially chose as high interest to be the peers most interested in interacting with them. Older participants tended to choose more faces of the opposite sex than younger ones. When they appraised anticipated interest from peers of high interest compared with low interest, older females showed more brain activity than younger females in circuitry that processes social emotion.

"This developmental shift suggested a change in socio-emotional calculus from avoidance to approach," noted Pine. The circuit is made up of the nucleus accumbens (reward and motivation), hypothalamus (hormonal activation), hippocampus (social memory) and insula (visceral/subjective feelings).

By contrast, males showed little change in the activity of most of these circuit areas with age, except for a decrease in activation of the insula. This may reflect a waning of interpersonal emotional ties over time in teenage males, as they shift their interest to groups, suggest Pine and colleagues.

"In females, absence of activation in areas associated with mood and anxiety disorders, such as the amygdala, suggests that emotional responses to peers may be driven more by a brain network related to approach than to one related to fear and withdrawal," said Pine. "This reflects resilience to psychosocial stress among healthy female adolescents during this vulnerable period."






Nodes of a brain circuit for social emotion and approach behavior activated more in teenage girls than in boys with age. Functional MRI data (red) superimposed on anatomical MRI images.

Source: NIMH Emotion and Development Branch







Teenage participants were first asked to rate their interest in peers with whom they might communicate in an internet chat room (left). Two weeks later, while in a brain scanner, they were asked to rate how interested the same peers were in interacting with them (right).

Source: NIMH Emotion and Development Branch

Reference
Probing the neural correlates of anticipated peer evaluation in adolescence. Guyer AE, McClure-Tone EB, Shiffrin ND, Pine DS, Nelson EE. July 2009, Child Development.

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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.