Against Utopia Issue #2: The Epistemology of Depression Part 2 - Grasshoppers, Squirrels, and Bears, oh my!

Hello, and welcome to Against Utopia, a newsletter that lifts the veil of authoritarian utopianism in science, technology, politics, culture, and medicine, and explores anti-authoritarian alternatives. This is Issue Two, published March 31st, 2018.

At the end of the last issue, we finished up by examining the complexity of serotonin physiology, it’s simplification by modern pharmaceutical approaches, and its idiosyncrasy across various organisms, specifically, squirrels, bears, and grasshoppers. Today, I want to lead you through a deeper examination of serotonin physiology in these three organisms, and talk about what that means for us as humans, and what possibilities it reveals in our thinking about depression.

Every winter, if you live in a part of the world with four seasons (or if you don’t live in California), you most likely experience seasonal fluctuations in serotonin (amongst many other, interconnected, interacting hormones). Here in Oregon, it is a common occurrence to hear people talk about their difficulty getting out of bed once the shorter days hit, and how the lack of sun is making them more tired, sluggish, or sometimes, depressed. It’s so common that it has a medicalized name - seasonal affective disorder.

In addition, humans have been known to accumulate serotonin’s precursor, tryptophan, in their white hairs, especially during winter, when some people begin to experience seasonal greying of hair in the winter. This seasonal change in hair color is indicative of changes in core metabolism and hormones associated with it. Specifically, the onset of a true winter experience (shorter days, colder temperatures, etc) slows the pathways involved in the conversion of tryptophan to niacin, converting much of the tryptophan to serotonin, and building up tryptophan in the scalp.

Serotonin, furthermore, has been shown to slow the mammalian and human metabolism by increasing glycolysis (the conversion of sugar to pyruvate and lactic acid) over oxidative metabolism. There are a multitude of cascading effects associated with the increase of glycolysis due to serotonin that we don’t have the scope to cover here, but some of them include what you would expect when you read “slow metabolism”: sluggishness, weight gain, lowered insulin sensitivity, and increased fat storage. Some of these frequently appear as side effects of common anti-depression drugs, specifically, selective serotonin reuptake inhibitors (SSRIs).

The red-cheeked ground squirrel is a common squirrel in Central Asia. When winter comes, an enzyme system that generates serotonin, tryptophan hydroxylase, kicks into high gear. Again, a common pattern occurs. Resources get scarce, days get shorter, nights get longer, temperatures get lower, and animals require an adaptation to help them bear the lack of energy producing resources in a plentiful environment. In squirrels in or nearing hibernation, serotonin production is approximately 50% higher than in squirrels not yet entering the early stages of torpor. This activation of serotonin producing systems occurs before the animals start to get cold, slow down, and enter hibernation, indicating that serotonin plays a key role in producing torpor, and that this resource scarcity is anticipated by the animal’s neurobiology. The increase in serotonin produces an over 50 degree drop in body temperature - from 98.6 degrees to 41 degrees F! This allows the animal to enter a state of somewhat restless torpor while expending very little energy. It’s not as restful as sleep, which takes energy to maintain, but it allows the animal to make it through the winter. When the spring rolls back around, in order to exit hibernation and resume normal activity, the system that generates serotonin grinds to a halt, and serotonin levels in the brain drop rapidly. The squirrels exit hibernation, its insulin sensitivity reverts to normal, and it begins to put on weight again.

In black and brown bears, which are also known to hibernate during winter, insulin sensitivity and hibernation are mediated by serotonin. As October approaches, the amount of a particular gene product, PTEN, goes up. PTEN indirectly promotes serotonin synthesis, and serotonin synthesis causes the bears to become almost literally diabetic. By the time hibernation is kicked off with appropriate levels of serotonin, like in the squirrels above, the bears have become fully insulin resistant and mirror what is known in humans as type 2 diabetes. High fat levels in their blood sustain them through winter, until serotonin levels drop off and hibernation ends, just as in the red squirrel. Bears are even more interesting in that their body temperature remains mostly the same, dropping only 2-4 degrees celsius, hence making their experience somewhat more comparable to humans. Again, the effects of increased serotonin here in bears are impaired insulin sensitivity, high fat metabolism, lowered body temperature, and increased torpor and sluggishness, much of which mirrors the side effects of SSRIs (which increase serotonin to treat depression) in humans. This increase in serotonin is precipitated by a real or perceived lack of resources in the environment by the organism, which can also explain why it’s so heavily conserved across species, but that bit we can save for another time.

