Brain Energy

Inow come back to the chemical imbalance theory. The theory of brain energy doesn’t challenge the observations that neurotransmitter imbalances play a role in mental disorders, nor does it challenge the clinical trials that have demonstrated improvement in symptoms using medications that affect neurotransmitters. And I certainly don’t mean to challenge the real-world experience of the many people who have been helped, or even saved, by psychiatric medications. All of these are true and based on an abundance of evidence. However, as I’ve already pointed out, the chemical imbalance theory leaves many questions unanswered and fails to restore lives for far too many people.

The brain energy theory offers new ways to understand neurotransmitter imbalances and the effects of medications. Mitochondria and metabolism explain the underactivity and overactivity/hyperexcitability of specific brain cells that result in these imbalances and the problem of either too much or too little neurotransmitter activity. However, neurotransmitters also go on to produce their own effects in target cells, resulting in stimulation or inhibition of mitochondria in those cells. This quickly becomes like a chain of dominoes, where metabolic disruption in one set of cells results in problems in other cells.

Many people talk about neurotransmitters as simple entities with simple functions. Serotonin makes us feel good. Dopamine drives psychosis and addiction. Norepinephrine helps us focus. Although there is some truth to these statements, these simplistic views of neurotransmitters and the disorders associated with them are almost farcical. The brain, neurotransmitters, and mental disorders are all much more complicated than that.

Neurotransmitters are not just simple on/off signals between cells. Research in the past decade has greatly expanded our view of their role in metabolism and mitochondrial function. Neurotransmitters and mitochondria are in a feedback cycle with each other. Mitochondria affect the balance of neurotransmitters. Neurotransmitters affect the balance of mitochondria and their function.

As mentioned in Chapter Seven, mitochondria play a key role in the production of many neurotransmitters, including acetylcholine, glutamate, norepinephrine, dopamine, GABA, and serotonin. Mitochondria also have receptors for some important neurotransmitters directly on their membranes, such as benzodiazepine and GABA receptors. These aren’t present on all mitochondria in all cells, but they have been identified in at least some cell types. Mitochondria also have one important enzyme known to most psychiatrists: monoamine oxidase. This enzyme is involved in the degradation and regulation of some very important neurotransmitters, such as dopamine, epinephrine, and norepinephrine. All these neurotransmitters directly impact the function of mitochondria, and mitochondria directly impact the balance of these neurotransmitters.

Serotonin, a neurotransmitter best known for its role in depression and anxiety disorders, has a very prominent and complex role in metabolism and mitochondrial function.¹ It is a primitive and highly conserved neurotransmitter found in all animals, worms, insects, fungi, and plants. It is known to control appetite, digestive tract functions, and metabolism of nutrients broadly. About 90 percent of the serotonin in the human body is actually located in the digestive tract, not the brain. Recent research has demonstrated a direct role of serotonin in regulating the production and function of mitochondria within cortical neurons, enhancing their production of ATP and decreasing oxidative stress.² So, not only does serotonin increase mitochondrial function immediately, it results in mitochondrial biogenesis—one of the ways to improve metabolism! In addition to this clear and direct link, there’s even more to the story. Serotonin is converted into melatonin, an important hormone in the regulation of sleep, which plays a powerful role in metabolism as well. Serotonin is also the product of an important metabolic pathway, the kynurenine pathway, that involves the fate of the amino acid tryptophan. When people eat protein that contains tryptophan, it has many possible fates. Two important ones are getting converted into serotonin or kynurenine. Kynurenine eventually leads to higher levels of the critically important molecule NAD that I already told you about. NAD has a profound influence on the health and function of mitochondria because it is essential to energy production and managing electrons. Problems with the kynurenine metabolic pathway have been found in many psychiatric and neurological disorders, including depression, schizophrenia, anxiety disorders, Tourette’s syndrome, dementia, and others. Obviously, medications that affect serotonin levels will have a direct impact on metabolism and mitochondria through all these mechanisms. This fact likely explains why and how these medications work for disorders like depression and anxiety.

