Akathisia II – Deep Dive

brightside

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FOR EASIER READABILITY, DOWNLOAD THE ATTACHED PDF. IT HAS IDENTICAL INFORMATION AS THIS POST, BUT FORMATTED NICELY. IT IS ALSO SLIGHTLY COLORCODED:​

BOLD TEXT = IMPORTANT​

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This is post 2 of 3. Post 1 is Akathisia I - My Story, and post 3 is Akathisia III - (my) Practical Application

Introduction​


Chronic Akathisia is a disorder caused by pharmaceutical drug use that is poorly understood and causes harm to the individual experiencing it. There are several theories on why akathisia occurs as a symptom of a drug, but there isn’t much information about chronic akathisia that occurs while “sober”. This means that people who have been harmed by a drug and experience chronic akathisia have almost nothing they can do but wait and hope that it goes away. There are somewhat effective treatments but taking more drugs might not be wisest next step. Besides, some people want to fix the issue with a holistic perspective and attack the root problem of the issue.
If the root cause of the symptoms is low dopamine, then steps can be taken to raise dopamine. Other possibilities might be explored, like beta blockers and benzodiazepines. These mainly deal with the body’s overcompensation to low dopamine, but don’t fix the root cause of the disorder and just target the symptom. Directly raising dopamine with drugs is almost never a good idea, unless used as a short-term pulse to relieve symptoms. The only option left then, is to figure out why there is low dopamine, and raise it by removing that pathology.
This post is then my attempt to identify reasons for lowered dopamine and to find a way to manage chronic akathisia by using mild treatments that help the entire body. However, it is also my belief that chronic akathisia is induced through epigenetic changes. There also seems to be a good deal of other symptoms that appear with akathisia, and fortunately, there seems to be a lot of things that can be done to manage their pathology. Epigenetic changes can be reversed, especially with time. In any case, it is my claim that chronic akathisia is caused by epigenetic
changes and decreases in activity of dopamine pathways and requires a failing metabolism, dysbiosis, and nutritional deficiency.

Context​


Proposed theory

To help understand the mechanisms of akathisia, it is worth exploring a potential explanation of the dysfunction. With the blockade of dopaminergic neurons, dopamine activity declines across the entire brain. One of these areas is the VTA[1], which sits next to the SN[2] and provides dopaminergic stimulation to many brain areas. The VTA mostly contains dopamine neurons (~50%), a GABAergic “brake” and some glutaminergic neurons.
Since the VTA supplies dopaminergic stimulation to other brain areas, a decrease of dopamine activity in the VTA results in a dramatic decrease of dopamine activity in the rest of the brain. Simply blocking dopamine receptors across the brain is bad enough, but the decline of dopamine activity is exaggerated when the VTA hypofunctional.
One of the areas that the VTA feeds into is the ventral striatum which contains the NA[3] and is associated with pleasure, motivation, reward, and learning. The NA consists of two distinct regions, the NA shell, and the NA core. The NA shell is responsible for motivating individuals to seek and act in a way that resolves their drive for something. This drive can be for something pleasureful, but that is not necessary.
Once dopamine declines, the LC[4] , another stimulatory brain region, makes up for the decrease of activity. The LC is an adrenergic cluster of neurons that is responsible for this compensation mechanism. The explanation for akathisia is that the LC stimulates only the NA shell and creates a disbalance between these two parts. When only the NA shell is stimulated it creates a seemingly purposeless behavior that seeks to improve the state of the individual, despite technically nothing being wrong or nothing being desired. This disbalance can also create dysphoria associated with akathisia [26]. Essentially, the brain goes into overdrive to look for a resolution for a problem that does not exist and makes the individual feel miserable until this is resolved.

The problems and my motivations

In general, antipsychotics are terrible drugs. Besides the negative effects of dopamine antagonism, and the other unintended effects (anticholinergic, antihistamine), they are also potent mitochondrial inhibitors [23]. The list of side effects is not short and includes involuntary movement disorders, gynecomastia and hyperprolactinemia, impotence, weight gain, sedation, blunted emotions and mood, metabolic syndrome, and akathisia.
Some are so toxic, that brain damage is an additional symptom [25]. The newer ones have less of this “side effect,” but they are more likely to destroy your body and mind through metabolic syndrome.
The current approach towards schizophrenia needs refinement. Hyperprolactinemia, metabolic syndrome, brain damage, akathisia, and suicide are non-negotiable outcomes when considering a drug’s success. Reduction of B1 required functions by metronidazole, and the B9 inhibiting properties of Bactrim are also complete failures as drugs and need adjustment to reduce side effects. The approach towards anxiety with benzodiazepines is reckless and unnecessary.
In general, most drugs are toxic, and many inhibit the mitochondria [22], which has massive unintended downstream effects. Part of my motivation is from that realization. My problems were caused by pharmaceuticals, and pharmaceuticals were not going to get me out. The bioenergetic approach is superior, and heavily influences this post. I would also like to credit Dr. Ray Peat for introducing me to an alternative approach to health.
Lastly, even if the class and purpose of drugs might be different, I think that they cause damage in similar ways. I spent most of my time looking at neuroleptics, but benzodiazepines, and SSRIs are also known to cause akathisia. They may all work differently, but in my opinion, they all cause dopaminergic decline (as evidenced by the symptoms) by at least some of the mechanisms that are mentioned in this post.

Extrapyramidal Symptoms and Parkinson’s

Akathisia can be seen as a sibling symptom of Parkinson’s; however, there are differences that differentiate the two. For one, akathisia is accompanied by DA decline in the VTA, not necessarily the SN. Second, akathisia can present without Parkinson’s symptoms, despite the SN being more vulnerable to external factors and dopaminergic decline. Third, different brain pathways and receptor types populate and innervate the two brain areas, which sets them clearly apart. Lastly, this difference is evident by symptoms of various drugs which can cause akathisia but not Parkinson’s and vice versa.

Is low dopamine the cause of akathisia?​


The short answer is, pretty much yes. Dopamine receptor 2 blockade results in akathisia, usually when inhibition reaches around 80%. There are some minor exclusions, but “the cause” generally isn’t contentious. In the treatment of schizophrenia or nausea, D2 antagonism is the intended effect, and managing extrapyramidal symptoms. such as akathisia, by use of D2 agonists is counterproductive. Typical treatments include anti-serotonergics to block 5HT2A and indirectly boost dopamine, and anticholinergics which are recommended for use in Parkinson’s related cases.
None of these solutions are good long-term solutions or are effective at improving the cause for low dopamine. Since this post is focusing on drug induced, chronic akathisia, removing the drug has already been done and the seemingly obvious cause of low dopamine has been “fixed”. Logically, the cause of the low dopamine is then not the drug but some long-term effect or modification by the drug, a pre-existing condition triggered by the drug, or permanent damage.
There are many ways of boosting dopamine, some more effective, some more dangerous, but the goal seems clear: boosting dopamine. However, simply shoving a bunch of dopamine into the synapse isn’t a good solution, and the exact mechanism needs to be elucidated to come up with a reasonable solution. Is the low dopamine from a dysfunction in synthesis, or perhaps it’s from a problem packaging or releasing it? The dopamine receptors also play in this, as do the proteins which breakdown dopamine. Proteins which take up dopamine back into the cell also have an effect. What if it is a dysfunction of the factors that regulate the dopaminergic pathways, such as the serotonin 5HT2A pathway, or the inhibitory GABAergic neurons that act as a brake on the VTA.
Since it has been established that low dopamine is the cause of akathisia, and that using pharmaceuticals is not recommended, this post looks in depth at the biological mechanisms that cause the decline of dopamine. Using some of these insights into the dopamine systems, an effective treatment strategy can be developed.
As a disclaimer, dopamine receptor 2 blockade and “low dopamine” are synonymous but not the same. There is massive overlap between these two states, but D2 blockade, or “low dopamine” do not fully explain akathisia. The balance of D2/D3 receptors, and the functioning of the glutaminergic and GABA-ergic inputs are important aspects that also need analysis. Other noteworthy contributors are the distribution of D2Lr and D2Sr subtypes and tonic, phasic signaling, not to mention hormonal, metabolic, and immunological contributors. Clearly, the issue is not as simple as “low dopamine” or “low D2r activation”. Regardless, reduced brain dopamine activity has a massive overlap with akathisia and the pathologies that frequently accompany it. For the sake of simplicity and coherency of my theory, that is mostly excluded.

