Underlying molecular mechanism of bipolar disorder

An international collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP), with major participation from Yokohama School of Medicine, Harvard Medical School, and UC San Diego, has identified the molecular mechanism behind lithium’s effectiveness in treating bipolar disorder patients.

The study, published in Proceedings of the National Academy of Sciences (PNAS), utilized human induced pluripotent stem cells (hiPS cells) to map lithium’s response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. It may also provide the basis to discover new drugs that are safer and more effective than lithium.

Bipolar disorder is a mental health condition causing extreme mood swings that include emotional highs (mania or hypomania) and lows (depression) and affects approximately 5.7 million adults in the U.S. Lithium is the first treatment explored after bipolar symptoms, but it has significant limitations. Only approximately one-third of patients respond to lithium treatment, and its effect is only found through a trial-and-error process that takes months — and sometimes years — of prescribing the drug and monitoring for response. Side effects of lithium treatment can be significant, including nausea, muscle tremors, emotional numbing, irregular heartbeat, weight gain, and birth defects, and many patients choose to stop taking the medicine as a result.

“Lithium has been used to treat bipolar disorder for generations, but up until now our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks,” said Evan Snyder, M.D., Ph.D., professor and director of the Center for Stem Cells and Regenerative Medicine at SBP, and senior author of the study. “Importantly, our findings open a clear path to finding safe and effective new drugs. Equally as important, it helped give us insight into what type of mechanisms cause psychiatric problems such as these.”

“We realized that studying the lithium response could be used as a ‘molecular can-opener’ to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene — in this case, CRMP2, an intracellular protein that regulates neural networks,” added Snyder.

In hiPS cells created from lithium-responsive and non-responsive patients, researchers observed a physiological difference in the regulation of CRMP2, which rendered the protein to be in a much more inactive state in responsive patients. However, the research showed that when lithium was administered to these cells, their regulatory mechanisms were corrected, restoring normal activity of CRMP2 and correcting the underlying cause of their disorder. Thus, the study demonstrated that bipolar disorder can be rooted in physiological — not necessarily genetic — mechanisms. The insights derived from the hiPS cells were validated in actual brain specimens from patients with bipolar disorder (on and off lithium), in animal models, and in the actions of living neurons.

“This ‘molecular can-opener’ approach — using a drug known to have a useful action without exactly knowing why — allowed us to examine and understand an underlying pathogenesis of bipolar disorder,” said Snyder. “The approach may be extended to additional complex disorders and diseases for which we don’t understand the underlying biology but do have drugs that may have some beneficial actions, such as depression, anxiety, schizophrenia and others in need of more effective therapies. One cannot improve a therapy until one knows what molecularly really needs to be fixed.”

This study was performed in collaboration with Veterans Administration Medical Center in La Jolla, University of California San Diego, Yokohama City University, Massachusetts General Hospital, Harvard Medical School, Mailman Research Center at McLean Hospital, University of Connecticut School of Medicine, University of Pittsburgh Medical Center, National Institute of Mental Health, Vala Sciences, Inc., Broad Institute of MIT and Harvard University, Dalhousie University, Beth-Israel Deaconess Medical Center, Örebro University, Janssen Research & Development Labs, Waseda University, and RIKEN .

Global bipolar disorder study reveals thinning of gray matter in brain regions responsible for inhibition and emotion

In the largest MRI study on patients with bipolar disorder to date, a global consortium published new research showing that people with the condition have differences in the brain regions that control inhibition and emotion.

The new study, published in Molecular Psychiatry on May 2, found brain abnormalities in people with bipolar disorder. By revealing clear and consistent alterations in key brain regions, the findings shed light on the underlying mechanisms of bipolar disorder.

“We created the first global map of bipolar disorder and how it affects the brain, resolving years of uncertainty on how people’s brains differ when they have this severe illness,” said Ole A. Andreassen, senior author of the study and a professor at the Norwegian Centre for Mental Disorders Research (NORMENT) at the University of Oslo.

Bipolar disorder affects 1 to 3 percent of the adult population worldwide. It is a debilitating psychiatric disorder with serious implications for those affected and their families. However, scientists have struggled to pinpoint neurobiological mechanisms of the disorder, partly due to the lack of sufficient brain scans.

The study was part of an international consortium called ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis), which spans 76 centers and includes 28 different research groups across the world, and is led by the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC. The researchers measured the MRI scans of 6,503 individuals, including 2,447 adults with bipolar disorder and 4,056 healthy controls. They also examined the effects of commonly used prescription medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions.

