A Common Variant of BDNF Predicts Non-Response to IV Ketamine
Valine
Brain-derived neurotrophic factor (BDNF) is a protein in the brain that protects neurons and is necessary for long-term memory and learning. Different people have different genetic variations in BDNF depending on which amino acid the gene that codes for it inserts into the protein, valine or methionine. There are three possible combinations that vary in their efficiency. The Val66Val allele of BDNF is the most efficient for secreting and transporting BDNF within the cell body to synapses on dendrites, and is also a risk factor for early onset of bipolar disorder and rapid cycling. Twenty-five percent of the population has a Met variant (either Val66Met or Met66Met), which functions less efficiently. These people have mild decrements in some cognitive processing.
Increases in BDNF are necessary to the antidepressant effects of intravenous ketamine. In animals, ketamine also rapidly changes returns dendritic spines that had atrophied back to their healthy mushroom shape in association with its antidepressant effects. According to research published by Gonzalo Laje and colleagues in the journal Biological Psychiatry in 2012, depressed patients with the better functioning Val66Val allele of BDNF respond best to ketamine, while those with the intermediate functioning Val66Met allele respond less well.
Researcher Ronald S. Duman of Yale University recently found that increases in BDNF in the medial prefrontal cortex are necessary to the antidepressant effects of ketamine. If antibodies to BDNF (which block its effects) are administered to the prefrontal cortex, antidepressant response to ketamine is not observed.
Duman also found that calcium influx through voltage sensitive L-type calcium channels is necessary for ketamine’s antidepressant effects. A genetic variation in CACNA1C, a gene that codes for a subunit of the dihydropiridine L-type calcium channel, is a well-replicated risk factor for bipolar disorder. One might predict that those patients with the CACNA1C risk allele, which allows more calcium influx into cells, would respond well to ketamine.
Gene for Calcium Channel Linked to Bipolar Disorder in Several Ways
No one gene explains the risk of developing bipolar disorder. Many genes are involved, each with a small effect. However, the effects of one particular gene have been validated in multiple different ways. The gene is called CACNA1C, and it codes for one subunit of the dihydropyridine L-type calcium channel. Calcium channels are structures on the membranes of neurons that allow calcium to enter cells and alter their excitability.
Different people can have different variants of the CACNA1C gene, depending on which nucleotides appear there: valine (Val) or methionine (Met). One particular variant (known as the Met/Met single nucleotide polymorphism, rs1006737) has been associated with executive function deficits compared to the Val/Val variant in multiple tests in patients with bipolar disorder. Executive function refers to abilities like planning, organizing, and retaining information. This was reported by Soeiro-de-Souza et al. in the journal Acta Psychiatrica Scandinavica in 2013.
Importantly, CACNA1C has also been linked to risk of bipolar disorder, a finding that was replicated in several large genome-wide association studies (GWAS). Autopsy studies of people who had been diagnosed with bipolar disorder show more calcium channels in their brains. The Met/Met variant of the CACNA1C gene also lets more calcium ions into cells. Those who have the gene variant also show differences in some brain structures known to be involved in the modulation of emotions compared to those without the variant.
In addition to these findings, more than a dozen studies report increased intracellular calcium in the white blood cells of people with bipolar disorder compared to controls. To the extent that these increases in intracellular calcium reflect changes in neurons, this would be consistent with the findings about CACNA1C. High levels of calcium influx and the associated intracellular calcium may increase cellular excitability and potentially dysregulate normal neuronal functioning.
The final piece of evidence linking altered calcium channel regulation to bipolar disorder is a direct therapeutic test of a drug that blocks calcium influx through the dihydropyridine L-type calcium channel. There is evidence that nimodipine, which selectively blocks dihydropyridine L-type calcium channels, has therapeutic effects in bipolar disorder.
Gene Mutation Induces Bipolar-Like Symptoms
A mutation in a gene related to circadian rhythms may help explain bipolar disorder. Animals with a mutation in the gene, known as CLOCK, typically exhibit behaviors that mimic human mania, such as increased locomotor activity and decreased anxiety.
Stress can lead to depression in bipolar patients, so researcher Nicole Edgar et al. exposed animals with the mutated “manic” version of the CLOCK gene to unpredictable chronic mild stress. The stress brought about decreased locomotor activity and increased anxiety, mimicking a switch into depression. These data suggest that alterations in CLOCK genes may provide a useful model for both mania and depression.
The research was presented at the 2013 meeting of the Society of Biological Psychiatry, and the abstract (#471) can be found in the meeting supplement, Volume 73, Number 9S of the journal Biological Psychiatry.
In another abstract (#472) at the same meeting, researcher Wilbur Williams et al. reported that alterations in related clock genes (that result in decreases in the proteins CRY-1 and SIRT1) are associated with manic-like behavior that could be reversed using lithium. These data further suggest that clock genes may provide a useful model for bipolar disorder.
