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Philadelphia, January 31, 2019 — A study by researchers at Yale University reveals a complex interplay of two different growth factors in the rapid and long-lasting antidepressant effects of ketamine. The study, published in Biological Psychiatry, reports that the antidepressant-like actions of brain-derived neurotrophic factor (BDNF) require the release of vascular endothelial growth factor (VEGF).
“Surprisingly, the reciprocal relationship was also observed, indicating that BDNF-VEGF interdependence plays a crucial role in the actions of rapid-acting antidepressants,” said senior author Ronald Duman, PhD.
Ketamine requires the release of both BDNF and VEGF to produce its rapid antidepressant effects, but the connection between the two growth factors–which have different functions and act through different mechanisms–was unknown.
Using mice to model behaviors of depression, the researchers investigated the interaction of BDNF and VEGF. Administering BDNF or VEGF to a brain region implicated in depression, the medial prefrontal cortex (mPFC), produces rapid and long-lasting antidepressant-like actions similar to those of ketamine. In the study, Dr. Duman and colleagues found that removing VEGF from the mPFC prevented the antidepressant-like effects of BDNF in mice. When they performed similar experiments but instead blocked BDNF, the antidepressant-like effects of VEGF were prevented.
Deeper analysis using neuron cultures to examine how the two factors depend on each other revealed that BDNF signaling stimulates VEGF release in neurons and requires VEGF to produce its neurotrophic effects. Conversely, VEGF stimulates the release of BDNF and requires BDNF signaling to produce its neurotrophic effects.
“This observation may have important clinical implications. VEGF inhibitors are widely used to treat various cancers and can be associated with increased risk for depression and cognitive impairments sometimes called the ‘fog of chemotherapy’.
“Since most antidepressant effects are mediated by BDNF, and therefore VEGF, how should we treat these forms of depression and cognitive impairments? The answer to this question may draw us to BDNF-independent effects of antidepressants and new insights into the biology and treatment of depression,” said John Krystal, MD, Editor of Biological Psychiatry.
The results provide the first evidence that reciprocal interdependence of BDNF and VEGF plays a crucial role in their rapid antidepressant-like effects, revealing key mechanisms of ketamine, which requires both BDNF and VEGF. The findings also highlight avenues of research to better understand how each of the factors may affect a person’s risk of depression or their response to antidepressant drugs.
Major depressive disorder is a widespread debilitating illness, affecting approximately 17% of the population in the United States and causing enormous personal and socioeconomic burden . Conventional antidepressants, notably monoamine reuptake inhibitors, take weeks to months to produce a therapeutic response and have limited efficacy, as approximately one third of patients with depression fail to respond to typical antidepressants and are considered treatment resistant . Recent studies demonstrate that a single subanesthetic dose of ketamine, an N -methyl-D-aspartate receptor (NMDAR) antagonist, produces rapid (within hours) and sustained (up to a week) antidepressant actions even in patients with treatment-resistant depression ; similar rapid and long-lasting effects are observed in rodent models .
Although the mechanisms underlying the pathophysiology of major depressive disorder and the therapeutic actions of ketamine remain unclear, growing evidence supports a neurotrophic hypothesis of depression and antidepressant response . This hypothesis is based on evidence that reduced neurotrophic factor levels, notably brain-derived neurotrophic factor (BDNF) and/or vascular endothelial growth factor (VEGF), are tightly linked with neuronal atrophy in brain regions implicated in major depressive disorder, including the prefrontal cortex (PFC) and hippocampus . BDNF and VEGF are two completely different pleiotropic growth factors that bind to and activate different tyrosine kinase receptors, neurotrophic receptor tyrosine kinase 2 (TRKB) and fetal liver kinase 1 (FLK1) (also known as VEGF receptor 2), respectively, that have unique as well as overlapping signaling pathways . In support of this hypothesis, neuroimaging studies have consistently reported decreased volume of the PFC and hippocampus in patients with depression ; neuronal atrophy and glial loss have also been reported in postmortem studies of depressive subjects and rodent chronic stress models . Postmortem studies of subjects with depression and studies of rodent chronic stress also report decreased levels of BDNF and VEGF, as well as their receptors, TRKB and FLK1, respectively, in the PFC and hippocampus ; the VEGF level is also decreased in the cerebrospinal fluid of persons who had attempted suicide .
