Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small variations in a number of genes that are closely linked to an increased risk of bipolar disorder, a mental illness that affects nearly six million Americans, according to the National Institute of Mental Health.
"Using samples from some 3,400 individuals, we identified several new variants in genes closely associated with bipolar disorder," said Scripps Florida Professor Ron Davis, who led the new study, which was published recently by the journal Translational Psychiatry.
A strong tendency towards bipolar disorder runs in families; children with a parent or sibling who has bipolar disorder are four to six times more likely to develop the illness, according to the National Institute of Mental Health.
While the genetic basis for bipolar disorder is complex and involves multiple genes, it appears to be associated with a biochemical pathway known as cyclic adenosine monophosphate (cAMP) signaling system. The Davis laboratory and others have previously shown that the cAMP signaling plays a critical role in learning and memory processes. The new study focused on this signaling pathway.
"As far as I know, this has not been done before -- to query a single signaling pathway," said Davis. "This is a new approach. The idea is if there are variants in one gene in the pathway that are associated with bipolar disorder, it makes sense there would be variants in other genes of the same signaling pathway also associated with the disorder."
The new study examined variations in 29 genes found in the two common types of bipolar disorder -- bipolar disorder I (the most common form and the most severe) and bipolar disorder II. Genes from a total of 1,172 individuals with bipolar disorder I; 516 individuals with bipolar disorder II; and 1,728 controls were analyzed.
Several statistically significant associations were noted between bipolar disorder I and variants in the PDE10A gene. Associations were also found between bipolar disorder II and variants in the DISC1 and GNAS genes.
Davis noted that the location of PDE10A gene expression in the striatum, the part of the brain associated with learning and memory, decision making and motivation, makes it especially interesting as a therapeutic target.
Thursday, 29 November 2012
Saturday, 24 November 2012
Giving Lithium to Those Who Need It
Lithium is a 'gold standard' drug for treating bipolar disorder, however not everyone responds in the same way. New research published in BioMed Central's open access journal Biology of Mood & Anxiety Disorders finds that this is true at the levels of gene activation, especially in the activation or repression of genes which alter the level the apoptosis (programmed cell death). Most notably BCL2, known to be important for the therapeutic effects of lithium, did not increase in non-responders. This can be tested in the blood of patients within four weeks of treatment.
A research team from Yale University School of Medicine measured the changing levels of gene activity in the blood of twenty depressed adult subjects with bipolar disorder before treatment, and then fortnightly once treatment with lithium carbonate had begun.
Over the eight weeks of treatment there were definite differences in the levels of gene expression between those who responded to lithium (measured using the Hamilton Depression Rating Scale) and those who failed to respond. Dr Robert Beech who led this study explained, "We found 127 genes that had different patterns of activity (turned up or down) and the most affected cellular signalling pathway was that controlled programmed cell death (apoptosis)."
For people who responded to lithium the genes which protect against apoptosis, including Bcl2 and IRS2, were up regulated, while those which promote apoptosis were down regulated, including BAD and BAK1.
The protein coded by BAK1 can open an anion channel in mitochondrial walls which leads to leakage of mitochondrial contents and activation of cell death pathways. Damage similar to this has been seen within the prefrontal cortex of the brain of patients with bipolar disorder. BAD protein is thought to promote BAK1 activity, while Bcl2 binds to BAK1 and prevents its ability to bind to the channel.
Dr Beech continued, "This positive swing in regulation of apoptosis for lithium responders was measurable as early as four weeks after the start of treatment, while in non-responders there was a measureable shift in the opposite direction. It seems then, that increased expression of BCL2 and related genes is necessary for the therapeutic effects of lithium. Understanding these differences in genes expression may lead towards personalized treatment for bipolar disorder in the future."
A research team from Yale University School of Medicine measured the changing levels of gene activity in the blood of twenty depressed adult subjects with bipolar disorder before treatment, and then fortnightly once treatment with lithium carbonate had begun.
Over the eight weeks of treatment there were definite differences in the levels of gene expression between those who responded to lithium (measured using the Hamilton Depression Rating Scale) and those who failed to respond. Dr Robert Beech who led this study explained, "We found 127 genes that had different patterns of activity (turned up or down) and the most affected cellular signalling pathway was that controlled programmed cell death (apoptosis)."
For people who responded to lithium the genes which protect against apoptosis, including Bcl2 and IRS2, were up regulated, while those which promote apoptosis were down regulated, including BAD and BAK1.
The protein coded by BAK1 can open an anion channel in mitochondrial walls which leads to leakage of mitochondrial contents and activation of cell death pathways. Damage similar to this has been seen within the prefrontal cortex of the brain of patients with bipolar disorder. BAD protein is thought to promote BAK1 activity, while Bcl2 binds to BAK1 and prevents its ability to bind to the channel.
