Bipolar treatment can be improved – by focusing less on antidepressants and more on lithium

by Daniel Smith, The Conversation

Credit: Shutterstock

Bipolar disorder is a serious condition of mood and behaviour that affects one in 50 people globally. Sufferers swing between episodes of mania (feeling high and overactive) and depression (feeling low, lethargic and hopeless). Sadly, it is estimated that as many as one in ten people with bipolar disorder will die by suicide.

28 jun 2019--In our recent research we used NHS data on more than 23,000 patients in Scotland to assess trends in treating bipolar disorder between 2009 and 2016. Our work was concerned with two main areas: the use of antidepressants and the use of lithium.

Antidepressants are effective for moderate to severe depressionand probably work by increasing the transmission of neurotransmitters such as serotonin and dopamine in the brain. Lithium is a mood stabiliser with a wide range of actions in the brain, including a neuroprotective effect that makes the brain more resilient under stress.

For some time now, we have known that antidepressants are not particularly effective for depressive episodes in people with bipolar disorder. In fact they may make some patients worse rather than better by causing mania (many experience their first episode of mania after taking antidepressants). In contrast, lithium is recommended around the world as the first-line, and most effective, medication for preventing mania and depression.

Decline of lithium as a treatment

What we found was surprising and disappointing. The most commonly prescribed treatments for bipolar disorder were antidepressants, despite their limited effectiveness and increased risk of making the long-term prognosis of bipolar disorder worse.

Only about one in five patients was taking lithium as their sole medication, and many were on combinations of different medications. There was also a very clear year-on-year decline in the use of lithium alongside greater use of antipsychotic medications. Antipsychotics primarily block dopamine pathways in the brain and are useful for mania and bipolar depression.

These findings suggest that many patients with bipolar disorder are not getting the best possible medications for their condition. This was a Scottish study but similar work in England and in other European countries have found a consistent decline in the use of lithium in recent years.

When I started as a trainee psychiatrist 20 years ago lithium clinics were commonplace in the NHS. Although their primary function was to monitor blood lithium levels in patients and keep an eye on thyroid and kidney function, (both of which can be affected by lithium), these clinics were busy and sociable places that provided a lot of informal support to patients.

But as expensive—and, we now know, less effective – alternatives to lithium were successfully promoted by drug companies, there has been a move away from lithium clinics. This change in prescribing culture occurred even though there was no evidence that lithium was less effective than other medications. But because of its potential toxicity and side effects in some patients, requiring regular blood monitoring, it is seen as less convenient for busy doctors.

Many of the current generation of psychiatrists now lack confidence in starting lithium therapy, in part because of a perception that it is complicated to prescribe. And of course side effects can be serious, such as long-term damage to kidney function, although the most recent data suggests that they can be managed successfully if properly monitored.

The reality is that lithium is cheap and can be life-changing for many patients with severe bipolar disorder. And is still only one of the few medications in psychiatry proven to be have a specific anti-suicidal effect.

What needs to be done

The key to successful management of bipolar disorder is the long-term prevention of episodes of mania and depression. Lithium is the best medication for this, but there are also psychological approaches that can prevent relapse.

Many antidepressants prescribed to bipolar patients have been shown to be less effective than lithium. Credit: Shutterstock

The most effective is group psychoeducation, where patients are taught about bipolar disorder and how to manage it within a supportive peer environment. Unfortunately, the provision of group psychoeducation across the NHS is very patchy at best.

One of the current drivers of this lack of emphasis on prevention is a greater focus on the "crisis care" of mental health within the NHS. This is of course very important, but we also need long-term therapeutic relationships and continuity, plus models of care that focus on the prevention of illness episodes.

The situation is worse for people with less severe forms of bipolar disorder, who often find themselves not unwell enough to qualify for psychiatric services but also too unwell for GPs to look after effectively. Very few GPs, for example, would be comfortable starting lithium therapy without input from their local psychiatric service.

In my clinical work I get referrals from colleagues to provide second opinion assessments of complex or difficult to treat bipolar disorder. In the past, these referrals tended to be for older patients who had been in the system for many years. But a worrying trend recently is an increase in younger people with bipolar disorder, possibly because of greater awareness that the condition usually starts during late adolescence. Almost none have been treated with lithium therapy, even though it could radically alter the long-term course of their illness.

Overall, the message we get from families—and many colleagues in mental health services would agree—is that the provision of care for bipolar disorder in the UK has become a lower priority and that the quality of long-term care could be much improved.

This issue doesn't need fancy new treatments—we know what works. The challenge is to do simple things effectively: fewer antidepressants; more lithium; more group psychoeducation. When it comes to treating people with bipolar disorder we need to look more at preventing fires rather than putting them out.

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Provided by The Conversation 

The real risks of growing up with bipolar parents

Bipolar disorder is characterized by transitions between depression and mania. Credit: Wikipedia

Bipolar disorder (BD) is among the 10 most burdensome medical conditions, according to the World Health Organization. The disorder is known for its dramatic highs of extreme euphoria, racing thoughts and decreased need for sleep, as well as its profound lows of sadness and despair.

11 jun 2014--Because it is also associated with a heightened risk of suicide, substance abuse, hypersexuality, familial discord and aggressive behaviour, BD affects not just those suffering from it, but also those around them—especially their children.

While previous research has shown that children of parents with BD are at a greater risk of developing psychiatric disorders, the psychosocial implications of being raised by parents with BD has been ignored—until now.

A new study conducted by Mark Ellenbogen, a psychology professor at Concordia University, and Rami Nijjar, a graduate student, reveals that children of parents with BD are more susceptible topsychosocial problems, most notably risky sexual behaviour. The study was published in the Journal of Affective Disorders.

Using a longitudinal approach, the researchers followed children of parents with bipolar disorder and children from families without mental disorder from ages four to 12 until early adulthood.

They assessed:

• Suicidal behaviour
• Self-harm
• Smoking
• Delinquent or criminal behaviour
• Risky sexual behaviour (sexual activity before age 16, unprotected sex, abortions)

For both genders, the researchers saw the biggest group difference in the last category, which can be seen as an extension of other tendencies.

"Risky sexual behaviour falls along the spectrum of general externalizing behaviours, like delinquency and aggression. We know it is predicted by externalizing behaviours in middle childhood," says Ellenbogen, who is also a member of Concordia's Centre for Research in Human Development.

What can concerned parents with BD do?

To prevent the offspring of parents with BD from engaging in risky behaviour, doctors need to look beyond the patient and give the entire family, including the children, the coping skills they need to live with the disorder. "In psychiatry, we tend to treat the patient—there's never any evaluation of their family or kids or partners. Across my career, I've been saying that's the wrong way of looking at the issues," Ellenbogen says. "The children of BD patients are at high risk of developing a number of psychiatric and psychosocial problems. We need to think about interventions that will work for all members of the family."

