An HIV-prevention program targeted at women receiving prenatal care may effectively reduce risks for HIV, sexually transmitted infections (STIs), and unplanned future pregnancies, according to NIMH-funded researchers. Bundling such interventions into existing health care models, like prenatal care, also may be more accessible to those who may not have the time, interest, or resources to attend a stand-alone HIV prevention program. Changing the way prenatal care is provided also may create sustainable advantages in reproductive health for all at-risk women. The study was published in the November 2009 issue of the American Journal of Public Health.

Background

The very behaviors that put young women at risk for pregnancy also put them at risk for STIs. Since they are no longer trying to prevent pregnancy, young, pregnant women are less likely to use condoms than their non-pregnant peers. This, in turn, puts them at high risk for contracting HIV and other STIs during and shortly after pregnancy. However, few HIV interventions have been developed to address the specific needs of young, pregnant women.

For their study, Jeanette Ickovics, Ph.D., of Yale University, and colleagues recruited 1,047 teens and young women (ages 14-25). All participants were in their second trimester of pregnancy and receiving prenatal care at one of two clinical sites during 2001-2004. The researchers randomly assigned the study participants to one of three care groups:

• Standard CenteringPregnancy group prenatal care

• CenteringPregnancy group prenatal care + HIV prevention components

• Standard individual prenatal care

CenteringPregnancy consisted of 10 two-hour sessions led by a midwife or obstetrician. During the sessions, women receive their prenatal care, engage in self-care activities (such as documenting their own weight and blood pressure), and attend a group discussion of important issues related to prenatal care, childbirth preparation, and postpartum care.

"CenteringPregnancy Plus" offered the same general content and structure of CenteringPregnancy, but three of the 10 sessions included 40 minutes of content related to preventing HIV. The HIV prevention components addressed the participants' perception of HIV risk, personal goals for safer sex behaviors during and after pregnancy, and skills for communicating about safer sex behaviors with sexual partners.

Study participants receiving standard individual prenatal care met with their health care providers on the same schedule and the same number of times as women in the other two care groups, but they only spent about 10-15 minutes with their prenatal care provider per appointment, as is considered standard.

After the initial assessment, the researchers conducted follow-up interviews for all participants during the third trimester, and at six and 12 months after postpartum.

Results of the Study

Participants who received CenteringPregnancy Plus were 51 percent less likely to become pregnant again within six months of giving birth, compared with women in the two other care groups. The CenteringPregnancy Plus program also increased condom use and safe sex communication between partners, and reduced incidences of unprotected sex, compared with the other study treatments.

Teens (ages 14-19) who received CenteringPregnancy Plus had significantly fewer new STIs than teens in the other study conditions (9 percent vs. 12.5 percent of teens in the CenteringPregnancy group and 20 percent in the standard care group). There were no differences in infection rates among young adults (ages 20-25) in the study.

Significance

According to the researchers, CenteringPregnancy Plus differs from other HIV interventions by integrating sexual risk prevention into the existing structure of prenatal care, drawing on women's motivations for a healthy pregnancy and their frequent contact with care providers.

Offering an HIV prevention program within the context of prenatal care may help to reduce the spread of HIV and other sexually transmitted infections by reaching an at-risk population that may not otherwise have had access to such programs. The researchers noted that the added time needed to deliver the HIV prevention did not come at the expense of prenatal care. However, they further cautioned that while the program was effective, the differences between groups were modest.

Past research has shown that among teenagers, repeat pregnancy shortly after giving birth increases parenting-related stress and negative parenting behaviors. Thus, by reducing or preventing repeat pregnancies, CenteringPregnancy Plus may help to improve the quality of life of young mothers and their children. The researchers suggest booster sessions of the program may prolong this effect beyond six months postpartum.

What's Next

The researchers note that pregnancy may be an important window of opportunity to promote changes in behavior and improve the health of women. This study demonstrates the possibility of creating integrated programs that positively influence a wide range of health problems, rather than dealing with each problem separately. Such research may impact the design and delivery of future prenatal care services.

Dr. Ickovics and co-author Trace Kershaw, Ph.D., are conducting a follow-up study, also funded by NIMH, to test the "real-world" effectiveness of CenteringPregnancy Plus when provided through 14 New York City community hospitals and health centers.

Reference

Kershaw TS, Magriples U, Westdahl C, Rising SS, Ickovics J. Pregnancy as a window of opportunity for HIV prevention: effects of an HIV intervention delivered within prenatal care . Am J Public Health. 2009 Nov;99(11):2079-86. Epub 2009 Sep 17. PubMed PMID: 19762662.

NIH: News IN Health

Premenopausal women with even mild depression have less bone mass than do their nondepressed peers, a study funded in part by the National Institute of Mental Health (NIMH), part of the National Institutes of Health (NIH), shows.  The level of bone loss is at least as high as that associated with recognized risk factors for osteoporosis, including smoking, low calcium intake, and lack of physical activity.

Hip bones, the site of frequent fractures among older people, were among those showing the most thinning in depressed premenopausal women.  The reduced bone mass puts them at higher risk of these costly, sometimes fatal fractures and others as they age, the researchers note in the November 26 issue of the Archives of Internal Medicine.  The report was submitted by Giovanni Cizza, MD, PhD, MHSc, of NIMH and the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Farideh Eskandari, MD, MHSc, of NIMH; and colleagues.

“Osteoporosis is a silent disease.  Too often, the first symptom a clinician sees is when a patient shows up with a broken bone.  Now we know that depression can serve as a red flag – that depressed women are more likely than other women to approach menopause already at higher risk of fractures,” said NIMH Deputy Director Richard Nakamura, PhD.