Dr Beech continued, "This positive swing in regulation of apoptosis for lithium responders was measurable as early as four weeks after the start of treatment, while in non-responders there was a measureable shift in the opposite direction. It seems then, that increased expression of BCL2 and related genes is necessary for the therapeutic effects of lithium. Understanding these differences in genes expression may lead towards personalized treatment for bipolar disorder in the future."
Tuesday, 20 November 2012
Pregnancy and Birth Complications More Likely in Mothers With Bipolar Disorder
Babies born to mothers with bipolar disorder are at increased risk of preterm birth (before 37 weeks) a study published today on bmj.com suggests.
Infants of mothers with untreated bipolar disorder are also at increased risks of outcomes related to fetal growth restriction.
Bipolar disorder (sometimes called manic depression) is a serious, long term condition involving extreme mood swings. Treatment with mood stabilising drugs like lithium, anticonvulsants or antipsychotics can help keep mood within normal limits.
Previous studies have suggested that these drugs may be linked to pregnancy and birth complications, whereas little is known about adverse outcomes in untreated women with bipolar disorder.
So researchers from Uppsala University and the Karolinska Institutet in Sweden investigated the risks of adverse pregnancy and birth outcomes in both treated and untreated women with bipolar disorder.
Using data from three national health registers, they identified 320 mothers with treated bipolar disorder and 554 untreated mothers. Treated and untreated women were compared with all other women giving birth (331,263) between 1 July 2005 and 31 December 2009. Results were adjusted for several factors including maternal age, weight, smoking status, cohabitation and a diagnosis of alcohol or substance use disorder.
Mothers with bipolar disorder were more often smokers, overweight and alcohol or substance abusers than unaffected mothers.
Both treated and untreated mothers with bipolar disorder had increased risks of caesarean delivery, instrumental delivery (use of a vacuum or forceps), and a non-spontaneous start to delivery (120/320 or 37.5% of treated women, 171/554 or 30.9% of untreated women, 68 533/331 263 or 20.7% of other women). Treated and untreated mothers also had 50% increased risks of preterm birth compared with unaffected mothers (26/320 or 8.1% of treated women, 42/554 or 7.6% of untreated women, 15 785/331 263 or 4.8% of other women).
Untreated mothers were also more likely to give birth to a baby with a small head (microcephaly) and with episodes of low blood sugar levels (neonatal hypoglycaemia) compared with unaffected mothers.
The researchers conclude that "mood-stabilising treatment is probably not the sole reason for the increased risk of adverse pregnancy and birth outcomes previously observed in mothers with bipolar disorder." They also suggest that the role of treatment is still unclear as the overall outcomes "generally did not support a significant difference between untreated and treated" mothers.
In an accompanying editorial, mental health expert, Dr Salvatore Gentile says the question is not "to treat or not to treat?" but "how to treat optimally?" Because no drug is without risks, clinicians cannot hope to identify a "safe choice," but merely a "less harmful" one.
He adds that patients must be properly counselled about the risks of treatment versus the risks associated with the untreated psychiatric disorder, and doctors should "encourage and facilitate social integration, especially for women from disadvantaged social groups and those who are isolated."
Infants of mothers with untreated bipolar disorder are also at increased risks of outcomes related to fetal growth restriction.
Bipolar disorder (sometimes called manic depression) is a serious, long term condition involving extreme mood swings. Treatment with mood stabilising drugs like lithium, anticonvulsants or antipsychotics can help keep mood within normal limits.
Previous studies have suggested that these drugs may be linked to pregnancy and birth complications, whereas little is known about adverse outcomes in untreated women with bipolar disorder.
So researchers from Uppsala University and the Karolinska Institutet in Sweden investigated the risks of adverse pregnancy and birth outcomes in both treated and untreated women with bipolar disorder.
Using data from three national health registers, they identified 320 mothers with treated bipolar disorder and 554 untreated mothers. Treated and untreated women were compared with all other women giving birth (331,263) between 1 July 2005 and 31 December 2009. Results were adjusted for several factors including maternal age, weight, smoking status, cohabitation and a diagnosis of alcohol or substance use disorder.
Mothers with bipolar disorder were more often smokers, overweight and alcohol or substance abusers than unaffected mothers.
Both treated and untreated mothers with bipolar disorder had increased risks of caesarean delivery, instrumental delivery (use of a vacuum or forceps), and a non-spontaneous start to delivery (120/320 or 37.5% of treated women, 171/554 or 30.9% of untreated women, 68 533/331 263 or 20.7% of other women). Treated and untreated mothers also had 50% increased risks of preterm birth compared with unaffected mothers (26/320 or 8.1% of treated women, 42/554 or 7.6% of untreated women, 15 785/331 263 or 4.8% of other women).
