Brain Changes in Mood Disorders

(updated 12/2014)



Two things I’d love for you to learn here:

  1. Psychiatry isn’t about Freud anymore.  We understand so much more than 70 years ago, or even 10 years ago.  Although many pieces of the puzzle of depression are still missing, a picture has emerged that explains all the way from stress to brain changes in depression, molecule by molecule.
  2. Depression is not a moral weakness. Some people are more susceptible than others even before they are born.  This story provides the genetic and molecular proof.  You have to cope with whatever genes and childhood you inherited, but it’s not a “level playing field”.  Some people start the race ahead of others, some way behind (ouch).

Everybody knows: stress causes depression: the more stressful life events you have, the more likely you are to become depressed.  But how does that work? How does stress change the brain? Amazingly, we now have enough puzzle pieces to assemble a fairly clear picture of the answer.

Below you’ll find a really short version of the whole story. Then follow links to 12 brief chapters on the mechanism of depression in the human brain.

But first, a moral comment.  Is depression a personal weakness, flaw, or failure? Is it something you should be able to fix on your own, “pulling yourself up by your bootstraps”? Certainly a lot of people think so, right? And there is some truth to their point of view. But very good evidence now shows that for many people depression began and can persist because of factors beyond their control.

Mind you now, an explanation is not an excuse. Allow me to say that again, as this is one of the places people get stuck: an explanation is not an excuse. You can still take responsibility for what you’ve got, even if you’re not the basis of how it got that way. Indeed, you have to take responsibility for all that you are — there is no one else who can, for one thing.  Our laws, and our ways of relating to one another, are based on the expectation that whatever’s going on inside your skin is not an excuse for what your body ends up doing.

However, knowing how you may have come to be the way you are, at least in part, can often be helpful in coping with how you are. So, this is the story of how researchers are working to understand depression, starting from social stresses like poverty and loss of loved ones, then working all the way through the brain systems involved to the level of cells and molecules and even some genes which appear to be related.

Short version: what causes depression?

Several genes have been very consistently identified with depression. The first 5 chapters focus on one we know a lot about. If you got the protective version of this gene, you can tolerate a lot more stress than those who got the susceptible version. But childhood experience is an even more powerful factor: a safe childhood wipes out the genetic effects. Moral:  childhood trauma  (emotional, physical, sexual abuse and neglect)  has lifelong effects. An obvious place to put health care resources.

The gene associated with depression also affects people’s level of fear when frightening things happen.  The same gene is associated with alcohol use.  Puzzling, then: why is it still around? Answer: it looks like children learn more quickly how to adapt to their environment when they get the riskier version, and maybe can do better than their peers if they get the right environment to grow up in. But don’t go rushing off to get your genes studied. We know far too little about how genes interact to know what to make of one single gene result.

Now, back to the big story: what happens in the brain when people get depressed? Briefly (see chapters 6-12 for much more detail): parts of the brain that serve memory and attention lose their vigor. Okay, you knew that, if you’ve ever been depressed.   But we can now show exactly how that loss of vigor occurs; which molecules are involved; how our existing treatments affect those molecular pathways; and how, eventually, the molecular chain leads to loss of neurons. And the good news: treatments that work can reverse this loss, at least some.  (You might think this is bad news: one of them is exercise. No surprise, though, eh?)

The molecules that help neurons stay vigorous are called “neurotrophic factors”. Effective treatments increase those factors. Stress decreases them. It’s a tug of war in the brain between the neurotrophic factors and other molecules that cause cells to shrink and die. When the bad guys are winning, people get depressed (to dramatically oversimplify).

The following chapters tell this story in detail. Each links to the next. Jump forward when you’ve had enough.

12 brief chapters on the biological basis of depression

 Part One — From Genes to Experience

  • Chapter 1: Why are some people so affected by stress?
    A big part of what causes depression is in a single gene.
  • Chapter 2: Short genes are involved in more than depression?
    Yes, fear responses are also influenced by the same gene.
  • Chapter 3: Short genes affect alcohol use?
    It may depend on childhood experience!
  • Chapter 4: Why are there “shorts and longs”?
    What does this genetic difference do?
  • Chapter 5: Hey, where do I get my genes tested?
    If you could, would you want to?

Part Two:  Stress Mechanisms, From Molecules to Brains

  • Chapter 6: What happens to people’s brains when they’re depressed?  How brains reshape during mood disorders.
  • Chapter 7: Why does this re-shaping happen? Cell shrinkage, and fewer new cells
  • Chapter 8: The role of stress hormones — and the short gene story again
  • Chapter 9: Some good news: anti-shrink factors
    (no, we’re not talking about psychiatrists)
  • Chapter 10: All the Players on One Stage
    This diagram is overwhelming; let’s build it one step at a time.
  • Chapter 11: Can the shrinkage be reversed? Does treatment help? Yes — at least somewhat — in depression, PTSD, and bipolar disorder.
  • Chapter 12: The Big Picture: Putting all these chapters together

Start with Chapter 1.