THEORETICAL ARTICLE—ELMÉLETI ÖSSZEFOGLALÁS THE ROLE OF (AND INTRACELLULAR pH) IN THE PATHOMECHANISM OF SEVERAL MENTAL DISORDERS ARE THE DISEASES OF CIVILIZATION CAUSED BY LEARNT BEHAVIOUR, NOT THE STRESS ITSELF?

ANDRÁS SIKTER , GÁBOR FALUDI , ZOLTÁN RIHMER 1 Municipal Clinic of Szentendre, Section of Internal Medicine 2 Dept of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest ELMÉLETI ÖSSZEFOGLALÁS Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173

A SZÉNDIOXID (ÉS AZ INTRACELLULÁRIS matikus betegségek patomechanizmusában. Fel- pH) SZEREPE NÉHÁNY MENTÁLIS tételezik, hogy a civilizációs betegségeket nem BETEGSÉG PATOMECHANIZMUSÁBAN maga a stressz, hanem annak le nem reagálása Nem maga a stressz, hanem tanult okozza azáltal, hogy a CO2 szint tartósan eltér a viselkedési formák okoznák a civilizációs fiziológiástól. A növekvõ agyi pCO2, acidotikus betegségeket? citoszol pH, és/vagy emelkedett bazális citoszol A széndioxid szerepe alábecsült a neuropszichi- Ca2+ koncentráció csökkenti a citoszolba történõ átriai betegségek patomechanizmusában, ugyan- Ca2+ beáramlást és az arousalt – dysthymiát, de- akkor fontos kapocs a lélek és a test között. A pressziót okozhatnak. Ez többnyire ATP hiány- mindenkori lelki állapot többnyire a légzést is nyal és a citoszol Mg2+ tartalmának csökkenésé- befolyásolja (lassítja, gyorsítja, irregulárissá te- vel is jár. Ez az energetikai és ionkonstelláció jel- szi), ezért változik a pH. Másrészt a neuronok lemzõ az életkor emelkedésével korrelációt mu- citoszoljának aktuális pH-ja a Ca2+ konduktivitás tató krónikus szervi betegségekre is, és a legfon- egyik legfontosabb modifikátora, ezért a légzés a tosabb kapcsolat az organikus betegségekkel, Ca2+-on keresztül közvetlenül, gyorsan, hatéko- például az iszkémiás szívbetegséggel. A felvá- nyan befolyásolja a “second messenger” rend- zolt modellbe beleillik, hogy egyes farmakológi- szert. (A csökkenõ CO2 koncentráció mindig al- ai szerek (katecholaminok, szerotonin, litium, kalózis, az emelkedõ pedig acidózis irányában triacetiluridin, tiroxin), valamint az alvásmegvo- viszi el a pH-t, íly módon az elõbbi gyorsít, növe- nás okozta H+ és/vagy Ca2+ metabolizmus válto- li az arousalt, míg az utóbbi lassít, csökkenti az zás szintén a logikailag kívánt irányban hat. + arousalt.) A H ion koncentráció állandóságának KULCSSZAVAK: arousal, bipoláris betegség, megõrzése, helyreállítása az egyik legfontosabb civilizációs betegségek, delírium, depresszió, homeosztatikus funkció, ezért a széndioxid szint GAD, hyperventilációs szindróma, locus mino- megváltozása az ellenregulációs változások ris resistentiae, milieu interieur, pánikbetegség, egész sorozatát indítja el. Mindazonáltal bizo- stressz, széndioxid, viselkedés nyítható, hogy nincs tökéletes kompenzáció, ezért a kompenzáló mechanizmusok pszichoszo- SUMMARY matikus betegségeket generálhatnak, minthogy The role of carbon dioxide (CO2) is underesti- másodlagos eltéréseket okoznak a “milieu in- mated in the pathomechanism of neuropsychiat- terieur”-ban. A szerzõk tárgyalják a CO2 rendha- ric disorders, though it is an important link be- gyó fizikókémiai tulajdonságait, a CO2 és a kate- tween psyche and corpus. The actual spiritual sta- cholamin szintek összefonódó változásainak tör- tus also influences respiration (we start breathing vényszerûségeit (feedback), az akut és krónikus rarely, frequently, irregularly, etc.) causing pH hipokapnia szerepét néhány hyperarousal kór- alteration in the organism; on the other hand the képben (delirium, pánikbetegség, hiperventilá- actual cytosolic pH of neurons is one of the main ciós szindróma, GAD, bipoláris betegség), a “lo- modifiers of Ca2+-conductance, hence breathing cus minoris resistentiae” szerepét a pszichoszo- directly, quickly, and effectively influences the

Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 161 ELMÉLETI ÖSSZEFOGLALÁS ANDRÁS SIKTER , GÁBOR FALUDI , ZOLTÁN RIHMER

second messenger system through Ca2+-currents. man instinctive reaction to it, and this would (Decreasing pCO2 turns pH into alkalic direc- cause long-lasting CO2 alteration. Increased tion, augments psychic arousal, while increasing brain-pCO2, acidic pH and/or increased 2+ 2+ pCO2 turns pH acidic, diminishes arousal.) One basal cytosolic Ca level diminish inward Ca - of the most important homeostatic function is to current into cytosol, decrease arousal – they may maintain or restore the permanence of H+-con- cause dysthymia or depression. This state usu- centration, hence the alteration of CO2 level ally co-exists with ATP-deficiency and de- starts cascades of contraregulation. However it creased cytosolic Mg2+ content. This energetical- can be proved that there is no perfect compensa- and ion-constellation is also typical of ageing- tion, therefore compensational mechanisms may associated and chronic organic disorders. It is the generate psychosomatic disorders causing sec- most important link between depression and or- ondary alterations in the “milieu interieur”. Au- ganic disorders (e.g. coronary heart disease). The thors discuss the special physico-chemical fea- above-mentioned model is supported by the fact + 2+ tures of CO2, the laws of interweaving alterations that H and/or Ca metabolism is affected by of pCO2 and catecholamine levels (their feed- several drugs (catecholemines, serotonin, lith- back mechanism), the role of acute and chronic ium, triaecetyluridine, thyroxine) and sleep de- hypocapnia in several hyperarousal disorders privation, they act for the logically right direc- (delirium, panic disorder, hyperventilation syn- tion. drome, generalized anxiety disorder, bipolar dis- KEYWORDS: arousal, behaviour, bipolar disorder, order), the role of “locus minoris resistentiae” in carbon dioxide, delirium, depression, diseases of civi- the pathomechanism of psychosomatic disorders. lization, generalized anxiety disorder, hyperventila- It is supposed that the diseases of civilization are tion syndrome, locus minoris resistentiae, milieu caused not by the stress itself but the lack of hu- interieur, panic disorder, stress

