Perinatal antidepressant stunts brain development in rats

Miswired brain circuitry traced to early exposure – NIH-funded study

Rats exposed to an antidepressant just before and after birth showed substantial brain abnormalities and behaviors, in a study funded by the National Institutes of Health.

After receiving citalopram, a serotonin-selective reuptake inhibitor (SSRI), during this critical period, long-distance connections between the two hemispheres of the brain showed stunted growth and degeneration. The animals also became excessively fearful when faced with new situations and failed to play normally with peers – behaviors reminiscent of novelty avoidance and social impairments seen in autism. The abnormalities were more pronounced in male than female rats, just as autism affects 3-4 times more boys than girls.

“Our findings underscore the importance of balanced serotonin levels – not too high or low -- for proper brain maturation,” explained Rick Lin, Ph.D., of the University of Mississippi Medical Center, Jackson, a Eureka Award grantee of the NIH’s National Institute of Mental Health.

Lin and colleagues report on their discovery online during the week of Oct. 24, 2011, in the Proceedings of the National Academy of Sciences.

Last July, a study reported an association between mothers taking antidepressants and increased autism risk in their children. It found that children of mothers who took SSRI’s during the year prior to giving birth ran twice the normal risk of developing autism – with treatment during the first trimester of pregnancy showing the strongest effect. A study published last month linked the duration of a pregnant mother’s exposure to SSRIs to modest lags in coordination of movement – but within the normal range – in their newborns counselor ceus

“While one must always be cautious extrapolating from medication effects in rats to medication effects in people, these new results suggest an opportunity to study the mechanisms by which antidepressants influence brain and behavioral development,” said NIMH Director Thomas R. Insel, M.D. “These studies will help to balance the mental health needs of pregnant mothers with possible increased risk to their offspring.”

Earlier studies had hinted that serotonin plays an important role in shaping the still-forming brain in the days just after a rat is born, which corresponds to the end of the third trimester of fetal development in humans. Experimental manipulations of the chemical messenger during this period interfered with formation of sensory-processing regions of the cortex, or outer mantle, and triggered aggressive and anxiety-related behaviors in rodents.

There is also recent evidence in humans that serotonin from the placenta helps shape development of the fetal brain early in pregnancy. Disrupted serotonin has been linked to mood and anxiety disorders. SSRIs, the mainstay medication treatment for these disorders, boost serotonin activity.

Lin and colleagues gave citalopram to male and female rat pups prenatally and postnatally and examined their brains and behavior as they grew up. Male, but not female, SSRI exposed rat pups abnormally froze when they heard an unfamiliar tone and balked at exploring their environment in the presence of unfamiliar objects or scents. These behaviors persisted into adulthood. The male pups especially also shunned normal juvenile play behavior – mimicking traits often seen in children with autism.

A key brain serotonin circuit, the raphe system, known to shape the developing brain during the critical period when the animals were exposed to the drug, showed dramatic reductions in density of neuronal fibers. Evidence of stunted development in the circuit coursed through much of the cortex and other regions important for thinking and emotion, such as the hippocampus.

The researchers also discovered miswiring in the structure responsible for communications between the brain’s left and right hemispheres, called the corpus collosum. Extensions of neurons, called axons, through which such long-distance communications are conducted, were deformed. A protective sheath, called myelin, that normally wraps and boosts axons’ efficiency-- like insulation on an electrical wire – was reduced by one-third in the treated animals. This damage was three times worse in male than in female pups and would likely result in abnormal communication between the two hemispheres, say the researchers.

Moreover, the perinatally exposed animals showed evidence of neurons firing out of sync and other electrophysiological abnormalities, suggesting faulty organization of neuronal networks in the cortex.

The research also was supported by the NIH’s National Center for Research Resources, National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Human Development.


Cross-sections of the part of the rat brain that connects the left and right hemisphere (corpus collosum) show stunted development of neuronal wiring, called axons, in an animal that received an antidepressant (right) during a critical period around the time of birth. A protective sheath, called myelin (visible in normal animal at left), that normally wraps the axons and boosts their efficiency, failed to develop normally in the treated animal. The resultant inefficient neuronal communications could underlie the pattern of deficits seen in autism.
Source: Rick C.S. Lin, Ph.D., University of Mississippi Medical Center

Reference

Perinatal antidepressant exposure alters cortical network function in rodents. Simpson KL, Weaver KJ, de Villers-Sidani E, Lu JY-F, Cai Z, Pang Y, Rodriguez-Porcel F, Paul IA, Merzenich M, Lin RCS. 2011, Oct. 24, PNAS.