A new pilot prevention program that is open to the public

Ellenbogen is now working to establish the first prevention program for children of parents with BD. Entitled Reducing Unwanted Stress in the Home (RUSH), the intervention will consist of 12 sessions of group therapy, with one group to teach children effective coping strategies and another to teach their parents the skills to manage stress, family discord and children. The pilot program, open to families in the Montreal area, will launch this summer. It will operate in groups of five to six families.

Ellenbogen and his team will monitor the behaviour, hormone levels and mental health of the children before and after the intervention in order to assess the effectiveness of the RUSH program.

"These parents need additional help in organizing family life, parenting, dealing with spouses and coping with stress," Ellenbogen says. "The ultimate goal is to reduce the levels of stress in the family, which we believe will then reduce negative outcomes in their children."

Provided by Concordia University

Understanding the basic biology of bipolar disorder

Brain regions (cropped)

15 feb 2014—Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness's genetic causes, researchers at UCLA tried a new approach.

Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behavior measures. Using the new method, UCLA investigators—working with collaborators from UC San Francisco, Colombia's University of Antioquia and the University of Costa Rica—identified about 50 brain and behavioral measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.

The results are published in the Feb. 12 edition of the journal JAMA Psychiatry.

A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows—to the point of not wanting to get out of bed when they're feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior. 

Bipolar disorder and brain regions

"The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder," Bearden said. "This is an innovative approach to identifying genetically influenced brain and behavioral measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are."

The researchers assessed 738 adults, 181 of whom have severe bipolar disorder. They used high-resolution 3-D images of the brain, questionnaires evaluating temperament and personality traits of individuals diagnosed with bipolar disorder and their non-bipolar relatives, and an extensive battery of cognitive tests assessing long-term memory, attention, inhibitory control and other neurocognitive abilities. 

Approximately 50 of these measures showed strong evidence of being influenced by genetics. Particularly interesting was the discovery that the thickness of the gray matter in the brain's temporal and prefrontal regions—the structures that are critical for language and for higher-order cognitive functions like self-control and problem-solving—were the most promising candidate traits for genetic mapping, based on both their strong genetic basis and association with the disease.

"These findings are really just the first step in getting us a little closer to the roots of bipolar disorder," Bearden said. "What was really exciting about this project was that we were able to collect the most extensive set of traits associated with bipolar disorder ever assessed within any study sample. These data will be a really valuable resource for the field."

The individuals assessed in this study are members of large families living in Costa Rica's central valley and Antioquia, Colombia. The families were founded by European and native Amerindian populations about 400 years ago and have a very high incidence of bipolar disorder. The groups were chosen because they have remained fairly isolated since their founding and their genetics are therefore simpler for scientists to study than those of general populations. 

The fact that the findings aligned so closely with those of previous, smaller studies in other populations was surprising even to the scientists, given the subjects' unique genetic background and living environments. 

"This suggests that even if the specific genetic variants we identify may be unique to this population, the biological pathways they disrupt are likely to also influence disease risk in other populations," Bearden said.

The researchers' next step is to use the genomic data they collected from the families—including full genome sequences and gene expression data— to begin identifying the specific genes that contribute to risk for bipolar disorder. The researchers also plan to extend their investigation into the children and teens in these families. They hypothesize that many of the bipolar-related brain and behavioral differences found in adults with bipolar disorder had their origins in adolescent neurodevelopment.

Provided by University of California, Los Angeles

The Lancet Series on bipolar disorder

Bipolar disorder – where patients experience recurrent episodes of mood disturbance, ranging from extreme elation (mania) to severe depression – is thought to affect roughly 2% of the world's population in its most pronounced forms (bipolar I and II), with milder forms of the disorder affecting another 2%. A new Lancet Series provides a comprehensive overview of the genetics, diagnosis, and treatment of bipolar disorder, outlining future challenges, and debating imminent changes to the criteria that psychiatrists use to diagnose the illness.

10 may 2013--According to a Lancet Editorial accompanying the Series, "Bipolar disorder is not just about the extremes of emotion: it is also about the individual who exists both at, and between, those extremes. The psychiatrist of the future must be able to ally human and scientific understanding; to collaborate meaningfully and respectfully with patients in planning care; and to be confident and pragmatic, but receptive to new discoveries that may challenge the very basis of his or her understanding of mental illness. Psychiatry demands exceptional doctors."

Series paper 1 – Scientists may be on verge of identifying biological mechanisms that lead to bipolar disorder

Bipolar disorder is currently diagnosed purely on the basis of clinical symptoms, typically presenting as alternating periods of depression and mania. These episodes may differ in severity and may be accompanied by other symptoms such as hallucination and delusions. However, there is now compelling evidence that genes affect predisposition to bipolar disorder, and the authors of the first Series paper review current knowledge in this area.

While the contribution of environmental and social factors towards an individual's risk of developing bipolar disorder should not be underestimated, scientists' growing knowledge of the contribution of genetics to bipolar disorder nonetheless leads to the tantalising possibility that scientists might be on the verge of being able to identify some of the biological systems that lead to illness in bipolar disorder, which could in turn lead to substantial improvements in diagnosis and treatment of the illness.

According to Professor Nick Craddock, one of the paper's authors, "The association between genotype and phenotype for psychiatric disorders is clearly complex. Reductionist thinking has no place, and to think of any case as being either genetic or environmental, or to talk about a gene for bipolar disorder, makes no sense. The key point is that most cases of bipolar disorder involve the interplay of several genes or more complex genetic mechanisms, together with the effects of the environment, and chance."

The authors emphasise that bipolar disorder research now needs to follow up genetic studies with imaging and psychological studies, to try to unravel the complex biological mechanisms involved in bipolar disorder, and bring biological understanding closer to the experience of the patient. While several genes which increase a patient's risk of acquiring bipolar disorder have been discovered, to date, no clear biological mechanism to explain why these genes affect a person's risk of developing bipolar has been elucidated.

Series Paper 2 – Neuroimaging research could transform bipolar diagnosis

The second Series paper outlines the substantial difficulties in diagnosing bipolar disorder: misdiagnosis of bipolar as unipolar depression is thought to occur in many patients seeking treatment for depression, and there is an average delay of 5 – 10 years between the onset of bipolar disorder and diagnosis. Depressive symptoms are considerably more prevalent than manic symptoms over the course of the illness for most people with bipolar disorder, and people are more likely to seek treatment for depressive symptoms.

Evidence suggests that a proportion of people diagnosed with unipolar depression may, in fact, have bipolar disorder, and this can be a major problem, because medication used to treat unipolar depression is not the same as that used to treat bipolar disorder, and medicine for unipolar depression could even exacerbate the manic symptoms seen in bipolar.

