Can Early Symptoms Predict Bipolar Disorder? Evidence Shows Differing Patterns of Risk Factors

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Two patterns of antecedent or “prodromal” psychiatric symptoms may help to identify young persons at increased risk of developing bipolar disorder (BD), according to a new analysis in the Harvard Review of Psychiatry.

Early signs of BD can fall into a relatively characteristic “homotypic” pattern, consisting mainly of symptoms or other features associated with mood disorders; or a “heterotypic” pattern of other symptoms including anxiety and disruptive behavior. Environmental risk factors and exposures can also contribute to BD risk, according to the analysis by Ciro Marangoni, MD, at the Department of Mental Health, Mater Salutis Hospital, Legnato, Italy; Gianni L. Faedda, MD, Director of the Mood Disorder Center of New York, NY, and Co-Chairman of a Task Force of the International Society for Bipolar Disorders on this topic; and Professor Ross J. Baldessarini, MD, Director of the International Consortium for Bipolar & Psychotic Disorders Research of the Mailman Research Center at McLean Hospital in Belmont, Mass.

The authors reviewed and analyzed data from 39 studies of prodromal symptoms and risk factors for later development of BD. Their analysis focused on high-quality evidence from prospective studies in which data on early symptoms and risk factors were gathered before BD was diagnosed.

BD is commonly preceded by early depression or other symptoms of mental illness, sometimes years before BD develops, as indicated by onset of mania or hypomania. Nevertheless, the authors note that “the prodromal phase of BD remains incompletely characterized, limiting early detection of BD and delaying interventions that might limit future morbidity.”

The evidence reviewed suggested two patterns of early symptoms that “precede and predict” later BD. A homotypic pattern consisted of affective or mood-associated symptoms that are related to, but fall short of, standard diagnostic criteria for BD: for example, mood swings, relatively mild symptoms of excitement, or major depression, sometimes severe and with psychotic symptoms.
The authors note that homotypic symptoms have “low sensitivity” — that is, most young people with these mood symptoms do not later develop BD. However, this symptom pattern also had “moderate to high specificity” — homotypic symptoms do occur in many patients who go on to develop BD.

The heterotypic pattern consisted of other types of prodromal symptoms, such as early anxiety and disorders of attention or behavior. This pattern had low sensitivity and specificity: relatively few patients with such symptoms develop BD, while many young people without heterotopic symptoms do develop BD.

The study findings also associate several other factors with an increased risk of developing BD, including preterm birth, head injury, drug exposures (especially cocaine), physical or sexual abuse, and other forms of stress. However, for most of these risk factors, both sensitivity and specificity are low.

Although many elements of the reported patterns of prodromal symptoms and risk factors have been identified previously, the study increases confidence that they are related to the later occurrence of BD. The researchers note that the findings of high-quality data from prospective studies are “encouragingly similar” to those of previous retrospective and family-risk studies.

“There was evidence of a wide range of [psychiatric] symptoms, behavioral changes, and exposures with statistically significant associations with later diagnoses of BD,” the authors conclude. With further study, the patterns of prodromal symptoms and risk factors may lead to new approaches to identifying young persons who are likely to develop BD, and might benefit from early treatment. The investigators add that predictive value might be even higher with combinations of multiple risk factors, rather than single predictors.

Materials provided by Wolters Kluwer Health

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Brain Training Shows Promise For Patients With Bipolar Disorder

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Researchers at McLean Hospital, an affiliate of Harvard Medical School, have discovered for the first time that computerized brain training can result in improved cognitive skills in individuals with bipolar disorder.

In a paper published in the October 17, 2017, edition of The Journal of Clinical Psychiatry, the researchers suggest that brain exercises could be an effective non-pharmaceutical treatment for helping those with bipolar disorder function more effectively in everyday life.