What lowers dopamine?​


Energetic deficiency lowers dopamine

The mainstream view of energy production is binary, it either works, or it does not. I want to challenge that and think of energy production as a middleman connecting all these factors together, while also providing the energy for the cell to adapt to the problems. Brain disorders are ridiculously complex, and often it is hard to pinpoint a single problem that needs to be fixed, however, the production of energy often gets overlooked despite it being fundamental and ubiquitous. Energy feeds life, and it is foolish to ignore such a key factor.
The brain is responsible for a fifth of our body’s daily energy expenditure. Neurons are so expensive to upkeep that they require their own support cells [1]. Naturally, fluctuations in brain energy will have massive impacts on brain function. The body has ways to upkeep blood sugar to maintain adequate supply to the brain, but problems arise when that sugar is not burned efficiently and in sufficient quantities. This is the case with decreased level of thyroid hormone that stimulates the production of energy, but it can also occur with various inhibitors of the entire process of energy production.
It seems redundant to say that energy is needed for all parts of the cell to function, but unfortunately it is often overlooked. Massive amounts of energy are spent to maintain the correct gradient that allows signals to be sent, and another large chunk is used at the synapses. Plenty of energy is also spent in cleaning up various messes created by cell, especially in catecholic neurons.
To put things into perspective, a single cortical neuron can consume 5 billion ATP per second. These energy transferring molecules need to be synthesized and their levels need to be maintained. The requirements for this to happen are numerous, and the exact conditions are insanely specific. A slight impairment would have drastic consequences, as less essential processes would get dialed down. This altered activity is compounded when considering the brain and the billions of neurons that make it up. Since the brain is a complex organ built on many individual parts, is it not reasonable to think that general dysfunction of the individual parts will noticeably impact brain function?
One specific consequence of energy deficiency is the impairment of the antioxidant pathways [1]. This is self-evident but often not fully acknowledged. One of the first biochemical changes that occur in Parkinson’s disease is the depletion of GSH[5] levels [1]. Considering that a decreased metabolism will produce more ROS[6] than a fast and efficient one [6][7], a dysfunction of the antioxidant systems due to energetic deficiency compounds the problem. Energy falls, impairing antioxidant production, and at the same time oxidative stress increases, further stressing the already decreased antioxidant capacity.
Energy deficiency also results in a dysfunction of VMAT2 which leads to an increase of the oxidation of dopamine and oxidative stress [19]. This protein and its specific mechanisms are discussed in more detail in the later sections.
More importantly, a deficiency of energy typically occurs as a systemic problem which implies a partial dysfunction of most organ systems. Therefore, an energy deficiency will not only harm dopamine neurons through oxidative stress but will increase dysfunction of various bodily systems such as the gut and the liver. In turn, this will increase the two other main factors overgrowth and nutritional deficiency, which will further reduce the ability to produce dopamine.

Oxidative stress lowers dopamine

2.1 Oxidative stress signals the cell to downregulate dopamine while destroying important machinery.

Keeping oxidative stress low is crucial for good health. Oxidative stress is the bullet of the metabolic dysfunction gun that does all the damage. When a critical point of damage has been reached and mitochondrial components start leaking, apoptosis gets triggered, and the cell dies. Compared to other neurons, dopaminergic neurons are especially sensitive to oxidative stress [1]. On top of that, out the brain’s total 86,000,000,000 (86 billion) neurons [64], dopamine neurons in the SN and VTA make up only a tiny fraction, around 450,000 [63]. Not only are dopamine neurons sensitive, but there is a small amount of them, therefore preserving them is key. The management of oxidative stress is an important aspect of maintaining high dopamine activity by maintaining high activity and preventing cell death.
Oxidative stress’s effects are numerous, but the worst is damage to DNA and OXPHOS[7] machinery. Damage to mitochondrial DNA can result in decreased mitochondrial output, and eventual cell death. Downregulation of the ETC[8] is also observed with oxidative stress increases. NO[9] is partially responsible for this effect, but NO increases more with inflammation. Oxidative stress can also inhibit KGDH[10], a key enzyme in the Krebs cycle, which has been implicated in neurodegeneration [49] [50].
Besides NO, the formation of another harmful particle, peroxynitrite, can result in the inhibition of complex-I and complex-IV. Peroxynitrite also attacks the rest of the cell including various proteins, lipids, and thiols [38]. Peroxynitrite is one of the byproducts of increased dopamine in the cell, however it also disables TH[11] activity, reducing its own production [39].
Lastly, oxidative stress increases nutrient deficiency. Oxidative stress is a constant drain on the body’s antioxidant pathways and induces selenium and B vitamin deficiency [55]. General nutrients also get used up to repair all the damaged machinery.

2.2 Metabolic Responses to Oxidative Stress

Given the severe consequences of oxidative stress (death), dopaminergic neurons have many methods of monitoring oxidative stress levels and adjusting their activity. Naturally, catecholamines downregulate TH activity, however other proteins also exist to monitor oxidative stress and modify TH activity. Additionally, various functional proteins also affect TH activity. Some of these proteins include: 14-3-3, DJ-1, a-synuclein, VMAT2, AADC, and GTPCH.

2.2.1 BH4 and GTPCH​

Biopterin, or commonly known as BH4, is a co-factor in dopamine synthesis. It is synthesized by the enzyme GTPCH. Excess levels of BH4 downregulate TH activity, however this is balanced out through an interaction mechanism of TH with GTPCH. This is done by GTPCH blocking BH4’s ability to downregulate the activity of TH. The result is a boosted TH, and boosted GTPCH resulting in boosted BH4, which fuels the increased TH. Without the synergism between TH and GTPCH, increased BH4 would lower increased TH activity and the net dopamine production would be lower. This essentially creates a careful balance between TH, BH4, and GTPCH. In conditions of OS, BH4 will get used up and TH will be unable to create as much DA due to a decrease of the co-factor. In good conditions, TH and GTPCH both increase each other’s activity while keeping BH4 in ample conditions but preventing excess which would block TH [39].
BH4 is therefore needed in very specific amounts, and decreases of it are usually from cell dysfunction. It can act as an antioxidant and prevent cell death from iron buildup, and it can be used to create NO, both of which occur due to some dysfunction (inflammation, or nutrient deficiency). A decline of BH4 recycling from methyl and subsequent folate cycle stagnation would also result from metabolic dysfunction or deficiency. Therefore, dopamine synthesis roughly follows folate and methyl cycles. This connection is important because it can serve as a brake on dopamine synthesis, as a decrease of available SAMe[12] would result in an impeded ability to destroy released dopamine.

