Patients with broadly defined bipolar schizoaffective features either have a strong genetic contribution to their condition or are genetically homogenous compared with other bipolar groups, conclude UK researchers.

While the descriptive criteria currently used to define psychiatric phenotypes have acceptable reliability, the phenotypes themselves are not necessarily valid clinical entities, which may have an impact on the basis for clinical practice.

To examine the relative genetic support for different descriptive diagnostic categories, Nick Craddock, from Cardiff University, and colleagues examined genome-wide genetic association data on 1868 bipolar disorder patients and 2938 controls from the Wellcome Trust Case Control Consortium study.

The patients consisted of 1316 with bipolar I disorder, 279 with schizoaffective disorder bipolar type, 171 with bipolar II disorder, and 102 with manic disorder using the Research Diagnostic Criteria (RDC), and 1594 with bipolar I disorder, 98 with schizoaffective disorder bipolar type, 134 with bipolar II disorder, and 42 with bipolar disorder not otherwise specified using the DSM-IV criteria.

Using stringent quality filters, the researchers selected 276,122 singe nucleotide polymorphisms (SNPs) for analysis, determining association with bipolar disorder group versus controls, with the number of significantly associated independent SNPs used as a metric for the overall genetic signal.

The results demonstrated that, compared with controls, the category RDC schizoaffective disorder bipolar type had significantly more associated independent SNPs than the other categories, at nine hits versus ?5 hits.

Assessing the independent SNPs for the number of nearby SNPs in linkage disequilibrium with the index SNP, the team found an additional SNP on chromosome 16p13.3 (rs4786811) that had an acceptable clusterplot and a closely correlated SNP. Genes with ?1 associated SNP included B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTRG, GIRK2, and CDH12.

“Strong consideration is currently being given to abolishing the schizoaffective concept and category from the revisions of the official psychiatric diagnostic classifications,” the team writes in the British Journal of Psychiatry.

“This is unlikely to be unhelpful to the progress of psychiatric knowledge, given that it is emerging as a diagnostic entity that receives strong research support. We hope that psychiatry is moving towards the time when our patients can benefit from diagnostic concepts that are built on solid foundations of empirical biological evidence rather than being perched precariously on the shifting sands of expert opinion.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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The offspring of bipolar disorder patients have an increased risk for anxiety, sleep, mood, and substance use disorders, which, in turn, places them at an increased risk for bipolar disorder, say Canadian scientists.

A broad range of symptoms and disorders from across the spectrum of psychiatric problems have been diagnosed in bipolar offspring. It has not been established, however, whether or not there is a predictable clinical sequence from non-specific, non-mood psychopathology to specific, mood psychopathology in offspring.

Anne Duffy, from Dalhousie University in Halifax, Nova Scotia, and colleagues therefore studied 207 offspring with one bipolar disorder parent (high risk individuals) and 87 offspring with two parents who did not have a major psychiatric disorder (controls).

The participants were assessed annually or at any time that symptoms developed for up to 15 years using the Schedule for Affective Disorders and Schizophrenia for School-Age Children ??” Present and Lifetime Version (KSADS-PL).

All available clinical material were reviewed to make blind DSM-IV diagnoses, and the age-adjusted risks for lifetime psychopathology were compared between high-risk and control participants.

The results show that high-risk participants had, compared with control individuals, significantly higher age-adjusted rates of major mood, anxiety, sleep, and substance use disorders, at 52.8% versus 1.3%, 23.2% versus 7.8%, 18.0% versus 0.0%, and 25.7% versus 1.6%, respectively.

However, there were no significant differences in the prevalence of minor mood disorders and attention deficit/hyperactivity disorder and/or learning disabilities, the team notes in the Journal of Affective Disorders.

Cox proportional hazards analysis revealed that the presence of an anxiety disorder increased the risk for a major mood disorder among high-risk individuals, from 40% to 85%, at an odd ratio of 2.60. In all patients with both an anxiety and mood disorder, the anxiety disorder preceded the onset of the index major mood episode by an average of 8 years.

The presence of a substance use disorder increased the risk for a major mood disorder, at a hazard ratio of 2.12. In addition, the presence of major mood disorder significantly increased the risk for substance use disorder from 18% to 35%, at a hazard ratio of 2.4.

