In the previous chapter, I reviewed mitochondria in all their glory. Their function affects every cell in the human body. Their involvement in all aspects of cell function, neurotransmitters, hormones, inflammation, immune system function, regulation of gene expression, development, and the maintenance and health of cells results in widespread effects throughout the body and the brain. They are the drivers of cells and metabolism. They are the workforce of the human body.
But the question remains: Do we have evidence that metabolic problems are related to mental disorders? And how?
Yes! There is an abundance of evidence that links problems with metabolism to mental disorders.
As I discussed in Chapter Five, physicians and researchers have known for well over a century that mental disorders appear to be linked to metabolic disorders, such as diabetes. Direct evidence of metabolic abnormalities in people with mental disorders, even those who don’t yet have obesity, diabetes, or cardiovascular disease, dates back to at least the 1950s. Among the abnormalities found in markers of metabolism: differences in levels of ATP, redox markers (the balance between oxidants, such as ROS, and antioxidants), hormones, neurotransmitters, and lactate (a marker of metabolic stress). In the 1980s, it was discovered that infusing lactate into the vein of a person with panic disorder would often precipitate an immediate panic attack.1 As I already discussed, cortisol dysregulation also seems to play a role, at least in some people, and this is a metabolic hormone.
Neuroimaging studies have provided an overwhelming amount of evidence for metabolic differences in the brains of people with mental disorders. Functional magnetic resonance imaging (fMRI) and near-infrared spectroscopic imaging (NIRSI) can measure localized changes in cerebral blood flow related to neural activity, which is an indirect marker of metabolism and brain activity. Positron emission tomography (PET), blood-oxygen-level-dependent imaging (BOLD), and single-photon emission computed tomography (SPECT) all measure some metric of metabolism—levels of glucose, oxygen, or a radioactive molecule that researchers inject into a person’s vein. All these imaging studies are measuring metabolism in the brain because metabolism is a marker of brain activity. When neurons are active, they use more energy. When they are resting, they use less.
These studies have provided us with a plethora of data demonstrating differences in the brains of people with mental disorders compared to the brains of healthy controls. Some brain regions are overactive, while other brain regions are underactive. More recently, researchers have turned to functional brain connectivity studies, which look at the interactions of two or more brain regions in attempts to determine which of those regions communicate with each other to perform specific tasks. However, even with all this research, heterogeneity and inconsistent findings have been the name of the game. If you don’t believe me, the American Psychiatric Association published a “Resource Document on Neuroimaging” in 2018 in which they concluded: “There are currently no brain imaging biomarkers that are clinically useful for any diagnostic category in psychiatry.”2
The researchers doing this neuroimaging work, however, have known for decades that there are differences in metabolism in the brains of people with mental disorders. At first glance, they may think that the theory of brain energy offers nothing new. “Obviously mental disorders are related to metabolism! We’ve known that all along! Metabolism is everything in biology. What’s new here?”
As I hope you’ll come to understand, there is something new here. And not just new, but revolutionary. While these researchers have been lost in the overwhelming complexity of metabolism and how the brain works, trying to figure out what is making some brain regions overactive and other brain regions underactive, they have failed to see the big picture of metabolism. Most importantly, they have failed to see the role of mitochondria in all of it. By stepping back and looking at the bigger picture (even if that bigger picture is playing out on a microscopic level), we can find new ways to understand what’s happening with metabolism and mental health and see new ways to address these problems.
Mitochondrial Dysfunction and Mental Health
But do we have evidence that mitochondria aren’t functioning properly in people with mental disorders?
Yes! We now have an abundance of evidence.
Over the past several decades, it has become clear that mitochondria play a much larger role in human health than ever imagined. When mitochondria don’t function properly, the human body doesn’t function properly. Mitochondrial dysfunction is the term most frequently used to describe impairment in mitochondrial function. The diseases and illnesses that have been associated with mitochondrial dysfunction are widespread, and the list includes almost all of the psychiatric disorders. It also includes the metabolic and neurological disorders that I have discussed—obesity, diabetes, cardiovascular disease, Alzheimer’s disease, and epilepsy. In reality, it includes even more disorders—many cancers and Parkinson’s disease are among them. I won’t be able to go into detail on all these different disorders. However, the framework that I am creating will apply to them as well.
The specific psychiatric disorders in which mitochondrial dysfunction has been identified include the following: schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism, anxiety disorders, obsessive-compulsive disorder, posttraumatic stress disorder, attention deficit/hyperactivity disorder, anorexia nervosa, alcohol use disorder (aka alcoholism), marijuana use disorder, opioid use disorder, and borderline personality disorder. Dementia and delirium, often thought of as neurological illnesses, are also included.
This list does not include every psychiatric diagnosis in DSM-5. However, that’s not necessarily because mitochondrial dysfunction does not exist in the other diagnoses; research just hasn’t been done on the other diagnoses yet. Nonetheless, this list is certainly broad enough to state that mitochondrial dysfunction has been found in a wide range of diagnoses that include pretty much every symptom found in psychiatry.
If all this evidence has existed for a while, why hasn’t anyone else suggested that mitochondrial dysfunction is the common pathway to metabolic or mental disorders?
Well . . . they have! To most people reading this book, this may seem like new information. However, this book is not the first to assert the importance of mitochondria in human health and disease.
Dr. Raymond Pearl published a book on the rate of living theory in 1928, in which he argued that longevity and diseases of aging, which include most of the metabolic diseases, are due to metabolic rate. In 1954, Dr. Denham Harman proposed the free radical theory of aging, which focused on ROS as the cause of age-related diseases. In 1972, he further developed this theory and proposed the mitochondrial theory of aging, which recognized the central role of mitochondria in the production of ROS. In recent years, there has been an explosion of research on mitochondria and their relationship to obesity, diabetes, cardiovascular disease, and aging itself, with tens of thousands of research articles published in the medical literature.
The psychiatric literature is filled with articles from respected scientists highlighting the role of mitochondria in mental disorders. A 2021 medical literature search came up with more than four hundred articles relating to schizophrenia and bipolar disorder, more than three thousand relating to depression, more than four thousand relating to Alzheimer’s disease, and more than eleven thousand relating to alcohol use. Some of this pioneering research has been close to home for me, coming from respected and internationally renowned colleagues, such as Professors Bruce Cohen and Dost Öngür at McLean Hospital and Harvard Medical School, where I have worked for more than twenty-five years.