2.2.2 DJ-1​

DJ-1 is an interesting protein that manages dopaminergic cells. It boosts TH activity, stimulates mitochondrial function, rescues dopamine cells from death, stimulates VMAT2, and has some chaperone functions. If DJ-1 oxidizes from an increase of oxidative stress, its TH promoting activity will decline and so will its other functions [1] [60]. DJ-1 has been shown to be a big player in prevention of Parkinson’s; therefore, keeping oxidative stress is a good way to ensure optimal functioning of DJ-1 which supercharges the health of dopaminergic neurons.

2.2.3 Tyrosine Hydroxylase​

TH itself is sensitive to damage, and oxidative stress directly lowers TH. TH is especially sensitive to peroxynitrite. Additionally, TH is more stable in the inactive dephosphorylated state and is more likely to exist in that state during disruptions. Some proteins that downregulate TH, like AADC[13], decrease expression when their own activity increases. Therefore, an increase in L-dopa and its conversion through AADC would slow down the tyrosine conversion through TH. Bypassing TH and using L-dopa would downregulate TH expression.

2.2.4 Neuromelanin​

Dopamine neurons in the VTA and SN have an additional layer of protection, neuromelanin. Neuromelanin is composed of dopamine metabolites, iron, and other proteins and metals. Neuromelanin can absorb free radicals reducing oxidative stress. On top of that, it can also absorb dopamine itself, and release it later. In this sense, it serves as a backup system that can accept various molecules when there is an excess. However, it can get overwhelmed, and start release free radicals itself, usually from an excess of iron [59]. Interestingly, neuromelanin only starts developing 1-2 years after birth as a response to aging and the stress of existence [37]. Therefore, managing iron metabolism is important in neurological diseases, especially those involving dopamine neurons.
It is clear that dopaminergic neurons have many methods of maintaining balance and ensuring survival while allowing for optimal activity. These cannot be bypassed easily, and attempts will come with side effects.

2.3 Oxidative Stress Sources

Naturally, the question arises, where is the oxidative stress coming from and how can it be stopped?
The degradation of CA[14] by MAO[15] also produces oxidative stress by formation of hydrogen peroxide. This is normal, and a byproduct of regular function, however, it does increase the vulnerability of the cell to stressors and death.
An important contributor is dopamine itself. The reason for this is dopamine’s propensity to oxidize. To prevent this, dopamine is stored in special holding vessels called vesicles. These vesicles have a lower pH and are tightly regulated. Once it is time for release, this vesicle gets squeezed out into the synaptic cleft.
Dopamine and L-Dopa can undergo various reactions generating superoxide and become DA-quinone and DOPA-quinone respectively. These two quinones can later form other toxic metabolites, including salsolinol and 6-hydroxydopamine-quinone. Salsolinol is a neurotoxin and inhibits the ETC, TH, COMT, MAO, and DA-B-hydroxylase. The quinones also react with structural proteins and inhibit normal cell functioning. Eventually, DA-quinones react with glutathione by conjugation and decrease the total available antioxidant capacity of the cell, since glutathione is mostly recycled, not conjugated. Avoiding the oxidation of dopamine and subsequent formation of quinones is the first step to preventing dopamine induced damage. Therefore, maintaining high energy production is vital to ensure optimal VMAT2 function and reduced dopamine oxidation.
Regular metabolism produces a constant supply of ROS that needs to be dealt with. The body has numerous enzymes and proteins that manage these radicals and protect the cells. Inhibiting complexes in the ETC forces the electrons to leak everywhere, increasing oxidative stress. ROS can also originate from easily oxidizable molecules in the cells, especially iron containing proteins.
There are countless things that can inhibit the mitochondria and ETC and cause oxidative stress including many drugs and effort should be made to avoid them [22]. Other sources of mitochondrial disruptors and promoters of oxidative stress include fluoride [14], PUFA [27] [28], NO [2] [3] [4], pesticides [29] [31], heavy metals [30], air pollution [32], BPA [33], food additives [34] [35], plastics [36] and many more.
A deficiency of Vitamin E and C, and minerals that are required to synthesize antioxidant enzymes and proteins also results in an increase of oxidative stress. The increase is due to the decreased function of the antioxidant pathways, which can get overwhelmed even from normal metabolism. It is therefore vital to ensure nutrient sufficiency.

Bacterial overgrowth lowers dopamine.

3.1 Bacterial overgrowth exerts its effects mostly through inflammation.

It is no secret that bacterial growth in the wrong places can cause issues, however the general view of infection lacks nuance and ignores a variety of “infections” that are problematic. One commonly ignored issue is the overgrowth of bacteria, especially in the small intestine. When bacterial waste leaks into the blood, huge metabolic shifts occur to fight the supposed infection. This constant poisoning predisposes people to chronic and debilitating diseases and paves the way for common diseases that plague the western world. This destruction is mainly mediated through low grade, but chronic inflammation.
Inflammation is an important function of the body and is vital to survival. Inflammation’s purpose is to eliminate the initial cause of injury, remove dead cells and promote repair. Given that part of inflammatory response is to inflict damage, a dysregulated or chronic inflammatory state will hurt instead of helping. This is evident in cases of autoimmune disease, or diseases that are characterized by increased inflammation, like obesity or diabetes.
Endotoxin, or LPS[16], is the cell wall of gram-negative bacteria and is one of the inflammation provoking factors. Endotoxin can get absorbed into the bloodstream, where it causes a strong inflammatory response. It can get absorbed for various reasons like excess growth in the small intestine, compromised gut barrier function, decreased bile acids release, slow motility, and an energy deficient gut.
Short term exposure to small amounts of endotoxin is usually not an issue, as this can happen from a minor infection, but a chronic drip of even small amounts of endotoxin will cause persistent inflammation that will wreak havoc on the entire body. Since the liver typically deals with circulating endotoxin, inflammation of the liver is inevitable. Liver inflammation will result in energetic decline and eventual liver fattening. Endotoxin stimulates inflammatory cytokines which promote emergency defenses. Specifically, TNF-a[17] which lowers the production of energy, destroys mitochondrial components, and increases oxidative stress. Liver dysfunction will impact proper bile function and result in a vicious cycle of endotoxin absorption due to decreased antibacterial ability.

3.2 Inflammation lowers energy production through oxidative stress

The typical response to LPS is inflammation. There are numerous inflammatory markers that rise in response to increased LPS, but a notable one is TNF-a. Through TNF-a, the cells are stimulated to release NO, which is what does the damage. Acutely, NO is beneficial by dilating blood vessels, serving many signaling functions, as well as damaging the invading organisms. However, NO is toxic because it is a free radical and elevated NO is harmful. NO inhibits the ETC, specifically by competing with oxygen at complex-IV and blocking complex-I [2][3]. This creates a cycle, since oxidative stress itself can increase inflammation and stimulate the release of TNF-a and IL-6 [38]. Through these mechanisms, inflammation causes dopamine cell death and neurodegeneration [20][46][47].
Additionally, inflammation has been shown to alter the activity of enzymes in the mitochondria, reducing energy output. For example, TNF-a inhibiting PDH[18] [48], or LPS mediated inflammation blocking KGDH [49].

3.3 Inflammation lowers dopamine directly

Inflammation acts directly on dopaminergic pathways to reduce dopamine synthesis and packaging, and decreases the time spent by dopamine in the synaptic cleft. Some of the observed pathways include a decrease in BH4, a decrease in VMAT2 expression and function, a decrease in dopamine neuron stimulation through decreased glutamine transmission, increased DAT[19] expression and function, and inhibition of dopamine neurons by serotonin.

3.3.1 BH4​

During inflammation, BH4 is partially diverted to create NO. However, the enzyme catalyzing the reaction might be uncoupled and instead produce ROS instead of NO. Not only will this waste available BH4, but given that BH4 itself is sensitive to oxidation, the levels of BH4 will rapidly decline and not allow for adequate levels optimal DA synthesis [5].

