January 24, 2013
The Relationship Between Depression And PTSD, And Getting Past The Negative Bias
Alan McStravick — Exclusive for redOrbit.com
The study of serotonin levels, the relation between depression and PTSD, and getting past the negative biases in human study reporting
It is not uncommon to associate depression with sadness, frustration and a general sense of ennui. Anyone who has suffered from depression knows there isn´t anything good about it. Or is there?
At the recent conference called Rat Genomics and Models at the MÃ¸ller Centre at Cambridge University, Dr. Judith Homberg, associate professor at the Donders Institute for Brain Cognition & Behavior at Radboud University, presented her findings on how levels of serotonin in the brain might play an important role in both depression and post-traumatic stress disorder (PTSD). Her work, as one might infer from the name and subject of the conference, used the rat as a model for her study.
A term that was bandied about often at the conference was ℠knockout rat´. A knockout rat is one that has been genetically engineered to have a single gene in its genome turned off through the process of targeted mutation. This is done in order to mimic human diseases, making the animal a particularly valuable tool in studying gene function as well as the discovery and development of pharmaceuticals.
After Dr. Homberg´s presentation, I had the opportunity to speak with her further about her work and how she came to be interested in this particular field of study. According to Homberg, she chose this avenue because she wanted to find a comparative link between her own study and human studies that focused on serotonin levels in the brain. But what she found surprised her.
“I discovered there was a strong bias in the human literature toward the negative effects [of depression] but no literature on the positive effects. If there were only negative effects, then it should be finished.” By “finished,” she meant that the negative phenotype — i.e. the gene for depression — should have disappeared at some point in mankind´s evolutionary history. This led Homberg to question what, if any, could be the positive effects of such a gene or group of genes.
For this task, knockout rats provide a very useful way of exploring gene function. “Knockouts [are] interesting, because we do not have them in humans,” she explained. “We have genes that have mutated but none that have stopped working altogether.”
The yin to the knockout rat´s yang is the so-called knockdown rat. Homberg´s team produced these knockdown rats for their study utilizing adult rats. They opted to affect these rats´ serotonin production as adults since their neural development is completed at this stage thus providing less opportunity for the reduction of the expression of the serotonin supporters in the brain.
“This is because in our research there is the question of whether the phenotypes we see in the knockout animals, and also in people with polymorphism, are based on their developmental changes,” Homberg explained. “Serotonin, it is known, plays a major role in neural development. One can imagine that if you have a lot of serotonin already during neural development, you might change how the brain is developed.”
When testing both the knockout and knockdown rats, the team presented the animals with a series of anxiety tests. To their surprise, the researchers actually observed the same behavior in both types of rat. “Based on that, we think this is mainly due to high serotonin levels in these animals,” Homberg explained. “They showed elevated anxiety which increased their responsivity to the environment. We do not believe their response was affected by early developmental changes.”
Although not directly discussed in her presentation, Homberg noted that both the knockout and knockdown rats were tested on their cocaine cell administration paradigms.
“Both models show an increase in cocaine cell administration. What this data shows is that both are more anxious and, therefore, more sensitive to adverse stimuli, but also, more sensitive to positive, or re-wiring, stimuli. And because they are looking very similarly [sic], at least in behavioral phenotypes, we think it is more because of the high serotonin levels than the neuro-developmental changes. This might bring an advantage if you become ill because of exposure to stressful stimuli. It is due to the high serotonin levels that the individual becomes more vigilant to the environment.”
AN OUTSIDE-THE-BOX APPROACH TO DEPRESSION
In what could best be described as a ℠through the looking glass´ approach, she wanted to explore what could make someone vulnerable to depression and, by extension, another serotonin-related disorder, PTSD.
“The idea that stress, in this susceptible population, leads to depression “¦ We can also ask the question the other way around. ℠If these people are so adaptive to their environment, what is actually needed to get them depressed?´” For the purposes of her study, Homberg says, this is a very fair question because it allows us to look into depression from the other side.
Medically and psychiatrically, depression is actually a very poorly defined disease. We know its symptoms and outcomes but we have little concrete understanding of its specific causes at the genetic and neurobiological level. It has yet to be linked to any specific area of the brain, and the effects of depression are as wide-ranging as the people who suffer from it. Some patients become agitated and aggressive while others withdraw and simply shut down. So what is depression actually?
“Of course if you have a depressed patient, you can see the person is suffering, but to some extent depression can just be an adaptive response to a situation they face. But for some people, that gets worse.” Finding and understanding that trigger is a fascinating proposition for Homberg.
One possible trigger for elevated serotonin levels comes from the essential amino acid from which serotonin is derived. Tryptophan is delivered to the system through oral administration. We all usually get a fairly good dose around Thanksgiving, for instance, in those tryptophan-rich turkeys on which we gorge ourselves. And since oral ingestion is the primary delivery for the amino acid, one can actively manipulate the amount of serotonin in their brain by decreasing the amounts of tryptophan that an individual consumes.