After bone mass reaches its peak in youth, bone-thinning continues throughout life, accelerating after menopause.  Preliminary studies had suggested that depression may be a risk factor for lower-than-average bone mass even in young, premenopausal women.  Results of the current study lend considerable weight to those earlier findings.  The study’s design reduced the possibility that the lower bone mass was linked to factors other than depression.

Study participants included 89 depressed women and 44 nondepressed women, for comparison. All were between 21 and 45 years old and were premenopausal.  Except for depression, the two groups were similar in risk factors, including calcium, caffeine, and alcohol intake; smoking; level of physical fitness; use of oral contraceptives; and age of first menstrual period.  Both groups were of relatively high socioeconomic status and were well nourished. 

One difference was that the depressed women were taking antidepressant medications.  A previous study suggested that older adults taking antidepressants called selective serotonin reuptake inhibitors had more bone fractures than others.  However, the current study showed that these medications were not linked to low bone mass in premenopausal women. 

The researchers found that 17 percent of the depressed women had thinner bone in a vulnerable part of the hip called the femoral neck, compared with 2 percent of those who were not depressed.  Low bone mass in the lumbar spine, in the lower back, was found in 20 percent of depressed women, but in only 9 percent of nondepressed women.  Bone mass was measured via an X-ray technique called DXA scanning.

There was no significant link between the degree of bone loss and the severity of depression or the cumulative number of depressive episodes, the researchers found.  The depressed women had been diagnosed with mild depression and were having, or had recently had, a depressive episode.

“Depression generally isn’t on clinicians’ radar screens as a major risk factor for osteoporosis, particularly for premenopausal women.  It should be,” said Cizza.

Blood and urine samples also showed that depressed women have imbalances in immune-system substances, including those that produce inflammation, compared to their healthy peers.  This additional finding strengthens the case for a suspected link between depression-induced imbalances in the immune system and accelerated bone loss.  The blood and urine samples were taken every hour for a full day, providing a truer picture than does less frequent testing, as had been done in previous studies.

The immune-system imbalances may be tied to excess adrenalin, since the part of the nervous system that produces adrenalin is over-active in depressed people.  Increased adrenalin can over-stimulate the immune system.  Compared to the others, the depressed women in this study had higher levels of immune-system proteins that promote inflammation, and lower levels of those that prevent it. 

One of these inflammation-promoting proteins, IL-6, is known to promote bone loss.  At the molecular level, bones routinely break down, and their minerals, notably calcium, are reabsorbed into the blood, where they travel throughout the body to perform crucial functions in cells.  At the same time, the body builds the bone back up.  Imbalances in this normal loop of bone re-absorption and build-up, such as high levels of IL-6, could promote bone loss, the researchers suggest.

Other NIH contributors to the study, in addition to NIMH and NIDDK , included the NIH Clinical Center  and the National Center for Complementary and Alternative Medicine .

About the National Institute of Mental Health (NIMH): 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 .

Source: NIMH, NIH

Numerous studies have suggested that depression runs in families. Children of depressed parents are 2–3 times as likely to develop depression as compared to children who do not have a family history of the disorder.¹ Other studies have shown that remission of depression in mothers is associated with improvements in psychiatric symptoms in their children.² Despite all signs encouraging mothers to prioritize their own mental health, many suffer from untreated depression while managing treatment for their children's emotional or behavioral problems.³

An NIH Challenge grant was awarded on behalf of NIMH to Judy Garber, Ph.D., of Vanderbilt University, to develop and test a method encouraging depressed mothers to follow treatment recommendations. For this study, Garber is recruiting 200 mothers of children receiving psychiatric treatment at a community mental health center.

All study participants will receive a referral for treatment and an information pamphlet describing the symptoms of depression and anxiety, possible effects of depression on children, and different types of treatments. Randomly assigned participants will also receive a brief, one-session Enhanced Motivation Intervention (EMI). EMI uses special interviewing techniques to identify and resolve a person's concerns about and practical barriers to treatment.

The researchers anticipate that EMI will result in more participants getting treatment for mental disorders compared with the control group. If successful, such interventions would not only benefit the depressed individual, but may improve the well-being of her children as well.

The NIH Challenge Grants in Health and Science Research  program is a new initiative funded through the American Recovery and Reinvestment Act of 2009 (Recovery Act) . This program supports research on 15 broad Challenge Areas that address specific scientific and health research challenges in biomedical and behavioral research that will benefit from an influx of significant two-year funds to quickly advance the area.

Within these Challenge Areas, NIMH identified 35 topics of particular funding interest that advance the Institute's mission and the objectives outlined in the NIMH Strategic Plan, the Trans-NIH Plan for HIV-Related Research , and the National Advisory Mental Health Council report on research training. These topics can be found at NIMH's Challenge Grant web page.

Citations

¹Weissman MM, Wickramaratne P, Nomura Y, Warner V, Pilowsky D, Verdeli H. Offspring of depressed parents: 20 years later. Am J Psychiatry. 2006 Jun;163(6):1001-8. PubMed PMID: 16741200.

²Pilowsky DJ, Wickramaratne P, Talati A, Tang M, Hughes CW, Garber J, Malloy E, King C, Cerda G, Sood AB, Alpert JE, Trivedi MH, Fava M, Rush AJ, Wisniewski S, Weissman MM. Children of depressed mothers 1 year after the initiation of maternal treatment: findings from the STAR*D-Child Study. Am J Psychiatry. 2008 Sep;165(9):1136-47. Epub 2008 Jun 16. PubMed PMID: 18558646.