An Animal Model of Poor Judgment in Adolescence: Previous Learning Suppressed
As young mice transition into adolescence, they experience a “sensitive” period in which their context-based fear memories are temporarily suppressed. In a recent study, young animals learned to avoid an environment associated with a mild shock. Later, when they entered adolescence, this learning was temporarily forgotten or suppressed. However, when the same mice aged into adulthood, they reacquired this learned fear memory and began to again avoid the environment associated with the earlier shock. This temporary loss of fear memory differs in mice depending on their genes.
At the 2012 meeting of the Society of Biological Psychiatry, researcher Francis S. Lee reported that mice with a certain genetic variation display an impairment of this fear memory process. There are several common variants of the gene responsible for the production of brain-derived neurotrophic factor (BDNF), which protects neurons and is necessary for long-term memory. Mice with the poorer functioning variant known as Val66Met (as opposed to the better functioning Val66Val) fail to recall the earlier fear-related events not only in adolescence, but also in adulthood when the fear memory is usually retrievable again.
Editor’s Note: In mice and humans, Val66Val is the most frequently occurring allele in the population, but Val66Met is also a fairly common variation of the BDNF gene. It is this Val66Met allele that is associated with not retaining earlier learned experience about a “dangerous” environment that should be avoided.
These data suggest an intriguing explanation for some of the “wild” behavior and poor judgment to which even the smartest adolescents are prone. This kind of behavior may be based in part on the temporary forgetting in adolescence of earlier learning about which situations or environments are safe versus which ones are dangerous. Read more
Genetic Risk Factors for Onset of Bipolar Disorder
A Genetic Risk Factor For Bipolar Disorder: The CACNA1C Gene
In an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders, Sophia Frangou reported on the CACNA1C polymorphism, a genetic variation that has been associated with the risk of developing bipolar disorder in several genome-wide association studies that search for links between genes and illnesses. Frangou found that those people with the genetic variation had increased volume in some parts of the brain, including the right hypothalamus and the right amygdala, and decreased volume in others, including the putamen, as well as alterations in the functional connectivity of different cortical areas.
Location of the CACNA1C gene
These data may be related to findings that calcium influx may play a role in bipolar disorder. In people with the genetic variation, the risk allele binds to a subunit of the voltage-dependent calcium channel, which modulates the influx of calcium from the outside to the inside the neuron.
Increased amounts of calcium are consistently found in the white cells and platelets of patients with bipolar disorder compared to controls. Moreover, the drug nimodipine, a dihydropyridine L-type calcium channel blocker, is effective in the prevention of manic and depressive episodes in a subgroup of patients, particularly those with cycling patterns that are ultra-rapid (4+ episodes per month) or ultradian (including a mood switch within a 24-hour period 4+ times per month). A large randomized study of patients with bipolar disorder presented by H.R. Chaudhry at the 2010 meeting of the Society of Biological Psychiatry also found that while lithium was associated with a 50% response rate, the combination of lithium and nimodipine was associated with a 73% response rate, again suggesting the additional efficacy of blocking L-type calcium channels.
Immune Abnormalities May Predict Onset of Bipolar Disorder in Children at High Risk
At the 5th Biennial Conference of the International Society for Bipolar Disorders E. Mesman discussed connections between immunity and bipolar disorder. Mesman and colleagues followed offspring of parents with confirmed bipolar disorder for 12 years and compared them to children in the general population. In the children of bipolar parents they found higher levels of immune markers called cytokines (PTX3 and sCD25) in circulating monocytes, a type of white blood cell. In the children of bipolar parents they also found a high inflammatory setpoint in the monocytes. T-effector and T-regulatory cells were also different in the offspring of bipolar parents.
While these findings were present in children who had already become ill with bipolar disorder, they were also present in those who had yet to experience a mood disorder, suggesting that these immune and inflammatory markers may ultimately be an important risk marker for the onset of bipolar disorder.
Editor’s Note: These are among the first studies suggesting that immune and inflammatory abnormalities may precede the onset of bipolar disorder. Many studies have shown that patients with active bipolar disorder show more inflammation, including increases in inflammatory markers interleukin 1 (IL-1), interleukin 6 (IL-6), C reactive protein (CRP), and tumor necrosis factor alpha (TNFa). The new data are of considerable importance not only because inflammation could serve as a marker of illness onset, but also because inflammation could become a potential target for therapeutics (i.e. using anti-inflammatory and immune-suppressing agents to treat bipolar disorder).