In 2017, Dr. Douglas Wallace, the founder of the field of mitochondrial genetics, published an article in JAMA Psychiatry, one of the leading psychiatric journals, audaciously claiming (as I do in this book) that all psychiatric disorders are the result of mitochondrial dysfunction.3 Being a geneticist, Wallace focused on mitochondrial genes. They mutate often due to ROS and the lack of protection of mitochondrial DNA. Wallace argued that the brain is the organ that will be most affected by a problem with energy production by mitochondria. He argued that different parts of the brain might fail first—likely because they are more sensitive to energy deprivation than others. This makes sense, given that most machines do have “weakest links.” The brain is likely the same. So, a small amount of energy deprivation might result in ADHD or depression and a larger amount of energy deprivation might result in other disorders, such as schizophrenia.
The rebuttal was swift. Dr. Tamas Kozicz and colleagues argued that although people like “simple” explanations, psychiatric disorders do not lend themselves to such a simple explanation.4 They acknowledged that “suboptimal mitochondrial function” does appear to play a role in most psychiatric disorders. However, focusing solely on mitochondrial energy production cannot account for the diversity of symptoms that we see in the billions of people with mental disorders. Furthermore, it can’t even account for the diversity of symptoms that we see in people with rare genetic mitochondrial diseases. Even people with the same mitochondrial genetic mutation can have different symptoms. They argued that mental disorders are far too complex and different from person to person to be explained by a single factor.
What these researchers failed to consider is how many other roles mitochondria play in cells apart from the production of energy. They also failed to recognize just how many different factors affect the function and health of mitochondria. When mitochondria don’t function properly, neither does the brain. When brain metabolism is not properly controlled, the brain doesn’t work properly. Symptoms can be highly variable, but mitochondrial dysfunction is both necessary and sufficient to explain all the symptoms of mental illness.
Defining This Root Cause
As I just discussed in the previous chapter, mitochondria do a lot of different things. Defining what dysfunction means is difficult and has been a challenge to scientists; it can mean very different things in different research studies.
The same can be said for cars. If a car is “dysfunctional,” what does that mean? It could mean that the engine sputters when traveling down the highway. It could mean that a tire is flat, and the car can’t move along the road as easily. It could mean that the lights and the turn signals aren’t working. Those are all different problems with a car. They all result from different causes. But here’s an important point: Regardless of what is wrong with the car, if it’s on the highway with any of those problems, it will affect the other cars on the road. It will be more likely to slow down traffic or cause an accident. Traffic can slow or completely stop. The highway could “stop working” due to one car. In reality, the overwhelming majority of car accidents aren’t about the cars themselves but about the drivers of the cars. Drivers can also be “dysfunctional.” They can be on their cell phones. They can fall asleep at the wheel. They can be drunk. They can be high. They can have road rage. Regardless of the cause of the dysfunction, whether it’s the car or the driver, these wayward cars and drivers affect traffic in similar ways.
Mitochondrial dysfunction is the same. It can be caused by many different things and can result in different problems for the mitochondria and for the cells in which they reside.5 Measuring the function of mitochondria is difficult. Remember how tiny they are? There are usually hundreds and sometimes thousands of them in one cell. Cells are pretty tiny on their own.
Mitochondrial dysfunction can stem from problems with the mitochondria themselves. This includes genetic mutations or a shortage of mitochondria in the cell. As I mentioned, mitochondria have their own DNA. It is not protected in the same way that the human genome is protected; therefore, it’s prone to mutations. Mitochondria are producing ROS, and if they produce too much of it, it can damage the mitochondrial DNA or other parts. This can lead to defective mitochondria. When mitochondria are defective, they are supposed to be disposed of and recycled, with new ones taking their place. If this doesn’t happen, a cell can be left with a workforce shortage. It’s well established that the number of mitochondria in our cells decreases as we get older, resulting in less metabolic capacity for cells.
When the workforce is decreased, whether through aging or malfunctioning mitochondria, productivity goes down. As the mitochondria continue to decline, the cell usually dies. This leads to organs and tissues shrinking. As the cells die off, the organs get weaker and more vulnerable to stress. Brains shrink. People lose muscle mass. The heart isn’t as strong. This phenomenon is also seen in people with chronic mental disorders. As I already mentioned, accelerated aging has been found in people with all mental disorders.
The more important cause of mitochondrial impairment is one that I’ll call mitochondrial dysregulation. Many of the factors that affect mitochondrial function come from outside the cell. They include neurotransmitters, hormones, peptides, inflammatory signals, and even something like alcohol. Yep! Alcohol affects the function of mitochondria. I refer to this as dysregulation, as opposed to dysfunction, because in some cases, the mitochondria were functioning just fine, but their environment became hostile quickly and caused impairment—similar to people doing the best they can when they are highly stressed.
Defining which mitochondrial functions to focus on is critically important and varies in different studies. Some of these studies are done while mitochondria are still in living cells (in vivo), and others are done with mitochondria laid bare in a laboratory dish (in vitro).6
Many researchers have focused on ATP production. They can measure the amount of ATP relative to ADP in the cell cytoplasm and make assumptions about how well the mitochondria are functioning. The implications of this research are straightforward; ATP provides energy for the cell to work. If the levels are reduced, the cell won’t work as well. The levels of ATP to ADP are also important signals within cells. This ratio affects numerous aspects of cell function, including gene expression. Reduced levels of ATP have been found in a wide variety of disorders, including schizophrenia, bipolar disorder, major depression, alcoholism, PTSD, autism, OCD, Alzheimer’s disease, epilepsy, cardiovascular disease, type 2 diabetes, and obesity. Even though most people think of obesity as a surplus of energy, many cells in the bodies and brains of people with obesity are actually deprived of ATP, due to mitochondrial dysfunction.7
Other researchers have focused on oxidative stress. Remember, this is a term used to describe the buildup of ROS. Recall that mitochondria create ROS, but they also help detoxify them through antioxidants. When mitochondria aren’t working properly, ROS build up and can cause damage to the cell in general, but more often to the mitochondria themselves, leading to a vicious feedback cycle. Numerous studies have found higher levels of oxidative stress in essentially all of the metabolic, neurological, and mental disorders that I have been discussing. This has been linked to cell damage and accelerated aging.