The study showed thinning of cortical gray matter in the brains of patients with bipolar disorder when compared with healthy controls. The greatest deficits were found in parts of the brain that control inhibition and emotion — the frontal and temporal regions.

Bipolar disorder patients with a history of psychosis showed greater deficits in the brain’s gray matter. The findings also showed different brain signatures in patients who took lithium, antipsychotics and anti-epileptic treatments. Lithium treatment was associated with less thinning of gray matter, which suggests a protective effect of this medication on the brain.

“These are important clues as to where to look in the brain for therapeutic effects of these drugs,” said Derrek Hibar, first author of the paper and a professor at the USC Mark and Mary Stevens Neuroimaging and Informatics Institute when the study was conducted. He was a former visiting researcher at the University of Oslo and is now a senior scientist at Janssen Research and Development, LLC.

“Mapping the brain regions affected is also important for early detection and prevention,” said Paul Thompson director of the ENIGMA consortium and an associate director of the USC Mark and Mary Stevens Neuroimaging and Informatics Institute.

Future research will test how well different medications and treatments can shift or modify these brain measures as well as improve symptoms and clinical outcomes for patients.

“This new map of the bipolar brain gives us a roadmap of where to look for treatment effects. By bringing together psychiatrists worldwide, we now have a new source of power to discover treatments that improve patients’ lives,” said Thompson.

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Researchers create a roadmap of bipolar disorder and how it affects the brain

A new study has found brain abnormalities in people with bipolar disorder.

In the largest MRI study to date on patients with bipolar disorder, a global consortium published new research showing that people with the condition have differences in the brain regions that control inhibition and emotion.

By revealing clear and consistent alterations in key brain regions, the findings published in Molecular Psychiatry on May 2 offer insight to the underlying mechanisms of bipolar disorder.

“We created the first global map of bipolar disorder and how it affects the brain, resolving years of uncertainty on how people’s brains differ when they have this severe illness,” said Ole A. Andreassen, senior author of the study and a professor at the Norwegian Centre for Mental Disorders Research at the University of Oslo.

Bipolar disorder affects about 60 million people worldwide, according to the World Health Organization. It is a debilitating psychiatric disorder with serious implications for those affected and their families. However, scientists have struggled to pinpoint neurobiological mechanisms of the disorder, partly due to the lack of sufficient brain scans.

The study was part of an international consortium led by the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC: ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) spans 76 centers and includes 26 different research groups around the world.

Thousands of MRI scans

The researchers measured the MRI scans of 6,503 individuals, including 2,447 adults with bipolar disorder and 4,056 healthy controls. They also examined the effects of commonly used prescription medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions.

The study showed thinning of gray matter in the brains of patients with bipolar disorder when compared with healthy controls. The greatest deficits were found in parts of the brain that control inhibition and motivation — the frontal and temporal regions.

Some of the bipolar disorder patients with a history of psychosis showed greater deficits in the brain’s gray matter. The findings also showed different brain signatures in patients who took lithium, anti-psychotics and anti-epileptic treatments. Lithium treatment was associated with less thinning of gray matter, which suggests a protective effect of this medication on the brain.

“These are important clues as to where to look in the brain for therapeutic effects of these drugs,” said Derrek Hibar, first author of the paper and a professor at the USC Stevens Neuroimaging and Informatics Institute when the study was conducted. He was a former visiting researcher at the University of Oslo and is now a senior scientist at Janssen Research and Development, LLC.

Early detection

Future research will test how well different medications and treatments can shift or modify these brain measures as well as improve symptoms and clinical outcomes for patients.

Mapping the affected brain regions is also important for early detection and prevention, said Paul Thompson, director of the ENIGMA consortium and co-author of the study.

“This new map of the bipolar brain gives us a roadmap of where to look for treatment effects,” said Thompson, an associate director of the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine. “By bringing together psychiatrists worldwide, we now have a new source of power to discover treatments that improve patients’ lives.”

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Materials provided by University of Southern California. Note: Content may be edited for style and length.

Analysis of letters written by ‘Mad’ King George III supports psychiatric diagnosis of mania

Researchers have concluded that King George III was probably suffering from a mental illness after computer analysis of hundreds of his letters.

When programmed to ‘read’ historical texts by scanning for certain features, a computer ‘learned’ to predict the King’s mental illness from the characteristics of his writing.

