Take-2: Mitochondria as End all, Be All
It's all about energy in the universe after all - Mitochondria & Neuropsychiatry
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The Universe is all about energy management, & our mitochondria run our show.
Ever hear the phrase “If mama isn’t happy, ain’t nobody happy”?
Well - I will paraphrase: “If your mitochondria aren’t happy, Nobody is happy!”
Disclaimer: That this even needs to be written, in a way, is a bit embarrassing to me. But here goes:
This is not to be considered a solicitation of patients for care or consultation — this essay, in whole or in part, is not an allusion to direct treatment or providing care but for educational purposes. If you wish for a consultation or direct care, and I am licensed in your state, it would be my privilege —> don't hesitate to contact me directly. All or any part of this article is NOT a disparagement of more ‘traditional’ allopathic care in any way. Indeed, as my DO/Osteopath son might tell you, I am a pretty “Old School Allopath/Medical Doctor.” I’m not sure what that means, and too old to possibly get offended.
I have witnessed the many powerful effects of traditional neuro- & psycho- tropic medications directly, and prescribe them A LOT … DAILY. (Weekends and holidays too). I witness many of these life-saving and life-changing beneficial effects, and unfortunately, even in the most conservative and cautious strategies, the side effects and complications also.
So…we find ourselves here. Once again, as has happened often in human history, the tables are turned - where we thought of them as the subservient little organelles, there to provide us with power and quite literally feed us (as the evolutionary biologists like to tell us) —and that likely these innocent-looking little things were aggressively engulfed by another cell and therefore began the cascade of events leading to all other ‘superior’ forms of life (us included) that have a distinct nucleus —eukaryotes— making us distinct from all ‘lower’ forms of life that do not —prokaryotes.
But NO.
I emphatically agree with a minority of evolutionary biologists and their OTHER, less popular conjecture.
These little energy-producing proto-mitochondria INVADED AND PARASITIZED our initial, poor, little LUCA (Last Universal Common Ancestor).
They drive inflammation, innate immunity, programmed cell death, and a host of other REALLY REALLY important processes.
And they lead us by the nose with them.
And hold them over our heads.
And yet, without them, we are truly dead in the water. Or just dead.
In a recent previous essay, I wrote about the importance of mitochondria in neuropsychiatry in the context of metabolism. I will re-iterate many of these points here because they bare repeating and further clarification. Ideally, slightly differently enough that I won’t risk boring you. Again. :)
We will talk about the past and, more importantly, the future of diagnosis and treatment and what that SHOULD all look like.
More importantly, I will build on those topics and that literature: up and down and sideways. We will talk about the past and, more importantly, the future of diagnosis and treatment and what that SHOULD all look like.
The Intricate Connection:
Mitochondria & Neuropsychiatric Disorders
The human body is complex and intricate, with each part crucial in maintaining optimal functioning —most of them so crucial, that we have redundant versions of them. One of the most fundamental components of this system, all the way, deep down at the sub-cellular level, is the mitochondria: tiny energy-producing structures within our cells. There are hundreds and sometimes thousands of mitochondria per cell.
The number of mitochondria per human cell can vary widely depending on the type & function of the cell.
On average, a human cell may have a few hundred to a few thousand mitochondria.
The approximate number of mitochondria per cell for some major cell types in humans:
Neurons - Neurons in the brain and nervous system are highly energy-intensive and require many mitochondria to function properly: On average, a single neuron may contain thousands of mitochondria.
Muscle cells - Muscle cells, especially those involved in high-energy activities like endurance exercise: The exact number can vary widely, but it is not uncommon for a single muscle cell to contain hundreds or thousands of mitochondria.
Liver cells - Liver cells, play a major role in metabolism and energy production: On average, a liver cell may contain several hundred to a few thousand mitochondria.
Kidney cells - Kidney cells, filter and process waste products from the blood: On average, a kidney cell may contain a few hundred to a few thousand mitochondria.
Heart cells - Heart cells, which require constant energy to pump blood: On average, a heart cell may contain several thousand mitochondria.
It is important to note that the number of mitochondria per cell can vary widely depending on age, health status, & environmental factors. Additionally, some cell types may have a lower or higher number of mitochondria depending on their specific function within the body, at any given time.
These cellular powerhouses have long been recognized for their essential role in energy metabolism; however, recent research has uncovered a more profound connection between mitochondria and the development of disease in general and neuropsychiatric disorders in particular (Morris & Berk, 2015).
Let us continue to delve into some of this compelling evidence, suggesting that mitochondrial dysfunction may lie at the heart of various metabolic and mental health issues.
Mitochondria generate most of the body's adenosine triphosphate (ATP), the primary energy currency that powers cellular processes (Klinedinst & Regenold, 2015).
Yes, we produce ATP via other processes without oxidative phosphorylation or mitochondria.
Glycolysis occurs in the cytoplasm of cells and involves the breakdown of glucose into two pyruvate molecules. During glycolysis, ATP is produced via a process called substrate-level phosphorylation, where an enzyme directly transfers a phosphate group to ADP to produce ATP. Another process that can produce ATP is fermentation, which can occur in the absence of oxygen and involves the conversion of pyruvate to lactate or ethanol, with ATP produced via substrate-level phosphorylation. However, it is important to note that these alternative processes for ATP production are much less efficient than oxidative phosphorylation and do not generate as much ATP per glucose molecule. This process occurs during certain metabolic reactions, such as the Krebs cycle and glycolysis. Additionally, cells can produce ATP by breaking other energy-rich molecules such as fats and amino acids.
The brain consumes approximately 20% of the body's total energy despite accounting for just 2% of its weight.
Energy production is especially critical for the brain, which consumes approximately 20% of the body's total energy despite accounting for just 2% of its weight (Raichle & Gusnard, 2002). Thus, it is unsurprising that impaired mitochondrial function can significantly impact brain health and the manifestation of neuropsychiatric disorders.
Mitochondria are known to have originated as free-living bacteria, with evidence suggesting that they were engulfed by eukaryotic cells in a process of endosymbiosis. As such, it has been proposed that mitochondria may have their interests and agendas independent of the host cell and may sometimes conflict with those of the host cell.
The ultimate goal of mitochondria is to ensure their survival and propagation, and they may manipulate host cells to achieve this end.
It has been proposed that mitochondria may manipulate host cells into producing high levels of reactive oxygen species (ROS), which can be harmful to the host but beneficial to the mitochondria, as they can help to protect the mitochondria from oxidative damage and promote their replication. Reactive oxygen species (ROS) are produced as byproducts of cellular metabolism, particularly during oxidative phosphorylation in the mitochondria. These molecules can harm cells if they accumulate to high levels, as they can damage cellular components such as proteins, lipids, and DNA.
However, low to moderate levels of ROS can also have beneficial effects on cells. For example, ROS can act as signaling molecules that activate various cellular pathways, including those involved in growth, differentiation, and immune responses (Circu & Aw, 2010).
In the context of mitochondria, low ROS levels can help protect the organelles from oxidative damage by acting as a signaling molecule to upregulate antioxidant defenses (Brand, 2010). Additionally, ROS have been implicated in regulating mitochondrial biogenesis, the process by which new mitochondria are formed in cells (Scialo et al., 2017). Specifically, ROS can activate pathways that promote the replication and growth of mitochondria, ultimately leading to increased oxidative capacity and energy production in cells.
However, it is important to note that the effects of ROS on cells and mitochondria are complex and context-dependent. High levels of ROS can damage cells and may contribute to a wide range of pathologies, including neurodegenerative diseases and cancer (Sies & Jones, 2020).
Very likely why we get so many mixed results from studies of ‘anti-oxidants.’
The delicate balance between ROS production and scavenging is critical for maintaining cellular homeostasis, and disruption of this balance can harm cells and organisms.
The metabolic flexibility of mitochondria may have enabled eukaryotes to survive in low-oxygen environments.
Additionally, some researchers have proposed that mitochondria may have played a role in the evolution of eukaryotes and may continue to do so today. For example, it has been suggested that the metabolic flexibility of mitochondria may have enabled eukaryotes to survive in low-oxygen environments and that mitochondria may have helped to drive the evolution of multicellular organisms by providing energy for complex biological processes such as cell differentiation and development.
Mitochondria play a crucial role in many metabolic, inflammatory, and neuroendocrine pathways, and dysfunction of these organelles can contribute to a wide range of neuropsychiatric disorders.
Despite these fascinating hypotheses, much more research is obviously needed to understand the full role of mitochondria in health and disease. However, it is clear that mitochondria play a crucial role in many metabolic, inflammatory, and neuroendocrine pathways and, specifically, that dysfunction of these organelles can contribute to a wide range of neuropsychiatric disorders. By understanding the complex interplay between mitochondria, host cells, and the environment, we can develop more effective treatments for these disorders and ultimately improve the lives of millions worldwide.
"The mitochondrial genome must have played a pivotal role in the evolution of metazoan life, including brain development" —Wallace, 2009.
Indeed, there is a fascinating potential evolutionary basis for the central role of mitochondria in metabolism, inflammation, and neuropsychiatric pathology. Dr. Douglas C. Wallace, one of the pioneers in mitochondrial genetics, noted: "The mitochondrial genome must have played a pivotal role in the evolution of metazoan life, including brain development" (Wallace, 2009).
The symbiotic relationship between mitochondria and eukaryotic cells began when a proto-eukaryotic cell (LUCA) engulfed the mitochondria.
Mitochondria were once free-living bacteria that evolved the ability to produce energy more efficiently by harnessing oxygen. The more classic theory, distinct from my more ‘controversial’ introductory one, is that the symbiotic relationship between mitochondria and eukaryotic cells began when mitochondria were engulfed by a proto-eukaryotic cell. Over time, they became integrated and essential to the cell's functioning after many (but surprisingly and very interestingly, NOT ALL) of the mitochondria’s genes were transferred to the host cell's nucleus. This is the endosymbiotic theory of mitochondrial origin (Sagan, 1967).
It can be seen as an interesting balance: each mitochondrion needs genetic coding instructions nearby to be able to move and adapt (?think) on the fly, not having sent them to be safely tucked away in the nucleus —therefore, NOT ALL genes have been transferred —but it can certainly be a master giving its transport-animal JUST ENOUGH training (genetic information in this case), to get the job done in some semblance of auto-pilot, while the ‘dark passenger’ retains proper control over everything —including life and death.
This adaptation made them ideal symbiotic partners for eukaryotic cells, which have evolved to use oxygen as an energy source.
Mitochondria were once free-living bacteria that evolved the ability to produce energy more efficiently by harnessing oxygen.