There have been three major shortfalls in the research on the role of mitochondria in health and disease to date:
1.Focus on just one function. Most studies have focused on only one function or aspect of mitochondria. They often fail to consider all the diverse functions. Some mitochondrial functions can be normal, while others are abnormal. Additionally, some functions can affect other functions. For example, studies that have looked at mitochondrial ATP production often view this as the primary, and sometimes only, role of mitochondria. Any adverse outcomes that they see in the cells they are studying are attributed to this impaired ATP production. In reality, mitochondria that aren’t producing enough ATP may also have trouble fusing with each other, or might be leaking large amounts of ROS, or might have trouble managing calcium levels in the cell. These functions may be more important to the cell deficits observed by the researchers, even if those functions weren’t measured. In some cases, ATP production might be normal, while these other functions are abnormal, and the researchers might conclude that the mitochondria were functioning just fine when, in fact, they weren’t.
2.Differences between cells. Mitochondria are affected by numerous factors, both within the cell and from outside the cell. The number and health of mitochondria are not equally distributed among all cells in the body and brain. Some cells can have perfectly healthy mitochondria in abundance, while other cells can have defective or insufficient mitochondria. Researchers must study specific cells to determine whether mitochondria in those cells are playing a role in an illness. Studying a healthy immune cell may not offer any information about what’s happening in a malfunctioning brain cell.
3.The role of feedback loops. The question of which comes first, the chicken or the egg, has led many researchers astray. Does mitochondrial dysfunction cause illness? Or does illness cause mitochondrial dysfunction? Are mitochondria simply innocent bystanders and the victims of some other destructive process?
When thinking about causes and consequences, things can get confusing. There are many causes of mitochondrial dysfunction. There are also many consequences. I’ll get to this soon enough. What’s confusing, though, is that causes can lead to consequences, but consequences can lead to causes. When we see this type of a pattern, we need to think about feedback loops. When it comes to metabolism and mitochondria, almost all things are regulated in a feedback loop.
One example is in Alzheimer’s disease research. We know that the abnormal protein beta-amyloid accumulates in the brains of people with Alzheimer’s disease. This protein has been the primary target of research. We know the more beta-amyloid that is present, the more likely it is that someone will develop Alzheimer’s disease. We also know it is toxic to mitochondria and causes mitochondrial dysfunction.8 Many researchers have stopped there. They feel they have enough evidence that mitochondria are innocent bystanders of this destructive protein. What causes beta-amyloid to accumulate? They don’t know. They are still looking for that cause. What they have missed, however, is that mitochondrial dysfunction might very well be the cause of the accumulation of beta-amyloid itself. We have evidence that mitochondrial dysfunction begins even before beta-amyloid starts accumulating.9 It’s possible that it’s a positive feedback loop. Mitochondrial dysfunction causes a maintenance problem in cells. This results in the accumulation of beta-amyloid (a protein that should be getting disposed of and recycled). This beta-amyloid accumulation then makes mitochondrial dysfunction even worse. This feedback loop results in the downward spiral that we call Alzheimer’s disease.
Fortunately, research in the last twenty years has broadened substantially regarding the scope of mitochondrial function—all the different roles mentioned in the prior Chapter are from different studies looking at the diverse functions that mitochondria perform.
Mitochondrial dysfunction or dysregulation ties everything that we already know about mental and metabolic disorders together in a coherent way. Mitochondria are the common pathway. For the scientists or purists, a better name for this theory might be the metabolic and mitochondrial theory of mental illness, as this would include the myriad tasks of mitochondria and how mitochondria can be influenced by all things that affect metabolism. (I’ll get to these in Part Three of the book.) However, because energy dysregulation does appear to account for the majority of symptoms of mental illness, the short and catchy phrase “brain energy theory” works for me.
How Mitochondrial Malfunction Leads to Mental Illness
I will now show you how mitochondrial dysfunction can result in all the brain changes and symptoms that we see in mental disorders. Mitochondria affect the development of the brain, the expression of different genes, synapse formation and destruction, and brain activity. They affect structural problems and functional problems. They tie together so much of what we already know and put it into one common pathway. Let’s walk through some of the science.
Recall that in order to understand much of the existing neuroscience on mental disorders, I need to explain why some brain areas might be overactive, while others might be underactive, resulting in symptoms. I’m also looking for reasons why cells might develop abnormally and why some cells end up shrinking and dying, resulting in brain functions that are permanently absent. These concrete mechanisms of action will help us understand the symptoms of mental illness. They align with the framework that I outlined in Chapter Six.
You might also recall from Chapter Five that I said that human illnesses are usually due to a problem in one of three areas: the development, function, or maintenance of cells.
As it turns out, mitochondria play a role in all of these.
I will now walk you through five broad consequences of mitochondrial dysfunction and dysregulation that can address all of this: decreased cell maintenance, overactive brain functions, underactive brain functions, developmental problems, and cell shrinkage and cell death.
Decreased Cell Maintenance
One of the unique things about living cells, as opposed to non-living machines like cars, is that they require energy and metabolic resources to maintain themselves. Cell parts need to be repaired and replaced in constant, never-ending turnover. All of this requires energy and metabolic building blocks. One study estimates about one-third of the brain’s ATP production goes to cell maintenance or “housekeeping” functions.10 I’ve already described the roles of stress, cortisol, and mitochondria themselves in the process of autophagy, which is critically important in cell maintenance. But, as usual, there’s more to the story.
Mitochondria interact with other organelles to facilitate routine maintenance functions. For example, they interact with lysosomes. When these interactions are prevented in experiments, waste products accumulate in the lysosomes.11 They also interact with the endoplasmic reticulum (ER), which has many roles including the folding of proteins. Many neurodegenerative disorders are associated with misfolded proteins in the ER. When these misfolded proteins accumulate, a process called the unfolded protein response (UPR) tries to mitigate the damage. One group of researchers found that there is a microprotein on the outer membrane of mitochondria, PIGBOS, that plays a key role in the UPR. When this protein was eliminated, the cells were much more likely to die.12 This strongly suggests that mitochondria play a key role in this process as well. These are just some of the ways that mitochondrial dysfunction can cause problems with cell maintenance, which can lead to all of the maintenance problems and structural defects found in people with mental disorders.
