My Hypothesis:

I suggest to you that …..

….. anhedonia, depression, euphoria, anxiety, migraine, initial loss of weight, malaise, paranoia, delusions, hallucinations, mania, cognitive impairment, motor activity and speed changes, and changes to the autonomic nervous system vital signs are neurotoxic symptoms

same as the neurotoxic symptoms seen with different levels of intoxication or poisoning.  And I think that all organ systems are affected.

Instead of exogenous poisoning, I suggest that these neurotoxic changes are endogenous, due to unknown difficulty breathing, and made much worse by insomnia.

My hypothesis is that depression is a neurotoxic symptom 

caused by unknown failure in properly moving air in and out of the body, thus producing some level of hypercapniaCarbon dioxide is produced inside the body due to ongoing metabolism of food into energy and the only way to control PaC02 is by exhaling the proper ratio.  

The autonomic nervous system regulates respiratory rate, depth and pattern in order to do this, but peripheral injury to the motor skeletal ventilatory system [including internal structures in the neck and chest]. can make this more or less difficult.

 And too much endogenous carbon dioxide being retained is very very very unpleasant to experience [apparently]  and quite invisible without further medical investigation….[invisible except for internal perceptions that the patient is aware of  and except for accompanying changes in behavior -including motor frequency and speed] .  It is kind of like a range of  symptoms from internal suffocation [without an obvious external source],  therefore no one thinks of it.

Where is the evidence for this hypothesis?

1] chronic depression.  is not a normal emotion… [and neither is chronic euphoria- also not a normal emotion] . Its effects on cognition and on sleep and on the heart and the development of delusions, paranoia, hallucinations, and psychosis in some with depression,   are  exactly the same symptoms as the symptoms that come from exogenous intoxication and poisons. [and interestingly, from extreme sleep deprivation].

2]. Most attacks of severe depression begin with a bout of insomnia or disturbed sleep and 

3]. …apparently sleep deprivation [even one night of SD] can affect the “control of breathing” in any person, never mind psychiatrically ill persons.  [see the paper below]………

The paper below discusses the effect of one night’s sleep deprivation on respiratory control;

“.In this issue of the Journal, Rault and colleagues (pp. 976–983) assessed the effect of one night of sleep deprivation on respiratory motor output and inspiratory endurance in 20 healthy men (1). Inspiratory endurance was decreased by 50%, and preinspiratory motor potentials, thought to reflect activity of the supplementary motor area, were decreased by 40%Dyspnea developed more rapidly after sleep deprivation. The investigators conclude that one night of sleep deprivation decreases cortical contribution to respiratory motor output, with a consequent decrement in inspiratory endurance.   Am J Respir Crit Care Med. 2020 Apr 15; 201(8): 894–895. 

Published online 2020 Apr 15. doi: 10.1164/rccm.201912-2493ED.    Clarifying the Effect of Sleep Deprivation on the Respiratory Muscles

Franco Laghi1,2 and  Hameeda Shaikh1,2

Dyspnea is a sign of ventilatory failure. .,or%20activity%20of%20the%20system.

The cause of the sleep deprivation is not always clear but can start in any person after a period of physical illness.
Once the sleep disturbance starts, then the consequences can be astonishing.


4]. There is evidence that sleep deprivation can disturb “control of breathing and even precipitate [hidden] respiratory  failure,  due to [reversible] messing with connections between the brain and the respiratory muscles.    [I am not a scientist or doctor so…]

Impact of Sleep Deprivation on Respiratory Motor Output and Endurance. A Physiological Study

” One night of sleep deprivation reduces respiratory motor output by altering its cortical component with subsequent reduction of inspiratory endurance by half. These results suggest that altered sleep triggers severebrain dysfunctions that could precipitate respiratory failure.” 

Am J Respir Crit Care Med

. 2020 Apr 15;201(8):976-983. doi: 10.1164/rccm.201904-0819OC.

Impact of Sleep Deprivation on Respiratory Motor Output and Endurance. A Physiological Study

Christophe Rault 1 2Aude Sangaré 3Véronique Diaz 1 2Stéphanie Ragot 1 4Jean-Pierre Frat 1 5Mathieu Raux 6 7Thomas Similowski 6 8René Robert 1 5Arnaud W Thille 1 5Xavier Drouot 1 2 3 9 and   please   see. …….  [again]….

Am J Respir Crit Care Med

. 2020 Apr 15;201(8):894-895.

doi: 10.1164/rccm.201912-2493ED.