3.3.2 VMAT2​

Since VMAT2 is responsible for putting synthesized DA into vesicles, a dysfunction of VMAT2 would not only reduce dopamine available to be released into the synaptic cleft, but also increase the oxidative stress due to oxidation of dopamine. Inflammation can also target VMAT2 in some cases, and IL-1 and TNF have been found to decrease the expression of VMAT2 in rat enterochromaffin-like cells [5]. On the other hand, anti-inflammatory compounds have been found to rescue VMAT2 function after inflammatory insults [57].

3.3.3 DAT​

LPS and IFN-a[20] activated MAPK[21] pathways have been shown to increase DAT activity. This means that dopamine spends less time at the synaptic cleft and has less overall ability to activate receptors. This results in a less overall dopamine activity [5].

3.3.4 IDO and Kynurenine​

Dopamine release can be decreased indirectly through the action of the enzyme indoleamine 2,3-dioxygenase (IDO). This enzyme catalyzes the catabolism of tryptophan into Kynurenine. This is useful in some infections and is a method of synthesizing NAD. In response to viral load, it removes available tryptophan by converting it into a non-usable metabolite which stagnates growth of the virus. However, the activity of this enzyme can be implicated in endotoxin poisoning and blocking this enzyme has been shown to decrease many inflammatory markers and increase anti-inflammatory interleukins [5].
Once in the brain, kynurenine can be metabolized by astrocytes and glia into secondary metabolites which can be toxic and lower dopamine. KY metabolized by astrocytes converts into Kynurenic acid which can antagonize glutaminergic receptors. This antagonism lowers input into DA neurons and reduces overall dopamine activity. When this happens in the striatum, dopamine activity declines [5].
KY metabolized by microglia forms quinolinic acid which is a known neurotoxin. This neurotoxin can increase oxidative stress through ROS generation. More importantly, QUIN activates NMDAr and causes excitotoxicity, potentially killing neurons. Protecting neurons from NMDA activation by memantine led to decreased neuronal cell death when infected with a virus that strongly stimulates IDO. Additionally, glia themselves release glutamate, and inflammatory cytokines increase this output. This glutamate may have preferential access to extra-synaptic NMDAr, and this leads to a decreased production of trophic factors, such as BDNF [5].

3.3.5 D2 Function​

Chronic inflammation has also been shown to reduce dopamine binding to D2 receptors. This resulted in anhedonia-like behavior in monkeys [57].

3.3.6 Inflammation stimulated Serotonin​

Another mechanism of dopamine suppression occurs through serotonin and the 5HT2A receptor. Serotonin can rise for a few reasons, like increased bacterial irritation, and rises in inflammation. The 5HT2A receptors are found in heavily dopaminergic areas and reduce dopamine activity when stimulated. Serotonin also works in tandem with inflammation to reduce energy and promote fatigue [17].
There are other functions of serotonin such as initiating the stress response, which play a big role in increasing inflammation, stress, and dysfunction. For more information on serotonin, the work of Dr. Ray Peat is a good starting point (raypeat.com).

3.4 Bacterial overgrowth promotes nutritional deficiency.


3.4.1 Villous atrophy and bacterial consumption of nutrients​

The idea that an overgrowth of bacteria in the small intestine leads to nutritional deficiency should be obvious, but it is still worth mentioning. Not only will bacteria “eat” the food that is meant for you, but they will also ferment or putrefy the food in the small intestine and create huge amounts of inflammation. This inflammation will destroy your ability to absorb foods by damaging villi, which will strengthen the vicious cycle of destruction.

3.4.2 Anemia of chronic disease/ inflammation induced iron deficiency​

Assuming nutritional requirements are met, inflammation can lower usable iron. When the body senses bacterial or viral infection and inflammation rises, iron and zinc get removed from the blood and get stored away to prevent the invading organism from accessing the resources. This response also happens when you receive a hit of endotoxin or inflammation from the gut despite there not being an active infection. This means that a bacterial overgrowth can force your body to be starved of iron despite an adequate dietary intake.
One of my first “ah-a” moments was when I read about this idea and my symptoms finally started making sense. This idea is called the “anemia of chronic disease” and results in anemia and other metabolic dysfunction.

Nutritional Deficiency lowers dopamine

4.1 Protein deficiency

Protein is ubiquitous in the human body. Naturally, many signaling molecules are also made of protein, including dopamine. Dopamine is synthesized from tyrosine; therefore, an adequate protein intake should be maintained. Supplementing L-Tyrosine is also a simple way to boost dopamine on top of a decent diet. The effect of L-Tyrosine is both proven and tested by many nootropics fanatics, including myself.
Protein deficiency can result in decreased dopamine through an indirect mechanism of decreased antioxidant support. Glycine is an amino acid and a potential rate-limiter of GSH even in a “normally fed” person. Given that the body synthesizes a few grams of glycine, it has been deemed non-essential and most diets don’t focus on its consumption. This could result in glycine insufficiency, which would prevent the full potential of GSH synthesis [40].

4.2 Iron deficiency

Iron is a highly useful and important metal. It is used in the enzyme tyrosine hydroxylase to synthesize dopamine. Additionally, iron has a role in the functioning of D2 receptors, and an iron deficiency leads to a reduction in the sensitivity of D2 [61]. Therefore, iron deficiency has a direct role in reducing dopamine activity.
Iron deficiency also lowers energy production which indirectly will also lower dopamine. Iron chelation from cells has devastating effects on energy production [24]. This is because iron is not only used in several enzymes in the Krebs cycle, but also used in a few of the complexes in the ETC. Iron deficiency leads to malfunctioning mitochondria [65] and a decreased energetic output. Eventually this degenerates into an accumulation of malfunctioning mitochondria and cell death.
In the context of drug induced akathisia, some neuroleptics chelate iron, specifically the phenothiazines. However, this excludes other akathisia inducing neuroleptics such as aripiprazole and haloperidol. Regardless, the chelation can increase oxidative stress, and induce iron deficiency, further increasing oxidative stress through the reduction of metabolism. It is not all black and white, however, as some iron chelating neuroleptics have been shown to increase brain iron. The neuroleptic prochlorperazine, when combined with an iron chelator, induced greater neurotoxicity than the iron chelator alone [61]. A possible explanation is the reduction of iron turnover, and clearance from the brain, leading to accumulation which implies a dual action of iron dysregulation, chelation, and reduction of clearance.
It has been found that PD patients also have increased iron in the brain. This iron is not stored in ferritin, and probably exists in a toxic form [61]. Slow clearance might be the cause here too, however, iron homeostasis involves many moving pieces, therefore it is hard to identify the exact reason.
In my opinion, the conclusion to draw here, is that iron is needed in specific amounts, and the focus should be on maintaining regulatory mechanisms after a decent dietary intake has been established. Both iron excess, and iron deficiency have devastating effects on the brain and the body as a whole [61][62], therefore the “goldi-locks” zone of iron status should be focused on.

4.3 Vitamin A & Copper

Virtually no free iron exists in the body and all the usable and unusable iron is bound to various handling and storage proteins. This means that iron deficiency can also occur from a mismanagement of the carrier proteins. One of these management proteins is ceruloplasmin, which takes iron from its storage form (fe2+) into a transport form (fe3+).

4.3.1. Ceruloplasmin​

Vitamin A and copper are both needed to synthesize ceruloplasmin, and an inadequate vitamin A and copper intake will result in iron deficiency despite adequate intake of iron. In ceruloplasmin deficiency, the iron absorbed from food will enter the body, get bound and increase blood levels for some time and then be used or stored away. By not maximizing iron availability, copper, and vitamin A deficiency lower dopamine activity.