Conversely, preclinical studies reveal that ketamine and other rapid-acting antidepressants act at least in part by producing the opposite effects, increasing BDNF and/or VEGF release and signaling in the PFC and hippocampus . Ketamine blockade of NMDARs located on gamma-aminobutyric acidergic interneurons leads to disinhibition and a rapid and transient glutamate burst that activates postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, resulting in stimulation of calcium ion (Ca 2+ ) influx through voltage-dependent calcium channels that activates BDNF release ; this increases and reverses the synaptic deficits in the PFC caused by chronic stress , and it is required for the antidepressant-like behavioral actions of ketamine . The actions of conventional antidepressants are also linked to BDNF and VEGF, although these monoaminergic agents increase trophic factor levels only after long-term treatment and increase only expression but not release of BDNF and VEGF .
We have recently reported that neuronal VEGF-FLK1 signaling in the medial PFC (mPFC) is also required for the neurotrophic and antidepressant-like behavioral actions of ketamine . Since BDNF is reported to stimulate VEGF expression and release in neuroblastoma cells , we hypothesized that VEGF signaling acts downstream of BDNF to produce the neurotrophic and antidepressant-like actions. The current study addresses this hypothesis as well as the interdependence between BDNF and VEGF signaling.
The current results demonstrate several important points. First, a single intra-mPFC infusion of BDNF produces rapid and sustained antidepressant-like actions similar to those of ketamine and intra-mPFC VEGF infusion, consistent with our recent findings . Second, the antidepressant-like actions of BDNF in three different behavioral paradigms require neuronal-derived extracellular VEGF. Third, BDNF-TRKB signaling stimulates VEGF release in primary cortical neurons, consistent with a previous report showing BDNF-induced VEGF release in a neuroblastoma cell line . Fourth, BDNF-induced neurotrophic actions on dendrite complexity require VEGF-FLK1 signaling in primary cortical neurons. Fifth, the results also demonstrate a reciprocal interdependence, showing that the antidepressant-like and neurotrophic actions of VEGF require BDNF and that VEGF stimulates BDNF release in primary cortical neurons. These results provide the first evidence of a crucial role for interplay between BDNF and VEGF signaling in the neurotrophic and rapid and/or sustained antidepressant-like responses of these factors. Because these studies were conducted in male mice, further studies are needed to determine whether similar effects are observed in female mice.
Previous studies showed that the rapid antidepressant-like actions of ketamine are blocked by the infusion of a BDNF nAb into the mPFC and are blocked in mice with a knockin of the BDNF Val66Met polymorphism (valine at position 66 replaced by methionine), which blocks activity-dependent BDNF release . The behavioral actions of two other rapid-acting antidepressants, rapastinel (an NMDAR modulator) and scopolamine (a nonselective muscarinic acetylcholine receptor antagonist), are also blocked by intra-mPFC infusion of a BDNF nAb and are blocked in Val66Met knockin mice . These effects differ from those of typical monoaminergic antidepressants, which increase the expression but not the release of BDNF, and they indicate that BDNF release accounts for the rapid actions of ketamine and other rapid-acting agents . In addition, we have recently demonstrated that VEGF release in the mPFC is also required for the rapid antidepressant-like actions of ketamine .
