Chapter 4

Could It All Be Related?

What if I told you this common pathway that we’re searching for might not be limited to mental health conditions?

As we’ve seen, the medical field currently separates mental disorders from other medical disorders. They are viewed as separate categories that have little to nothing to do with each other.

But there are many medical disorders that commonly co-occur with mental disorders and vice versa. Yes—here we go again with bidirectional relationships: Not only do mental disorders have strong bidirectional relationships with one another, many metabolic and neurological disorders also have strong bidirectional relationships with mental disorders. These relationships provide important clues about the nature of the common pathway that will help us solve the puzzle of mental illness.

To explore these relationships, I’m going to focus on three metabolic disorders (obesity, diabetes, cardiovascular disease) and two neurological disorders (Alzheimer’s disease and epilepsy). All five of these conditions are commonly associated with mental symptoms like depression, anxiety, insomnia, and even psychosis. On the flip side, people who have mental disorders are at much higher risk of developing these five medical disorders. Clearly not all people with these medical disorders have a mental illness, and not all people with a mental illness develop any of these medical disorders.

When patients with one of these medical conditions do have mental illness symptoms, they’re sometimes overlooked as normal reactions to difficult diseases. Those with heart failure are often depressed, which is presented as understandable given the severity of heart failure. And whether people with these conditions who are experiencing mental symptoms get diagnosed with a “mental” disorder is up to clinicians, who have the discretion to attribute these mental symptoms to the “organic” illnesses. In the end, though, the symptoms are the same regardless of what cause they are attributed to. Depression is the same. Anxiety is the same. Paranoia is the same. The treatments are the same as well: antidepressants, anti-anxiety medications, and antipsychotics are all commonly used in people with these “organic” disorders.

Looking at these disorders more closely will illuminate the connections between metabolism, metabolic disorders, and disorders of the brain, whether mental or neurological. They will help us put the final pieces of the puzzle in place.

Metabolic Disorders

Let’s start with our three metabolic disorders: obesity, diabetes, and cardiovascular disease. The term “metabolic disorders” actually includes many more disorders, but it most commonly refers to disorders associated with metabolic syndrome. This is a syndrome that is diagnosed when people have three or more of the following conditions: increased blood pressure, high blood sugar, excess body fat around the waist, high triglycerides, and low HDL (or “good cholesterol”). People with metabolic syndrome are at increased risk for developing type 2 diabetes, heart attacks, and strokes.

Diabetes

The connection between diabetes and mental illness has been known for more than a century. In 1879, Sir Henry Maudsley wrote, “Diabetes is a disease that often shows itself in families in which insanity prevails.” Many mental disorders are associated with higher rates of diabetes. People with schizophrenia are three times more likely to develop diabetes.¹ People diagnosed with depression are 60 percent more likely to develop diabetes.²

What about the other way around? Are people with diabetes more likely to develop mental disorders? Yes. Most of the research has focused on depression and diabetes. People with diabetes are two to three times more likely to develop major depression. Furthermore, when they get depressed, the depression lasts four times longer than it does in those without diabetes. At any given time, about one in four people with diabetes has clinically significant depression.³ What’s more, the depression appears to affect blood-glucose levels—diabetics with depression tend to have higher glucose readings than those without depression. However, it’s not just depression. One study of 1.3 million adolescents looked at rates of mental illness over the following ten years. Adolescents with diabetes were more likely to suffer from a mood disorder, attempt suicide, visit a psychiatrist, or develop any psychiatric disorder.⁴

Obesity

We know that people with mental disorders are more likely to be overweight or obese. One study followed people diagnosed with schizophrenia and bipolar disorder for twenty years. When they were first diagnosed, the majority were not obese. Twenty years later, 62 percent of those with schizophrenia and 50 percent of those with bipolar disorder were obese.⁵ The obesity rate at the time for all adults in New York State, where the study was conducted, was 27 percent. Children with autism are 40 percent more likely to be obese.⁶ One meta-analysis of 120 studies found that people with serious mental illness were three times more likely to be obese than people without a mental illness.⁷

Many people assume that our treatments are causing this obesity. While there’s no doubt that psychiatric medications are associated with weight gain—in fact it’s a common side effect of antidepressants and antipsychotics—treatments alone don’t provide the entire explanation. For example, one study looked at people with ADHD who were either treated or not treated with medications, and then it assessed their rates of obesity over the ensuing years compared to people without ADHD. They found that all people with ADHD, whether treated or not, were more likely to develop obesity. Even though the primary treatment for ADHD is usually a stimulant medication, which generally suppresses appetite, the people with ADHD who were treated with stimulants were still more likely to develop obesity than those without ADHD. Those who didn’t take stimulants were even more likely to become obese.⁸

What about people who are obese? Are they more likely to develop a mental disorder? Again, the answer is yes. People who are obese are 25 percent more likely to develop depression or an anxiety disorder and 50 percent more likely to develop bipolar disorder. One study found that weight gain around the time of puberty was associated with a fourfold increase in the risk of depression by age twenty-four.⁹ Obesity has been found to affect brain function in ways known to lead to mental disorders as well. For example, people with obesity have been found to have altered connections between brain regions as well as alterations in a region of the brain called the hypothalamus¹⁰ that are common in people with mental disorders.