4.3.2. Vitamin A​

Vitamin A has many biological functions which impact dopamine activity. Vitamin A boosts tyrosine hydroxylase activity by altering genetic expression of the enzyme [11]. It also increases the genetic expression of D2 receptors [8]. It increases energy production by acting as a modulator of OXPHOS, and a deficiency of Vitamin A causes oxidative stress and a reduced output of energy despite not actually directly being involved in the process [12].

4.3.3. Copper​

Besides being involved in ceruloplasmin synthesis, copper is also used in the enzyme superoxide dismutase, or commonly known as SOD. Specifically, SOD1 and SOD3 contain copper and convert more harmful superoxide into O2 and H2O2 which can be further converted into water. Lack of copper can increase oxidative stress due to the decreased antioxidant capabilities. Lastly, copper is a requirement for the synthesis and function of one of the ETC complexes, complex-IV or cytochrome C oxidase. Copper deficiency results in a decreased ability to utilize oxygen and leads to negative mitochondrial changes, along with a switch from OXPHOS to glycolysis [21].
Copper is also a requirement for Methionine Synthase, the primary enzyme that drives the methylation cycle. Without sufficient copper (also B12), demyelination can occur.
Clearly iron, vitamin A, and copper cannot be ignored when discussion dopamine and energy production, and metabolism. To summarize, iron is required in energy production and dopamine synthesis, while vitamin A serves as a regulator of energy production, increases the expression of tyrosine hydroxylase and dopamine receptors, and together with copper increases available iron, and reduces oxidative stress.

4.4 B Vitamins

Besides being required for energy production, cell replication, and many other uses, B vitamins are also needed to synthesize neurotransmitters including dopamine.

4.4.1 Vitamin B1​

This vitamin has proved to be a significant therapeutic tool for treatment of neurodegenerative diseases [44]. When used in very high doses, it works to stimulate the efficient production of energy which provides the energy needed to maintain normal brain functions. This restores brains of Parkinson’s patients and puts their symptoms into remission. This potent mechanism is highly dopaminergic and has been lifesaving. I am writing another post going into detail about my experience and everything revolving that, so I will refrain from writing much more about it.

4.4.2 Methylation and B2, B6, B9, B12​

Methylation is a cycle that moves around single carbon groups called methyl groups. This cycle is vital for many processes that require methyl groups and include the synthesis and breakdown of neurotransmitters such as dopamine and norepinephrine. This cycle utilizes b2, b6, b9, and b12. A deficiency of any B vitamin will either slow the cycle down or utilize backup pathways slowing down other processes that rely on the methylation cycle.

One of these other processes is the recycling of BH4. Since BH4 is a necessary cofactor for dopamine synthesis, dopamine levels decline with impaired methylation. Additionally, an excess of oxidative stress will oxidize BH4 and reduce the ability to synthesize dopamine and put pressure on the methylation and folate cycles.

4.4.3 Vitamin B6​

Vitamin B6 is a necessary cofactor in the enzyme AADC which converts L-Dopa into dopamine. A deficiency of B6 will cause a decline of dopamine levels [53]. Vitamin B6 is also a necessary part of the methylation cycle.
B6 is also required for sulfur processing enzymes which directly impacts GSH synthesis. This is probably why vitamin B6 has been shown to promote to health of the brain by reducing oxidative stress damage [51]. Additionally, the only current vitamin treatments for akathisia consist of iron and B vitamin supplementation, with a focus on B6. This could be a potential explanation, besides its role in AADC.

4.4.4 B5 & B7​

Vitamin B5 is required in the production of energy. It also is required to synthesize acetylcholine, which is needed for good gut function. Maintaining adequate levels is necessary for preventing overgrowth and energy deficiency.
Vitamin B7, or biotin, is also used in the production of energy. A deficiency of this vitamin disrupts proper sugar burning and blood glucose levels.

4.4.5 Vitamin B3​

Vitamin B3, or niacin is a B vitamin that serves many roles, most notably it is used to synthesize a vital molecule called NAD. NAD is used in many reactions, most commonly in the production of energy by accepting hydrogen and electrons and passing them where they are needed. The main location that NAD passes electrons is the ETC, however, reduced NAD is also useful in the antioxidant systems. NAD can help regenerate GSSG into GSH. With the loss of NAD, the ability to create energy, and the ability to neutralize threats declines, eventually leading to cell death [56].
Supplementing the NAD pool with B3 has the potential to signal dysfunctional mitochondria to resume normal function and prevent neuron death. This has big implications in Parkinson’s, but other diseases too [58].

4.5. Selenium, Vitamin C, Vitamin E

Maintaining adequate antioxidant support is vital for brain health. The synthesis of one of the most common and powerful antioxidants, glutathione (GSH), is dependent on selenium (and recycling on B2). Selenium has many important functions such as conversion of T4 to T3. At a more basic level, selenium potentiates dopamine activity in some brain areas [13]. It also protects against drug induced dopamine injury [45].
Interestingly, low GSH has been hypothesized to be part of the pathology of schizophrenia, and ironically, giving people neuroleptics induces massive amounts of oxidative stress, driving GSH lower. Selenium is a first-line treatment against oxidative stress along with the appropriate B vitamins.
Additionally, Vitamin C and Vitamin E are both antioxidant nutrients that need to be constantly replenished. While vitamin C is easy to replenish, Vitamin E is not. It is slower to replenish and more complicated (form). The typical western diet contains excessive amounts of PUFA and a puny amount of vitamin E, therefore special attention should be given to this vitamin. Interestingly, supplementing with Vitamin E has been beneficial in improving extrapyramidal symptoms (TD) in some studies [61].

4.6 Vitamin D, calcium, Vitamin K

I cannot discuss dopamine without mentioning calcium, vitamin D, and vitamin K. Vitamin D is a powerful compound that has countless effects on the human body. One of those effects is immune regulation, which results in lower levels of inflammation with sufficient levels [9]. Additionally, it helps reduce excessive oxidative stress. This of course improves dopamine activity, but Vitamin D has also been shown to increase TH and DA content of tissues treated with it [10].
Potentially inadequate levels of Vitamin D may result in schizophrenia. Vitamin D helps with the differentiation of dopamine neurons and a low vitamin D intake has been associated with a risk of schizophrenia. This is mainly relevant during the development of the brain; however adult brains need vitamin D just as much [10].
Proper handling of calcium is dependent of Vitamin K. Adequate K status is associated with better bones and healthier cardiovascular system. Vitamin K encourages bone cells to deposit calcium correctly, while also discouraging calcium deposition in blood vessels. Vitamin K needs to be in every conversation about Vit D, as it ensures proper calcium metabolism [52].
Low blood calcium stimulates the release of PTH, a stress hormone intended to extract calcium from bones to maintain adequate blood levels. According to Ray Peat, increased PTH reduces efficient energy production, and increases production of lactate [15]. Calcium is used inside the cell to stimulate energy production, and is needed for many enzymes, like PDH [67]. Calcium also required for the TH enzyme to be properly activated and to synthesize dopamine [16]. Calcium serves as a cellular signaling molecule that promotes and modulates dopamine activity. Ensuring optimal calcium intake is therefore vital to maintain a high metabolism and proper dopamine activity.

4.7 Electrolytes

4.7.1 Magnesium​

Magnesium is a highly important electrolyte that has countless functions in the body. It helps regulate other electrolytes, stabilizes the ATP molecule allowing for high energy production, promote regularity, and helps synthesize neurotransmitters. Magnesium deficiency has been observed to cause a decline in antioxidant capacity as well. Lastly, magnesium works together with thiamine in the production of energy [41].

