Category: Bipolar Disorder

Neuroscientists at the Indiana University School of Medicine have created the first comprehensive map of genes likely to be involved in bipolar disorder, according to research published online Nov. 21 in the American Journal of Medical Genetics.

The researchers combined data from the latest large-scale international gene hunting studies for bipolar disorder with information from their own studies and have identified the best candidate genes for the illness.

The methodology developed at the IU Institute of Psychiatric Research enabled Alexander B. Niculescu III, M.D., Ph.D., and his team to mine the data from the genome-wide association studies and other study results on the levels of gene activity in human blood samples and in animal models. Genes with the highest levels of prominence were determined to be the most active in contributing to the disorder.

The researchers also were able to analyze how these genes work together and created a comprehensive biological model of bipolar disorder.

"Based on our work, we now project that there will be hundreds of genes – possibly as much as 10 percent of the human genome – involved in this illness," said Dr. Niculescu, who is an assistant professor of psychiatry and director of the laboratory of neurophenomics at the IU School of Medicine. "Not all genetic mutations will occur in every individual with bipolar disorder. Different individuals will have different combinations of genetic mutations. This genetic complexity is most likely what made past attempts to identify genes for the disorder through genetic-only studies so difficult and inconsistent."

Dr. Niculescu compared the process to a Web search. "The process was similar to a Google approach, the more links there are to a page on the Internet, the more likely it is to come up at the top of your search list. The more experimental lines of evidence for a gene, the higher it comes up on your priority list of genes involved in the disorder."

Until now there have been few statistically significant findings in searches of the human genome as it applies to bipolar disorder, he said.

"By integrating the findings of multiple studies, we were able to sort through, identify genes that were most likely to be involved in bipolar disorder, and achieve this major breakthrough in our understanding of the illness," Dr. Niculescu said.

Bipolar disorder, sometimes called manic depression, affects nearly 2.3 million Americans. A serious illness, people who suffer from it can experience mild or dramatic mood swings, shifts in energy and a diminished capacity to function.

Dr. Niculescu, a practicing psychiatrist and a molecular geneticist, said this work opens exciting avenues for psychiatric researchers and clinicians, as well as for patients and their families.

"First and foremost, these studies will lead to a better understanding of bipolar and related disorders," he explained. "Second, the researchers now plan to study individuals to see which combination of genes is present in individuals to come up with a genetic risk score."

The goal, he said, is to be able to apply the risk score to test individuals even before the illness manifests itself for preventive measures – lifestyle changes, counseling, low-dose medications – or to delay or stop the illness from developing.

"Third, in individuals who already have the illness, genetic testing in combination with blood biomarkers for the disease, could help determine which treatments works best so personalized treatments could be developed," Dr. Niculescu said.

The research was done in collaboration with colleagues at the Scripps Research Institute, the University of California- San Diego, SUNY Upstate medical University and the National Institute of Mental Health. IU researchers involved were Helen Le-Niculescu, Ph.D., John I. Nurnberger, M.D., Ph.D., Meghana Bhat, M.D., and Sagar Patel.

Grant funding for the research was provided by National Institute of Mental Health.

Men and women who have tried to kill themselves and are suffering from unipolar disorder (major depression), bipolar disorder (manic depression) or schizophrenia are at a very high risk of committing suicide within a year of their first attempt, concludes a study published on the British Medical Journal website.

This is the first time research has identified a link between specific psychiatric disorders and increased suicide risk in such a large study of people who have attempted suicide. The authors call for prevention programmes to target these high risk groups.

It is well known that there is a 30-40 times increased risk of death from suicide in individuals who have previously attempted suicide compared with the general population. But little is known about the impact of coexisting psychiatric disorders on the risk of suicide in this group.

Dag Tidemalm and colleagues from the Karolinska Institutet in Stockholm studied nearly 40 000 individuals (53% women) who were admitted to hospital in Sweden following a suicide attempt during 1973-82. They analysed how many suicides were completed during the 30 year follow-up and if the risk varied with type of psychiatric disorder.