³Verdeli H, Ferro T, Wickramaratne P, Greenwald S, Blanco C, Weissman MM. Treatment of depressed mothers of depressed children: pilot study of feasibility. Depress Anxiety. 2004;19(1):51-8. PubMed PMID: 14978786.

Source: NIMH, NIH

June 11, 2013 • Science Update

Once considered a childhood rite of passage, bullying lingers well into adulthood. Bullies and victims alike are at risk for psychiatric problems such as anxiety, depression, substance abuse, and suicide when they become adults, reported a study partially funded by the National Institute of Mental Health (NIMH) that was published in the April issue of JAMA Psychiatry.

Background

Bullying is a repetitive, aggressive act done to abuse or intimidate others. It can take on various forms—primarily verbal, emotional, and physical, although cyberbullying is also on the rise. Typically these scenes occur inside school or on the playground, but they can also happen at home or at work. A power imbalance usually is involved in which one child or a group of children torments another child who is considered “weaker.” Methods employed by bullies include threats, rumor-spreading, and exclusion.

Most of what experts know about the effects of bullying comes from short-term observational studies. These studies reflect general society’s view that most people overcome these events by the time they become adults.

“Initially I too was skeptical about these long-term effects,” says study author William Copeland, Ph.D., at Duke University, who as an epidemiologist knew of other traumatic events that do not linger psychologically, such as maltreatment and physical abuse. “Yet this is something that stays with people. A large number of people express lasting effects decades after their childhood experiences.”

Copeland and his colleagues tapped into a local population sample of 1,420 children from 11 Western North Carolina counties. Starting at the ages of 9, 11, and 13, the kids, along with their parents, were interviewed annually until the age of 16, fielding questions about peer relations and home and community settings. The participating children were again interviewed at 19, 21, and 24 to 26 years of age. Four groups emerged from this longitudinal study: people who were never involved in bullying, people who were victims, people who were bullies, and people who were both.

Results of the Study

More than half of the study’s youth reported being neither a bully nor a victim. Around a quarter of the study group claimed that they were victimized. About 7 percent confessed to being a bully. A similar percentage said that they were both, a group the researchers labeled as “bully-victims.”

Compared to those who went through childhood unscathed, victims had four times the prevalence of agoraphobia, generalized anxiety, and panic disorder when they became adults. Overall, bullies had four times the risk of developing antisocial personality disorder. These disorders still stood even after other factors were taken into account, such as preexisting psychiatric problems or family hardships.

Bully-victims fared the worst. Also known as “loners,” these individuals start out with less developed social skills and are seen as more impulsive and aggressive. When picked on, they respond by picking on others. Their numbers, compared to those never involved in bullying, tell the story: 14 times the risk of panic disorder, 5 times the risk of depressive disorders, and 10 times the risk of suicidal thoughts and behavior.

“Victims report the greatest anxiety problems. They might become successful people later on, but they still think about the event and hold onto it. Bullies are socially adept and may find ways in adulthood to use these skills in a pro-social manner. Folks really underestimate who are the bully-victims. These are the ones who end up having the most significant emotional problems including suicidality,” explained Copeland, who is also a father of two.

Significance

All these disorders impart a great emotional and financial cost to society. Lowering and/or preventing bullying could possibly reduce human suffering and long-term health costs—not to mention creating a safer environment for children to grow up in.

Research into resilience or why some are able to bounce back in adulthood is ongoing. Some key molecules and brain circuit pathways have been identified in animals. Other research areas under exploration include physiology, genetics, epigenetics, and cognitive therapies.

What’s Next

Studies looking into which interventions work best for bullying are underway. Once these interventions are identified, research is needed to see at what stages in life they should they be administered. Lastly, other factors that play a role in bullying and victimization, such as sexual orientation, need exploration.

“This study suggests that we should pay attention to what’s going on between peers,” said Copeland, adding that kids spend more time each day with their peers, including school and online, than with their parents. “What happens to kids when they’re with their peers is as important, or may be more important, than what happens at home,” said Copeland.

Reference

Copeland WE, Wolke D, Angold A, Costello EJ. Adult Psychiatric Outcomes of Bullying and Being Bullied by Peers in Childhood and Adolescence. JAMA Psychiatry , published April 2013.

Grant number: K23 MH080230 

Source: NIMH, NIH

Five Major Mental Disorders Share Genetic Roots

March 1, 2013 • Science Update

Five major mental disorders share some of the same genetic risk factors, the largest genome-wide study of its kind has found. Evidence for such genetic overlap had previously been limited to pairs of disorders.

National Institutes of Health-funded researchers discovered that people with disorders traditionally thought to be distinct – autism, ADHD, bipolar disorder, major depression and schizophrenia – were more likely to have suspect genetic variation at the same four chromosomal sites. These included risk versions of two genes that regulate the flow of calcium into cells.

Source: Jordan Smoller, M.D., Massachusetts General Hospital

“These results will help us move toward diagnostic classification informed by disease cause,” said Jordan Smoller, M.D. , of Massachusetts General Hospital, Boston, a coordinator of the study, which was supported by NIH’s National Institute of Mental Health. “Although statistically significant, each of these genetic associations individually can account for only a small amount of risk for mental illness, making them insufficient for predictive or diagnostic usefulness by themselves.”

Smoller, Kenneth Kendler, M.D., , Virginia Commonwealth University, Richmond; Nicholas Craddock, PhD. , Cardiff University, England; Stephan Ripke, M.D. , Massachusetts General, Patrick Sullivan, M.D. , University of North Carolina at Chapel Hill, and colleagues in the Cross-Disorder Group of the Psychiatric Genomics Consortium, report on their findings February 28, 2013 in The Lancet.