The 1994 film The Madness of King George portrayed aspects of the King’s behaviour and researchers now say his letters reveals that the cause of his illness was most likely to be due to a mental health problem rather than a physical disease. In a control condition, the computer found no difference between the language used in circumstances that could also have influenced the King’s mental state, such as the different seasons, or periods when the country was at war or in peacetime.

This implied that the differences the computer did identify were specific to mental illness — probably an ‘acute mania’- a term used to describe an excitable, hyperactive condition. In today’s modern psychiatric terminology this might form part of a diagnosis of bipolar disorder.

The researchers at St George’s, University of London had previously argued that the King probably suffered from episodes of ‘acute mania’, rejecting the once popular notion that his well described periods of strange behaviour were the result of the inherited condition porphyria.

Peter Garrard, Professor of Neurology at St George’s, said: “King George wrote very differently when unwell, compared to when he was healthy. In the manic periods we could see that he used less rich vocabulary and fewer adverbs. He repeated words less often and there was a lower degree of redundancy, or wordiness.”

Professor Garrard has previously shown how language changes can give clues to the behaviour of other well-known figures, including the onset of dementia in the novelist Iris Murdoch and the development of hubristic tendencies in British Prime Ministers. He concluded: “It would be fascinating to look at how modern patients write during the manic phase of bipolar disorder, as this could create a definite link to King George and possibly other historical cases of the illness.

“The technique could then be applied to the analysis other historical figures’ language in periods of health and illness, as well as patterns of language production in contemporary politicians such as the new US President Donald Trump.”

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Bipolar disorder: New method predicts who will respond to lithium therapy

For roughly one-third of people diagnosed with bipolar disorder, lithium is a miracle drug, effectively treating both their mania and depression. But once someone is diagnosed, it can take up to a year to learn whether that person will be among the 30 percent who respond to lithium or the 70 percent who do not.

Now, scientists at the Salk Institute report a way to predict, with 92 percent accuracy, whether an individual with bipolar disorder will be a lithium responder. The work, which appeared online in Molecular Psychiatry on February 28, 2017, validates the lab’s 2015 discovery of a cellular basis for the disorder and could benefit not only those who will respond to lithium but also the vast majority who will not, sparing them an ineffective treatment.

“What’s remarkable about this system is that you don’t need to use 500 or 600 cells from multiple patients,” says Rusty Gage, a professor in Salk’s Laboratory of Genetics and senior author of the new work. “Five cells from one patient is enough to define whether someone is responsive or nonresponsive to lithium.”

More than five million Americans suffer from bipolar disorder, a progressive psychiatric condition that, left untreated, puts sufferers at high risk for suicide. Lithium is the preferred drug to treat the disorder, but it isn’t clear why it works for some people and not others. The Gage team’s previous breakthrough, published in Nature on October 28, 2015, suggested a reason, revealing that the neurons of people with bipolar disorder are more easily stimulated, firing electrical impulses more rapidly than the neurons of people without the disorder. The team found that maintaining some people’s neurons in a lithium-infused medium calmed this hyperexcitability.

“In 2015 we discovered that the brain cells of people with bipolar disorder are more sensitive to stimuli than those of other people,” says Gage. “Since then, we have been able to characterize that sensitivity in greater detail and discern clear patterns in the neurons of bipolar patients that allow us to predict who will respond to lithium and who will not.”

The new study sought to better understand why, despite seemingly equivalent hyperactivity, some bipolar patients’ neurons respond to lithium while others’ do not. This time, instead of using skin cells, the team reprogrammed lymphocytes (immune cells) from six entirely new bipolar patients, some of whom are known lithium responders. The team found the same hyperexcitability in the lymphocyte-derived neurons, validating their earlier results.

“But then we started to see something more,” says Shani Stern, a Salk research associate and co-first author of the new paper. “Although responders and nonresponders both produce more electrical impulses and spontaneous activity, when we look at the electrophysiological properties, the two groups are very different from each other.”

The Salk team characterized the electrical firing patterns of all six patients’ neuronal lines, measuring spike height, spike width, the threshold for evoking a reaction and other qualities. The overall patterns were noticeably different in responders versus nonresponders.

“This work was exciting because we replicated the previous finding of neuron hyperexcitability in neurons derived from a new cohort of patients diagnosed by a different psychiatrist, confirming the robustness of this characteristic and its potential use for drug development,” says Renata Santos, co-first author and a Salk research collaborator.

