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.

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.

Source: Debra Bangasser, Ph.D., The Children’s Hospital of Philadelphia

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.

Source: Debra Bangasser, Ph.D., The Children’s Hospital of Philadelphia

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

Background

Bipolar disorder (BD) is a potentially debilitating illness marked by severe swings in mood, energy, and behavior. Episodes of depression alternate with spells of mania but depressive episodes tend to be more frequent and longer-lasting and the depression is difficult to treat. BD is usually treated with mood stabilizing medications such as lithium, valproate, carbamazepine or other medications with the goal of preventing mood episode relapse. Antidepressant medications are often used in addition to a mood stabilizer for depressive episodes, but antidepressants typically take weeks to have an effect and many patients do not respond adequately to existing medications.

Previous research has suggested that a disruption of signaling between neurons involving the neurotransmitter glutamate is likely to play a role in depression. The anesthetic medication ketamine shuts down one class of receptor for glutamate (NMDA receptors).

This Study

Eighteen people with BD participated in this study of ketamine. All received maintenance treatment with a mood stabilizer medication during the study. All had previously been unsuccessfully treated with at least one antidepressant medication and a mood stabilizer; the average number of medications they had tried unsuccessfully was seven.

In the first phase of the study, each person was randomly assigned to receive a single dose of either intravenous ketamine or placebo (saline). After two weeks, treatment was switched, so those initially receiving ketamine received placebo, and vice versa. Neither patients nor those treating them were told whether they were receiving ketamine or placebo. Investigators used standard surveys of depression symptoms to assess the effect of medication.

Within 40 minutes, 9 of 16 (56 percent) patients receiving ketamine had at least a 50 percent reduction in symptoms, and 2 of 16 (13 percent) became nearly symptom-free. The response to ketamine lasted an average of about a week. By contrast, no patients receiving placebo had declines in symptoms close to the magnitude seen with ketamine within the first 3 days.

Significance

In this study, carried out by scientists Nancy Diazgranados, Carlos Zarate, Jr., and colleagues at the Experimental Therapeutics & Pathophysiology Branch of NIMH’s intramural research program, a single intravenous dose of ketamine brought relief from depression in severely treatment resistant patients with BD, in over half of them within 40 minutes. This study supports a previous one by the same group in which they also found a rapid antidepressant effect in patients with treatment-resistant major depression (unipolar). (NIMH press release, August 7, 2006). The authors note that the rapid antidepressant response observed in these two different disorders (major depressive disorder and bipolar disorder) highlights the importance of the NMDA receptor in developing treatments with a rapid onset of action.

The work adds to the evidence of the potential of medications targeting the glutamate system for rapid relief from depression, even in cases of people who have failed to respond to other existing therapies. Rapid and effective treatment of depression is an urgent public health need. BD can be disabling—nearly all the patients in this study were unemployed as a result of the severity of their illness. BD is among the psychiatric disorders with the highest risk of suicide.

Continuing research is focusing on developing NMDA-targeting medications that are suitable for clinical use; and investigating the use of this class of drugs for long-term maintenance of the rapid antidepressant effect seen in this study.

Reference

Diazgranados, N., Ibrahim, L., Brutsche, N.E., Newberg, A., Kronstein, P., Khalife, S., Kammerer, W. A., Quezado, Z., Luckenbaugh, D.A., Salvadore, G., Machado-Vieira, R., Manji, H.K., and Zarate, C. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry 2010;67(8):793-802.

For information on this study and other research conducted at NIMH please see http://patientinfo.nimh.nih.gov/ or email: nimhcore@mail.nih.gov, telephone 301-496-5645.

The story is about a caterpillar that has a fantastic life full of games, friends, school and leaf eating. He is stunned when, one day at caterpillar school, he learns that he is expected to  build a chrysalis and become a butterfly. Harry vows to remain a caterpillar forever, as his friends build their chrysalises and move on.  Eventually, Harry  learns to accept change as a necessary part of life, and  joins his friends as a butterfly. There are tips in the back of the book to help parents and educators use the story as a vehicle to talk to kids about their feelings, teach them coping strategies, and help them view change in a more positive light.

The book is beautifully illustrated by Kathy Voerg. It  is appropriate for children ages 4-10. It is part of New Horizon Press’s “Let’s Talk” series for young children.