Cardiovascular Diseases

Cardiovascular diseases—particularly heart attacks and strokes—also have bidirectional relationships with mental disorders. Again looking at depression, we find that 20 percent of people with heart attacks, 33 percent with congestive heart failure, and 31 percent with strokes experience major depression within a year of the event or condition.¹¹ These rates of occurrence are three to five times higher than those in the US population as a whole.

This seems easy to understand on the surface. Most people would be worried or depressed following a traumatic event like a heart attack or stroke. However, we’re witnessing another bidirectional relationship, suggesting this is more than just a psychological reaction.

We know that depression affects the heart. In people who have never suffered a heart attack, experiencing major depression increases the risk of having a future heart attack by 50 to 100 percent.¹² In people who have already suffered a heart attack, being depressed doubles the chances that they’ll have another heart attack in the next year.

And it doesn’t stop with depression. People diagnosed with schizophrenia and bipolar disorder are 53 percent more likely to develop premature cardiovascular disease.¹³ This is even after controlling for risk factors like obesity and diabetes. A thirteen-year study of almost one million veterans found that individuals who were diagnosed with PTSD were twice as likely to have a transient ischemic attack (temporary symptoms of a stroke) and 62 percent more likely to have a stroke.¹⁴

We’ve long known that people with serious mental disorders such as schizophrenia, bipolar disorder, and severe chronic depression die at a much younger age than they should. On average, they lose between thirteen and thirty years from their normal lifespans.¹⁵ Recent research from a Danish population database of more than seven million people suggests something more alarming.¹⁶ It’s not just the “serious” mental disorders that result in a shortened lifespan. All mental disorders—even mild or common ones, like anxiety disorders or ADHD—are associated with shortened lifespans. On average, men with mental disorders lose ten years of life and women lose seven.

What are these people dying from so early? Most think suicide is responsible, but it’s not. Although suicide rates are definitely higher in the mentally ill, the early deaths in this group are primarily due to heart attacks, strokes, and diabetes—metabolic disorders. We have just seen that people with mental disorders have much higher rates of these conditions.

Even before they die, we now know that people with chronic mental disorders appear to be aging prematurely. We can see this through a variety of metrics of the aging process. One such metric is the length of telomeres, which are the end caps of chromosomes. They tend to get shorter as people age. Shortened telomeres have been found in people with diseases that you would expect to be associated with aging, such as obesity, cancer, cardiovascular disease, and diabetes. They have also been found to be shorter in people with depression, bipolar disorder, PTSD, and substance use disorders.¹⁷

Neurological Disorders

Even though both neurological and mental disorders affect the brain and both commonly include “mental” symptoms, they are distinguished based on one thing: Neurological disorders have at least one objective test or pathological finding that can be used in diagnosing the disorder. This can be an abnormality on a brain scan or EEG, or it can be a specific pathological finding in brain tissue or the fluid surrounding the brain. As I’ve already shared with you, mental disorders have no objective tests that can be used in diagnosis.

Alzheimer’s

Alzheimer’s disease is the most common form of dementia, which is a group of neurological disorders that impair brain function over time. Common symptoms of all dementias include memory disturbances, changes in personality, and compromised judgment. The hallmark findings in Alzheimer’s disease are plaques and tangles in the brain. As people get older, their risk for Alzheimer’s goes up exponentially, doubling every five years after sixty-five. By age eighty-five, about 33 percent of all people will have Alzheimer’s disease.¹⁸ There are types of early-onset Alzheimer’s disease that can be caused by rare genetic mutations or Down’s syndrome. However, for everyone else, it’s not clear exactly what causes it. Besides age, some of the known risk factors include a family history of the disease, head trauma . . . and metabolic disorders.

Obesity in midlife, diabetes, and heart disease all increase the risk of developing Alzheimer’s. So do the risk factors for metabolic disorders, like smoking cigarettes, high blood pressure, high cholesterol, and a lack of exercise. Interestingly, one of the genetic risk factors involves a gene variant called APOE4—which codes for an enzyme related to fat and cholesterol metabolism.