The authors found that schizophrenia and unipolar/bipolar disorder were the strongest predictors of completed suicide throughout the follow-up period. In patients suffering from unipolar/bipolar disorder, 64% of all suicides in men and 42% of suicides in women occurred within the first year of follow-up; the matching figures for schizophrenia were 56% in men and 54% in women.

Death from suicide occurred mostly within the five years after the initial suicide attempt.

People suffering with most other psychiatric disorders had a lower but still significantly increased risk of suicide. Interestingly, individuals suffering from adjustment disorder, post-traumatic stress disorder and alcohol abuse (men only) were not at significantly increased risk of re-attempting suicide compared to suicide attempters without a psychiatric diagnosis at baseline.

The authors call for patients who have unipolar/bipolar disorder or schizophrenia and previous suicidal behaviour to be given more intensive after-care, especially in the first few years after trying to kill themselves.

In an accompanying editorial, Dr Udo Reulbach from the National Suicide Research Foundation in Ireland and Professor Stefan Bleich from the Medical School of Hannover in Germany, explain that suicide is one of the 10 leading causes of death worldwide with predictions of 1.5 million people dying from suicide each year by 2020. Therefore, they say, suicide prevention must be made a health service and public health priority on medical, ethical and cost effectiveness grounds.

In another research paper, Professor David Gunnell from the University of Bristol and colleagues report that non-fatal self-harm may occur in over 10% of adults discharged from psychiatric inpatient care in England and Wales, and that the risk is greatest in the first month. Patients who had previous self-harming behaviour were at the greatest risk. Others at increased risk included women, the young, and those with depression, personality disorders and substance misuse.

These findings suggest the need to develop interventions to reduce the risk of fatal and non-fatal self-harm in the weeks immediately after hospital discharge—these might include improved discharge arrangements and clear crisis plans and lines of communication with specialist staff.

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Journal Reference:

1. Dag Tidemalm, Niklas Långström, Paul Lichtenstein, Bo Runeson. Suicide risk after a suicide attempt by psychiatric disorder: Long-term total population follow-up of 39,685 suicide attempters. British Medical Journal, 19 November 2008

About 44 percent of individuals who had bipolar disorder as children continue to have manic episodes as young adults, according to a report in the October issue of Archives of General Psychiatry, one of the JAMA/Archives journals. This rate, along with the severity of the disease at young ages, strongly suggest that bipolar disorder can be continuous from childhood to adulthood, the authors note.

Recent data has demonstrated an enormous increase in the diagnosis of pediatric bipolar disorder, a severe mood disorder involving episodes of mania and depression, according to background information in the article. However, skepticism continues to exist regarding the existence of the condition in children. Given increased media attention to the issue, there is a need to further increase the validity of childhood diagnoses.

Barbara Geller, M.D., and colleagues at Washington University in St. Louis studied 115 children (average age 11.1) diagnosed with bipolar disorder beginning in 1995 to 1998. At the beginning of the study and again during nine follow-up visits conducted over eight years, the children and their parents were interviewed separately about their symptoms, diagnoses, daily cycles of mania and depression and interactions with others.

A total of 108 (93.9 percent) of the children completed the study (average age at follow-up, 18.1 years). During the eight-year follow-up, they spent 60.2 percent of weeks with any mood episodes and 39.6 percent of weeks with episodes of mania. Although 87.8 percent recovered from mania, 73.3 percent relapsed. The researchers also examined the characteristics of children's second and third episodes of mania and found that like the first episodes, they were characterized by psychosis, daily cycling between mania and depression and a long duration (55.2 weeks for the second and 40 weeks for the third episode).

At the end of the follow-up period, 54 patients were age 18 or older. Of those, 44.4 percent continued to have manic episodes and 35.2 percent had substance use disorders, a rate similar to those diagnosed with bipolar disorder as adults.

"In grown-up subjects with child bipolar disorder I, the 44.4 percent frequency of manic episodes was 13 to 44 times higher than population prevalences, strongly supporting continuity between child and adult bipolar disorder I," the authors write. "Subjects with child bipolar disorder I who were grown up at the eight-year follow-up constituted approximately half the sample. However, even if all subjects younger than 18 years at the eight-year follow-up never had episodes of bipolar disorder I as adults, the overall significance of the findings would be similar, because the rate would still be six to 22 times higher than population prevalences."