According to Professor Mary Phillips, one of the paper's authors, "Identifying objective biomarkers that differ between bipolar and unipolar depression would not only lead to more accurate diagnosis but potentially to new, personalised treatments, yet very little research has been undertaken in this area. For instance, very few neuroimaging studies have been done in which the brains of people with bipolar disorder have been compared to those of people with unipolar disorder, and further research into this area is urgently needed."

Series paper 3 – Search for new treatments for bipolar is being hampered by scarce knowledge of basic disease mechanisms

There have been no fundamental advances in the search for more effective treatment for bipolar disorder in the last twenty years, despite a substantial expansion of research into the subject. The authors of the third Series paper point out that development of effective treatments is being hampered by scarce knowledge of basic disease mechanisms or clear targets for medicines.

Treating bipolar is complex, because the same treatments that alleviate depression can cause mania or mood swings, and treatments that reduce mania might cause rebound depressive episodes. While antidepressants are commonly used to treat the depressive phase of the disorder, there is scarce evidence for their efficacy.

Lithium – first introduced in 1949 – remains the best established long-term treatment for bipolar disorder, but its benefits are restricted by adverse effects, and alternatives are often needed for long-term treatment.

According to Professor John Geddes, one of the paper's authors, "Combining psychosocial treatments – which can include not just psychotherapy for the patient, but family therapy involving education for their family or caregiver – with mood stabilising drugs might well be one of the most promising lines of treatment for bipolar disorder. However, drug and psychological treatment studies have largely proceeded independently of one another, and research including both would help to move the field forward."

Viewpoint – Working Group members explain new thinking on stress-related mental disorders in ICD-11

WHO is currently developing the International Classification of Diseases, version 11 (ICD-11), a comprehensive, internationally-recognised diagnostic guide for all major diseases, including psychiatric illness. In a Viewpoint published alongside the Series, members of the ICD-11 Working Group on mental disorders associated with stress outline the reasoning behind some of the updates in this area that will appear in the new edition. This includes a substantial tightening of the way in which ICD describes post-traumatic stress disorder (PTSD), a description of normal stress responses that are not considered disorders; the addition of "complex PTSD" to describe extensive reactions arising from severe and prolonged stressors; and inclusion of "prolonged grief disorder", used to describe patients that undergo an intensely painful, disabling, and abnormally persistent response to bereavement.

Comment – DSM-5 criteria for bipolar will "further obfuscate an already confusing diagnostic landscape"

Preparation for an updated version of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has been underway for some years, and the manual is due to appear this month, but in a Comment published alongside the Series, Professor Gin Malhi of the University of Sydney, Australia, expresses concern that the inclusion of a "mixed states specifier" (broadly defined as the coexistence of depressive and manic features) in the criteria for bipolar disorder may lead to diagnostic confusion, and complicate treatment implications. According to Professor Malhi, "the risk is that the diagnostic criterion of mixed states will be used loosely and its application will expand far beyond the most pronounced type of bipolar disorder across the whole bipolar spectrum, without any prognostic significance of therapeutic benefit. The present mix of features in bipolar disorder that will be 'specified' by the new classificatory system will produce a myriad of manifestations and further obfuscate an already confusing diagnostic landscape."

More information: www.thelancet.com/… lar-disorder

Provided by Lancet

Specialty care costs for patients with bipolar disorder are higher than diabetes and other chronic diseases

SAN FRANCISCO, 22 may 2009 -- Mayo Clinic researchers have found that bipolar disorder is more costly than other chronic conditions such as diabetes, depression, asthma or coronary artery disease. These findings are based on a review of health care claim costs. Specialty care costs (the costs of seeing any specialist and all tests ordered) were especially higher for bipolar patients. Results of this review are being presented today at the Annual Meeting of the American Psychiatric Association in San Francisco.

"Psychiatric care costs represented only a portion of the specialty care costs for these chronic conditions," explains Mark Williams, M.D., a Mayo Clinic psychiatrist and lead researcher. "This suggests that many of the specialty costs for bipolar patients are not directly related to seeing a mental health provider."

A data review of health care claims over a four-year period, showed patients with bipolar disorder had significantly higher total per member per month costs compared with patients who had the other conditions. Only patients with both coronary artery disease and diabetes had higher costs than patients with bipolar disorder. Total costs, specialty care visits, specialty care costs, outpatient psychiatric costs, and outpatient psychiatric visits were compared. "The goal of this study is to drive practice changes that improve the efficiency and value of care for bipolar disorder with hopes to improve care while reducing costs," explains Dr. Williams.

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Other authors on the Mayo Clinic study include Nilay Shah, Ph.D.; Mark Frye, M.D.; Jeanette Ziegenfuss, Ph.D.; Amy Wagie; and Douglas Wood, M.D.

Largest study of its kind implicates gene abnormalities in bipolar disorder
Links sodium, calcium imbalances to manic depressive episodes

18 aug 2008--The largest genetic analysis of its kind to date for bipolar disorder has implicated machinery involved in the balance of sodium and calcium in brain cells. Researchers supported in part by the National Institute of Mental Health, part of the National Institutes of Health, found an association between the disorder and variation in two genes that make components of channels that manage the flow of the elements into and out of cells, including neurons.
"A neuron's excitability – whether it will fire – hinges on this delicate equilibrium," explained Pamela Sklar, M.D., Ph.D., of Massachusetts General Hospital (MGH) and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, who led the research. "Finding statistically robust associations linked to two proteins that may be involved in regulating such ion channels – and that are also thought to be targets of drugs used to clinically to treat bipolar disorder – is astonishing."
Although it's not yet known if or how the suspect genetic variation might affect the balance machinery, the results point to the possibility that bipolar disorder might stem, at least in part, from malfunction of ion channels.
Sklar, Shaun Purcell, Ph.D., also of MGH and the Stanley Center, and Nick Craddock, M.D., Ph.D., of Cardiff University and the Wellcome Trust Case Control Consortiuum in the United Kingdom and a large group of international collaborators report on their findings online Aug. 17, 2008 in Nature Genetics.
"Faced with little agreement among previous studies searching for the genomic hot spots in bipolar disorder, these researchers pooled their data for maximal statistical power and unearthed surprising results," said NIMH Director Thomas R. Insel, M.D. "Improved understanding of these abnormalities could lead to new hope for the millions of Americans affected by bipolar disorder."
In the first such genome-wide association study for bipolar disorder, NIMH researchers last fall reported the strongest signal associated with the illness in a gene that makes an enzyme involved the action of the anti-manic medication lithium. However, other chromosomal locations were most strongly associated with the disorder in two subsequent studies.
Since bipolar disorder is thought to involve many different gene variants, each exerting relatively small effects, researchers need large samples to detect relatively weak signals of illness association.
To boost their odds, Sklar and colleagues pooled data from the latter two previously published and one new study of their own. They also added additional samples from the STEP-BD study and Scottish and Irish families, and controls from the NIMH Genetics Repository. After examining about 1.8 million sites of genetic variation in 10,596 people – including 4,387 with bipolar disorder – the researchers found the two genes showing the strongest association among 14 disorder-associated chromosomal regions.
Variation in a gene called Ankyrin 3 (ANK3) showed the strongest association with bipolar disorder. The ANK3 protein is strategically located in the first part of neuronal extensions called axons and is part of the cellular machinery that decides whether a neuron will fire. Co-authors of the paper had shown last year in mouse brain that lithium, the most common medication for preventing bipolar disorder episodes, reduces expression of ANK3.
Variation in a calcium channel gene found in the brain showed the second strongest association with bipolar disorder. This CACNA1C protein similarly regulates the influx and outflow of calcium and is the site of interaction for a hypertension medication that has also been used in the treatment of bipolar disorder.
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In addition to NIMH, the research was also funded by NARSAD (National Alliance for Research on Schizophrenia and Depression), the Wellcome Trust, Johnson & Johnson Pharmaceutical Research & Development, the Johnson & Johnson Foundation, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute, the Dauten Family, the Merck Genome Research Institute, and the National Health and Medical Research Council of Australia.
There is a videocast associated with this release:
Pamela Sklar, M.D., Ph.D., Massachusetts General Hospital (MGH) and the Stanley Center for Psychiatric Research at the Broad Institute, discusses her recent findings on the genetics of schizophrenia and bipolar disorder.
NIH Neuroscience Seminar Series Monday, March 17, 2008, 12:00:00 PM Runtime: 01:09:43