Introduction alkalic cytoplasm allowes Ca2+ to enter in the The role of carbon dioxide is underestimated not cytosol. If we keep on this kind of breathing for a only in the pathomechanism of somatic diseases long time, our pulse will slowly come back to the but of mental disorders too (Gardner). It is a fact incipient frequency because the organism com- pensates the alteration of pH in the cytosol. The that the intracellular pH is strictly regulated in + brain cells, and also marginal aberration of H+ lack of H in cytosol increases conductance of 2+ - concentration may cause big functional deviation Ca and some other ions (Harvey et al.), thus it in 2 - in neurons (Tombaugh & Somjen). The regulation creases contraction, metabolism and O require of intracellular pH is complex, there are several ment (Laffey et al.), and also increases excitability compensational mechanisms (Boron). Carbon di- of neurons in the peripherium (Macefield et al.) and in the brain (Stenkamp et al.). All these events oxide concentration is one of the most important + factor which influences the intra- and extracellular can be explained by the simple fact that lack of H (=alkalosis) increases transmembrane conduc- pH. Why? CO2 is extremely diffusible and in this way we can rapidly send or extract H+ ions to or tance of ions and (consequently) increases active - from all tissues, all cells (nearly the same time) ion-pumping mechanisms too (because the origi - drawing breath rarely or frequently. It is because nal ion-status has to be restored). By contrast, aci dosis decreases the transmembrane Ca2+-conduc- CO2 passes very quickly through the cellmemb- tance (Tombaugh & Somjen), decreases excitabil- ranes and it forms carbonic with H2O which 2+ + - gives H ions. On the other hand ions get slowly ity of neurons, and the decreased Ca -conduc + tance can dramatically affect neurotransmitter re- through membranes, even H -ion itself. That is 2+ because they have electric charge and become hy- lease (Dodge et al..). In some cells the Ca entry into cytosol itself increases cytosolic H+ concen- drated, and this multiplies their radius, but CO2 tration, which physiological acidosis then limits does not have either of them and it is soluble in 2+ lipids (Sikter, 2007a). If we take our breath deeply further Ca entry. (It is supposed to be a novel feedback mechanism:Tombaugh et al. 1998). or frequently our pulse speeds up proving that CO2 has left the pacemaker cells of heart, and the Alteration of carbon dioxide concentration can appear in the whole organism at the same time. If

162 Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 THE ROLE OF CARBON DIOXIDE IN THE PATHOMECHANISM… ELMÉLETI ÖSSZEFOGLALÁS it endures for a long time (several hours to one way they get a good chance to restore the de- week), the organism starts to “compensate”. Sta- creased carbon dioxide level. Contrarily human bility of extra- and intracellular pH is of high pri- acute stress response mostly differs from that be- ority. Renal function and tissular buffer mecha- cause of their learnt behaviour. They mostly re- nisms (mostly) restore the pH in the cytosol of the strain their temper, the physical activity will fail cells and in the extracellular space, but the con- and the hyperventilation/hypocapnia endures long centration of other ions is altered in the cytosol at causing a range of ion-movements through mem- the same time. The development of the new ion- branes and causing metabolic and endocrine alter- milieu needs 5-7 days (Gennari et al.). The new ations and illnesses because of the alteration of ion-milieu of cells differs from the physiological “milieu interieur”. Namely, diseases of civiliza- one. (The restoration of original ionmilieu would tion are caused by the distress evoked by the lack need also 5-7 days at least.) Then chronic hypo- of instinctive reaction to stress. Nowadays some capnia or hypercapnia is followed by cascades researchers start to discover the theoretical signifi- which alter the whole ionmileu in the cells, they cance of hyperventilation in stress induced ill- may alter even the neurotransmitter/endocrine sta- nesses (Schleifer et al.). tus (Dodge et al.). Therefore, it is inappropriate to Several animals (e.g. opossum, newborn deer call that process a “compensational mechanism”, calves, some fish species, amphibians, reptiles, this name suggests that it is all right, while it is birds) react in another way to stress, they show not! According to Claude Bernard alteration of “freezing behaviour” and “play dead”. This hypo- milieu interieur can result in illness. It is very im- arousal condition brings slow breathing and bra- portant that the new ionmilieu is similarly stable dycardia. Freezing behaviour is supposed to be as the original one and it does not allow the organ- caused (at least partly) by hypoventilation and ism to restore the original status. Therefore we hypercapnic acidosis. There is also a third model should name this happening a „complication” (in- of wild animal reaction observed by Steen et al. in stead of “compensation”). willow ptermigan hens (Steen et al.). In this case The fact that intracellular pH is very strictly first the bird shows a freezing behaviour (but does regulated does not mean it can not go wrong. Hu- not play dead) with hypoventilation, bradycardia, man is a species especially endangered by the then after several minutes she starts to hyperventi- long-term altereation of carbon dioxide level, we late, and this way the hypoarousal condition con- think. This is because he/she becomes hypo- or verts to a very vigorous hyperarousal one. In this hypercapnic not only because of organic diseases, case a hypercapnic period is followed by a hypo- but of mental disorders too, and – most impor- capnic one, similarly to symptoms of human panic tantly — because of his/her behaviour! The last disorder (Sikter et al. 2007b). one is dangerous, because it may cause diseases of The acute intentional hypocapnia (produced by civilization. Why? It is frequently asserted that it voluntary hyperventilation) causes alkalosis in is the “stress of life” itself that causes diseases of cells, because the compensational mechanism is civilization (induced by “stress-hormones”) (Se- much slower than the ventilation. This acute alka- lye). This statement might be wrong, because wild losis fairly resembles to sympathicotonia (tachy- animals don’t get diseases of civilization, even cardia, increased metabolism and O2 requirement, though they are at least as much stressed as human increased Ca2+-conductance, increased ion-pump- beings. In stress situations wild animals behave ing activities, etc.), although catacholamine level according to their instincts. The main behaviour is is normal or decreased (Sikter et al., 2007b).On – according to Cannon – the “fight or flight” re- the other hand the acute hypercapnia (acidosis) in- sponse, which is a hyperarousal condition (Can- creases the output of catecholamines in the organ- non). The most important (according to our view- ism (Bailey et al.), e.g. in the locus coeruleus point) in this acute stress response is that in this (Filosa et al.). In acute hypercapnia the catechol- condition there is a strong catecholamine (adrena- amine level is eleveted, although it seems to be line, noradrenaline) rush and an acute hypocapnia parasympathicotonia. Why? According to Tenney as well. Wild animals during this hyperarousal there is a feedback mechanism beetween carbon condition will fight or flee, they take physical ex- dioxide level and catecholamine output of the or- ercise, and this physical activity/muscle-work re- ganism (Tenney). In acidic condition catechol- sults in increased carbon dioxide production – this amine responsibility dramatically decreases, mean-

Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 163 ELMÉLETI ÖSSZEFOGLALÁS ANDRÁS SIKTER , GÁBOR FALUDI , ZOLTÁN RIHMER

while catecholamine output increases, but in spite mainly amino and “cytoplasm building ions” of this compensation acidosis makes sympathico- (K+,Mg2+,Zn2+, and inorganic phosphates) in tonia decrease (Kuijpers et al.). Contrarily, in alka- strictly given proportions (Sikter, 2007a). Cells losis catecholamine responsibility and sympathi- build-in the ions first into the cytoplasm with cotonia increases (although catecholamine output ATP energy (with pumping mechanisms). The slightly decreases) (Tenney, Schleifer et al., Sik- available electrolytes in the extracellular space ter et al 2007b). Catecholamines, e.g. noradrena- usually are not enough to supply “hungry” repair- line increase the Na+/H+ exchange in the cells ing cells – they struggle against each other for (Smith et al.), that causes alkalosis in the cytosol, electrolytes. Those cells having worse metabo- similarly to the effect of hypocapnia. We do not lism and less ATP-content will lose fighting, they think it is a coincidence. It is evident that cate- remain or become more and more ill. They are the cholamines take effect (at least partly) through LMR of an organism: they are the weakest link. causing intracellular alkalosis. Cannon’s “fight or In case a weak harmful noxa affects the tis- flight” response means a strong sympathicotonia/ sues/cells of the organism (e.g. moderate hypo- hyperarousal, because both catecholaminemia phosphatemia and alkalosis induced by hypocap- and hyperventilation cause alkalosis in the cyto- nia), cells are able to repair themselves conti- sol. “Freezing behaviour” causes parasympathico- nously and fight against the damage. They restore nia/hypoarousal, because acidosis caused by hy- their original ionmilieu, but not completely and poventilation is not totally compensated by in- not equally in the whole organism, the weakest creased catecholamine levels. In Steen’s animal cells/tissues get the worst of them, and they be- model hyperarousal appears at the end because come ill, at first functionally, then organically 2 the initial hypoventilation/hypercapnia generates (Sikter et al, 2007b). If they lose about /3 of their heavy catecholamine output and then the cells/ ATP content, they may die. Cells may tolerate tissues become alkalic following hyperventila- damage differently even in the same organ or tion. This ending is similar to Cannon’s acute same tissue by having different kinds of metabo- stress response but the pathomechanism is totally lism and different ATP energy contents. That different. The final arousal might be higher in statement is particularly important in organs con- Steen’s “biphasic” than in Cannon’s “fight or taining electrically excitable cells (e.g. CNS or flight” response animal model. heart). That means certain cells will become func- tionally affected (and they start firing frequently Locus minoris resistentiae or slowly) while other cells will not. This is why a noxious agent (like acute or chronic hypocapnia) Organic diseases (e.g. organic pulmonary disor- can cause different mental, organic or psychoso- ders as asthma bronchiale) often cause hyper- matic disorders in different patients. arousal mental disorders too (Dratcu), on the other hand hyperarousal mental disorders often cause High arousal conditions (or activate) asthma bronchiale which is thought to be sometimes purely psychogenic (Henderson). According to the second-messenger theory the Why does a pathogenic substance (in our exam- neurotransmitters do not get into the cell, but send ple: hyperventilation or hypophosphatemia in- a “second-messenger” instead. Ca2+ is the clas- duced by hypocapnia) cause different illnesses in sical second messenger (Rasmussen et al.). Very different patients (Knochel), and why do different simply written: the amount of Ca2+ entering into pathogenic substances cause (or worsen) illnesses the cytosol determines how strong is the response on the same organ in a given patient? It may be given by the neuron (e.g. during neurotransmitter explained with the theory of “locus minoris resis- release) (Dodge et al., Cooke et al.). Ca2+ enters tentiae” (LMR). the cytosol partly through the plasma membrane In case seriously harmful noxa affects the or- as a result of action potential, partly from the ganism (e.g. hyperacute illness, cancer), it causes intracellular organelles (from sacroplasmic reti- catabolism and degrades a part of (cells)-cyto- culums and mitochondria). The bigger the Ca2+ plasm. In this case the (anabolic) reparation of tis- extracytosolic/intracytosolic (EC/IC) chemical sues/cells cannot start until the harmful effect ex- potential is, the larger amount of Ca2+ will enter ists. If it stops, cells start to repair themselves, into the cytosol. That is why Ca2+ pumping mech- they start rebuilding cytoplasm, which consists of anisms (which need ATP energy) have great im-

