The future of behavior medication?

We don’t actually know how behavior medications work. We know how they change the operations of cells — for example, we know facts like “this medication makes cells slower to recycle this particular chemical.” But we don’t have a good idea of how those cellular-level changes result in behavior-level changes. We don’t know how these medications make individuals feel better.

And that’s a problem, because not every individual responds to a particular behavior med in the same way. A pathologically fearful dog might have nasty side effects on one med, no response to a second, and then respond beautifully to a third. It’s hard on owners to have to try a variety of medications before finding the right one, especially as it takes a month or two to be sure that a particular medication is or isn’t working. (Oh, yeah, and the same is true for humans who use these drugs.)

If we knew how these medications worked, we might be able to figure out who they would work on without so much cumbersome trial-and-error. Imagine taking your shy dog to a veterinary behaviorist, who would do a genetic test and prescribe the right drug based on the results, to go along with behavior modification exercises.

My current work focuses on gene networks that differ in the brain between animals who are shy and aggressive and animals who are confident and friendly. I've always felt that my requests for funding have been a little hand-wavy as I have argued that surely my findings may help us understand behavioral medications better... You know, someday. Someday maybe my findings will help us design better medications, in fact. But that day seemed a really long way off.

Until I read Ed Yong's story “CRISPR’s most exciting uses have nothing to do with gene editing”. CRISPR is a fancy new gene editing technology that has everyone talking about science fiction coming to pass: being able to edit human (and animal) genes to make designer babies (and animals). Edit out the gene variants for genetic diseases before a baby is born! (But hopefully don't slide down the slippery slope to editing height, skin color, eye color, personality...)

But it turns out that CRISPR may have a more subtle use: gene regulation. Soon, scientists may be able use it to tell individual genes to turn on and off (to make more or less of their product). Rather than permanently editing genes in embryos, we could temporarily modify the output of genes in adults. Suddenly my quest to find the sets of genes affecting shyness seems less quixotic. Maybe my discoveries (do you like how I assume I’ll have discoveries? Let’s just pretend it’s a sure thing) won't have to wait for drug discovery work to be useful. Maybe we’ll be able to directly turn the volume up or down on those particular genes, directly affecting pathological shyness.

Scary? Yeah, it's not something I foresee being used therapeutically in the next few years, not until we understand the brain well enough to be able to predict side effects. But it’s really cool to imagine that some day we may have this sort of fine-tuned control over psychological diseases.

How antidepressants work: the good parts version

[Author’s note: Please consider my last post, How do antidepressants work (in dogs and the rest of us)?, to be the director’s cut of this topic: fairly long and juicy, with some bits in which I indulge my inner geek and perhaps go into more detail than is truly necessary. This, then, is the good parts version: the same material, but presented as an overview from a higher altitude, with fewer details and assuming less scientific knowledge. These posts are both intended as material for my upcoming online class with APDT, and I want to make sure students of all levels of science background are covered. Also, it’s good for me to take a step back from time to time and remember that not everyone wants to know every gory detail about this brain stuff.]

We don’t fully understand what causes depression in humans, and we don’t fully understand how the medications we use to treat depression work. We do know that those medications work well in dogs just as they do in us. In dogs, however, they are more often used to treat fearfulness or aggression. We know that antidepressants generally take effect only after several weeks of constant use, and that they work much better if they are paired with behavior modification training in dogs or therapy in humans. And we actually do know enough about how they work to take a guess at why that's true.

You can buy your very own Prozac bone sticker!

Depression in humans and fearfulness and aggression in dogs are related to stress: something in our lives that we can't control and can’t quite adjust to. In humans, that might be extended unemployment or long term caretaking for a sick family member. In dogs, it can be the inability to control who comes to visit your house (that terrifying mailman) or perhaps a lack of understanding of the big scary world (for undersocialized dogs).

Sometimes training or therapy aren’t enough to help us deal with these problems; some problems are too hard for our brains to cope with on their own. Antidepressants seem to help our brains adapt, however. A part of the brain deeply involved in learning and memory, the hippocampus, tends to be smaller in people who are depressed and tends to get larger again when they take antidepressants. This change may be associated with an improved ability to make new mental connections.

So that’s why antidepressants take weeks to take effect: that part of the brain is growing and changing, which doesn’t happen after just one pill. And that may also be why antidepressants work so much better in the context of training or therapy. It’s nice for your brain to be more able to learn new ways of coping with a difficult world, but the ability to learn is not the same as actual learning. To learn, you have to get out there and do: talk through your problems and find the way to feel differently about them and take new approaches to solutions if you’re a human, or get to practice new ways of interacting with the mailman if you’re a dog.

