Luo Minmin on Covid and Depression

Luo Minmin, “The Epidemic Will Eventually End, But How Should We Deal with the Trauma of Social Depression?”[1]

Introduction and Translation by David Ownby

Introduction
 
The world’s eyes were rivted on China this week, as anger over continuing lockdowns and other coercive measures meant to contain the pandemic fueled nationwide demonstrations on a scale unseen since Tiananmen.  Unsurprisingly, Chinese establishment intellectuals had little to say in print about lockdowns or the demonstrations, although I imagine their WeChat groups were full of the same expressions of frustration that we saw on Chinese social media.  I similarly assume that journals and journalists in China would love to cover these topics, just as they would have loved to cover the many dramas produced during 20th Party Congress, but they can’t, at least not directly.
 
The text translated here was published on November 30, 2022, during the peak of the demonstrations.  It appeared on the online platform of The Intellectual, a journal which, despite its name, covers scientific issues such as public health and climate change, among others, and is perhaps a rough equivalent of Scientific American (on the following day, December 1, The Intellectual published an article entitled “Is the Coronavirus Growing Increasingly Weak?” which appears to question a talking point that is part of the government’s timid steps toward a new, less coercive covid management strategy).  The author of the translated text, Luo Minmin, is a neurobiologist, and he writes here about depression, particularly in the context of the stress imposed by three years of unpredictable and often very repressive policies.
 
Most of Luo’s text is straightforward and scientific.  I readily admit that DeepL and Google Translate did most of the heavy lifting here, as I claim no particular knowledge of the etiology and treatment of depression in Chinese or in any language (I learned the Chinese word for “depression” for the first time here, for example--Chinese is a very humbling language).  I had someone with more expertise on the issue read through the text to make sure there were no glaring errors, but I doubt that readers of this blog are looking for insights into how Chinese scientists talk about depression. Luo’s footnotes, which I did not include, are almost exclusively to Western authors or to Chinese authors who publish in Western scientific journals, so there is absolutely no claim here to “depression treatment with Chinese characteristics.”  Luo seems to suggest, in fact, that depression is probably under-reported and under-treated in China, but that the pandemic may well change that.
 
For readers of this blog, the last few paragraphs are perhaps all that is worth reading, beginning from part 5, “Environmental factors in the onset of depression.”  Here, it is difficult not to read the author’s discussion of prolonged stress, unpredictability, and lack of control as factors that can lead to depression as an expression of sympathy and understanding not necessarily for those demonstrating in the streets, but for all Chinese—and particularly young Chinese—who have been living with the fear and stress of lockdowns for too long.  And perhaps a plea to China’s authorities to respond with something other than their customary harshness.  Of course, the author did not write his piece on November 30, and it may be mere happenstance that the editors decided to publish it on that day, but the title caught my eye as I was reading through the Chinese media this week.
 
Translation
 
Because my own research is somewhat related to the topic, recently, friends have been mentioning a trend of increasing depression. As an optimist, I hope the pandemic will soon be over, and here share my personal understanding of depression and my initial thoughts on promoting mental health throughout society in the post-epidemic era.
 
1  What is Depression?
 
Depression (major depressive disorder; MDD) is an emotional disorder. According to the commonly used criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5), published by the American Psychiatric Association, depression is characterized by low affect (persistent feelings of sadness) and/or loss of pleasure (marked loss of interest or pleasure in daily activities) on an almost daily basis for at least two consecutive weeks. It also includes three to four of the following symptoms: intense feelings of guilt or helplessness, irritability, fatigue, difficulty concentrating, sensory dullness to the point where it is apparent to others, suicidal thoughts or even behaviors, difficulty sleeping or excessive sleep, changes in eating habits and significant changes in weight, and pain with no clear physiological cause. Outside the DSM5 criteria, depressed patients often feel lonely and show social withdrawal.

Depression is not a single disorder and can be classified as major depression, mild depression, psychotic depression, postpartum depression, seasonal depression, and (bipolar) manic depression depending on the clinical presentation and cause.
 