Prior to the study, researchers had turned up evidence of shared genetic risk factors for pairs of disorders, such as schizophenia and bipolar disorder, autism and schizophrenia and depression and bipolar disorder. Such evidence of overlap at the genetic level has blurred the boundaries of traditional diagnostic categories and given rise to research domain criteria, or RDoC, an NIMH initiative to develop new ways of classifying psychopathology for research based on neuroscience and genetics as well as observed behavior.

To learn more, the consortium researchers analyzed the five key disorders as if they were the same illness. They screened for evidence of illness-associated genetic variation across the genomes of 33,332 patients with all five disorders and 27,888 controls, drawing on samples from previous consortium mega-analyses.

For the first time, specific variations significantly associated with all five disorders were among several suspect genomic sites that turned up. These included variation in two genes that code for the cellular machinery for regulating the flow of calcium into neurons. Variation in one of these, called CACNA1C, which had previously been implicated in susceptibility to bipolar disorder, schizophrenia and major depression, is known to impact brain circuitry involved in emotion, thinking, attention and memory – functions disrupted in mental illnesses. Variation in another calcium channel gene, called CACNB2, was also linked to the disorders.

Alterations in calcium-channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology, suggest the researchers.

They also discovered illness-linked variation for all five disorders in certain regions of chromosomes 3 and 10. Each of these sites spans several genes, and the specific causal factors within them remain elusive. However, one region, called 3p21, which produced the strongest signal of illness association, harbors suspect variations identified in previous genome-wide studies of bipolar disorder and schizophrenia.

References

Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. The Lancet, February 28, 2013

Source: NIMH, NIH

Ethnic Disparities Persist in Depression Diagnosis and Treatment Among Older Americans

January 26, 2012 • Science Update

Older racial and ethnic minorities living in the community are less likely to be diagnosed with depression than their white counterparts, but are also less likely to get treated, according to a recent NIMH-funded analysis published online ahead of print December 15, 2011, in the American Journal of Public Health.

Background

Depression is a significant health concern for older adults, regardless of ethnic or racial status. Previous studies have found racial and ethnic differences in the diagnosis and treatment of depression among the general population.

Using 2001-2005 data from the nationally representative Medicare Current Beneficiary Survey (MCBS), Ayse Akincigil Ph.D., of Rutgers University and colleagues examined rates of depression diagnosis and treatment among older adults living in the community. The survey asked questions about health care use and costs, insurance coverage beyond Medicare, access to care, and use of services.

Results

The survey found that about 6.4 percent of whites, 4.2 percent of African Americans, and 7.2 percent of Hispanics were diagnosed with depression. Among those diagnosed, 73 percent of whites received treatment (either with antidepressants, psychotherapy or both), while 60 percent of African Americans received treatment and 63.4 percent of Hispanics received treatment. These kinds of diagnosis and treatment differences are consistent with previous studies, the researchers noted. They also noted pronounced differences in socioeconomic status and quality of insurance coverage across ethnicities. Fewer whites reported having low incomes than ethnic minorities. However, these differences did not appear to account for the disparities in diagnosis or treatment rates.

Significance

The findings are consistent with the notion that depression continues to be under-recognized and undertreated among older minorities. According to the researchers, future research should investigate cultural factors such as help-seeking patterns, stigma, and patient attitudes and knowledge about depression as potential factors contributing to the disparities. For instance, ethnic minorities may be less likely to seek help for a mood disorder, and those with lower incomes may have more difficulty gaining access to specialized health care. In addition, they may be more likely to seek help from nonmedical providers, such as pastors or lay counselors, according to the researchers. Other research has suggested that minorities tend to cite stigma or shame associated with having a mental disorder as a reason for not seeking help for depression.

Differences in diagnosis rates may also reflect the notion that African Americans tend to have a greater sense of distrust of doctors in general compared to white patients, said the researchers. In addition, minority patients also may be more likely to present with more physical aspects of depression such as sleep problems or pain, rather than mood or cognitive symptoms, which can complicate detection and diagnosis of depression.

What’s Next

The researchers suggest possible ways to minimize the disparities in depression diagnosis and treatment among older minorities. For instance, psychiatrists and other health care workers could be offered public financial incentives for practicing in poorer communities where depressed older people may go untreated. In addition, adding cross-cultural education into professional training opportunities for health care workers could further reduce disparities. In the meantime, promising approaches such as universal depression screening programs could be implemented, the researchers concluded.

Citation

Akincigil A, Olfson M, Siegel M, Zurlo K, Walkup J, Crystal S. Racial and ethnic disparities in depression care in community-dwelling elderly in the United States. American Journal of Public Health. Online ahead of print Dec. 15, 2011.

Source: NIMH, NIH

Nearly 40 percent of people with major depression may also have subthreshold hypomania, a form of mania that does not fully meet current diagnostic criteria for bipolar disorder, according to a new NIMH-funded study. The study was published online ahead of print August 15, 2010, in the American Journal of Psychiatry.

Background

Mania is a symptom of bipolar disorder. According to the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV), it is generally defined as a discrete period of increased energy, activity, euphoria or irritability that leads to marked impairment in one’s daily life. The DSM-IV states that a manic episode lasts for one week or more, and may sometimes require hospitalization.  Hypomania is defined as a milder form of mania that lasts for four days at a time, but does not interfere with one’s daily activities. The majority of people diagnosed with bipolar disorder experience repeated episodes of hypomania rather than mania.