The take home message for dog owners? Don’t expect your dog to respond to antidepressants immediately; it will take a few weeks. And don’t expect your dog to respond without behavior modification. Antidepressants aren’t magic bullets and they won’t fix the problem on their own. But they will make it easier for all the training you do to take effect.

How do antidepressants work (in dogs and the rest of us)?

There are plenty of humans and dogs on antidepressants, and we believe that the mechanisms of these medications are much the same in both human and dog brains. But despite the fact that these are widely used medications, we aren’t completely clear how they work. Yes, this is going to be another post in which I ask a question and then don’t really tell you the answer. But I’ll tell you what we do know.

You can buy your very own Prozac bone sticker!

What is depression?

There are probably many different kinds of depression, so that the disease is slightly different in many (or all) people and dogs. As a result, getting a handle on the mechanisms of depression and its treatments is difficult. So studies about depression and antidepressants have to speak in generalities, such as “this is true for 50% of people with depression.”

In general, then, depression is triggered by chronic stress, which results in increased levels of stress hormones. The major stress hormone in humans and dogs is cortisol, so that’s the term I’ll use in this post. The major stress hormone in mice and rats is the closely-related corticosterone, so if you delve into more of the research in this area, you may find that hormone mentioned as well. It’s basically the same as cortisol. Note that while I’ll talk about depression in this post, in dogs we more commonly perceive stress-related problems as behavior problems, such as shyness or aggression. These problems, in certain cases, can be very successfully treated with antidepressants in combination with training.

Depression and the hippocampus

The area of the brain which is the most sensitive to increased levels of cortisol is the hippocampus, a part of the limbic system which is involved in learning, memory, and emotion. The cells of the hippocampus are armed with little widgets called glucocorticoid receptors, or GR, which grab cortisol molecules as they float by. Once a GR has attached itself to some cortisol, it becomes active, and takes itself over to the cell’s DNA. Here it tells the cell to activate some genes and deactivate other genes. This is how cortisol effects stress-related changes in our body: by telling the massive recipe-book inside our cells which genes to cook up and which ones to leave idle.

Image courtesy of Wikipedia

So the first generality about depression is that it results in more cortisol than normal. The second generality is that it also results in a smaller hippocampus than normal. We can guess, though we’re not sure, that this is somehow related to all that GR activation. We know that in depression, fewer new neurons are born in the hippocampus, so that is probably part of the answer. However, it’s not the whole answer, because even in healthy people, new neurons are created at a very low rate, not fast enough to explain this decrease in size of the hippocampus. Another possibility is that the shape of individual neurons changes. Neurons branch out like trees to touch lots of other neurons, and the neurons of depressed people have fewer branches. So the problem could be caused by fewer neurons, or by neurons that have fewer branches and therefore less communication with other neurons. We’re not sure which, but either way, the changes are significant.

Antidepressants and the GR

Antidepressants affect many substances in the brain (most famously, the class of antidepressants of which Prozac is a member affect serotonin levels). We have trouble picking out cause and effect here. We assume that antidepressants aren’t affecting all of these substances directly; we assume that some of these affects are indirect, in other words, side effects. We’d like to know which substances antidepressants directly affect in the brain, in other words, what their mechanisms are, but we’re still not sure.

We do know that they affect the GR, though we don’t know if they do so directly or indirectly. So far, we haven’t found any direct effects on the GR. One theory is that antidepressants affect another widget, one which pumps cortisol out of cells so that the GR can’t grab it and become active. The decrease in number of active GR, then, causes the changes in the brain which result in mood improvement.

We do know that depressed people on antidepressants start to have increased birth of new neurons in their hippocampus, which itself increases in size. Why does this affect mood? We don’t know, but we can hypothesize that improved ability to make new mental connections and learn is at the heart of the change. This helps us understand why antidepressants typically take several weeks to work: our brains are changing, growing, and that takes time.

Antidepressants and dogs
 
As usual, all the research on how this stuff works was done in rats, mice, and humans. But we do think that the mechanisms are similar in dogs, and indeed in most or all mammals. Many dogs are on antidepressants with positive effects, including my shy dog Jenny, who receives both buspirone and lots of counter-conditioning. As research continues to get us more answers about how these medications actually work in the brain, we will do better and better at understanding which kinds of antidepressants are better for which individuals, when to start them, and when to stop them.



Anacker C., Livia A. Carvalho & Carmine M. Pariante (2011). The glucocorticoid receptor: Pivot of depression and of antidepressant treatment?, Psychoneuroendocrinology, 36 (3) 415-425. DOI: http://dx.doi.org/10.1016/j.psyneuen.2010.03.007

For further reading, check out related posts by Scicurious:

• If low serotonin levels aren't responsible for depression, what is?
• Stress and antidepressants: by their powers combined