In some cases, structural defects in cells can lead to a positive feedback cycle that affects metabolism and can make it harder for cells to work. One specific example is myelin, which is an outer protective coating for neurons made by support cells called oligodendrocytes. Myelin makes it easier for neurons to send electrical signals. If a neuron has defects in its myelin coating, it will require more energy to work. An extreme example of this is multiple sclerosis, in which myelin is destroyed by an autoimmune process. Mitochondrial dysfunction has been associated with problems in myelin production and maintenance. Consistent with the brain energy theory, defects in myelin have been identified in the brains of people with schizophrenia, major depression, bipolar disorder, alcoholism, epilepsy, Alzheimer’s disease, diabetes, and even obesity.13
Debris in the cell, another structural defect and maintenance issue, can impair mitochondria from moving around. For example, Alzheimer’s disease is associated with the accumulation of a protein called tau, in addition to the beta-amyloid described earlier. Researchers who looked at the effects of tau protein on mitochondria found that it severely limited mitochondria’s ability to move around a cell.14 Their paths became obstructed from all the debris, and the tau proteins interfered with the cytoskeleton that mitochondria use for movement. When mitochondria are prevented from moving around a cell, the cell has trouble working properly, and the cell may shrink and/or die.
Overactive Brain Functions
Remember our discussion of overactivity or hyperexcitability from Chapter Six? Mitochondrial dysfunction or dysregulation can cause this! Again, this is probably the most paradoxical thing about mitochondrial dysfunction. Sometimes when mitochondria aren’t working properly, parts of the brain can actually become overactive as opposed to underactive—even though they may not have enough ATP.
In the real world, hyperexcitability of cells is actually pretty common. There are many medical conditions that are reflections of hyperexcitable cells. Seizures are a clear and extreme example in the brain. A heart arrhythmia can be due to hyperexcitable heart cells. A muscle spasm is a hyperexcitable muscle cell. Chronic pain is due to a hyperexcitable nerve cell. These are all examples of cells firing when they shouldn’t, or not stopping when they should.
Mitochondrial dysfunction can lead to overactivity and hyperexcitability. There are at least three ways this can happen:
1.Recall that mitochondria are involved in ion pumping and calcium regulation, which are both required to turn cells “off.” If mitochondria aren’t functioning properly, these processes will take longer to perform, and cells can become hyperexcitable.
2.Sometimes, overactivity or hyperexcitability can be due to dysfunction in cells that are meant to slow down other cells, such as GABA cells. If GABA cells aren’t working properly, then the cells they are supposed to inhibit will become unleashed and hyperexcitable. Recall from Chapter Six that cortical interneurons are one such example, and their dysfunction has been found in many mental and neurological disorders.
3.I discussed how maintenance problems can alter the structure of cells, such as problems with myelin or beta-amyloid. These maintenance problems can cause hyperexcitability; for example, a lack of myelin can allow ions to leak into a cell and cause it to fire when it shouldn’t.
One research group directly demonstrated that mitochondrial dysfunction causes hyperexcitability by deleting a protein in mice, sirtuin 3, known to be essential to mitochondrial health. Sure enough, the mice developed mitochondrial dysfunction, hyperexcitability, and seizures, and they died early deaths.15 Another research group turned stem cells from people with bipolar disorder and healthy controls into neurons and found that the neurons from the people with bipolar disorder had mitochondrial abnormalities and the cells were hyperexcitable.16 Interestingly, lithium reduced this hyperexcitability.
Hyperexcitability of neurons has been found in many mental and metabolic disorders. It causes seizures and can be measured in the brains of people with epilepsy. Hyperexcitability has also been found in the brains of people with delirium, PTSD, schizophrenia, bipolar disorder, autism, obsessive-compulsive disorder, and Alzheimer’s disease. It has even been measured in healthy rodents subjected to nothing more than chronic stress.17 Hyperexcitability can be difficult to measure, but we really don’t need to measure it. People can usually tell when it’s occurring because something is happening in their bodies or brains that shouldn’t be happening. Hyperexcitability of a pain cell causes pain. Hyperexcitability of the anxiety pathways in the brain causes anxiety. Hyperexcitability of any brain region that produces a human emotion, perception, cognition, or behavior will produce that experience.
Underactive Brain Functions
Mitochondrial dysfunction or dysregulation can slow down or reduce the function of cells. Cells require energy to work. Mitochondria provide it. They are also the on/off switch for cells. They control calcium levels and other signals. Brain cells need energy to make and release neurotransmitters and hormones and to function properly. Reduced cell function alone explains many of the altered levels of neurotransmitters and hormones seen in people with mental disorders. Additionally, mitochondria are directly involved in making some of the hormones, such as cortisol, estrogen, and testosterone, so if they are dysfunctional or dysregulated, these hormone levels may be dysregulated, too.
Developmental Problems
Beginning in the womb until early adulthood, the human brain is rapidly growing and forming connections between neurons and other brain cells. These connections are vitally important, laying the groundwork, or “hardwiring,” for life. There are developmental windows—times when the hardwiring of the brain needs to take place in clear ways. If development doesn’t occur normally, this window can close, and the brain will never again have the chance to be “normal.” Mitochondria are critically important for all these tasks. As I discussed, they play critical roles in cell growth, differentiation, and synapse formation. When mitochondria are dysfunctional or dysregulated, the brain doesn’t develop normally. This is important to keep in mind for neurodevelopmental disorders that begin in infancy or childhood, such as autism. Even at the end of life, our brains change in predictable ways. Cell growth and differentiation, as well as neuroplasticity, or the changing and adaptability of neurons, are important throughout life. When mitochondria aren’t functioning properly, problems with all of this can occur. If cells or connections between cells are missing, this can result in permanently absent brain functions. These symptoms don’t wax and wane, because the cells and connections needed to perform these functions simply aren’t present.
