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Mania symptoms and bipolar disorder II more likely to lead to substance abuse than depression

January 9, 2008 • Science Update

September 7, 2011 • Science Update

Source: NIMH

Chronic use of stimulant medication to treat attention deficit hyperactivity disorder (ADHD) in children does not appear to increase risk for high blood pressure over the long term, but it may have modest effects on heart rate, according to follow-up data from the NIMH-funded Multimodal Treatment Study of Children with ADHD (MTA). The study was published online ahead of print Sept 2, 2011, in the American Journal of Psychiatry.

Background

The MTA was the first major multi-site trial comparing different treatments for ADHD in childhood. The initial results of the 14-month study, in which 579 children were randomly assigned to one of three intensive treatment groups (medication management alone, behavioral treatment alone, a combination of both) or to routine community care, were published in 1999. The researchers found that medication management alone or in combination with behavioral therapy produced better symptomatic relief for children with ADHD than just behavioral therapy or usual community care.

After the study ended, participants returned to community treatment and were free to pursue whatever treatment course they wished. MTA researchers gathered follow-up data from MTA study participants at 2, 3, 6, 8, and 10 years after study entry.

ADHD is often a chronic condition that continues into adolescence, so some children take stimulants for years. Because stimulants can affect the heart, doctors are concerned about the possible risks for rapid heart rate, hypertension (high blood pressure) or other cardiovascular effects after many years of use. But studies have been inconsistent about whether the effects are long-lasting.

For this most recent data analysis, Benedetto Vitiello, M.D., of NIMH, and MTA colleagues examined the MTA follow-up data to determine if there was an association between chronic use of stimulant medication and changes in blood pressure or heart rate over a 10-year period.

Results of the Study

At the end of the 14-month study, children who were randomized to stimulant treatment in the study had, on average, higher heart rates compared to the children who were randomized to non-medication or community care. Heart rates for the children who continued to take stimulants after the end of the study were slightly elevated at subsequent checks, but they did not have an abnormally elevated heart rate (e.g., tachycardia).

The researchers concluded that stimulant medication did not appear to increase the risk for abnormal elevations in blood pressure or heart rate over a 10-year period. However, because some epidemiological studies have indicated that even modest elevations in heart rate may increase a person’s lifetime risk for cardiovascular problems, the persistent effect of continuous stimulant treatment on heart rate should not be dismissed.

Significance

The results of this study indicate that the effect of stimulants on heart rate can be detected even after years of use, suggesting that the body does not get completely used to it. However, after 10 years of treatment, researchers found no increased risk for hypertension. In addition, none of the children reported any adverse cardiovascular events over the 10-year period.

The researchers do note that the effect on heart rate may be clinically significant for individuals who have underlying heart conditions. Therefore, children taking stimulants over the long-term should be monitored regularly for potential cardiovascular complications.

Citation

Vitiello B, Elliott GR, Swanson JM, Arnold E, Hechtman L, Abikoff H, Molina BSG, Wells K, Wigal T, Jensen PS, Greenhill LL, Kaltman JR, Severe JB, Odbert C, Hur K, Gibbons R. Blood pressure and heart rate in the multimodal treatment of attention deficit/hyperactivity disorder study over 10 years. American Journal of Psychiatry. Online ahead of print Sept 2, 2011.

September 28, 2011 • Press Release

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.

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.

An experimental drug that lifts depression in hours likely works by rapidly stimulating connections between brain cells, a study in rats has revealed. The drug, called ketamine, quickly generated such synapses in a brain circuit implicated in human depression by triggering a key enzyme.

“Discovery of this cellular mechanism helps point the way to development of a ketamine-like agent that could become a practical, rapid-acting treatment for depression,” said NIMH grantee Dr. Ronald Duman, of Yale University, who led the research team.

Duman, Dr. George Aghajanian, and colleagues, report on their findings in the August 20, 2010 issue of the journal Science.¹

Background

Conventional antidepressants fail to help up to 40 percent of depressed patients and take at least a few weeks to begin working. Studies in both major depressive disorder and bipolar depression by NIMH intramural scientists have found that 70 percent of such treatment-resistant patients improve dramatically within a day after receiving just one dose of ketamine.² Since it must be administered intravenously and risks significant side effects, ketamine itself isn’t a practical treatment. So it has spurred a hunt for more suitable agents that work via the same mechanism. Until now, that mechanism was not well understood.

Commonly prescribed antidepressants work primarily through the brain’s serotonin chemical messenger system, while ketamine works mainly through the glutamate system. Evidence suggests that the serotonin drugs trigger a cascade of events that stimulate the birth of new neurons, which eventually establish connections, or synapses, with other neurons, enhancing brain circuit activity. Since this process takes a few weeks, it’s thought to explain the delay in response to the medications. Ketamine’s speedy effects suggest that the glutamate mechanism is acting more directly — via pathways closer to the root of the problem.