APA: Bipolar Disorder Both Under- and Overdiagnosed

By John Gever
WASHINGTON, 09 may 2008-- More than half the patients who were told they have bipolar disorder may have been misdiagnosed, even as it goes unrecognized in a substantial number of those who really do have it, a researcher said here.
In 145 psychiatric outpatients who said they had been previously diagnosed with bipolar disorder, the condition was ruled out in 56.6% after they underwent the Structured Clinical Interview for DSM-IV, the diagnostic "gold standard," said Mark Zimmerman, M.D., of Brown University in Providence, R.I.
The structured evaluation also revealed that, of 555 other patients who had not previously received a diagnosis of bipolar disorder, 27 actually did have the condition, Dr. Zimmerman told attendees at the American Psychiatric Association meeting.
All told, out of 700 psychiatric outpatients, 90 were diagnosed with bipolar disorder with the structured interview. The disorder had gone unrecognized in nearly one-third of them, Dr. Zimmerman said.
The research was also published simultaneously online in the Journal of Clinical Psychiatry.
Dr. Zimmerman blamed the overdiagnosis of bipolar disorder on drug companies and others seeking to reduce under-diagnosis, which he said was also a real problem.
"I think there has been a marketing campaign and it has had an impact," Dr. Zimmerman said.
Noting the frequency with which patients ask if they are bipolar, he added, "I've never had a patient come into my office and ask, 'Do I have borderline personality disorder?'"
The study was part of a larger investigation in which 2,500 patients presenting at an outpatient psychiatric clinic filled out questionnaires. For the most recent 700 patients, the questionnaire asked whether the patient had previously received a diagnosis of bipolar disorder.
Dr. Zimmerman acknowledged that the reliance on self-reports, without review of clinical records, was a limitation of the study.
All patients were subsequently evaluated with the Structured Clinical Interview for DSM-IV and other validated instruments.
The evaluation confirmed the diagnosis of bipolar disorder in only 63 of the 145 patients reporting a previous bipolar diagnosis.
The investigators examined family histories of those who did not have a bipolar diagnosis. They found no differences in the prevalence of bipolar disorder in first-degree relatives between those never diagnosed with the condition and those whose initial diagnosis was overturned in the structured interview.
Dr. Zimmerman said the finding confirmed the validity of the structured evaluation process.
He said that overdiagnosis of bipolar disorder leads to over-treatment with mood stabilizers, putting patients at risk for liver, kidney, and metabolic side effects. Patients with such diagnoses may also be more likely to receive drug therapies than counseling.
Although Dr. Zimmerman's presentation was titled "Is Bipolar Disorder Overdiagnosed?", he said the study also supported the more prevalent view that it is under-diagnosed, given that bipolar disease had been missed in 27 of 90 genuinely bipolar patients.
He said bipolar disorder may go unrecognized for a variety of reasons. Depression symptoms typically last much longer than mania, hypomanic patients usually don't seek treatment, and clinicians often fail to ask enough questions to arrive at a correct diagnosis.
The study's single-center design was a limitation, Dr. Zimmerman said. Patients were predominantly white and female, and 40% were college graduates, so it may not be entirely generalizable to other populations.
Funding information was not provided. No potential conflicts of interest were reported.
Primary source: Journal of Clinical PsychiatrySource reference:Zimmerman M, et al "Is bipolar disorder overdiagnosed?" Journal of Clinical Psychiatry 2008; 69:e1-e6/pii: ej07m03888.