Clarifying the Effect of Sleep Deprivation on the Respiratory Muscles

Franco Laghi12Hameeda Shaikh12

  • PMID: 31951467

Free PMC article

“The elegant investigation of Rault and colleagues (1) is provocative. The investigators have set the stage for the objective study of the physiologic maze that accompanies sleep deprivation. One challenge will be to unravel the sex-specific effect of sleep deprivation on dyspnea, spinal and supraspinal reflex inhibition, and function of the primary motor cortex. Another challenge will be to determine the effect of sleep deprivation in critically ill patients, including those who fail invasive and noninvasive ventilation. The challenge is formidable, but now is the time to tackle it.”

This is truly new and truly fascinating.

I think that this not only may apply to bipolar patients but may apply to long COVID and many other syndromes.

I think that patients who develop long COVID [or patients who have serious psychological problems with their chronic illness, may have unknown ventilatory and respiratory issues that they may not have considered, which puts them at risk.  

5] Daytime “Control of breathing” can be permanently affected by peripheral injury to the ventilatory system.  [think of people who have been choked [damaging nerve fibres] , head injuries impacting on the neck and nerve fibres linking to homeostatic sensors and also to skeletal muscle, physical abuse damaging the chest, neglect resulting in malnutrition and thus muscle weakness, impacting on the ability to move air in and out, accidents [ie being hit by a car] damaging parts of the body necessary for the nerve-skeletal motor system as part of the ventilatory system, etc…..]. Daytime control of breathing is easy to measure. Counting the respiration rate per minute is an easy starting to point. Resting respiratory rates that are too high at baseline or too low will require further medical investigation, especially in cases where the patient complains of brain fog or if patient looks and acts bewildered and befuddled and is not their usual self.

I will use bipolar patients as an example of my hypothesis of neurotoxic effects.

I think that bipolar patients are hardy, healthy young adults experiencing the neurotoxic effects of neuro-skeletal ventilatory failure.   I think that this needs to be investigated; with pulse oximetry and blood gas investigations during untreated severe attacks. ……  Let us look at the evidence for this hypothesis: 

Dr Emile Kraepelin, over 100 years ago, found abnormal daytime ventilation in thousands of untreated bipolar depressed and manic patients .  Manic Depressive Insanity Chapter 3 Bodily Symptoms. 1926

No one has attempted to replicate his findings, yet, although it would be easy to do so.

Abnormal daytime breathing [hidden]  plus insomnia would easily disturb blood gas homeostasis and lead to cumulative hypo or hyper capnia or intermittent and cumulative hypoxia;   pulse oximetry,  sleep tests and serial arterial blood gas tests would help identify such syndromes during severe depression or mania.

Abnormal blood gases, such as PaC02, would explain the abnormal mood, cognitive and motor states of depression and mania, made chronic by abnormal daytime breathing and continued sleep disturbances.

I suggest to you not only that “control of breathing is abnormal in these patients [untreated] but that the symptoms they report are due to neurotoxic effects of their condition.…..Severe depression, cognitive impairment, memory impairment, fatigue, insomnia, muscle wasting, psychosis, delirium, reversible [?] dementia, altered mental status……….these are neurotoxic symptoms that we know occur with exogenous poisons and intoxicants.

….These symptoms can also occur due to endogenous poisons occurring with metabolic problems interfering with metabolism of food and of air.  Certainly the buildup of metabolic PaC02 [hypercapnia] would  definately explain the neurotoxic effects seen in manic depressive insanity.  Hypercapnia, abnormal pH, and/or intermittent hypoxia is known to produce these symptoms. Severe depression may, in fact, be a neurotoxic sign of ventilatory failure and consist of the effects of unknown hypercapnia, which today, can be treated.

Indeed, major depression and bipolar depression are not the same as any normal emotion, it is a physical sign, suggesting that at the very least, that nurses and doctors carefully examine how well the skeletal ventilatory system is working.

I am concerned that no one [except for Dr Emile Kraepelin, over 100 years ago], is looking for possible hidden physical injury in manic depressive patients. Injury to respiratory skeletal muscles,  making control of endogenous carbon dioxide in the blood much more difficult.   It is easy to look for signs of injury; one has only to measure the autonomic nervous system vital signs [baseline respiratory rate at rest , blood pressure, heart rate and body temperature at rest.]  ………..And now we know to look at effects of insomnia on the skeletal ventilatory muscle system.