Wondering whether the differences could be predictive, the team trained a computer program to recognize the variations between the profiles of responders and nonresponders using the firing patterns of 450 total neurons over six independent training rounds. In each round, they started fresh with the neurons of five of the patients to train the system. They then tested the system with the neurons of the sixth patient, whose lithium status was known to the team but not to the program. They repeated the process five more times, which allowed them to build essentially six independent models. Each model was trained on the data from five out of the six patients, leaving a different patient out of the training data each time, and then letting the model classify this remaining patient as a responder or nonresponder. Using the firing patterns of just five of any patient’s neurons, the system identified the person as a responder or nonresponder with 92 percent accuracy.

“These stem cell-based studies are technically challenging, in addition to being labor- and resource-intensive. As a result, many of the studies published up to now describe only two or three patient stem cell lines,” says David Panchision, who oversees the NIMH’s National Cooperative Reprogrammed Cell Research Group (NCRCRG) program, which supported this work. “The fact that Gage’s group can replicate the hyperexcitability characteristic in neurons from additional bipolar disorder patients is very important. Findings like these are needed to utilize these cells to develop new drugs to treat mental illnesses.”

The team says their method could be applied to lymphocytes taken from bipolar patients’ blood samples, to find out whether specific individuals would be good candidates for lithium therapy.

“Replication of scientific results is not very sexy, but it’s crucial,” says Gage. “When different scientists are able to get the same results in different cells from different patients, we can have more confidence that we are really on to something that will be beneficial for patients.”

Zapping between channels in the retina

Visual information is processed long before it reaches the brain. As early as in the retina, numerous types of cells are responsible for decomposing images into their diverse components, and for feeding these to the brain on several parallel channels. Here the so-called bipolar cells play a central role, as the first retinal layer to process the output of the light-sensitive cells in the eye. Recently, Tübingen neuroscientists have studied the functional organisation of bipolar cells in detail, publishing their findings in Nature.

We ceaselessly sense our surroundings: we hear, feel, smell and taste it. Yet the dominant factor feeding our view of the world is the way we see it. How does information about our visual surroundings, projected into our eyes as patterns of light, enter our brain to create our internal representation of the world? Seeing is not as simple as assembling an image from many individual dots, like a digital photo. Our visual system processes information using many channels simultaneously, literally creating a multi-layered ‘bigger picture’. The very first level of the visual system, the retina, already provides information on colour, contrast, movement, and brightness. We notice individual objects ‘at a glance’ because they jump out from what we see as mere background. Moving stimuli likewise command immediate attention.

For visual information to reach the brain through such parallel channels, images are pre-processed in the retina. For years, a team of scientists led by Prof. Thomas Euler (CIN — Werner Reichardt Centre for Integrative Neuroscience at the University of Tübingen) has been investigating the retinal ‘switchboard’ responsible for much of this processing. Recently, they focused on bipolar cells. Bipolar cells link the light-sensitive photoreceptor cells in the eye with retinal ganglion cells, which in turn forward the retinal output to the brain. Genetically and anatomically, 14 different types of bipolar cells have been identified. The Tübingen researchers therefore tested the hypothesis that each of these 14 cell types represents one visual channel, each with its own function. But how are these channels different from each other, and what are the mechanisms involved?

To answer this question, the scientists projected many different patterns of light onto mouse retinas. Simultaneously, they made use of a genetically encoded fluorescent protein to measure bipolar cell output. With this method, they were able to take measurements from a very large number of individual synapses (more than 13,000), and from all types of bipolar cells.

The results showed one surprising fact: when subjected to small spots of light, the 14 bipolar cell types’ functions seemed very similar. Only larger stimuli covering far more than one cell’s receptive field — the area where a bipolar cell collects photoreceptor inputs — generated different signals across multiple channels. Further experimentation showed that the bipolar cells’ neighbours, so-called amacrine cells, are responsible for this diversification of encoded information.

Katrin Franke, who designed the study and performed the experiments, explains the findings like this: ‘Instead of simply telling the brain “in my receptive field, it is currently bright/dark/green/blue,” bipolar cells that receive input from amacrine cells can tell the brain more detailed information, like “it is bright here, but right next to where I am, it is dark.” This level of detail allows the brain to assemble a complex layered impression including transitions, contrast, edges and movement.’