GABA is also an important neurotransmitter with a wide range of functions. It is best known for its role in anxiety disorders because medications that increase GABA activity, such as Valium, Klonopin, and Xanax, produce a calming, anti-anxiety effect. However, abnormalities of GABA neurotransmission have also been found in other disorders, including schizophrenia and autism. Mitochondria directly influence and sometimes control GABA activity. One group of researchers found that mitochondrial ROS levels regulate the strength of GABA activity.³

Fascinatingly, another research group demonstrated a more direct link between GABA, mitochondria, and mental symptoms. This study was done in flies and involved a known, but rare, genetic defect associated with both autism and schizophrenia. The researchers showed that mitochondria actually sequester GABA inside themselves, thereby directly controlling its release. When this process was prevented by the genetic defect, social deficits resulted. When the researchers corrected GABA levels or the function of mitochondria, the social deficits were corrected. These researchers directly tied a known, but rare, genetic defect to mitochondrial function, GABA, and social deficit symptoms.⁴

GABA doesn’t just affect mental functions, it also plays a role in metabolic disorders like obesity. One group of researchers found that GABA plays an important role in brown adipose tissue, a special type of fat that gets turned on when you get cold and also plays an important role in overall body metabolism. Problems with GABA signaling in this type of fat result in mitochondrial calcium overload and metabolic abnormalities often found in people who are obese.⁵ So, these few examples illustrate how mitochondria can control GABA activity, and GABA activity can affect mitochondrial function, creating a feedback cycle.

One final example is dopamine. Dopamine is released from neurons, binds to receptors, and then is usually taken back up into the releasing neuron for another round. However, some of it ends up inside cells and needs to be managed . . . by, you guessed it, mitochondria. They have the enzyme, monoamine oxidase, that degrades it. This process directly stimulates mitochondria to produce more ATP.⁶ But there’s more to the story. A recent discovery showed that dopamine is directly involved in the regulation of glucose and metabolism.⁷ The dopamine D2 receptor is well known to most psychiatrists because almost all antipsychotic medications affect this specific receptor. We now know that dopamine D2 receptors aren’t located just in the brain, they are also found in the pancreas and play a critical role in the release of insulin and glucagon. It has long been known that antipsychotic medications can affect weight, diabetes, and metabolism. The science is now catching up to explain why. More intriguing, however, is the possibility that these effects on insulin might be playing a direct role in the antipsychotic effect. It may have nothing to do with dopamine D2 receptors in the brain. I’ll share more about insulin and why this might be possible in the next chapter.

These few examples illustrate some of the connections between neurotransmitters, mitochondria, and metabolism.

Psychiatric Medications, Metabolism, and Mitochondria

Medications that increase or decrease the levels of serotonin, GABA, or dopamine will clearly have an impact on mitochondria and metabolism through the mechanisms that I have already outlined. This includes many classes of antidepressants, anti-anxiety medications, and antipsychotics.

As an example, we all know that Valium can reduce anxiety. One study looked directly at the impact of Valium on anxiety and social dominance behaviors in rats to determine precisely how it was working.⁸ The researchers already knew that reduced mitochondrial function in an area of the brain called the nucleus accumbens (NAc) causes social anxiety behaviors, so they wanted to determine if Valium was somehow affecting this area. They found that Valium was working by activating another area of the brain called the ventral tegmental area (VTA), which sends dopamine to the NAc. This dopamine increases mitochondrial function in the NAc, resulting in higher ATP levels, and this leads to reduced anxiety and enhanced social dominance. When the researchers blocked the effects of dopamine, this therapeutic effect was lost. But here’s the kicker—when they blocked mitochondrial respiration in the NAc, the therapeutic effects were also lost, even though those cells were still getting the enhanced dopamine. These researchers concluded that their findings “highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.”⁹

Different medications affect mitochondria in vastly different ways. One review article, “Effect of Neuropsychiatric Medications on Mitochondrial Function: For Better or For Worse,”¹⁰ highlights a paradox: some medications appear to improve mitochondrial functions while others impair mitochondrial functions.