Homberg points out that this specific association has yet to undergo scientific evaluation, but notes that, “it may be interesting to see whether such a modification of all of the drugs that increase serotonin synthesis by pharmacological approaches could, in fact, affect the behavior of these animals. “¦ Then you can use both an environmental approach to help these people along who have become ill because of the environment by utilizing a positive environmental therapy, possibly in conjunction with diet modification and the use of pharmaceutical therapies.”
Homberg´s believes that her work is good news for the long-suffering patients of both depression and PTSD. And while her hypothesis has yet to undergo formal testing, her enthusiasm for the subject is in no way limited by that fact.
It was while her team was attempting to look at depression and its causes that they first noted similarities between sufferers of both depression and PTSD. What these two groups have in common is that when they have been exposed to a highly emotional or traumatic event, they are unable to forget the instigating incident. Negative events are typically remembered very well and its recall is often extremely vivid and even traumatic.
Homberg points out that the current bias in viewing depression in terms of only strongly negative stimuli may cast a shadow on the efficacy of future research on both disorders. “I think that process is very flexible. If you subject these individuals to more positive environments, you can, more or less, distract attention from these negatives toward more of the positive things in life. And I think that is something we should work on more. Not only through medicines that only work for part of the population, but also to use the environment,” she explained. “If you can get ill from the environment, you should also be able to recover, at least for a part, from the environment.”
As Homberg had already pointed to the similarities between depression and PTSD in that they both exhibit elevated serotonin levels, I asked her if she had any insight as to why they might react so differently when confronted with identical stressors. “Of course what we see in the knockout rats and also in people with the short allele is that they react stronger to stressful stimuli. But it could also be an adaptation because sometimes it might be very good to react to stress because there is that stress and you have to do something with that.”
DEPRESSION AND THE 'LEARNED HELPLESSNESS' PHENOMENON
Another experiment conducted by the research team involved maternal separation of the rat pups from their mothers at an early stage of development. She sees this experiment as a model for maternal neglect. Previous models have shown that this neglect and subsequent lack of attention often leads to depression-like phenotypes. It would be expected that knockout rats would be more sensitive to stress and would therefore be more likely to react to triggers that bring about depression.
To test this hypothesis, the team utilized what is known as the ℠learned helplessness´ test. According to Homberg, learned helplessness is also a feature of depression. The test involves exposing the rats to a significant amount of inescapable stress. After being subjected to a constant and inescapable stress, the rats are then presented with a possibility of escape. “Our idea is that animals that are helpless, they don´t escape anymore because they learned, ℠Oh, I cannot do anything here, it just overcomes me [the stress] and I cannot do anything about it.´”
The full knockout rats performed very well in all conditions to affect their escape. The heterozygous knockout rats only showed escape potential among the early maternally separated groups. Speaking to this, Homberg states, “What we think then is that these knockout rats are already very well adapted in nature to do well in bad situations. We find they are adapted at trying to make the best out of a bad situation.”
To collect this data, Holmberg℠s team utilized a split cage with a closed door in the middle. On the side of the cage where the rat was placed was a floor fitted with sensors that would deliver a low-power shock to the rat. This shock was given in order to provide a minor stress factor that would motivate them to seek out new conditions.
Even after the door in the center of the cage was opened to present an obvious escape route from the current environment, the less adaptive rats tended to remain in the side of the cage that delivered the stressor to them. The knockout rats made their escape to the other side of the cage, even though they didn´t necessarily know whether it would be better or worse than the side on which they were receiving the stressor.
When looking at the less environmentally adaptive rats, the question became: What is the stress situation that really makes people become depressed? Homberg elaborated, “In relation to your question on whether some may go into withdrawal while others develop more coping strategies, what I have seen with my animals is that they can develop anything. It just depends on the situation.”
“For instance, if they are in a situation from which they cannot escape, then being immobile, or freezing, that is the best response because you can´t do anything. But if you see escape possibilities, then you escape or recognize opportunities to either flee or fight. Human subjects with the shorter allele, or the comparable rats that have this knockout, are focused very much on their environment, so they see, they notice what is the best reaction in this condition. They can actually present all coping strategies.”
Homberg is also looking into prenatal exposure to serotonin re-uptake inhibitors (SSRIs). SSRIs are commonly prescribed pharmaceuticals used in the treatment of depression and other psychiatric disorders. Some of the most well known examples include brand-name antidepressants like Prozac, Lexapro, Zoloft and Paxil. The use of SSRIs has been deemed safe for use by adult patients.
However, pregnancy has been recognized as an increased risk-factor for the development of depression, and it is imperative to treat women who experience the onset of this disease during gestation. SSRI´s, however, do not discriminate when coursing through a pregnant body and travel freely through the placenta and into the fetus´ blood stream. As a result, the fetus is exposed to high levels of serotonin in much the same way as Homberg´s knockdown rats.
“Our studies of the offspring show they tend to exhibit higher rates of depression and anxiety. This is fascinating because we know the effects they will have on the adult patient, but we are only now learning how they will affect younger subjects. It is important to further study the dangers associated with anti-depressant medications.”