164 Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 THE ROLE OF CARBON DIOXIDE IN THE PATHOMECHANISM… ELMÉLETI ÖSSZEFOGLALÁS portance. The most important pumping mecha- tains a pathological balance. After abrupt with- nism is SERCA which pumps Ca2+ into the sarco- drawal of alcohol the balance falls over. The cells plasmatic reticulum (SR) and mitochondria: of the organism start to regenerate but there is in- SERCA decreases the Ca2+ concentration of the sufficient material for building up the cytoplasm, cytosol, and thus allows more Ca2+ to re-enter. especially the “cytoplasm building minerals” are According to recent discoveries thyroxine acts missing. Developing hypophosphatemia can through activating SERCA (Periasamy et al.). De- cause acute energy deficiency mainly in the CNS, creased H+ concentration (intracellular alkalosis, because hyperventilation, hypocapnia (which is an e.g. decreasing carbon dioxide concentartion in obligatory symptom of delirium tremens) (Victor) the case of acute hyperventilation) increases trans- decreases cerebral circulation, O2 supply and on membrane Ca2+conductance, thus increases the the other hand it increases energy demand and amount of Ca2+ entering into the cytosol (Tom- causes high arousal. Flink pointed out that alcohol baugh & Somjen). Catecholamines activate the abuse causes negative magnesium balance, and Na+/H+ exchange mechanism, causing intracellu- contrary after alcohol withdrawal the magnesium lar alkalosis as well. Therefore everything that balance becomes positive (Flink), meanwhile hypo- decreases the concentration of intracellular (cyto- magnesemia, hypokalemia, hypophosphaetemia solic) Ca2+ and/or H+ concentration — in rest- often develop accompanying hyperventilation. ing/basal state of cells — increases the Ca2+-con- Although only a few researchers recognized the ductance in neurons and the excitability. H+ connection between hypophosphatemia and delir- seems to be the most important ion which modi- ium tremens (Funabiki et al.), that is because se- fies Ca2+-conductance, it can be considered a mo- rum Pi test is not a routine examination. However difier of second messenger Ca2+. E.g. intracellular incidence of hypophosphatemia is 30-50% among alkalosis, acute hypocapnia, thyroxin and cate- hospitalized alcoholics. Othervise hyperventilation cholamines increase arousal. itself causes hypophosphatemia too, it is the most common cause of hypophosphatemia in hospital- Delirium ized patients (Ratkovic-Gusic et al.). There is an It is very hard or impossible to differentiate be- inverse correlation between pCO2 level and hyper- tween symptoms of delirium and those symptoms arousal symptoms of CNS during alcohol with- caused by severe hypophosphatemia in the central drawal (Victor), that hyperventilation plays an im- nervous system (CNS) (Knochel). Severe hypo- portant role in the pathomechanism of delirium phosphatemia causes critically low ATP level in tremens. Hyperventilation and anxiety are part of cells, especially in cells and organs of the “locus subacute alcohol withdrawal syndrome too (Roe- minoris resistentiae” of the organism (Sikter, 2007a). lofs et al.), and probably play a decisive role in Delirium is observed to develop during incorrect craving for alcohol and in the relapses. It may be a refeeding after long-lasting starvation (Keys et strategy to precede hyperventilation periods after al.). (Delirium is one of the symptoms of so called alcohol withdrawal and in this way to precede “refeeding syndrome”.) Giving less minerals and hyperarousal and craving for alcohol. Patients know more protein to malnurished, chronically starving from their experience that drinking of alcohol patients, severe electrolyte deficiency can develop abolishes symptoms of hyperarousal and craving. in the extracellular space too. Especially the hypo- (That is because alcohol restores previous patho- phosphatemia is dangerous because it directly logical balance of the organism – see above). causes a lack of ATP in cells (see chemical equa- Delirium often occurs in demented patients. We tion: ADP+Pi= ATP), severe dysfunction or even suppose that the pathomechanism of delirium de- cell death. Acute energy deficiency of the CNS veloping in demented patients is similar to the can appear among symptoms of delirium. (But pa- above-mentioned. We did not find any data either tients did not drink alcohol at all.) in relation to hypophosphatemia or hyperventila- Delirium in “refeeding syndrome” is the key to tion, although Miyamoto et al. created an animal other types of delirium. After chronic alcohol ab- model of “postoperative delirium in elderly” (Mi- use delirium tremens frequently develops after al- yamoto et al.). Postoperative delirium develops in cohol withdrawal. Chronic exposure to alcohol that groups of elderly patients, in it might occur causes persistent toxic damage to cells of the or- spontaneously too. It is supposed that these two ganism in case of chronic alcoholism, but it main- pathomechanisms are similar. Precondition of de-

Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 165 ELMÉLETI ÖSSZEFOGLALÁS ANDRÁS SIKTER , GÁBOR FALUDI , ZOLTÁN RIHMER veloping delirium is pre-existing brain damage or perventilation would have a significant role in the significant cerebrovascular insufficiency. Dam- pathomechanism of panic disorder (Lum, Ley). aged, sick cells usually have a lower resting mem- That is because the carbon dioxide challenge test brane voltage potencial, the threshold potential is widely used to provoke panic (Griez), but vol- gets closer to resting potential (Sikter, 2007a), that untary hyperventilation is only a weak challenger is why the damaged cells are often more excitable. (Nardi et al.). We made an attempt to integrate the Hyperventilation/hypocapnia plays an essential three main theories (Sikter et al., 2007b. See the role in the cases of postoperative delirium under full text article: http://www. scielo.br/pdf/rbp/ mechanical ventilation. Patients that are mechani- v29n4/a15v29n4.pdf) about the relationship be- cally hyperventilated keep on overbreathing for a tween hyperventilation and panic disorder, even while even after the operation, that is why they go though according to Wilhelm et al. (2001a), these into delirium. Hypocapnia further decreases cere- theories would include antagonistic contradictions. bral circulation meanwhile it increases O2 demand The three statements are: A/ hyperventilation is a and causes hyperarousal. Levkoff et al. analysed protective/preventive mechanism against panic delirium among elderly hospitalized patients, attacks; B/ it is a physiological response to hyper- 34% of patients experienced individual symptoms capnia; C/ it can induce panic attacks. of delirium without meeting full criteria, 31,3% We think that panic attack is a cascade of events developed new-onset delirium. About 80% of pa- where hyperventilation has different roles in dif- tients had residual cognitive impairment even 6 ferent times. Chronic hyperventilation is probably months later (Levkoff et al). These data suggest a precondition of (respiratory subtype) panic at- that delirium is a common disorder that may be tack, although it defends against panic. While it substantially less transient than currently believed exsists, spontaneous panic attacks cannot arise and that incomplete manifestations of the syn- (see statement A). Chronic hyperventilation can be drome may be frequent. Delirium developing after generated by either organic diseases (e.g. asthma hospitalization might be caused by Cannon’s “fight bronchiale) or mental conditions (e.g. sighing or or flight’ response, because patients having dam- crying for a tragedy). Compensational mechanisms aged brain did not perceive the situation properly set off metabolic acidosis that neurtralizes hyper- and they suppose to be in danger. Feeling horror ventilational alkalosis, this compensational process they can release enormous amount of catechol- lasts at least for a week. In the state of compen- amines and start hyperventilating. We suppose sated hypocapnic alkalosis extra- and intracellular that a vicious circle develops in the cases of spon- pH stays in the normal range. The depressed pCO2 taneously evolving delirium in elderly. Patients level starts to go up to the normal level (or slightly with damaged brain tend to get involved in hyper- higher) before the attack. The elevating carbon di- ventilation and delirium – frequent delirium causes oxide promptly diffuses into cells and causes aci- hypoperfusion of brain and harms it, causing more dosis, which increases catecholamine release from brain damage, etc. different cells (e.g. noradrenaline release from lo- Therefore delirium evolves if the brain is dam- cus coeruleus) (Filosa et al.). On the other hand, aged (functionally or structurally too), suddenly a elevating carbon dioxide level also evokes acute disproportion develops between supply and de- hyperventilation (through a brainstem reflex), mand of ATP energy and of “cytoplasm building which may be more vigorous than previously. (see minerals” (because of developing hypophosphat- statement B). At this point hypercatecholamin- emia, hypomagnesemia, etc.) Hyperventilation is emia (induced by previous acidosis) and alkalosis an obligatory part of delirium: it increases metab- (abruptly decreasing pCO2 level) evolve at the olism, O2 demand, causes high arousal, and at the same time. Alkalosis multiplies CNS-responsive- same time it causes hypoperfusion in the brain. ness to catecholamine levels, and it lasts for sev- eral minutes to break down catecholemines. This Panic disorder coexistence means an intense sympathicotonia, a Although panic disorder (PD) seems to be a typi- very high arousal. (The cascade of events is simi- cal hyperarousal condition, not only the patho- lar to Steen’s animal model – a hypercapnic period genetic role of hyperventilation, but even its exis- is followed by a hypocapnic one) (Steen et al.). tence was denied by many researchers for a long High catecholamine level/sympathicotonia can time. The minority of authors now think that hy- provoke panic attacks (Cameron et al.). Panic at-

166 Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 THE ROLE OF CARBON DIOXIDE IN THE PATHOMECHANISM… ELMÉLETI ÖSSZEFOGLALÁS tack is precipitated by this second (acute) hypo- GAD (generalized anxiety disorder) is patho- capnia (see statement C) plus catecholaminemia genetically also like PD, but with important diffe- induced by previous acidosis. rences. pCO2 level shows great variability in PD We have illustrated panic attack on a theoretical (mainly in the hypocapnic range), but it seems to diagram. According to this panic theory intra- and be around the normal level in case of GAD patients extracellular pH is thoroughly compensated before (Wilhelm et al. 2001b). Respiration is extremely the attack, but the acidosis would be overcom- unstable and irregular in PD. Respiration varia- pensated by acute hypocapnic alkalosis during the bility in GAD is lower than in PD, though it is attack. The main problem is that the different higher than physiologically. Alteration of pCO2 compensational mechanisms work out at different level makes catecholamine levels fluctuate be- rates. Carbon dioxide level can change in the whole cause of altering pH. Actual catecholamine levels organism in a few seconds, the elimination of interfere with actual pCO2 levels, which results in catecholamines lasts for several minutes, and the arousal alterations (like PD). Namely both pCO2 clearing of blood from metabolic (“titratable”) and catecholamine levels are fluctuating but with acidity takes at least one week. This is one of the different rates – their effects on arousal sometimes many reasons there is no perfect compensational added together, sometimes substructed. Another mechanism. mechanism which intensifies alteration of arousal: changes of carbon dioxide and catecholamine level Hyperventilation syndrome, GAD may affect on most neurons similarly. Neurons in Somatic symptoms of hyperventilation syndrome the brain are working together. Those neurons lin- are similar to those of panic disorder, except for ked to each other in a row are able to multiply both the panic attack itself (Cowley et al.). Acute and hypo- and hyperarousal. chronic hyperventilation may cause alterations and We suppose there is a fluctuating pCO2 level symptoms in almost any organs, not only in the slightly around the normal values at GAD patients. CNS (Gardner, Laffey et al.). Intracellular pCO2/pH and catecholamine level would keep changing permanently, causing more