The proposed sequence of non-mood to minor mood/adjustment to major depression to hypomania/mania was occurred in 71% of 21 participants who met a lifetime diagnostic criteria of bipolar disorder, while 90% showed a progression from non-mood to minor mood/adjustment disorders to major mood disorders.

Noting that the findings could help to explain illness progression to bipolar disorder, the team concludes: “For now, it is clear that we need to incorporate the family history and the nature of the longitudinal course in diagnostic assessments of young patients manifesting psychiatric symptoms in order to put these relatively non-specific early presentations in a clinically meaningful context.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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Attitudes toward medication among bipolar disorder patients, as revealed by the Necessity-Concerns Framework, have a significant impact on adherence, UK researchers have discovered.

Medication non-adherence in bipolar disorder is a common and costly problem that is associated with poor clinical outcomes. While treatment studies have suggested that the adverse effect profile of medications is the main cause of non-adherence, this is unlikely to be the primary factor, as rates have not changed since the 1950s.

To investigate further, Rob Horne, from the University of London, and colleagues administered the Medication Adherence Report Scale (MARS) and the Beliefs About Medication Questionnaire to 2223 patients prescribed bipolar disorder medication recruited via an advert in a bipolar disorder newsletter.

The average age of the patients was 48 years, the average duration of illness was 14.0 years, and 90% had been hospitalized at least once. MARS scores revealed that 30.2% of the patients were low adherers, while Beck Depression Inventory and Altman Self-Rating Mania Scale scores were 14.4 and 3.8, respectively, suggesting the presence of moderate sub-syndromal symptoms.

The median number of medications prescribed per patient was three, with the most commonly prescribed being lithium (52%), anticonvulsant mood stabilizers (45%), antidepressants (41%), and atypical antipsychotics (40%), the team reports in the Journal of Affective Disorders.

The Necessity-Concerns Framework revealed that low adherers had, compared with high adherers, a significantly lower perceived need for treatment and greater concerns about treatment.

This was confirmed on logistic regression analysis, which showed that, after controlling for current mood state, illness, and demographic characteristics, low adherence was associated with both greater concerns about treatment and a lower perceived need for treatment, at odds ratios of 2.00 and 0.50, respectively.

While noting the limitations of the study, the team writes: “Prescribing is unlikely to be associated with adherence unless it incorporates a process of eliciting and responding to individuals’ personal beliefs about the treatment.

“The potential importance of the Necessity-Concerns Framework is that it could provide clinicians in day-to-day practice with a meaningful and readily applicable approach to identifying common barriers to adherence with proposed treatment and offers a template for them to make targeted interventions.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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A multi-national group of investigators, including a scientist at the University of North Carolina at Chapel Hill, has discovered that nearly a third of the genetic basis of schizophrenia may be attributed to the cumulative actions of thousands of common genetic variants. The effects of each of these genetic changes, innocuous on its own, add up to a significant risk for developing both schizophrenia and bipolar disorder.

The finding, published online July 1, 2009, in the journal Nature, suggests that schizophrenia is much more complex than previously thought, and can arise not only from both rare genetic variants but also from a significant number of common ones.

“This is an enormous first for our field,” said co-author Patrick Sullivan, M.D., Ray M. Hayworth and Family Distinguished Professor of Psychiatry in the department of genetics at the UNC School of Medicine. “You could say that we now have the outline of the puzzle, and we just need to take all of these pieces that we have identified and see how they fit them together.”

Schizophrenia is a chronic and often devastating mental illness that affects one person in every 100 in the course of their lives. Scientists have long recognized that the disease which can run in families — has a strong genetic component. However, only recently have they begun to pinpoint the exact spots in our genetic material that contribute to the illness. Last year, the International Schizophrenia Consortium found that rare chromosomal structural variants elevate the risk of developing schizophrenia.

In this study, Sullivan and other investigators in the Consortium used “genechip” technology to identify 30,000 genetic variants (single nucleotide polymorphisms or “SNPs”) that were more common in 3,000 individuals with schizophrenia than in 3,000 comparison subjects without schizophrenia. This pattern was found in three separate samples of individuals with schizophrenia and two samples with bipolar disorder indicating a previously unrecognized overlap between the two diseases. These risk variants were not present in patients with other non-psychiatric diseases, such as hypertension or diabetes.