“Problems with memory, executive function, and processing speed are common symptoms of bipolar disorder, and have a direct and negative impact on an individual’s daily functioning and overall quality of life,” said lead investigator Eve Lewandowski, PhD, director of clinical programming for one of McLean’s schizophrenia and bipolar disorder programs and an assistant professor at Harvard Medical School. “Improving these cognitive dysfunctions is crucial to helping patients with bipolar disorder improve their ability to thrive in the community,” Lewandowski added.

Lewandowski and her colleagues knew from previous studies that this type of intervention had helped patients with schizophrenia improve cognitive functions. “There is considerable overlap in cognitive symptoms between bipolar disorder and schizophrenia,” Lewandowski noted.

The researchers therefore decided to test the impact of brain exercises in the bipolar population. They randomly assigned patients with bipolar disorder, aged 18-50, to either an intervention group or an active comparison group (used as a control). The intervention group was asked to use a special regimen of neuroplasticity-based exercises from Posit Science — maker of the BrainHQ online exercises and apps — for a total of 70 hours over the course of 24 weeks. These exercises use a “bottom-up” approach, targeting more basic cognitive processes early in the treatment to strengthen cognitive foundations, then moving on to training focused on more complex cognitive functions later in the program. The control group was asked to spend an equivalent amount of time on computerized exercises that focused on quiz-style games, like identifying locations on maps, solving basic math problems, or answering questions about popular culture.

At the end of the study, the participants in the intervention group displayed significant improvements in their overall cognitive performance as well as in specific domains, such as cognitive speed, visual learning, and memory. “The intervention group maintained cognitive improvements six months after the end of the treatment, and in some areas even showed continued improvements,” Lewandowski reported.

Lewandowski is encouraged by the findings, as they demonstrate that “this type of non-pharmaceutical intervention can significantly improve cognition in patients with bipolar disorder,” she said. “These findings suggest that once the brain is better able to perform cognitive tasks, it will continue to strengthen those processes even after patients stop using the treatment.” In addition, Lewandowski said, “The study indicates that affordable and easily accessible web-based interventions can be effective for a broad group of patients.”

Lewandowski noted that further research is needed to determine how the improvements in these cognitive skills impact work and leisure activities and daily functioning in patients with bipolar disorder.

Text provided by McLean Hospital.

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Scientists Link Bipolar Disorder to Unexpected Brain Region

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While bipolar disorder is one of the most-studied neurological disorders—the Greeks noticed symptoms of the disease as early as the first century—it’s possible that scientists have overlooked an important part of the brain for its source.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown for the first time that ensembles of genes within the striatum—a part of the brain that coordinates many primary aspects of our behavior, such as motor and action planning, motivation, and reward perception—could be deeply involved in the disorder. Most modern studies of bipolar disorder have concentrated on the brain’s cortex, the largest part of the brain in humans, associated with higher-level thought and action.

“This is the first real study of gene expression in the striatum for bipolar disorder,” said Ron Davis, chair of the Department of Neuroscience at TSRI, who directed the study. “We now have a snapshot of the genes and proteins expressed in that region.”

The study, published recently online ahead of print in the journal Molecular Psychiatry, also points to several pathways as potential targets for treatment.

Bipolar disorder is a mental illness that affects about 2.6 percent of the U.S. adult population—some 5.7 million Americans—with a sizable majority of these cases classified as severe. The disease runs in families, and more than two-thirds of people with bipolar disorder have at least one close relative with the illness or with unipolar major depression, according to the National Institute of Mental Health.

In the new research, tissue samples from 35 bipolar and non-bipolar control subjects were analyzed. The number of genes differentially expressed in tissue samples from the two groups turned out to be surprisingly small—just 14 in all. However, co-expression network analysis also revealed two modules of interconnected genes that were particularly rich in genetic variations associated with bipolar disorder, suggestive of a causal role in the disorder. One of these two modules was particularly striking, as it seemed to be highly specific to the striatum.

