Study results show that bipolar disorder (BD) patients in a manic state have increased levels of proinflammatory cytokines, which seem to be related to mood state.

“This study provides further support to investigate the immune system as a target for further treatment development,” say Flávio Kapczinski (Hospital de Clinicas de Porto Alegre, UFRGS, Brazil) and co-authors.

Previous studies have suggested that an association of mania and bipolar depression with a proinflammatory state. However, such studies have not compared cytokine levels in all phases of BD.

The researchers therefore compared cytokine levels examined by flow cytometry involved in th1/Th2 balance, such as tumor necrosis factor-?, interleukin (IL)-2, IL-4, IL-6, IL-10, and intereferon (IFN)-?, in 61 medicated patients with bipolar I disorder and 25 healthy individuals. Of the patients, 14 were in euthymic state, 23 in manic, and 24 in depressive episodes.

Kapczinski and team found that only IL-4 levels were increased in euthymic patients compared with healthy controls who showed no median increase in any of the cytokines measured (2.10 vs 0.00 pg/ml, respectively).

The authors say that this finding should be interpreted with caution as there was no control of the time of euthymia to inclusion in the study.

Manic patients had increased levels of IL-2 (3.20 pg/ml), IL-4 (1.90 pg/ml), and IL-6 (3.30 pg/ml) compared with controls. Patients in a depressive episode showed only increased IL-6 (2.20 pg/ml) levels relative to those seen in healthy individuals.

“Demonstration of similar levels of the majority of proinflammatory cytokines between euthymic bipolar patients and control individuals could be an indication that inflammatory changes may probably be associated with acute mood episodes, especially acute mania,” says the team.

Mood symptoms were positively correlated with IL-6 and IL-2 levels, as were manic symptoms indicated by the Young Mania Rating Scale. Depressive symptoms, as indicated by the Hamilton Depression Rating Scale, were positively correlated only with IL-6.

“Studies comparing cytokine levels in medicated versus unmedicated BD patients, and also before and after pharmacological treatment are warranted,” conclude the researchers.

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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Variations in the D-amino acid oxidase activator gene (DAOA) are linked to the development of bipolar disorder and schizophrenia, although they account for only a part of genetic susceptibility, UK study findings suggest.

Previous studies have associated the DAOA/G30 locus or the neighboring region of chromosome 13q33.2 with both bipolar disorder and schizophrenia, while four single nucleotide polymorphisms (SNPs) at 12q24.11 have been linked to schizophrenia. However, the results have been conflicting.

Hugh Gurling, from University College London, and colleagues therefore genotyped 431 schizophrenia patients, 303 bipolar disorder patients, and 442 ancestrally matched controls with no history of mental disorder.

All participants were genotyped for 11 SNPs at the DAOA locus, with schizophrenia patients and controls also genotyped for three SNPs at the D-amino acid oxidase gene (DAO) locus on chromosome 12.

The results, published in the journal Behavioral and Brain Functions, reveal that the SNP rs3918342 (M23) at the DAOA locus was significantly associated with schizophrenia, bipolar disorder, and both conditions combined.

There was a trend toward association with schizophrenia for the SNPs rs3916967 (M14) and rs1421292 (M24), with the latter also marginally significantly associated with both conditions combined.

The team also found that there was a haplotypic association with schizophrenia for the markers rs778293 (M22), rs3918342 (M23), and rs1421292 (M42), with alleles G, T, A increasing the risk for schizophrenia at an estimated frequency of 1.8% in controls and 3.6% in patients. None of the three DOA SNPs were associated with schizophrenia.

The team concludes: “Our findings point to a role for DAOA in both schizophrenia and bipolar disorder. However, it is evident that this locus can account for only a small proportion of genetic susceptibility to these disorders.”

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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Criminal behavior and violent crimes among patients with affective disorder are associated with more than just overall diagnosis, say German scientists who found a range of factors linked to such behavior.

There has been a great deal of research into criminal and violent behavior in schizophrenia patients. In contrast, there have been few studies of violent and criminal behavior in individuals with affective disorders, and those that have been conducted have, in the main, not differentiated between bipolar disorder, mania, and depression.

To investigate further, Michael Soyka, from Ludwig-Maximilian-University in Munich, and colleagues examined data from the German national crime register of criminal offenses for nonviolent and violent behavior committed by 1561 affective disorder patients, of whom 756 had bipolar disorder, 89 manic disorder, and 702 major depressive disorder (MDD).

The average age of the patients was 53.26 years. In all, 2.1% were single, 47.9% were married or living with a partner, 18.8% were separated or divorced, and 11.2% were widowed. The average hospital stay was 64.39 days. Lack of insight at discharge was observed in just 1.4% of patients. In addition, 21.1% of patients reported a history of substance use problems.