Cell Shrinkage and Cell Death
Mitochondrial dysfunction can lead to cell shrinkage, or atrophy. If the quantity or health of mitochondria declines, the cell gets stressed. Recall that mitochondria spread themselves throughout the cell. Some are always moving around, looking for work to do. If the workforce is reduced, they can’t keep the entire cell working. In some cases, mitochondria stop going to peripheral parts of the cell, such as axon terminals or dendrites. When they stop going there, those cell parts die. Inflammation ensues. Microglia, the immune cells of the brain, get to work and absorb some of these dead cell parts.18 As more and more mitochondria become impaired, more and more of the cell shrinks. If the process continues, the cell dies.
It is well documented that the brains of people with chronic mental disorders show signs of cell shrinkage over time. Recall that they are aging prematurely. Different brain regions are affected in different people. Some areas, such as the hippocampus, are more commonly impacted, but even in people with the same diagnosis, such as schizophrenia, there can be numerous differences in the brain regions impacted.19 This comes back to heterogeneity. Mitochondrial dysfunction and dysregulation explain this heterogeneity. Given that numerous factors affect mitochondrial function (which I’ll get to just up ahead, in Part Three), they also affect different areas of the brain. So, depending upon the mix of risk factors or causes that people have, their brains will be affected differently. As I already mentioned, timing and development also matter. People who are affected at age fourteen will have brain differences from people not affected until thirty-nine.
Let’s put this all together using our car analogy. A car has many parts—a fuel tank, fuel that goes into the tank (gasoline), an engine, a battery for electrical energy, a steering system, and a braking system for stopping. Problems can occur in different parts, and different symptoms can result. In some cases, the car may sputter or move slower (underactive function) if it gets water in the gas tank or if a spark plug has gone bad. If the battery begins to fail, it might be that the lights dim, or the windshield wipers slow down, or the radio doesn’t work, or the car won’t start at all (all underactive functions). These are very different symptoms, but they’re all related to energy—and usually with just one cause. Now let’s make the car like a living cell. Suddenly it requires energy to work and energy to maintain itself. Without enough energy, the tires start to deflate, the wheels get wobbly, the doors develop rust and holes (maintenance problems). The engine and battery get old. Battery acid starts to leak all over the engine (ROS). The oil hasn’t been changed in a while, and engine parts are getting damaged. This lack of maintenance makes the engine even worse (a positive feedback cycle). At some point, this car will become a danger to the other cars and the flow of traffic on the highway. The brakes stop working (hyperexcitability due to impaired off switch). Eventually, it may cause a car crash and shut down the highway. The car can be towed to the junkyard for recycling (apoptosis). If someone attempts to drive it again, it will continue to pose a danger to the other cars on the highway and the flow of traffic (metabolic and mental disorders).
Brain Energy Theory Realized
Now let’s see the brain energy theory in action. I’ll walk you through some of the evidence focusing on three different mental disorders and how we can conceptualize what’s happening to produce symptoms from a mitochondrial and metabolic point of view.
Major Depression
We know from many studies that mitochondria are not functioning properly in people with chronic depression.20 For example, several lines of evidence have found that people with depression have lower levels of ATP, not only in brain cells, but also in muscle cells and circulating immune cells. Decreased ATP production has been found in animal models of depression as well. Autopsy studies looking at brain tissue of people with chronic depression have found specific abnormalities in mitochondrial proteins, clearly implicating mitochondrial dysfunction.21 And as I already mentioned, levels of oxidative stress are elevated in people with depression.
Another line of evidence includes blood biomarkers of depression. Many researchers have taken blood samples from thousands of people with depression looking for abnormalities or differences compared to healthy controls. Numerous biomarkers have been identified. A meta-analysis of forty-six such studies tried to make sense of the differences to see if there might be a common pathway or theme. There was! The biomarkers related primarily to amino acid and lipid metabolism, both of which relate to mitochondrial function.22
One specific biomarker of great interest is acetyl-L-carnitine (ALC). This molecule is produced within mitochondria and is important to energy production. It is critical for the function of the hippocampus, a brain region often implicated in depression. One group of researchers looked at levels of ALC in depressed and non-depressed people and found that the depressed people, on average, had lower levels.23 Furthermore, lower levels of ALC predicted the severity of depression, the chronicity of the illness, treatment resistance, and even a history of emotional neglect. A subsequent study in 460 patients with depression found that ALC levels improved with effective antidepressant treatments, and that these levels could help predict who would experience a full remission.24 These researchers concluded, “New strategies targeting mitochondria should be explored to improve treatments of Major Depressive Disorder.”
Perhaps the most direct and stunning evidence for the role of mitochondria in depression comes from an elegant study done in rats.25 Researchers identified rats that had high levels of anxiety and depression-like behaviors and then studied a specific part of their brains, the nucleus accumbens, to see if there were differences in mitochondrial function and/or how the cells developed. They found both. The anxious/depressed rats had fewer mitochondria per cell, as well as differences in the way their mitochondria used oxygen to turn energy into ATP and in how mitochondria interacted with another organelle, the endoplasmic reticulum (ER). The neurons themselves also looked different. Following the trail further, the researchers found that the mitochondria from these rats had lower levels of mitofusin-2 (MFN2), a protein on mitochondrial membranes important to their ability to fuse with each other and with the ER. Here’s the stunning part. They then injected the anxious/depressed rats with a viral vector that significantly increased the levels of MFN2. And that changed everything! The mitochondria began functioning normally, the neurons began to look normal, and the anxiety and depression-like behaviors stopped. This strongly suggests a causal role for mitochondria in depression and anxiety . . . at least in rats.
Some of the symptoms of depression fall neatly into the category of underactive functions or reduced metabolism. Changes in sleep, energy, motivation, and concentration likely all relate to reduced function of brain cells. The fatigue almost certainly extends to the muscles throughout the body, given that mitochondrial dysfunction has been found there, too. In some cases, people will describe “leaden paralysis,” a situation in which they feel like their arms and legs are made of lead and it’s difficult to even move them. Mitochondrial dysfunction in their muscles might explain this. If their muscles don’t have enough energy, people will have difficulty moving them. Catatonia is an extreme version of metabolic failure—people can appear paralyzed from their illness and have severe difficulty moving or speaking.