Monoamine oxidase inhibitors, a class of antidepressants, increase the amounts of epinephrine, norepinephrine, and dopamine right outside of mitochondria. These stimulate mitochondrial activity. Lithium, a mood stabilizer, has been found to increase ATP production, enhance antioxidant capacities, and improve calcium signaling within cells, all related to mitochondria.¹¹

Quite a few antipsychotic medications are known to cause serious neurological problems, sometimes permanent ones, like tremors, muscle rigidity, and tardive dyskinesia (TD), an involuntary movement disorder. Many studies have documented impairment in mitochondrial function at the cellular level, including decreased energy production and increased oxidative stress, caused by these medications.¹² One study looked at spinal fluid from patients with schizophrenia, some of whom had TD, and found a direct correlation between markers of impaired mitochondrial energy metabolism and the symptoms of TD.¹³ These and many other researchers have concluded that mitochondrial dysfunction is the most likely explanation for these neurological side effects.

In my own work with patients for more than twenty-five years now, I have seen firsthand how psychiatric medications can impair metabolism. Weight gain, metabolic syndrome, diabetes, cardiovascular disease, and even premature death are all well-known side effects for many of these medications.

How does this make sense? If mental symptoms are due to mitochondrial dysfunction/dysregulation, how can impairing them further reduce mental symptoms?

The answer comes down to hyperexcitable cells. When a cell is hyperexcitable, there are two ways to reduce symptoms:

1.Improve mitochondrial function and energy production so that the cell can repair itself and function normally again. However, this strategy comes with the risk that symptoms might get worse initially, given that hyperexcitable cells can’t stop themselves sometimes. Therefore, when they get more energy initially, they may not be prepared to manage it appropriately, and hyperexcitability may occur.

2.Manage these cells by shutting them down—in other words, suppress their function by inhibiting their mitochondria. This will stop symptoms, at least in the short run. However, this strategy comes with the risk that it might make matters worse over time because it may worsen the mitochondrial dysfunction.

This is obviously a very concerning situation. A treatment that can help in the short run might make things worse in the long run. Unfortunately, the dilemma of hyperexcitability isn’t even this simple. The brain is complicated, and so is this issue. There are two other considerations:

1.All cells are likely not impacted in the same ways. Recall that cells have different inputs. Medications target specific cells. Some cells may have improved mitochondrial function, while other cells may not be affected, while still others may have impairment. In all the studies done, the researchers had to choose specific cells to study. They certainly didn’t study all the cells in the brain and body.

2.Even if medications impair mitochondrial function broadly, we need to consider the consequences of not treating the person. Hyperexcitable cells spewing out lots of neurotransmitters, such as glutamate or dopamine, are known to be toxic to the brain. The overall benefits to the person may still outweigh the risks. An extreme example is when someone is seizing—they are clearly suffering from a case of hyperexcitable brain cells. Stopping them is of paramount importance. People can die if they seize too long. And in fact, many epilepsy treatments, such as Depakote, are known to impair mitochondrial function, which then slows, and, with hope, stops the hyperexcitability.¹⁴

I know that people crave simple answers to dilemmas like this. “So, should people take medications that are known to impair mitochondria? Yes or no?” Unfortunately, I can’t offer a universal answer to this question because different situations require different interventions. Clearly, in dangerous or life-threatening situations, these medications can be lifesaving. However, I’ve mapped out some of the issues to consider. The good news is that these questions can be addressed in research studies, so more research might better inform our treatment approaches in the future. What is clear already, however, is that suppressing mitochondrial function long-term is not a path to healing. At best, it’s a path to reducing symptoms.