The results of the current study demonstrate that infusion of a VEGF nAb into the mPFC is sufficient to block the antidepressant-like effects of BDNF. The dependence on VEGF was observed in three different antidepressant behavioral paradigms, including models of behavioral despair (FST), motivation and reward (FUST), and anxiety (NSF). While future studies will be needed to test this BDNF–VEGF interaction in chronic stress models, such as chronic unpredictable stress or social defeat , the current results indicate a broad effect across these different behavioral paradigms. Together, the results demonstrate that the antidepressant-like behavioral actions of BDNF are dependent on release of VEGF from excitatory neurons in the mPFC. The results of immunoblot analysis demonstrate that the VEGF nAb does not cross-react with recombinant BDNF, but further studies are needed to demonstrate the lack of cross-reactivity under physiological conditions. In any case, the results of the nAb approach were confirmed with an independent approach, neuronal deletion of VEGF ( CaMKIIα-Crerecombinase line crossed with a Vegfa flox/flox ) . Here we show that the antidepressant-like behavioral actions of BDNF in all three behavioral paradigms are also blocked in the neuronal VEGF–deletion mutants. Since VEGF is expressed by multiple cell types, including neurons, astrocytes, and endothelial cells , we cannot rule out the possibility that VEGF derived from one or more of the other cell types contributes to the BDNF response. However, the results indicate an essential role for VEGF derived from neurons.
Analysis of VEGF release in vivo is technically difficult, so we utilized a primary cortical neuron cell culture system to demonstrate that ketamine stimulates BDNF release . Here we show that incubation with BDNF increases the release of VEGF in primary cortical neurons, and that coincubation with a selective TRKB inhibitor blocks both BDNF-induced and basal VEGF release. The mechanisms underlying BDNF-TRKB–stimulated VEGF release are unclear, but they could involve effects on neuronal activity or signaling pathways linked with neurotrophic factor release. Evidence for an activity-dependent mechanism is provided by previous studies reporting that infusion of BDNF into the mPFC or hippocampus induces c-Fos expression . Induction of c-Fos is coupled with neuronal activity, although stimulation of intracellular signaling pathways independent of neuronal activity can also increase this immediate early gene. More direct evidence is provided by electrophysiological studies demonstrating that BDNF potentiates glutamatergic transmission by increasing the probability of presynaptic release in hippocampal primary neurons or slices and in visual cortex slices . BDNF stimulates the release of Ca 2+ from intracellular stores via activation of phospholipase Cγ , which could stimulate VEGF release ( Figure 6 ). These findings are consistent with the possibility that BDNF-enhancement of glutamatergic transmission stimulates activity-dependent VEGF release. There is also evidence that BDNF stimulates VEGF expression and release via the mechanistic target of rapamycin complex 1 pathway and induction of hypoxia-inducible factor-1α in a neuroblastoma cell line . These reports raise the possibility that activity-dependent, as well as intracellular, signaling could be involved in VEGF release, and further studies are needed to determine the exact pathways.
Ketamine rapidly increases the number and function of spine synapses on layer V pyramidal neurons in the mPFC, and these synaptic effects require activity-dependent BDNF and VEGF release . Similar to ketamine, rapastinel and scopolamine also increase the number and function of spine synapses in the mPFC . All of these rapid-acting antidepressants produce neurotrophic actions in primary cortical neurons, including increased BDNF release and increased dendrite complexity . We have also reported that ketamine, as well as VEGF induction of dendrite complexity, is completely blocked by a selective FLK1 inhibitor . The current study demonstrates that BDNF increases dendrite complexity in primary neurons and that these neurotrophic effects are completely blocked by incubation with a selective FLK1 inhibitor. These findings provide further evidence that VEGF is required for the neurotrophic actions of BDNF on dendrite complexity.
The results clearly demonstrate a requirement for VEGF in the antidepressant-like and neurotrophic actions of BDNF, but we also examined reciprocal interactions between these two factors. Somewhat surprisingly, we found that the antidepressant-like and neurotrophic effects of VEGF required BDNF release and TRKB signaling. Using similar experimental approaches, the results show that coinfusion of a BDNF nAb into the mPFC blocks the antidepressant-like behavioral responses of VEGF in the three behavioral paradigms tested. The neutralizing antibody used for these studies was specific to BDNF as there was no cross-reactivity with VEGF examined by immunoblot analysis. We also found that incubation of primary cortical neurons with VEGF stimulates the release of BDNF into the culture media, and that this effect is blocked by a selective FLK1 antagonist. In addition, the results show that VEGF stimulation of dendrite complexity is blocked by incubation with a selective TRKB receptor antagonist. The mechanisms underlying VEGF stimulation of BDNF release are unclear but could also involve activity-dependent effects. VEGF increases presynaptic glutamate release probability, leading to enhanced glutamatergic transmission in primary hippocampal slices , and it also increases excitatory transmission via postsynaptic NMDARs . VEGF also stimulates the release of Ca 2+ from intracellular stores via activation of phospholipase Cγ , which could stimulate BDNF release ( Figure 6 ).
