Friday, October 07, 2022

The Neural Basis of Sex Differences in Depression

I finally got back to this with my comments based on what I heard.

Steve and Corey interview researcher AJ Robison over at Manifold podcast. There is a transcript at the link as well, for those of you who prefer that. I got bogged down about halfway through with the details of the excitability of a circuit in a mouse brain, but it picks up near the end as well. I will add my own comments in the next day or two, but I wanted to get this out there for those who like this stuff.  Some very interesting remarks about depression in humans, research in general, and pitfalls of oversimplifying.

There was a lot of kerfuffle when evidence was put forward that serotonin levels were not the key to depression. Robison's team's research focuses instead on the possibility that the antidepressants contribute to neurogenesis. This is immediately controversial because it is not agreed up that neurogenesis, the creation of new neurons in the brain, occurs at all, never mind whether antidepressants cause or facilitate it. It can be shown to happen in animals, and behavioral changes are observed subsequently, but the possibility in humans is only a majority, not a universal opinion. That multiple categories of antidepressants create the effect in animals (and improve depression in humans) would argue in support of the neurogenesis idea, as it would not be particular chemicals, but some deeper mechanism which several categories of chemicals might affect.

Depression is twice as common among human females than males, even after accounting for their greater willingness to cop to having a difficulty and showing up at a clinicians office. The counterintuitive piece, which has been known for 20 years but still denied in some circles, is that this is even more pronounced in countries with greater gender equity. The theories that might occur to you why that is are already being fought about, yes.  It's not supposed to be that way.  The correct answer is supposed to be that women have additional burdens because of sexism, increasing their vulnerability to depression. (My own guess is the mismatch theory, that the greater opportunity for advancement in what society considers the main or important areas does not replace the biological and social aspirations, only adds to them.*  Women's media has much more written by women about "having it all." But that's just my favorite theory at the moment.) 

But it's never good to want a particular answer before you have your data.

Interesting bit is that you will notice carefully worded research involving mice or other animals will not use the word "depression" in mice.  It is not artificial to refrain from that and only focus on the component parts that go into such a diagnosis in humans, such as anhedonia or change in appetite. Jumping to the conclusion that of course they are depressed because they are acting like depressed humans is unwarranted, because "depression" may be how we put disparate symptoms into a larger category in order to deal with it. It is we who tie the cues together and treat others differently in protective fashion, or resolve to take some action on ourselves. We might make long-term and short term plans differently if we think of ourselves or a loved one as depressed. Animals cannot connect the various strands in their brains.

You can't ask mice if they are depressed. Well, you can ask, but they don't answer.

I had never heard a credible defense of why until twenty years ago, mole depression research was on males, even though more females experience depression. The reasoning was that "depression is depression," not really different in men and women, and the important this was to learn to understand it.  In order to do research, one eliminates as many variables as possible, and hormones the estrus cycle, which do have an influence on depression, make it harder to see what is happening in the pure situation. Once the simple version could be treated in everyone - men, women, children, geriatrics - refinements could be added.  We don't do it that way anymore, but I did at least see the point.

On that score, the positive effect that testosterone has on depression is intriguing. It does not reliably lighten mood, but it may have a protective factor the binding of some chemicals onto neural receptors. It seems to have more effect three weeks or more down the road than in the moment of depression. The "high" feeling is reel, but temporary.

Regarding social withdrawal as a cause of depression my be confusing the cart with the horse.  "People who get out and see others more are less depressed.  So make yourself go out and see people." Except it may be that people who feel better are just more likely to go out, and making yourself do that may have no effect, or even sap valuable energy.  Blondes have more individual hairs, but lightening your hair won't give you more follicles. Patients and families used to complain at us that the sufferer used to have a decent life with friends and a job before they came to us, but had been psychotic/depressed/anxious ever since. Yeah, and your boy used to run happily in a field all day until we treated him for that broken leg, too. It's a type of error we make in social programs as well.

*GK Chesterton thought what were the victories of women a hundred years ago were in fact their final defeat.  Since the beginning of humanity, women had been putting forth their energy into convincing men that people and the family were more important than jobs and tools. For women to take up jobs and tools was their capitualtion, not their conquering.  Edith Stein's thinking in the same era has some similarity in the absolute necessity of specifically female gifts in the operation of society.


Grim said...

"On that score, the positive effect that testosterone has on depression is intriguing. It does not reliably lighten mood, but it may have a protective factor the binding of some chemicals onto neural receptors."

Is there a negative effect of estrogen, I wonder? Has that been studied?

Assistant Village Idiot said...

Yes, estrogen both increases vulnerability to depression and slows recovery. From this, one would think "Well hell, let's just give everyone susceptible to depression a little testosterone and make sure we don't increase their estrogen levels, but it is not that simple. With hormones, it gets complicated quickly, partly because women change over both the life cycle and a monthly cycle, and men change quickly in response to perceived threats.