Science

Psychiatry's Big Bang

How two landmark studies are changing how we think.

There are two related studies that keep reappearing together so often on this Website that I am seriously contemplating a name change to "McMan’s Short Allele Serotonin Transporter Gene What’s Happening Now Web."

On March 30, 2006, a panel of NIH brain researchers reported on their respective science projects to the NIMH Pediatric Bipolar Disorder Conference, held in Bethesda, MD. What emerged from their presentations was the truly seminal impact of these two studies on our understanding of the biology of human behavior.

Taken together, these studies and their successor findings have everything – a suspect gene, genes in collusion, tell-tale neurotransmitter trails, a smoking amygdala, limbic system accomplices, cortical funny dealings, and a complicit environment, all combining to create a deadly destructive swath of emotional mayhem.

The First Study

In an article in the July 19, 2002 Science, NIMH researchers (Ahmad Hariri PhD, lead author) reported on what may be the first study in humans to link genes to emotions.

Healthy subjects performed a simple task as their brains were being scanned in an MRI machine. In response to a set of photos of "scary faces," something major happened. In some of the subjects, a certain part of their brain lit up, the amygdala, which plays a major role in fear and arousal.

It turns out that the subjects with the hyperactive amygdala also had a certain gene variation. The gene in question involves the serotonin transporter in the neuron, the reuptake pump targeted by SSRI antidepressants. Just to show you how significant this gene is, it comes with two abbreviations, 5-HTT and SERT. Its more formal genetic designation is SLC6A4, with the chromosomal address of 17q21. Another abbreviation, 5-HTTLPR, has something to do with promoter regions (don’t ask).

There are two variations to the 5-HTT gene, what geneticists refer to as the "short allele" and the "long allele," respectively.

In the Hariri study, the individuals with the short allele drew the short genetic straw. What their brain scans showed was that their amygdala worked way too efficiently for their own good, like a smoke alarm that goes off for no apparent reason. This may be fine if you dropped hot coffee onto your lap while swerving to avoid a spent plutonium rod flying off a truck on the New Jersey Turnpike. But slightly less panicky is the way to go when you need to explain to airport security how that same plutonium wound up in those tennis ball containers in your carry-on.

Okay, time to test this in the field …

The Second Study

About 35 years ago, researchers from the University of Otago recruited a "birth cohort" of more than 1,000 infants born in Dunedin, New Zealand, and subsequently assessed them every two or so years. "Longitudinal" findings of this sort represent the gold standard of population studies, as opposed to "retrospective" findings based on recalled events. Over the years, this cohort has been to medical and psychiatric and behavioral research what wild Tanzanian chimps have been to Jane Goodall.

On July 18, 2003, Science magazine published the latest installment coming out of Dunedin. The year before, the same research team, from Kings College and the University of Wisconsin, had identified certain childhood risk factors in antisocial behavior, together with a strong link to a suspect gene (acting on the enzyme MAO-A). This time, the researchers (Avshalom Caspi PhD, lead author) analyzed the cohort for stressful events over the past five years, such as death in the family, losing a job, or breakup with a partner.

Lo and behold, among those meeting the criteria for four recent stressful events, 43 percent of those with the short allele to the serotonin transporter gene experienced depression vs just 17 percent with the long allele.

In a field where researchers are accustomed to teasing out frustratingly small statistical blips, these numbers represent something truly seismic.

It is important to note that the researchers did not identify this variation as a "depression gene." Rather, drawing the short genetic straw makes one susceptible to stress and its downstream effects (which may include depression). One also needs to have regard for the fact that not all depressions are caused by stress.

Think of the short allele as a "vulnerability gene." Those with the long allele, by contrast, may be regarded as the proud owners of a "resilience gene."

To further clarify the resilience factor, the depression rates for those with the long allele did not vary, regardless of whether they had experienced zero recent stressful events or four or more. Those with the short allele, by contrast, only experienced this same low depression rate as the long allele group when not exposed to any major stress, period.

For years, we had been subjected ad nauseum to arguments about nature vs nurture. As this study forcefully demonstrates, we are talking about nature via nurture. Put another way, in the words of one of the authors of the first study, Daniel Weinberger PhD of the NIMH, to last year’s American Psychiatric Association’s annual meeting, this particular gene "impacts on how threatening the environment feels." Or, as Andreas Meyer-Lindenberg MD, PhD of the NIMH told the Pediatric Bipolar Disorder Conference, the short allele "impairs your ability to respond to what life throws at you."

Noted the Dec 19, 2003 Science magazine: "Together, these studies suggest that the gene variant biases people to perceive the world as highly menacing, which amplifies life stresses to the point of inducing depression."