In conclusion, the current results in combination with our recent findings demonstrate a key interdependence between BDNF and VEGF signaling in the mPFC and suggest that this reciprocal dependence plays a crucial role in the neurotrophic and antidepressant-like effects of rapid-acting antidepressants. This is particularly clear for the antidepressant-like actions of ketamine, which are blocked by inhibition of either BDNF or VEGF . Although the requirement for VEGF in the actions of other agents, notably rapastinel and scopolamine, have not been tested and the role of VEGF in patients with depression remains unclear, the prediction is that there is also a requirement for VEGF. These findings raise several interesting possibilities regarding the consequences of this interdependence. For example, previous studies demonstrate that deletion of either BDNF or VEGF in mice is insufficient to produce depressive behaviors, possibly because of the antidepressant-like and neurotrophic actions of the remaining factor , and it would be interesting to determine whether dual-deletion mutants display depressive-like behaviors. A related consequence is whether a functional polymorphism of one factor would increase vulnerability but is insufficient alone to produce depression, which appears to be the case for the BDNF Val66Met polymorphism . In contrast, the antidepressant actions of ketamine and other rapid-acting agents could be attenuated by a functional polymorphism of one factor, as reported for the ketamine response in carriers of the BDNF Met allele , although this effect also appears to be race specific . The present results provide new insights on the complex interdependence of these two critical neurotrophic factors that could have important consequences for understanding the pathophysiology and treatment of depression.
The VAL66MET polymporphism may predict response to Ketamine and suggest additional therapies to add on to those who do not respond:
Our results suggest that MDD patients with the Val/Val BDNF allele at rs6265 are more likely to exhibit increased antidepressant response to ketamine than Met carriers. Liu and colleagues
(8) alluded to the possibility that the weakened antidepressant response to ketamine infusion typically seen in approximately
30% of patients might be related to the Val66Met polymorphism. Our finding is consistent with their hypothesis that rs6265 genotypes could help separate ketamine responders from nonresponders. They also suggested that it may be possible to administer BDNF-enhancing compounds to Met allele-carrying patients before administering ketamine. Standard antidepressants, electroconvulsive therapy, and brain stimulation techniques such as transcranial magnetic stimulation all increase BDNF levels (11,12); exercise also has BDNF secretion-enhancing effects (13).
In contrast, a previous report that included the large STAR*D cohort found no association between traditional antidepressants and rs6265 (14). This suggests that the Val66Met variant
may play a different role in patients treated with traditional antidepressants as opposed to those treated with rapid-acting antidepressants such as ketamine.