Depression is a global disease, and epidemiological studies in the United States have reported that people with at least one episode of depression in 2020 account for roughly 8% of the total population, with a female to male incidence ratio of approximately 2:1 and a peak of first onset at the age of 18-25 years. Past surveys in China have indicated an annual incidence of 1%-4%, but the reported incidence may actually be higher in the future as society becomes more aware of depression and patients actively seek help. According to projections, depression will result in trillions of dollars in global social costs by 2030, making it one of the most harmful of diseases.
 
2 The Etiology of Depression
 
The etiology of depression, like the vast majority of psychiatric disorders, includes genetic and environmental factors.
 
Familial and twin studies have shown that the genetic contribution to depression is approximately 0.4, and a large number of genetic studies have shown that depression is a polygenic disorder with hundreds of genetic variants associated with depression, while single genetic variants have little effect on overall disease risk. The more studied genes include monoamine neurotransmitter-related genes, hypothalamic-pituitary-adrenal axis (HPA axis) stress hormone-related genes, cytokine-related genes associated with inflammation, and circadian rhythm-related genes.
 
It is generally accepted in the field that depression is caused by the interaction of multiple genetic factors with physiological and environmental factors. Physiological factors include changes in cerebral blood flow, dramatic changes in hormone levels, chronic inflammation, other diseases (e.g., cancer, stroke, epilepsy, chronic pain), and drug reactions (e.g., chemotherapy). Environmental factors include mainly chronic stress (described separately in the final subsection).

3  The Biological Basis of Depression
 
Depression is essentially a mood disorder with a considerable subjective emotional component and no biomarkers that are universally accepted across the field to date. At the population level, the levels of some pro-inflammatory cytokines in the peripheral blood of depressed patients are significantly high, but this high level is also associated with a variety of other disorders (e.g., schizophrenia, neurodegenerative diseases), and thus the accuracy of the diagnosis of depression at the individual level is low.
 
One of the most influential theories regarding depression in terms of neurobiological research is the monoamine hypothesis. This hypothesis is based on the clinical observation that isoproterenolide and promethazine, two drugs that increase monoamine neurotransmitters in the brain, improve the symptoms of depression and was first proposed by J. Schildkraut in the 1960s. Most of the most effective antidepressants to date increase monoamine neurotransmitters in the brain, such as pentraxin and norepinephrine. However, animal and human genetic studies do not support the theory that low levels of monoamine neurotransmitters are a major contributor to depression.
 
Other influential theories include the hypothesis of neuroplasticity and neuronal neogenesis and the hypothesis of excessive activation of the HPA axis, all of which are convincing but also have limitations. For example, the former hypothesis is consistent with experimental data that some antidepressants increase neuroplasticity and neuronal neogenesis, but less consistent with clinical observations of a high prevalence of depression in adolescents (when neuroplasticity is high), and the theory of HPA axis hyperactivation is consistent with animal models of chronic stress-induced depression and our social intuition, but less consistent with the observation that some antidepressants activate the HPA axis. Over the past 20 years, chronic inflammation has been clinically observed to be associated with depression, and this has driven research on the relationship between hyperactivation of immune cells (microglia) in the brain and depression. However, the anti-inflammatory effect of antidepressant drugs is not optimal and many anti-inflammatory drugs do not have an antidepressant effect, which means that the exact mechanism of microglia and depression onset needs to be further investigated.

In terms of neural circuits, the more studied brain regions include the medial prefrontal, anterior cingulate, amygdala, and ventral hippocampus, which are associated with emotion perception, and the dorsal nucleus of the middle suture, ventral tegmental area of the midbrain, and lateral rigid nucleus, which are associated with reward processing. The more accepted view is that the onset of depression is associated with inactivation of reward-related loops and overactivation of stress-related loops. Most of these studies are supported by results from animal experiments, although it is still debated whether they relate specifically to the human brain due to the limitations of animal models of depression, and most of these animal results also do not explain the specific mechanisms underlying changes in neural loop activity.
 