"In conclusion, mounting data support the existence of child bipolar disorder I, and the severity and chronicity of this disorder argue strongly for large efforts toward understanding the neurobiology and for developing prevention and intervention strategies," they write.

Editorial: Examination Lays Groundwork for Future Research

"Extending previous seminal work on pediatric bipolar disorder, Geller et al present the first longitudinal study following up a large sample of youth diagnosed with pediatric bipolar disorder into adulthood," writes Ellen Leibenluft, M.D., of the National Institute of Mental Health, Bethesda, Md., in an accompanying editorial.

"Just as the children in this important study have matured over the last decade, so has research on pediatric bipolar disorder," Dr. Leibenluft writes. More articles on the condition were published in January 2008 than in the decade between 1986 and 1996.

"This upsurge both results from and contributes to a growing awareness that serious mental illnesses do not emerge de novo when individuals reach adulthood, but rather reflect early developmental processes. This awareness has profound implications for future research, highlighting the need for longitudinal studies such as that of Geller et al as well as pathophysiological research in children, studies comparing adults and youth with bipolar disorder and studies of youth at familial risk for bipolar disorder," Dr. Leibenluft concludes.

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Journal References:

1. Barbara Geller, Rebecca Tillman, Kristine Bolhofner, Betsy Zimerman. Child Bipolar I Disorder: Prospective Continuity With Adult Bipolar I Disorder; Characteristics of Second and Third Episodes; Predictors of 8-Year Outcome. Arch Gen Psychiatry, 2008; 65 (10): 1125-1133 [link]
2. Ellen Leibenluft. Pediatric Bipolar Disorder Comes of Age. Arch Gen Psychiatry, 2008; 65 (10): 1122-1124 [link]

 Lingering depression is a serious and common problem in bipolar disorder, and does not resolve well with existing treatments.

Because individuals with both depression and bipolar disorder experience a glutathione deficiency, an antioxidant that protects cells from toxins, researchers in a new study scheduled for publication in the September 15th issue of Biological Psychiatry sought to evaluate whether N-acetyl cysteine (NAC), an over-the-counter supplement that increases brain glutathione, might help alleviate depressive symptoms.

Dr. Michael Berk and colleagues, in a randomized, double-blind, placebo-controlled trial, evaluated the mood symptoms of individuals with bipolar disorder, half of whom received placebo and half of whom received NAC, as an add-on therapy to their usual treatment.

Over the 24 weeks of the study, NAC was well tolerated, and induced a marked and significant improvement in depressive symptoms. Ashley Bush, M.D., Ph.D., the article’s corresponding author, further explains: “Glutathione is the brain’s primary antioxidant defense, and there is evidence of increased oxidative stress in bipolar disorder. Therefore, we studied the potential benefit of NAC treatment in bipolar disorder and found that it impressively remedied residual depressive symptoms.”

John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, comments: “The preliminary evidence of efficacy of NAC is very interesting.

This study might suggest a number of novel approaches to treating depression. In subsequent efforts to replicate this preliminary finding, it will be important to determine how much NAC reaches the brain after oral administration.”

As noted by both the authors and Dr. Krystal, additional studies will be necessary to further evaluate and replicate these findings. However, as Dr. Berk observes, “Brain glutathione metabolism appears to be a valuable new treatment target for psychiatric disorders, and we hope the impressive results of this study opens up a new treatment option.”

Family-focused therapy, when combined with medication, appears effective in stabilizing symptoms of depression among teens with bipolar disorder, according to a new report.

Between one-half and two-thirds of patients with bipolar disorder develop the condition before age 18, according to background information in the article. "Early onset of illness is associated with an unremitting course of illness, frequent switches of polarity, mixed episodes, psychosis, a high risk of suicide and poor functioning or quality of life," the authors write. "The past decade has witnessed a remarkable increase in diagnoses of bipolar disorder in children and adolescents and, correspondingly, drug trials for patients with early-onset disorder. There has been comparatively little controlled examination of psychotherapy for pediatric patients."