A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene,
a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with
alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We
generated a variant BDNF mouse (BDNFMet/Met) that reproduces the phenotypic hallmarks in
humans with the variant allele. BDNFMet was expressed in brain at normal levels, but its secretion
from neurons was defective. When placed in stressful settings, BDNFMet/Met mice exhibited increased
anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant
BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.Human Biomarkers of Rapid Antidepressant EffectsMood disorders such as major depressive disorder and bipolar disorder—and their consequent effects on the individual and
society—are among the most disabling and costly of all medical illnesses. Although a number of antidepressant treatments are available
in clinical practice, many patients still undergo multiple and lengthy medication trials before experiencing relief of symptoms. Therefore
a tremendous need exists to improve current treatment options and to facilitate more rapid, successful treatment in patients suffering
from the deleterious neurobiological effects of ongoing depression. Toward that end, ongoing research is exploring the identification of
biomarkers that might be involved in prevention, diagnosis, treatment response, severity, or prognosis of depression. Biomarkers
evaluating treatment response will be the focus of this review, given the importance of providing relief to patients in a more expedient
and systematic manner. A novel approach to developing such biomarkers of response would incorporate interventions with a rapid
onset of action—such as sleep deprivation or intravenous drugs (e.g., ketamine or scopolamine). This alternative translational model for
new treatments in psychiatry would facilitate shorter studies, improve feasibility, and increase higher compound throughput testing for
these devastating disorders.________________________________________________________________________Predictors of Response to Ketamine in Treatment Resistant Depression and Bipolar DisorderAbstract: Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects
in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD)
and bipolar disorder (BD). The identification of depressed sub-populations that are more likely
to benefit from ketamine treatment remains a priority. In keeping with this view, the present
narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as
part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov,
and Scopus were searched for relevant articles from inception to January 2018. The search term
ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder,
predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of
response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family
history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels),
polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate
ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF
allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of
alcohol use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression
more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding,
metabolic-inflammatory alterations are emerging as possible pretreatment response predictors
of depressive symptom improvement, most notably being cognitive impairment. Sophisticated
data-driven computational methods that are iterative and agnostic are more likely to provide
actionable baseline pretreatment predictive information.In addition to pretreatment pro-inflammatory cytokines potentially moderating response to
ketamine, preliminary evidence indicates that circulating vitamin B12 levels may affect the treatment
outcomes with ketamine . Previous reports indicate that higher levels of circulating vitamin B12
are associated with a greater probability of response to conventional antidepressants .To contextualize the foregoing results, a single small study with 20 subjects identified vitamin
B12 levels were cross-sectionally associated with bipolar depression. Specifically, ketamine treatment
“responders” had higher levels of circulating vitamin B12 when compared to “non-responders”,
where “responders” were subjects with a 50% or greater reduction of HDRS, as compared to baseline,
on the seventh day after infusion. This result is consistent with studies showing that higher levels of
vitamin B12 are positively correlated with the conventional antidepressant response [21,35].3.5. Neurochemistry Variables
Abnormalities in amino acid neurotransmitter systems are postulated to play a critical role in the
pathoetiology of MDD . Stress-induced depression and cognitive impairment have been found
to be associated with the reduced expression of the gamma-aminobutyric acid (GABA) receptors in
the brain .
Using proton magnetic resonance spectroscopy (1H-MRS), Salvadore et al. (2012) measured levels
of the amino acid neurotransmitters gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate
(a surrogate marker of glutamine), in the ventromedial and the dorsomedial/dorsal anterolateral
prefrontal cortex before and after IV ketamine treatment in subjects with MDD (n = 14). Following
ketamine infusion, depressive symptoms significantly improved after 230 min, as assessed by the
changes in the mean MADRS score. The authors reported that while pretreatment GABA and glutamate
did not correlate with an improvement of depressive symptoms, pretreatment Glx/glutamate
ratio was found to be significantly and inversely correlated with the symptomatic improvement
with ketamine .
On a driving-based motor learning task subjects with this genotype showed greater error during short-term learning and poorer retention over 4 days, relative to subjects without the polymorphism. The presence of this BDNF polymorphism is associated with differences in brain motor system function, altered short-term plasticity, and greater error in short-term motor learning. [PMID 19745020]
Next time you get cut off by a another driver, consider giving the offender a break: One-third of Americans might be genetically predisposed to crappy driving.
No, really, it’s not just your imagination.
In a new study of college undergraduates, those with a common genetic variation scored 20 percent worse in a driving simulator than their counterparts.
“The people who had this genetic variation performed more poorly from the get-go and learned more slowly as they went along,” said Steven Cramer, a University of California, Irvine neurologist, who works on helping stroke victims recover. “Then, when we brought them back four days later, they had more forgetting.”
The single nucleotide polymorphism, or SNP, is just one of millions of single-letter variations between humans’ genetic codes. This one occurs in a gene that produces a protein called brain-derived neurotrophic factor, which helps regulate the formation of new synapses, and the maintenance of old ones. BDNF plays a very important role in what’s called neuroplasticity, or the brain’s ability to rewire itself on the fly.