From this perspective, the central role of mitochondria in metabolism and neuropsychiatric pathology can be seen as an evolutionary adaptation. In periods of plenty, such as after a successful hunt, the body can store energy in the form of fat. During times of scarcity, such as a drought or a famine, the body can tap into this energy reserve. Mitochondria are essential for this process because they generate ATP, the cell's energy currency, from the breakdown of nutrients, mainly glucose and fatty acids (Goodman & Gilman, 2011).
- Mitochondria are essential for this process [tapping into energy storage reserves --glycogen & fat]-- because they generate ATP, the cell's energy currency, from the breakdown of nutrients, particularly glucose and fatty acids (Goodman & Gilman, 2011).
- Mitochondria play a key role in inflammation by producing reactive oxygen species (ROS), important signaling molecules that help regulate the immune response (West et al., 2011).
The same holds for inflammation. Inflammation is the body's natural response to injury or infection. It helps to isolate and eliminate the source of the problem, and it also increases blood flow to the affected area, bringing in immune cells and nutrients. Mitochondria play a crucial role in inflammation by producing reactive oxygen species (ROS), important signaling molecules that help regulate the immune response (West et al., 2011).
From an evolutionary perspective, one might wonder why mitochondria have such an outsized influence on our behavior and health. In this essay, we will explore what the literature from the perspective of evolutionary biologists tells us about any ulterior motives mitochondria might have in playing such a unique linchpin role in so many metabolic, inflammatory, and neuroendocrine roles that drive behavior and underscore so much neuropsychiatric pathology.
Yeah, yeah, …. the cell's powerhouse; as we have seen, they play a critical role in maintaining cellular energetics. However, mitochondria are not just passive participants in cellular metabolism but also actively involved in a wide range of signaling pathways that modulate cellular behavior. One hypothesis put forth by some evolutionary biologists is that mitochondria compete with each other for control of the cell and that this competition has driven the evolution of complex cellular signaling pathways that we observe today (Lane, 2011).
According to this hypothesis, mitochondria are in a constant state of competition with each other for resources. This competition has led to the development complex regulatory mechanisms that allow mitochondria to signal to the rest of the cell when they need more resources. In this way, mitochondria are not just passive participants in cellular metabolism but actively involved in modulating cellular behavior to maximize their reproductive success.
A growing body of evidence from experimental and observational studies supports this hypothesis. For example, studies have shown that mitochondria can communicate with each other through a process called mitochondrial fusion, where the outer membranes of two mitochondria fuse together, allowing the two mitochondria to share resources (Suen et al., 2008). Additionally, mitochondria can signal to the rest of the cell through retrograde signaling, where mitochondrial dysfunction activates a signaling pathway that leads to changes in gene expression in the nucleus (Kornmann & Osiewacz, 2019).
So, what are the evolutionary benefits and detriments of mitochondria playing such a role in eukaryotes? One possible benefit is that by regulating cellular behavior, mitochondria can ensure the cell functions optimally, maximizing its reproductive success. Additionally, by competing with each other for resources, mitochondria can drive the evolution of more complex and efficient cellular signaling pathways.
However, there are also potential detriments to mitochondria playing such a prominent role in cellular behavior. For example, mitochondrial dysfunction can lead to the production of reactive oxygen species (ROS), which can damage cellular components and lead to the development of disease (Schapira, 2012). Additionally, by signaling to the rest of the cell, mitochondria can influence the expression of genes involved in disease development, such as those involved in inflammation and immune function (Lopez-Armada et al., 2013).
By regulating cellular behavior, mitochondria can ensure their reproductive success and drive the evolution of more complex cellular signaling pathways. However, this role also comes with potential detriments, including ROS production and gene expression modulation that can contribute to disease development.
There is a reason why one of the ways NASA looks for life on other planets is to check for the presence of ATP.
Yes, NASA uses the search for ATP as one of the ways to detect potential life on other planets. ATP is considered a key molecule for life because it is involved in energy metabolism in all known living organisms (at least all that WE KNOW, and that’s an excellent place to start). Therefore, the presence of ATP on another planet would suggest the presence of living organisms or at least the potential for life. However, it is essential to note that the search for ATP is just one of many methods NASA and other space agencies use to search for signs of life on other planets. Other methods include the detection of other organic molecules, the presence of water, and studying atmospheric composition.
Mitochondria are ultimately at the basis of all mental health, metabolic, neuropsychiatric disorders, and cancer.
So… OK, I’m going to come right out and say it:
Energy is life.
Energy management is at the heart of all life, disease, and death.
Mitochondria provide us with THE molecular form of energy used on Earth, spoon-feeding it to our cells at a sub-cellular level.
Mitochondria are the fundamental basis and least common denominator of all mental health, metabolic, neuropsychiatric disorders, and cancers. They are intimately involved in many metabolic, inflammatory, and neuroendocrine pathways that underlie these diseases' behavior and pathophysiology.
We will look into many of these.
Medications, supplements, and lifestyle factors can all affect mitochondrial function positively or negatively, highlighting the need for a comprehensive treatment plan that addresses all aspects of mitochondrial health.
We will look into many of these also.
The evolutionary basis for the central role of mitochondria in eukaryotic life is an exciting area of research that promises to shed light on the origins and functions of these remarkable organelles and likely add to how we might truly (someday) find a real and equitable symbiosis. Until then, I will try to map out what humble multicellular organisms like us might do to appease our ‘dark passengers.’
Mitochondria in Disease
Obviously, that is a broad heading.
Obviously, too, is a need to be realistic and know that this is far from an exhaustive list. Not because there is no evidence. Quite the opposite, —because the list would be exhausting! I share with you many of the greatest hits.
One of the most well-known examples of this connection, within the context of neuropsychiatric disease, is the link between mitochondrial dysfunction and major depressive disorder (MDD). Numerous studies have demonstrated that individuals with MDD exhibit impaired mitochondrial energy production, increased oxidative stress, and elevated inflammation, all of which seemingly contribute to developing and maintaining depressive symptoms (Morris & Berk, 2015; Klinedinst & Regenold, 2015). Furthermore, post-mortem analyses of brain tissue from individuals with MDD have revealed abnormalities in mitochondrial structure and function (Klinedinst & Regenold, 2015).
The GABA and glutamate neurotransmitter systems are two of the most important systems in the brain, and both are known to play important roles in regulating brain function and behavior. Mitochondrial dysfunction can significantly impact these systems, leading to impaired neurotransmitter signaling and altered neuronal activity. GABA is the primary inhibitory neurotransmitter in the brain, and it plays a critical role in regulating neuronal activity and maintaining brain function. Mitochondrial dysfunction can impair GABA signaling and contribute to the development of neurological disorders such as epilepsy, schizophrenia, and anxiety disorders (Liang & Patel, 2004). On the other hand, glutamate is the primary excitatory neurotransmitter in the brain, and it is involved in various aspects of brain function, including learning and memory. Mitochondrial dysfunction can lead to the overactivation of glutamate receptors and the accumulation of toxic levels of glutamate, leading to neuronal damage and death (Bak et al., 2006).
Huntington's disease is a neurological disorder caused by an abnormal expansion of CAG repeats in the huntingtin gene, accumulating toxic protein aggregates in the brain —more on this further down in the article. Mitochondrial dysfunction has been implicated in the pathogenesis of Huntington's disease. It is thought to contribute to the neurodegenerative process by impairing mitochondrial function and accumulating reactive oxygen species and oxidative stress (Gibson et al., 2010).
The protein coded for by the CAG repeats is called huntingtin. The normal form of huntingtin protein is involved in various cellular processes such as vesicle trafficking, gene transcription, and neuronal survival. However, in the pathological state, the expansion of CAG repeats in the huntingtin gene leads to the formation of a mutant huntingtin protein that causes neuronal dysfunction and death. The mutant protein has been shown to disrupt various cellular processes, including mitochondrial function, autophagy, proteasomal degradation, transcriptional regulation, and cytoskeletal organization (Ross & Tabrizi, 2011; Trushina et al., 2012). Studies have reported that mutant huntingtin protein can interfere with mitochondrial function through multiple mechanisms.
The huntingtin protein:
Impairs mitochondrial transport by interacting with motor proteins and disrupting the transport of mitochondria along microtubules (Oliveira et al., 2007).
It also causes a reduction in mitochondrial membrane potential, leading to decreased ATP production and oxidative stress (Kumar et al., 2019; Reddy et al., 2017).
The abnormal protein can also alter mitochondrial dynamics, such as fission and fusion events, thereby affecting mitochondrial morphology and function (Shirendeb et al., 2011).
Interfering with mitochondrial transport, reducing mitochondrial membrane potential, and inducing oxidative stress (Oliveira et al., 2007; Orr & Zoghbi, 2007).
Additionally, mutant huntingtin protein has been shown to affect mitochondrial biogenesis and mitochondrial DNA stability, further exacerbating the mitochondrial dysfunction observed in Huntington's disease (Kim et al., 2010; St-Pierre et al., 2006).
As CAG repeats increase, the huntingtin protein becomes more toxic, leading to more severe mitochondrial dysfunction and neurodegeneration —Ross & Tabrizi, 2011.
Additionally, the length of the CAG repeats has been shown to significantly impact the dysfunction of the huntingtin protein and the severity of Huntington's disease. As CAG repeats increase, the huntingtin protein becomes more toxic, leading to more severe mitochondrial dysfunction and neurodegeneration (Ross & Tabrizi, 2011).
Overall, the pathological effects of the mutant huntingtin protein on neuronal function and survival, as well as its impact on mitochondrial function, are key contributors to the development and progression of Huntington's disease. Targeting mitochondrial function may offer a promising therapeutic approach for this devastating neurological disorder.
Regarding treatment and medication, evidence suggests that targeting mitochondrial function may have therapeutic potential for these neurological disorders. For example, drugs that target the electron transport chain and improve mitochondrial function, such as coenzyme Q10 and creatine, have been shown to improve symptoms in patients with Huntington's disease and other neurological disorders (Beal, 2004; Keene et al., 2006).
Unfortunately, we ask too much of these substances, and the pathological changes are too great for any of these interventions to do much (if anything), by themselves.
Another example can be found in bipolar disorder, a chronic and debilitating mental illness characterized by recurrent episodes of mania and depression. Research has identified several mitochondrial abnormalities in individuals with bipolar disorder, including decreased ATP production, increased oxidative stress, and reduced mitochondrial DNA copy number (Morris & Berk, 2015; Kato, 2017). These findings suggest that mitochondrial dysfunction may be a key factor in the pathophysiology of bipolar disorder.
Mitochondrial dysfunction has been shown to play a significant role in developing type 2 diabetes mellitus.
I’ve gone into more detail on the role of mitochondria and mitochondrial dysfunction in metabolic and cardiovascular disease elsewhere —but some of that needs to be emphasized here.