Things often considered to be “mental” are also risk factors. Having depression earlier in life doubles a person’s chances of developing Alzheimer’s disease.¹⁹ Schizophrenia dramatically increases the chances, too—one study of more than eight million people found that if someone with schizophrenia lives to the relatively young age of sixty-six, they are twenty times more likely to be diagnosed with dementia than those without schizophrenia.²⁰ And remember that large study of the Danish population that found bidirectional relationships among all the different psychiatric disorders? Alzheimer’s disease was included under the category of organic mental disorders, the label used to classify mental symptoms due to medical conditions, such as delirium and other types of dementia. In that study, every psychiatric disorder increased the chances of developing an organic mental disorder—anywhere from a 50 percent increase up to a twentyfold increase. Unfortunately, Alzheimer’s disease wasn’t separated from the other organic mental illnesses, but the two most common organic mental disorders are delirium and Alzheimer’s disease.

The first signs of Alzheimer’s disease are usually forgetfulness and “mental” symptoms, such as depression, anxiety, or personality changes. Once Alzheimer’s is diagnosed, almost all patients will develop psychiatric symptoms—97 percent in one study.²¹ These can include just about any you can think of—anxiety, depression, personality changes, agitation, insomnia, social withdrawal, you name it. About 50 percent of Alzheimer’s patients will develop psychotic symptoms like hallucinations and delusions.²²

So, essentially every psychiatric symptom can emerge with Alzheimer’s disease. If that’s the case, what’s causing these symptoms? Is it the same cause as in people who develop mental symptoms and disorders earlier in life? One thing is certain: this overlap of identical symptoms means we can’t truly address the question of what causes mental illness without looking at Alzheimer’s disease.

Epilepsy

Epilepsy is a relatively rare brain disorder that also has a bidirectional relationship with mental disorders. Epilepsy can begin at any age, but it most often begins in childhood, affecting about one in 150 children. Sometimes the cause is due to a clearly identified brain abnormality, such as a stroke, brain injury, tumor, or a rare genetic mutation. For most, however, the cause is unknown.

People with epilepsy often have psychiatric symptoms. Sometimes these symptoms lead to a diagnosis of a mental disorder. Other times, however, the symptoms are assumed to be due to the seizures themselves. There is no question that seizures can produce emotions, sensations, or behaviors that are unusual. However, people with epilepsy are also more likely to experience mental symptoms even when they are not seizing.

Twenty to forty percent of children with epilepsy also have an intellectual disability, ADHD, or autism diagnosis.²³ Anxiety disorders are also common in those with epilepsy, occurring at a three- to sixfold higher rate compared to the general population.²⁴ One study found that 55 percent of people with epilepsy suffered depression, with one-third of all epileptics reporting at least one suicide attempt.²⁵ Interestingly, the suicide attempts often occurred before the epilepsy diagnosis.²⁶ Other studies have found a sixfold increase in bipolar disorder and a ninefold increase in schizophrenia.²⁷ The data make clear that psychiatric diagnoses—across the board—are extraordinarily common with epilepsy.

What about the other way around? Indeed, it appears that people with mental disorders are more likely to have epilepsy or experience seizures in general. Anywhere between 6 to 27 percent of children with autism will develop seizures.²⁸ Signs of epilepsy show up on the EEGs of 16 percent of children with ADHD.²⁹ Additionally, children who have seizures are two and a half times more likely to already be diagnosed with ADHD.³⁰ Later in life, a diagnosis of major depression increases the chances of having an unprovoked seizure sixfold.³¹

Seizures offer us an important clue on the way to our common pathway, further connecting the dots between metabolic, mental, and neurological disorders: not only is there a relationship between epilepsy and mental illness, there is a relationship between epilepsy and metabolic disorders as well.

We’ve long known that hypoglycemia (low blood sugar) can cause seizures. This is commonly seen in diabetics—both types 1 and 2. Diabetics can get low blood sugar from either too much medication or not eating enough. However, are people with diabetes more likely to have seizures unrelated to severe hypoglycemia? Yes. Children with type 1 diabetes are three times more likely to develop epilepsy³²—six times more likely if the diabetes begins before age six.³³ Adults sixty-five and over with type 2 diabetes were found to have a 50 percent higher chance of developing epilepsy.³⁴

What about obesity? You might think weight has nothing to do with epilepsy, and yet a large study showed that people who are extremely underweight or overweight were 60 to 70 percent more likely to develop epilepsy than people of a normal weight.³⁵ That both being over- and underweight are risk factors may be a surprise, but as I’ll explain later, both extremes are stressful to metabolism. Additionally, women who are obese during pregnancy are more likely to give birth to children who go on to develop epilepsy, with rates increasing as the mothers get heavier. Women with a BMI greater than 40 have an 82 percent higher risk of having children with epilepsy—almost double the risk in the general population.³⁶

Hiding in Plain Sight

So here we are, faced with the curious fact that mental disorders have bidirectional relationships not only with each other, but with these seemingly very different medical disorders as well. Recall that bidirectional relationships suggest a possible common pathway—something in common that is causing or contributing to all these disorders. Is that possible?