As described in a paper published in the journal Cerebral Cortex, study participants were asked to drive 16 laps in a driving simulator that was essentially a screen with a steering wheel. As they drove around the course, they attempted to keep their cars on a black strip in the center of the road. The software grades their ability to complete that task quantitatively. And, of a small sample of 29 students, people with that single genetic difference, called Val66Met, performed more poorly than their demographically similar counterparts.
“It’s a very nice study, well designed, and the questions they ask are good,” said Clifford Nass, a co-founder of Stanford’s CarLab, an interdisciplinary research institute. He was not part of the study.
Cramer considers the simulation a good proxy not just for driving, but for other complex motor skills tasks. Because it’s not controlling a motor vehicle, per se, that he’s interested in, but how the brain learns, or relearns complex tasks.
When people have a stroke, and a portion of their brain dies, they have to relearn tasks using different parts of their brains. Individual genes are only part of the symphony of influences that determine individual behavior, but the Val66Met variation appears to have an unusually strong influence on the brain’s activity.
“There is mounting evidence that the one in three people who have this variation have less plasticity than the two-thirds of people who lack that genetic variation,” Cramer said.
Results from a separate study reported earlier this year in Scientific American also found that genetic variation in BDNF helped determined people’s skill at a simple computer game.
The effect is so pronounced, in fact, that Cramer said he could imagine future stroke patient routing within hospitals based on the SNP.
“I wonder if there aren’t going to be treatments, when they have traumatic brain injury and you’re in the rehab ward, where they test the gene and say, ‘Send them to the BDNF ward,'” he said.
So, if the presence of the gene makes you a worse driver, a slower stroke-victim recoverer and possibly has other negative effects, why is the variant still present?
“Variations can stick around just for the fact that they are not that bad for you,” said Bruce Teter, a geneticist who studies the brain at UCLA. “They don’t kill you before you reproduce, in which case, there is no selective advantage or disadvantage.”
But it also turns out that people with the Val66Met variant could be less susceptible to degenerative neurological disorders like Parkinson’s and Huntington’s.
“Originally people thought plasticity had to be good, as it’s related to the ability of the brain to adapt and learn and things like that,” Teter said. “But neuroplasticity can also be bad for you in situations where the kinds of changes that are seen are deleterious.”
But if you want to stay out of car accidents, it’s better to have the dominant BDNF variant, Cramer’s study suggests. And if further work continues to support that idea, the question is, can or should we do anything with that information?
“Let’s pretend that the one in three people are more prone to car accidents,” Cramer said. “It’s up to society to say, how do we deal with that fact?”
New research suggests that your skills behind the wheel may be affected by your genes.
To better understand the effects of a variant in the BDNF gene on motor skills learning, Steven Cramer and colleagues at UC Irvine tested 29 subjects in a driving simulator. Their results, published in the journal Cerebral Cortex, might make you think twice about whom you go on your next road trip with.
Subjects sat in front of a screen with their hands firmly planted at “10 and 2” on a steering wheel and guided their “car” around a track, attempting to stay centered over a black line. The steering was tuned so that subjects had to begin turning before the screen actually changed.
Over the course of 15 trials, all of the study subjects got better at the driving task. But the seven people who had a T improved less than those with two Cs. When subjects returned to the lab four days later for a final lap, everyone had forgotten how to drive the simulator a little bit, but those with a T did worse.
“These people [with a T at ] make more errors from the get-go, and they forget more of what they learned after time away,” Cramer said in a press release.
The BDNF protein helps to regulate how nerve cells make new connections and maintain old ones. The T version of the variant, also known as the Val66Met, reduces the amount of BDNF available in the brain and has been linked to impaired learning and memory. Studies have shown that stroke victims with this variant don’t recover as well as those who lack it.
But there may be an upside: the variant seems to have a beneficial effect on cognition in people with Parkinson’s disease, Huntington’s disease, lupus and multiple sclerosis.