It was known that ketamine blocks the binding of glutamate to a receptor protein on cell membranes called the NMDA receptor. To find out how this leads to an antidepressant effect, Duman’s team explored the path of the signal triggered by the receptor blockade.

Findings

In the executive hub at the front of the brain — or prefrontal cortex — of rats, they discovered that a low dose of ketamine rapidly activates an enzyme, called the mammalian target of rapamycin (mTOR), that makes proteins forming the connections between neurons, or synapses. Neither conventional antidepressants nor ECT similarly activated mTOR.

Stress and depression produce the opposite effect of ketamine, causing synapses to shrivel. A single dose of ketamine boosted levels of synapse-associated proteins within 2 hours and increased the number of neuronal “spines” — or budding synapses — within 24 hours. It also rapidly reversed depression-like behavior that developed in rats exposed to stress. These effects lasted at least a week. Injection of rapamycin, which blocks mTOR, blocked ketamine’s ability to produce such beneficial neuronal and behavioral effects. Another agent that also blocks the NMDA receptor performed similarly to ketamine in these tests.

Significance

The research identifies the key cellular signaling pathway by which ketamine works. It demonstrates that mTOR is required for ketamine to enhance synapse formation.

While the serotonin antidepressant mechanism seems to work by triggering the birth of new neurons, or neurogenesis, in the brain’s hippocampus, the glutamate mechanism appears to work by stimulating connections of existing neurons, or synaptogenesis, in the brain’s prefrontal cortex — a quicker, more direct, process.

“Rapid activation of the mTOR signaling pathway may be an important and novel strategy for the rational design of fast-acting antidepressants,” note the authors of an accompanying editorial in the same issue of Science.³ “The exciting results also demonstrate that ketamine may be a useful tool to identify molecular mediators of rapid antidepressant effects.”

What’s next?

Ketamine’s effects appear to be specific to the mTOR brain pathway, according to Duman. Any new treatment targeting the same pathway would have to be similarly specific, since mTOR also makes proteins in other parts of the body, and has been implicated in some types of cancers. Duman said his lab is currently investigating how stress affects the growth of neuronal spines, where synapses form, and how ketamine affects this process.

The new findings in rats complement ongoing human studies with ketamine at the NIMH Division of Intramural Research Programs. For example, the researchers there recently identified a brain signaldetectible using a MEG scanner that predicts whether a patient will likely respond to ketamine treatment.

“Contrary to traditional notions of drug development, examining drug effects on brain cells and molecules in animals after clinical human trials is revealing much in the unfolding ketamine story ,” noted Dr. Carlos Zarate, Chief of the NIMH Experimental Therapeutics & Pathophysiology Branch, who directs the intramural ketamine studies.

Neuronal spines, budding connections between brain cells, or synapses, sprouted in rats within hours of receiving ketamine (arrows). By contrast, fewer spines developed on neurons of control rats that didn’t receive the drug. The boost in neuronal connectivity is thought to produce an antidepressant effect by enhancing brain circuit activity. The highly magnified two photon imaging pictures show extensions of neurons in rat prefrontal cortex.

Patients taking medications to treat bipolar disorder are more likely to get well faster and stay well if they receive intensive psychotherapy, according to results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), funded by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH). The results are published in the April 2007 issue of the Archives of General Psychiatry.

Bipolar disorder is a debilitating illness marked by severe mood swings between depression and mania that affects 2.6 percent of Americans in any given year. “We know that medication is an important component in the treatment of bipolar illness. These new results suggest that adding specific, targeted psychotherapy to medication may help give patients a better shot at lasting recovery,” said NIH Director Dr. Elias A. Zerhouni.

“STEP-BD is helping us identify the best tools—both medications and psychosocial treatments—that patients and their clinicians can use to battle the symptoms of this illness,” said NIMH Director Thomas R. Insel, M.D.

Psychotherapy is routinely employed as a means to treat bipolar illness in conjunction with medication, but the extent to which psychotherapy is effective has been unclear. In addition, most psychotherapeutic studies have been limited to a single site and compared only one type of treatment to routine care. Thus, in addition to examining the role of medication, STEP-BD set out to compare several types of psychotherapy and pinpoint the most effective treatments and treatment combinations.

With 293 participants, David Miklowitz, Ph.D., of the University of Colorado and colleagues set out to test the effectiveness of three types of standardized, intensive, nine-month-long psychotherapy compared to a control group that received a three-session, psychoeducational program called collaborative care. The intensive therapies were

• family-focused therapy, which required the participation and input of patients’ family members and focused on enhancing family coping, communication and problem-solving;
• cognitive behavioral therapy, which focused on helping the patient understand distortions in thinking and activity, and learn new ways of coping with the illness; and
• interpersonal and social rhythm therapy, which focused on helping the patient stabilize his or her daily routines and sleep/wake cycles, and solve key relationship problems.

