Chapter 12

CONTRIBUTING CAUSE

Hormones and Metabolic Regulators

Hormones are chemical messengers that are produced in one type of cell and then travel through the body to impact other cells. The human body produces numerous hormones. All of them affect mitochondrial function and cause epigenetic changes in their target cells. Hormones change the metabolism of cells. In turn, they can play a role in both mental and metabolic disorders.

As I’ve discussed, mitochondria supply energy for the production and release of hormones, and they initiate the process for several key hormones.

Hormone levels are affected by a wide variety of factors. These include biological, psychological, and social factors. Hormones are one mechanism for the body to respond to stress and opportunities in the environment. In some cases, just the normal release of specific hormones can affect mood, energy, thoughts, motivations, and behaviors. Testosterone is an obvious example. Think of all the effects that it can have on men. Hormonal imbalances can be caused by many factors, including autoimmune disorders, stress, aging, and mitochondrial dysfunction in the cells that make the hormones.

There are many regulators of metabolism and mitochondrial function beyond hormones and neurotransmitters. They include things like neuropeptides, mitokines, adipokines, myokines, RNA molecules, and other messengers. Why so many factors? Because they all control different aspects of metabolic function in different cells under different circumstances. When thinking about the control of traffic, most of the stoplights in a city are activated independently of each other. However, there are some stoplights on long roads that might be coordinated with each other. These hormones and metabolic regulators, like the different stoplights, are controlling metabolism in different cells to produce desired effects. There are many roads and desired effects in the human body, hence the need for so many regulators.

I won’t provide a review of all the hormones and their relationships to mental and metabolic health. That could fill an entire book. Instead, I’ll briefly review a few—cortisol, insulin, estrogen, and thyroid hormone—in order to illustrate some of the connections between hormones, metabolism, and mitochondria.

Cortisol

There is no question that cortisol, metabolism, mitochondria, and mental symptoms are all interconnected, as I’ve discussed in previous chapters. Cortisol plays an important role in the stress response. High levels have been associated with all the metabolic disorders and numerous mental symptoms, including anxiety, fear, depression, mania, psychosis, and cognitive impairment. High levels in utero affect fetal development and play a role in epigenetics, which can lead to the later development of both metabolic and mental disorders.

Cortisol always begins in mitochondria, which have the enzyme that initiates its production. After cortisol gets released into the bloodstream, it enters cells and binds to the glucocorticoid receptor (GR), which then turns thousands of genes on or off by binding to specific sites on DNA called glucocorticoid response elements (GREs). The proteins from these genes then have widespread effects on cells, all related to metabolism. In addition to GRs in the cytoplasm and GREs located within the cell nucleus, it turns out that they are also located directly on/in mitochondria, too. In some ways, it’s fair to say that cortisol begins and ends with mitochondria.

At one point in psychiatry, there was hope that cortisol would be the first definitive biomarker for mental illness. The dexamethasone suppression test, which measures fluctuations in cortisol throughout the day, was widely studied. Unfortunately, cortisol levels can actually be too high or too low in different psychiatric patients. Some people have high levels throughout the day while others, especially those with severe trauma histories, can have abnormally low levels. The story gets complicated quickly, and there’s still debate about how and why this happens. However, my purpose is simply to illustrate that cortisol is a hormone that directly connects metabolism and mitochondria with both metabolic and mental disorders. That much is clear and unequivocal.

Insulin

Most people know insulin for its role in diabetes. People with type 1 diabetes have low levels because the pancreas is not making enough. People with type 2 diabetes are “insulin resistant,” meaning that insulin isn’t working effectively to allow glucose to be used as an energy source. I’ve already discussed the strong bidirectional relationships between diabetes and mental disorders.

Emerging evidence over the past fifteen years suggests that mitochondria are important regulators of insulin production and secretion. Mitochondria are involved in glucose metabolism and sensing how much glucose is available. They ramp up production and secretion of insulin as needed.¹

Mitochondria are known to play a significant role in both types 1 and 2 diabetes, with some experts speculating that mitochondrial dysfunction may be the primary cause. Numerous lines of evidence support these views. One review paper outlining some of the evidence suggests that mitochondria appear to be important to the cause, complications, management, and prevention of both types 1 and 2 diabetes.² Insulin itself stimulates mitochondria to produce more ATP and also stimulates mitochondrial biogenesis, as measured in muscle tissue.³ However, when researchers did this study in people with type 2 diabetes, these effects were blunted or absent. This means that diabetics, over time, may develop even more mitochondrial dysfunction due to insulin resistance—sparking a vicious cycle. It suggests that insulin resistance can be both a cause and a consequence of mitochondrial dysfunction.