Genetic Markers of Response to Lithium
At the 5th Biennial Conference of the International Society for Bipolar Disorders and the 67th Annual Meeting of the Society of Biological Psychiatry, John Kelsoe presented his research on personalized pharmacotherapy for bipolar disorder, describing genetic predictors of response to lithium.
In his research Kelsoe found that a variant of the gene that codes for neurotrophic receptor type II (NTRK2), the receptor for brain-derived neurotrophic factor (BDNF), was associated with good response to lithium in patients with a family history of bipolar disorder or a history of euphoric mania. The “T” allele of rs1387923 was associated with better response to lithium retrospectively, and these results were replicated in a prospective study.
Editors Note: These data are among the first to indicate that genetic information could be used to make treatment decisions. Lithium increases BDNF and neurogenesis, thus it makes some sense that a variation in the BDNF receptor would affect clinical responsiveness to lithium.
In a similar vein, Janusz K. Rybakowski reported at the Society of Biological Psychiatry meeting on another possible predictor of long-term excellent response to lithium in bipolar disorder. Due to normal genetic variation, different people have different versions of BDNF. Rybakowski found that the patients with a version of BDNF known as Val66Val who had bipolar disorder performed significantly better on the Wisconsin Card Sorting Test, which evaluates abstract reasoning. However, he found that patients with a methionine amino acid in the place of one of the valine amino acids (resulting in a Val66Met allele, which is associated with minor cognitive difficulties) showed significantly better response to preventative treatment with lithium. It is noteworthy that these excellent lithium responders also performed better on a complex neuropsychological battery than those who were less good responders to lithium. The good responders’ performance on these tests was not different from healthy controls.
Editor’s Note: These data add to the possibility that prediction of lithium response is linked to common gene variations in neuroprotective factors or their receptors. It is interesting that the patients with the Val66Met allele, which works less efficiently, show the best long-term response to lithium. This is consistent with the view that lithium, which increases BDNF, is most effective in those who have a sluggish functioning of their BDNF due to having the Met allele. As we have written before, those with the Met allele have slight decrements in working memory, and in animal models, those with the Met allele show deficits in long-term potentiation (LTP), which suggest problems with long-term memory. Thus, using lithium to increase BDNF function in those with a “sluggish” variation in their BDNF makes sense and may ultimately be clinically useful.
Heading Off Early Symptoms of Bipolar Disorder in Children at High Risk
At the American Academy of Child and Adolescent Psychiatry (AACAP) annual meeting in Toronto in October 2011, there was a symposium on risk and resilience factors in the onset of bipolar disorder in children who have a parent with the disorder.
Family Focused Therapy Highly Encouraged
Amy Garrett reported that family focused therapy (FFT) in those at risk for bipolar disorder was effective in ameliorating symptomatology compared to treatment as usual. Family focused therapy, pioneered by Dave Miklowitz, PhD of UCLA involves three components. The first component is education about the illness and methods of self-management. The second is enhancement of communication in the family with practice and rehearsal of new modes of conversation. The third component is assistance with problem solving.
In Garrett’s study, 50 children aged 7 to 17 were randomized to family focused treatment or treatment as usual. These children were not only at high risk for bipolar disorder, they were already prodromal, meaning they were already diagnosable with bipolar not otherwise specified (BP-NOS), cyclothymia, or major depressive disorder, and had also shown concurrent depressive and/or manic symptoms in the two weeks prior to the study. At baseline, compared to controls, these children at high risk for full-blown bipolar disorder by virtue of a parental history of the illness showed increased activation of the amygdala and decreased activation of the prefrontal cortex. Most interestingly, after improvement with the family focused therapy (FFT), amygdala reactivity to emotional faces became less prominent and dorsolateral prefrontal cortical activity increased in proportion to the degree of the patient’s improvement.
The discussant for the symposium was Kiki Chang of Stanford University, who indicated that the results of this study of family focused therapy were already sufficient to convince him that FFT was a useful therapeutic procedure in children at high risk for bipolar disorder by virtue of having a parent with a history of bipolar illness. Chang is now employing the therapy routinely in all of his high-risk patients.
Editors Note: This is an extremely important recommendation as it gives families a specific therapeutic process in which to engage children and others in the family when affective behavior begins to become abnormal, even if it does not meet full criteria for a bipolar I or bipolar II disorder.
FFT also meets all the important criteria needed for putting it into widespread clinical practice. Family focused therapy has repeatedly been shown to be effective in adults and adolescents with bipolar illness and now also in these children who are prodromal. The psychoeducational part of FFT is common sense, and dealing with communication difficulties and assisting with problem solving also have merit in terms of stress reduction. Finally, this treatment intervention appears to be not only safe but also highly effective in a variety of different prodromal presentations of affect disorders even if children do not meet full criteria for bipolar disorder. While the few studies of early intervention with psychopharmacological agents have not yet identified efficacious medications for the prodromes of bipolar disorder and in particular medications with a high degree of safety, such family focused therapy appears to be an ideal early intervention.