For this new study, Kathleen Merikangas, PhD., of NIMH, and colleagues aimed to characterize the full spectrum of mania by identifying hypomanic episodes that last less than four days among those diagnosed with major depression. They described this type of hypomania as subthreshold hypomania. Merikangas and colleagues used data from 5,692 respondents of the National Comorbidity Survey Replication (NCS-R), a nationally representative survey of American adults ages 18 and older.

Results of the Study

The researchers found that nearly 40 percent of those identified as having major depression also had symptoms of subthreshold hypomania. Compared to those with major depression alone, those with depression plus subthreshold hypomania tended to be younger at age of onset and to have had more coexisting health problems, more episodes of depression and more suicide attempts.  They also found that among those with subthreshold hypomania, a family history of mania was just as common as it was among people with bipolar disorder.

Significance

According to the researchers, the findings indicate that many adults with major depression may in fact have mild but clinically significant symptoms of bipolar disorder.  In addition, because many with subthreshold hypomania had a family history of mania, the researchers suggest that subthreshold hypomania may be predictive of future hypomania or mania. Previous research has indicated that young people with subthreshold hypomania symptoms are more likely to develop bipolar disorder over time, compared to those without subthreshold hypomania, said the authors. 

What’s Next

The researchers suggest that depression and mania may be defined as dimensions, rather than as discrete diagnostic categories. Clinicians should be aware that patients who report repeated episodes of subthreshold hypomania may have a risk of developing mania, the researcher concluded.

Reference

Angst J, Cui L, Swendsen J, Rothen S, Cravchik A, Kessler R, Merikangas K. Major depressive disorder with sub-threshold bipolarity in the National Comorbidity Survey Replication. American Journal of Psychiatry. Online ahead of print August 15, 2010.

Source: NIMH, NIH

A study in rats has revealed striking gender differences in the brain's stress response that could shed light on women's proneness to mood and anxiety disorders. Female rat brain cells were more sensitive to a key stress hormone than males', which could adapt to the hormone in a way female cells couldn't.

In the male brain under stress, many of the hormone's receptors retreated into the cell, making the brain less stress reactive. A molecular dance unique to the male brain, between the receptor and an enabling protein, accounted for its resilient adaptation. By contrast, in the female brain under stress, receptors remained exposed on neuron membranes and the brain stayed sensitive to the hormone.

"Although more research is necessary to determine whether this translates to humans, these findings may help to explain why women are twice as vulnerable as men to many stress-related disorders," explained NIMH grantee Rita Valentino Ph.D., of The Children's Hospital of Philadelphia.

A team of researchers led by Valentino and Debra Bangasser, Ph.D., reported on their discovery online June 15, 2010 in the journal Molecular Psychiatry.

Background

An understanding of why women experience more stress-related mental disorders like depression and PTSD has until now eluded science.

Corticotropin releasing factor (CRF), which acts as both a hormone and a neurotransmitter, is likely a key player. In response to a stressor, CRF binds to receptors on cells in an alarm center deep in the brainstem, called the locus ceruleus. This telegraphs heightened emotional arousal throughout the brain via the chemical messenger norepinephrine. Such hyper-arousal can be adaptive for brief periods, but not if it becomes chronic. Runaway CRF is a core feature of depression.

Previous studies suggested that this alarm system is more sensitive to CRF and stress in the female brain. To pinpoint how this works at the level of cells and molecules, Valentino, Bangasser and colleagues used antibodies and an electron microscope to see how the CRF receptor responds in male versus female rats — both unstressed and after exposure to a stressful swim.

Results

Even in the absence of any stress, the researchers found the female stress signaling system to be more sensitive from the start. CRF receptors had stronger connections, or coupling, with relay proteins inside the cell than those of male rats. So it took lower levels of CRF to activate neurons in the unstressed females compared to males. CRF levels that had no effect in males turned on cells in female rats.

After stress, CRF receptors remained exposed on the neuronal membrane in the female rat, allowing CRF to persist in its effect. In the stressed male rat, the receptors interacted with internal proteins called arrestins, enabling some to retreat into the cell's interior, where they couldn't bind with the hormone. Such receptor internalization helped the male brain adapt its sensitivity to the stressor. Although the arrestin proteins are present in the female neurons, the receptors did not interact with them.

Significance

In females, certain brain cells are more sensitive to CRF and less able to adapt to too much CRF. The greater coupling of CRF receptors to relay proteins and their inability to internalize could translate into a lower threshold for stress-induced activation of the alarm system. This could increase risk for chronic activation and impair the brain's ability to cope with high levels of CRF, as occurs in depression and PTSD, say the researchers. The study is the first to uncover sex differences at the level of receptor signaling, according to Valentino.

What's Next?

The next step is to examine the male and female CRF receptors for structural differences that might account for the functional differences, said Valentino. Since most rodent models of mood and anxiety disorders use males exclusively, the new findings of gender differences in stress signaling mechanisms call for a more gender-balanced approach — especially for disorders that disproportionately affect females. The gender differences in stress signaling should also be factored-in as medication treatments based on blocking the CRF receptor are developed, say the researchers.

Molecular Dance of CRF Receptors

When the going gets tough inside a locus ceruleus neuron, it's the female brain that acts "macho." In response to a stressor, receptors for the stress hormone CRF remained exposed on the neuronal membrane in the female rat — taking the full hit. This increased CRF binding heightened the brain's stress reactivity. By contrast, in the stressed male rat, CRF receptors danced with internal proteins called arrestins (green), which enabled some to retreat into the cell's interior, where they couldn't bind with CRF. This adaptation — unique to the male brain — toned-down the neuron's stress sensitivity. Lack of such receptor internalization in the female brain could translate into impaired ability to cope with high levels of CRF — as occurs in depression and PTSD.