“It’s as if nature is trying to determine the best approach,” Cramer said. “If you want to learn a new skill or have had a stroke and need to regenerate brain cells, there’s evidence that having the variant is not good. But if you’ve got a disease that affects cognitive function, there’s evidence it can act in your favor. The variant brings a different balance between flexibility and stability.”
Welcome to Mind Matterswhere top researchers in neuroscience, psychology, and psychiatry explain and discuss the findings and theories driving their fields. Readers can join them. We hope you will. This week: Genes, Environment, and Depression:How Nurture Can Save You from Your Own Genes _____________________ Introductionby David DobbsEditor, Mind MattersAmong biology’s more riveting inquiries is the investigation of gene-environment interactions — the demonstration that a person’s genes constantly react to experience in a way that changes behavior, which in turn shapes environment, which in turn alters gene expression and so on. As David Olds described a few weeks ago, this new subdiscipline is yielding startling insights about how nature and nurture mix to help determine one’s health and character. This week reviewer Charles Glatt reviews a study that takes this investigation a level deeper, examining how two different gene variants show their power — or not — depending on whether a child is abused, nurtured, or both. As Glatt describes, this study, despite its grim subject, suggests promising things about the power of nurture to magnify nature’s gifts or lift its burdens. _____________________ Gene-Environment Interactions:When Nurture Wears a White Hat Charles GlattWeill Cornell Medical College, New York, NY For centuries, philosophers, theologians and biologists have debated the relative roles of inborn traits versus environmentally defined experiences in determining what and who we are. This nature-nurture debate carries fundamental implications for our understanding of self-determination, or free will. Indeed, as research has begun to identify genetic risk factors for certain behavioral traits, these risk factors have already been used in court (see here and here)to argue that punishment should be lessened for convicted felons — the presumption being that their genes made them inherently more likely to misbehave.The importance and challenge of the nature-nurture debate in behavior has recently spawned a new area of research that looks at the interaction between genetic risk factors and experience in the development of psychopathology. A study led by Joan Kaufman and Joel Gelernter, both of Yale, and published in Biological Psychiatry, has demonstrated what many of us have intuitively concluded, which is that both nature and nurture contribute to who we are. In this particular study, genetic and environmental factors interact to determine risk for depression. In their study, “Brain-Derived Neurotrophic Factor-5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children,” Kaufman, Gelernter and colleagues found distinct gene-environment interactions in the risk for depressive symptoms. Other studies have found similar interactions, but looked mainly at interactions between single genetic and single environmental risk factors. This study ups the ante by examining various interactions among two genetic and two environmental factors, including a four-way interaction with two genetic and two environmental variables. Where the Money Is Kaufman and colleagues took the approach of bank robber Willie Sutton who, when asked why he robbed banks, is said to have replied, “Because that’s where the money is.” Kaufman and colleagues focused on the most well known and accepted genetic and environmental risk factors for depression to see how they interacted with one another to alter risk. On the nature side, they focused on polymorphisms — genetic differences between individuals — that have been implicated in depression through a variety of methods. The first polymorphism is in the regulatory region of the gene for the serotonin transporter. This polymorphism is the 5-HTTLPR, which stands for the serotonin (5-hydroxytryptamine, 5-HT) transporter linked polymorphism. The 5-HTTLPR has received much research attention because it appears to alter the expression of the serotonin transporter molecule, which is the target of the commonly prescribed serotonin-selective reuptake inhibitor (SSRI) class of antidepressants and is itself implicated in depression. Caspi and Moffit and other research groups have repeatedly found this polymorphism to be associated with depression in the presence of stressful life events. The second polymorphism Kaufman studied is the gene for brain-derived neurotrophic factor, or BDNF. BDNF is a molecule that seems to encourage the growth of new neurons; it appears to be central to brain growth and learning. This polymorphism in the BNDF gene alters the efficiency of secretion of this molecule. Recent studies in animals and humans have shown that BDNF levels are decreased during stress and depression and that SSRIs act at least in part