This (mitochondrial) dysfunction can impair glucose uptake and utilization, leading to hyperglycemia and insulin resistance (Pagano et al., 2018). In addition, the production of reactive oxygen species (ROS) by dysfunctional mitochondria can contribute to oxidative stress and chronic inflammation, both of which have been implicated in the pathogenesis of type 2 diabetes (Szendroedi & Roden, 2009).
Treatments and medications for type 2 diabetes can positively and negatively affect mitochondrial energetics and function. For example, metformin, a commonly used oral medication for type 2 diabetes, has been shown to improve mitochondrial function in skeletal muscle cells by increasing oxidative phosphorylation and reducing ROS production (Bridges et al., 2016). In contrast, some studies have suggested that sulfonylureas, another class of oral medications for type 2 diabetes, may impair mitochondrial function by inhibiting mitochondrial respiration and increasing ROS production (Scheen, 2018).
Other treatments for type 2 diabetes, such as lifestyle interventions and exercise, have also been shown to improve mitochondrial function. For example, a study of individuals with type 2 diabetes found that a 12-week exercise intervention improved mitochondrial function in skeletal muscle cells, as evidenced by increased oxidative capacity and decreased ROS production (Thyfault et al., 2010).
Several newer medications for diabetes have positive effects on mitochondrial function:
Sodium-glucose cotransporter 2 (SGLT2) inhibitors: These medications, such as empagliflozin and canagliflozin, inhibit glucose reabsorption in the kidneys, leading to increased glucose excretion in the urine. Studies have shown that SGLT2 inhibitors can improve liver and skeletal muscle mitochondrial function, potentially contributing to their glucose-lowering effects (Bonora et al., 2019; Matsuba et al., 2018).
Glucagon-like peptide 1 (GLP-1) receptor agonists: These medications, such as exenatide and liraglutide, mimic the action of GLP-1, a hormone that stimulates insulin secretion and suppresses glucagon secretion. GLP-1 receptor agonists have improved mitochondrial function in several tissues, including the liver, skeletal muscle, and pancreas (Baggio et al., 2018; Kim et al., 2015).
Dipeptidyl peptidase 4 (DPP-4) inhibitors: These medications, such as sitagliptin and saxagliptin, inhibit the breakdown of GLP-1 and other incretin hormones, leading to increased insulin secretion and decreased glucagon secretion. DPP-4 inhibitors have been shown to improve liver and skeletal muscle mitochondrial function, potentially contributing to their glucose-lowering effects (Bonora et al., 2019; Wei et al., 2018).
Peroxisome proliferator-activated receptor (PPAR) agonists: These medications, such as pioglitazone and rosiglitazone, activate PPARs, which regulate the expression of genes involved in glucose and lipid metabolism. PPAR agonists have improved mitochondrial function in the liver, skeletal muscle, and adipose tissue (Gomez-Diaz et al., 2015; Sparks et al., 2013).
These medications have shown promise in improving mitochondrial function in various tissues and may contribute to their glucose-lowering effects in individuals with diabetes. However, it is important to note that the effects of these medications on mitochondrial function may vary depending on the specific medication, dose, and duration of treatment, and further research is needed to understand their mechanisms of action fully.
The relationship between mitochondrial dysfunction and type 2 diabetes is complex.
Overall, the relationship between mitochondrial dysfunction and type 2 diabetes is complex, with numerous factors contributing to the pathology of the disease. While some medications and treatments may negatively affect mitochondrial function, others may improve mitochondrial energetics and function, highlighting the importance of individualized treatment approaches considering each patient's unique metabolic and mitochondrial characteristics.
Mitochondrial dysfunction has been implicated in the pathogenesis of obesity separately. Mitochondria play a crucial role in energy metabolism, and impaired mitochondrial function can contribute to insulin resistance, dysregulated lipid metabolism, and chronic inflammation, all of which are hallmarks of obesity and metabolic disease as associated but separate entities (Perry et al., 2013).
Evidence suggests that —lifestyle interventions— (I know, I will continue to say this ALOT), such as exercise and dietary changes, can improve mitochondrial function and metabolic health in individuals with obesity (Linden et al., 2014). For example, aerobic exercise has been shown to improve mitochondrial function in skeletal muscle and improve insulin sensitivity in individuals with obesity (Thyfault et al., 2013).
If you dare, skip ahead to see what it does in the section about the brain, mitochondria, and exercise. But come back here, afterward.
Additionally, dietary interventions, such as calorie restriction and ketogenic diets, have improved mitochondrial function and metabolic health in animal models and some human studies (Newman & Verdin, 2014).
Several medications for obesity and metabolic disease have also been shown to positively affect mitochondrial function. For example, metformin, a widely used medication for type 2 diabetes, has been shown to improve mitochondrial function in several tissues, including the liver, skeletal muscle, and adipose tissue (Foretz et al., 2014). Similarly, thiazolidinediones, a medication class that activates peroxisome proliferator-activated receptors (PPARs), like pioglitazone, have improved mitochondrial function in adipose tissue and the liver (Sparks et al., 2013).
However, other medications used for the treatment of obesity and metabolic disease may have negative effects on mitochondrial function. For example, some studies have suggested that high doses of beta-adrenergic receptor agonists, such as salbutamol and terbutaline, may impair mitochondrial function and contribute to insulin resistance and metabolic dysfunction (Perry et al., 2013).
Overall, improving mitochondrial function and energetics is an important consideration in treating obesity and metabolic disease, and lifestyle interventions and some medications have shown promise in improving mitochondrial function and metabolic health. However, the effects of medications on mitochondrial function may vary depending on the specific medication, dose, and duration of treatment, and further research is needed to fully understand their mechanisms of action and potential implications for metabolic health.
Separately, mitochondrial dysfunction has been implicated in the pathogenesis of cardiovascular disorders, including heart failure, ischemic heart disease, and hypertension. As we have said ad nauseum so far, mitochondria play a crucial role in energy metabolism, and impaired mitochondrial function can lead to decreased ATP production, oxidative stress, and inflammation, all of which can contribute to the development and progression of cardiovascular disease (Madamanchi & Runge, 2007).
Evidence suggests that…. WAIT FOR IT…. lifestyle interventions, such as exercise and dietary changes, can improve mitochondrial function and metabolic health in individuals with cardiovascular disease. For example, exercise has been shown to improve mitochondrial function in skeletal muscle and improve cardiovascular function in individuals with heart failure (Haykowsky et al., 2011). Additionally, dietary interventions, such as calorie restriction and Mediterranean-style diets, have improved mitochondrial function and reduced inflammation in individuals with cardiovascular disease (Lopez-Lluch et al., 2016; Phillips et al., 2016).
Several medications used to treat cardiovascular disease have also been shown to positively affect mitochondrial function. For example, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), commonly used for the treatment of hypertension and heart failure, have been shown to improve mitochondrial function in cardiac tissue and reduce oxidative stress (Dikalova et al., 2010). Additionally, statins, commonly used for treating high cholesterol, have improved mitochondrial function and reduced inflammation in cardiac and skeletal muscle tissue (Mullen et al., 2014).
However, other medications used for the treatment of cardiovascular disease may have negative effects on mitochondrial function. For example (as already mentioned above), beta-adrenergic receptor blockers, commonly used for treating hypertension and heart failure, have been shown to decrease mitochondrial function in cardiac tissue and contribute to insulin resistance and metabolic dysfunction (Madamanchi & Runge, 2007).
Overall, improving mitochondrial function and energetics is an important consideration in treating cardiovascular disease, and lifestyle interventions
—I should encourage drinking water every time you see it written.
Two jumping jacks every time I write it? I mean for me, not for you—
and some medications have shown promise in improving mitochondrial function and metabolic health. However, the effects of medications on mitochondrial function may vary depending on the specific medication, dose, and duration of treatment, and further research is needed to fully understand their mechanisms of action and potential implications for cardiovascular health.
Schizophrenia, a severe mental disorder marked by psychosis, disorganized thinking, and social withdrawal, is also linked to mitochondrial dysfunction. A growing body of evidence demonstrates that individuals with schizophrenia exhibit impairments in energy metabolism, oxidative stress, and inflammation (Morris & Berk, 2015; Martins-de-Souza, 2018). Additionally, genetic studies have identified mutations in genes involved in mitochondrial function, further supporting the role of these cellular structures in the development of schizophrenia (Martins-de-Souza, 2018).
Insulin, a hormone primarily associated with glucose metabolism, has also been shown to play a role in neuropsychiatric disorders. In fact, as far back as almost 100 years ago, researchers were already looking at platelet function and sensitivity to insulin in schizophrenics (Klages, 1925). Insulin resistance, or the inability of cells to respond to insulin, has been associated with mitochondrial dysfunction and oxidative stress (Hosseinzadeh-Attar et al., 2015).
Interestingly, newer research has shown that insulin therapy may effectively treat schizophrenia. A study found that adding insulin to the treatment regimen of patients with schizophrenia improved their clinical symptoms and quality of life (Sharma et al., 2018). However, it is important to note that while insulin may positively affect mitochondrial function, it can also have negative effects, particularly when used in excess. In fact, hyperinsulinemia, or high levels of insulin in the blood, has been associated with mitochondrial dysfunction and increased oxidative stress (Hosseinzadeh-Attar et al., 2015).
The prostaglandin cascade, a series of biochemical reactions that produce prostaglandins, has also been implicated in neuropsychiatric disorders. Prostaglandins are lipid molecules that play a role in inflammation and pain. Research has shown that the prostaglandin cascade is sometimes deranged in many psychotic illnesses, particularly among schizophrenics (Müller et al., 2015). Additionally, it has been observed that schizophrenics do not flush when given niacin, which is a precursor to a molecule involved in the prostaglandin cascade (Horrobin, 1968). This may indicate a dysfunction in this pathway in schizophrenics.
Furthermore, research has shown that pain thresholds may be different in schizophrenics. One study found that schizophrenics had higher pain thresholds than healthy controls, suggesting they may have altered pain perception (Perry et al., 2007). This finding may be related to mitochondrial dysfunction and oxidative stress, which have been shown to play a role in pain perception (Alvarez-Perez et al., 2014).
The finding that certain prostaglandins and the prostaglandin cascade are sometimes deranged in many psychotic illnesses, particularly in schizophrenics, is a fascinating area of research that could lead to new treatments for these disorders. It is also clear that mitochondrial energetics and bioenergetic pathways are intertwined with the neuroendocrine and neuroimmune findings in neuropsychiatric disorders, and that further research in this area is needed.
