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It has long been a puzzle what exactly causes the intense highs and lows of bipolar disorder, an illness that pushes people back and forth from periods of intense energy and excitement to periods of deep sadness and hopelessness. But evidence is stacking up that this disorder may involve abnormalities in metabolism, the wide range of chemical reactions that help sustain the body and brain.

Now, a research team has found previously unobserved structural differences in the brains of people with bipolar disorder that may reflect disruptions to metabolism, suggesting those processes may broadly contribute to the illness. Their study was published January 6th inMolecular Psychiatry.

Led by John A. Wemmie, M.D., Ph.D., of the University of Iowa––a 2004 and 2007 NARSAD Young Investigator (YI) grantee and 2013 NARSAD Independent Investigator (II) grantee––the team looked at levels in the brain of a signal called T1ρ. This signal has proven sensitive to different brain abnormalities linked to bipolar disorder, including unusual concentrations of metabolites, the chemical reactants and byproducts of the body’s metabolic systems. Using a unique imaging method not typically applied to psychiatric conditions, the team found that T1ρ levels were higher in certain parts of the brain for people with bipolar disorder compared to those who do not have the illness. In particular, T1ρ was high in white matter portions of the cerebral cortex, which contains cells that shape communication within the brain, and also in the cerebellum, which controls motor functions.

Since T1ρ is sensitive to a number of brain features linked with bipolar disorder, the team tested whether the high levels of this signal stemmed from other factors besides metabolism. Their analyses suggested that those other factors did not affect the findings, pointing to irregular metabolism as the root of the high T1ρ levels. This possibility likely will be more closely studied in the future using other imaging techniques.

Importantly, this study also found that medication affected T1ρ levels. Among people in the study with bipolar disorder, those who were taking the mood regulator lithium had normal T1ρ levels in the cerebellum, compared to elevated levels found in those not taking the drug. Lithium, then, may help specifically to reverse abnormalities in the cerebellum among people with bipolar disorder.

Because this study looked at people with bipolar disorder who were experiencing neither an intense high nor intense low period, it’s not yet known what T1ρ levels look like during those states. It is also an open question whether the observed cerebral white matter and cerebellum abnormalities appear in other conditions that affect mood, including schizophrenia anddepression.

When people with bipolar disorder experience depressive episodes, the reward circuits in their brains show impairments similar to those that affect people diagnosed with major depressive disorder (MDD), scientists reported March 13th in the journal Neuropsychopharmacology. When these circuits are weakened, people’s ability to experience pleasure diminishes.

Most clinical studies exploring how depression affects the brain have focused on people with MDD. Because patients with the two disorders may respond differently to antidepressant medications, it’s important to understand the neurobiology of both groups in order to develop effective treatments.

In patients with bipolar disorder and major depressive disorder, connections between different reward processing regions of the brain were weaker than they were in people without depression. This weakening was greater in patients with more severe depression in both groups.

The scientists did find differences between the two groups of depressed patients. Winning money activated a reward center––the ventral striatum––more strongly in patients with bipolar disorder than it did in those with major depressive disorder. And the strength of certain circuit connections was stronger in patients with bipolar disorder than it was in patients with major depressive disorder. These differences might reflect the two groups’ different risks for manic episodes, during which reward responses appear to be heightened rather than dampened, the scientists say.

Why is it so important to distinguish among brain responses to reward? First, symptoms of depression–– which may be more linked to reward-system dysfunction such as loss of pleasure––tend to be less responsive to standard treatments. “Attenuated reward system response may therefore evolve to be a useful biomarker in drug discovery and clinical trials for mood disorders,” Dr. Satterthwaite says. Second, because many people with bipolar disorder first seek clinical help during depressive episodes, identifying differences between bipolar disorder and major depressive disorder could help ensure patients are accurately diagnosed from the start and receive treatment specifically designed to relieve their symptoms.

Former NFL Player Helps Others After Facing His Diagnosis

Dreams and reality were always at odds for Keith O’Neil. With a former NFL player for a father and an early love for the game, he longed to play professional football, even as a child. “I always had a dream about playing in the league,” he says.

But severe anxiety clouded that childhood vision. “I couldn’t sleep at night,” he recalls. “My mind would just keep going.” Around age 12, he began having suicidal thoughts—not crafting plans, but staring at the bottles in his parents’ medicine cabinet. “I’d want to die,” he says. “I’d want everything just to end.”

His parents knew he was moody, but because he would snap out of it, they never suspected an underlying illness. The symptoms receded during high school, and his love for football—the competition, camaraderie, and physicality—flourished.

Keith attended Northern Arizona University on an athletic scholarship, playing football for all four years. But the symptoms resumed, and he turned to alcohol. “I needed a release from the stress I put on myself,” he says. “I think drinking was a coping mechanism.”