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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 Center for Research Resources (NCRR), a part of NIH, provides laboratory scientists and clinical researchers with the resources and training they need to understand, detect, treat and prevent a wide range of diseases. NCRR supports all aspects of translational and clinical research, connecting researchers, patients and communities across the nation. For more information, visit www.ncrr.nih.gov. NINDS is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease — a burden borne by every age group, by every segment of society, by people all over the world.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

About the National Institutes of Health (NIH): 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. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

White House Names NIMH a “Champion of Change” for its Suicide Prevention Efforts

Source: White House

The National Institute of Mental Health (NIMH) was named by the White House as a “Champion of Change” on August 25, 2011, for its efforts in supporting research on suicide prevention. Jane Pearson, Ph.D., and Kevin Quinn, Ph.D., of NIMH accepted the award at a ceremony and roundtable event at the White House, where they joined White House policy officials and others for a discussion of suicide prevention best practices. In addition to NIMH, the Suicide Prevention Resource Center (SPRC); Suicide Prevention Action Network; SAVE Foundation; the American Foundation for Suicide Prevention; National Suicide Prevention Lifeline; Blue Star Families; the Gay, Lesbian, and Straight Education Network (GLSEN); the Creative Coalition; and the Trevor Project, all of whom are dedicated to preventing suicide, were honored.

The White House Champions of Change initiative celebrates individuals and organizations from all walks of life who are making an impact in communities and helping the country rise to the challenges of the 21st century.

The roundtable discussion was moderated by Pamela J. Hyde, Administrator of the Substance Abuse and Mental Health Services Administration (SAMHSA); Andrea Palm, Senior Advisor for Health at the White House Domestic Policy Council; and Deborah Temkin, Research and Policy Coordinator for Bullying Prevention Initiatives at the Department of Education. The discussion focused on numerous issues important to suicide prevention including:
Media influences: how the media—including social media—has encouraged people to show their support of individuals in crisis ceus for counselors

Best practices: how the SPRC, which acts as a clearinghouse of evidence-based information related to suicide prevention, helps spread the word. The National Suicide Prevention Lifeline also continues to improve counseling services by using best practices.
Working Together: how each organization learns from the others. For instance, NIMH funds research associated with the National Suicide Prevention Lifeline, including research on the training of crisis counselors in an effort to improve counselors’ assessment and referral skills.
Prioritizing Next Steps: including identifying technological opportunities to help reduce suicide,(e.g., developing and testing phone apps for helping someone in crisis).
Early intervention: all agreed that for children, early intervention programs aimed at decreasing aggression and improving problem-solving skills are vital to ensuring children do not become bullies or reach a suicidal crisis.

NIMH is deeply honored to be identified as a Champion of Change. If you or someone you know is in crisis or considering suicide, call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255), a free, 24-hour hotline that seamlessly connects anyone in suicidal crisis or emotional distress with their nearest crisis center.

National Survey Dispels Notion that Social Phobia is the Same as Shyness

Source: NIMH

Normal human shyness is not being confused with the psychiatric anxiety disorder known as social phobia, according to an NIMH survey comparing the prevalence rates of the two among U.S. youth. The study was published online ahead of print October 17, 2011, in the journal Pediatrics.

Background

Social phobia is a disabling anxiety disorder characterized by overwhelming anxiety and excessive self-consciousness in everyday social or performance situations. Critics of the diagnosis have suggested that psychiatrists and pharmaceutical companies publicize social phobia, also known as social anxiety disorder, in order to increase sales of psychotropic medications, especially among youth. In addition, some have debated whether social phobia is just a “medicalization” of a normal variation in human temperament.

In response, Marcy Burstein, Ph.D., and colleagues at NIMH examined the rate of normal shyness among youth and its overlap with social phobia using data from the National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey of more than 10,000 teens aged 13-18 sponsored by NIMH. Social phobia was assessed using standard diagnostic criteria set by the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-IV). To assess shyness, teens were asked to rate how shy they felt around peers that they did not know well.

Results of the Study

The authors found that while about half of youth identified themselves as shy, only 12 percent of shy youth also met criteria for social phobia in their lifetime. Moreover, among youth who did not identify themselves as shy, about 5 percent met criteria for social phobia, suggesting that social phobia and shyness are not necessarily directly related. Rather, the presence of social phobia may be independent of shyness in some instances.

In addition, those with social phobia were consistently more likely to also have another psychiatric disorder in their lifetime, like depression or a behavior or drug use disorder, compared to those who identified themselves as shy. Those with social phobia also showed higher levels of impairment in work or school, or among family or peers, though they were no more likely to be receiving professional treatment than those who were shy.