David J. Miklowitz, Ph.D., of the University of Colorado, Boulder, and colleagues conducted an outpatient randomized controlled trial among 58 adolescents (average age 14.5) with bipolar disorder who had experienced a mood episode in the prior three months. Between 2002 and 2005, 30 teens were randomly assigned to receive pharmacotherapy plus family-focused treatment for adolescents. Over nine months, they participated in 21 50-minute sessions. Therapy included the patient, parents and siblings and consisted of education about their disease, communication training and problem-solving skills training.

The other 28 teens were assigned to pharmacotherapy plus enhanced care, which involved three 50-minute family sessions that focused on preventing relapse. Independent evaluators, who did not know patient group assignments, assessed the teens every three to six months for two years.

A total of 60 percent of the family-focused therapy group and 64.3 percent of the enhanced care group completed the two-year follow-up; of those, 53 (91.4 percent) experienced a full recovery from their original mood episode. There were no differences between the two groups in rates of recovery or in the amount of time that elapsed before a subsequent mood episode. However, patients in the family-focused therapy group recovered from depressive symptoms more quickly, spent fewer weeks in depressive episodes over the two-year period and had an overall more favorable trajectory of depressive symptoms than those in the enhanced care group.

"To enhance full symptomatic and functional recovery among adolescents, family-focused treatment for adolescents may need to be supplemented with collaborative care interventions found effective in mania stabilization," the authors conclude. The program's emphasis on "reducing conflict in family relationships, enhancing social supports and teaching interpersonal skills may underlie its stronger effects on bipolar depression."

This study was supported by National Institute of Mental Health grants, a Distinguished Investigator Award from the National Alliance for Research on Schizophrenia and Depression and a Faculty Fellowship from the University of Colorado Council on Research and Creative Work (Dr. Miklowitz).

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Journal Reference:

1. David J. Miklowitz, PhD; David A. Axelson, MD; Boris Birmaher, MD; Elizabeth L. George, PhD; Dawn O. Taylor, PhD; Christopher D. Schneck, MD; Carol A. Beresford, MD; L. Miriam Dickinson, PhD; W. Edward Craighead, PhD; David A. Brent, MD. Family-Focused Treatment for Adolescents With Bipolar Disorder. Arch Gen Psychiatry, 2008;65(9):1053-1061

Older age among fathers may be associated with an increased risk for bipolar disorder in their offspring, according to a new report.

Bipolar disorder is a common, severe mood disorder involving episodes of mania and depression, according to background information in the article. Other than a family history of psychotic disorders, few risk factors for the condition have been identified. Older paternal age has previously been associated with a higher risk of complex neurodevelopmental disorders, including schizophrenia and autism.

Emma M. Frans, M.Med.Sc., of the Karolinska Institutet, Stockholm, Sweden, and colleagues identified 13,428 patients in Swedish registers with a diagnosis of bipolar disorder. For each one, they randomly selected from the registers five controls who were the same sex and born the same year but did not have bipolar disorder.

When comparing the two groups, the older an individual's father, the more likely he or she was to have bipolar disorder. After adjusting for the age of the mother, participants with fathers older than 29 years had an increased risk. "After controlling for parity [number of children], maternal age, socioeconomic status and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 times more likely to be diagnosed as having bipolar disorder than the offspring of men aged 20 to 24 years," the authors write.

The offspring of older mothers also had an increased risk, but it was less pronounced than the paternal effect, the authors note. For early-onset bipolar disorder (diagnosed before age 20), the effect of the father's age was much stronger and there was no association with the mother's age.

"Personality of older fathers has been suggested to explain the association between mental disorders and advancing paternal age," the authors write. "However, the mental disorders associated with increasing paternal age are under considerable genetic influence." Therefore, there may be a genetic link between advancing age of the father and bipolar and other disorders in offspring.

"As men age, successive germ cell replications occur, and de novo [new, not passed from parent to offspring] mutations accumulate monotonously as a result of DNA copy errors," the authors continue. "Women are born with their full supply of eggs that have gone through only 23 replications, a number that does not change as they age. Therefore, DNA copy errors should not increase in number with maternal age. Consistent with this notion, we found smaller effects of increased maternal age on the risk of bipolar disorder in the offspring."