Cindy Jett is a licensed clinical social worker. She has a masters degree from the National Catholic School of Social Service, and has had a psychotherapy practice in Washington, DC for ten years.

Contact:

Cindy Jett, LICSW

cindyjett@hotmail.com

http://harrythehappycaterpillar.com

(Heath.com) — As recently as 10 years ago, doctors advised women with bipolar disorder not to have children. While that thinking is now dated, bipolar women often face tough decisions about how to handle their medication during pregnancy.

Most drugs prescribed for bipolar disorder carry some risk of birth defects, yet women who discontinue medication risk relapsing into a manic or depressive episode; during the postpartum phase the relapse rate is as high as 50 percent to 70 percent, by some estimates.

Even more alarming, bipolar women are 100 times more likely than other women to experience postpartum psychosis, a severe mood disorder that, at its very worst, can result in infanticide.

Sally, 38, started taking lithium after a severe manic episode eight years ago. She eventually switched to other drugs, but in 2007 she stopped her medication altogether when she learned that she was pregnant.

The pregnancy was uneventful. Her daughter, Stella, did arrive six weeks early, but after 21 days in the hospital Stella was finally at home and thriving.

Sally, meanwhile, was falling apart.

“I was extremely hyperactive,” she says. “I was going a million miles an hour.” Everyone had told her, “When the baby sleeps, you sleep” — but she couldn’t rest. While Stella napped, Sally would clean her Jackson, New Jersey, home yet again, wiping down doorknobs and light switches. She baked blueberry cobbler at 6 a.m. and pulled weeds into the night.

Though she had restarted her meds the day she gave birth to Stella, after a string of sleepless nights several months later Sally finally realized that lithium was the only thing that would bring her back to her senses. And it did.

Yet Sally continued to have doubts that she was strong enough to be a mother. These are doubts that many women with bipolar disorder share.

Say no to drugs?

Meredith, 27, of Dix Hills, New York, was diagnosed with bipolar disorder in 2007 and began taking lithium. Two years later, as she was planning her wedding, she took a cocktail of mood stabilizers, antidepressants, and antipsychotics: lithium, Abilify, propranolol (Inderal), and escitalopram (Lexapro).

“I was grateful for the lithium at first,” says Meredith, who did not want her last name used. “But then I was like, ‘There go all my options for having kids.’”

When it was first approved by the FDA in 1970, lithium was believed to cause heart-valve defects in an extremely high percentage of infants born to mothers who were on the drug (about 1 in 50). Decades later, new research has downgraded the risk, to about 1 in 1,000 to 2,000.

Bipolar medications aren’t considered as risky during pregnancy as they once were, but they aren’t exactly harmless either. According to the FDA’s letter-grade system for drug safety during pregnancy, most psychotropic drugs pose a potential risk to the fetus. Studies have found that the anticonvulsants valproic acid (Depakote) and carbemazepine (Tegretol) can cause birth defects ranging from physical deformities to spina bifida, for instance, while some research suggests that another anticonvulsant, lamotrigine, may carry an increased risk of cleft palate.

The risk of birth defects is small, yet the decision to stop taking medication is common, even among women with severe psychiatric illness. In 2008, after she got engaged, and after consulting her psychiatrist, Meredith decided to start tapering off lithium. “I, personally, would like to not be on any medication,” she says, when considering a future pregnancy. “I just don’t want to take any chances.”

Should bipolar women discontinue their medication? According to reproductive psychiatrist Catherine Birndorf, M.D., the founding director of the Payne Whitney Women’s Program at New York Presbyterian Hospital, “There’s not just one answer.” The severity of bipolar disorder varies widely from person to person, and for this reason it’s difficult to standardize care for pregnant women with the disorder, Birndorf explains. “Each case must be considered on an individual basis,” she says.

But what many of Bindorf’s patients do not initially realize is that untreated illness — and not just medication — can be risky. According to a 2007 study in the American Journal of Psychiatry, women who discontinued mood stabilizers during pregnancy spent over 40 percent of their pregnancy in an “illness episode.” And research suggests that the effects of maternal depression on the fetus can lead to complications both during and after pregnancy.

Still, many bipolar women believe they have to stop taking all of their medications for the sake of their child — and often psychiatrists or OB/GYNs steer women away from medication, according to Margaret Spinelli, M.D., director of the Women’s Program in Psychiatry at Columbia University.