4.7.2 Potassium​

Potassium is a vital electrolyte that often gets overlooked. It helps balance out excess sodium and works in tandem with sodium to send signals along neurons. Low potassium causes fatigue and decreases intestinal peristalsis, while also disrupting the function of the intestinal barrier which promotes both, the growth of bacteria and the absorption of their endotoxin [54]. During bacterial overload, potassium can be lost in large amounts, which will severely impact the ability to produce energy, and do any work with that energy. The gut is controlled by many nerves and ensuring that they have all the resources lets the correct signals get sent. This will go a long way in managing bacterial overgrowth, and improving energy production, and subsequently dopamine.

4.8 Other

There are other nutrients I did not mention, or glossed over, as it is simply too much information to jam into a single post. The nutrients mentioned above have been the most helpful, therefore I focused on them.
Manganese is an interesting trace mineral that is needed for proper glucose metabolism and antioxidant function of the cell. Manganese is used in pyruvate carboxylase that has vital functions such as maintaining adequate substrates, preventing conversion of pyruvate into lactate, and maintaining steady blood sugars. Inside the mitochondria, it serves as part the antioxidant enzyme, SOD2.
Zinc is another metal that has many functions that are vital to good health. Zinc, encourages gut barrier function [43], plays a role in the methylation cycle, and more. Zinc is required for good immune system function, and a deficiency exacerbates inflammation [42].
Lastly, choline supplies methyl groups to the methylation cycle. It is also the backbone of the neurotransmitter acetylcholine, which drives many gut functions. Maximizing choline intake ensures proper functioning of many organ systems.

Epigenetic changes lower dopamine

Epigenetic modifications to DNA expression imply the adjustment of any protein or process in the body. Because of this, it is impossible for me to accurately say what kind of epigenetic changes occur to produce the specific pathology in chronic akathisia. However, while not proving anything, an example with similar pathology can be used to better explain chronic akathisia.
A single neuron damaging event can induce chronic activation of microglia. This has been observed in humans from MPTP, and in rats from LPS and is called reactive microgliosis. Reactive microgliosis results in highly sensitive microglia which over-react to stimuli and results in prolonged and excessive inflammation. Like discussed before, inflammation damages neurons, and reactive microgliosis puts that into overdrive.
Specifically, a rat injected with a septic dose of LPS lost up to 47% of its tyrosine hydroxylase immune reactive cells in the substantia nigra. After the initial injection, TNF-a levels in the blood normalized but stayed elevated in the brain. After 7 months 23% of the TH-IR neurons were gone, and in 3 more months 47% were dead [4].
Interestingly, this effect was less pronounced in the VTA, which is also resistant to MPTP damage. Akathisia is partially a decline of DA in the VTA, not SN, therefore, this study isn’t fully applicable. However, my main point is to illustrate the effects of drugs on epigenetics and the consequences of that. There could be other epigenetic changes occurring to other proteins exclusive to the VTA, or DA neurons about which we don’t yet know.
In my specific situation, I was injured with Metronidazole, which heavily impacted my ability to create energy. High dose thiamine supplementation has restored that to a decent extent. High dose thiamine works like a drug and upregulates various enzymes (PDH, KGDH) in the energy production system, so the metronidazole downregulated them, and altered my epigenetics to maintain the enzymes low. The mechanism might be similar with other drugs, but there are other possibilities.
Fortunately, epigenetics is not deterministic and can “follow” the organism. Twins with identical DNA have vastly different epigenetic expressions once they grow up, because their choices and their environment changed their epigenetics. Technically, thoughts directly impact your brain, and alter genetic expression.
While I have no idea which epigenetic changes result in an increased chance of akathisia, I know that epigenetics can be modified. In my opinion, a good way to target them is to produce an environment in the cells which signals abundance and a lack of stress. Whether this will significantly impact the specific epigenetic changes implicated in akathisia or not, focusing on nutritional sufficiency, high metabolism, energy production, and a controlled population of bacteria will do a lot to help relieve symptoms and prevent further damage.

Conclusion​


Assuming the idea of akathisia occurring from decreased dopamine is true, then increasing dopamine production, packaging, and release is a smart method to increase overall dopamine activity and improve akathisia. Given that most of the reasons for dopamine decline, especially to the extent of akathisia, are from metabolic disorder, reestablishing order is the most sensible option. I hope this post was able to illustrate that disorder, and the vicious cycles maintain it.
Reduced metabolic energy, dysbiosis, and malnutrition create a very tightly connected cycle that destroys the ability to sit still and enjoy life. Each of these three factors has many mechanisms by which they exert their effects and maintain the cycle; therefore, it is only logical that to stop the cycle, a multi-faceted approach is necessary. Simply agonizing dopamine receptors with bromocriptine, increasing dopamine with L-dopa, taking antibiotics, or supplementing a B-complex will probably not be enough or not be sustainable.
By studying the metabolic pathways that were discussed in this post, various strategies can be implemented to potentially improve the metabolic state and subsequently, akathisia. The third post on akathisia discusses my strategies and explores my reasons.



AK-chart-2.jpg





References​




 

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Peatful

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Are you in med school?

Who diagnosed you with the title AKATHISIA?
 

ALS

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"The current approach towards schizophrenia needs refinement. Hyperprolactinemia, metabolic syndrome, brain damage, akathisia, and suicide are non-negotiable outcomes when considering a drug’s success. Reduction of B1 required functions by metronidazole, and the B9 inhibiting properties of Bactrim are also complete failures as drugs and need adjustment to reduce side effects. The approach towards anxiety with benzodiazepines is reckless and unnecessary."

There is a thread somewhere about a Dr. who used B3 to successfully treat schizophrenia in a large number of patients.

Dr, Daniel Amen (Amen clinics) uses brain scans and / or questionnaires to determine which sector of the brain is not functioning well, then will prescribe either a supplement or pharmaceutical Rx to treat it.
 
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brightside

brightside

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Are you in med school?

Who diagnosed you with the title AKATHISIA?
No. I have no formal education.

Nobody. I figured it out myself after six or so months. It would be near impossible to get a official diagnosis, especially because many doctors don't even know what it is.. Besides, I have it from an antibiotic, not a neuroleptic which would make it even harder. Doctors would have a problem believing that an antibiotic can cause that, unless they recently read the literature. On top of all that, akathisia often gets mistaken for anxiety, because, again, the doctors don't really know much about it. The frantic movements lead them to believe that the person is simply panicking.
 

Peatful

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Peat would more than likely say this is an issue of cellular respiration or energy.
 
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brightside

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Peat would more than likely say this is an issue of cellular respiration or energy.
Yes..? Its inspired by Peat, and I mention energy in the introduction.

In any case, it is my claim that chronic akathisia is caused by epigenetic changes and decreases in activity of dopamine pathways and requires a failing metabolism, dysbiosis, and nutritional deficiency.
 

Peatful

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Yes..? Its inspired by Peat, and I mention energy in the introduction.
I am pointing out the embracing of a diagnosis that you wrote extensively on.

I personally wouldn’t label myself anything.

Let’s say im infertile.
I wouldn’t write several pdfs on infertility.
I would look at hormone balancing and healing at a cellular level.

Ray was a genius but simple in his approach.
And it comes down to mitochondrial respiration and cellular energy.

My opinion.

Best.
 
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Peatress

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Thank you for this. What an accomplishment in view of the medical establishment that tries to discredit side effects. Many genetic conditions have been invented to explain away drug reaction and if that doesn’t stick then why not try psychosomatic? I’ve not heard about Akathisia until I saw your post. The information you provide in this thread and your other threads will help others who are suffering in silence and perhaps being gas lighted by their doctors. I found this list of drugs that can cause some of the symptoms you describe.

