Science Update
November 18, 2009

Long-term Depression Treatment Leads to Sustained Recovery for Most Teens

Long-term treatment of adolescents with major depression is associated with continuous and persistent improvement of depression symptoms in most cases, according to the most recent analysis of follow-up data from the NIMH-funded Treatment of Adolescents with Depression Study (TADS). The report, along with a commentary compiling the take-home messages of the study, was published in the October 2009 issue of the American Journal of Psychiatry.

Background

The TADS team randomly assigned 439 adolescents aged 12 to 17 to one of four treatment strategies for 36 weeks—the antidepressant fluoxetine (Prozac) only, cognitive behavioral therapy (CBT) only, the combination of the two, or placebo (inactive or “sugar” pill). After the first 12 weeks, the placebo group was discontinued, while the participants assigned to the active interventions continued treatment for another six months. Overall, the combination therapy was found to be the most effective in speeding up remission. Visit the NIMH website for more information about TADS results.

After the trial ended, the teens who had been assigned to the active treatments were assessed up to four times during the following year to determine if improvements were sustained over time. TADS treatments were no longer offered, but participants were encouraged to continue to seek treatment within their communities.

Participants who had been assigned to the placebo group received open treatment during the one-year follow-up period and were not included in this follow-up assessment. About 66 percent of TADS subjects (not including those who had been in the placebo group) participated in at least one assessment during the follow-up year.

Results of the Study

By the end of the 36-week trial, 82 percent of participants had improved and 59 percent had reached full remission. During the follow-up year, most participants maintained their improvements, and the remission rate climbed to 68 percent. However, about 30 percent of the participants who were in remission at week 36 became depressed again during the following year.

In addition, while 91 percent of participants showed no evidence of suicidal thinking or behavior at the end of the trial, 6 percent developed suicidal thinking during the follow-up year, with no statistically significant differences among the treatment groups.

Significance

The longer-term treatment of TADS, regardless of treatment strategy, was associated with lasting benefits for the majority of participants. However, a significant number of those who had recovered worsened during the follow-up period, indicating a need for continuous clinical monitoring and further improvement in long-term treatment of youth with major depression.

What’s Next?

The final results of TADS suggest that for most teens with depression, long-term, evidence-based treatments are effective and sustainable. But future research should concentrate on improving treatment strategies to reduce the rate of depression relapse or deterioration. The authors suggest that a randomized maintenance therapy trial would help determine how long active treatment should last to ensure the effects of treatment will endure over time.

References

TADS Team. The Treatment for Adolescents with Depression Study (TADS): Outcomes over one year of naturalistic follow-up. American Journal of Psychiatry. 2009 Oct. 166(10): 1141-1149.

March JS and Vitiello B. Take home messages from the Treatment for Adolescents with Depression Study (TADS). American Journal of Psychiatry. 2009 Oct.166(10):1118-1123.

Press Release
November 20, 2009

Parent Training Complements Medication for Treating Behavioral Problems in Children with Pervasive Developmental Disorders

Treatment that includes medication plus a structured training program for parents reduces serious behavioral problems in children with autism and related conditions, according to a study funded by the National Institute of Mental Health (NIMH). The study, which was part of the NIMH Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, was published in the December 2009 issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

Results from a previous RUPP study reported in 2002 showed that the antipsychotic medication risperidone (Risperdal) reduced such behavior problems as tantrums, aggression and self-injury in children with autism. However, most children’s symptoms returned when the medication was discontinued. Although effective, risperidone is associated with adverse effects such as weight gain, which can lead to metabolic changes, obesity and related health problems.

“Medication alone has been shown to help with some symptoms of autism, but its potential is limited,” said NIMH Director Thomas R. Insel. “This study shows promise of a more effective treatment protocol that could improve life for children with autism and their families.”

In the study, the RUPP group tested the benefits of medication alone compared to medication plus a parent training program that actively involves parents in managing their children’s severely disruptive and noncompliant behavior. Parents were taught to modify their children’s behavior and learned to enhance their children’s daily living skills.

The 24-week, three-site trial included 124 children ages 4 to 13 with pervasive developmental disorders (PDD) such as autism, Asperger’s or related disorders accompanied by tantrums, aggression and self-injury. The children were randomized to a combination of risperidone and parent training, or to risperidone only. Parents in combination therapy received an average of 11 sessions of training over the course of the study.