Light Treatment Benefits Depression in Bipolar Disorder

PITTSBURGH, Jan. 4 -- Depression symptoms in women with bipolar disorder improved following light-box therapy delivered at midday, researchers here said. Four of nine women exposed to 7,000 lux of light therapy for 15 to 60 minutes a day for up to six weeks had complete relief and two others showed partial responses, Dorothy Sit, M.D., of the University of Pittsburgh, and colleagues reported in the December issue of Bipolar Disorders. Most of the improvements came with treatment delivered between noon and 2 p.m. The first four participants received treatment in the morning, but three of them developed symptoms of both mania and depression, forcing two to quit treatment entirely. The remaining patients were then treated at midday without manic flare-ups.
Action Points --->
Explain that the study found that women with bipolar depression showed significant improvement following light-box therapy, with the most consistent benefit seen with midday treatment.
Point out that the study involved a small patient sample and needs confirmation in a larger, placebo-controlled trial.
"We found the optimal response was at 7,000 lux midday light for 45 or 60 minutes," the researchers said.
Among nonresponders to the midday treatment, one had a full response when switched to a morning schedule, they said. Another had partial symptom relief with morning treatment.
Light therapy is used frequently in patients with seasonal affective disorder, and has been shown to be beneficial in some patients with nonseasonal unipolar depression as well. But it has not been well studied in bipolar depression, Dr. Sit said.
Patients were included in the current study if they had a diagnosis of type I or II bipolar disorder without a seasonal pattern and persistent depressive symptoms that had not responded adequately to other treatments. Those with other psychiatric or physical disorders, including recent drug abuse, were excluded. The women took antimanic drugs beginning four weeks before starting light therapy and continuing through the study period.
Treatment response was defined as improvement of at least 50% from baseline in scores on the Structured Interview Guide for the Hamilton Depression Scale with Atypical Depression Supplement.
Treatment began with a two-week run-in phase in which participants received 30 minutes of dim (50 lux) red light to serve as a control. Active treatment then began at 15 minutes daily for two weeks, followed by 30 minutes a day for two weeks and then 45 minutes a day for two weeks.
Most patients showed mild improvement during the run-in phase, with mean improvement in depression scores of 8.3 points from a mean at baseline of 27.2 points.
In two patients who showed partial responses at 45 minutes a day without adverse effects, the daily dose was increased further to 60 minutes. Both patients then had full responses.
Intended as a dose-finding pilot study, the protocol did not include a parallel control group. The researchers said the results justify a randomized, placebo-controlled trial to explore the effectiveness of midday light therapy in men as well as women.
Dr. Sit said that it was unlikely that spontaneous remission could account for the depression relief seen in the study. Such remissions do occur in bipolar depression, but much less frequently than the response rate seen in this study.
The most important adverse effects were the onset of mixed manic and depressive symptoms in three of four patients treated in the morning, and significant uterine bleeding in three patients.
The study experience with timing of treatment could be important for future research, Dr. Sit said. "People with bipolar disorder are exquisitely sensitive to morning light, so this profound effect of morning treatment leading to mixed states is very informative and forces us to ask more questions," she said. "Did we introduce light too early and disrupt circadian rhythms and sleep patterns?"
The researchers said their findings support an emerging theory that midday treatment suppresses manic symptoms by holding circadian rhythms steady, while light treatment early in the day destabilizes these rhythms. An opposing camp holds that phase advancement of circadian rhythms is essential to therapeutic responses in bipolar disorder.
The bleeding complications were not related to menstruation or malignancy. Their origin remains unknown, Dr. Sit said, although some cases have been reported previously in patients treated with light therapy.
"We probably need to track that more closely in future studies," she said.
Dr. Sit said she was now seeking funding for a randomized, controlled trial of light therapy in bipolar depression.
Funding for the study was provided by the Stanley Foundation.
Dr. Sit has received funding from the National Alliance for Research on Schizophrenia and Depression. One co-author reported relationships with Pfizer and GlaxoSmithKline.
Primary source: Bipolar DisordersSource reference:Sit D, et al "Light therapy for bipolar disorder: a case series in women" Bipolar Disorders 2007: 9: 918-27.

Studies find stable sleep patterns and regular routines may improve outcomes in bipolar disorder

Findings provide insight into influence of circadian rhythms
Boca Raton, FL, December 8, 2007 – Bipolar disorder, commonly known as manic-depressive disorder, is highly influenced by the circadian system – the body’s internal clock – and a specific kind of psychotherapy may help decrease irregularities in the circadian system that can trigger key symptoms of bipolar disorder, according to a study presented today at the American College of Neuropsychopharmacology (ACNP) annual meeting. The results are important because they show for the first time that psychotherapy which focuses on practical lifestyle changes can ease the symptoms of bipolar disorder. Every year nearly six million American adults suffer from bipolar disorder, a brain disorder which causes severe shifts in mood, energy, and ability to function, according to the National Institute of Mental Health.
Maintaining a consistent sleep schedule and wake time can help balance the circadian system, which in turn can help people avoid nighttime sleeplessness or daytime exhaustion, which can increase the risk of new episodes of mania or depression. “Having already found that disruption in daily routines can make individuals with bipolar disorder vulnerable to new episodes of illness, we have now learned that working with patients to achieve and maintain regular social rhythms – including regular sleep patterns and adequate physical activity – will help to protect them against episodes of mania or depression,” says Ellen Frank, Ph.D., clinical psychologist and professor of psychiatry and psychology at the University of Pittsburgh School of Medicine.
People with bipolar disorder tend to have extremely sensitive circadian systems, which makes it much more difficult for them to recover from disruptions in sleep and routine. In contrast, people without bipolar disorder generally recover fairly quickly if their systems are thrown off by a change in routine or loss of sleep and might even be temporarily energized by these alterations.
Frank studied 175 adult patients with bipolar disorder and compared the effects of two approaches when combined with a common medical treatment for bipolar disorder, usually lithium carbonate: the first was interpersonal and social rhythm therapy, in which patients use a self-monitoring instrument to record and monitor the regularity of their daily routines—for example, their sleep patterns, meal times and physical activity. The second approach involved an intensive clinical management paradigm focusing just on patients’ mood symptoms and management of medication side effects.
The study found that patients who participated in interpersonal and social rhythm therapy in the earlier phases of the trial were able to go longer without a new episode of mania or depression than those who received clinical management.
Frank notes that many study participants had other medical and psychiatric conditions that also had important effects on their treatment outcomes. She adds that her study was conducted in an academic environment using highly trained therapists, so results from other settings might be different.
In a related study presented at the meeting, researchers studying circadian rhythms in mice found that the genes that regulate these rhythms also control the activity of neurons in the brain that utilize dopamine, a neurotransmitter implicated in motivation and emotion. Mice that are lacking some of the key circadian genes closely resemble bipolar patients in the manic state.
Lead researcher Colleen McClung, Ph.D., assistant professor of psychiatry at the University of Texas Southwest Medical Center, says these mice are the most well characterized animal models of human mania that have been described. Symptoms of mania include increased energy, activity, and restlessness; excessively good, euphoric mood; and poor judgment.
While there has long been an association between circadian rhythms and bipolar disorder, no studies have examined whether these rhythmic disruptions contribute to the symptoms associated with bipolar disorder. McClung says the findings of this study bring researchers one small step closer to discovering why bipolar disorder occurs at all, even though the study was done in mice, not humans, and that many more studies will be needed to discover a cure.

