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February 4 - April 8, 2025
The short burst of energy during a manic phase isn’t enough to correct the longstanding problems associated with mitochondrial dysfunction. It’s not enough energy or time to repair the cells. Instead, it’s enough to cause major problems, like psychotic symptoms, anxiety, and agitation.
mitochondrial dysfunction in people with PTSD, including autopsy studies showing abnormalities in mitochondrial gene expression, reductions in total mitochondria, increased levels of oxidative stress, and reduced levels of ATP.30
Almost all medical disorders can cause delirium. This includes things like infections, cancer, autoimmune disorders, heart attacks, and strokes. The more serious they are, the more likely they are to cause delirium. People admitted to intensive care units (ICUs) are much more likely to have delirium, with anywhere from 35 to 80 percent of critically ill patients being diagnosed with it, depending upon the study.
Medications can also do it. People starting new medications can have reactions that can cause delirium. Withdrawal from medications or substances,
The elderly are particularly vulnerable to delirium.
they all affect mitochondrial function.
Physicians will often give people psychiatric medications, such as benzodiazepines, to reduce their anxiety. In this early phase, they usually don’t diagnose delirium or a psychiatric disorder, even though they are prescribing a psychiatric medication. The anxiety is often seen as a normal, understandable reaction. However, if these anxiety symptoms are the start of delirium, the symptoms usually become more dramatic.
the brain simply isn’t working right under the stress of a heart attack. They will attribute any and all new psychiatric symptoms to the heart attack.
Although it was due to an infection in the bladder, the symptoms came from the brain. Why? Because the brain is the most sensitive organ to energy deprivation, or mitochondrial dysfunction. It is the weakest link. It almost always shows at least some subtle signs first.
At this point, the medical community doesn’t have a coherent theory, but the brain energy theory offers one.
George Engel, the developer of the biopsychosocial model, proposed that delirium is due to disturbed brain energy metabolism, or “cerebral metabolic insufficiency.”
We use medications to help with the symptoms, but really, we wait for the underlying medical condition to be fully treated. The symptoms of delirium usually go away once the medical condition resolves. It’s a temporary case of mitochondrial dysfunction.
some cardiologists will ignore mental symptoms in the context of a heart attack. To them, the problem is plain and clear—it’s a heart attack. Whether the person is anxious or not doesn’t really matter. Even if a person is hallucinating, they might think that doesn’t matter either. That is a problem for a consulting psychiatrist to deal with. It doesn’t pertain to the heart or the cardiologist’s job.
If the brain energy theory is correct, people with delirium should have more widespread or severe mitochondrial dysfunction than people without delirium. The “mental” symptoms are giving us a warning sign. If this is true, more widespread and severe mitochondrial dysfunction should mean a whole host of things. It should mean that people with delirium will be more likely to develop a mental disorder, dementia, or a seizure. It should also mean they will be more likely to die. Are any of these things true? It turns out they all are.
delirium in older people results in an eightfold increased risk of subsequent dementia.
People with delirium are more likely to die early. During a hospital admission, people with delirium are twice as likely to die early as those without delirium.
Delirium tells us that there is mitochondrial dysfunction in the brain. Sometimes it can be reversible, and the person completely recovers. But not always.
Mitochondria in the cells can become damaged—a reduction in the workforce of the cells. This leaves cells more vulnerable to continued dysfunction. Some of the cells themselves can actually die and not get replaced. All of this results in a reduction in the reserve capacity of different brain regions. Any of these can lead to mental disorders, Alzheimer’s disease, or seizures.
After an ICU stay, patients with depression were 47 percent more likely to die than those without depression in the two years following discharge.
any mental symptoms, even if not formally diagnosed as delirium, are associated with higher rates of premature death.
mental symptoms are like the canary in the coal mine; they are sometimes the first indication of metabo...
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students are taught a mantra of the dying process—“seizures, coma, death.” This is the sequence of events that commonly occur as people are dying. What this leaves out is delirium, which is almost universal.
Mitochondrial dysfunction or dysregulation provides an explanation for an unlimited number of symptoms in different people.