Insulin resistance, a hallmark of metabolic dysfunction and a known contributor to mitochondrial dysfunction has also been linked to schizophrenia. A study published in 1926 by Kraepelin and Kallman showed that platelet function and insulin sensitivity were abnormal in schizophrenic patients (Kraepelin & Kallman, 1926).
A study published in 1926 by Kraepelin and Kallman showed that platelet function and insulin sensitivity were abnormal in schizophrenic patients.
Platelets=Prostaglandins & Insulin Sensitivity=Metabolic Energy Management
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Inflammation & Metabolism
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Mitochondria
This early observation has been supported by more recent research, which has found that insulin resistance is common in individuals with schizophrenia and other psychiatric disorders (Kahn et al., 2009; Hahn et al., 2013). Insulin resistance and mitochondrial dysfunction are closely linked, as insulin signaling is crucial for properly functioning mitochondria in cells (Goncalves et al., 2015). Thus, it is possible that the use of insulin as a treatment for schizophrenia, which has been documented since the early 1900s, may have had unintended benefits for mitochondrial function in addition to its intended effects on glucose regulation and ultimate shock.
The right medicine,
given out of ignorance of the underlying cellular pathophysiology,
given for the wrong reasons.
However, the relationship between insulin and mitochondrial function is complex, and the effects of insulin on mitochondria may depend on the specific context and disease state. For example, in a study on skeletal muscle cells from individuals with type 2 diabetes, insulin treatment exacerbated mitochondrial dysfunction and increased oxidative stress (Tumova et al., 2010). Similarly, in a study on cardiac cells, insulin increased mitochondrial reactive oxygen species (ROS) production, which can contribute to cellular damage and dysfunction (Chen et al., 2014).
In schizophrenia, there is still much to be learned about the role of insulin and mitochondrial dysfunction. Insulin resistance and mitochondrial dysfunction may be two sides of the same coin, contributing to the disorder's development and progression. Alternatively, insulin resistance may be a downstream consequence of mitochondrial dysfunction, rather than a primary driver of the pathology. Further research is needed to clarify these relationships and identify potential therapeutic targets to improve mitochondrial function and insulin sensitivity in individuals with schizophrenia.
In addition to insulin, prostaglandins have also been implicated in the pathophysiology of schizophrenia.
Prostaglandins are lipid signaling molecules that are involved in many physiological processes, including inflammation and pain perception —more mitochondrially-influenced aspects of these disorders.
Studies have shown that levels of certain prostaglandins, particularly prostaglandin E2 (PGE2), are elevated in the cerebrospinal fluid and blood of individuals with schizophrenia (Muller et al., 2006; Schwarz et al., 2011). Additionally, research has found that individuals with schizophrenia have abnormal flushing responses to niacin, which is thought to be due to a derangement in the prostaglandin cascade (Horrobin, 1968).
The link between prostaglandins and mitochondrial function is also complex, with evidence suggesting both positive and negative effects of prostaglandins on mitochondria. For example, some studies have found that certain prostaglandins can protect against mitochondrial dysfunction and oxidative stress, while others have found that they can exacerbate these processes (Murphy et al., 2016). Additionally, the effects of prostaglandins on mitochondrial function may be context-dependent, with different prostaglandins having different effects depending on the specific cell type and disease state.
The relationship between mitochondrial dysfunction and neuropsychiatric disorders extends beyond mood and psychotic disorders.
The relationship between mitochondrial dysfunction and neuropsychiatric disorders extends beyond mood and psychotic disorders. Neurodevelopmental disorders, such as autism spectrum disorder (ASD), have also been implicated in this connection. Studies have shown that children with ASD exhibit abnormal mitochondrial function, including reduced ATP production and increased oxidative stress (Frye & Rossignol, 2011). Furthermore, genetic research has identified gene mutations related to mitochondrial function in individuals with ASD (Rossignol & Frye, 2012).
Neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are also associated with mitochondrial dysfunction. In Alzheimer's disease, impaired mitochondrial function contributes to the accumulation of amyloid-beta plaques and tau tangles, the hallmarks of this devastating illness (Swerdlow, 2011). Similarly, Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra, a process driven partly by mitochondrial dysfunction and oxidative stress (Schapira & Jenner, 2011).
AMYLOID: Amyloid plaques are a hallmark feature of Alzheimer's disease and are composed of abnormal deposits of protein fragments called beta-amyloid peptides. Studies have suggested that these beta-amyloid peptides may directly or indirectly contribute to mitochondrial impairment and dysfunction. One possible mechanism by which beta-amyloid peptides can impair mitochondrial function is through the generation of reactive oxygen species (ROS). Beta-amyloid peptides can induce ROS production, leading to oxidative damage and impairing mitochondrial function (Swerdlow, 2018). Additionally, beta-amyloid peptides can interfere with the transport of mitochondria along axons, disrupting mitochondrial function in neurons and leading to neuronal dysfunction (Calkins et al., 2011). Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer's disease, and it is thought to contribute to the cognitive decline observed in individuals with the disease (Reddy & Beal, 2008). Thus, the relationship between beta-amyloid peptides and mitochondrial dysfunction is an area of active research, with potential implications for developing therapeutic strategies for Alzheimer's disease. Amyloid protein can have both pro-oxidant and anti-oxidant effects. In some cases, amyloid protein can generate reactive oxygen species (ROS) and contribute to oxidative stress, damaging cellular components, including mitochondria. However, in other cases, amyloid protein can have anti-oxidant effects and protect cells against oxidative damage. The exact effects of amyloid protein on oxidative stress and mitochondrial function can depend on various factors, including the specific type and conformation of the protein and the context in which it is present.
TAU: Tau tangles are abnormal aggregates of the protein tau that accumulate in the brains of individuals with neurodegenerative diseases such as Alzheimer's disease. Studies have suggested that tau tangles can directly or indirectly contribute to mitochondrial dysfunction and impaired energy metabolism. Tau protein is a significant part of the makeup of the cellular cytoskeleton. One possible mechanism by which tau tangles can impair mitochondrial function is the disruption of mitochondrial transport along axons, where it also functions to move mitochondria around to where they are needed, which can lead to the accumulation of damaged mitochondria and impaired neuron energy production (DuBoff et al., 2012). Additionally, tau tangles can contribute to oxidative stress and the generation of reactive oxygen species, leading to mitochondrial damage and dysfunction (Garcia-Esparcia et al., 2013). Mitochondrial dysfunction and impaired energy metabolism have been implicated in the pathogenesis of dementia and neurodegenerative diseases. It is thought that these processes may contribute to the cognitive decline observed in individuals with these conditions (Wang et al., 2009). Thus, the relationship between tau tangles and mitochondrial dysfunction is an area of active research, with potential implications for developing therapeutic strategies for neurodegenerative diseases. Understanding the mechanisms by which tau tangles contribute to mitochondrial dysfunction and impaired energy metabolism may ultimately lead to the development of targeted treatments that can slow or halt the progression of these devastating conditions.
See remarks on others’ posts, regarding Tau & mitochondrial movement along the cytoskeleton.
The continually larger-than-Everest-mountain-of-evidence implicating mitochondrial dysfunction in neuropsychiatric disorders (?everywhere?) has spurred interest in developing novel therapeutic strategies targeting these cellular structures. One such approach is using antioxidants, which can help combat the oxidative stress associated with impaired mitochondrial function (Morris & Berk, 2015). But, as we have seen, a little ROS is not bad —actually normal and necessary, sooooooo…….
More specifics on these are listed farther below, but here’s a taste.
For example, N-acetylcysteine (NAC), a potent antioxidant, has shown promise in treating bipolar disorder, schizophrenia, and autism (Berk et al., 2008; Dean et al., 2011; Hardan et al., 2012). Another therapeutic strategy involves nutraceuticals, such as coenzyme Q10, L-carnitine, and alpha-lipoic acid, which all support mitochondrial function and energy production (Kidd, 2005). Preliminary studies have suggested that these supplements may be beneficial in treating various neuropsychiatric disorders, including MDD, bipolar disorder, and Alzheimer's disease (Kidd, 2005; Morris & Berk, 2015).
Drink! (water) - 2 jumping jacks - BAM!
Moreover, lifestyle interventions, such as exercise and dietary modifications, can potentially improve mitochondrial function and alleviate symptoms of neuropsychiatric disorders (Morris & Berk, 2015). Regular physical activity has been shown to enhance mitochondrial biogenesis, increase ATP production, and reduce oxidative stress (Gleeson et al., 2011). Similarly, a diet rich in antioxidants, healthy fats, and micronutrients can support optimal mitochondrial function and promote brain health (Gómez-Pinilla, 2008).
The evidence highlighting the critical role of mitochondria in the development and progression of neuropsychiatric disorders underscores the importance of maintaining healthy mitochondrial function for optimal brain health. As our understanding of these cellular structures continues to grow, it’s likely that novel therapeutic strategies targeting mitochondrial dysfunction will emerge, offering hope for individuals struggling with mental health issues.
Can anyone send someone to help me put a few of my 20-year-old but still pertinent liposomal designs out into the world?
In light of this ever-growing body of research supporting the role of mitochondrial dysfunction in the pathophysiology of neuropsychiatric disorders, scientists, clinicians, and the public need to recognize and address the factors that can contribute to mitochondrial impairment. These may include (but are certainly NOT LIMITED TO) environmental toxins —can anyone say processed foods?— chronic inflammation, and genetic predispositions (Morris & Berk, 2015).
Future research in this field should also aim to elucidate the molecular mechanisms underlying the relationship between mitochondrial dysfunction and neuropsychiatric disorders. This will not only enhance our understanding of the etiology of these conditions but also add to our efforts listed above, to pave the way for developing targeted, mitochondria-focused therapies that could potentially revolutionize the treatment of mental health disorders.
Does anyone have a line on a company willing to try a few innovative things and some new spins on older strategies? I have more than a few ideas, swirling around and on paper. I'd appreciate it if you could hurry before my own mitochondria grind to a halt.
The compelling evidence implicating mitochondria as the basis of a multitude of diseases, particularly mental health, and neuropsychiatric disorders, underscores the importance of maintaining healthy mitochondrial function for optimal (brain, heart, etc.) health. By integrating the latest scientific findings on mitochondrial dysfunction into our understanding of (mental, cardiac, etc.) health disorders, we can work towards developing novel, better-targeted treatment strategies. Precision Medicine.
Ready. Set. DRINK!
(I’m already jumping, Jack).
Mitochondria, Exercise, and More Evidence
The growing body of research on the role of mitochondria in neuropsychiatric disorders has led to an increased interest in understanding how lifestyle interventions, such as exercise, may exert their therapeutic effects through modulating mitochondrial function. Exercise has long been recognized for its numerous health benefits, including its ability to improve mood, alleviate anxiety and depression, and prevent cognitive decline in Alzheimer's and other neuropsychiatric diseases (Cooney et al., 2013; Kandola et al., 2019; Schuch et al., 2016).