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Journal Reference:

1. Frans et al. Advancing Paternal Age and Bipolar Disorder. Archives of General Psychiatry, 2008; 65 (9): 1034 DOI: 10.1001/archpsyc.65.9.1034

Bipolar disorder is one of the most important psychiatric diseases, often associated with considerable treatment needs and tremendous social and occupational burden for both the individual and family (Pini et al., 2005). Previously also labelled manic-depressive illness, bipolar disorder is typically referred to as an episodic, yet lifelong and clinically severe mood (or affective) disorder.

Mood in bipolar disorder may swing from euphoria and/or extreme irritability (defined as ´mania´) to depressed mood or loss of interest or pleasure (´bipolar depression´). Less severe mood elevation (hypomanic episodes) characterise so-called Bipolar II disorder. Thus bipolar disorder may be divided into two major subtypes – Bipolar I and Bipolar II – although emerging data reveal that further extension of the bipolar spectrum (at the expense of unipolar depression) may be of broad clinical relevance.

• Bipolar I disorder is characterized by a history of at least one manic episode, with or without depressive symptoms.
• Bipolar II disorder is characterized by the presence of both depressive symptoms and a less severe form of mania (´hypomania´).

Acute episodes may vary in duration as well as intensity over time. Early in the course of the disease, for example, the periods between acute episodes may last months or even years, but later these symptom-free periods tend to decrease. ´Rapid cycling´ a not infrequent course variant is defined as suffering from 4 or more episodes per year. Clinical decisions pertaining to the treatment of bipolar disorder essentially are grouped around the topics of depression, mania, and rapid cycling/mixed states.

The highlights of the recently published ECNP consensus statement on bipolar depression were presented by the British researcher Guy M. Goodwin, Oxford. The apparent differences between unipolar and bipolar depression arise in diagnosis and epidemiology, bipolar depression in children as well as adults, the use of rating scales, and finally treatment studies to optimize pharmacotherapy and clinical outcome.

Epidemiology

Recent studies have suggested that bipolar disorders are much more frequent than previously thought. Almost 2% of the EU-population is or will be suffering from bipolar disorders in the course of their lives. When the wider range of the bipolar spectrum conditions is considered, estimates might be increase to as much as 6% (Pini et al., 2005). The estimates of the frequency of bipolar disorder are relatively stable: they show little indication of substantial variation by culture and region, there is convergent evidence for relatively early onset of illness in the mid-teenage years and twenties, and there is little evidence that the disorder is increasing substantially over time.

The first onset of bipolar disorders tends to be earlier than that of unipolar major depression in population samples, which may indicate that bipolar disorder have partly different causal factors promoting the illness. The risk for this illness is highest in the time period between late adolescence and the third decade and is substantially decreased after this age; conversely, the overall the risk of unipolar major depression continues to grow further on into the old age (Wittchen et al., 2003).

A consequence of the symptoms of bipolar disorder is that patients experience a debilitating decrease in functioning not only during their acute stages of illness, but increasingly also inbetween episodes. Typically they have for example difficulty in maintaining long-term relationships and they perform poorly at school or work, which impacts on opportunities for employment and finances.

The early onset of bipolar disorder potentially implies a severe burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to the acute depression episodes.

Bipolar depression: a major treatment challenge

Bipolar disorder may be defined by the existence of depression and (hypo-)mania, but its long-term course is almost always dominated by depressive rather than (hypo)manic symptoms. Patients with bipolar disorders are at a substantially increased risk of suicide, particularly during depressive episodes. Furthermore, in bipolar patients a high degree of concurrent and sequential comorbidity with other mental disorders and physical illnesses is common.

Unfortunately, all too often patients with bipolar disorders remain unrecognized by health professionals, untreated or improperly treated, which clearly is associated with a lower life expectancy, a more malignant course and an altogether lower quality of life. In particular bipolar II disorder has been under-recognized until recently, in part owing to difficulties in distinguishing bipolar from unipolar depression (Berk et al., 2005). Thus, a major challenge in the treatment of patients with mood disorders is the distinction between bipolar and unipolar depression, since these mood disorders require different approaches to treatments.