All participants were already taking medication for their bipolar disorder, and most were also enrolled in a STEP-BD medication studyreported in the New England Journal of Medicine on March 28, 2007. The researchers compared patients’ time to recovery and their stability over one year.

Over the course of the year, 64 percent of those in the intensive psychotherapy groups had become well, compared with 52 percent of those in collaborative care therapy. Patients in intensive psychotherapy also became well an average of 110 days faster than those in collaborative care. In addition, patients who received intensive psychotherapy were one and a half times more likely to be clinically well during any month out of the study year than those who received collaborative care. Discontinuation rates among the groups were similar—36 percent of those in the intensive programs discontinued and 31 percent of those in collaborative care discontinued. None of the three intensive psychotherapies appeared to be significantly more effective than the others, although rates of recovery were higher among those in family-focused therapy compared to the other groups.

“Intensive psychotherapy, when used as an adjunctive treatment to medication, can significantly enhance a person’s chances for recovering from depression and staying healthy over the long term,” said Dr. Miklowitz. “It should be considered a vital part of the effort to treat bipolar illness.”

Reference

Miklowitz D. et al. Psychosocial Treatments for Bipolar Depression .Archives of General Psychiatry. Apr 2007; 164.

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 theNIH website .

A new study supports earlier estimates of the prevalence of bipolar disorder in the U.S. population, and suggests the illness may be more accurately characterized as a spectrum disorder. It also finds that many people with the illness are not receiving appropriate treatment. The study, published in the May 2007 issue of Archives of General Psychiatry, analyzed data from the National Comorbidity Survey Replication (NCS-R), a nationwide survey of mental disorders among 9,282 Americans ages 18 and older. The NCS-R was funded by the National Institutes of Health’s National Institute of Mental Health (NIMH).

NIMH researcher Kathleen Merikangas, Ph.D. and colleagues identified prevalence rates of three subtypes of bipolar spectrum disorder among adults. Bipolar I is considered the classic form of the illness, in which a person experiences recurrent episodes of mania and depression. People with bipolar II experience a milder form of mania called hypomania that alternates with depressive episodes. People with bipolar disorder not otherwise specified (BD-NOS), sometimes called subthreshold bipolar disorder, have manic and depressive symptoms as well, but they do not meet strict criteria for any specific type of bipolar disorder noted in the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV), the reference manual for psychiatric disorders. Nonetheless, BD-NOS still can significantly impair those who have it.

The results indicate that bipolar I and bipolar II each occur in about 1 percent of the population; BD-NOS occurs in about 2.4 percent of the population. The findings support international studies suggesting that, given its multi-dimensional nature, bipolar disorder may be better characterized as a spectrum disorder.

“Bipolar disorder can manifest itself in several different ways. But regardless of type, the illness takes a huge toll,” said NIMH Director Thomas R. Insel, M.D. “The survey’s findings reiterate the need for a more refined understanding of bipolar symptoms, so we can better target treatment.”

Most respondents with bipolar disorder reported receiving treatment. Nearly everyone who had bipolar I or II (89 to 95 percent) received some type of treatment, while 69 percent of those with BD-NOS were getting treatment. Those with bipolar I or II were more commonly treated by psychiatric specialists, while those with BD-NOS were more commonly treated by general medical professionals.

However, not everyone received treatment considered optimal for bipolar disorder. Up to 97 percent of those who had some type of bipolar illness said they had coexisting psychiatric conditions, such as anxiety, depression or substance abuse disorders, and many were in treatment for those conditions rather than bipolar disorder. The researchers found that many were receiving medication treatment considered “inappropriate” for bipolar disorder, e.g., they were taking an antidepressant or other psychotropic medication in the absence of a mood stabilizing medication such as lithium, valproate, or carbamazepine. Only about 40 percent were receiving appropriate medication, considered a mood stabilizer, anticonvulsant or antipsychotic medication.

“Such a high rate of inappropriate medication use among people with bipolar spectrum disorder is a concern,” said Dr. Merikangas. “It is potentially dangerous because use of an antidepressant without the benefit of a mood stabilizer may actually worsen the condition.”

Merikangas and colleagues speculate that as people seek treatment for anxiety, depression or substance abuse disorders, their doctors, especially if they are not mental health specialists, may not be detecting an underlying bipolar condition in their patients.

“Because bipolar spectrum disorder commonly coexists with other illnesses, it is likely underrecognized, and therefore, undertreated. We need better screening tools and procedures for identifying bipolar spectrum disorder, and work with clinicians to help them better spot these bipolar symptoms,” concluded Dr. Merikangas.

Reference

Merikangas KR, et al. Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication.Archives of General Psychiatry. May 2007; 64.

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 theNIH website .