Overall, 95.8% of patients had no conviction after discharge, at 84.3% of manic disorder patients, 97.8% of bipolar disorder patients, and 95.3% of MDD patients, the team notes in the Journal of Affective Disorders. Sixty five patients committed criminal acts, at an average of 4.72 per patient. Defalcation, theft, and fraud were the most common crimes, while physical assault was the most common violent behavior. There was one murder.

Among patients who committed criminal and violent behavior, men were substantially more likely to commit both criminal and violent behavior after discharge than women, at 64.6% versus 35.4% and 85.7% versus 14.3%, respectively. The gender differences were even greater among manic patients (78.6% vs 21.4% and 100.0% vs 0.0%, respectively) and among those with MDD (60.6% vs 39.4% and 90.0% vs 10.0%, respectively).

Separated, divorced, and widowed patients committed offenses more frequently than other individuals. There was no association with age, educational status, length of hospital stay, lack of insight at diagnosis, or history of substance abuse.

The team concludes: “The findings of this study may stimulate further research to identify social and psychopathological predictors for future violent and criminal behavior.”

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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Using diffusion tensor imaging (DTI), researchers have found evidence of microstructural white matter modifications in euthymic bipolar patients suggestive of increases in white matter axonal organization.

Bipolar disorder has been associated with macrostructural white matter abnormalities, observed as changes in fractional anisotropy (FA) and mean diffusivity (MD) when measuring the integrity of white matter tracts using DTI.

Michèle Wessa (Central Institute of Mental Health, Mannheim, Germany) and colleagues say that, so far, DTI studies in bipolar patients have focused on frontal/prefrontal brain regions only.

To investigate further, the researchers performed DTI with diffusion gradients applied along 41 directions in 22 bipolar I and II disorder patients in remission, with no lifetime or present comorbidities of substance abuse, and 21 gender- and age-matched healthy controls with no history of mental illness.

The study showed an increase of functional anisotropy (FA) in medial frontal, precentral, inferior parietal, and occipital cortical areas in euthymic bipolar patients compared with healthy individuals, with no changes in mean diffusivity seen between the groups.

FA and MD did not correlatie with duration of illness or number of episodes, andpatients did not differ in FA measurements with respect to medication type.

The researchers say that an increase in FA without modification in MD most likely reflects an “increase in the directional coherence and thus axonal organization of the [white matter] fibers rather than increases in axonal myelination,” as FA is rendered an estimate of white matter bundle integrity.

However, previous DTI studies have reported decreased FA in bipolar patients in prefrontal, callosal, and occipital white matter. Wessa and team suggest that this discrepancy may be the result of previous studies using patients in various mood states and with a previous history of subst

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Bipolar disorder patients do not have accelerated prefrontal gyrification index (GI) loss, but having at least one brain-derived neurotrophic factor (BDNF) gene variant may increase loss, UK scientists have found.

Brain structural abnormalities, including temporal lobe and prefrontal cortex volume reductions, have been identified in bipolar disorder patients. However, it is not clear whether the abnormalities are present at disease onset or whether they develop over time.

Noting that the BDNF valine (val)⁶⁶methionine (met) variant has been linked to such brain changes, Ajay Mirakur and colleagues from the University of Edinburgh performed magnetic resonance imaging (MRI) at baseline and after 4 years in 18 bipolar I disorder patients and 18 healthy controls.

The GI was calculated as the ratio of folded inner contour to exposed outer contour. In addition, the participants underwent clinical assessment and were genotyped for BDNF val⁶⁶met.

Both bipolar disorder patients and healthy controls were found to have a significant decrease in GI over 4 years in all prefrontal quadrants, and there was no significant difference in the rate of change of GI between patients and controls.

Comparing bipolar disorder patients with and without at least one BDNF val⁶⁶met met allele, the team discovered that having at least one met allele was associated with a significantly increased change in GI over 4 years in all four prefrontal quadrants, but particularly in the right dorsal prefrontal cortex.

Carriers of a met allele were significantly older than val/val homozygotes, at 43.9 years versus 35.1 years. When taking age into account, there was a trend toward a significant difference in change in GI between met carriers and val/val homozygotes in the ventral quadrants, and a significant difference in dorsal quadrants.

The researchers conclude in the journal Biological Psychiatry: “We show that GI decreases significantly over time and that the rate of change in GI is not different in bipolar patients compared with control subjects but is accelerated in bipolar participants possessing at least one BDNF allele.

“These findings suggest that GI is not purely a neurodevelopmental measure and raise the possibility that GI may be a sensitive measure of morphological change with time.”

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 pathological process of bipolar disorder and schizophrenia may be due, in part, to oxidative damage, say Canadian researchers in findings that may point to novel treatment approaches.

There is increasing evidence to suggest that mitochondrial dysfunction is present in the brains of bipolar disorder patients. Furthermore, the mitochondrial electron transport chain is a major source of reactive oxygen species, which cause oxidative stress.