Lastly, locusts get a really bad rap. From the Old Testament, to modern day farmers in Australia, they wreak havoc on crops and food supplies, in a somewhat predictable seasonal manner, and are universally reviled for it. But, did you know that locusts are actually just grasshoppers who have morphed into a more gregarious state? I didn’t until recently. A group of researchers has shown that grasshoppers, when in close proximity to each other, close enough to scratch each other basically, can trigger metamorphosis into the locust state. The close proximity and scratching triggers the production of serotonin in the grasshoppers, and this scratching is interpreted as a signal that the environment contains dwindling resources to support the population. Better to begin transformation into a voracious horde of locusts, and feast on what you can while the getting is good! Again, the close clustering comes with a neurobiological, experiential interpretation that comports with the perceived lack of resources. The animal’s metabolism is altered by an upsurge in serotonin, and precautionary steps are taken to make sure that the animal can make it through this perceived lack of resources.

This brings us back full circle to humans. If this observed relationship between high serotonin, torpor and hibernation, low metabolism, and environmental scarcity is seemingly conserved in bears, squirrels, and locusts (even hamsters, which I didn’t talk about), what is to be said about our approach to serotonin drugs for depression in humans? The first line prescription drug for treating depression in humans, let’s be clear, increases the concentration of serotonin in the brain areas where it acts. How plausible is it really for serotonin physiology to operate in a directly opposite manner in humans, as it does in most other animals studied? Could it be that the heroic simplification of the serotonin system and its application to the experience of depression is actually completely backward? In order to understand how we got here, we have to look back at the history of the development of serotonin influencing drugs, and gain a deeper understanding of medical epistemology, and how drugs are developed from it.

Which is exactly what we’ll go into in Issue #3: The Medical Epistemology of Drug Development for Antidepressants. Thanks for reading.

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Notes

1. Anticancer Research. “The Effect of PTEN on Serotonin Synthesis and Secretion from the Carcinoid Cell Line BON”. Silva SR, Zaytseva YY, Jackson LN, Lee EY, Weiss HL, Bowen KA, Townsend CM Jr, Evers BM.

2. Journal of Neuroscience. “Peptide Inhibitors Disrupt the Serotonin 5-HT2C Receptor Interaction with Phosphatase and Tensin Homolog to Allosterically Modulate Cellular Signaling and Behavior”. Anastasio NC, Gilbertson SR, Bubar MJ, Agarkov A, Stutz SJ, Jeng Y, Bremer NM, Smith TD, Fox RG, Swinford SE, Seitz PK, Charendoff MN, Craft JW Jr, Laezza FM, Watson CS, Briggs JM, Cunningham KA.

3. Pharmacol Biochem Behav. 1993 Sep;46(1):9-13. “Involvement of brain tryptophan hydroxylase in the mechanism of hibernation.” Popova NK, Voronova IP, Kulikov AV.

4. Pharmacol Biochem Behav. 1981 Jun;14(6):773-7. “Brain serotonin metabolism in hibernation.” Popova NK, Voitenko NN.

5. J Comp Physiol B. “Mitochondrial metabolism in hibernation and daily torpor: a review.” Staples JF, Brown JC.

6. J Comp Physiol B. “Life in the fat lane: seasonal regulation of insulin sensitivity, food intake, and adipose biology in brown bears.” Rigano KS, Gehring JL, Evans Hutzenbiler BD, Chen AV, Nelson OL, Vella CA, Robbins CT, Jansen HT.

7. Il Farmaco. "Tryptophan in human hair: correlation with pigmentation.” Biasiolo M, Bertazzo A, Costa CV, Allegri G.

8. Science. “Serotonin mediates behavioral gregarization underlying swarm formation in desert locusts.” Anstey ML, Rogers SM, Ott SR, Burrows M, Simpson SJ.

9. Am J Physiol. “Does serotonin play a role in entrance into hibernation?” Canguilhem B, Miro JL, Kempf E, Schmitt P.

10. Genes, Brain, and Behavior. “The brain 5‐HT1A receptor gene expression in hibernation” V. S. Naumenko S. E. Tkachev A. V. Kulikov T. P. Semenova Z. G. Amerhanov N. P. Smirnova N. K. Popova.

11. Int. Conf. Bear Res. and Manage. “Insulin and Glucagon Responses in the Hibernating Black Bear.” PJ Palumbo.