Science magazine was reporting on what it considered the top ten scientific breakthroughs of the year. This pair of findings (plus several others) ranked number two. The origin of the universe came in first, and we’re not about to argue with the big bang and all that. In terms of gaining an insight into our illness, however, the Hariri and Caspi findings constitute big bang enough.

Events Leading Up to the Big Bang

It is fair to describe Klaus-Peter Lesch MD of the University of Wurtzburg as the father of research into the serotonin transporter gene. His published studies on the topic, according to a PubMed search, span from 1992 to April this year. In 1996, Dr Lesch was part of a team that teased out the allelic variations to this gene (first isolated in 1993), and suggested that these variations "may play a role in the expression and modulation of complex traits and behavior."

Similar work was going on at other centers, including a research team from Royal Edinburgh Hospital, who the same year advanced the hypothesis that these variations "may contribute to susceptibility for both major depression and bipolar disorder."

In 1998, however, a German research team tested the hypothesis and came up empty. After investigating a population of 115 patients and 284 controls, the researchers reported that "no association between alleles conveying functional differences in serotonin transport gene expression and major depressive disorder or bipolar disorder could be found."

Based on their data, the authors of the study concluded that this gene "is not commonly involved in the susceptibility to mood disorders." In all, there would be some eight studies involving failure to make a depression connection.

Subsequent studies explored possible associations between both alleles and illnesses such as Alzheimer’s, alcoholism, anxiety, autism, and personality disorders.

Clearly, these alleles had to be involved in something, one reads into these studies, but what? The title to one article dating from 2000 has a decidedly desperate ring to it: "A rare short allele of the serotonin transporter promoter region found in an aggressive schizophrenic patient of Jewish Libyan origin."

Meanwhile, researchers began checking out the side entrances to a mood connection, such as possible associations to suicidal behavior or response to SSRIs. The first Eureka! came in the form of a 2000 French study that investigated stress in mice lacking the serotonin transporter gene.

The second one came two years later from an NIH team investigating rhesus monkeys.

The stage was set for the human brain’s big bang.

Building on the Big Bang

The most important theme to emerge from listening to brain scientists talk at the NIMH Pediatric Bipolar Disorder Conference was their enthusiasm for carrying the research to new levels of understanding. A sampling …

The Fringe Connection

At the Pediatric Bipolar Conference conference, Andreas Meyer-Lindenberg MD, PhD of the NIMH turned in some of his recent homework. In his first study, from 2005 (Pezawas lead author), healthy individuals were placed in an MRI machine and exposed to the same scary faces from the Hariri study. This time, the scans revealed that those with the short allele showed less structural and functional connectivity in the circuitry linking the amygdala to the cingulate.

The cingulate is positioned below the cortex and is central to both top-down and bottom-up communication in the brain. With compromised circuitry, there was nothing to dampen the signal from the amygdala to the cingulate. The amygdala was coming in loud and clear, way too loud and clear for comfort.

Moreover, the researchers found a 30 percent deviation in scores of "harm avoidance" (an inherited anxiety trait), that corresponded to the condition of this circuitry.

5-HTT is not the only gene in play. You may recall that Dr Caspi’s 2003 Dunedin Cohort short allele study was preceded by a 2002 MAO-A study involving childhood risk factors (such as being abused) for antisocial behavior and violence. Once again, we are talking about a gene that influences how we react to external situations.

MAO is an enzyme that breaks down the three neurotransmitters we are all familiar with, especially serotonin. Mice genetically engineered to lack the MAO-A gene have been found to have higher levels of dopamine, serotonin, and norepinephrine and enhanced amygdala-dependent emotional learning, with the males displaying violent behavior.

In a 2006 study, Dr Meyer-Lindenberg and his colleagues once more rounded up the usual suspects and placed them in an MRI machine. (Not all at the same time. I think he had them line up single file outside the door.)

As with the previous brain scan studies, the subjects were exposed to scary faces. Yet again, there were structural and functional deficiencies in the amygdala-cingulate circuitry, plus areas of the cortex, this time involving individuals with the "l-allele" (as opposed to the "h-allele") of the MAO-A gene. At the same time, only the men in the study (in response to different tasks), had increased activity in the amygdala and hippocampus (involved in emotional memory) and failed to activate the cingulate cortex (responsible for inhibiting behavior).

In addition, an NIMH study under review shows the ventromedial prefrontal cortex modulating amygdala activity through the cingulate. Ah, a part of the brain associated with "thinking," your protection against lashing out like a caged beast. Thus, if you happen to be in the middle of a heated marital dispute, this is probably the time to draw in a slow breath and very calmly say, "I hear you. I think we can work something out."