The theory of brain energy answers numerous questions that the mental health field has been unable to answer to date. It outlines why medications that target serotonin, norepinephrine, and dopamine can all be used to treat depression. They all enhance the function of mitochondria. A logical question, then, is “Why doesn’t everyone respond to the same medications?” This comes back to preexisting vulnerabilities and different inputs to different cells. For example, the symptoms of depression come from many brain regions, not just one. Brain circuits are connected and communicate with each other. If one area is malfunctioning, it will impact the other areas, too. Some will be more responsive to serotonin while others will be more responsive to norepinephrine, and yet they are connected. So, if one brain region is metabolically compromised, it will impact the other brain regions, just like a traffic jam in one part of the city slowly backing up traffic in other parts of the city. Metabolic problems are connected and can spread.

This theory also helps us understand why medications take time to work. For example, SSRIs are likely working by increasing mitochondrial biogenesis and improving the function of mitochondria. This process takes time; it doesn’t occur overnight, even though SSRIs increase serotonin in a matter of hours. It’s not the serotonin per se that results in improvement, but the impact that serotonin has on mitochondria and metabolism. Restoring metabolic health takes time—probably about two to six weeks—which is the time it usually takes for SSRIs to start working as well.

We can also understand why one medication can be used for a wide variety of disorders. For example, antipsychotic medications can be used for schizophrenia, bipolar disorder, depression, anxiety, insomnia, and agitation in dementia because they reduce hyperexcitability in many cell types. Suppressing mitochondrial function can stop the problematic symptoms. But anyone who has taken these medications knows that they come with side effects, like reduced function in cognitive areas of the brain and increased appetite. In the elderly, they even come with a warning of increased risk of death.

Furthermore, we can now understand why some psychiatric medications can induce other symptoms, such as antidepressants inducing anxiety, mania, and psychosis in some people. Antidepressants generally increase energy in the brain. In people with preexisting vulnerabilities who already have metabolically compromised cells, this can quickly lead to hyperexcitability and associated symptoms.

On top of the usual psychiatric medications, the brain energy theory offers reasons why “metabolic” medications might also play a role in mental health. Interestingly, psychiatrists have been using some of these for decades now.

Many blood pressure medications, such as clonidine, prazosin, and propranolol, are used in psychiatry. These medications are prescribed for a wide variety of disorders, including ADHD, PTSD, anxiety disorders, substance use disorders, and Tourette’s syndrome.

One study looked at three classes of “metabolic” medications in more than 140,000 patients with schizophrenia, bipolar disorder, or other psychotic disorders to see if these medications had any impact on self-harm or the need for psychiatric hospitalization.¹⁵ They found that they did. The drug classes included “statins” for cholesterol (hydroxylmethyl glutaryl coenzyme A reductase inhibitors), blood pressure medicines (L-type calcium channel antagonists), and diabetes medicines like metformin (biguanides). Across the board, these medications had an impact on the “mental” metrics, especially in reducing self-harm. The brain energy theory offers explanations for why these might help. Statins are known to impair mitochondrial function and reduce inflammation, calcium channel blockers reduce hyperexcitability by decreasing the amount of calcium in cells, and metformin is also known to play a direct role in mitochondrial function. Metformin gets confusing quickly, however, as the effects appear to be dependent upon the dose. Most studies have found that metformin impairs mitochondrial function, but some have found an increase in mitochondrial biogenesis and ATP production.¹⁶

Finally, I want to point out that reducing or stopping psychiatric medications can be difficult and dangerous. This always needs to be done with the supervision of a medical professional. Symptoms can get worse quickly and new symptoms can emerge. Many patients become acutely depressed, suicidal, manic, or psychotic when they stop medications abruptly or decrease them too rapidly. This doesn’t mean that people can’t discontinue medications; it just means that it isn’t something to undertake on your own.

Summing Up

•Psychiatric medications have helped countless people with mental disorders. They will continue to play a role for many.

•The brain energy theory offers new ways to understand how and why medications work.

•It’s important to understand what impact your medications are having on your metabolism and mitochondria.