But the story of insulin in brain health only begins with diabetes. It plays a powerful and direct role in brain function, too.⁴ Insulin receptors are located throughout the brain, and they are involved in regulating whole-body metabolism, appetite, reproductive functions, liver functions, fat stores, and body temperature. Brain insulin also modulates neurotransmitter activity and mitochondrial function within brain cells. Changes in insulin signaling have been associated with impairment of neuronal function and synapse formation.

Insulin has been shown to influence GABA, serotonin, and dopamine neurons specifically.⁵ One group of researchers demonstrated that insulin alone can increase GABA activity.⁶ We know that insulin resistance can occur in the brain. When it does, it can result in mitochondrial dysfunction, which can then lead to neurotransmitter imbalances, which can then lead to overactivity and underactivity of neurons. I’ll walk you through a sample of the evidence to support this.

In addition to being located on neurons, insulin receptors are also found on support cells, such as astrocytes, that play a role in providing energy for neurons. These cells can affect mood and behaviors. In animal experiments, when these insulin receptors were genetically removed, it resulted in changes in brain energy metabolism and also anxiety and depressive behaviors.⁷ Insulin resistance would have similar effects.

Another animal study more directly linked brain insulin with mitochondrial dysfunction and behavioral abnormalities.⁸ The researchers genetically removed brain-specific insulin receptors. This resulted in mitochondrial dysfunction, as measured by decreased ATP production and increased ROS. And sure enough, the animals displayed anxiety and depressive-like behaviors.

We have evidence that insulin resistance might be playing a role in people, too. Dr. Virginie-Anne Chouinard and colleagues of mine at Harvard and McLean Hospital did brain scans in people with schizophrenia and bipolar disorder and looked at the levels of insulin resistance in their brains.⁹ They included people with recent-onset psychosis, but also their siblings who did not have psychiatric symptoms and healthy controls. We know the siblings are at higher risk of developing a mental disorder since their family members developed one. What they found was fascinating. The brains of the people with psychosis had insulin resistance compared to the healthy controls, but the normal siblings also showed signs of insulin resistance, suggesting that insulin resistance might be a risk factor that runs in families. These researchers went on to find differences in mitochondrial function between the patients with psychosis and their normal siblings. This all suggests that insulin resistance might come first, which then leads to mitochondrial dysfunction, which then leads to psychosis. Interestingly, none of the groups (patients, siblings, or controls) differed in terms of body mass index, body fat, cholesterol levels, or physical activity—so you would never be able to tell they had insulin resistance in their brains by looking at their outward appearance or talking to them about exercise.

An even more compelling study followed almost 15,000 children as they grew from the ages of one to twenty-four.¹⁰ The researchers measured fasting insulin levels at ages nine, fifteen, eighteen, and twenty-four. They also measured the children’s risk for psychosis. What they found was alarming. Children who had persistently high insulin levels (a sign of insulin resistance) beginning at age nine were five times more likely to be at risk for psychosis, meaning that they were showing at least some worrisome signs, and they were three times more likely to already be diagnosed with bipolar disorder or schizophrenia by the time they turned twenty-four. This study clearly demonstrated that insulin resistance comes first, then psychosis.

Alzheimer’s disease is also known to involve insulin resistance in the brain. Some are calling it “type 3 diabetes.” Strong evidence has emerged that the brains of people with Alzheimer’s disease are not getting enough energy from glucose due to insulin resistance, and that this results in mitochondrial dysfunction. The areas of the brain most affected have the most plaques and tangles, the hallmarks of this disorder.¹¹

Insulin as a Treatment

So, based on all this evidence, can insulin play a role in treating mental disorders?

Interestingly, the use of insulin in psychiatry isn’t new. From 1927 to the 1960s, insulin coma therapy was widely used in the treatment of serious mental disorders. Clinicians would inject patients with large doses of insulin until they went into a coma. This process was repeated a few times per week. Most reports from that era suggested that it was a highly effective treatment, at least for some people. At one point, it was the most widely used treatment for psychosis and severe depression in the Western world. It fell out of favor due to the advent of psychiatric medications. By no means do I want it to come back. However, insulin is making a comeback in the mental health field.