To examine associations between bipolar disorder and oxidative stress, Jun-Feng Wang and colleagues from the University of British Columbia in Vancouver studied postmortem anterior cingulate brain sections from 15 bipolar disorder patients, 15 major depressive disorder (MDD), patients, 15 schizophrenia patients, and 15 controls matched for age, gender, postmortem interval (PMI), pH, and messenger RNA quality.

As a surrogate for oxidative stress, levels of 4-hydroxynonenal (4-HNE), which s a major product of lipid peroxidation, were determined via immunohistochemical analysis of 4-HNE protein adducts.

Compared with controls, 4-HNE levels were significantly increased in bipolar disorder and schizophrenia patients by 59% and 47%, respectively. Although levels were 33% higher in MDD patients than in controls, the difference was not significant.

Studying medication-free patients only, the team found that 4-HNE levels were increased significantly compared with controls in both bipolar disorder and schizophrenia patients, at 94% and 72%, respectively, with no change recorded in MDD patients.

Four-HNE levels were unaffected by age, gender, and PMI. In all brain samples, 4-HNE levels were negatively correlated with pH, the team says in the journal Bipolar Disorders.

However, 4-HNE levels were still significantly increased in bipolar disorder patients and there was a trend for an increase in schizophrenia patients when pH was used as a covariate. In addition, 4-HNE levels were negatively correlated with pH only in bipolar disorder patients.

“Oxidative damage in the brain may contribute to the pathological process of bipolar disorder and schizophrenia, and anti-oxidative stress may well serve as an alternative approach to pharmacological treatment of these psychiatric disorders, the researchers 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

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A new study from Thomson Reuters found that patients with bipolar disorder were at greater risk for a wide range of medical conditions than a control group of patients with no mental health diagnoses.

The study analyzed de-identified insurance claims for more than 600,000 Americans with employer-sponsored insurance. It is available here and an interactive graphic charting bipolar patients’ risk of comorbid disorders is available here. Key findings include the following:

– Trauma or Adverse Reactions to Treatment: Patients diagnosed with bipolar disorder were 3.13 times more likely than the control group to have a trauma or adverse reaction to treatment. Approximately 7 percent of bipolar cases had at least one such episode in the two-year study period.

– Neurological Episodes: Neurological conditions — such as headaches and spinal cord injuries — occurred 2.27 times more frequently among bipolar patients. Approximately one-fourth of all enrollees with a bipolar episode also had at least one episode involving the neurological system.

– Female Reproduction: Conditions involving the female reproductive system — such as dysfunctional uterine bleeding and breast cancer — were 25 percent more common among bipolar patients.

The study is based on data contained in the 2006-2007 MarketScan(R) Commercial Claims and Encounters Database. The Thomson Reuters Medical Episode Grouper was used to group each enrollee’s claims into distinct episodes of care based on the disease for which treatment was received.

“Medication use and behavioral characteristics are known to increase the risk of disease among bipolar patients, but much is still unknown about the reasons for increased rates of comorbidities among this population and ways to reduce them,” said William D. Marder, Ph.D., senior vice president and general manager for the Healthcare & Science business of Thomson Reuters and one of the study’s authors. “Our analysis underscores the urgent need for further exploration of how to best increase providers’ capacity to address, monitor and ultimately improve the psychiatric and physical health of their bipolar patients.”

About Thomson Reuters

Thomson Reuters is the world’s leading source of intelligent information for businesses and professionals. We combine industry expertise with innovative technology to deliver critical information to leading decision makers in the financial, legal, tax and accounting, scientific, healthcare and media markets, powered by the world’s most trusted news organization. With headquarters in New York and major operations in London and Eagan, Minnesota, Thomson Reuters employs more than 50,000 people in 93 countries

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The Stanford University School of Medicine will host its fifth annual Bipolar Education Day on July 25. Individuals with bipolar disorder, their families, caregivers, friends and interested community members are invited to attend.

The free event will be held at the William R. Hewlett Teaching Center at 370 Serra St., located on the main campus.

More than 5.7 million Americans have bipolar disorder, a psychiatric illness that causes unusually intense shifts in mood, energy and behavior. Bipolar Education Day gives scientists and clinicians an opportunity to discuss the previous year’s research findings with individuals and families affected by the disorder.

This year’s speakers include Terence Ketter, MD, professor of psychiatry and behavioral sciences and chief of Stanford’s Bipolar Disorders Clinic; Po Wang, MD, and Jenifer Culver, PhD, from the Stanford Bipolar Disorders Clinic; Manpreet Singh, MD, from the Stanford Pediatric Bipolar Disorders Program; and representatives from the National Alliance on Mental Illness and the Depression and Bipolar Support Alliance. Speakers will discuss treatment options that can help patients manage their symptoms. An afternoon question-and-answer session will follow the talks.