Finally, rates of prescribed medication use were low for all groups. Only about 2.3 percent of those with social phobia were taking the antidepressant paroxetine (commonly used to treat anxiety disorders), while 0.9 percent who described themselves as shy were taking it. In addition, those with social phobia were no more likely to be taking any prescribed psychiatric medication compared to the other groups.

Significance

The results suggest that social phobia is not simply shyness that has been inappropriately medicalized. Rather, social phobia affects a minority of youth and only a fraction of those who consider themselves to be shy. In addition, despite the greater disability that youth with social phobia experience and the greater likelihood that they will have another disorder, they are not more likely to be getting treatment compared to their peers, questioning the notion that these youth are being unnecessarily medicated continuing education for counselors

Citation

Burstein M, Ameli-Grillon L, Merikangas M. Shyness versus social phobia in U.S. youth. Pediatrics. Online ahead of print Oct 17, 2011.

Adding Psychotherapy to Medication Treatment Improves Outcomes in Pediatric OCD

Source: NIMH

Youth with obsessive compulsive disorder (OCD) who are already taking antidepressant medication benefit by adding a type of psychotherapy called cognitive behavior therapy (CBT), according to an NIMH-funded study published September 21, 2011, in the Journal of the American Medical Association social worker continuing education

Background

Several studies have shown that, among adults with OCD, a form of CBT involving controlled exposure to feared situations plus training that helps the person refrain from compulsions is effective both alone and in combination with antidepressant medication. However, few studies of this type of combination therapy have been conducted among children. In addition, many children with OCD tend to respond only partially to antidepressant medication. Studies have found that among adults who only partially respond to antidepressant medication, adding CBT can be effective. However, until now, there have been no studies testing this same approach in youth.

Martin Franklin Ph.D., of the University of Pennsylvania, Jennifer Freeman Ph.D., of Brown University, John March M.D.,MPH, of Duke University, and colleagues set out to determine whether CBT can effectively augment antidepressant treatment in children who partially respond to the medication. Among 124 children ages 7-17, they compared three treatment options:
Medication management only (MM), prescribed and managed by a physician. All patients were taking a type of antidepressant known as a selective serotonin reuptake inhibitor (SSRI).
MM plus Instructional CBT (I-CBT), a shorter, less intensive version of CBT administered by the prescribing physician.
MM plus CBT provided by a trained CBT therapist. The CBT included a type of therapy called exposure plus response prevention (ERP), in which children are exposed to feared situations and taught how to respond to the resulting anxiety without engaging in compulsions.

Results

After 12 weeks of treatment, nearly 69 percent of those receiving MM+CBT had responded to treatment, compared to 34 percent receiving MM+I-CBT and 30 percent receiving MM. Those receiving MM+CBT showed more improvement in all respects, compared to those receiving MM and MM+I-CBT.

Significance

The findings are consistent with other studies demonstrating that ERP is an effective treatment strategy for OCD, both alone and in combination with SSRIs. The researchers conclude that the full version of CBT with ERP should be widely disseminated as opposed to a brief version that may not be effective.

What’s next

The researchers were unsure why there was so little difference in treatment response between the MM group and the MM+I-CBT group. They reasoned that the I-CBT was generally ineffective because it was brief and less intensive than the CBT. It also did not include key treatment components that are central to the full CBT protocol, such as exposure practices during the treatment sessions themselves. Future efforts should focus on making the full CBT with ERP more widely available in community settings, they concluded.

Citation

Franklin ME, Sapyta J, Freeman JB, Khanna M, Compton S, Almirall D, Moore P, Choate-Summers M, Garcia A, Edson AL, Foa EB, March JS. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive compulsive disorder: the Pediatric OCD Treatment Study (POTS II) randomized controlled trial. Journal of the American Medical Association. 21 Sept 2011

Brain Chemical Linked to Joylessness Provides Insight Into Teen Depression

Depressed teens with anhedonia, or the inability to experience pleasure, have lower levels of the neurotransmitter GABA in a key mood-regulating region of the brain, according to an NIMH-funded study published online October 3, in the Archives of General Psychiatry. The researchers note that focusing on specific symptoms and using different types of measures may offer new clues to the pathways and processes underlying depression and other mental disorders continuing education for social workers

Background

Symptoms of depression in teens can be highly varied and tend to overlap with signs of other disorders. Because of this, adolescent depression can be hard to study using conventional research tools and methods.