Fig. 1. Schematic diagram of (respiratory subtype) panic attack

PERIOD A/ (preconditional situation): chronic hypocapnic alkalosis is compensated by chronic metabolic acidosis (pH is in normal range). Arousal is normal. PERIOD B/ pCO level starts to normalize (is elevating): intracellular acidosis arises, catecholamine output increases.Arousal is normal or decreased. PERIOD C/ pCO level reflexivelydecreases,responsibilityof neuronesto catecholaminesincreases,catecholaminelevel is still high – panic attack may arise. (PERIOD D/ Feeling and fearing of somatic sensation may elevate catecholamine level and slows down panic attack relief.) (Veltman et al.) (Period D is not on the diagram!)

Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 167 ELMÉLETI ÖSSZEFOGLALÁS ANDRÁS SIKTER , GÁBOR FALUDI , ZOLTÁN RIHMER or less arousal than in the healthy controls. That is pathomechanisms take place in both kinds of dis- why arousal fluctuates permanently, even dys- orders. (See LMR.) It is proved that intracellular thymia can arise (Pini et al.). If this statement is pH is one of the most important factors influenc- right, we could call GAD “bipolar anxiety” too. ing inward Ca2+-current in hippocampal neurons too We think that every hyperarousal condition in- (Tombaugh & Somjen, Tombaugh 2008). There is volves hypoarousal periods too. One of the rea- frequent (20-60%) comorbidity between bipolar sons for this may be that pH elevation (and pCO2 disorder (BD) and PD (MacKinnon et al. 2006) and decrease) has to be corrected from time to time. both have episodic courses. MacKinnon et al. (2009) (Cytosolic pH is limited in a narrow range even in found heightened anxiety responses among BD pa- pathological conditions.) tients during CO2 challange test, which is some- Both alkalosis and acidosis increases cytosolic what similar to PD patients’ answer, but BD pa- Ca2+ in the cells. While acidosis increases basal tients were not examined whether they would have cytosolic Ca2+ level (Bers et al.), alkalosis in- been chronically hyperventilating or not. Anyway creases inward Ca2+-current. This Ca2+ overload it is possible that hyperventilation/hypocapnia requires more pumping activity and ATP energy plays a role in the pathomechanism of BD too. — the energy supply may become insufficient af- It is an important similarity of both of these dis- ter a long-lasting alkalosis. Therefore basal cyto- orders, that particular regions of the brain have el- solic Ca2+ may rise even in resting state in hyper- evated lactate levels (Dager et al.). This may be arousal conditions too. That is why GAD increases the key to solve the problem. Dager et al. investi- the risk of coronary heart disease even in the ab- gated miscellaneous intermadiate chemical mat- sence of major depressive disorder (Barger et al.), ters with a special “PEPSI” technique in the hip- and GAD can turn into depression, we think. pocampus of medication-free BD patients. They SSRIs may be effective in PD and in GAD be- only found the lactate to be significantly elevated cause of increased basal cytosolic Ca2+ level. It is in both types of BD patients. (BDI patients had evident that cytosolic Mg-ATP complex and Mg2+ higher level lactate than BDII.) Lactate level was itself often decrease, which are inseparable from much higher in the gray matter signalling where it elevated cytosolic Ca2+ level – in hyperarousal arose. Elevated lactate level usually coexists with disorders, too (Durlach et al., Barbagallo et al., hypocapnia in the brain, but it is not often clear Bobkowski et al., Sikter 2007a). which of them is the cause and the consequence. It GAD means permanently fluctuating ventila- is an important fact that lactate arises in cells only tion and altering arousal, which hypo- and hyper- in alkalic conditions (Maddock), then it diffuses arousal conditions affect each other and may cause into the extracellular space causing acidosis. Only vicious circles through psychogenic mechanisms. the quickly spreading hypocapnic alkalosis is able This fluent alteration may result in depression to keep step with the also diffusible lactate. They and/or psychosomatic disorders. Being human we can compensate each other. Perhaps the pH is not have to behave ourselves, and our activities often homogeneous in all neurons’ cytosol. There may separate from stress-induced hyperarousal. It be a certain “pH-mosaicism” in neurons, because seems plausible that doing physical execises fre- lactate-CO2 equilibrium might not be perfect, on quently would be preventive or curative on the the the other hand the places of lactate production harmful effects of stress. EITHER we can learn how and utilisation might be separated. We think that we could control our breathing to maintain eu- certain neurons of the hippocampus should be ventilation, and this way the milieu interieur of alkalic in medication-free BD patients, other neu- cells/tissues, OR we can try to restore the ion- rons might have acidic cytosol. “Alternating car- alterations in tissues by giving special electrolyte bon dioxide level theory” would be suitable to ex- mixtures (this issue needs further research). plain the episodic courses of BD. Although this is AND/OR: It is also a curative process to break psy- merely a hypothesis because there are no direct chogenic vicious circles off (e.g. by psychother- data for the coexistence of hyperventilation and apy). BD, intracellular metabolic alkalosis may be an alternative pathomechanism to increase Ca2+-con- Bipolar disorder ductance and/or to produce lactate, e.g. by im- Mood and anxiety disorders appear in different proper ion-pumping mechanisms (Boron). brain structures, thus it is possible that the same