Breast Cancer Drug Tames Acute Mania in Bipolar Disorder

BETHESDA, Md., Sept. 12 -- Tamoxifen significantly decreased symptoms of acute mania beginning as early as five days in patients with bipolar disorder in a small pilot study.The drug, approved to treat breast cancer, maintained its effect throughout a three-week trial with a response rate of 63% for tamoxifen versus 13% for placebo, Carlos A. Zarate, Jr., M.D., of the National Institute of Mental Health, and colleagues reported online in the Sept. issue of Bipolar Disorders.
Tamoxifen is a relatively selective protein kinase C inhibitor with the advantage that it crosses the blood-brain barrier, the researchers wrote.
They reasoned that because tamoxifen inhibits protein kinase C directly, it would produce anti-manic effects more rapidly than previously achieved with lithium or valproate (Depacon).
Those two drugs, they said, exert their primary effect considerably upstream of protein kinase C and ultimately work through an indirect cascade of events.
Although there have been substantial gains with lithium, valproate, carbamazepine, and atypical antipsychotic drugs, the researchers said, those drugs may take more than a week to start working and many patients don't respond adequately to or can't tolerate the side effects of the treatment.
The researchers acknowledge that tamoxifen is unlikely to become the drug of choice because it may cause endometrial cancer if taken for extended periods. However, they noted, by pointing to protein kinase C as a target for new medications, the study raises the possibility of developing faster-acting treatments for the often-destructive early manic phase of the illness.
The tamoxifen findings came from a double-blind, placebo-controlled pilot study of 16 patients with manic or mixed bipolar disorder, with or without psychotic features.
The study included 14 men and two women, mean age 35.4, with a mean length of illness of 16.4 years, and a mean duration of the current manic episode of 33.9 days. Of these more than half had a lifetime diagnosis of any substance abuse or dependence.
The patients were randomly assigned to receive tamoxifen (20-140 mg/day) or placebo for three weeks. Primary efficacy was assessed by the Young Mania Rating Scale.
The eight patients on tamoxifen showed significant improvement in mania compared with placebo as early as five days (d=0.59, 95% CI, 0.17-1.00), a 50% or greater effect that remained significant throughout the three-week trial (d=1.11, CI, 0.59-1.64).
The placebo group showed no significant change from baseline at any point.
After three weeks, the researchers said, the effect size for the drug difference was "very large" (d=1.08, 95% C.I., 0.45 to 1.71 (P=0.001).
At the end of the study, response rates were 63% for tamoxifen (five of eight patients) and 13% (one of eight) for placebo (Fisher's Exact P=0.12), the researchers reported.
The tamoxifen group showed a decrease of 18.3 points from baseline to endpoint on the Young Mania scale, while the placebo patients' mania worsened 4.7 points. These findings support the results of an earlier single-blind study and that of other recent studies with tamoxifen, the researchers said.
Lorazepam (Ativan) was used during the trial for four of the tamoxifen patients and six of the placebo patients. And it has been suggested that the anti-manic effects seen with tamoxifen were related to the lorazepam, which also has anti-manic effects. However, the researchers noted, lorazepam dose as a time-dependent covariate did not alter the tamoxifen results.
Overall, tamoxifen was well tolerated, they said, with loss of appetite the main side effect. Contrary to previous reports that tamoxifen might cause depression, the researchers said they found no such effect.
An unavoidable limitation of the study, the researchers noted, is that tamoxifen is not entirely protein kinase C-selective and also has anti-estrogen effects. Thus, they said, they could not clearly exclude the potential contributory effect of estrogen receptor blockade.
The preliminary results of this pilot study need to be interpreted with caution, Dr. Zarate said. First, the group size was small, although the results were sufficiently positive to suggest pursuing larger controlled trials with protein kinase inhibitors in mania.
Second, the results may not be generalizable to patients with certain characteristics, for example, those with current substance abuse disorders. Finally, he said, these results may not apply beyond the acute treatment phase of bipolar mania.
The findings of this pilot study suggest that protein kinase inhibition might be relevant to the anti-manic effects of lithium and valproate. Large controlled studies with selective protein kinase C inhibitors in acute bipolar mania are warranted, the researchers said.
The researchers reported no financial conflicts.
The study was supported by the Intramural Research Program at the National Institute of Mental Health, the National Institutes of Health, and the Department of Health & Human Services. Co-author Jaskaran B. Singh, M.D., is currently at Johnson & Johnson Pharmaceutical Research and Development L.L.C. Primary source: Bipolar DisordersSource reference: Zarate, Jr. CA, et al "Efficacy of a Protein Kinase C Inhibitor (Tamoxifen) in the Treatment of Acute Mania: A Pilot Study" Bipolar Disorders 2007; Sept. online

Shortage of talk therapy for bipolar

By MALCOLM RITTER
Psychological therapy can greatly boost the effectiveness of drugs in treating bipolar disorder, but these specialized talk therapies aren't as widely available as they should be, experts say.
"There are probably several dozen places in the country where you can get these treatments," said Dr. Holly Swartz, an assistant professor of psychiatry at the University of Pittsburgh. "It's not available in the majority of the country."
Much of the problem is lack of training in the specialized techniques for psychologists, psychiatrists and social workers, said David Miklowitz, a professor of psychology and psychiatry at the University of Colorado at Boulder. The techniques should become part of the regular curriculum for them, he said.
And just as drug companies trumpet the effectiveness of their drugs, advocates for talk therapy have to advertise the impact of their techniques, Miklowitz said.
"There's a lot of work that needs to be done to get these treatments into day-to-day use in community practice," he said.
Basically, the talk therapies work by helping patients deal with stress, function socially and stick with their medications, he said.
They come in three styles:
_Family-focused therapy includes the patient's family and deals with their relationships. Goals include improving communication and problem-solving and providing for family intervention at the earliest signs of relapse.
_Cognitive-behavioral therapy is done with the patient alone. It helps patients change harmful thinking patterns of depression and mania, and teaches them to recognize their early warning signs of relapse to either extreme of the illness.
_Interpersonal and social rhythm therapy addresses ways to deal with interpersonal issues like marriage problems, and promotes a regular daily schedule of sleeping, waking, eating and other activities. Sticking to a regular schedule is thought to help stabilize and prevent bipolar symptoms.
Miklowitz is studying whether family-focused therapy can delay the first appearance of bipolar disorder or reduce its severity in children at risk. Those children have suggestive symptoms and a family history of bipolar disorder but do not yet have the full-blown condition.