Guided by findings in adults, Vilma Gabbay, M.D., of New York University School of Medicine, and colleagues decided to focus on the neurotransmitter GABA. GABA has many important roles throughout the body and is involved in regulating communication between brain cells. Abnormalities in GABA production or function in the brain have been linked to several mental disorders, including schizophrenia and postpartum depression, and possibly learning disorders. GABA has also been linked to anhedonia, a symptom present in up to 59 percent of depressed teens.

The researchers used a type of specialized MRI to measure GABA levels in the brain region known as the anterior cingulate cortex (ACC) in 20 teens with depression, half of whom also had anhedonia. They were compared to 21 matched controls who did not have depression or anhedonia. Levels of anhedonia were scored numerically according to clinician- and self-rated assessments.

Results of the Study

Compared to controls, teens with depression and anhedonia had significantly lower ACC GABA levels. Lower ACC GABA levels were associated with more severe anhedonia symptoms among all participants.

Significance

The findings support a role for GABA in anhedonia and depression among teens. Also, by correlating GABA levels with numeric measures of anhedonia severity, the researchers were able to assess participants’ symptoms along a continuum. Compared to traditional measures that categorize symptoms only as being either present or absent, such continuous or “dimensional” measurements may provide greater specificity to disease evaluations in research.

What’s Next

Additional studies in larger populations are needed to confirm these findings. Advances in imaging techniques and technology may help to identify differing roles for other neurotransmitters associated with depression.

Reference

Gabbay V, Mao X, Klein RG, Ely BA, Babb JS, Panzer AM, Alonso CM, Shungu DC. Anterior Cingulate Cortex {gamma}-Aminobutyric Acid in Depressed Adolescents: Relationship to Anhedonia. Arch Gen Psychiatry. 2011 Oct 3. [Epub ahead of print] PubMed PMID: 21969419.

Prescribed stimulant use for ADHD continues to rise steadily

NIH and AHRQ study finds pace of the rise has slowed in recent years


Source: NIMH

The prescribed use of stimulant medications to treat attention deficit hyperactivity disorder (ADHD) rose slowly but steadily from 1996 to 2008, according to a study conducted by the National Institutes of Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ). The study was published online ahead of print September 28, 2011, in the American Journal of Psychiatry continuing education for Social Workers

ADHD is one of the most common childhood disorders, and can continue through adolescence and adulthood. Symptoms include difficulty staying focused and paying attention, difficulty controlling behavior, and hyperactivity (over-activity). The condition is frequently treated with stimulants such as methylphenidate (e.g., Ritalin), amphetamines (e.g., Adderall) or other types of medications. Behavioral therapies can also be effective.

During the 1990s, stimulant prescription use increased significantly, going from a prevalence rate among youth of 0.6 percent in 1987 to 2.7 percent in 1997, with the rate stabilizing around 2.9 percent in 2002. Recent reports, however, suggest that the prescribed use of these medications and the diagnosis of ADHD have continued to rise. Based on the Health Resources and Services Administration's National Survey of Children's Health, the percentage of children age 4-17 years diagnosed with ADHD increased from 7.8 percent in 2003 to 9.5 percent in 2007.

"Stimulant medications work well to control ADHD symptoms, but they are only one method of treatment for the condition. Experts estimate that about 60 percent of children with ADHD are treated with medication," said co-author Benedetto Vitiello, M.D., of NIH's National Institute of Mental Health (NIMH).

For this most recent survey, Dr. Vitiello and Samuel Zuvekas Ph.D., of AHRQ examined data from the AHRQ-sponsored Medical Expenditure Panel Survey, a nationally representative annual survey of U.S. households, to determine prescribed stimulant use among children under age 19 from 1996-2008. They found a slow but steady increase — from 2.4 percent in 1996 to 3.5 percent in 2008.The rate grew an average of 3.4 percent each year, which is substantially less than the growth rate between 1987 and 1996, which averaged about 17 percent per year.

Overall, prescription use among 6-12-year-olds was highest, going from 4.2 percent in 1996 to 5.1 percent in 2008. But the fastest growth of prescribed use occurred among 13-18-year-olds, going from 2.3 percent in 1996 to 4.9 percent in 2008. "This continuous increase among teens likely reflects a recent realization that ADHD often persists as children age. They do not always grow out of their symptoms," said Dr. Vitiello.