“I’m looking forward to a chance to share some of the latest advances in research at this year’s Education Day,” said Ketter.

The program runs from 8:30 a.m. to 2:30 p.m. and includes complimentary morning beverages and an afternoon snack. Pre-registration is required. For more information or to register, please visit http://www.bipolar.org or contact Meredith Childers at mchilder@stanford.edu.

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A shortened version of integrated group therapy is an effective treatment for bipolar disorder patients with substance dependence, with better outcomes than group drug counseling, US study findings indicate.

While previous studies have demonstrated that integrated group therapy reduces substance use in bipolar disorder patients, its adoption in community treatment programs may be limited by the need for 20 sessions and highly trained therapists.

To determine the benefits of a shorter version of the therapy led by substance use disorder counselors without previous cognitive-behavioral training (CBT) or bipolar disorder experience, Roger Weiss (Harvard Medical School, Boston, Massachusetts) and colleagues randomly assigned 61 bipolar disorder patients with substance dependence treated with mood stabilizers to 12 sessions of integrated group therapy or group drug counseling.

Both drug and alcohol dependence was recorded in 65.6% of patients. Alcohol dependence only was identified in 26.2% and drug dependence only in 8.2%. The most commonly used drugs were cocaine and marijuana.

Integrated group therapy decreased the days of substance use from baseline marginally significantly more than drug counseling, at an additional 2.7 days by the end of treatment and 2.9 days by the end of follow-up.

Patients assigned to integrated group therapy were significantly more likely to achieve ?1 month total abstinence during treatment and throughout all 3 months of treatment than those assigned to group drug counseling, at 71.0% versus 40.0% and 35.5% versus 13.3%, respectively. They also had a significantly shorter time to the first abstinent month, at a hazard ratio of 2.02.

Furthermore, the risk for a mood episode decreased significantly more with integrated group therapy than with group drug counseling, at an 82% versus 67% relative reduction by the end of treatment, with the risk for both depression and mania episodes significantly reduced.

The composite measure of good clinical outcome for both substance use and mood favored integrated group therapy at the end of treatment, as 45.2% of patients on integrated group therapy achieved abstinence and no weeks ill with a mood episode in the final month of treatment compared with 20% of patients participating in drug counseling.

“It is noteworthy that integrated group therapy can be delivered with a high degree of fidelity and competence by substance use disorder counselors without previous CBT experience or knowledge of bipolar disorder; this finding supports the feasibility of implementing integrated group therapy in real-world substance use disorder community treatment settings,” the team writes in the journal Drug and Alcohol Dependence.

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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Study results suggest that bipolar spectrum disorders in young patients are episodic disorders characterized most often by subsyndromal than syndromal episodes, with mainly depressive and mixed symptoms and rapid mood changes.

In this study, Boris Birmaher (University of Pittsburgh Medical Center, Pennsylvania, USA) and co-authors extended findings from the Course and Outcome of Bipolar Youth (COBY) program in a larger sample of youths (ages 7??”17 years) with bipolar I disorder (n=244), bipolar II disorder (n=28), and bipolar disorder not otherwise specified (n=141). Symptoms were retrospectively evaluated on average every 9.4 months for 4 years.

The researchers found that 81.4% of patients had fully recovered approximately 2.5 years after the onset of the first episode. A lower likelihood of full recovery was associated with a diagnosis of bipolar disorder not otherwise specified (hazard ratio [HR]=0.62), children with childhood onset as opposed to adolescents with adolescent onset (HR=0.50) or childhood onset (HR=0.70), non-Caucasian race (HR=0.60), longer duration of illness (HR=0.83 per year of illness), and a family history of mania/hypomania in first- or second-degree relatives (HR=0.79).

Of the patients who recovered, 62.5% had a syndromal recurrence approximately 1.5 years later, which was mainly a major depressive episode (59.5%). One-third of patients had one syndromal recurrence and 30% had two or more.

The authors further found that the polarity of the index episode predicted that of subsequent episodes.

Youths with bipolar spectrum disorders were symptomatic during 60% of the follow-up period, during which they spent about 2.5 times more time with subsyndromal (mixed and depressive) than with syndromal (manic) symptomatology.

Patients with bipolar II disorders spent more time in hypomania than did those with bipolar disorder not otherwise specified, and more time in depression than did others.

Lastly, 25% of youths with bipolar II converted to bipolar I disorder, and 38% of those with bipolar disorder not otherwise specified converted to bipolar I or II.

“The course of bipolar disorder, the relative infrequency of syndromal DSM manic episodes, the effects of development in symptom manifestation, and the high prevalence of comorbid disorder may account, at least in part, for the difficulties in recognizing and managing this illness in youths,” conclude the authors in the American Journal of Psychiatry.

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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