Electron microscope photo of unstressed male rat brain locus ceruleus (left) shows CRF receptors (black spots with arrows) on the cell membrane. Following exposure to a stressor (right), receptors have retreated into the interior of the cell (black spots without arrows). Such receptor internalization enables the male brain to regulate its sensitivity to stressors. This adaptation does not occur in the female brain, which could account for increased vulnerability to stress-related disorders.

Reference

Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology . Bangasser DA, Curtis A, Reyes BA, Bethea TT, Parastatidis I, Ischiropoulos H, Van Bockstaele EJ, Valentino RJ. Mol Psychiatry. 2010 Jun 15. [Epub ahead of print]PMID: 20548297.

Source: NIMH, NIH

Doctors spend little time discussing mental health issues with their older patients and rarely refer them to a mental health specialist even if they show symptoms of severe depression, according to an NIMH-funded study published December 2007 in the Journal of the American Geriatrics Society.

People age 65 and older represent 12 percent of the U.S. population, but they accounted for a disproportionate 16 percent of suicide deaths in 2004.¹ Improved mental health screening in primary care may improve detection and treatment of mental disorders before drastic consequences, such as suicide, can occur.

To determine how doctors deliver mental health care to their elderly patients, researcher Ming Tai-Seale, Ph.D., of Texas A&M Health Science Center and colleagues analyzed 385 videotaped visits of 35 doctors with 366 of their elderly patients. The researchers identified topics discussed and how much time was devoted to each topic. Mental health-related topics occurred in 22 percent of visits, typically lasting about two minutes. An average visit lasted about 16 minutes overall. The majority of that time was spent discussing biomedical and other topics.

Efforts to treat or provide care for a mental health issue varied widely among the doctors participating in the study. Most fell into one of three patterns of care: 1) listening to the patient for an extended period of time and referring him or her to a mental health care specialist; 2) gathering information but providing inadequate treatment; or 3) being dismissive toward the patient and his or her emotional distress, and failing to follow up.

More female patients (27 percent) discussed a mental health topic during a typical visit than male patients (12 percent). In addition, the researchers found that the gender pairing of doctor and patient affected the likelihood of discussing mental health issues. Female-to-female doctor-patient pairs were most likely to discuss mental health, while male-to-male doctor-patient pairs were least likely. 

The results indicate that primary care doctors need more support in how to identify, treat and refer patients to mental health specialists, concluded the researchers.

Reference

Tai-Seale M. McGuire T. Colenda C. Rosen D. Cook MA. Two-minute mental health care for elderly patients: inside primary care visits. Journal of the American Geriatrics Society. 2007 Dec. 55:1903-1911.

1. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Web-based Injury Statistics Query and Reporting System (WISQARS) [online]. (2005). Available at: http://www.cdc.gov/ncipc/wisqars 

Source: NIMH, NIH

Adolescents with treatment-resistant depression who have a history of abuse—especially physical abuse—are less likely to respond to combination treatment than to medication alone, according to data from the NIMH-funded Treatment of Resistant Depression in Adolescents (TORDIA) study. The new study was published in the March 2011 issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

Background

Although the relationship between childhood abuse and risk for depression or other mental disorder is well-established, few studies have examined whether a history of abuse may affect response to treatment, especially among adolescents. Some studies have suggested that a history of abuse is associated with a lower response to cognitive behavioral therapy (CBT), a type of psychotherapy that emphasizes problem-solving and behavior change.

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 CBT

• Switch to venlafaxine (Effexor), a different type of antidepressant called a serotonin and norepinephrine reuptake inhibitor (SNRI)

• Switch to venlafaxine plus CBT

As reported in May 2010, about 40 percent of those who completed 24 weeks of treatment achieved remission, regardless of the treatment to which they had initially been assigned. The risk for relapse remained high, however.

About 13 percent of TORDIA participants had a history of physical abuse, 17 percent had a history of sexual abuse, and 5 percent had a history of both. In this most recent study, Wael Shamseddeen, M.D., MPH, of Rosalind Franklin University of Medicine and Sciences in North Chicago, and colleagues examined the association between having a history of physical or sexual abuse and response to combination treatment among TORDIA participants.

Results of the Study

The researchers found that teens without a history of abuse had a higher response rate to combination therapy compared to medication-only therapy (63 percent vs. 37.6 percent). Those with a history of sexual abuse responded similarly to combination and medication-only therapy (48 percent vs. 42 percent). However, those with a history of physical abuse had a much lower response rate to combination therapy (18.4 percent) compared to medication-only (52.4 percent).

Significance

The researchers were unable to identify the specific mechanism that might affect response to combination therapy among teens with a history of physical abuse. They suggest that because abuse can affect a child's brain development, abused youth may need psychotherapeutic approaches that target trauma before engaging in traditional CBT designed to treat depression. The researchers also suggest that abused youth may have a tendency to avoid unpleasant emotions, and therefore may have been averse to CBT. It is possible that therapeutic approaches that focus more on behavior and do not rely heavily on the processing of negative thoughts and emotions may be more acceptable and effective for these youth.

What's Next

The researchers concluded that more research is needed into the ways in which abuse history can confer treatment resistance among teens with hard-to-treat depression, and in developing alternative treatment approaches that are more effective.