by normalizing the levels of BDNF. (BNDF levels have been shown to rise in response to successful SSRI treatment, as well as in response to successful psychotherapy and, for that matter, exercise. An earlier Mind Matters by Francis Lee and Larry Tecott reviewed a rare paper finding a downside to BNDF. ) Thus it is not hard to imagine that polymorphisms (that is, certain variants) of the BDNF gene might interact with other factors to contribute to depression risk. BNDF and 5-HTTLPR, then, were the “nature” factors Kaufman and colleagues examined. From the “nurture,” or environment/experience, side they added two epidemiologically established modifiers of risk for depression — childhood abuse/maltreatment on one hand and, on the other, positive social support.Please Interact Amongst Yourselves The researchers studied 109 children who had been removed from their parents’ care due to reports of abuse or neglect and 87 control children with no reports of abuse or maltreatment. They scored all the children for depressive symptoms such as irritability, crying and reluctance to see friends. High scores on this scale indicate greater depression. They then compared the distribution of these scores in children with different combinations of the 5-HTTLPR and BDNF polymorphisms described above. They found that children with the “bad” form of 5-HTTLPR had higher depressive symptom scores — but only if they had a history of maltreatment. Bad 5-HTTLPR made it more likely (but not certain) that an abused child would develop depression. But it created no effect on depression scores in children without a history of maltreatment. It was like a seed that had to be watered by abuse. This replicates similar findings in studies by Caspi and Moffit and other groups. Kaufman and colleagues then looked at how the different forms of BDNF might affect this picture. They found that a certain version (or allele) of the BDNF gene amplified the effects of the 5-HTTLPR gene, making it even more likely that a given child would develop depression — but again, only if the child had suffered abuse. Finally, Kaufman and colleagues looked at the effects of social support. They asked the children about people in their lives whom they could talk to about personal things, count on to buy them things they needed and other, similar signs of supportive relationships, and from the answers derived a social support score. Children were then characterized as having high or low support. The researchers found that high levels of such nurturing counteracted the effects of the genetic risk factors almost completely.Balance of Power As with any behavioral genetic study, one must be careful not to overinterpret these findings, because virtually no study in behavioral genetics is consistently or completely replicated. Nonetheless, some additional points about this paper can help inform us on the nature-nurture debate. First, depression scores and categorical diagnoses of depression were significantly higher in children with a history of maltreatment versus controls even before any genetic analysis was factored in. In a similar vein, the highest average depression score of any genotype category in the unabused control children was lower than the average depression score for any genotype category in the maltreated children; genes alone weren’t likely to make the child depressed, but maltreatment alone could. These findings suggest that, at least regarding these specific polymorphisms, nurture beats nature. This conclusion will come as a relief to believers in human free will. It also argues strongly for the identification of children at risk for maltreatment and strong actions to reverse the negative effects of this experience.
Objective:To evaluate the antidepressant effect of oral scopolamine as an adjunct to citalopram.
Method:In this randomized double-blind placebo-controlled study, patients were assessed in the outpatient clinics of 2 large hospitals from November 2011 to January 2012. Forty patients (18–55 years) with major depressive disorder (DSM-IV-TR criteria) and 17-Item Hamilton Depression Rating Scale (HDRS) score ≥22 were randomly assigned to scopolamine hydrobromide (1 mg/d) (n=20) or placebo (n=20) in addition to citalopram for 6 weeks. HDRS score was measured at baseline and days 4, 7, 14, 28, and 42. The primary outcome measure was HDRS score change from baseline to week 6 in the scopolamine group versus the placebo group. Response was defined as ≥50% decrease in HDRS score; remission, as HDRS score ≤7.
Results: Augmentation with scopolamine was significantly more effective than placebo (F1,38=5.831, P=.021). Patients receiving scopolamine showed higher rates of response (65%, 13/20 at week 4) and remission (65%, 13/20 at week 6) than the placebo group (30%, 6/20 and 20%, 4/20, respectively; P=.027, P=.004, respectively). Patients in the scopolamine group showed higher rates of dry mouth, blurred vision, and dizziness than the placebo group.
Conclusions: Oral scopolamine is a safe and effective adjunct for treatment of patients with moderate to severe major depressive disorder.