“Our finding of a link between bipolar disorder and the striatum at the molecular level complements studies that implicate the same brain region in bipolar disorder at the anatomical level, including functional imaging studies that show altered activity in the striatum of bipolar subjects during tasks that involve balancing reward and risk,” said TSRI Research Associate Rodrigo Pacifico, who was first author of the new study. Analyzing reactions to risk was important because bipolar patients may act impulsively and engage in high-risk activities during periods of mania.

Pathway analysis also found changes in genes linked to the immune system, the body’s inflammatory response, and cells’ energy metabolism. Davis noted, “We don’t know if these changes are a cause of the disease or the result of it. But they provide additional gene markers in bipolar disorder that could potentially lead to the future development of diagnostics or treatments.”

The study, “Transcriptome Sequencing Implicates Dorsal Striatum-Specific Gene Network, Immune Response and Energy Metabolism Pathways in Bipolar Disorder,” was supported by funding from the State of Florida.

Text</a< from the Scripps Research Institute.

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Brain Protein Targeted to Develop New Bipolar Disorder Therapies

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A new study by scientists from the Florida campus of The Scripps Research Institute (TSRI) has identified specific genetic variations closely associated with increased susceptibility to bipolar disorder and other conditions. The discovery may provide a target for new therapies.

 

In the new study, the researchers focused on a gene known as PDE10A, one of the many genes that has been linked to bipolar disorder, and the proteins this gene produces. These proteins help regulate intracellular levels of a messenger molecule called cAMP (cyclic adenosine monophosphate), which is involved in a variety of biological processes including learning and memory.

“We began with the idea that behavioral changes in bipolar subjects might be due to these genetic variations in the cAMP messenger pathway,” said Ron Davis, chair of TSRI’s Department of Neuroscience. “We did find that this was the case and, indeed, that these variations were in one specific gene for the cAMP messenger pathway called PDE10A. The variations that we found in the gene may alter the function of one form of PDE10A and lead to susceptibility to bipolar disorder.”

The research, published recently by the journal Translational Psychiatry, examined human brain tissue from patients with bipolar disorder, as well as brain tissue from individuals without the psychiatric disorder.

“The PDE10A19 protein is interesting because we previously didn’t know it even existed in the human brain and because it’s found only in other primates—not mice or rats,” said Research Assistant Courtney MacMullen, the first author of the study. “Once we understand how this protein helps neurons remain healthy, we might be able to develop medications to treat neurons when they function abnormally, such as in patients with bipolar disorder and schizophrenia.”

The results suggested abnormal variations in PDE10A19 might alter cAMP signaling by interacting with another protein known as PDE10A2, restricting its activity and disrupting the entire process.

Davis said that the complexity of gene expression in the human brain is greatly underestimated, and that future neurogenetic studies ought to begin with a deep study of each gene’s ability to code for proteins to avoid false conclusions, particularly when it comes to the development of potential therapies.

“We need to know much more about this large family of enzymes and the roles they play in disorders like bipolar disorder,” he said.

Text taken from the Scripps Research Institute.

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Scientists Conclude After 12-year Study That Bipolar Disorder Has Seven Causes

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After more than a decade of observing 1,100 study participants, University of Michigan researchers have classified bipolar disorder’s causes into seven different phenotypes, or observable characteristics.

 

In a new paper in the International Journal of Epidemiology, the U-M team reports the results of thousands of data points of the study participants, including genetics, emotions, life experiences, medical histories, motivations, diets, temperaments, sleep patterns and thought patterns. More than 700 research volunteers suffer from bipolar disorder, and 277 do not.

The research team is part of U-M’s Heinz C. Prechter Bipolar Research Program, funded by many donors and named after a successful Detroit car baron who battled bipolar disorder.

In addition to the standard measures doctors use to diagnose bipolar disorder, the seven “phenoclasses” include:

  • changes in thinking, reasoning, and the processing of emotions;
  • personality and temperament;
  • “motivated behaviors” — related to substance use or abuse;
  • family and intimate relationships;
  • sleep patterns; and
  • how patients respond to treatment.