Alzheimer’s disease researchers have been using intranasal insulin in clinical trials for a few years now. Squirting insulin into the nose is the easiest and quickest way to get high levels of insulin directly into the brain, which overrides insulin resistance. Early results were promising. A pilot trial of intranasal insulin in 105 participants with mild cognitive impairment or Alzheimer’s disease showed maintenance of cognitive abilities and improved brain glucose metabolism as measured by PET imaging over four months.¹² Unfortunately, a larger subsequent trial in 289 people over twelve months showed no benefit, but there were concerns that the insulin delivery device may have malfunctioned.¹³

One research study used intranasal insulin in sixty-two patients with bipolar disorder to see if it could improve their cognitive function over eight weeks. The people who got insulin showed improvement in executive function compared to those who got placebo.¹⁴

Clearly, more research is needed before insulin makes it into clinical practice, but some researchers are working on that.

Much more important for treatment, however, is measuring your insulin and blood glucose levels to identify problems like insulin resistance, hypoglycemia, and other issues. Although the correlation between what’s happening in the brain and what can be measured from the blood in your veins isn’t always direct, this information can be helpful, and sometimes invaluable. There are many tests and tools available—fasting glucose and insulin levels, oral glucose tolerance tests, continuous glucose monitoring devices, and others. You’ll need to work with your healthcare provider to get these. If you identify a problem, there is a good chance this could be playing a role in your mental symptoms. There are many ways to address this problem that I’ll discuss in the coming chapters. Lifestyle changes can be a powerful intervention—in particular, diet and exercise.

Estrogen

Most people think of estrogen as it relates to reproductive capacity in women, but that’s only one of its many roles. The title of a science review article says it all, “Estrogen: A Master Regulator of Bioenergetic Systems in the Brain and Body.”¹⁵

Estrogen has profound effects on metabolism. It is known to play an important role in mental health, obesity, diabetes, and cardiovascular disease. It also impacts brain metabolism directly and has widespread effects on mood, cognition, and other brain functions.

Mitochondria make estrogen. As with cortisol, they control the first step in its synthesis. Mitochondria also contain estrogen receptors. Like cortisol, estrogen can sometimes begin and end with mitochondria. Most estrogen receptors, however, are not on mitochondria but instead on the outside of cells. They are found widely throughout the brain on both neurons and glial cells, in both men and women. They are also found widely throughout the body. Nonetheless, many of the signaling pathways of estrogen, even when it binds to the receptor outside the cell, end up converging on mitochondria.

Estrogen levels fluctuate throughout the month in menstruating women. Many women experience “mental” and “metabolic” symptoms related to changes in estrogen levels. This can include changes in mood, appetite, and cravings. In fact, there is a diagnosis—premenstrual dysphoric disorder (PMDD)—to describe some of the mental symptoms when they are severe. But for women diagnosed with other mental disorders, symptoms can also fluctuate like clockwork around their periods. This goes for all mental symptoms—depression, anxiety, bipolar symptoms, psychotic symptoms, concentration problems, etc.—true to the theory of brain energy. As I discussed earlier, women are twice as likely to develop depression as men. These hormonal fluctuations and their effects on women’s metabolism may explain some of this. Additionally, the blood loss from menstruation results in the loss of metabolic resources, such as iron, which can also take a metabolic toll.

Pregnancy and the postpartum period are times of high risk for mental symptoms, likely due to both hormonal changes and, more importantly, the metabolic toll of pregnancy. The nutrients and metabolic resources that it takes to create a child are enormous. This leaves women’s bodies metabolically vulnerable. If you think about it, pregnancy comes with increased risks for both metabolic and mental disorders—weight gain (more than needed to carry a healthy child), gestational diabetes, eclampsia (which includes hypertension and seizures), and, of course, exacerbations of most mental disorders. Postpartum depression is well known, but some women experience postpartum mania or psychosis.

Menopause is associated with plummeting estrogen levels. Many women experience mental symptoms, including depression, anxiety, mania, and even psychosis. Women who had depression prior to menopause are five times more likely to become depressed around the time of menopause. Brain energy metabolism decreases broadly. One study looked at forty-three women over their transition into menopause and found that not only did brain energy metabolism decline, but this was directly correlated with a reduction in mitochondrial health.¹⁶ After menopause, women are known to be at elevated risk for developing Alzheimer’s disease compared to men. In some women, these brain metabolism abnormalities can correct themselves over time, but in others, they appear to become permanent, likely putting these women at increased risk for mental disorders and Alzheimer’s disease. Researchers found a direct link between memory, estrogen, and mitochondria in rhesus monkeys.¹⁷ They found that female monkeys with poor memory had more malformed, donut-shaped mitochondria at synapses in the prefrontal cortex. When they surgically induced menopause in the monkeys, sure enough, they showed signs of memory impairment and the numbers of malformed, donut-shaped mitochondria increased. When they gave the monkeys estrogen replacement therapy, the memory problems and the mitochondrial abnormalities both improved.