“I hope that women will come to a perinatal psychiatrist to get an evaluation,” says Spinelli. “Because they can become so ill. And the problem is that if they become really ill during the pregnancy off the medication, it may take a lot more medication to stabilize them.”

Postpartum planning

A complication-free pregnancy with or without medication doesn’t mean a woman is in the clear. For any bipolar mother, the trickiest time is not the pregnancy itself but the postpartum period.

Postpartum difficulties are not limited to bipolar women, of course. Many women experience the crying episodes known as the “baby blues,” and an estimated 10% of women go through a more severe postpartum depression. Women with bipolar disorder are at much higher risk, however; postpartum psychosis — which is believed to be a form of bipolar disorder — occurs in as many as 25 percent to 50 percent of deliveries.

While postpartum psychosis is a serious risk, it’s a risk that can be treated, and often prevented, with medication. It’s extremely important for a woman with bipolar disorder to have a plan in place with her family and her doctors in the event that she does become psychotic, says Spinelli. Due to the high risk of psychosis, bipolar women should “really start medicines at least before they deliver,” she adds.

As the field of perinatal psychiatry grows, many bipolar women are choosing to stay on medications to avoid any chance of postpartum psychosis or manic episodes. “I’d heard so many horror stories of people harming the baby,” says Michele Noll, 38, of Atlanta, who has delivered two healthy babies while taking mood stabilizers.

“I did not have mood swings,” Noll says of her pregnancy and postpartum period. “Nobody even knew I was bipolar.”

Breast-feeding presents another challenge. Even though some medications are safe while nursing, feeding a baby requires waking up often throughout the night. And in people with bipolar disorder, sleep deprivation can trigger a manic episode.

Shanun Carey, 26, of Manchester, N.H., became so manic while breast-feeding that she was “bouncing off the walls,” eventually volunteering to clean her neighbors’ apartments to burn off excess energy. When her daughter was six months old, Carey realized she had to stop breast-feeding to get healthy again; she switched to formula so she could resume her medications and a regular sleep schedule.

Formula isn’t the only solution. Rachael Bender, 31, of Naples, Florida, who writes a blog called My Bipolar Pregnancy, realized that losing sleep would be a huge challenge in trying to breast-feed. But she did want to try, so she and her husband worked out a system when her daughter was an infant.

To save Bender from getting the baby up and back to sleep, her husband slept in the guest room, next to the bassinet, and brought the baby in to Bender when the baby was hungry. “The hardest thing about the whole pregnancy,” Bender says, “was the sleep after she was born.”

The next generation

Sally, who lapsed into depression after the lithium got her mania under control, still struggles with the ups and downs of bipolar disorder. Because she is committed to being a great parent to Stella, she has made what she says is the most difficult decision of her life.

“Absolutely, I will not have another baby,” Sally says, acknowledging that no matter how many times her healthy daughter kisses her, or her husband tells her she’s a wonderful mother, she still has doubts related to her bipolar disorder and the amount of attention it requires. “I want to be the best mother I can be, and if I had two children I’d worry that I was spreading myself too thin,” she says.

Meredith knows that pregnancy will be “a difficult time,” and people have already questioned her decision to have children; a family friend even told her that it would be a “heartache” for her if she did have a child with bipolar disorder. Bipolar disorder does tend to run in families: Studies show that a person is 10 times more likely to develop the disorder if a parent is bipolar.

None of this has swayed Meredith’s desire to be a mother.

“I’m not going to not have a child because I’m afraid they’re going to be bipolar,” says Meredith. “I’ve seen so many wonderful things and I’ve done so many wonderful things, and I plan to do a lot more. My kid will have a better life than a lot of kids out there. This isn’t going to stop me.”

Background

The Air Force Suicide Prevention Program (AFSPP) was implemented in 1997. Based on the premise that individuals at risk for suicide exhibit early warning signs, AFSPP emphasizes leadership and community involvement in reducing suicide by encouraging Air Force leaders to actively support and get involved with suicide prevention efforts. It trains commanders in how and when to seek out mental health services for their troops, provides training to all military and civilian personnel in suicide prevention, and incorporates other community-based components.

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

Results of the Study

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

Significance

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

What’s Next

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

Reference

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