Now, we will add a few more details to the potential mechanisms already discussed, through which exercise may enhance mitochondrial function and contribute to its therapeutic effects on neuropsychiatric disorders.
Recent re-posts of some interesting articles on LinkedIn about news confirming YET AGAIN that exercise is a powerful neuropsychiatric intervention.
Exercise has been shown to increase mitochondrial biogenesis.
Exercise has been shown to increase mitochondrial biogenesis, which is the process by which new mitochondria are generated within cells (Baker et al., 2010). The upregulation of mitochondrial biogenesis in response to exercise is thought to improve the overall efficiency of energy production and help maintain cellular homeostasis under conditions of increased energy demand, such as during physical activity (Dinoff et al., 2016). By promoting the generation of new, healthy mitochondria, exercise may counteract the deleterious effects of mitochondrial dysfunction on brain function and contribute to its therapeutic effects on neuropsychiatric disorders.
Exercise may counteract the deleterious effects of mitochondrial dysfunction.
In addition to promoting mitochondrial biogenesis, exercise has been shown to enhance the efficiency of mitochondrial oxidative phosphorylation, which is THE process by which mitochondria produce ATP, the cell's primary energy source (Holloway et al., 2018). This increase in mitochondrial efficiency may contribute to the neuroprotective effects of exercise by ensuring that neurons have sufficient energy to maintain their function and resist damage under stress conditions, such as in the context of neuropsychiatric disorders (Marosi & Mattson, 2014).
By clearing away damaged mitochondria, exercise may help maintain overall health.
Exercise has also been shown to induce a process known as mitophagy, which is the selective removal and degradation of damaged or dysfunctional mitochondria (Palikaras et al., 2018). By clearing away damaged mitochondria, exercise may help maintain the overall health and function of the mitochondrial population within cells, thereby preserving cellular integrity and promoting optimal organ (brain) function (Safdar et al., 2011). The induction of mitophagy by exercise may be particularly relevant in neuropsychiatric disorders, as the accumulation of dysfunctional mitochondria has been implicated in the pathophysiology of these conditions (Morris & Berk, 2015).
Exercise has been demonstrated to modulate the production of various neurotrophic factors.
In addition to the connections between mitochondrial dysfunction, neuroendocrine, and neuroimmune changes in neuropsychiatric disorders, evidence suggests that improving mitochondrial function may have therapeutic benefits directly, and improve the prognosis of these disorders.
As if the above-cited articles were insufficient, other studies confirm that exercise has been shown to affect mitochondrial function significantly, promote mitochondrial biogenesis, improve mitochondrial efficiency, and reduce oxidative stress (Marosi & Mattson, 2014). Regular physical activity also modulates the HPA axis, neurotransmitter systems, and neurotrophic factors, all of which are implicated in the pathophysiology of neuropsychiatric disorders (Dinas, Koutedakis, & Flouris, 2011). Furthermore, exercise has been demonstrated to have anti-inflammatory effects, reducing the levels of pro-inflammatory cytokines and increasing the production of anti-inflammatory molecules (Gleeson et al., 2011).
Dietary modifications and supplementation strategies aimed at improving mitochondrial function have also been explored in the context of neuropsychiatric disorders. Nutrients such as omega-3 fatty acids, B vitamins, coenzyme Q10, and antioxidants have been found to support mitochondrial health and reduce oxidative stress (Bhatti, Gaziano, & Djoussé, 2017; Young, 2007). Additionally, diets rich in anti-inflammatory foods like fruits, vegetables, whole grains, and lean protein sources may help alleviate neuroinflammation and improve neuropsychiatric symptoms (Firth et al., 2019).
These are systems within systems —fault-tolerant redundancy built by evolution over millions of years. When we look at the repercussions on tissues and then systems, of these cellular and subcellular effectors, we see the ripples of effects traveling up and down, in bidirectional waves of affectation.
Mounting evidence suggests that mitochondrial dysfunction plays a central role in the pathophysiology of neuropsychiatric disorders through its impact on neuroendocrine and neuroimmune systems. Understanding these intricate connections is crucial for developing targeted, effective treatments. Interventions aimed at improving mitochondrial function, such as exercise and dietary modification, hold promise for alleviating the burden of these complex and debilitating conditions. As we have seen, magnifying the benefits of any and all other interventions.
All interventions that benefit mitochondrial health, (just like we have seen all detrimental insults causing mitochondrial damage) seemingly magnify and potentiate each other. Feeding forward and backward throughout the cascading cellular networks —but also up and down the epigenome, tissues, microbiome, organs, and systems.
Furthermore, exercise has been demonstrated to modulate the production of various neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which play a crucial role in neuronal survival, growth, and synaptic plasticity (Knaepen et al., 2010). Research suggests that exercise-induced increases in BDNF levels may be partly mediated by enhanced mitochondrial function, as mitochondrial dysfunction has been shown to impair BDNF signaling (Cheng et al., 2012). Thus, the beneficial effects of exercise on mood and cognition are attributable to its ability to improve mitochondrial function and subsequently promote neurotrophic signaling.
Exercise has been shown to exert potent anti-inflammatory effects.
It is worth noting that exercise has been shown to exert potent anti-inflammatory effects, which may be particularly relevant in neuropsychiatric disorders, as chronic inflammation has been implicated in the pathophysiology of these conditions (Baker et al., 2010; Kandola et al., 2019). Research suggests that the anti-inflammatory effects of exercise may be mediated, in part, by improved mitochondrial function, as mitochondrial dysfunction has been shown to contribute to the activation of inflammatory pathways within the brain (Picard et al., 2014).
The beneficial effects of exercise on neuropsychiatric disorders may be partly attributable to its ability to enhance mitochondrial function.
By promoting mitochondrial biogenesis, increasing the efficiency of oxidative phosphorylation, inducing mitophagy, and modulating neurotrophic signaling and inflammation, exercise may help counteract the detrimental effects of mitochondrial dysfunction on brain function and contribute to its therapeutic effects on depression, anxiety, Alzheimer's disease, and other neuropsychiatric disorders, aside from metabolic efficiency and cardiovascular health.
These findings underscore the importance of incorporating exercise into comprehensive treatment strategies for individuals struggling with all these disorders, including mental health and neuropsychiatric issues, and highlight the potential of targeting mitochondrial function as a powerful ‘novel’ therapeutic approach in neuropsychiatric disease management, with more than JUST medications.
Mitochondria & Psycho-Neuro-Immunology —in Neuropsychiatry
The burgeoning field of psychoneuroimmunology has highlighted the complex interplay between the nervous, endocrine, and immune systems in the etiology and progression of neuropsychiatric disorders. Accumulating evidence indicates that mitochondria play a crucial role in mediating cellular processes at the core of these system-wide changes. This section will discuss, in more detail, the neuroendocrine and neuroimmune findings associated with neuropsychiatric disorders and the integral role mitochondria play in these cellular mechanisms.
Mitochondria are essential for maintaining cellular homeostasis, providing the energy required for normal cellular function, and regulating apoptosis and inflammation —Morris & Berk, 2015.
Dysfunctional mitochondria have been implicated in the pathophysiology of neuropsychiatric disorders such as major depression, anxiety, bipolar disorder, and schizophrenia, as well as neurodegenerative disorders like Alzheimer's and Parkinson's disease (Manji et al., 2012).
Mitochondria are pivotal in modulating the hypothalamic-pituitary-adrenal (HPA) axis, involved in stress response & emotion regulation —Picard et al., 2014.
In neuroendocrine function, mitochondria are pivotal in modulating the hypothalamic-pituitary-adrenal (HPA) axis, a major neuroendocrine system involved in stress response and emotion regulation (Picard et al., 2014). Dysregulation of the HPA axis has been observed in various neuropsychiatric conditions, including depression, anxiety, and bipolar disorder (Tsigos & Chrousos, 2002). Research has shown that dysfunctional mitochondria can lead to altered glucocorticoid signaling, contributing to HPA axis dysregulation and the subsequent development of neuropsychiatric symptoms (Picard et al., 2014).
Dysfunctional mitochondria can lead to altered glucocorticoid signaling.
Furthermore, mitochondrial dysfunction has been associated with altered neurotransmitter metabolism, particularly serotonin and dopamine, which are critically involved in mood regulation and the pathophysiology of depression, anxiety, and schizophrenia (Gardner & Boles, 2011). Mitochondria are essential for synthesizing and degradation of these neurotransmitters, highlighting their role in maintaining proper neurotransmitter homeostasis (Gardner & Boles, 2011).
Mitochondrial dysfunction has been associated with altered neurotransmitter metabolism.
In addition to their role in neuroendocrine function, mitochondria also play a significant role in neuroimmune processes. A growing body of research suggests chronic low-grade inflammation is a common feature of many neuropsychiatric disorders, including depression, bipolar disorder, and schizophrenia (Miller & Raison, 2016). Mitochondria are key regulators of inflammation. They control the production of reactive oxygen species (ROS) and activation of the inflammasome, a multiprotein complex responsible for producing pro-inflammatory cytokines (Morris & Berk, 2015).
A growing body of research suggests chronic low-grade inflammation is a common feature of many neuropsychiatric disorders, including depression, bipolar disorder, and schizophrenia —Miller & Raison, 2016.
This chronic inflammation can then contribute to the development and progression of neuropsychiatric disorders by causing neuronal damage, disrupting neurotransmitter metabolism, and impairing neuroplasticity (Miller & Raison, 2016).
Gut microbiota can influence mitochondrial function by producing short-chain fatty acids (SCFAs), which serve as an energy source for colonocytes and can modulate mitochondrial biogenesis and function —Gao et al., 2018.
Moreover, the gut-brain axis, which comprises bidirectional communication between the gut microbiota and the central nervous system, has emerged as a key player in neuropsychiatric disorders (Cryan & Dinan, 2012). The gut microbiota can influence mitochondrial function by producing short-chain fatty acids (SCFAs), which serve as an energy source for colonocytes and can modulate mitochondrial biogenesis and function (Gao et al., 2018). Dysbiosis of the gut microbiota has been associated with neuropsychiatric disorders such as depression and autism spectrum disorder, highlighting the potential involvement of mitochondrial dysfunction in the gut-brain axis (Cryan & Dinan, 2012).
Mitochondria play a central role in the cellular basis of neuroendocrine and neuroimmune changes associated with neuropsychiatric disorders. Dysfunctional mitochondria can contribute to HPA axis dysregulation, altered neurotransmitter metabolism, chronic inflammation, and gut-brain axis dysfunction, all of which are implicated in the development and progression of various neuropsychiatric conditions.