Dr Kraepelin knew that his findings  meant that respiratory acidosis could explain the range of neurotoxic symptoms seen in bipolar illness.

  Again, nobody has tried to replicate his studies.

  Dr Kraepelin and his research associates  even used respiratory plethysmography to make sure that respiratory rates were being measured accurately.   One can see that these patients are at increased risk of ventilatory failure when the respiratory load overwhelms their ability to breathe.

Depression with cognitive impairment and psychomotor slowing accompanies many illnesses besides psychiatric ones.  Again, I think that any severe depression is a neurotoxic symptom due to buildup of endogenous products in the body.   I would think that PaC02 or pH of the blood would be important to investigate; as would investigation of intermittent hypoxia.

I am concerned about daytime weakness of skeletal muscles in bipolar illness,and I am concerned about bipolar symptoms being a pattern of chronic delirium  [all motor subtypes] – from hidden blood gas problems resulting in neurotoxic symptoms of cumulative hyper or hypocapnia or hypoxia.  –   [all of which may be reversible with supportive medical treatment to bolster the weakened skeletal muscles and to allow them to recover to their baseline.]

I am concerned that no one seems to be looking at the obvious; silent disturbances to homeostasis and possible broken feedback mechanisms [due to injury] and other vital signs disturbances that the patient is – of course, unaware of –  [vital signs being part of the silent autonomic nervous system function] .  None of this may be  visible due to unseen, unknown skeletal muscle weakness and atrophy,  the only visible symptoms being the pattern of neurotoxic changes to mood, motor activity and behavior..

Ventilatory failure during and after respiratory illness or after blood loss or malnutrition is possible, especially in patients with unknown and unconscious abnormal baseline breathing who subsequently develop sleep deprivation.  Sleep deprivation can disrupt control of breathing in normal individuals, never mind individuals with hidden unknown daytime ventilatory issues.

Researchers, Have you done any studies where arterial blood gas results are obtained during episodes of ill health and cognitive impairment and sleep deprivation ?

Depression is not a normal emotion; depression and cognitive impairment [ and dyspnea], I think, are neurotoxic symptoms that have causes that, in modern times, can be treated .

I think that it is about time that the physical causes of major depression and bipolar illness be investigated.

To start, daytime vital signs must be measured; including respiratory rates and reflex mechanisms to deal with accumulation of PaC02… see if these are normal or not. Then, the effects of nighttime sleep disturbance must be investigated during periods of mental confusion AND insomnia.

This involves a change in thinking.

The information we collect must be relevant and involve careful measurement of the autonomic nervous system vital signs [respiratory rate, blood pressure, heart rate, body temperature] for a start. 

Kraepelin found that all were abnormal, in different patterns in research subjects during their episodes. 

Living with neurotoxic symptoms is awful.

Addressing these neurotoxic symptoms may return the patient to a normal state and a normal life.

Does anyone know of any researcher researching neurotoxicity due to hypercapnia, hypomania or hypoxia in bipolar illness [or in cardiovascular disease with sleep deprivation] ?

This would need knowledge of an untreated patient’s baseline resting respiratory rate, knowledge of pulse oximetry during depressive insanity episodes, getting sleep studies during insomnia [including pulse oximetry] , and arterial blood gas results during depressive episodes.

Plus, confused depressed or manic patients may not know that they are experiencing dyspnea...further complicating things.    Certainly, this was true of my friend, Paula, who did not know she had decreased ventilation and did not recognize the sensation of dyspnea that she was experiencing.

It would not have been hard to measure her basic vital signs [RR,BP,HR, Temperature]. but no one did.   No one ever does, I think.  Yet many clues lie in knowing the pattern of basic vital signs.

Why do doctors not do it?  Why do they not pay more attention?

Kraepelin did….and he understood the issue the bipolar patients were facing , as a result. [it is not rocket science if you know that the daytime respiratory rate is abnormal and you know that the patient cannot sleep and you know anything about blood gases and the ventilatory system]…..even I can understand it…..The findings about sleep deprivation triggering [hidden] ventilatory muscle failure is fascinating and should be pursued. 

I think that only these kinds of studies will help us to figure out what is going wrong during bipolar attacks and will help with effective treatment.

I think that studies of the effects of sleep deprivation in any illness, psychiatric or not, will help us to give supportive medical treatments to avoid ventilatory failure and to eliminate most neurotoxic symptoms, allowing people to return to their normal state and lives.


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