If your amygdala is doing the talking, however, it may come out something like this: "And besides, you’re lousy in bed!"

At this stage, storming out the door in a huff may be your best option. The amygdala is getting through to the cortex, but the cortex is clearly having difficulty getting through to the amygdala. You probably will be sleeping on the couch tonight, but thankfully you can count on your cortex not to let your behavior escalate from regrettable to extreme. But suppose your top-down circuitry is faulty?

As Dr Meyer-Lindenberg explained, we need a breakdown in the brain’s control mechanisms to become violent.

When Push Comes to Shove

Klaus Miczek PhD of Tufts University (and frequent NIH collaborator) is a leading expert on the biology of aggression. The title of his talk was "Mesocorticolimbic 5-HT and GABA Interactions," which is about to be made into a big-budget slasher movie. Significantly, the Caspi MAO-A study was his starting point.

Dr Miczek pointed out that violence is more complex than merely a serotonin deficiency (which he referred to as a "romantic myth"). A 2003 study of his involving aggressive rats found that dopamine levels rose and serotonin decreased in anticipation of combat. The dopamine and serotonin levels in the control rats remained the same.

The GABA part of the talk had to do with alcohol. Alcohol interferes with GABA’s role in modulating over-excitement in the brain. A certain subgroup of individuals are exceedingly aggressive with alcohol, Dr Miczek explained.

Hmm. Suppose a stressed-out individual starts drinking. Time to look at the 5HTT gene again …

Everyone’s Favorite Candidate Gene

Christina Barr VMD, PhD of the National Institute of Alcohol Abuse told the NIMH conference that the serotonin transporter gene is everyone’s favorite candidate gene. Depression may be just one outcome of stress. Harm avoidance may be another. What about alcoholism?

Dr Barr described her 2004 study involving rhesus monkeys, in which "short allele" female youngsters raised apart from their mothers displayed a stronger appetite for alcohol than their "long allele" counterparts.

This is not the same as saying that alcoholism is caused by stress. Indeed, there is strong evidence of other genes in play. But we are also beginning to see why some of us may need a drink at the end of a very trying day.

So what is going on? Dr Barr referred to "allostatic load." The opposite of "allostasis" is "homeostasis." In this context, in homeostasis the body is in a state of equilibrium and stability, or as Dr Barr describes it, "the regulation of a physiological setpoint in order to maintain internal viability." Allostasis, by contrast is "achieving stability through change." This may be okay if the system habituates to repeated challenge, but failure to adapt can result in system overload.

Dr Barr reeled off some of the stress-sensitive systems in the brain. These include: proteins that promote the growth and plasticity of neurons (such as BDNF); proteins that regulate cell death (such as bcl-2); the HPA axis (which releases cortisol into the system); and neurotransmitter systems (including serotonin, dopamine, GABA, glutamate, and various neuropeptides such as CRH).

Throw in a "hippocampal endangerment hypothesis" and other theories, and one begins to develop an appreciation for why homeostasis is what those of us with mood disorders need to aspire to.

Almost Done

In a 2006 article he co-authored with Dr Weinberger, Dr Meyer-Lindenberg talks about "intermediate phenotype," also referred to as "endophenotype." In this context, we are not necessarily looking for a "depression gene" or a "bipolar gene." It was only when researchers looked further upstream from mood that they found spectacular evidence of how a certain gene may actually affect our ups and downs.

As Drs Weinberger and Meyer-Lindenberg explain, the purpose is to link genes "to structural and functional variations in brain systems related to cognition and emotion."

There is always the possibility that the success of the 5HTT studies and related findings are nothing more than flukes, and that years from now we will be looking back in wonder over how naive we were. But the early returns suggest otherwise. Be encouraged. Everyone is getting smarter.

Final Word

We may not be able to trade in our factory reject short alleles for high-performance long ones, but that does not mean we are slaves to our genes and biology and upbringing. Quite the contrary, armed with foreknowledge of our vulnerabilities, we can plan ahead accordingly. There are many ways, for instance, to handle the stress that sets us up for mood episodes, from scheduling our lives to minimize tense situations to honing skills that take some of the worry out of personal dealings to picking up a wide range of coping mechanisms to employing sensible lifestyle routines.

Also, the fact that some of our brain circuitry may be faulty does not necessarily mean it is permanently hardwired. The brain is always in a constant state of laying down new roadwork, much of it guided from the top down by our own conscious efforts. Never underestimate the power of healing, and make the term, neuroplasticity, your new mantra. Live well …

May 9, 2007, reviewed Feb 11, 2008