Estrogen as a Treatment

Oral contraception is used by millions of women. These pills usually contain both estrogen and progesterone. They sometimes have adverse mood effects, but ironically, are also sometimes used to treat mood symptoms, such as PMDD. So, it can be confusing: Do they help, or do they hurt? In the end, there are likely differences between women, with some experiencing benefits and others experiencing adverse effects. One study looked at more than one million women between the ages of fifteen and thirty-four taking birth control pills and found that they were somewhat more likely to experience depression or use an antidepressant compared to women not on the pills.¹⁸ Another study looked at half a million fifteen-year-old women and found that those who were taking birth control were twice as likely to attempt suicide and three times more likely to commit suicide.¹⁹ Birth control pills don’t have the same levels of hormones that naturally occur in the body, so this may explain these findings. It’s important for women with mood symptoms to work with their doctors to manage the risk of unwanted pregnancy and also their mental health needs.

Hormone replacement therapy after menopause may play a role for some women. In fact, with all this emerging evidence for the role of estrogen in the brain, doses of estrogen may need to be reevaluated to optimize brain health.

Thyroid Hormone

Thyroid hormone is known as the master regulator of metabolism. As far as researchers can tell, it acts on every cell in the human body. Thyroid hormone increases metabolism, revving up mitochondria. It plays a profound role in growth, development, temperature regulation, and the function of every organ, especially the brain. When people have too much or too little thyroid hormone, problems are almost always evident.

Although some of the mechanisms of action of thyroid hormone are still being worked out, what is clear and unequivocal are its effects on mitochondria. Thyroid hormone, either directly or indirectly, stimulates mitochondria to produce ATP or heat. Mitochondria have thyroid hormone receptors, so they sometimes get the signal directly. However, thyroid hormone also acts through genes in the nucleus, which then impact mitochondria. Thyroid hormone is also known to stimulate mitochondrial biogenesis, increasing the total number of mitochondria in cells.²⁰ It also induces mitophagy—the mitochondrial repair process.²¹ As you know by now, these have powerful effects on human health.

Hypothyroidism occurs when the thyroid gland is underactive, producing less thyroid hormone than the body requires. It’s most commonly due to an autoimmune disorder, but there are several other causes, too. It can lead to many metabolic and mental symptoms, including weight gain, obesity, heart disease, fatigue, brain fog, and depression. What is less well known is that it is also linked to bipolar disorder, schizophrenia, and dementia.²² When hypothyroidism occurs during development, it can lead to profound neurological deficits (cretinism). The brain energy theory offers new ways to understand all of this. It connects all of these seemingly different illnesses through one pathway: mitochondria.

Thyroid Hormone as a Treatment

Thyroid hormone has been used as a treatment for mental disorders for decades, even when people have normal levels. It is commonly used in treatment-resistant depression and bipolar disorder. However, the field has not been able to explain how or why it works. The brain energy theory provides an obvious explanation. Not only does thyroid hormone increase metabolism immediately, but it also increases the health and number of mitochondria. When you increase the workforce, cells function better. However, increasing metabolism comes with the risk of overstimulating cells, especially hyperexcitable ones. So for some people, thyroid hormone can cause or exacerbate unwanted symptoms.

Summing Up

Success Story: James—“It’s My Thyroid”

When I first met him, James was a fifty-four-year-old man with a thirty-year history of bipolar disorder. He had recurrent depression every fall that would last until spring, despite trying more than twenty antidepressants and mood-stabilizing medications. His depression was crippling, often leaving him unable to get out of bed. He had also been diagnosed with hypothyroidism, high blood pressure, high cholesterol, and sleep apnea. His normal doses of thyroid medication—enough to increase his hormone levels into the “healthy” range—had done nothing to improve his depression, but we decided to try high-dose thyroid hormone as a treatment. It made a huge difference! His levels of thyroid hormone were now abnormally high, so we had to keep an eye out for side effects, such as heart arrhythmias and osteoporosis. But overall, he tolerated it quite well, and it changed his life. His recurrent depressions were all but gone. After about ten years of treatment with a high-dose of thyroid hormone, he was able to decrease the dose to a normal range and has continued to do well to this day. He still uses a low-dose antidepressant and sleep medication occasionally, but he hasn’t experienced a severe depression in many years now. At the time I used this treatment with James, I didn’t know how or why it worked. Now I do: brain energy.