Drugs That Cause Akathisa

 
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brightside

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Thank you for this. What an accomplishment in view of the medical establishment that tries to discredit side effects. Many genetic conditions have been invented to explain away drug reaction and if that doesn’t stick then why not try psychosomatic? I’ve not heard about Akathisia until I saw your post. The information you provide in this thread and your other threads will help others who are suffering in silence and perhaps being gas lighted by their doctors. I found this list of drugs that can cause some of the symptoms you describe.

Drugs That Cause Akathisa

Thank you for taking the time to read, and the list as well.

Yep.. its quite depressing, honestly. It's as if the person with akathisia doesn't have enough problems and doctors essentially blaming people just adds more on top. On a different post I linked this interview which talks about this and various anecdotals. If you're interested, here it is.
 
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Peatress

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Thank you for taking the time to read, and the list as well.

Yep.. its quite depressing, honestly. It's as if the person with akathisia doesn't have enough problems and doctors essentially blaming people just adds more on top. On a different post I linked this interview which talks about this and various anecdotals. If you're interested, here it is.
This is painful to listen to. As if it's not bad enough dealing with doctors then you have to convince family and friends.
 
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brightside

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Not sure why I did not see this before, but here is a decent overview of akathisia's proposed mechanisms.
Dopamine-receptor blocking agent-associated akathisia: a summary of current understanding and proposal for a rational approach to treatment

Some noteworthy ideas:

Talking about propranolol:
The hypothetical mechanism of action, shared by the alpha-2 agonist clonidine, is suppression of compensatory noradrenergic signaling that may trigger psychomotor activation associated with akathisia. D2 stimulation in the locus coeruleus normally inhibits norepinephrine outflow, so it follows that reduced dopamine signaling caused by DRBAs subsequently increases norepinephrine signaling in the midbrain as part of a feedback response.
On top of this, I found evidence that LPS induces LC hyperactivity, potentially as a defensive measure. NE stimulation by the LC serves more purposes than just the properties of NE, and can suppress TNF-α induced by LPS while increasing IL-1β.

Amyloid plaques are associated with Alzheimer's, with LPS being a major contributing "stimulator" of this brain defense mechanism.
"It is hypothesized that LPS, in combination with other factors, leads to amyloid plaques, myelin injury and tau hyperphosphorylation in AD brain. !!!!Since the presence of LPS in human AD brain has been confirmed in different laboratories,!!!! treatment and prevention targets for sporadic AD could include LPS, TLR4/CD14 receptors, and Gram-negative bacteria. A vaccine against LPS to prevent AD could be considered if future studies continue to support a role of LPS in AD."


Massive fail, especially after finding LPS in people's brains. And the last part is just silly, illustrating the faulting thinking of the mainstream science.

Link

Anyways, the LC contributes to LPS defenses by increasing IL-1β, which works to suppress TLR-4, and sensitivity to LPS, which is presumably a good thing.
"Taken together, our results indicate that IL-1β can generate tolerance to LPS in vivo, and suggest that the regulation of mechanisms of the down-regulation of TLR4, as well as those involved in the expression of GcR and/or in the secretion of glucocorticoids, would be crucial for these effects."

Link

What's more is that a dysfunction (by lesion) of the LC leads to increased amyloid plaque deposition.
"In animal models, lesions of the LC have been shown to exacerbate tau and amyloid-β plaque deposition, leading to depletion of noradrenaline in LC target regions and impaired cognitive function."

And

"Interestingly, there is also evidence of noradrenergic hyperactivity in early disease, consistent with a number of reports of elevated levels of CSF noradrenaline and/or noradrenaline turnover in Alzheimer’s disease. Thus, hyperactivity in a structurally impaired LC might further accelerate the propagation of neuropathology in neurodegenerative disease via noradrenergic projections."

Link
From that I conclude that brain disease is inseparable from LPS, and that NE signaling plays an integral role in akathisia.
While the review above discusses akathisia from a acute, drug induced perspective, I think LPS plays a role in both pathologies, given that:
1. Average people aren't healthy and are exposed to LPS from slow metabolism, and
2. Neuroleptics are highly destructive drugs which cause all sorts of dysfunction, such as the destruction of metabolism which likely leads to increased LPS.

However, since this post focuses on specifically chronic akathisia, I think the studies above confirm my theories.

@gunther I think you might find this interesting.

lil-chart.PNG



Quetiapine has a much weaker D2 binding affinity than Clozapine, but since Clozapine's 5HT2A antagonism is much stronger, the likely hood of symptoms seems to be less. Of course, this is looking at only two of hundreds interactions of these drugs, regardless, I think it is interesting.

Here is what they say:
"Indeed, greater 5-HT2A compared with D2 receptor antagonism appears to negatively correlate with DRBA-A risk. Aripiprazole has serotonin 5-HT2A blocking effects that are less potent than D2, while quetiapine, which is associated with lower rates of DRBA-A, binds 5-HT2A to a greater extent than D2. This preferential binding to 5-HT2A over D2 is most striking with clozapine. Although DRBA-A from clozapine appears to be a rare clinical occurrence, there have been case reports of patients who both developed DRBA-A from clozapine and experienced a reduction of DRBA-A symptoms from clozapine. Serotonin receptor activity has also been linked to risk of DRBA-A caused by first-generation agents. Patients with schizophrenia and reduced 5-HT1B receptor density were found to develop more frequent and severe akathisia when taking haloperidol compared with those with normal 5-HT1B receptor density."

The last line is also interesting, and might be something worth looking into.

Also:
"Anticholinergic medications are commonly used to treat other forms of extrapyramidal symptoms related to DRBA therapy, such as dystonia and parkinsonism, and may be useful when akathisia is present in combination with these types of EPS. The purported mechanism of anticholinergics in the treatment of DRBA-A is restoration of dopamine signaling in areas of the brain where it is depleted by DRBAs. Specifically, D2 receptors located on cholinergic interneurons in the basal ganglia, which normally inhibit acetylcholine release, can activate the extrapyramidal pathway when blocked. This pathophysiologic theory is supported by the reduced rates of EPS seen with clozapine, which has greater intrinsic anti-muscarinic anticholinergic activity than other DRBAs. Excessive cholinergic outflow can be counteracted with the administration of agents such as benztropine, diphenhydramine, and trihexyphenidyl. Unfortunately, the use of anticholinergics is limited by adverse effects such as those related to cardiovascular, gastrointestinal, and cognitive dysfunction."

Perhaps that can kind of explain things for you, although, I would imagine it would have to do more with LC hyperactivity than the extrapyramidal pathway.

So many things to look into, with so little actual helpful information..
 
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brightside

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This is painful to listen to. As if it's not bad enough dealing with doctors then you have to convince family and friends.
I know! It's really quite depressing. Sorry to put a load on you.
Fortunately, I largely avoided doctors, but I never told my family much, since they are somewhat.. conservative? ..in their understanding of mental health.
 

gunther

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Not sure why I did not see this before, but here is a decent overview of akathisia's proposed mechanisms.
Dopamine-receptor blocking agent-associated akathisia: a summary of current understanding and proposal for a rational approach to treatment

It's interesting that both Diphenhydramine and Cyproheptadine are acetylcholine inhibitors (as well as histamine). Those two things calm me down, but don't effect my motivation at best or even slightly sedate me. At first diphenhydramine made me quite drowsy, but that kinda went away. I will still get drowsy if I take 25mg or more, but at 12.5mg I don't feel bad.

One of the hardest things I've dealt with in trying to figure out what works and what doesn't. Do you ever try to megadose something just to see if you can feel it's affects?
 