“While our study finds a surprising number of genetic effects, we fully expect that future work will assemble them into meaningful pathways that will teach us about the biology of schizophrenia and bipolar disorder,” says senior author Pamela Sklar, MD, PhD, associate director of the Department of Psychiatry and Center for Human Genetic Research at Massachusetts General Hospital (MGH) and a senior associate member of the Broad Institute of MIT and Harvard.

The researchers are also investigating how genes and environment interact to cause the disease. One additional finding of their study was the identification of the human leukocyte antigen (HLA) locus as a possible risk factor. Because this region plays an important role in immune response to infection, it could suggest that exposure to an infectious agent increases risk of developing psychiatric disease.

Funding for the studies led at UNC came from the National Institutes of Mental Health, the Sylvan C. Herman Foundation and the Stanley Medical Research Institute.

In addition to those from UNC, the consortium includes investigators from the University of Aberdeen, Cardiff University, University of Edinburgh, Karolinska Institutet, Massachusetts General Hospital, the Queensland Institute of Medical Research, University of Southern California, Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT, Trinity College Dublin and University College London.

Source: University of North Carolina

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A trio of genome-wide studies - collectively the largest to date - has pinpointed a vast array of genetic variation that cumulatively may account for at least one third of the genetic risk for schizophrenia. One of the studies traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods.

“These new results recommend a fresh look at our diagnostic categories,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. “If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development.”

Three schizophrenia genetics research consortia, each funded in part by NIMH, report separately on their genome-wide association studies online July 1, 2009, in the journal Nature. However, the SGENE, International Schizophrenia (ISC) and Molecular Genetics of Schizophrenia (MGS) consortia shared their results - making possible meta-analyses of a combined sample totaling 8,014 cases and 19,090 controls.

All three studies implicate an area of Chromosome 6 (6p22.1), which is known to harbor genes involved in immunity and controlling how and when genes turn on and off. This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness.

“Our study was unique in employing a new way of detecting the molecular signatures of genetic variations with very small effects on potential schizophrenia risk,” explained Pamela Sklar, M.D., Ph.D., of Harvard University and the Stanley Center for Psychiatric Research, who co-led the ISC team with Harvard’s Shaun Purcell, Ph.D.

“Individually, these common variants’ effects do not all rise to statistical significance, but cumulatively they play a major role, accounting for at least one third - and probably much more - of disease risk,” said Purcell.

Among sites showing the strongest associations with schizophrenia was a suspect area on Chromosome 22 and more than 450 variations in the suspect area on Chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes, say the researchers.

“There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders,” added Sklar. “We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders.”

Still, most of the genetic contribution to schizophrenia, which is estimated to be at least 70 percent heritable, remains unknown.

“Until this discovery, we could explain just a few percent of this contribution; now we have more than 30 percent accounted for,” said Thomas Lehner, Ph.D., MPH, chief of NIMH’s Genomics Research Branch. “The new findings tell us that many of these secrets have been hidden in complex neural networks, providing hints about where to look for the still elusive - and substantial - remaining genetic contribution.”

The MGS consortium pinpointed an association between schizophrenia and genes in the Chromosome 6 region that code for cellular components that control when genes turn on and off. For example, one of the strongest associations was seen in the vicinity of genes for proteins called histones that slap a molecular clamp on a gene’s turning on in response to the environment. Genetically rooted variation in the functioning of such regulatory mechanisms could help to explain the environmental component repeatedly implicated in schizophrenia risk.

The MGS study also found an association between schizophrenia and a genetic variation on Chromosome 1 (1p22.1) which has been implicated in multiple sclerosis, an autoimmune disorder.

“Our study results spotlight the importance not only of genes, but also the little-known DNA sequences between genes that control their expression,” said Pablo Gejman, M.D., of the NorthShore University HealthSystem Research Institute, of Evanston, ILL, who led the MGS consortium team. “Advances in biotechnology, statistics, population genetics, and psychiatry, in combination with the ability to recruit large samples, made the new findings possible.”

The SGENE consortium study pinpointed a site of variation in the suspect Chromosome 6 region that could implicate processes related to immunity and infection. It also found significant evidence of association with variation on Chromosomes 11 and 18 that could help account for the thinking and memory deficits of schizophrenia.