Prescription use among preschoolers remained very low at 0.1 percent from 2004 onward and decreased between 2002 and 2008, suggesting that stimulant use among very young children continues to be disfavored. Boys continued to be three times more likely to be prescribed a stimulant than girls, and use among white children continued to be higher than among black or Hispanic children (4.4 percent in 2008 among whites, compared to 2.9 percent in blacks and 2.1 percent in Hispanics). However, prescribed stimulant use is increasing among racial and ethnic minorities, likely suggesting more recognition of ADHD and acceptance of psychopharmacological treatment among these groups, according to the authors.

In addition, rates were substantially lower in Western states compared to other regions of the nation, with no increase in recent years, a finding consistent with other studies. In comparison, rates in the Northeast increased from 2.7 percent in 2002 to 4.6 percent in 2008.

"These persistent differences in prescribed stimulant use related to age, racial and ethnic background, and geographical location indicate substantial variability in how families and doctors approach ADHD treatment throughout the United States," said Dr. Zuvekas.

The researchers concluded that when comparing the rates of prescribed use with the estimated prevalence of ADHD diagnosis, it appears that many children with ADHD are not treated with stimulants. "The children with the most severe symptoms are more likely to be taking stimulants. Those with milder symptoms are more likely being treated with psychosocial treatments or other non-stimulant medications," they said.

Reference

Zuvekas S and Vitiello B. Stimulant medication use in children: a 12-year perspective. American Journal of Psychiatry. Online ahead of print September 28, 2011.

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The Agency for Healthcare Research and Quality (http://www.ahrq.gov) is part of the U.S. Department of Health and Human Services. AHRQ's mission is to improve the quality, safety, efficiency and effectiveness of health care for all Americans. AHRQ's research helps people make more informed decisions and improve the quality of health care services.

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.

About the National Institutes of Health (NIH): 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. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Adding Psychotherapy to Medication Treatment Improves Outcomes in Pediatric OCD

Source: NIMH

Youth with obsessive compulsive disorder (OCD) who are already taking antidepressant medication benefit by adding a type of psychotherapy called cognitive behavior therapy (CBT), according to an NIMH-funded study published September 21, 2011, in the Journal of the American Medical Association LCSW Continuing Education

Background

Several studies have shown that, among adults with OCD, a form of CBT involving controlled exposure to feared situations plus training that helps the person refrain from compulsions is effective both alone and in combination with antidepressant medication. However, few studies of this type of combination therapy have been conducted among children. In addition, many children with OCD tend to respond only partially to antidepressant medication. Studies have found that among adults who only partially respond to antidepressant medication, adding CBT can be effective. However, until now, there have been no studies testing this same approach in youth.

Martin Franklin Ph.D., of the University of Pennsylvania, Jennifer Freeman Ph.D., of Brown University, John March M.D.,MPH, of Duke University, and colleagues set out to determine whether CBT can effectively augment antidepressant treatment in children who partially respond to the medication. Among 124 children ages 7-17, they compared three treatment options:
Medication management only (MM), prescribed and managed by a physician. All patients were taking a type of antidepressant known as a selective serotonin reuptake inhibitor (SSRI).
MM plus Instructional CBT (I-CBT), a shorter, less intensive version of CBT administered by the prescribing physician.
MM plus CBT provided by a trained CBT therapist. The CBT included a type of therapy called exposure plus response prevention (ERP), in which children are exposed to feared situations and taught how to respond to the resulting anxiety without engaging in compulsions.

Results

After 12 weeks of treatment, nearly 69 percent of those receiving MM+CBT had responded to treatment, compared to 34 percent receiving MM+I-CBT and 30 percent receiving MM. Those receiving MM+CBT showed more improvement in all respects, compared to those receiving MM and MM+I-CBT.

Significance

The findings are consistent with other studies demonstrating that ERP is an effective treatment strategy for OCD, both alone and in combination with SSRIs. The researchers conclude that the full version of CBT with ERP should be widely disseminated as opposed to a brief version that may not be effective.

What’s next

The researchers were unsure why there was so little difference in treatment response between the MM group and the MM+I-CBT group. They reasoned that the I-CBT was generally ineffective because it was brief and less intensive than the CBT. It also did not include key treatment components that are central to the full CBT protocol, such as exposure practices during the treatment sessions themselves. Future efforts should focus on making the full CBT with ERP more widely available in community settings, they concluded.

Citation

Franklin ME, Sapyta J, Freeman JB, Khanna M, Compton S, Almirall D, Moore P, Choate-Summers M, Garcia A, Edson AL, Foa EB, March JS. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive compulsive disorder: the Pediatric OCD Treatment Study (POTS II) randomized controlled trial. Journal of the American Medical Association. 21 Sept 2011.