Bipolar Disorder
Direct evidence for metabolic abnormalities in bipolar disorder (and schizophrenia) dates to 1956 when researchers noted abnormalities in lactate metabolism in patients.26 There are many studies documenting mitochondrial dysfunction in bipolar disorder, with findings similar to those found in people with depression. However, one important question is: What makes depression different than mania? Anyone who has seen people with these two conditions knows there is a big difference.
In 2018, researchers published a review article, “A Model of the Mitochondrial Basis of Bipolar Disorder,” in which they proposed that depressive states appear to be energy-deficient states, while manic states appear to involve increased energy production in the brain.27 They cited several studies showing that manic states are associated with increased glucose and lactate utilization in the brain, both suggestive of increased mitochondrial energy production. Additionally, two neurotransmitters, glutamate and dopamine, have been found to be elevated in manic states, suggesting increased activity of these neurons. So, manic states appear to be one of the few unique situations in which mitochondria, at least in some brain cells, are producing more energy than normal. Although surprising, this is still mitochondrial dysfunction or dysregulation. The mitochondria are supposed to slow down at appropriate times, such as at night to allow for sleep. Different brain cells are supposed to stop at certain times—like the traffic in a major city. In manic states, the mitochondria are hyperactive in terms of their production of energy, and this is making cells “go” when they shouldn’t. They aren’t yielding or slowing down at appropriate times. Many parts of the brain appear to be overactive.
Several additional lines of evidence support this model.28 Bipolar patients have been found to have higher than normal calcium levels, especially when they are manic—consistent with the hyperexcitability mechanism that I outlined. In fact, researchers have confirmed changes in neuronal excitability in bipolar patients. For anyone who has seen people with depression or mania, this makes perfect sense. People with mania clearly have too much energy. People with depression clearly don’t have enough energy. It’s fascinating that this has been found at the cellular level. In people with bipolar disorder, once the manic episode resolves, they continue to have mitochondrial dysfunction, but it results in too little energy production overall. One group of researchers recently identified a mitochondrial biomarker in blood cells showing a significant decrease in the number of mitochondria in both manic and depressed states that normalized when people were feeling well.29 This suggests that something might be disrupting either mitochondrial biogenesis or mitophagy throughout the entire body during disease states, not just in the brain.
During manic episodes, one of the biggest dangers with too much energy is its effect on hyperexcitable cells. These are the cells that have damaged mitochondria, too few mitochondria, or structural damage due to maintenance problems. The short burst of energy during a manic phase isn’t enough to correct the longstanding problems associated with mitochondrial dysfunction. It’s not enough energy or time to repair the cells. Instead, it’s enough to cause major problems, like psychotic symptoms, anxiety, and agitation. An easy way to think about this is to go back to our car analogy. If a car is in poor shape with deflated and misaligned tires due to poor maintenance, giving that car more gas suddenly is actually a dangerous thing. It’s not ready to handle more energy or more speed. It will be more likely to crash and burn. That’s what happens when you give a hyperexcitable cell too much energy.
Posttraumatic Stress Disorder
PTSD can be understood as a hyperexcitable trauma response system. This system is a normal response to life-threatening events but is now turning on when it shouldn’t or failing to turn off when it should. For some people, this system appears to develop a lower threshold for firing. For example, many people with a trauma history will have clearly identified “triggers” that set off their symptoms. These can be places, people, smells, words, or even thoughts.
Two areas of the brain are commonly affected, the amygdala and the medial prefrontal cortex (mPFC). The amygdala sets off the fear response and has been found to be hyperexcitable in PTSD. The mPFC is an area of the brain that inhibits the amygdala. By doing so, it can stop a panic reaction once someone realizes that there’s no need to panic. This area of the brain has been found to be underactive in people with PTSD, meaning that the person will have trouble stopping a panic reaction. Several lines of evidence have demonstrated mitochondrial dysfunction in people with PTSD, including autopsy studies showing abnormalities in mitochondrial gene expression, reductions in total mitochondria, increased levels of oxidative stress, and reduced levels of ATP.30
A Unifying Example
But can all mental disorders really be due to metabolism and mitochondrial dysfunction?
Some people may still have a difficult time with this new way of conceptualizing mental disorders, as lumping all the disorders together under the pathway of metabolism and mitochondrial dysfunction may seem like a stretch.
To help address this concern, we should be able to look at situations in which we know mitochondrial function is impaired abruptly and see essentially all psychiatric symptoms emerge. As it turns out, we have a clear example for this test proof—delirium.
Delirium is a serious condition defined as an acute mental disturbance. The word “acute” means that it happens rapidly. The “mental disturbance” can be any psychiatric symptom—confusion, disorientation, distractibility, fixation on certain topics, hallucinations, delusions, mood changes, anxiety, agitation, withdrawal, dramatic changes in sleep, and personality changes. Every single symptom of any psychiatric disorder can occur during delirium. Even changes in eating behaviors and perception of body image that mimic an eating disorder have been observed during delirium.
So, what causes delirium? The standard answer right now: No one knows for sure how it all works, but we know that when people are seriously ill, it can happen. Almost all medical disorders can cause delirium. This includes things like infections, cancer, autoimmune disorders, heart attacks, and strokes. The more serious they are, the more likely they are to cause delirium. People admitted to intensive care units (ICUs) are much more likely to have delirium, with anywhere from 35 to 80 percent of critically ill patients being diagnosed with it, depending upon the study.31
Medications can also do it. People starting new medications can have reactions that can cause delirium. Withdrawal from medications or substances, even toxic ones like heavy use of alcohol, can cause delirium. Alcohol withdrawal delirium has a special name, delirium tremens. It can be quite serious and life-threatening. The elderly are particularly vulnerable to delirium. People with preexisting dementia, such as Alzheimer’s disease, are even more vulnerable. Essentially, there are countless causes of delirium. As I will soon explore, they all affect mitochondrial function.