One simple model would be to call all mental disorders delirium. Maybe we separate transient delirium and chronic delirium. The transient type resolves within two to three months, and the chronic type lasts longer.
we could, alternatively, call all mental disorders “metabolic brain dysfunction”
Mental disorders are metabolic disorders of the brain.
When mitochondria aren’t working properly, at least some of the cells in your body or brain won’t function properly.
contributing causes instead of risk factors.
Metabolism is the flow of traffic, and mitochondria are the drivers and workers inside the cars.
mitochondria are always involved in metabolism, but metabolic problems or challenges are not always due to mitochondrial “dysfunction.”
Others can be decisive and catastrophic assaults on mitochondria that result in severe mental symptoms immediately—such as mitochondrial poisons.
Caffeine stimulates mitochondria. But remember hyperexcitable cells? If they get too much energy, it can mean trouble—anxiety, psychosis, or seizures.
causes
the biological factors and end with psychological and social factors.
Experiences and exposures include the psychological and social experiences we’ve had, but they also include metabolic environmental exposures.
Metabolic failure of specific cells or brain networks is what causes mental symptoms,so these areas of vulnerability influence which symptoms develop first. In essence, our metabolism is only as strong as its weakest link.
Cells and the mitochondria within them are affected by many inputs, ones that impact different parts of the body and brain at different times.
Metabolism is the same. A problem in one area of the body will often spread over time. Why? Because metabolism is highly interconnected. It relies on feedback loops all over the body.
Treatments that remove or reduce things that are dysregulating mitochondria or metabolism, such as poor diet, sleep disturbances, alcohol or drug use, some medications, or psychological/social stressors.
Treatments that correct for metabolic imbalances,
Treatments that improve metabolism.
Since the HGP was completed, researchers have discovered about 1,800 genes responsible for various diseases and developed about two thousand genetic tests that can measure an individual’s genetic risk for certain diseases. Some patients can be tested to see if they will metabolize medications too slowly or fast. The effort has paid off in many ways. But sadly, not in psychiatry.
After these exhaustive searches, researchers identified a plethora of genes that might be related to psychiatric disorders, but they found almost no genes that confer significant risk to a significant portion of the people with the disorders. Some very rare genes were identified that can confer high levels of risk, but for most people with mental disorders, specific genes don’t confer large amounts of risk. On top of that, the vast majority of genes that have been found are not specific to individual disorders. Instead, they confer risk for many different psychiatric, metabolic, and
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The disappointment of not finding genetic answers to these inheritable disorders isn’t limited to psychiatry. It also applies to the metabolic disorders of obesity, diabetes, and cardiovascular disease. These, too, run in families—often the same families that have mental illness. These conditions, too, have eluded easy answers in human DNA.
a gene called DISC1 confers risk for schizophrenia, bipolar disorder, depression, and autism. Researchers continue to look at all the roles this protein plays in cell function, but it has been found within mitochondria and is known to influence mitochondrial movement, fusion, and contact with other parts of the cell. This, in turn, affects neuron development and plasticity.
This gene codes for a protein, Apolipoprotein E, that is related to fat and cholesterol transportation and metabolism. The gene comes in three forms: APOE2, APOE3, and APOE4. About 25 percent of people carry one copy of APOE4, and 2 to 3 percent have two copies. Those with one copy are three to four times more likely to develop Alzheimer’s,
People in their twenties who have the APOE4 gene are more likely to already show signs of impaired glucose metabolism in their brains, and this impairment worsens over time.6 Apolipoprotein E appears to have direct effects on mitochondria.
APOE4 impairs autophagy, mitochondrial function, and mitophagy.
APOE4 increase risk for all of the metabolic and mental disorders? It does increase the risk for cardiovascular disease, some other mental disorders, and epilepsy, but paradoxically, it appears to decrease the risk for obesity and type 2 diabetes.
Mitochondrial genetics are also complicated because mitochondria are influenced by genes in both the nucleus and within mitochondria themselves. The genes within mitochondria are much more susceptible to mutations. Genetic mutations in mitochondria have been directly linked to numerous aspects of brain function, including behavior, cognition, food intake, and the stress response.