The new findings could eventually lead to multi-gene signatures or biomarkers for severe mental disorders. As more is learned about the implicated gene pathways, it may be possible to sort out what’s shared by, or unique to, schizophrenia and bipolar disorder, the researchers say.

References:
Jianxin S, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. July 1, 2009, Nature


Stefansson H, et al. Common variants conferring risk of schizophrenia. July 1, 2009, Nature


Purcell SM, et al. Common polygenic variation contributes to risk of schizophrenia that overlaps with bipolar disorder. July 1, 2009, Nature

Source:
Jules Asher

NIH/National Institute of Mental Health

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US researchers have found thyroid function is inhibited in bipolar I disorder patients taking maintenance lithium monotherapy, which may exacerbate the illness, particularly in the depressive pole.

It is known that lithium can impair thyroid function, but the potential relationship between the induced thyroid changes and prospective mood changes has not been extensively studied.

To investigate, Mark Frye (Mayo Clinic, Rochester, Minnesota) and co-authors pooled data from two 18-month maintenance studies of lamotrigine and lithium monotherapy. The post hoc analysis included 109 bipolar I patients with normal thyroid-stimulating hormone (TSH) levels at baseline who received lamotrigine (n=55), lithium (n=32), or placebo (n=22) monotherapy for a mean period of 52 weeks.

The researchers found that by week 52, patients treated with lithium had a statistically significant increase in mean TSH levels from baseline (+1.0 µIU/ml) compared with those treated with lamotrigine (-0.2 µIU/ml) or placebo (+0.1 µIU/ml). Additionally, three patients taking lithium developed above normal TSH levels by week 52 (8.4, 6.5, and 7.8 µIU/ml).

“This finding is consistent with the possibility that llithium-associated inhibition of thyroid function might have contributed to the development of depressive symptoms. If so, then the results suggest that reduction in thyroid function can exacerbate bipolar symptoms even in euthyroid patients,” write Frye et al in the journal Acta Psychiatrica Scandinavica.

Furthermore, lithium-treated patients who required an intervention for a depressive episode had significantly higher TSH levels compared with those who did not need intervention (4.4 vs 2.4 µIU/ml). This significant difference was not seen in other groups or in the manic episode.

The authors suggest that this may indicate that bipolar depressive symptoms may be influenced by reductions in thyroid function that are captured as values within the normal range (0.3??”5.0 µIU/ml).

However, the team cautions that TSH at screening is not as accurate an assessment as levels at time of randomization due to the possibility of TSH changes prior to analysis.

“Studies prospectively designed to assess thyroid function and its association with subsyndromal and syndromal mood symptoms in patients receiving maintenance therapy for bipolar disorder should be considered,” they conclude.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract

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People with bipolar disorder commonly exhibit functional impairment despite being euthymic and clinically “in remission”, say the authors of a new study.

The team believes that a number of clinical factors can predict functional impairment in bipolar disorder, such as previous mixed mood episodes, current subclinical depression, previous hospitalization, and older age.

Eduard Vieta (University of Barcelona, Spain) and coworkers studied 71 patients with a diagnosis of bipolar disorder but currently defined as euthymic (scoring ?8 on the 17-item Hamilton Depression Rating Scale) and 61 healthy controls.

All subjects underwent a battery of tests including the Functioning Assessment Short Test (FAST), which assesses autonomy, occupational functioning, cognition, relationships, financial issues, and leisure time.

In all, 60% of the bipolar patients were considered to be functionally impaired (based on a FAST score >11) compared with just 13.1% of controls. In multivariate analysis, four variables ??” older age, depressive symptoms, previous mixed episodes, and previous hospitalizations ??” were significantly associated with impaired functioning.

Together, these four factors accounted for 44% of the variance in global functioning, Vieta’s team calculated.

Writing in Bipolar Disorders journal, the researchers say their study supports the hypothesis that more severe forms of bipolar disorder have long-term adverse consequences, notably cognitive and functional impairment, that are apparent in-between acute episodes.

“Psychosocial interventions in combination with pharmacotherapy should be considered to treat residual depressive symptoms and enhance the level of functioning,” write Vieta et al.

“In addition, low rates of functional recovery as shown here underscore the importance of including specific functioning measures as well as symptomatic assessments in the comprehensive evaluation of bipolar disorder.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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• Brain activity determines risk or resilience in bipolar disorder