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There is a growing amount of data showing that oidism with lithium is a reliable and quick method BD is a genetically determined disorder, and the to restore proper inward Ca2+-current and metabo- main alteration would be in mitochondria (Kon- lism (Akin et al.). We suppose rapid cycling courses radi et al.). Energetic insufficiency may only be a are caused by pCO2 level changes. Stable, deep consequence because ATP deficiency cannot cause depression may arise after energetical insuffici- hyperfunction, we think. According to an animal ency, when SERCA cannot restore basal cytosolic model there seems to be an increased Ca2+- con- Ca2+ level due to the lack of ATP. ductance from the mitochondria membrane to cy- tosol (Kubota et al.). The hyperactive Ca2+ dy- Low arousal conditions namics is proved in B lymphoblasts from BDI pa- As mentioned above, the hyperarousal conditions tients (Perova et al.). It is unknown what kind of 2+ are often followed by hypoarousal ones. Moder- mechanism increases Ca -conductance in mito- ate forms of “hypoarousal anxiety” usually are chondria. It might be a genetic failure which would considered to be normal, while we may call its cause alkalosis in the cytosol or in mitochondria definite form “neurotic depression” or dysthymia. by pumping mechanism (Boron), but non of the Dysthymia is lighter and more fluctuating than de- researchers found intracellular alkalosis in the pression. limbic system. (Perhaps recent methods are not ATP-content of cells decreases with ageing and sensitive enough, and the existing lactic acidosis illnesses (Barbagallo et al., Sikter 2007a,). Cells/ of brain might be disturbing as well.) Kato et al. 31 neurons struggle against equilibration of ions in found neutral pH during P-MRS technique in the their whole life, namely to maintain their chemical medication-free manic period, which turned potential between the extra- and intracytosolic acidic after lithium treatment, while patients be- spaces. Though the chemical potential of Ca2+EC/ came euthymic. We can construate a BD model, if Ca2+IC, Na+EC/Na+IC, H+EC/H+IC and of we accept Kato’s statements. (Although others Mg2+IC/Mg2+EC, K+IC/K+EC decreases parallel could not verify Kato’s results.) with ATP-content. When intracytosolic Ca2+-con- According to this model: BD is caused by an in- 2+ tent increases, responsibility of neurons decreases, crease (of unknown origin) of Ca -conductance because Ca2+-conductivity decreases. Contrarily in mitochondrial membranes. The increased in- when the chemical potential of Na+ and/or K+ de- ward Ca2+-current makes SERCA work harder creases, responsibility/excitability of neurons in- (to restore the original cytosolic milieu), that creases because the membrane potential usually needs more ATP energy. Therapeutically given 2+ also decreases and gets closer to threshold poten- lithium acidifies the neurons’ cytosol and Ca - tial, that is why (electrical) stimulation excites conductance becomes normal. In this hypothetical neurons easier then formerly. According to these model the intermittent hypocapnia/hyperventila- alterations the structure of arousal alters with age- tion would play only an episodic role in episodic ing. The incidence of GAD, PD and manic periods courses. It is known that lithium affects acid-base of BD decreases while that of depression and other metabolism (Kraut et al.). It is not known how hypoarousal conditions increases because of the lithium acidifies the cytosol, one of its intracel- elevated cytosolic Ca2+ level. Although the hypo- lular acidifying mechanism may be inhibiting the + capnic alkalosis is common in the elderly because Na :HCO3 cotransporter (Amlal et al.). It is likely of cardiovascular and other organic disorders, de- that the primer event is that lithium inhibits + lirium is the only hyperarousal condition which H -ATP-ase activity, at least in rats’ renal collect- occurs more often with ageing. Electrically excit- ing duct cells (Kim et al.). A similar blocking ac- able cells having higher resting/basal Ca2+ con- tion of lithium on limbic system neurones would centration react less to hypocapnic alkalosis, but if be fitting well into our model. Maybe that is why the membrane potential decreases, neurons be- lithium attenuates intracellular calcium mobiliza- come irritable again. We think that the elevated tion. basal cytosolic Ca2+-content is why depressed pa- We note that there are some similarities between tients show less heart rate variability and altered hyperthyreodism and BD. Although in hyperthyre- autonomic nervous system activity (Carney et al.). oidism the primer event is the activation of 2+ 2+ 2+ Elevated basal cytosolic Ca , decreased Mg are SERCA, increased inward Ca -current is only its the missing links which may join several endemic, cosenquence. Nevertheless treating hyperthyre- ageing-associated disorders together (Barbagallo

Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 169 ELMÉLETI ÖSSZEFOGLALÁS ANDRÁS SIKTER , GÁBOR FALUDI , ZOLTÁN RIHMER et al., Sikter 2007a.). This altered ionmilieu may cases of COPD (de Voogd et al.) (but anxiety was be the most important link between depression similarly common). Although depression played a and coronary heart disease too. The cytosolic Ca2+ significant role in mortality, there was no correla- accumulation-tendency (with ageing and ill- tion between elevated CO2 level and depressive nesses) refers to the whole organism. (Memento: symptoms. (Elevated CO2 level does not necessar- All of the cells have to struggle against the equili- ily mean also elevated H+ ion level in cytosol, be- bration of ions between extra- and intracytosolic cause of compensatory mechanisms.) In the cases space.) The ionic equilibration-tendency though is when COPD patients were given O2-therapy, they not homogenous in the whole organism because of fell into serious depression, or their existing de- the LMR phenomenon and contraregulation of en- pression worsened (Maurer et al.). It is understood docrine system (Sikter 2007a). The hypothesis of that O2-therapy is elevating carbon dioxide level, elevated basal cytosolic Ca2+ level in limbic sys- so it is evident that elevating carbon dioxide level tem neurones is an early depression theory (Du- itself (the acidic pH in neurons’ cytosol) is what bovsky et al.). Cytosolic H+ concentration rising causes the depressive symptoms, not hypoxia. tendency is similarly common with ageing and ill- Sleep deprivation is a useful therapeutic option in nesses due to erroneous H+-pumping mechanisms. the treatment of depressive disorders (Svestka et Several mechanisms lead to intracellular acidosis, al.). Carbon dioxide level is elevating also in physi- the lack of ATP is one of the most important (Sik- ological sleep, mainly in the NREM periods (Ca- ter 2007a). Bioenergetic insufficiency (the lack of sey et al.). Partial deprivation of REM-sleep may ATP) may cause cytosolic Ca2+ accumulation and be also (but less) effective in depression, perhaps Mg2+ deficiency as well. This state frequently oc- because pharynx muscles relax exaggeratedly curs in depression, furthermore it may be the during REM periods (in pathological conditions) cause of depression. Therapeutically given thy- causing hypoxia and hypercapnia in OSA. roxine may restore ATP level and improve depres- We can influence the cytosolic H+ and/or Ca2+ sion (Iosifescu et al.). milieu of the neurons in the limbic system giving drugs that are effective against depression. Nor- Depression adrenaline decreases H+ concentration in rat hip- + + According to our hypothesis, there are three ways pocampus CA1 cells due to activating Na /H ex- for the cytosolic ionmilieu of limbic system neu- change mechanism (Smith et al.). Triacetyluridine rons to become hypoaroused, and depression (TAU) is a less notorious drug curing depression, arise. We suppose that a very high basal cytosolic although Jensen et al. found that TAU decreased Ca2+ level exists in major depressive disorder, depressive symptoms and increased brain-pH in which is partly genetically determined. On the BD patients (Jensen et al.). SSRIs are elevating se- other hand plenty of organic disorders occur with rotonin level on their receptors. Serotonin also has increased intracellular Ca2+-content, though we a positive inotropic response on rat cardiomyo- cytes, increases SR Ca2+ content, and cytosolic in- don’t know exactly which genetic-endocrine con- 2+ stellation elevates the cytosolic Ca2+ content of ward Ca current. (Birkeland et al., authors do not mainly the limbic system. know which is the primer event, while basal cyto- solic Ca2+ level was not examined.)(Birkeland et Elevating carbon dioxide concentration certain- 2+ ly causes acidosis in the cells, because compensa- al.) This effect of serotonin on Ca -movement tory mechanisms follow carbon dioxide altera- fits well into our depression-model, although it may not be a primary event but a consequence of tions slowly. pCO2 is usually elevated in obstruc- + tive sleep apnea (OSA) syndrome, and it is elevat- decreasing cytosolic H -concentration. It was ing during the sleep. Perhaps that is why the inci- found that serotonin alkalinized both crypt and villus cells of rabbit ileum via inhibiting Cl-/ dence of depression is about 50% in this disease. + + Symptoms of depression practically disappear af- HCO3-exchange and/ or stimulating Na /H ex- ter continuous positive airway pressure treatment change (Sundaram et al.). (CPAP) (Schwartz et al.). Unfortunately, hypoxia As we saw, hyperarousal conditions are usually also coexists in OSA, that is why we do not know followed by hypoarousal conditions (GAD–dys- whether hypercapnia (acidosis) or hypoxia is the thymia, hyperarousal delirium–hypoarousal delir- actual cause of the depressive symptoms. Depres- ium, mania–depression, etc.) The only stable arous- sive symptoms were also present in 40-60% of the al condition is major depressive disorder. That is

170 Neuropsychopharmacologia Hungarica 2009, XI/3, 161-173 THE ROLE OF CARBON DIOXIDE IN THE PATHOMECHANISM… ELMÉLETI ÖSSZEFOGLALÁS why we can call it unipolar depression. That is be- BDI=Bipolar Disorder type I BDII=Bipolar Disorder type II cause we can easily drop from a high peak (hyper- CHD=coronary heart disease arousal), but it is hard to climb up from a deep pit CNS=central nervous system (depression) – the low energetic conditions are CPAP=Continuous Positive Airway Pressure stable. (Is it because the second law of thermody- COPD=Chronic Obstructive Pulmonary Disease namics?) Unipolar depression is an entity, but GAD=Generalized Anxiety Disoorder EC=ExtraCytosolic (SR and mitochondria are intracellular there are plenty of similar conditions. Most of the but extracytolosic!) serious ageing-associated disorders have a high IC=IntraCytosolic coincidence with depression (e.g. CNS organic LMR=locus minoris resistentiae disorders, cardiovascular disorders, pulmonary NREM=Non-Rapid Eye Movement pCO =partial Pressure of Carbon Dioxide disorders, uremia, cancer, malnutrition, etc), per- 2+ Pi= inorganic phosphate haps because of increased basal cytosolic Ca PD=Panic Disorder + and/or H concentration (Barbagallo et al., Sikter REM=Rapid Eye Movement 2007a). OSA=Obstructive Sleep Apnea It is important (both theoretically and practi- SERCA=SarcoplasmaticReticulum Ca2+-ATP-ase SR=Sarcoplasmatic Reticulum cally) that we can mobilize ATP energy and de- 2+ SSRI=Selective Serotonin Reuptake Inhibitor crease basal cytosolic Ca level by giving thyrox- TAU=TriAcetylUridine ine and activating SERCA in a part of depressive cases, even if hypothyroidism is not evident, in Levelezési cím: this way we can cure depression (Iosifescu et al.). András Sikter, MD Municipal Clinic of Szentendre ABBREVIATIONS Section of Internal Medicine ATP=Adenosine TriPhosphate Szentendre, Kanonok u. 1., 2000 Hungary BD=Bipolar Disorder phone: 00 3626501442 E-mail: [email protected], [email protected]

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