Overall, the biological basis of depression has made a great deal of progress in the last decades. Because depression is an extremely complex psychiatric disorder, more basic research is needed to elucidate the pathogenesis and to propose better treatment options.
 
4  The Treatment of Depression
 
The treatment of depression includes medication, physical stimulation (electrical and magnetic stimulation), and cognitive behavioral therapy. Pharmacological treatment is generally preferred as it is more effective and has low side effects in about 2/3 of depressed patients. Commonly used antidepressants include selective seratonin reuptake inhibitors (SSRIs), pentraxin and norepinephrine reuptake inhibitors (SNRIs), etc. These drugs are so widely used that they are readily detectable in the waste waters of major cities in some developed countries. Their main limitations include slow onset of action (several weeks), often requiring multiple adjustments to the drug class, and ultimately remaining ineffective in about 1/3 of patients. In the last decade or so, some psychiatric drugs such as ketamine and Xylazine have proven to be faster acting (effective within hours) with longer-term antidepressant effects (days to weeks) in clinical trials, as well as superior efficacy in a significant proportion of refractory depression, and are approved or likely to be approved in Europe and the United States, where the neurobiological mechanisms of their efficacy are a focus of neuroscientific research.
 
Other therapies that have gained clinical use include electroconvulsive therapy (ECT), deep brain stimulation (DBS), vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), and direct current stimulation (DCS), which have also shown some efficacy in some patients with depression. Work in our laboratory also suggests the possibility of gene therapy for major depression.
 
Cognitive behavioral therapy is easily overlooked, but it has been shown to be more effective for the cognitive component of depression, including feelings of helplessness, hopelessness, and guilt. My graduate advisor, Dr. Peter Sterling, even argued that most antidepressant medications and physical therapies such as electromagnetism, whose efficacy actually comes from the placebo effect of these therapies, are still essentially part of cognitive-behavioral therapy. This view is somewhat biased; after all, a necessary condition for the clinical approval of a therapy is that its antidepressant effect be significantly greater than that of placebo. However, given the critical role of social and environmental factors in the development of depression and the high plasticity of the human brain, we should be able to agree that cognitive-behavioral therapies have some value in the treatment of depression. 
 
5 Environmental Factors in the Onset of Depression
 
The feelings of helplessness, despair, guilt, and shame exhibited by people with depression are acquired and can also be reduced through education and cognitive-behavioral training.
 
The general public may believe that a person receiving excessive negative stimuli (pain, punishment, social failure, etc.) can lead to depression. This idea is at least partially false, but even stress experienced as mild in the moment may lead to depression if present for a long time. Building animal models of depression often requires prolonged stress. In rats and mice, which I consider happy animals, prolonged restrictive stress (around 3 weeks) can also lead to learned helplessness (forced abandonment of struggle in swimming tests) and pleasure deficit (reduced preference for sugar-water rewards).
 
In terms of the current epidemic, preventive measures have been in place for three years, and a percentage of the population has been living with high levels of chronic stress. In addition,  because the virus was quite harmful in the early period, the general population has developed a certain fear of viral infections. According to recent news reports of large-scale panic reactions regarding positive cases in their immediate surroundings among young people in some large companies, as well as among college students, it is clear that the fear level of some people remains quite high. For young people in their twenties, who do not yet have sufficient social experience and are in the sensitive period for first-onset depression, three years of fear is particularly heartbreaking. It is not difficult to predict that the incidence of depression has been rising and will continue to increase among young people unless new psychological interventions are made available. Data from the past six months in China shows that the vast majority of people who have tested positive for the virus have mild symptoms or are even asymptomatic, with very few severe and critical illnesses and deaths, indicating that the latest wave of the virus has become significantly less harmful, following vaccination campaigns and other measures. I hope that authoritative medical experts will come forward, and will use actual data to educate and guide the public, allowing people who have tested positive to speak out about their experiences, so that the public can overcome their fear as soon as possible.

