I wrote the following and posted it at The Winnower, a website dedicated to open-access science and post-publication peer review. The Winnower will allow science writers and bloggers to cross-post at their site, and they have been kind enough to allow me to do so.
This post may be of interest only to the more science-oriented of my readers.
I wrote this after noticing what was, to me, a strange fact, and that is the sheer number of psychoactive drugs used in the treatment of several mental illnesses that promote autophagy. The number seems way more than could be due to chance, as I point out in this article, which led me to the idea that promotion of autophagy is connected to their effects on the brain in treating mental illness.
What is the larger significance to this? Assuming that the idea is correct, then it means that the same processes that are so prominent in aging and disease, namely decreased autophagy and increased inflammation and oxidative stress, also have something to do with mental illness. Indeed, the prominence of inflammation in depression has been shown in the past two decades; see for example, Major Depression and Activation of The Inflammatory Response System by Michael Maes.
Since autophagy, inflammation, and oxidative stress are all linked through biochemical pathways, a drug that increases autophagy should in general have beneficial effects on the other two. For instance, a drug that activates AMPK will cause an increase in autophagy, and in turn an activation of Nrf2, which increases stress defense enzymes such as superoxide dismutase as well as the internal antioxidant glutathione, and decreases pro-inflammatory cytokines. Presumably, whatever areas of the brain that are affected in mental illness are then returned to a more normal state, mitochondria increase in quality and quantity, and cellular energetics are restored.
It will not escape notice that many processes and compounds I’ve written about on this blog also activate autophagy, such as fasting, exercise, and resveratrol and other phytochemicals. Indeed, as I point out below, rapamycin, which increases autophagy and extends lifespan in mice, also has an antidepressant effect.
All of this leads to the larger idea that in mental illness, something has gone awry with brain metabolism, whether through psychosocial stress, genetics, or environmental factors like diet and exercise. Or all of them at once, of course. My article follows.
Autophagy, literally “self-eating”, is the regulated process of cellular self-cleaning in which poorly functioning organelles, such as mitochondria, and misfolded proteins, are targeted for destruction. Autophagy declines with age¹ and its decline is prominent in diverse disease states such as heart disease, cancer, and neurodegenerative disorders.²
Autophagy is tightly regulated by a number of physiological sensors and hormones, such as mTOR, AMPK, and the growth hormone/IGF-1 axis. Processes and chemical compounds that increase the activity of AMPK increase the level of autophagy in a cell, and in turn, the Nrf2 transcription factor is upregulated, causing an increase in transcription of antioxidant enzymes and a decrease in transcription of pro-inflammatory cytokines.³ Activity of AMPK also declines with age, and this is related to an increase in pro-inflammatory cytokines and therefore inflammation.
Autophagy itself causes a decline in levels of inflammation by reducing the numbers of defective mitochondria, which are important generators of inflammatory signaling.4 Increased levels of autophagy result in decreased levels of inflammatory cytokines and inflammation.
Many psychoactive drugs used in the treatment of several mental illnesses activate autophagy, some of them quite strongly. A number of anti-psychotic drugs, including trifluoperazine and chlorpromazine, increased autophagy in an in vitro neuronal cell culture model four-fold, as did the antihistamine and sedative promethazine.5 Other psychoactive drugs in this model also increased autophagy, although not as strongly, and a few showed no increase.
Lithium has been used for decades in the treatment of bipolar disorder and in depression. Recently, it’s been found that lithium increases lifespan in the nematode C. elegans, and lithium in drinking water is associated with increased lifespan in humans.6 Lithium promotes autophagy in an mTOR-independent manner7, and this is likely to be its mechanism of action in extending lifespan in C. elegans.
Selective serotonin reuptake inhibitors (SSRIs) are used in the treatment of depression. At least one SSRI, citalopram, has been found to increase autophagy in neurons.8
We have evidence that representatives of four classes of psychoactive drugs, anti-psychotics, tricyclic antidepressants, lithium, and SSRIs, promote autophagy. Could this be, at least in part, their mechanism of action?