Untreated mothers were also more likely to give birth to a baby with a small head (microcephaly) and with episodes of low blood sugar levels (neonatal hypoglycaemia) compared with unaffected mothers.
The researchers conclude that "mood-stabilising treatment is probably not the sole reason for the increased risk of adverse pregnancy and birth outcomes previously observed in mothers with bipolar disorder." They also suggest that the role of treatment is still unclear as the overall outcomes "generally did not support a significant difference between untreated and treated" mothers.
In an accompanying editorial, mental health expert, Dr Salvatore Gentile says the question is not "to treat or not to treat?" but "how to treat optimally?" Because no drug is without risks, clinicians cannot hope to identify a "safe choice," but merely a "less harmful" one.
He adds that patients must be properly counselled about the risks of treatment versus the risks associated with the untreated psychiatric disorder, and doctors should "encourage and facilitate social integration, especially for women from disadvantaged social groups and those who are isolated."
Sunday, 18 November 2012
Risk Genes In Bipolar Disorder
One of the biggest challenges in psychiatric genetics has been to replicate findings across large studies.
Scientists at King's College London, Institute of Psychiatry have now performed one of the largest ever genetic replication studies of bipolar affective disorder, with 28,000 subjects recruited from 36 different research centers. Their findings provide compelling evidence that the chromosome 3p21.1 locus contains a common genetic risk for bipolar disorder, the PBRM1 gene.
The locus at 3p21.1 has also been previously associated with depression and schizophrenia. Using a separate dataset of over 34,000 subjects, they did not confirm association of this same variant with schizophrenia.
Thus, they replicated the association of the marker with bipolar disorder, but not with schizophrenia. This is an interesting finding, in that it distinguishes the heritable risk for bipolar disorder and schizophrenia. It contrasts with the majority of studies that have found that schizophrenia risk genes also contribute to the risk for bipolar disorder.
"This study adds to the recent rapid progress in identifying genes for mental illness. The last few years have seen the identification of about two dozen genetic loci for bipolar disorder and schizophrenia," commented first author Evangelos Vassos. "About half of these are shared between these two disorders, indicating they share some, but not all, genetic causes."
Due to the conflicting results, it is clear that more work is needed to determine the role this locus plays in psychosis, but the evidence seems solid that it is associated with bipolar disorder.
PBRM1, the gene implicated in this study, codes for a protein that is involved in chromatin remodeling or "epigenetics", meaning that it influences the ability of a variety of environmental exposures to influence the expression of a range of genes. It has also been previously implicated in the risk for a form of renal cancer.
"There is growing interest in epigenetic mechanisms that might contribute to the development of bipolar disorder. The implication of a gene involved in chromatin remodeling in bipolar disorder risk adds fuel to this fire," commented Dr. John Krystal, Editor of Biological Psychiatry.
Vassos concluded that "future studies may be able to use this information to develop new treatments for these disorders."
Scientists at King's College London, Institute of Psychiatry have now performed one of the largest ever genetic replication studies of bipolar affective disorder, with 28,000 subjects recruited from 36 different research centers. Their findings provide compelling evidence that the chromosome 3p21.1 locus contains a common genetic risk for bipolar disorder, the PBRM1 gene.
The locus at 3p21.1 has also been previously associated with depression and schizophrenia. Using a separate dataset of over 34,000 subjects, they did not confirm association of this same variant with schizophrenia.
Thus, they replicated the association of the marker with bipolar disorder, but not with schizophrenia. This is an interesting finding, in that it distinguishes the heritable risk for bipolar disorder and schizophrenia. It contrasts with the majority of studies that have found that schizophrenia risk genes also contribute to the risk for bipolar disorder.
"This study adds to the recent rapid progress in identifying genes for mental illness. The last few years have seen the identification of about two dozen genetic loci for bipolar disorder and schizophrenia," commented first author Evangelos Vassos. "About half of these are shared between these two disorders, indicating they share some, but not all, genetic causes."
Due to the conflicting results, it is clear that more work is needed to determine the role this locus plays in psychosis, but the evidence seems solid that it is associated with bipolar disorder.
PBRM1, the gene implicated in this study, codes for a protein that is involved in chromatin remodeling or "epigenetics", meaning that it influences the ability of a variety of environmental exposures to influence the expression of a range of genes. It has also been previously implicated in the risk for a form of renal cancer.
"There is growing interest in epigenetic mechanisms that might contribute to the development of bipolar disorder. The implication of a gene involved in chromatin remodeling in bipolar disorder risk adds fuel to this fire," commented Dr. John Krystal, Editor of Biological Psychiatry.
Vassos concluded that "future studies may be able to use this information to develop new treatments for these disorders."
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