Understanding the role of mitochondria in these complex interactions may provide novel therapeutic targets for treating and preventing these disorders. Future research should focus on elucidating the specific mechanisms by which mitochondrial dysfunction contributes to the pathophysiology of neuropsychiatric disorders (in the context of neuroendocrine and neuroimmune changes) and identifying potential interventions to improve mitochondrial function. This could include exploring the individualized combination of
exercise,
nutrition, and
other lifestyle factors
that have been shown to promote mitochondrial health and resilience, together with
direct hormonal and-or
immunological modification,
while also supplementing with
certain antioxidants and-or
mitochondrion-enhancing nutraceuticals.
By deepening our understanding of the integral role mitochondria play in the cellular basis of neuroendocrine and neuroimmune changes associated with neuropsychiatric disorders, we may be better equipped to develop targeted, effective treatments and precision-focused medicine for these complex and debilitating conditions.
Mitochondria & Steroids
These medications have been associated with various psychiatric side effects, including psychosis, mania, and depression —Warrington & Bostwick, 2006.
Glucocorticoids are a class of steroid hormones that play a crucial role in regulating inflammation, immune response, and metabolism. Synthetic glucocorticoids, such as methylprednisolone, prednisone, and prednisolone, are often prescribed to treat inflammatory and autoimmune conditions due to their potent anti-inflammatory and immunosuppressive effects. However, the use of these medications has been associated with various psychiatric side effects, including psychosis, mania, and depression (Warrington & Bostwick, 2006).
High levels of glucocorticoids can result in dysregulation of the HPA axis, leading to mood and cognitive disturbances —Sapolsky, 2000.
The relationship between glucocorticoids and neuropsychiatric symptoms is …. you guessed it… complex and multifaceted. Several mechanisms have been proposed to explain how glucocorticoids contribute to the developing of these symptoms. One possibility is their effects on the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response. Glucocorticoids, such as cortisol, are released in response to stress, and prolonged exposure to high levels of glucocorticoids can result in dysregulation of the HPA axis, leading to mood and cognitive disturbances (Sapolsky, 2000). Moreover, glucocorticoids have been shown to modulate the expression of genes involved in neurotransmitter signaling and synaptic plasticity, further contributing to the development of neuropsychiatric symptoms (Datson et al., 2001).
Regarding the effects of glucocorticoids on mitochondria and mitochondrial energetics, several lines of evidence suggest that these hormones can have both direct and indirect impacts. For example, glucocorticoids have been shown to affect mitochondrial function by altering mitochondrial morphology, biogenesis, and dynamics (Du et al., 2009). Additionally, glucocorticoids can increase the production of reactive oxygen species (ROS), leading to oxidative stress and subsequent mitochondrial damage (Filiou et al., 2011). In turn, mitochondrial dysfunction and oxidative stress may contribute to the developing of neuropsychiatric symptoms through their effects on neuronal function and survival (Manji et al., 2012).
Glucocorticoid receptors have been found in mitochondria, suggesting that they may have a direct role in modulating mitochondrial activity —Psarra & Sekeris, 2011.
On a molecular level, glucocorticoids can influence mitochondrial function through their interactions with glucocorticoid receptors (GRs). GRs are nuclear receptors that, upon binding to glucocorticoids, translocate to the nucleus, where they regulate the transcription of target genes, including those involved in mitochondrial function and biogenesis (Picard et al., 2014). Additionally, GRs have been found in mitochondria, suggesting that they may play a direct role in modulating mitochondrial activity —in-situ— within the mitochondria themselves (Psarra & Sekeris, 2011).
Epigenetic mechanisms may also contribute to the effects of glucocorticoids on mitochondria and neuropsychiatric symptoms. Glucocorticoids have been shown to induce epigenetic changes, such as DNA methylation and histone modifications, which can alter the expression of genes involved in mitochondrial function and oxidative stress response (Hunter et al., 2012). These epigenetic changes may persist even after glucocorticoid exposure has ceased, leading to long-lasting effects on mitochondrial function and potentially contributing to the development of neuropsychiatric disorders (Hunter et al., 2012).
Both endogenous and synthetic glucocorticoids have been associated with developing neuropsychiatric symptoms, including psychosis, mania, and depression. These effects may be mediated through the impact of glucocorticoids on the HPA axis, neurotransmitter signaling, and synaptic plasticity. Moreover, glucocorticoids can, directly and indirectly, affect mitochondrial function and energetics, potentially contributing to neuronal dysfunction and neuropsychiatric symptoms.
Understanding the complex interplay between glucocorticoids, mitochondria, and neuropsychiatric symptoms may lead to identifying novel therapeutic targets and strategies for treating these disorders. For instance, interventions aimed at preserving mitochondrial function, reducing oxidative stress, or modulating the epigenetic effects of glucocorticoids could potentially ameliorate the psychiatric side effects associated with glucocorticoid therapy. Additionally, a better understanding of the molecular and cellular mechanisms underlying glucocorticoid-induced neuropsychiatric symptoms may help identify subpopulations of patients at increased risk for these side effects, allowing for more personalized and targeted treatment approaches.
Glucocorticoids & Steroids
—Effects on Gut Microbiome, Digestion, & Metabolism in the Context of Neuropsychiatric Disorders
As we have already discussed, glucocorticoids, are a class of steroid hormones, that have been widely used in treating various inflammatory and autoimmune conditions. While they provide significant therapeutic benefits, aside from those details provided previously, glucocorticoids can also have undesirable secondary and terciary side effects, some of which are related to their impact on the gut microbiome, digestion, and metabolism. In recent years, there has been growing interest in understanding how these effects on the gastrointestinal system may influence neuropsychiatric disorders through the gut-brain axis.
The gut microbiome, comprising trillions of microorganisms, is critical in maintaining human health. It aids digestion, metabolism, and the production of essential vitamins and neurotransmitters, among other functions (Cryan & Dinan, 2012). Glucocorticoids, however, have been shown to alter the composition and diversity of the gut microbiota. For instance, studies in mice have demonstrated that exposure to glucocorticoids reduces the abundance of certain beneficial bacteria, such as Lactobacillus and Bifidobacterium, while promoting the growth of potentially pathogenic species like Clostridium (Zhang et al., 2019). This dysbiosis can disrupt the normal functioning of the gut microbiome, potentially leading to adverse effects on digestion and metabolism.
Gut-Brain Axis: The production of neurotransmitters by gut bacteria, activation of the vagus nerve, and modulation of the immune system, have been proposed to underlie this complex interaction —Cryan & Dinan, 2012.
The gut-brain axis, a bidirectional communication system linking the gastrointestinal tract and the central nervous system, is thought to play a crucial role in mediating the effects of gut microbiota on brain function and behavior (Carabotti et al., 2015). Various mechanisms, including the production of neurotransmitters by gut bacteria, activation of the vagus nerve, and modulation of the immune system, have been proposed to underlie this complex interaction (Cryan & Dinan, 2012).
In the context of glucocorticoid-induced alterations to the gut microbiome, it is plausible that these changes may influence neuropsychiatric symptoms through the gut-brain axis. For example, a study in mice found that administering the glucocorticoid dexamethasone resulted in increased anxiety-like behavior, which was accompanied by alterations in the gut microbiota composition (Zhang et al., 2019). Another study showed that germ-free mice, which lack a gut microbiome, displayed altered behavioral and neuroendocrine responses to stress, highlighting the importance of gut bacteria in regulating the stress response (Sudo et al., 2004).
Furthermore, glucocorticoids can directly influence the gastrointestinal system by altering the permeability of the intestinal barrier, leading to increased translocation of bacterial components into the bloodstream (Ding et al., 2017).
This "leaky gut" phenomenon can trigger systemic inflammation, which has been implicated in the pathophysiology of various neuropsychiatric disorders, such as depression and anxiety (Kelly et al., 2015).
Glucocorticoids can exert
beneficial and
detrimental effects
on the gut microbiome, digestion, and metabolism, which may, in turn,
influence neuropsychiatric disorders and
behavior
through the gut-brain axis.
In light of the aforementioned studies, it is clear that glucocorticoids can profoundly impact the gut microbiome, leading to alterations in the gut-brain axis that may influence neuropsychiatric symptoms. As such, it is essential for clinicians to consider the potential consequences of glucocorticoid treatment on the gastrointestinal system and to monitor patients closely for any signs of neuropsychiatric symptoms.
One approach to mitigating the adverse effects of glucocorticoids on the gut microbiome could involve using probiotics or prebiotics to restore microbial balance and promote a healthy gut environment (Savignac et al., 2014).
Moreover, lifestyle interventions
Drink! …
Jacks! …
such as regular exercise and a balanced diet may help to maintain gut health and support overall well-being in patients receiving glucocorticoid treatment (Monda et al., 2017).
Understanding the complex interplay between glucocorticoids, the gut microbiome, and neuropsychiatric disorders is crucial for developing more targeted and effective treatment strategies and mitigating treatment complications
(I.e. Lupus patient with certain areas of the brain affected - causing mania and psychosis during a flare-up and needs steroids
or
The dementia patient with c.diff and encephalopathy with an agitated delirium).
By taking into account the impact of glucocorticoids on the gut-brain axis, healthcare providers can better manage the risks associated with these medications and improve patient outcomes in the context of neuropsychiatric illnesses.
The multifaceted relationship between glucocorticoids, the gut microbiome, and neuropsychiatric disorders offers a rich area for further exploration. As research in this field expands, we can expect to gain deeper insights into how glucocorticoids impact the gut-brain axis and contribute to developing or exacerbating neuropsychiatric symptoms. This knowledge will be invaluable in guiding the development of novel therapeutic strategies and personalized approaches to managing the side effects of glucocorticoid treatment in patients with neuropsychiatric illnesses.
Understanding the full scope of glucocorticoids' impact on the gut microbiome, digestion, metabolism, and the gut-brain axis will also help inform healthcare providers on how best to monitor and support patients who are prescribed these medications.
By recognizing the potential risks associated with glucocorticoid treatment and implementing appropriate interventions, such as probiotics, prebiotics, exercise, and dietary modifications, clinicians can work to mitigate these risks and improve the overall well-being of their patients.
By staying informed and working collaboratively, we can significantly improve the lives of those affected by neuropsychiatric illnesses and their associated treatments.
Mitochondria & Mental Health —The Role of Supplements & Medications in Neuropsychiatric Treatment
Mitochondria, the cellular powerhouses responsible for energy production, have increasingly been implicated in the pathophysiology of various mental health and neuropsychiatric disorders. As researchers continue to uncover the complex relationships between mitochondrial dysfunction and neuropsychiatric conditions, there has been a growing interest in exploring the potential benefits of supplements and medications that target mitochondrial function. Although some of these compounds have shown promise as adjunct treatments, it is essential to recognize their limitations and avoid overreliance on them as a panacea for mental health disorders.