A better understanding of signal processing in the retina may be beneficial not only for basic research, but also in eye care medicine. For several years now, a retina implant for patients with degenerative eye conditions has been under development at the University of Tübingen’s eye clinic. This implant makes use of bipolar cells, as these form the second layer downstream of photoreceptor cells lost to the progress of disease. Accordingly, the new study’s insights promise to promote further application-oriented research in the field.

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Depressed patients with earlier and more severe symptoms have high genetic risk for major psychiatric disorders

Clinical features of major depressive disorder (MDD) may help identify specific subgroups of depressed patients based on associations with genetic risk for major psychiatric disorders, reports a study in Biological Psychiatry. Led by Brenda Penninx, PhD, of the VU University Medical Center in Amsterdam, the Netherlands, the study found that patients with an early age at onset and higher symptom severity have an increased genetic risk for MDD, bipolar disorder and schizophrenia.

The findings highlight genetic similarities between subgroups of MDD patients based on their clinical characteristics. Although researchers know that genetics play a role in the development of MDD, the heterogeneous nature of MDD patients has hindered the search for risk genes. The new findings suggest a way to stratify the wide range of patients with MDD, which may boost the likelihood of identifying culpable genes.

“This is of importance as it suggests that it is useful to create phenotypically more homogenous groups of depressed patients when searching for genes associated with MDD,” said co-first author Dr. Judith Verduijn.

In the study, Dr. Verduijn and Dr. Yuri Milaneschi, along with their colleagues, analyzed genome-wide data of 3331 people, 1539 of whom were diagnosed with MDD, from the Netherlands Study of Depression and Anxiety. For each patient, they calculated genomic risk profile scores for MDD, bipolar disorder and schizophrenia.

Only characteristics associated with a more severe form of depression, including an early age at onset, high symptom severity score and a high number of specific symptoms from the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, were associated with higher genetic load for the three psychiatric disorders. The analysis did not reveal any associations between genetic risk profile scores and duration of symptoms, family history of depression, recurring MDD episodes, or stage of MDD.

“This study supports the idea that psychiatric disorders are heterogeneous and that the early onset and more severe forms of depression are the ones with greater heritability,” said Dr. John Krystal, Editor of Biological Psychiatry.

Using an independent group of 1602 MDD patients and 1390 control participants from the RADIANT-UK study, the researchers also replicated their finding that patients with a high number of DSM symptoms have increased genetic risk for schizophrenia.

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Area of brain linked to bipolar disorder pinpointed

A volume decrease in specific parts of the brain’s hippocampus — long identified as a hub of mood and memory processing — was linked to bipolar disorder in a study led by researchers at The University of Texas Health Science Center at Houston (UTHealth). The research was published today in Molecular Psychiatry, part of the Nature Publishing Group.

“Our study is one of the first to locate possible damage of bipolar disorder in specific subfields within the hippocampus,” said Bo Cao, Ph.D., first and corresponding author and a postdoctoral fellow in the Department of Psychiatry and Behavioral Sciences at McGovern Medical School at UTHealth. “This is something that researchers have been trying to answer. The theory was that different subfields of the hippocampus may have different functions and may be affected differently in different mood disorders, such as bipolar disorder and major depression disorder.”

Cao hopes the study, which was funded in part by the National Institute of Mental Health (NIMH), will pioneer future research on details within the hippocampus as a marker for precise diagnosis and positive treatment response of bipolar disorder.

Approximately 6 million Americans suffer from bipolar disorder. Bipolar I disorder is characterized by mood changes that can swing from a high-energy, manic state to a low-energy, depressive state. The disorder can affect sleep, energy level and the ability to think clearly, according to the National Institutes of Health. It can interfere with a person’s ability to work and perform daily living activities, and could lead to suicide attempts. Patients with bipolar II disorder do not experience the full-blown manic episodes, but may have a less severe high-energy state.

The research team used a combination of magnetic resonance imaging (MRI) and a state-of-the-art segmentation approach to discover differences in the volumes of subfields of the hippocampus, a seahorse-shaped region in the brain. Subjects with bipolar disorder were compared to healthy subjects and subjects with major depressive disorder.

Researchers found that subjects with bipolar disorder had reduced volumes in subfield 4 of the cornu ammonis (CA), two cellular layers and the tail portion of hippocampus. The reduction was more severe in patients with bipolar I disorder than other mood disorders investigated.

Further, in patients with bipolar I disorder, the volumes of certain areas such as the right CA 1 decreased as the illness duration increased. Volumes of other CA areas and hippocampal tail were more reduced in subjects who had more manic episodes.

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