Just as his NFL dream came true—he joined the Dallas Cowboys after college—an old reality returned. Constantly anxious, he didn’t sleep for five nights straight during rookie training. “I was a mess,” he recalls. Gradually, he learned to manage his symptoms by preparing himself for sleep and sticking to a routine. He played with the Cowboys for two years.

When the Indianapolis Colts picked him up in 2005, Keith realized another dream: playing under revered coach Tony Dungy. But the anxiety worsened. He couldn’t stop thinking about the playbook, yet kept forgetting plays. He worried about days ahead and days past. He knew he had to make a decision: “I was going to quit the NFL or I was going to get help,” he says.

Keith confessed to Dungy not only about his present state but also his lifelong anxiety. Dungy rallied his staff to help. Keith began taking anti-anxiety medication and continued to play. In his fourth year with the team, the Colts won the Super Bowl.

His new reality soon came crashing down. He and his wife, Jill, who he’d met in college, returned to his hometown of Buffalo, New York. Keith got a job in medical device sales, and Jill became pregnant. But her miscarriage in December 2010 triggered a severe manic episode. After a few days of euphoria—he spent money, he felt great—Keith became paranoid and delusional. He thought a “higher being” was tapping his computer, phone, and even his thoughts. He hallucinated.

Lucid enough to know something was wrong, he researched his symptoms online and diagnosed himself with cyclothymia––a mood disorder in which emotions swing between mild depression and hypomania, or elevated mood. His friend’s mother, a psychologist, urged him to seek psychiatric help. The symptoms worsening, Jill had to make the appointment. “Without the support of my wife and family I don’t know what would have happened to me,” Keith says. Within a week, he had a clinical diagnosis of bipolar 1 disorder––severe mood swings from mania to depression––and began medication.

There was still an uphill battle to climb. Coping with the reality of his illness and medication side effects, Keith sank into an 18-month-long depression that persisted even after the birth of his son, Conor, in April 2012.

That summer, Keith met Steven L. Dubovsky M.D., a psychiatrist at the University of Buffalo. Dr. Dubovsky prescribed lithium, oxcarbepazine (Trileptal) and aripiprazole (Abilify), which “really made all the difference in the world,” says Keith. “I still deal with my moods but I’m as healthy as I can get.”

As he regained his life, Keith learned how many other people suffer from mental illness, often in silence. In October 2013, he founded 4th And Forever, a nonprofit organization dedicated to raising awareness, providing education, and funding research. Today, Keith travels the country speaking with communities and high school students. He has served as the keynote speaker at two Foundation Discovery to Recovery: A Path to Health Minds conferences; in September, 2014 in Washington DC and in February, 2015 in Los Angeles where he spoke about his experience and living a productive life.

Although Keith sometimes has normal performance anxiety before big talks, “the reaction I get from the crowd is well worth it,” he says.

Through 4th And Forever, Keith is realizing a new dream, easing the way for others and reducing the stigma surrounding mental illness. “I want to do something to help, to say ‘I went through this and it’s okay to talk about it.’”

Gene associated with schizophrenia, bipolar disorder, autism, ADHD, and depression linked to brain cell death in mice.

A new study shows the death of newborn brain cells may be linked to a genetic risk factor for five major psychiatric diseases, and at the same time shows a compound currently being developed for use in humans may have therapeutic value for these diseases by preventing the cells from dying.

In 2013, the largest genetic study of psychiatric illness to date implicated mutations in the gene called CACNA1C as a risk factor in five major forms of neuropsychiatric disease — schizophrenia, major depression, bipolar disorder, autism, and attention deficit hyperactivity disorder (ADHD). All the conditions also share the common clinical feature of high anxiety. By recognizing an overlap between several lines of research, scientists at the University of Iowa and Weill Cornell Medicine of Cornell University have now discovered a new and unexpected role for CACNA1C that may explain its association with these neuropsychiatric diseases and provide a new therapeutic target.

The new study, recently published in eNeuro, shows that loss of the CACNA1C gene from the forebrain of mice results in decreased survival of newborn neurons in the hippocampus, one of only two regions in the adult brain where new neurons are continually produced – a process known as neurogenesis. Death of these hippocampal neurons has been linked to a number of psychiatric conditions, including schizophrenia, depression, and anxiety.

“We have identified a new function for one of the most important genes in psychiatric illness,” says Andrew Pieper, MD, PhD, co-senior author of the study, professor of psychiatry at the UI Carver College of Medicine and a member of the Pappajohn Biomedical Institute at the UI. “It mediates survival of newborn neurons in the hippocampus, part of the brain that is important in learning and memory, mood and anxiety.”