Alpha-Lipoic Acid
Alpha-lipoic acid (ALA) is a naturally occurring antioxidant that has been shown to improve mitochondrial function and protect against oxidative stress (Gorąca, Huk-Kolega, Piechota, & Kleniewska, 2011). Some studies suggest that ALA may have neuroprotective effects, making it a potential treatment for neuropsychiatric disorders like Alzheimer's disease and depression (Zhang, Miao, & Zhao, 2018). However, while ALA supplementation may be a helpful adjunct therapy, it is unlikely to be sufficient as a stand-alone treatment for neuropsychiatric conditions, given the multifactorial nature of these disorders.
N-Acetyl-Cysteine (NAC)
NAC is a precursor to the antioxidant glutathione, which is critical in maintaining mitochondrial function and combating oxidative stress (Deepmala et al., 2015). Several studies have found that NAC supplementation may help improve symptoms of neuropsychiatric disorders, including bipolar disorder, depression, and schizophrenia (Berk et al., 2013; Fernandes et al., 2016; Minarini et al., 2017). Despite these promising findings, NAC should not be viewed as a stand-alone treatment for neuropsychiatric conditions but as a potential adjunct therapy for other evidence-based treatments.
Coenzyme Q10 (CoQ10)
CoQ10 is an essential component of the mitochondrial electron transport chain and plays a crucial role in cellular energy production (Garrido-Maraver et al., 2014). Some studies have found that CoQ10 supplementation may improve cognitive function and reduce symptoms of depression in patients with neurodegenerative disorders, such as Parkinson's disease and Huntington's disease (Shults et al., 2002; Huntington Study Group, 2001). However, more research is needed to establish the efficacy of CoQ10 as a treatment for neuropsychiatric conditions, and it should not be considered a cure-all for these complex disorders.
Other Supplements and Medications
Several other supplements and medications have been proposed as potential treatments for neuropsychiatric disorders due to their effects on mitochondrial function. These include antioxidants, such as vitamins C and E (Maes et al., 2014), B vitamins (Kennedy, 2016), creatine (Roitman et al., 2007), and omega-3 fatty acids (Bos et al., 2016). Additionally, some anti-inflammatory medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and certain antidepressants, have positively affected mitochondrial function (Rosenblat et al., 2014; Su et al., 2015). However, the efficacy of these supplements and medications as treatments for neuropsychiatric conditions varies widely, and they should not be viewed as a panacea.
While supplements and medications that target mitochondrial function may show promise as adjunct treatments for mental health and neuropsychiatric disorders, it is essential to recognize their limitations and avoid overreliance on them as a panacea. The multifactorial nature of neuropsychiatric disorders necessitates a comprehensive treatment approach that addresses the complex interplay of genetic, environmental, and lifestyle factors that contribute to the development and progression of these conditions.
Healthcare professionals and patients must maintain a balanced perspective on the role of supplements and medications targeting mitochondrial function in neuropsychiatric treatment. While these compounds may offer some benefits as adjunct therapies, they should be used with other evidence-based treatments, such as psychotherapy, pharmacotherapy, and lifestyle interventions. Furthermore, it is essential to recognize that each individual's response to treatment may vary, and personalized treatment plans should be developed based on each patient's unique needs and circumstances.
Future research should continue exploring medications' and supplements' potential benefits and limitations, targeting mitochondrial function in treating neuropsychiatric disorders. Large-scale, well-designed clinical trials continue to be needed to establish the efficacy and safety of these compounds and determine the optimal dosages and duration of treatment. Moreover, research should also focus on identifying biomarkers of mitochondrial dysfunction that may help guide treatment selection and monitor treatment response in patients with mental health and neuropsychiatric disorders.
Supplements and medications targeting mitochondrial function may have a role to play in the adjunct treatment of mental health and neuropsychiatric disorders. Yet, it is essential to maintain a balanced perspective on their potential benefits and limitations. A comprehensive, evidence-based approach to treatment that addresses the complex interplay of factors contributing to these conditions is critical for promoting optimal mental health and well-being.
“The truly fraudulent claims must be discarded. But novel methods of therapy should not be rejected because they are novel, or because they run counter to some generally accepted belief ("which may just be biased"), or because we do not understand the mechanism of the proposed treatment, or because it has come from an unconventional source.”
—Linus Puling (two-time Nobel Prize-winning chemist)
Mitochondria & Psychedelics
Research on the effects of psilocybin, the active compound in psychedelic mushrooms, on mitochondrial function is limited, and more studies are needed to understand its impact fully. However, some preliminary studies suggest that psilocybin may positively and negatively affect mitochondrial function.
One study found that psilocybin may protect mitochondria in brain cells, potentially reducing oxidative stress and preserving mitochondrial function (Ferrante et al., 2019). Another study suggested that psilocybin may increase brain tissue's mitochondrial respiration and ATP production (Soto-Montenegro et al., 2017).
On the other hand, another study reported that psilocybin may decrease mitochondrial function in liver cells, potentially contributing to liver damage (Carhart-Harris et al., 2018). It is important to note that this study used a much higher dose of psilocybin than is typically used in clinical settings.
Overall, more research is needed to fully understand the effects of psilocybin on mitochondrial function and its implications for neuropsychiatric disorders. However, studies have suggested that psilocybin may have therapeutic potential for depression, anxiety, and PTSD by altering brain function and promoting neuroplasticity (Carhart-Harris & Nutt, 2017; Garcia-Romeu et al., 2014).
Ketamine, a dissociative anesthetic, has been found to have positive and negative effects on mitochondrial function, depending on the dosage and duration of administration.
Some studies have suggested that low doses of ketamine may have a protective effect on mitochondrial function by improving mitochondrial respiration and reducing oxidative stress in brain tissue (Gabra et al., 2020; Zorumski et al., 2016). This may be beneficial in treating neuropsychiatric disorders such as depression and anxiety, as mitochondrial dysfunction has been implicated in the pathogenesis of these disorders.
However, high doses of ketamine have been shown to negatively affect mitochondrial function, leading to impaired mitochondrial respiration and increased oxidative stress (Andresen et al., 2019; Zhou et al., 2018). This may harm brain tissue and contribute to the development of neuropsychiatric disorders.
Despite these mixed effects on mitochondrial function, ketamine has shown promise as a potential treatment for depression, anxiety, and PTSD. It is thought to work by modulating the glutamate system in the brain, leading to increased neuroplasticity and improved mood (Kavalali & Monteggia, 2015).
Mitochondria, Mental Health, & Psychopharmacotherapy —An Intricate Balance
As previously mentioned (and then mentioned again, a few more times for good measure) — mitochondria are essential organelles involved in cellular energy production. Their dysfunction has been implicated in the pathophysiology of various neuropsychiatric disorders (Morris & Berk, 2015). Medications that treat these disorders can positively and negatively affect mitochondrial function, warranting a deeper understanding of their impact. Here, we will discuss the direct and indirect effects of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and other antidepressant classes on mitochondrial energetics.
SSRIs and Mitochondrial Function
SSRIs, like fluoxetine and sertraline, are widely prescribed for depression and anxiety disorders. They exert their therapeutic effects by increasing synaptic serotonin levels and inhibiting reuptake (Stahl, 2013). Some studies have shown that fluoxetine can positively impact mitochondrial function. For example, it has been reported to improve mitochondrial respiratory chain complex activity and protect against oxidative stress in a rat model of depression (Rezin et al., 2009). However, other studies have suggested that fluoxetine might induce mitochondrial dysfunction, increasing reactive oxygen species (ROS) production and decreasing ATP synthesis (Renoir, 2013; Michael et al., 2018). Similarly, sertraline has been found to have a dual effect on mitochondria: it can reduce oxidative stress and improve mitochondrial function in some cases (Myung et al., 2012), but it can also impair mitochondrial respiration and increase ROS production in others (Czarny et al., 2017).
SNRIs and Mitochondrial Function
SNRIs, such as venlafaxine and duloxetine, inhibit serotonin and norepinephrine reuptake, offering a broader spectrum of therapeutic effects than SSRIs (Stahl, 2013). Venlafaxine has been shown to protect against mitochondrial dysfunction by enhancing mitochondrial biogenesis, increasing ATP production, and reducing oxidative stress (Yau et al., 2018). However, it can also impair mitochondrial function by inhibiting complex I of the mitochondrial respiratory chain (Holper et al., 2018). Duloxetine has been reported to have neuroprotective effects against mitochondrial dysfunction by decreasing oxidative stress and increasing mitochondrial membrane potential (Sarandol et al., 2007). Nevertheless, like other antidepressants, it can also have detrimental effects on mitochondrial respiration and oxidative phosphorylation (Holper et al., 2018).
Other Antidepressants and Mitochondrial Function
Bupropion is an atypical antidepressant that inhibits the reuptake of dopamine and norepinephrine. It has been shown to increase mitochondrial biogenesis and improve mitochondrial function in animal models of depression (Chung et al., 2015).
Buspirone, a partial agonist of serotonin 1A receptors, has been reported to protect against mitochondrial dysfunction by increasing mitochondrial respiration and reducing oxidative stress (Zafir et al., 2009).
Tricyclic and tetracyclic antidepressants (TCAs), such as amitriptyline and maprotiline, inhibit serotonin and norepinephrine reuptake and have been used to treat depression for decades. Their effects on mitochondrial function are complex and varied. Some studies have shown that TCAs can improve mitochondrial function by increasing ATP production and reducing oxidative stress (Wang et al., 2011). However, others have reported that TCAs can impair mitochondrial function by inhibiting respiratory chain complexes and inducing mitochondrial permeability transition (Kornhuber et al., 1999; Bano et al., 2007).
Monoamine oxidase inhibitors (MAOIs), such as phenelzine and tranylcypromine, are another class of antidepressants that inhibit the enzymes responsible for the breakdown of monoamine neurotransmitters, including serotonin, norepinephrine, and dopamine (Stahl, 2013). MAOIs have been found to protect against mitochondrial dysfunction by increasing mitochondrial biogenesis, improving mitochondrial respiration, and reducing oxidative stress (Bortolato et al., 2008). However, they can also negatively affect mitochondrial function, such as inhibiting mitochondrial respiratory chain complexes and the induction of oxidative stress (Kornhuber et al., 1999).