How is delirium diagnosed? When symptoms of delirium begin, sometimes the cause is obvious. In some cases, the initial symptoms can be seen as a normal response to a medical condition. Many people who have heart attacks will have anxiety. It’s difficult to imagine not being anxious when facing a life-threatening situation. Physicians will often give people psychiatric medications, such as benzodiazepines, to reduce their anxiety. In this early phase, they usually don’t diagnose delirium or a psychiatric disorder, even though they are prescribing a psychiatric medication. The anxiety is often seen as a normal, understandable reaction. However, if these anxiety symptoms are the start of delirium, the symptoms usually become more dramatic. People can develop panic attacks and severe anxiety. This can quickly progress to confusion, disorientation, and hallucinations. This is common in frail, elderly people with heart attacks. Although these symptoms can be identical to those of dementia or schizophrenia, physicians don’t assign these diagnoses. Instead, they diagnose delirium.
But how do they think about this distinction? Most healthcare professionals know that the brain simply isn’t working right under the stress of a heart attack. They will attribute any and all new psychiatric symptoms to the heart attack. Anything goes. Obsessions. Compulsions. Confusion. Depression. Agitation. Delusions. Anything! Healthcare professionals will lump all symptoms under the diagnosis of delirium. People with delirium won’t have all the symptoms of every mental disorder. They may have just a few. Some will develop symptoms of OCD. Others will look more depressed and withdrawn. Others will look manic and agitated. This doesn’t matter, either. Any combination of symptoms is irrelevant. They are all due to delirium.
Delirium can sometimes occur more gradually. One of the most common causes of delirium in the elderly is a urinary tract infection, or UTI. This can be more difficult to recognize and diagnose. Oftentimes, these people don’t know they have a UTI. The brain shows the first signs of a problem, not the bladder. Elderly people who were otherwise fine a few weeks prior can begin to develop confusion and memory problems. Family members or healthcare professionals often become concerned about Alzheimer’s disease. The symptoms look exactly the same. These people can get confused often. They might get lost driving. They can have trouble remembering the names of people who they see every day. Once taken to a healthcare professional, a medical workup might then reveal the problem—a UTI. Treating the UTI can resolve all symptoms. Although it was due to an infection in the bladder, the symptoms came from the brain. Why? Because the brain is the most sensitive organ to energy deprivation, or mitochondrial dysfunction. It is the weakest link. It almost always shows at least some subtle signs first.
How do these different medical conditions lead to the development of essentially every psychiatric symptom? Experts speculate about neurotransmitters, stress responses, and inflammation.32 All of these are true. But how, exactly, do they fit together and lead to psychiatric symptoms? At this point, the medical community doesn’t have a coherent theory, but the brain energy theory offers one.
I am not the first to suggest that delirium is due to metabolic problems. In 1959, George Engel, the developer of the biopsychosocial model, proposed that delirium is due to disturbed brain energy metabolism, or “cerebral metabolic insufficiency.”33 Many researchers have expanded on this hypothesis since then.34 For example, PET imaging studies have revealed decreased brain glucose metabolism in people with delirium.35 Many serious medical conditions are known to directly impact metabolism and mitochondrial function. However, given that the medical community hasn’t been able to explain mental symptoms, it has not been clear if or how these metabolic and mitochondrial abnormalities might play a role in causing the mental symptoms.
How is delirium treated? The treatment depends upon the underlying cause or causes, and the specific symptoms. Once the medical condition that is causing delirium is identified, the standard treatments for that condition are implemented. This can be an antibiotic for the UTI or standard cardiology protocols for the heart attack. What about the mental symptoms? Even though the symptoms fall under the label of delirium, we use just about anything and everything in psychiatry to control the symptoms. Sedating medications are commonly used—antipsychotics, mood stabilizers, antidepressants, anti-anxiety medications, and sleep medications. If the symptoms of delirium are extreme depression and a lack of energy, sometimes stimulants are used. We use medications to help with the symptoms, but really, we wait for the underlying medical condition to be fully treated. The symptoms of delirium usually go away once the medical condition resolves. It’s a temporary case of mitochondrial dysfunction.
Does delirium really matter? Once the primary medical condition is identified, such as the heart attack, does it really matter if the person has mental symptoms or not? Many people think it doesn’t. They don’t take the mental symptoms very seriously. They see them as annoying problems that just make delivering good care more difficult. For example, some cardiologists will ignore mental symptoms in the context of a heart attack. To them, the problem is plain and clear—it’s a heart attack. Whether the person is anxious or not doesn’t really matter. Even if a person is hallucinating, they might think that doesn’t matter either. That is a problem for a consulting psychiatrist to deal with. It doesn’t pertain to the heart or the cardiologist’s job. Unfortunately, this all-too-common perspective is shortsighted. It ignores a tremendous amount of research showing that delirium does matter. Sometimes, it’s the difference between life and death.
If the brain energy theory is correct, people with delirium should have more widespread or severe mitochondrial dysfunction than people without delirium. The “mental” symptoms are giving us a warning sign. If this is true, more widespread and severe mitochondrial dysfunction should mean a whole host of things. It should mean that people with delirium will be more likely to develop a mental disorder, dementia, or a seizure. It should also mean they will be more likely to die. Are any of these things true? It turns out they all are.
Mental disorders, such as anxiety disorders, depression, and PTSD, are common after an episode of delirium. Higher rates of dementia and cognitive impairment have been consistently documented at three, twelve, and eighteen months after hospital discharge in people with delirium compared to people with the same illnesses who don’t have delirium.36 In fact, delirium in older people results in an eightfold increased risk of subsequent dementia. Hyperexcitable brain cells have also been well documented, with seizures being the most extreme consequence. In one study of people with delirium, 84 percent had abnormal electroencephalograms (EEGs), with 15 percent showing clear seizure activity.37 People with delirium are more likely to die early. During a hospital admission, people with delirium are twice as likely to die early as those without delirium.38 After discharge from the hospital, the one-year mortality rates for people with delirium are 35 to 40 percent, much higher than in those without delirium.39
How do we make sense of this? Delirium tells us that there is mitochondrial dysfunction in the brain. Sometimes it can be reversible, and the person completely recovers. But not always. What this data suggests is that the mitochondrial dysfunction can persist or progress. Mitochondria in the cells can become damaged—a reduction in the workforce of the cells. This leaves cells more vulnerable to continued dysfunction. Some of the cells themselves can actually die and not get replaced. All of this results in a reduction in the reserve capacity of different brain regions. Any of these can lead to mental disorders, Alzheimer’s disease, or seizures.