Scientists test new bipolar remedies

By MALCOLM RITTER
Scientists are casting a wide net to find better treatments for the crushing depression and uncontrolled manias of bipolar disorder, and some approaches they're testing seem pretty surprising.
Like skin patches that prevent seasickness. Or a drug that fights Lou Gehrig's disease. And then there's a newly invented device that resembles a hair dryer in a beauty salon.
Some of the strategies were identified by logic, and others by pure chance. Scientists already have evidence that they may someday prove useful against bipolar disorder, also called manic-depression.
Doctors yearn for better therapies to treat the condition, which can rip careers and marriages apart and drive people to suicide. It is so complex and mysterious that researchers haven't developed a medication specifically for it since lithium, more than half a century ago.
Bipolar disorder appears in various forms and degrees of severity in about one in every 25 American adults at some point in their lives, according to a major study published in May.
The disorder is characterized in part by episodes of mania, which are periods of boosted energy and restlessness that can run for a week or more.
"You have so much energy, you have so many great ideas" said Tamara, 26, a Pittsburgh resident who was diagnosed several years ago. She asked that her last name not be used.
"You feel like you're thinking so clear, you've got the answer for everybody. You need to tell them, you need to phone all your friends... It's so hard to sleep. You keep thinking of all sorts of things."
But mania can also bring extreme irritability. Tamara's energy and charisma made her the life of the party, but "if somebody spilled a drink on me, I would just explode," she recalled. "It's like all your emotions are just completely intensified."
She got into fights and experienced road rage. She made bad decisions, plagiarizing a college paper and behaving promiscuously.
"A lot of things sound like a good idea when you're manic," she said, "and they're really not."
During manic episodes many people even get hallucinations or delusions, and Tamara experienced those too. "I was convinced I could hear other people's thoughts, or at least know what they were," she recalled. "I thought everybody was saying bad things about me."
The disorder also brings episodes of depression that last a week or more.
"Nothing is interesting," Tamara said. "You're bored with everything... Nothing sounds fun anymore. All you want to do is sleep. I slept days and days away."
In her senior year of college, thoughts of suicide frightened her into seeking help.
Doctors currently treat bipolar with a variety of drugs including lithium, anticonvulsant medications that can stabilize mood, and antipsychotics. Psychological therapy and patient education greatly boost the effectiveness of the drugs.
Tamara takes lithium and another drug, and says, "I'm doing fine right now."
She's lucky. Bipolar disorder is hard to treat chiefly because the depressive episodes are more severe and more resistant to therapy than ordinary "unipolar" depression, notes Dr. Andrea Fagiolini, an associate professor of psychiatry at the University of Pittsburgh.
Overall, current medications for bipolar "certainly reduce symptoms but don't do a good enough job," said Dr. Husseini Manji of the National Institute of Mental Health. "Many patients are helped, but they're not well."
What's more, many patients can't tolerate current bipolar medications because of side effects like weight gain, sleepiness, tremor, and the sense of feeling "drugged," Fagiolini said. (Some patients also stop taking their medicine because they miss the "highs" of the disease, he noted).
A study of treated patients published last year found that about 60 percent got well for at least eight weeks, but only half of that group remained well when followed for up to two years. That was with very good therapy, noted Dr. Andrew Nierenberg, professor of psychiatry at Harvard Medical School.
"That means there's a lot of room for improvement," Nierenberg said. "That's why we need new treatments."
Just as heart attacks come from chronic heart disease, the manic and depressive episodes come from an underlying chronic brain disease. And "we just don't really understand what's behind the illness," said Dr. Gary Sachs, who directs bipolar research at Harvard's Massachusetts General Hospital.
The mystery and complexity of the disorder have discouraged scientists from trying to develop drugs for it, Manji said. Not since lithium have they developed a drug specifically for bipolar, Manji said.
Like lithium, some of the latest crop of early candidate drugs revealed their potential simply by chance.
Take the experience of NIMH researchers Maura Furey and Dr. Wayne Drevets with the drug scopolamine, which is normally used to keep people from getting seasick or carsick. Several years ago, they were studying whether scopolamine could improve memory and attention in depressed people. So they gave the drug intravenously to depressed patients, trying to find the right dose for a brain-imaging study.
They noticed that patients started feeling less depressed the night after the injections. Most antidepressants take weeks to kick in.
"Some patients would say it was the best night of sleep they'd had in many years, and the next morning they woke up feeling a substantial lifting of their depression," Drevets said. "In many cases that improvement persisted for weeks or even months."
Drevets and Furey quickly changed their research focus to test the drug's effect on depression itself. And in October 2006 they published an encouraging, though preliminary, result with a small group of depressed patients, some of whom were bipolar.
Now Furey is leading a study using scopolamine skin patches — like travelers wear to prevent motion sickness — to treat depression in bipolar disorder as well as ordinary depression. For now, people shouldn't try patch treatment for depression on their own, she said.
A similar bit of serendipity showed up at McLean Hospital in Belmont, Mass., in 2001. Depressed bipolar patients who were getting their brains scanned for a study of brain chemistry suddenly felt a lot better. Alerted by a research assistant, scientists started taking a closer look. And in 2004, they published their conclusion that the electric fields produced by the brain scans might lift depression. It's still not clear how.
Follow-up studies have had inconsistent results. But researchers have now built a device that resembles a hair-salon dryer to produce electric fields. They plan to start testing it this fall.
Researchers have also used the few insights they have into the disease to develop potential treatments.
That's the story with riluzole, now used to treat the paralyzing disorder Lou Gehrig's disease, also known as ALS or amyotrophic lateral sclerosis. Scientists found that a drug that's effective against depression in bipolar disorder boosts the abundance of a certain protein in rat brain cells, and that riluzole does too. So the researchers tried riluzole in a small number of depressed bipolar patients, and in some patients the symptoms virtually disappeared, Manji said.
So riluzole, which is distributed by Sanofi-Aventis, might become a treatment for bipolar disorder, he said.
Similar research used an off-the-shelf drug to get a lead for developing a new medication. Studies in rats showed that lithium and another anti-mania drug hamper the effect of a particular enzyme in the brain. That suggested other drugs that hamper the enzyme might work against mania too, Manji said.
The best available candidate: tamoxifen, used to fight breast cancer. Manji's recent study in a small group of bipolar patients found that tamoxifen quickly quelled mania. Other studies have found similar results, he said.
That shows the value of blocking the enzyme, and now Manji is trying to develop other drugs that will do that, perhaps for use in emergency rooms. He wants to avoid tamoxifen itself because of concern about long-term side effects, since his work requires a higher dose than women use to stave off breast cancer for years.
Scientists say the real key to unlocking the mysteries of bipolar disorder — and thereby exposing targets for drugs — lies in a new generation of research into DNA.
In recent months, scientific journals have begun to publish the early results of a revolution in DNA analysis: the ability to scan entire genomes in detail to find genetic variants that predispose people to particular diseases. Some of the new work is implicating dozens of variants in bipolar disorder.
Such work can expose the hidden biological underpinnings of disease, and tip off researchers to unsuspected targets for intervening.
"We've been stumbling in the dark for most of our history" of bipolar research, said gene expert Dr. Francis McMahon of NIMH. But "these kinds of studies ... will really give us the chance to reason from biological insights back to the patient."
Sachs, of Harvard, agreed: "I think these whole-genome scans will in fact be the important bridge to better treatments."
And not just in some far-distant future. The new gene studies, Sachs said, help give "a great potential to advance the field in our lifetimes and treat people who are living now."
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On the Net:
Bipolar information: http://www.nimh.nih.gov/healthinformation/bipolarmenu.cfm
National Alliance on Mental Illness: http://www.nami.org
Depression and Bipolar Support Alliance: http://www.ndmda.org
Disease treatment studies: http://www.clinicaltrials.gov