•Medications that increase metabolism and improve mitochondrial function can improve symptoms of underactive cells, but they come with the risk of exacerbating symptoms related to overactive or hyperexcitable cells.

•Medications that impair mitochondrial function should be used cautiously. Although it’s clear how and why these can reduce symptoms of hyperexcitable cells in the short run, it’s possible that they might interfere with your ability to heal and recover in the long run. In some cases, they might even be the cause of symptoms. Nonetheless, in dangerous and life-threatening situations, these medications can be lifesaving.

Success Story: Jane—Agitated in the Nursing Home

Early in my career, I worked in some nursing homes as a psychiatric consultant. One person that I met was Jane, an eighty-one-year-old woman with Alzheimer’s disease. I was asked to see her for “agitation.” The nurses reported that she would stay up at night screaming, and at other times sleep for more than twelve hours at a stretch. Her screaming was disturbing the other residents, and they wanted me to prescribe something to stop this behavior. It had been going on for more than six months, and she had already been prescribed five tranquilizing medications, including two antipsychotics and anti-anxiety medications. Nothing was working. A medical workup had already been conducted and they couldn’t find anything wrong with her.

I met with Jane for all of five minutes in the dining room, where she was propped into an adult high chair. When I sat down to speak with her, she couldn’t understand me. She was saying random words and phrases (something called “word salad” in psychiatry), and she was smearing her food all over herself and her high chair. I had enough information to make my diagnosis. She was delirious. The most likely cause? The sedating medications. I wrote my note and instructed the physician to get her off as many of those medications as possible, as quickly as possible, but to be mindful that some might need to be slowly tapered. The physician ended up stopping most of them right away.

I came back three weeks later. As I was walking down the hall, I was confronted by an elderly woman I had never met before. She asked me if I was Dr. Palmer, and I said I was. She reached out and hugged me, with tears in her eyes, and thanked me profusely for saving her sister. I told her that she must be mistaken; I didn’t know her or her sister. She then told me that her sister was Jane. It turns out that for the past couple of years, she had been visiting Jane three times a week. They used to have pleasant conversations and share meals, but the last six months had been a nightmare. Jane was angry, confused, and just not “human” anymore. This was heartbreaking for her sister to witness. But about ten days ago, her sister told me, things began to change. Jane had stopped screaming and her sleep was improving. She knew her sister again, and they could have conversations.

Anyone who has visited a nursing home knows this is not a rare story. It represents a common dilemma: people with dementia can become agitated and disruptive for a variety of reasons—an infection, poor sleep, or even a seemingly minor stressor, such as moving to a new room. These can all cause delirium. Jane was likely delirious when her symptoms began six months before I met her, before she was prescribed any psychiatric medications. Her screaming and sleep disruption were the reasons that these medications were prescribed in the first place. And they likely helped, at least temporarily. The nurses and physicians likely saw that these medications sedated Jane and decreased her screaming, and so they continued to prescribe them. When the symptoms came back, they tried increasing the doses or adding new medications.

On the surface, it’s understandable how Jane ended up on so many medications. However, several of them are known to impair mitochondrial function. This means that they can help in the short run, but they come with the risk of making matters worse in the long run. That appears to be what happened to Jane. By the time I saw her, whatever caused her initial delirium had probably passed, and she was delirious because of the treatments she was receiving.

Most healthcare professionals know that tranquilizing medications can sometimes make elderly people delirious. What’s going to be more difficult for the mental health field to grapple with is the possibility that this might happen in young people, too. The brain energy theory suggests that it could, and my own clinical practice for the past twenty-five years suggests that it probably does, at least in some cases. You’ll hear about one such person later in the book.

This doesn’t mean that antipsychotic and mood stabilizing medications shouldn’t be used or can’t put symptoms into remission. I believe they do work for some people, and I continue to prescribe them to this day. But for Jane, they clearly ended up making her mental symptoms even worse. Removing the offending medications brought Jane back.