Reference

Shamseddeen W, Asarnow JR, Clarke G, Vitiello B, Wagner KD, Birmaher B, Keller MB, Emslie G, Iyengar S, Ryan ND, McCracken JT, Porta G, Mayes T, Brent D. Impact of physical and sexual abuse on treatment response in the Treatment of Resistant Depression in Adolescents Study (TORDIA). Journal of the American Academy of Child and Adolescent Psychiatry. 2011 March. 50(3):293-301.

Source: NIMH, NIH

Depressed teens who report low levels of impairment related to drug or alcohol use tended to respond better to depression treatment than depressed teens with higher levels substance-related impairment, according to an analysis of data from the NIMH-funded Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study. However, it is unclear whether less substance-related impairment allowed for better response to depression treatment, or if better treatment response led to less substance-related impairment. The study was published in the December 2009 issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

Background

Substance use is more common among teens with depression than among those without depression. Researchers have also found that depression can inhibit teens' response to treatment of substance abuse, and substance abuse is associated with a poorer response to treatment of depression. Still, few trials have examined how coexisting depression and substance use among teens may affect treatment outcomes for both.

In the TORDIA study, 334 teens who did not respond to a type of antidepressant called a selective serotonin reuptake inhibitor (SSRI) before the trial were randomly assigned to one of four treatments for 12 weeks:

• Switch to another SSRI

• Switch to venlafaxine (Effexor), a different type of antidepressant

• Switch to another SSRI and add cognitive behavioral therapy (CBT), a type of psychotherapy

• Switch to venlafaxine and add CBT

Results of the trial were previously reported in February 2008. They showed that teens who received combination therapy, with either type of antidepressant, were more likely to improve than those on medication alone.

In this new analysis, Benjamin Goldstein, M.D., of the University of Toronto, and colleagues examined TORDIA data to determine the relationship, if any, between substance use, major depression and response to depression treatment. Substance use was defined as using alcohol or drugs without meeting criteria for having a full-blown substance abuse disorder. Teens who were diagnosed with a substance abuse disorder were excluded from the TORDIA study.

Results of the Study

Substance use was fairly common among TORDIA participants. At baseline, about 28 percent reported experimenting with drugs or alcohol. Those who showed more substance -related impairment were older, felt more hopeless, had greater family conflict, developed depression at an earlier age, were more likely to have a history of physical or sexual abuse, and were more likely to have coexisting oppositional defiant disorder (ODD) or conduct disorder (CD). Substance-related impairment included certain attitudes and behaviors such as craving the substance, feeling hooked on it, accidentally hurting oneself or others while using it, and other similar effects.

Participants with low levels of substance use and substance-related impairment throughout the study tended to respond better to depression treatment than those who showed persistently high or increasing levels of substance-related impairment. There were no significant differences in rates of substance use and impairment among the treatment groups.

Significance

This study is one of the first to examine the association between substance use and depression treatment among depressed teens. The findings are consistent with other studies that found depression severity to be associated with a history of physical or sexual abuse, coexisting ODD or CD, and substance-related impairment. However, the direction of the association is uncertain. The data could not determine whether low substance-related impairment facilitates improvement in depression symptoms, or whether improvement in depressed mood leads to a decrease in substance-related impairment.

What's Next

The authors caution that the study does not provide definitive conclusions about depression treatment and substance use. However, they do suggest that clinicians treating teens for depression screen for signs of substance use and address those issues as well, even if the teen does not meet criteria for a full-blown substance abuse disorder.

Reference

Goldstein BI, Shamseddeen W, Spirito A, Emslie G, Clarke G, Wagner KD, Asarnow JR, Vitiello B, Ryan N, Birmaher B, Mayes T, Onorato M, Zelazny J, Brent D. Substance use and the treatment of resistant depression in adolescents . Journal of the American Academy of Child and Adolescent Psychiatry. 2009 Dec. 48(12):1182-1192.

Source: NIMH, NIH

Certain circumstances may predict suicidal thinking or behavior among teens with treatment-resistant major depression who are undergoing second-step treatment, according to an analysis of data from an NIMH-funded study. The study was published online ahead of print February 17, 2009, in the American Journal of Psychiatry.

In the Treatment of SSRI-resistant Depression in Adolescents (TORDIA) study, 334 teens who did not get well after taking a type of antidepressant called a selective serotonin reuptake inhibitor (SSRI) before the trial were randomly assigned to one of four treatments for 12 weeks:

• Switch to another SSRI

• Switch to venlafaxine (Effexor), a different type of antidepressant

• Switch to another SSRI and add cognitive behavioral therapy (CBT), a type of psychotherapy

• Switch to venlafaxine and add CBT

Results of the trial were previously reported in February 2008. They showed that teens who received combination therapy, with either type of antidepressant, were more likely to get well than those on medication alone.

Using data from spontaneous reports by the participants and from systematic assessment by clinicians, David Brent, M.D., of the Western Psychiatric Institute and Clinic, and colleagues aimed to identify characteristics or circumstances that may predict whether a teen is likely to have suicidal thoughts or behavior during treatment. Nearly 60 percent of TORDIA participants had suicidal thinking or behavior at the beginning of the trial.

Fifty-eight suicidal events—which include serious suicidal thinking or a recent suicide attempt—occurred in 48 participants during the trial, most of which happened early in the trial. The researchers found that teens who had higher levels of suicidal thinking, higher levels of parent-child conflict, and who used drugs or alcohol at the trial's beginning were more likely to experience a suicidal event during treatment and less likely to respond to treatment. They were also less likely to have completed treatment.

"These new data may contribute to developing more targeted and individualized interventions." said NIMH co-author Benedetto Vitiello, M.D. "If we can know which teens may be more susceptible to suicidal thinking and behavior, we are better able to tailor safer treatments for them."