There is a considerable longitudinal risk – probably over 10% – that initial unipolar depressive patients ultimately turn out as bipolar patients in the longer run.

Bipolar depression in children

Bipolar disorder exists in children and adolescents, but the age at which bipolar disorder can first be diagnosed remains controversial. Although bipolar-like symptoms may be quite frequent, reliably defined bipolar I disorder is rare in prepubertal children. Since early intervention may improve diagnosis, treatment studies are an important objective for future research. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions via clinical networks. ECNP will aspire to facilitate such developments.

ECNP supports collaborating networks of clinicians in Europe who seek to improve treatment and research in children and in bipolar disorder.

Treatment studies in bipolar depression

Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled trials. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo-controls. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medications such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Thus, 12-week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessments at 6-8 weeks are required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time.

Switching from bipolar depression to mania or hypomania is the particular risk that requires a different approach to treatment from unipolar depression.

Long-term treatment

Long-term treatment is commonly required in bipolar disorder. Thus, trials to detect maintenance of effect or continued response in bipolar depression should follow a relapse prevention design: i.e. patients are treated in an episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. Thus, long periods of mood stabilization for up to 3 months may appear desirable, but protocol compliance may then be difficult to achieve in practice and certainly will make studies more difficult and expensive to conduct.

The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse also is clinically informative. Finally, besides the traditional measures of outcome based on symptom severity rating scales, it would be advisable to include measures addressing functionality such as neuropsychological tests of attention, memory and executive function, and quality of life.

Long term prevention of relapse is the major challenge in bipolar disorder. Success requires a mature therapeutic alliance between doctor and patient, effective self-management by the patients and their families and effective well tolerated treatments.

Conference Paper: Goodwin GM, Anderson I, Arango C, et al. ECNP consensus meeting. Bipolar depression. Nice, March 2007. European Neuropsychopharmacology 2008;18:535-549 –

The full paper of the ECNP Consensus document on bipolar depression is available through the ECNP website: http://www.ecnp.eu

References

• Pini S, de Queiroz V, Pagnin D, et al. Prevalence and burden of bipolar disorders in European countries. European Neuropsychopharmacology 2005;15:425-434
• Berk M, Hallam K, Lucas N, et al. Health-related quality of life and functioning in bipolar disorder: the impact of pharmacotherapy. Expert Rev Pharmacoeconomics Outcomes Res 2006;6:509-523
• Wittchen HU, Mhlig S, Pezawas L. Natural course and burden of bipolar disorders. Int J Neuropsychopharmacol 2003;6:145-154

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.

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.

Psychiatry has begun the laborious effort of preparing the DSM-V, the new iteration of its diagnostic manual. In so doing, it once again wrestles with the task set by Carl Linnaeus, to "cleave nature at its joints." However, these "joints," the boundaries between psychiatric disorders, such as that between bipolar disorder and schizophrenia, are far from clear.

Prior versions of DSM followed the path outlined by Emil Kraeplin in separating these disorders into distinct categories. Yet, we now know that symptoms of bipolar disorder may be seen in patients with schizophrenia and the reverse is true, as well.

Further, our certainty about the boundary of these disorders is undermined by growing evidence that both schizophrenia and bipolar disorder emerge, in part, from the cumulative impact of a large number of risk genes, each of which conveys a relatively small component of the vulnerability to these disorders. And since many versions of these genes appear to contribute vulnerability to both disorders, the study of common gene variations has raised the possibility that there may be diagnostic, prognostic, and therapeutic meaning embedded in the high degree of variability in the clinical presentations of patients with each disorder.

In addition, many symptoms of schizophrenia and bipolar disorder are traits that are present in the healthy population but are more exaggerated in patient populations. To borrow from Einstein, who struggled to reconcile the wave and particle features of light, our psychiatric diagnoses behave like waves (i.e., spectra of clinical presentations) and particles (traditional categorical diagnoses). Although new genetic approaches may revise our current thinking, such as studies of microdeletions, microinsertions, and microtranslocations of the genome, the wave/particle approach to psychiatric diagnosis places a premium on understanding the "real" clustering of patients into subtypes as opposed to groups created to correspond to the current DSM-IV.