Moreover, the scientists were able to restore normal neurogenesis in mice lacking the CACNA1C gene using a neuroprotective compound called P7C3-A20, which Pieper’s group discovered and which is currently under development as a potential therapy for neurodegenerative diseases. The finding suggests that the P7C3 compounds may also be of interest as potential therapies for these neuropsychiatric conditions, which affect millions of people worldwide and which often are difficult to treat.

A new study on the epigenetics of lactose intolerance may provide an approach to understanding schizophrenia and other complex, serious illnesses.

Both lactose intolerance and schizophrenia are inherited. In addition, neither condition emerges in the first years of life, but rather both appear years or even decades later, says senior author Dr. Arturas Petronis, head of the Krembil Family Epigenetics Laboratory in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH).

The study, published in Nature Structural & Molecular Biology, showed that a combination of genetics and epigenetics – factors that turn genes on or off – could explain how lactose intolerance develops over time. These basic principles can be applied to the study of more complex mental illnesses such as schizophrenia, bipolar disorder or Alzheimer’s disease. All these conditions also have DNA risk factors but take decades before clinical symptoms develop, says Dr. Petronis, who also is the Tapscott Chair in Schizophrenia Studies at the University of Toronto.

More than 65 per cent of adults worldwide are lactose intolerant and cannot process the milk sugar lactose. Lactose intolerance is influenced by one gene, which determines if a person will lose the ability to process lactose over time. More specifically, those with some variants of this gene will gradually produce less lactase, the enzyme that breaks down lactose, as they age.

“The question we asked is why does this change happen over time? All newborns are able to digest lactose, independently from their genetic variation,” says Dr. Petronis. “Now, we know that epigenetic factors accumulate at a very different pace in each person, depending on the genetic variants of the lactase gene.”

Over time, these epigenetic changes build up and inactivate the lactase gene in some – but not all – individuals. At this point, these individuals would start experiencing symptoms of lactose intolerance.

Unravelling the epigenetic control of the lactase gene involved a collaborative effort of CAMH, University of Toronto, the Hospital for Sick Children, Vilnius University and the Lithuanian University of Health Sciences.

Mental illnesses are much more complex, and many more genes with their epigenetic “surroundings” are implicated. But in essence, the same molecular mechanisms may account for the delayed age of onset of illnesses, such as schizophrenia, in early adulthood, says Dr. Petronis.

The combination of genes and epigenetic factors that build up over time with age, provide a plausible avenue to investigate in illnesses such as schizophrenia. “We came up with interesting hypotheses, and possibly insights, into risk factors for brain disease by studying aging intestines,” he says.

Long delays mean missed opportunities for early intervention to reduce the severity of episodes of bipolar disorder.

Crucial opportunities to manage bipolar disorder early are being lost because individuals are waiting an average of almost six years after the onset of the condition before diagnosis and treatment.

That is the key finding of a joint UNSW Australia and Italian study published in the Canadian Journal of Psychiatry.

The meta-analysis of 9,415 patients from 27 studies, the largest of its kind, was led by clinical psychiatrist and Conjoint Professor Matthew Large from UNSW’s School of Psychiatry and his colleague, Dr Giovanni de Girolamo, from the St John of God Research Centre, Italy.

Many patients experience distressing and disruptive symptoms for many years until receiving proper treatment for bipolar disorder, which was previously known as manic depressive illness.

According to the lead researcher, Professor Large, a psychiatrist at Prince of Wales Hospital, the delay is often longer for young people because moodiness is sometimes mistaken by parents and doctors as the ups and downs of the teenage years rather than the emergence of bipolar disorder, which can be effectively treated with mood stabilising medication.

“This is a lost opportunity because the severity and frequency of episodes can be reduced with medication and other interventions,” Professor Large said.

“While some patients, particularly those who present with psychosis, probably do receive timely treatment, the diagnosis of the early phase of bipolar disorder can be difficult”.

“This is because mental health clinicians are sometimes unable to distinguish the depressed phase of bipolar disorder from other types of depression.”

“The diagnosis of bipolar disorder can also be missed because it relies on a detailed life history and corroborative information from carers and family, information that takes time and care to gather”.

“Clinicians should look more closely at a patient’s history of mood symptoms, looking for distinct changes in mood, and other risk factors, for example, a family history and mood swings caused by external events such as treatment withantidepressants, overseas travel and taking drugs,” Professor Large said.

The researchers are calling for a consistent approach to the recording of the onset of symptoms of bipolar disorder, further studies on the early symptoms and predictors of bipolar disorder and the reasons for treatment delay.

The study was conducted in collaboration with researchers from St Vincent’s Hospital, Sydney and Italy’s St John of God Clinical Research Centre and University of Bari.