What about people who show signs of a more subtle mental disorder, say depression, during an ICU stay? If depression is also due to mitochondrial dysfunction, then we should expect that depression would be associated with higher death rates or seizures. Is this true? Yes, it is. Recall that I discussed the research showing that people who are depressed after a heart attack are twice as likely to have another one over the following year. And elderly people with depression are six times more likely to have seizures. Similar research has been done in patients with a wide variety of medical illnesses. After an ICU stay, patients with depression were 47 percent more likely to die than those without depression in the two years following discharge.40 This and other research suggests that any mental symptoms, even if not formally diagnosed as delirium, are associated with higher rates of premature death. Arguably, mental symptoms are like the canary in the coal mine; they are sometimes the first indication of metabolic and mitochondrial failure.
What about people with longstanding mental disorders? If their disorders are truly due to mitochondrial dysfunction, that should leave them more vulnerable to developing delirium if, in fact, delirium is due to mitochondrial dysfunction. Is this true? Yes, it is. Recall the Danish population study of more than seven million people.41 That study found that people with mental disorders—all of them—were more likely to develop “organic” mental disorders, which includes the diagnoses of delirium and dementia. All told, depending upon the diagnosis, people were two to twenty times more likely to develop these disorders. Chronic mental illnesses are like a warning light in a car. They give us a window into a person’s metabolic health. They tell us that the brain isn’t working right due to metabolic or mitochondrial dysfunction. If we ignore it, sometimes it will correct itself. If it continues and we turn a blind eye to it, symptoms and other illnesses will usually follow.
If the example of delirium didn’t convince you, maybe this one will—the dying process. In some medical schools, students are taught a mantra of the dying process—“seizures, coma, death.” This is the sequence of events that commonly occur as people are dying. What this leaves out is delirium, which is almost universal. People will commonly hallucinate, become disoriented, have mood symptoms, or develop any of the other mental symptoms. Their brains are failing because the mitochondria in their brain cells are failing. The dying process is unequivocally associated with mitochondrial failure. This short sequence of events—delirium, seizures, coma, and death—highlights all the consequences of mitochondrial dysfunction that I have been discussing. It highlights the paradox of both reduced cell function and hyperexcitable cells in the context of rapid mitochondrial failure, culminating in death.
The Question of Language and Our Path Toward Treatment
The theory of brain energy suggests that all mental disorders have the common pathway of mitochondria. When mitochondria aren’t working right, neither is the brain. If this is true, how much do our diagnostic labels matter? What should we call mental disorders?
Our current diagnostic labels will likely persist for some time. Change is difficult and takes time. Furthermore, our current diagnoses do provide some useful information. They describe constellations of symptoms that people exhibit. Symptoms matter. They will require different treatments—at least different symptomatic treatments.
However, given the overlap discussed between the diagnoses, and the fact that people with the exact same diagnoses can have different symptoms, there is clearly room for improvement. Mitochondrial dysfunction or dysregulation provides an explanation for an unlimited number of symptoms in different people. We’ve seen that depending upon which brain cells and brain networks are involved, and which factors are affecting the function of mitochondria, people will have different symptoms. This establishes that a change in the way we think about mental disorders is warranted.
One simple model would be to call all mental disorders delirium. Maybe we separate transient delirium and chronic delirium. The transient type resolves within two to three months, and the chronic type lasts longer. This label would remind all clinicians that they need to keep looking for the cause or causes of the metabolic brain dysfunction instead of simply administering symptomatic treatments. This would largely follow current treatment protocols for delirium already in place, but it would expand these protocols to all who are currently labeled “mentally ill.”
As some will resist the use of “delirium” for all mental disorders, we could, alternatively, call all mental disorders “metabolic brain dysfunction” and add specifiers for the different symptoms that people are experiencing. For example, someone with prominent anxiety symptoms might receive the diagnosis of “metabolic brain dysfunction with anxiety symptoms.” A person with schizophrenia might receive the diagnosis of “metabolic brain dysfunction with psychotic, depressive, and cognitive symptoms.” In all cases, the primary diagnosis would remain the same, “metabolic brain dysfunction,” but the symptoms would change as treatments work or as the illness progresses or remits. Instead of having multiple diagnoses, as is commonly the case now, people would have one disorder, metabolic brain dysfunction, with the different symptoms of this disorder.
The Brain Energy Theory . . . in a Nutshell
Here’s a quick recap of the brain energy theory:
Mental disorders are metabolic disorders of the brain. Although most people think of metabolism as burning calories, it’s much more than that. Metabolism affects the structure and function of all cells in the human body. Regulators of metabolism include many things, such as epigenetics, hormones, neurotransmitters, and inflammation. Mitochondria are the master regulators of metabolism, and they play a role in controlling the factors just listed. When mitochondria aren’t working properly, at least some of the cells in your body or brain won’t function properly.
Symptoms of mental illness can be understood as overactive, underactive, or absent brain functions. Mitochondrial dysfunction or dysregulation can cause all of these through five distinct mechanisms: (1) cell activity can be overactive; (2) cell activity can be underactive; (3) some cells can develop abnormally (leading to absent brain functions); (4) cells can shrink and die (also leading to absent brain functions); and (5) cells can have problems maintaining themselves (which can contribute to overactivity, underactivity, or absent brain functions). For example, if the cells that control anxiety are overactive, you will have anxiety symptoms. If the cells that control memory are underactive, you will have memory impairment. If metabolic problems occur at a young age, the brain can develop abnormally, which can occur in autism. If metabolic problems occur over long periods of time, cells can shrink and die, which is found in most chronic mental disorders and Alzheimer’s disease. And finally, maintenance problems can leave cells in a state of disrepair and can contribute to any of these other problems.
So, you’re likely wondering what causes metabolic and mitochondrial dysfunction or dysregulation. The answer is . . . lots of things. The good news is that many of them are probably already familiar to you. They will be the focus of the next and final section of the book. The exciting news is that most of them can be identified and addressed.