Latent class analysis is one statistical approach for estimating the clustering of subjects into groups. In their study of 270 Irish families, published in the July 15th issue of Biological Psychiatry, Fanous and colleagues conducted this type of analysis, with subjects clustered into the following groups: bipolar, schizoaffective, mania, schizomania, deficit syndrome, and core schizophrenia. When they divided the affected individuals in the study using this approach, they found four regions of the chromosome that were linked to the risk for these syndromes that were not implicated when subjects were categorized according to DSM-IV diagnoses. Dr. Fanous notes that this finding "suggests that schizophrenia as we currently define it may in fact represent more than one genetic subtype, or disease process."

According to John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System: "Their findings advance the hypothesis that the variability in the clinical presentation of patients diagnosed using DSM-IV categories is meaningful, providing information that may be useful as DSM-V is prepared. However, we do not yet know whether the categories generated by this latent class analysis will generalize to other populations." This paper highlights an important aspect of the complexity of establishing valid psychiatric diagnoses using a framework adopted from traditional categorical models.

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Journal Reference:

1. Fanous et al. Novel Linkage to Chromosome 20p Using Latent Classes of Psychotic Illness in 270 Irish High-Density Families. Biological Psychiatry, 2008; 64 (2): 121 DOI: 10.1016/j.biopsych.2007.11.023

A research abstract that will be presented on June 12 at SLEEP 2008, the 22nd Annual Meeting of the Associated Professional Sleep Societies (APSS), finds a link between poor sleep and suicidal behavior among children and adolescents with depressive episodes.

The study, authored by Maria-Cecilia Lopes, MD, PhD, of Sao Paulo University in Brazil, focused on 303 individuals with pediatric bipolar disorder and pediatric unipolar disorder during depressive episodes. The presence of sleep complaints and suicidal behavior were detected by face-to-face interviews during depressive episodes.

According to the results, 83.8 percent of the patients had sleep disturbances. Poor sleep was more frequent among those with pediatric bipolar disorder and pediatric unipolar disorder, and this was clearly detected by the presence of initial insomnia and sleep maintenance insomnia. Surprisingly, there was a significant association between suicidal behavior and the presence of sleep complaints in both groups. The proportion of subjects who reported suicidal behaviors with sleep complaints was higher among bipolar than unipolar patients.

"There is a strong association between depression and sleep deprivation. The suicidal behavior associated with depression has been described as a public health problem and that the full implication might not be scientifically addressed in relation to children and adolescents to the depth that it should be. Moreover, the suicidal behavior in adults can start in childhood and it should be recognized early," said Dr. Lopes.

The presence of sleep complaints during depressive episodes in pediatric bipolar and unipolar disorders must lead to a search for suicidal behavior, said Dr. Lopes, adding that there are clinical neurobiological issues about these findings that need to be clarified.

"In my opinion, these differences show that sleep complaints between both groups can help the diagnosis processes, and that a follow-up of the pediatric population with their depressive episodes should be adhered to," noted Dr. Lopes.

It is recommended that adolescents get nine hours of nightly sleep and school-aged children between 10-11 hours.

The American Academy of Sleep Medicine (AASM) offers the following tips to adolescents on how to get a good night's sleep:

• Follow a consistent bedtime routine.
• Establish a relaxing setting at bedtime.
• Get a full night's sleep every night.
• Avoid foods or drinks that contain caffeine, as well as any medicine that has a stimulant, prior to bedtime.
• Do not stay up all hours of the night to "cram" for an exam, do homework, etc. If after-school activities are proving to be too time-consuming, consider cutting back on these activities.
• Keep computers and TVs out of the bedroom.
• Do not go to bed hungry, but don't eat a big meal before bedtime either.
• Avoid any rigorous exercise within six hours of your bedtime.
• Make your bedroom quiet, dark and a little bit cool.
• Get up at the same time every morning.