Many people think they already know the reason for some of these connections, especially those between metabolic and mental disorders. We’ve talked about the stigma around mental disorders, but when it comes to metabolic disorders, people are often quick to judge as well. They think those who are obese, diabetic, or have heart attacks are simply not taking good care of themselves. They eat too much, smoke, and/or don’t exercise enough. By and large, many believe these conditions arise from negligence—that they’re the fault of the diagnosed. Similarly, it seems obvious to many that mental disorders cause people to not take good care of themselves. For instance, depression causes people to lose energy and motivation. When that happens, they sit around all day, watch TV, and eat. They gain weight. They don’t exercise. Everyone knows that “stress” contributes to unhealthy habits. Almost by definition, people with mental disorders have more stress than most, or at least it feels that way to them. So, again, people with these stressful symptoms eat poorly and don’t exercise enough. It’s no wonder that people with mental disorders have higher rates of metabolic disorders. What it really comes down to, in the eyes of many, is simple—these are issues of willpower and discipline.

Here’s the conundrum, though. The rates of all these disorders have been skyrocketing over the past fifty years. Obesity, diabetes, cardiovascular disease, and mental disorders. Why is that? Have we had an epidemic of laziness or self-destructive health behaviors in our society? Are people no longer capable of self-discipline? Do they just not care about their health? If you would answer “yes” to these questions, which many would, another question remains: Why? What has caused this “epidemic of laziness”?

As we touched on in Chapter One, some might say it’s society. The faster pace of everything and the demands of that pace. The stress of modern life. Constant emails to attend to. Social media posts stacking up and vying for our attention. The pull to pick up your cell phone and always be watching, searching, scrolling, or checking. Others might say it’s the food supply—artificial ingredients and processed foods.

As it turns out, these are likely contributing factors, but are they true causes? How do we get from any one of these “causes” to laziness, apathy, and burnout, which then cause people to overeat and not exercise, which then cause them to develop mental or metabolic disorders? How does that all actually work in the body and brain? And why doesn’t everyone subject to these forces end up diabetic and depressed? And where do the connections with neurological disorders, acknowledged as physical brain diseases, fit into all this talk of modern life and poor health habits? While most people think these mental and metabolic relationships are easy to explain, when you get down to the specifics of human physiology, things get significantly murkier.

When providers talk to people about changing their health behaviors—eating less or exercising more—they often get similar answers: “It’s too hard,” or, “I don’t have enough energy.” These answers are almost always met with strong disapproval. They are viewed as excuses for laziness, or signs of not taking the issue seriously enough, or of a lack of discipline. But is it possible that instead of being excuses, answers like “It’s too hard” and “I don’t have enough energy” are actually clues giving us important information? Could inertia and lack of motivation be symptoms of a metabolic problem? Is it possible that these people literally don’t have enough energy?

As it turns out, it’s not just possible; there’s an abundance of evidence that it’s true. You see, metabolism involves the production of energy inside cells. As you’ll see in the coming chapters, people who have metabolic or mental illnesses have been found to have deficits in energy production inside their cells. These people are telling the truth. They really don’t have enough energy.

It’s not a motivational problem. It’s a metabolic one.

We have been missing the elephant in the room.

Let’s do a quick recap.

Already, this may seem impossible to reconcile. You might be yelling, “But these are all different diseases!" Schizophrenia is not the same thing as an eating disorder or a mild anxiety disorder. Cardiovascular disease, bipolar disorder, epilepsy, diabetes, and depression are all different. They have different symptoms. They affect different parts of the body. They appear at different ages. Some of them, like a stroke, can kill people quickly. Others, like mild depression that lasts only a few months, might come and go away without any intervention.

It’s difficult to imagine that all these disorders share one common pathway. If there is such a common pathway, it will have to be involved in many different aspects of how the body works. It will need to tie together everything that we already know about these different disorders—their risk factors and symptoms, the treatments that work. That’s a huge role for any bodily process or function to fill.

As you will see in Part Two, metabolism fills this role.

Yes: we have arrived at our common thread, the underpinning factor that lets us answer our tangled questions about causes and treatments, symptoms and overlaps.

Mental disorders—all of them—are metabolic disorders of the brain.