Other key findings include:

  • Migraine headaches occure three and a half times more frequently in people with bipolar disorder. Eating disorders and anxiety disorders are also more common, as well as alcohol abuse.
  • People with bipolar disorder tend to have a history of childhood trauma.
  • People suffering from bipolar disorder eat more saturated fats, and levels of certain fat molecules in the blood of patients are associated with higher levels of symptoms.
  • There is less diversity of gut bacteria in people taking antipsychotic medications. Lower levels of a key bacteria type in the gut were also found.
  • Poor sleep affects depression in female participants. Other gender differences were found.
  • Neurotic people with bipolar disorder were more likely to have severe illness. Especially men.
  • People with bipolar disorder have poorer memories, executive functioning, and motor skills.
  • Speech patterns can predict mood states. 

     

    The research team hopes that their study will enable a multi-pronged approach to diagnosis and treatment of patients with bipolar disorder.

    Materials provided by Michigan Medicine – University of Michigan.

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Molecular Mechanism Behind Lithium’s Effectiveness Identified

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Scientists have identified the molecular mechanism behind lithium’s effectiveness in treating bipolar disorder in an international study published in Proceedings of the National Academy of Sciences (PNAS). Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP), Yokohama School of Medicine, Harvard Medical School, and UC San Diego collaborated on the study, which used human induced pluripotent stem cells (hiPS cells) to map lithium’s response pathway.

Lithium is a salt which has long been considered the gold-standard for bipolar treatment. The side effects–such as nausea, weight gain, and birth defects–are a trial for many people who take the drug. Only about one-third of people who suffer from bipolar disorder respond to lithium treatment. Before researchers at the Salk institute developed a test to predict who will respond to lithium with 92 percent accuracy, there was no test, and the drug’s effect was only found through a trial-and-error process which could take months or years.

In the study, scientists used hiPs cells created from lithium-responsive and non-responsive patience to observe a physiological difference in a protein called CRMP2: the protein was in a much more inactive state in responsive patients. However, when the researchers applied lithium, CRMP2 worked properly. So the study shows that bipolar disorder has a physiological–not necessarily genetic–cause.

This study is the first to explain the molecular basis of bipolar disorder. Scientists hope to use the results to develop a blood test for the disease, as well as further tests that can predict whether people who suffer from bipolar disorder will respond to lithium. Research leading from this study may also discover safer and more effective drugs to treat the disorder.

Edited to Add: Here is the link to the study, as requested.

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Hippocampus Volume Decreases Linked to Bipolar Disorder

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In a new study by researchers at The University of Texas Health Science Center at Houston (UTHealth) , damage to the hippocampus–the brain’s seahorse-shaped center for mood and memory–was linked to bipolar disorder. This study is groundbreaking; it’s one of the first to link volume decreases in specific parts of the hippocampus to bipolar, something scientists have been trying to answer.

 

Different subfields of the hippocampus may have different functions and may be affected differently by mood disorders like depression or anxiety disorders. The researchers at UTHealth used magnetic resonance imaging (MRI) and segmentation approaches–which includes the delineation of brain features using image contrasts–to discover differences in the volumes of subfields of the hippocampus. Patients with bipolar disorder were compared to healthy controls as well as patients with major depressive disorder.

The study found that people who suffer from bipolar disorder had reduced volumes in subfield 4 of the cornu ammonis (CA) of the hippocampus. In patients with bipolar I disorder, the reduction was even more severe. Also, as the illness went on, the volumes of areas such as the right CA 1 decreased. People who had manic episodes had even more reduced volumes in the hippocampal tail and other CA areas.

The researchers hope that the study will be able to encourage more research pinpointing the details of the hippocampus as it relates to bipolar disorder, thus creating better treatments for the disease.

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