No statistically significant differences in suicidal events or non-suicidal self-injury were found among the treatment options. However, the use of venlafaxine was associated with a higher rate of self-injury in participants who had more severe suicidal thinking at the trial's beginning. These results suggest that SSRIs are preferred over venlafaxine in the treatment of depressed teens who are at risk for suicidal thinking or behavior, according to the researchers.

Although CBT was found to have a protective effect over the long-term among teens with depression in the NIMH-funded Treatment for Adolescents with Depression Study (TADS), it did not appear to reduce the rate of suicidal events in TORDIA. The researchers theorize that because the suicidal events tended to occur soon after treatment began, the CBT did not have enough time to deliver a protective dose.

Finally, Brent and colleagues found that the use of anti-anxiety medications called benzodiazepines was associated with a higher likelihood of, and faster time to, a suicidal event—an unexpected result not found in other similar studies. The researchers theorize that participants who were taking a benzodiazepine in addition to an antidepressant may have been much more severely ill and therefore may have been more prone to suicidal thoughts or behavior. But more study is warranted on the potential role of anti-anxiety medications in suicidal thinking and actions among patients also taking an antidepressant.

"Because the suicidal events tended to happen early in the treatment process, interventions that address safety, emotion regulation and family conflict should be some of the first to be implemented," concluded Dr. Brent. "With this data, we are in a better position to design future interventions that could lessen the risks of suicide even further among this vulnerable population."

Reference

Brent D, Emslie G, Clark G, Wagner KD, Asarnow JR, Spirito A, Ritz L, Vitiello B, Iyengar S, Birmaher B, Ryan N, Zelazny J, Onorato M, Kennard B, Mayes T, DeBar L, McCracken J, Strober M, Suddath R, Leonard H, Porta G, Keller M. Predictors of spontaneous and systematically assessed suicidal adverse events in the Treatment of SSRI-resistant Depression in Adolescents (TORDIA) study. American Journal of Psychiatry. Online ahead of print February 16, 2009.

Source: NIMH, NIH

Some teens with treatment-resistant depression are more likely than others to get well during a second treatment attempt of combination therapy, but various factors can hamper their recovery, according to an NIMH-funded study published online ahead of print February 4, 2009, in the Journal of the American Academy of Child and Adolescent Psychiatry.

Background

About 40 percent of teens with major depression do not get well after a first treatment attempt with an antidepressant medication. The NIMH-funded Treatment of Resistant Depression in Adolescents (TORDIA) study was designed to test second-step treatment strategies for these teens.

In TORDIA, 334 teens who did not get well after taking a type of antidepressant called a selective serotonin reuptake inhibitor (SSRI) before the trial were randomly assigned to one of four treatments for 12 weeks:

• Switch to another SSRI

• Switch to venlafaxine, a different type of antidepressant

• Switch to another SSRI and add cognitive behavioral therapy (CBT), a type of psychotherapy

• Switch to venlafaxine and add CBT

Results of the trial, which were reported in February 2008, showed that the teens who received medication plus CBT were more likely to get well than those who switched medications only. In this most recent data analysis, Joan Rosenbaum Asarnow, Ph.D., of the University of California Los Angeles, and colleagues aimed to identify how to better predict a teen's response to treatment, and any factors that might affect response.

Results of the Study

Many predictors were similar to those found in studies of first-step treatments, such as the NIMH-funded Treatment for Adolescents with Depression Study (TADS), underscoring the importance of early treatment before the depression becomes chronic. For instance, like in TADS, teens in the TORDIA study were less likely to respond to treatment if they had very severe depression or higher levels of suicidal thinking. In addition, teens prone to self-harming behavior and family conflict were less likely to respond to treatment.

In contrast to TADS, however, the TORDIA teens with coexisting disorders, such as an anxiety disorder, attention deficit hyperactivity disorder (ADHD), or others, did respond to TORDIA's combination therapy. The researchers theorize that in this SSRI-resistant group, adding a CBT framework may have helped the teens deal with difficulties associated with coexisting disorders. In addition, the type of CBT used in the trial included general strategies for coping with a wide range of disorders, such as ways of solving problems and improving social functioning. Because community settings often must treat patients with coexisting disorders, this finding supports the use of CBT with patients who have complex diagnoses, according to the researchers.

Combination treatment, however, was not as beneficial for teens with a history of abuse, and those reporting high levels of hopelessness. This suggests a need to strengthen treatment strategies for teens suffering from these problems, said the researchers.

Significance

Knowing predictors and moderators of treatment response may help identify the most appropriate treatment for each individual.

"Selecting the optimal treatment for teens with depression is particularly crucial for those who do not respond to an initial treatment, because when depression is unremitting, teens and their parents often give up, which makes them less likely to stick to treatment," concluded Dr. Asarnow. "With this new data, personalizing depression treatment based on a teen's individual circumstances becomes a real possibility."

What's Next

Future studies can help confirm these findings and therefore contribute to a more personalized approach to the treatment of depression in adolescence. In addition, the researchers conclude that findings from this study can inform efforts to build better treatment strategies.

Reference

Asarnow JR, Emslie G, Clarke G, Wagner KD, Spirito A, Vitiello B, Iyengar S, Shamseddeen W, Ritz L, Birmaher B, Ryan N, Kennard B, Mayes T, DeBar L, McCracken J, Strober M, Suddath R, Leonard H, Porta G, Keller M, Brent D. Treatment of SSRI-resistant depression in adolescents: predictors and moderators of treatment response . Journal of the American Academy of Child and Adolescent Psychiatry. Published online ahead of print February 4, 2009.

Source: NIMH, NIH