It’s now well-established that inflammatory processes play a substantial, perhaps even pivotal, role in depression.9 Inflammation is thought to lead to neurodegeneration, which is also seen in depression. In schizophrenia, inflammatory genes are upregulated.10 Inflammation also appears to be crucial in the pathogenesis of bipolar disorder.11
Psychoactive drugs used to treat depression, psychosis, and bipolar disorder may owe some of their efficacy to their ability to increase levels of autophagy. At the least, it’s a striking fact that representative drugs from different classes of psychoactive compounds do this. Rapamycin, an immunosuppressant of an entirely different class that inhibits mTOR, increases autophagy, and increases lifespan in mice, also has antidepressant effects.12 Yet in a recent study that screened 1,120 FDA-approved compounds for inducing autophagy, only 38 compounds were found to be potential autophagy activators.13
Autophagy activators can be expected to reduce inflammation and oxidative stress, and increase energy generation in neurons, and this could be their mechanism of action in mental illness.
1. Rubinsztein, David C., Guillermo Mariño, and Guido Kroemer. “Autophagy and aging.” Cell 146, no. 5 (2011): 682-695.
2. Levine, Beth, and Guido Kroemer. “Autophagy in the pathogenesis of disease.”Cell 132, no. 1 (2008): 27-42.
3. Salminen, Antero, and Kai Kaarniranta. “AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.” Ageing research reviews 11, no. 2 (2012): 230-241.
4. Green, Douglas R., Lorenzo Galluzzi, and Guido Kroemer. “Mitochondria and the autophagy–inflammation–cell death axis in organismal aging.” Science 333, no. 6046 (2011): 1109-1112.
5. Tsvetkov, Andrey S., Jason Miller, Montserrat Arrasate, Jinny S. Wong, Michael A. Pleiss, and Steven Finkbeiner. “A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model.” Proceedings of the National Academy of Sciences 107, no. 39 (2010): 16982-16987.
6. Zarse, Kim, et al. “Low-dose lithium uptake promotes longevity in humans and metazoans.” European journal of nutrition 50.5 (2011): 387-389.
7. Sarkar, Sovan, R. Andres Floto, Zdenek Berger, Sara Imarisio, Axelle Cordenier, Matthieu Pasco, Lynnette J. Cook, and David C. Rubinsztein. “Lithium induces autophagy by inhibiting inositol monophosphatase.” The Journal of cell biology 170, no. 7 (2005): 1101-1111.
8. Zschocke, Jürgen, et al. “Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons—dissociation from cholesterol homeostasis.” Neuropsychopharmacology 36.8 (2011): 1754-1768.
9. Maes, Michael, Raz Yirmyia, Jens Noraberg, Stefan Brene, Joe Hibbeln, Giulia Perini, Marta Kubera, Petr Bob, Bernard Lerer, and Mario Maj. “The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression.” Metabolic brain disease 24, no. 1 (2009): 27-53.
10. Saetre, Peter, Lina Emilsson, Elin Axelsson, Johan Kreuger, Eva Lindholm, and Elena Jazin. “Inflammation-related genes up-regulated in schizophrenia brains.” Bmc Psychiatry 7, no. 1 (2007): 46.
11. Berk, Michael, et al. “Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors.” Neuroscience & biobehavioral reviews 35.3 (2011): 804-817.
12. Cleary, C., J. A. S. Linde, K. M. Hiscock, I. Hadas, R. H. Belmaker, G. Agam, S. Flaisher-Grinberg, and H. Einat. “Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders.” Brain research bulletin 76, no. 5 (2008): 469-473.
13. Hundeshagen, Phillip, Anne Hamacher-Brady, Roland Eils, and Nathan R. Brady. “Concurrent detection of autolysosome formation and lysosomal degradation by flow cytometry in a high-content screen for inducers of autophagy.” BMC biology 9, no. 1 (2011): 38.