Researchers Detect Variations in DNA That Underlie Seven Common Diseases

Applying a new genomic technique to a large group of patients, researchers in Britain have detected DNA variations that underlie seven common diseases, discovering unexpected links between them.
The variations pinpoint biological pathways underlying each of the diseases, and researchers hope that as the pathways are analyzed, new drugs and treatments will emerge.
The seven common diseases are bipolar disorder, coronary artery disease, Crohn’s disease, hypertension, rheumatoid arthritis, and Type 1 and Type 2 diabetes.
Unveiling the complex genetics of common diseases was the promised payoff of the $3 billion human genome project, completed in 2003, but progress was slow until the recent development of devices that in a single operation can read the DNA sequence at up to 500,000 points across an individual’s genome. With the devices, called chips, researchers can compare large numbers of patients with healthy individuals, looking for points of differences in their genomes that may be associated with disease.
The approach is known as whole genome association, and studies on Type 2 diabetes, heart disease and breast cancer have been reported within the last few weeks. Those and the new study, which was financed by the Wellcome Trust of London, demonstrate the power and reliability of the whole genome association method, which stands in contrast to the many uncorroborated claims of disease genes made previously.
“It’s now absolutely clear that this is a new dawn in the genetics of common human diseases,” said Peter Donnelly, a statistical geneticist at Oxford University who was chairman of the consortium of 50 institutions involved in the Wellcome Trust study.
The consortium compared 2,000 patients with each disease from across Britain with 3,000 healthy individuals as controls, half of whom were born in a single week in 1958. The consortium’s findings are published in today’s Nature, along with reports from two groups that largely confirm the consortium’s genomic hits in independent patient groups suffering from Crohn’s disease and Type 1 diabetes.
The consortium discovered some 24 variants strongly linked to disease, about half of which have been found already by other groups and half of which are new.
Among its most interesting findings is that genetic variants close to a gene known as PTPN2 are associated with both Crohn’s disease and Type 1 diabetes. The link may be that both are autoimmune diseases and that the gene helps regulate the immune system. Researchers hope that analysis of the gene’s operations may produce a treatment for the two diseases.
The consortium also found a genetic variant on chromosome 7 that carries a high risk of rheumatoid arthritis for women, but none for men. Very few such variants are known in diseases common to both sexes, Dr. Donnelly said.
Anne Bowcock, a geneticist at the Washington University School of Medicine in St. Louis, said the Wellcome Trust study was a “tour de force” that established how large-scale studies should be conducted.
Marie Nierras, an official of the Juvenile Diabetes Research Foundation, which supported the companion study of Type 1 diabetes, said the research was “a significant advance that identifies additional pathways that need to be looked at.”
Dr. Kari Stefansson, chief executive of DeCode Genetics, an Icelandic company that has dominated the search for common disease genes until the arrival of the whole genome association method, said the Wellcome Trust study was “a large body of work, done by very good people” but that it “hadn’t come up with any big discovery.”
Dr. Stefansson said the study had been delayed because of problems with the Affymetrix chip it used, and would have had greater impact in the fast-moving field if it had appeared several months earlier.
In the course of screening for any geographically related genetic bias, the Wellcome Trust researchers discovered a southeast-to-northwest gradient across Britain composed of 13 genes. The genes were probably under natural selection in the people who became the island’s first inhabitants.
One of the genes, which arose among Europe’s first cattle herders 5,000 years ago, enables people to drink milk in adulthood, an ability known as lactose tolerance. The other genes, the researchers speculate, may confer resistance to former scourges like pellagra, tuberculosis and leprosy.
Another possible source of statistical bias relates to race. The Wellcome Trust consortium asked their 17,000 subjects to identify their race, then genetically tested them and excluded 153 people who had non-European ancestry. The procedure is necessary because whole genome association studies look for small differences between patients and controls, which can be confounded by the genetic differences between races.
The Wellcome Trust’s findings apply to populations of European descent and need to be verified in other races. Geneticists do not yet know what proportion of the genetic variants associated with common disease will be found in all races, but hope the overall biology will be much the same.
“The genetics gives us a whole new foothold into the biology of disease,” Dr. Donnelly said. “If you find a variant in one population you might learn a lot about that disease which is relevant to the disease in other populations.”
Because whole genome association studies work only in people of a single race, researchers are concerned that follow-up studies should then be done in other races. “I think everyone is committed to make sure that is the case,” said Mark Daly, a geneticist at Massachusetts General Hospital.

Intensive Therapy Helps Bipolar

Intensive Psychotherapy, in Addition to Medication, May Be Better Than Brief Therapy

By Miranda Hitti WebMD Medical News
Reviewed by Louise Chang, MD

April 2, 2007 -- Treating bipolar depression with intensive psychotherapy plus medication may be more effective than brief psychotherapy plus medication.
That news comes from a study of nearly 300 U.S. adults with bipolar disorder, which is marked by extreme mood shifts from depression to mania.
All of the patients were experiencing bipolar depression (the depressive phase of bipolar disorder) when the study started.
The patients who got intensive psychotherapy plus medication had their depression lift sooner and were more likely to maintain stable moods than those who got brief psychotherapy plus medication.
Intensive psychotherapy "should be considered a vital part of the effort to treat bipolar illness," says researcher David Miklowitz, PhD, in a news release.
Miklowitz and colleagues report their findings in the Archives of General Psychiatry.
Bipolar Depression Study
All patients took mood-stabilizing drugs such as lithium during the study. About 30% of patients were also taking antidepressants.
The researchers split the patients into two main groups:
One group got intensive psychotherapy (up to 30 psychotherapy sessions over nine months) in addition to medication. Those patients got one of the following three types of therapy:
Family-focused therapy, which includes the patient and their relatives
Cognitive behavior therapy, which teaches new coping strategies
Interpersonal and social rhythm therapy, which includes solving relationship problems and setting healthy daily routines for sleep, exercise, and eating
Patients in the second group got brief psychotherapy (three sessions in six weeks) plus medication. The brief therapy sessions included a videotape and a workbook for patients to use.
Study's Results
The researchers followed the patients for one year.
On average, patients in the intensive-therapy group took nearly four months to have their depression ease, compared with nearly five months for those in the brief-therapy group.
By the end of the study, nearly two-thirds of the patients in the intensive-psychotherapy group (64%) had had at least two months of stable moods, compared with about half (51%) of those in the brief-therapy group.
Patients in the intensive-psychotherapy group were about 1.5 times more likely to have stable moods during any given month of the study than those who got brief psychotherapy.
Antidepressants were not responsible for the difference between the two groups' outcomes, according to Miklowitz and colleagues.
The study doesn't show whether one type of intensive psychotherapy was more effective than the others. Future studies should look into that, note the researchers

Study sheds light on medication treatment options for bipolar disorder

For depressed people with bipolar disorder who are taking a mood stabilizer, adding an antidepressant medication is no more effective than a placebo (sugar pill), according to results published online on March 28, 2007 in the New England Journal of Medicine. The results are part of the large-scale, multi-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a $26.8 million clinical trial funded by the National Institutes of Health's National Institute of Mental Health (NIMH).
Bipolar disorder, a sometimes debilitating illness marked by severe mood swings between depression and mania, is usually treated with mood stabilizers such as lithium, valproate, carbamazepine or other medications that reduce mania. However, depression is more common than mania in bipolar disorder, and depressive episodes tend to last longer than episodes of mania. Antidepressant medications are often used in addition to a mood stabilizer for treating bipolar depression, but they are thought to confer a serious risk of a switch from a depressive episode to a manic episode.