I would concur with Dr. Chang’s assessment. Family focused therapy (FFT) should be offered to all children with this high-risk status who have begun to be symptomatic. Early onset of unipolar depressive disorder or of bipolar disorder carries a more adverse prognosis than the adult onset variety and thus should not be ignored. If more serious illness is headed off early, it even raises the possibility that the full-blown illness will not develop at all.
Gray Matter Volume Abnormalities
Tomas Hajek of Dalhousie University in Halifax presented data indicating that in children at high risk for bipolar disorder, gray matter volume in the right inferior frontal gyrus is increased. Read more
Common Genetic Variation Linked to Response to Antidepressants
Brain-derived neurotrophic factor (BDNF) protects neurons and is important for long-term learning and memory. There are several genetic variations in BDNF depending on which amino acid—valine or methionine—falls at a particular position when the proBDNF protein is being made. Most people have the val-66-val allele, some have the val-66-met, and a few have the met-66-met allele.
Researcher Jessica C. Levenson, working with David Kupfer and Ellen Frank at the University of Pittsburgh, reported at the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011 that patients with unipolar depression who have the val-66-val allele of proBDNF have better clinical responsiveness to antidepressants than those with the slightly less common variant, val-66-met.
Editor’s note: The val-66-val allele is more effective in enhancing synaptic plasticity and is more easily transported from the nucleus to the dendrites of neurons (where it is necessary for learning and memory) than the val-66-met allele or the least effective met-66-met variant.
These findings are intriguing because antidepressant treatments tend to increase BDNF, regardless of their mechanisms of action. Moreover, BDNF levels are low in patients with depression, usually in direct relationship to the severity of depression. Thus, the ability of antidepressants to increase BDNF may lead to a more effective treatment response in those with the better functioning val-66-val allele of BDNF. This remains to be further documented, but the study provides a preliminary example of how genotyping may eventually be able to help predict individual clinical response to a given treatment and thus foster the development of personalized medicine.
Genetic Basis for Childhood Onset of Bipolar Illness
Eric Mick of Massachusetts General Hospital reviewed the latest genetics data on bipolar disorder and reported at the 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry that 20% of people with childhood-onset bipolar illness have a first-degree relative with bipolar disorder, while only 10% of those with adult-onset bipolar disorder have a first-degree relative with bipolar disorder. These data are consistent with others that indicate that there is an increased genetic/familial risk for bipolar disorder in childhood- compared with adult-onset illness.
Mick reviewed a number of findings that suggest that alterations in genes involved in intracellular signaling and in the development and maintenance of long-term memory may also be implicated in bipolar disorder. Classical genome-wide association studies (GWAS), in which a link between any human gene and bipolar disorder is sought, have not found any genes with a large effect or a high predictive value for bipolar illness. In the meantime, other strategies for finding genetic links to bipolar disorder are being pursued, including studying rare gene variants. There is some evidence that these variants occur more frequently in children with early onset bipolar illness.
Schizophrenia v. Bipolar Disorder: Different Risk Factors
Robin Murray gave a plenary presentation at the 65th Annual Scientific Convention of the Society of Biological Psychiatry this year, in which he indicated that the genetic risk for schizophrenia and other major mental disorders may be overestimated. He suggested that even in identical twins there are considerable differences in incidence of major psychiatric illnesses, and sharing an environment could further inflate the appearance of genetic risk.
Evidence of some genetic vulnerability factors, such as neuregulin, disbindin, DISC-1, zinc finger transcription factors, and neurexin, has been replicated. However, these genes appear to contribute only about 1% of the vulnerability to schizophrenia or bipolar illness. Copy number variations (CNVs, extra or missing copies of a gene, which may alter its activity) and gene micro-deletions (in which small bits of DNA are missing) have been found in about 5% of patients with schizophrenia, in some patients with autism and mental disabilities, but not in those with bipolar illness.
Murray emphasized the importance of psychosocial and neuromotor markers of neural development in determining risk of subsequent major psychiatric illness, rather than the relatively weak genetic effects. He cited the work of MacCabe (2009), who collected information from 907,000 individuals in Sweden. Their scholastic achievement at age 15?16 was rated, and hospitalizations for psychosis were recorded from age 17?31. Of the 315,000 followed for the long term, 493 developed schizophrenia and 208 developed bipolar disorder.
Predictors of cognitive and motor development in these two major psychiatric illnesses appeared to differ. In those who went on to develop schizophrenia, there was a slower rate of motor development, receptive language, and overall IQ in adolescence, while in those who went on to develop bipolar disorder, there was a faster rate of motor development, more language facility, and higher IQ in adolescence.