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Peatress

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I know! It's really quite depressing. Sorry to put a load on you.
Fortunately, I largely avoided doctors, but I never told my family much, since they are somewhat.. conservative? ..in their understanding of mental health.
Not a load. The information is useful. It will help others. Thank you.
 
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redsun

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@brightside ever experimented with forskolin? It enhances cyclic AMP which then activates cAMP-dependent protein kinase to phosphorylate tyrosine hydroxylase, stimulating dopamine synthesis.


" Tyrosine hydroxylase [tyrosine monooxygenase, L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] was highly purified from rat caudate nuclei. When the pure hydroxylase was phosphorylated by incubation with cyclic AMP-dependent protein kinase and [32P]ATP, 32P and tyrosine hydroxylase activity were detected after polyacrylamide gel electrophoresis in a single protein band. After sodium dodecyl sulfate gel electrophoresis, 32P was detected only in a probably active subunit of tyrosine hydroxylase of molecular weight 62,000. Phosphorylation of the hydroxylase increased its activity by 2-fold, and was associated with an increase in Vm without any change in Km for either substrate or cofactor. We propose that the pool of native tyrosine hydroxylase is composed of a mixture of enzyme molecules in both active and probably inactive forms, that the active form is phosphorylated, and that phosphorylation produces an active form of the enzyme at the expense of an inactive one."

If you never experimented with iodine supplementation, it can also achieve a similar effect through thyroid hormones.
 
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brightside

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@redsun

No, I haven't.

This actually ties into what I have been thinking about for a while, but I won't write about it just yet. I obviously overlooked the importance of cAMP. cAMP seems to be a part of a larger and way more complex system involving calcium signaling, gene transcription, and many other secondary molecules such as endocannabinoids and various peptides such as CCK. Also, glutaminergic inputs seem to play a fundamental role, especially through the NMDAr which increases intracellular calcium.

I have actually been hypothesizing that dysfunctional calcium signaling was the main problem I have, but maybe that's only partially true. Forskolin can also increase D2r(cAMP -> PKA -> CREB), which may or may not be a good thing. Although, I imagine that the increased DA is a good idea regardless, given that D2 can be functional even at low DA concentrations, while D1 seem to not.

Therefore, basal dopamine concentrations, which have been reported to be around 10 nM, are insufficient to activate D1R and induce the activation of D1R-MSN, but are adequate to activate D2R and suppress D2R-MSN activity.
Although, this might not necessarily apply, since the NAc MSM's seem to be quite unique.

On the other hand, activation of D2 leads to a decreased TH and PKA, which is it's main function. It's kind of unclear why D2 agonists would help akathisia sufferers, even though the proposed mechanism of tardive akathisia is actually upregulated D2r. Obviously, its very complicated, and I have yet to understand even 1% of it, which is why I focused my post on generic mechanisms in the first place. The general "increasing dopamine" advice seems to work, but its clearly not just an inadequacy of a certain receptor.

It would be interesting to try some Forskolin, though. I might buy some if I will be making an online purchase. Thanks for the idea.
 

redsun

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@redsun

No, I haven't.

This actually ties into what I have been thinking about for a while, but I won't write about it just yet. I obviously overlooked the importance of cAMP. cAMP seems to be a part of a larger and way more complex system involving calcium signaling, gene transcription, and many other secondary molecules such as endocannabinoids and various peptides such as CCK. Also, glutaminergic inputs seem to play a fundamental role, especially through the NMDAr which increases intracellular calcium.

I have actually been hypothesizing that dysfunctional calcium signaling was the main problem I have, but maybe that's only partially true. Forskolin can also increase D2r(cAMP -> PKA -> CREB), which may or may not be a good thing. Although, I imagine that the increased DA is a good idea regardless, given that D2 can be functional even at low DA concentrations, while D1 seem to not.


Although, this might not necessarily apply, since the NAc MSM's seem to be quite unique.

On the other hand, activation of D2 leads to a decreased TH and PKA, which is it's main function. It's kind of unclear why D2 agonists would help akathisia sufferers, even though the proposed mechanism of tardive akathisia is actually upregulated D2r. Obviously, its very complicated, and I have yet to understand even 1% of it, which is why I focused my post on generic mechanisms in the first place. The general "increasing dopamine" advice seems to work, but its clearly not just an inadequacy of a certain receptor.

It would be interesting to try some Forskolin, though. I might buy some if I will be making an online purchase. Thanks for the idea.
I have seen that the D2S receptor is what inhibits dopamine. D2L does not. Also my understanding was it was less about the dopamine itself but more about the D2 receptor activation inhibiting norepinephrine in the locus coeruleus, which is considered the issue with akathisia. When you raise the synthesis of dopamine, the activity of the D2 receptor will increase, inhibiting norepinephrine.

Your diet is also lower in glycine since you do not eat much meat. Low glycine intake may be compromising NMDA activity since it is a necessary co-agonist. You may see improvement from L-glycine supplementation of 3-5g a day. Also something to be wary about is excess copper and zinc supplementation. Both metals block NMDA receptors, and thus will lead to reduced calcium channel activity. I am surprised you have not noticed worsening symptoms from all that copper.

@redsun

Have you taken forskolin? I've got some, but never gave it a fair try. Generally, I'm suspect of dopamine agonists.
I haven't tried myself. Its not a dopamine agonist. Its a well known cAMP inducer which indirectly affects dopamine but also other processes in the body.
 
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brightside

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@redsun

redsun said:
Also my understanding was it was less about the dopamine itself but more about the D2 receptor activation inhibiting norepinephrine in the locus coeruleus, which is considered the issue with akathisia.
Thank you for pointing that out, by the way. I have read that earlier, but forgot to mention it.

Sure, and perhaps that is the case with pure D2 antagonism, but in my situation there is clear dopaminergic decline, which cannot be explained by that mechanism alone. Also I think there needs to be reduced stimulation in the NAc from the mesolimbic pathway, otherwise, you would get normal arousal by the LC. That is kind of the problem, I never took d2 antagonists, and I have a permanent change (as opposed to a withdrawal period). It's clearly something both specific, and also fundamental. Heck, after a long day's work, I could eat some sugar and get a dramatic increase in akathisia, which to me, implies energy problems.

I recently discovered that if you block calcium influx into SN mitochondria, the SN is unable to maintain normal spiking, and degenerates into irregular patterns (due to energy depletion, from a lack of Ca2+ in the mito). If pushed enough, this turns into a complete block. In fact, some studies propose this as the mechanism of action of antipsychotics, basically, D2 antagonism -> overexcitation -> depleted energy -> low DA (in addition to their D everything blockade). They did say that this effect took a while to develop in rats, though.

redsun said:
Your diet is also lower in glycine since you do not eat much meat. Low glycine intake may be compromising NMDA activity since it is a necessary co-agonist. You may see improvement from L-glycine supplementation of 3-5g a day.
I have eaten that amount through collaged for long stretches of time, noticing only mild improvement in gut symptoms. Occasionally I also did small bursts of ~3g for a week or so, and also noticed no improvement.

redsun said:
Also something to be wary about is excess copper and zinc supplementation. Both metals block NMDA receptors, and thus will lead to reduced calcium channel activity. I am surprised you have not noticed worsening symptoms from all that copper.
Well, I think it's mainly my malabsorption that is protecting me. Besides, I have read that zinc can upregulate NMDA in the prefrontal cortex, while downregulating NMDA in the hippocampus (or vice versa), meaning that it's not always clear-cut. In fact, I find that my rumination is almost at a zero when I take enough minerals, especially zinc and copper.
 
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