Another key factor regarding negative stimuli leading to depression is unpredictability and uncontrollability. Animal experiments have shown that if two rats receive the same number of painful electrical stimuli, while one receives a warning before the shock (e.g., a sound) or can terminate the shock through its own behavior (i.e., pressing a lever), the one with more control is less prone to depression-like behavior. The other rat, which has no control over its environment and passively receives random electric shocks, is prone to such behavior.  A common tool for modeling depression is chronic unpredictable mild stress (CUMS), which can effectively produce depressive-like behaviors. This is very different from positive rewards: the unpredictability of rewards has a significant boost on the motivation of some people to seek them. Casino and online game vendors understand this and use it to increase the addictive nature of the related consumption behavior.

When I was a kid, I farmed and sold vegetables,  so I can empathize with vegetable farmers, which I use here as an example of uncertainty during the pandemic. A vegetable farmer who spent money and effort to grow vegetables this year cannot know which days the roads will be closed so he can’t get to the market, or if the roads are open, he cannot know when the market is closed so he can’t set up his stall, and if he manages to set up his stall, he may be quarantined at any time.  There is nothing he can do about any of these things, and even if he is lucky enough to finally sell is vegetables, the psychological pressure remains nonetheless quite high. An important part of business school courses about organizational management includes how to handle things when the company is in turmoil. Good company managers give their employees early warning of difficulties, a sense of control, and clear expectations of how the crisis will end.

Guilt is also a result of acquired learning. Facing the same setbacks, a person can blame external factors, such as natural disasters or bad luck, or he or she can blame themselves. Nine out of ten things in life are not as good as they should be. Psychologically strong people tend to attribute failure to external circumstances and explain failure as a necessary process for eventual success. However, a person who has failed for a long period of time and is blamed for his or her own abilities or personality problems is prone to feelings of guilt and shame. One of the principles of the psychotherapist's approach to guilt is to guide the patient to direct his or her own frustrations to external factors and to redefine past failures as part of future successes.

For highly social animals like humans, there is also a large social-behavioral component to depression. The success of human survival and reproduction depends on complex social cooperation, and thus social interactions have a large reward effect on humans. When people reduce social interactions as a measure of epidemic prevention, not only do they make fewer new friends, they interact less with parents, classmates, and old friends. Even more important, social interactions became associated with the risk of virus transmission, so that those interactions that do occur are less rewarding due to fear.

Conclusion: Even Greater Efforts will be Needed to Repair the Wounds of the Epidemic

Over the past three years, our society has demonstrated the highest levels of solidarity, obedience, and discipline. Compared to some Western societies where there are still heated debates and protests over whether to wear masks, our behavior stands out as almost a miracle in the world context. But this process has left some people dealing with long-term fear, as their productive lives are under unpredictable and uncontrollable stress, in addition to the possibility of being implicitly accused of lacking discipline and patience.  At the same time, social interactions have not only diminished but can also lead to harm, all of which indeed creates feelings of despair, helplessness, guilt, loneliness, and ultimately an increase in the prevalence of depression in those who are prone to such conditions.

The epidemic was a great psychological trauma for all of humanity, and  even once the epidemic is over, repairing these wounds will require an even greater effort. Natural disasters are inevitable, and China’s response has generally been quite successful. For the mental health of society in the post-pandemic era, whether the duration and the level of stress experienced by the population can be reduced, whether the stress can become more predictable and manageable, and whether family and friendships can be restored are all issues that need to be considered and require the efforts of society as a whole rather than a single sector. I hope our society will release a reopening plan with clear milestones as soon as possible, educate and guide the public to shake off of the chronic fear of the virus, increase psychological counseling for young people, make efforts to reduce the stress in people's lives even as we  propose more stable management measures, allowing people to use their personal creativity to improve their own living standards, and encourage and promote social interaction, so as to achieve the goal of improving the mental health of society as a whole.

Notes

[1]罗敏敏, “疫情终将过去，如何直面社会抑郁创伤?” published on the online platform of 知识分子/The Intellectual on November 30, 2022.