Although both groups improved over the six-month trial, the group receiving combination therapy showed greater reduction in behavioral problems like irritability, tantrums and impulsiveness compared to the group receiving medication only. The combination therapy group also ended the trial taking an average dose of 1.98 milligrams (mg) per day of risperidone, compared to 2.26 mg/day in the medication-only group—a 14-percent lower dose. However, children in both groups gained weight, indicating “a need to learn more about the metabolic consequences of medications like risperidone,” said the authors.

“The combination group was able to achieve its gains with a lower dose of medication. Plus, it appeared that the benefits of added behavioral treatment increased over time, a strong signal that actively including parents in the treatment of children with PDD could only benefit families, ” said lead author Michael Aman, Ph.D., of the Ohio State University.

“Future studies will evaluate whether the benefits of parent training endure over a long period of time,” concluded the authors. The investigators also plan to apply the parent training to younger children with PDD to prevent the evolution of serious behavioral problems. Future studies may also look for ways in which the parent training program can be used in schools and community clinics.

Reference

Aman MG, McDougle CJ, Scahill L, Handen B, Arnold LE, Johnson C, Stigler KA, Bearss K, Butter E, Swiezy NB, Sukhodolsky DD, Ramadan Y, Pozdol SL, Nikolov R, Lecavalier L, Kohn AE, Koenig K, Hollway JA, Korzekwa P, Gavaletz A, Mulick JA, Hall KL, Dziura J, Ritz L, Trollinger S, Yu S, Vitiello B, Wagner A, for the Research Units on Pediatric Psychopharmacology Autism Network. Medication and parent training in children with pervasive developmental disorders and serious behavior problems: results from a randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry. 2009 Dec. 48(12):1143-1154.

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.

Science Update
December 02, 2008

Anxious and Depressed Teens and Adults: Same Version of Mood Gene, Different Brain Reactions

An NIMH study using brain imaging shows that some anxious and depressed adolescents react differently from adult patients when looking at frightful faces. This difference occurs even though the adolescent and adult patients have the same version of a mood gene. Researchers in the NIMH Mood and Anxiety Disorders Program and colleagues reported these findings online October 31, 2008, in the journal Biological Psychiatry.

Background

Anxiety and depression are influenced by the processing of the mood-regulating brain chemical called serotonin. A protein known as the serotonin transporter directs serotonin from the space between nerve cells back into the cells, where it can be reused. Changes in the gene that codes for the serotonin transporter can lead to decreased transport of serotonin back into the brain’s nerve cells. Abnormalities in the serotonin system are associated with anxiety and depression.

Everyone inherits two copies of the serotonin transporter gene—one from each parent. The gene has various versions—one version is short, and one version is long. A person may have two copies of the same version or one copy each of two different versions. Previous studies in adults have linked versions of the gene to increased risk for mood and anxiety disorders. Adults who have one copy of the short version tend to be more anxious and depressed than adults who have two copies of the long version.

Previous brain imaging studies in adults linked gene versions to different responses of the brain’s fear hub—the amygdala—to frightful faces. In both healthy and affected adults who have at least one copy of the short version, the amygdala reacts more than it does in healthy or affected adults who have two copies of the long version of the gene. Whether these findings in adults also hold true for adolescents was unknown.

Using functional magnetic resonance imaging (fMRI), Jennifer Y. F. Lau, Ph.D., then at NIMH and now at the University of Oxford, U.K., and colleagues at NIH scanned the brains of 33 healthy teens and 31 teens with depression and anxiety disorders while they viewed pictures of frightful faces. Then the investigators compared the amygdala reactions in the two groups.

Findings of This Study

Lau and colleagues found that in healthy adolescents who have at least one copy of the short version of the gene, the amygdala reacts more than it does in healthy adolescents who have two copies of the long version. This result is the same in healthy adults. However, in anxious or depressed adolescents, the opposite results were found. In affected adolescents who have at least one copy of the short version, the amygdala reacts less than it does in affected adolescents who have two copies of the long version.

Significance

This finding in affected teens with two long version genes is the opposite of that observed in anxious or depressed adults. It is surprising because anxiety and depression during adolescence tend to predict these disorders during adulthood.

What’s Next?

The unexpected finding may be explained by the fact that anxious adults and anxious adolescents react differently when presented with threats. But further research is needed to fully understand the difference, the investigators say.

Reference

Lau JY, Goldman D, Buzas B, Fromm SJ, Guyer AE, Hodgkinson C, Monk CS, Nelson EE, Shen PH, Pine DS, Ernst M. Amygdala Function and 5-HTT Gene Variants in Adolescent Anxiety and Major Depressive Disorder. Biological Psychiatry. 2008 Oct 23. [Epub ahead of print].

Press Release
July 15, 2009

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.

“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 (see picture below).

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.

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.