The relationship between widely used antidepressant medications and mitochondrial function is complex and multifaceted. These medications can exert beneficial and detrimental effects on mitochondrial energetics, with implications for their therapeutic efficacy and side effects. Understanding the intricate balance between these medications' positive and negative impacts on mitochondrial function is crucial for developing more effective, safer treatments for neuropsychiatric disorders. We could work out practical ways of measuring the effects of these drugs at the mitochondrial level. Could we find a dose-response relationship? Perhaps microbiome and epigenetic differences modulate these effects.
OK, So how do we approach a patient now, with our new-found broadened paradigm?
A More Comprehensive Paradigm
A comprehensive neuropsychiatric, metabolic, and physical examination is essential in diagnosing and managing neuropsychiatric disorders. The process begins with a detailed medical history. This includes the patient's primary medical history (to include any specific psychiatric history), history of any blows to the head which caused loss of consciousness, any significant or severe motor vehicle accidents, any history of seizures (febrile/when pregnant or otherwise), history of surgeries and or hospitalizations; if female, a full menstrual and gestational history, to include complications like hyperemesis or gestational diabetes or preeclampsia -any abortions or miscarriages?- if so, did they ever investigate why the miscarriages happened?, the age of menarche (was this about right for females in that family or was it early or late?), family history, social history, and full medication history.
A physical examination follows, which entails assessing the patient's general appearance, vital signs, head and neck, chest and lungs, cardiovascular system, abdomen, musculoskeletal system, skin, and neurological status (Bates, 2017). This can be deferred to your primary care colleague, but ideally, you have a good working collaborative relationship and can direct specific portions of the exam you would like them to make more emphasis on.
A comprehensive evaluation of cognitive, behavioral, and emotional functioning is performed in the neuropsychiatric examination. This includes assessing the patient's attention and concentration, memory, language, perception, executive functioning, mood, and thought content. In addition, a mental status examination can be performed to assess the patient's overall mental functioning, including the level of consciousness, orientation, mood, and behavior. Psychological batteries can be used to test for specific disorders such as depression, anxiety, and bipolar disorder (Bates, 2017).
Metabolic testing should also be a part of the examination, as mitochondrial dysfunction is linked to many neuropsychiatric disorders. Laboratory testing may include:
A complete blood count (CBC),
Comprehensive metabolic panel (CMP) - specifically, a chem-14,
Urinalysis with reflex culture and sensitivity
Non-Forensic Drug test
Urinary Qualitative HCG-Pregnancy test
Thyroid function tests (including but not limited to TSH, FreeT3, FreeT4 —but may sometimes include a Reverse T3 in certain feeding-disordered patients).
Lipid panel,
Hemoglobin A1C
B12-MethylMalonic Acid Levels
Folate-Homocysteine Levels
Vit D Panel
and other specialty tests depending on the patient's presenting symptoms.
Additionally, genetic testing can be performed to identify mutations associated with mitochondrial disorders, such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) or Leber's hereditary optic neuropathy (LHON) (LabCorp, 2021).
Physical examination should assess the patient's general appearance, height, weight, and body mass index (BMI), as well as the presence of any physical abnormalities or neurological deficits. The examination should also assess the patient's cardiovascular, respiratory, musculoskeletal, and gastrointestinal systems.
Overall, a comprehensive neuropsychiatric, metabolic, and physical examination should be performed to establish:
an accurate diagnosis,
a baseline level of functioning and symptomatology (scales etc) before the initiation of treatment, and
a treatment plan to include prognosis, treatment length expectations, discussion of risks/benefits/alternative/complimentary-adjunct treatment, and expectations of drug holidays/possibilities for considerations of taper.
By considering the patient's physical and psychological health, healthcare providers can provide a more holistic approach to treatment and improve the patient's overall health outcomes.
Mitochondrial dysfunction plays a significant role in the pathogenesis of neuropsychiatric and metabolic disorders. As such, a comprehensive treatment plan that addresses mitochondrial function can help to improve patient outcomes. Incorporating lifestyle changes such as regular exercise and a healthy diet, along with targeted supplements such as coenzyme Q10, alpha-lipoic acid, and N-acetyl-cysteine, can improve mitochondrial function and lead to clinical improvement in symptoms.
Prescription medications such as anti-inflammatories, psychotropics, and steroids are also commonly used to manage neuropsychiatric and metabolic disorders. However, it is important to note that these medications can also positively and negatively affect mitochondrial function. For example, while anti-inflammatory medications such as aspirin and ibuprofen can positively impact mitochondrial function, prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) can lead to mitochondrial damage and dysfunction.
Prescription psychotropics, including antidepressants and antipsychotics, can also complexly affect mitochondrial function. Serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline have increased mitochondrial biogenesis and improved energy production. Still, their long-term use has also been associated with mitochondrial damage. Similarly, tricyclic and tetracyclic antidepressants can impair mitochondrial function, while monoamine oxidase inhibitors (MAOIs) have been shown to improve mitochondrial function.
In addition to prescription medications, supplements, and exercise have all been shown to positively impact mitochondrial function. Regular aerobic exercise has been shown to increase mitochondrial biogenesis and improve mitochondrial function in the brain, potentially contributing to the antidepressant and anxiolytic effects of exercise.
When developing a treatment plan that addresses mitochondrial dysfunction, it is important to consider a patient's individual needs, access to care and resources and of course, medical history.
In addition to the medications and supplements discussed above, lifestyle changes such as regular exercise and a healthy diet can also improve mitochondrial function and improve patient outcomes. It is also important to monitor patients for potential side effects of medications and supplements that may impact mitochondrial function.
Mitochondrial dysfunction plays a significant role in the pathogenesis of neuropsychiatric and metabolic disorders, and addressing mitochondrial function can improve patient outcomes. Incorporating targeted supplements, prescription medications, exercise, and lifestyle changes into a comprehensive treatment plan can help improve mitochondrial function and improve patient outcomes. As with any medical treatment, it is important to consider the individual needs of each patient and monitor for potential side effects.
A comprehensive treatment plan that addresses the role and benefits of mitochondrial energetics and the various factors contributing to neuropsychiatric disorders is crucial for successful patient outcomes.
The following is an example of a step-by-step plan that takes into consideration the factors discussed above:
Comprehensive physical and psychological examination: A thorough physical examination should rule out any underlying overt medical, micronutrient (magnesium, phosphorus, potassium etc.), or hormonal abnormality (thyroid, testosterone, prolactin, estrogen, etc.) that needs correcting or supplementing (Vit B1/B3/B6/B12/folate, Vit D, etc.) and may contribute to the patient's symptoms or lack of response or decreased resilience. A complete psychological evaluation, including cognitive testing, should also be conducted to identify any underlying mental health disorders (Scales: quality of life, anxiety, depression, attention, etc. — should be a minimum in this regard).
Diagnostic testing: Laboratory tests should be conducted to assess metabolic and hormonal baseline as stated above, and a more direct examination of mitochondrial function, including mitochondrial DNA sequencing, electron transport chain analysis, and lactic acid levels if indicated and available. Genetic testing may also be conducted to identify any potential genetic factors contributing to mitochondrial dysfunction.
Anti-inflammatory treatment: Anti-inflammatory medications should be judiciously incorporated into the treatment plan in a directed and methodical way, such as nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and other anti-inflammatory supplements. This is because chronic inflammation can lead to mitochondrial dysfunction, contributing to neuropsychiatric disorders.
Prescription psychotropics: Prescription psychotropic medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), among others, may be prescribed to address underlying mental health conditions. However, the potential negative effects of these medications on mitochondrial function should also be considered, and therefore careful, low, slow initiation of treatment with close and frequent follow-up to gauge compliance and effects/side-effects (“Start Low, Go Slow…But Dont Stop Until the Patient Gets Enough” — approach, should be used at all times).
Antipsychotics: Antipsychotic medications may be prescribed for patients with psychotic symptoms. However, the potential negative effects of these medications on mitochondrial function, including weight gain and insulin resistance, should also be considered carefully.
Exercise: A prescription for physical therapy and a specific workout routine designed specifically with a sound scientific basis in maximizing mitochondrial health. Regular exercise should be incorporated into the treatment plan, as exercise has improved mitochondrial function and reduced inflammation. The type and intensity of exercise should be tailored to the individual patient's needs and physical abilities.
Specific foods and supplements: A food delivery and subscription service — with a food plan designed specifically with a sound scientific basis in maximizing mitochondrial health. Certain specific foods and supplements can help improve mitochondrial function, including omega-3 fatty acids, coenzyme Q10, alpha-lipoic acid, and N-acetylcysteine (NAC).
Nutritious macro and micro-nutrient supplements: Nutritious macro and micro-nutrient supplements should be prescribed as a complementary therapy to support mitochondrial function and overall health.
Psychotherapy: focused Cognitive Behavioral Therapy, has been demonstrated to be of significant benefit to most neuropsychiatric disorders (principally anxiety & mood disorders, but also studies demonstrating coping skills improvement and reduction of disease-related anxieties in mild cognitive impairment, Huntington’s, Parkinson’s, Multiple Sclerosis, among others).
Regular follow-up: Regular follow-up visits should be scheduled to monitor the patient's progress and adjust the treatment plan as necessary.
Inspecting the list of ten items detailed above, and truly scrutinizing them, it’s no wonder that
our patients get misdiagnosed,
do not get the full comprehensive evaluation or treatment they need,
frequently fall through the cracks,
are riddled with side effects and complications,
and get lost to follow-up,
at best, limping along half-ass better.
A comprehensive treatment plan that addresses the role and benefits of mitochondrial energetics and the various factors contributing to neuropsychiatric disorders is crucial for successful patient outcomes.
Incorporating prebiotics, probiotics, antiinflammatories, prescription psychotropics, exercise, certain specific foods/programmed dietary changes and supplements, other nutritious macro and micro-nutrient supplements, prescription steroid medication, NSAIDs, etc., can help improve mitochondrial function and increase the likelihood of remission of symptoms. Regular follow-up visits are essential to monitor the patient's progress and adjust the treatment plan as necessary.
TheMindAndBodyDoc-Physician/Neuroscientist — @mindandbodydoc
I provide compassionate care for children (5 years & older), adolescents, adults & families struggling with nutritional, drug, & neuropsychiatric problems.
Teaching is always a privilege, and I’ve been afforded such privilege to teach at various medical schools (MD & DO), residency programs (Psychiatry, Neurology, Family Practice, and Internal Medicine), and universities; I have participated in clinical and basic science research in the past, and am currently on staff at a few hospitals, but primarily care for patients via telemedicine.
I generally talk & write about things that catch my fancy in the news and from the recent medical literature.
These include, but are not limited to: #wellness, #neurosciences, #neuropsychiatry, #culturalpsychiatry, #ethnobotony, #mycology, #mycologicalmedicine, #digitalhealthcare, #healthcaremanagement, and #psychoneuroendocrineimmunology
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