Medical Hypotheses (2005) 65, 829–840                                                                              http://...
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Metabolic depression in hibernation and major depression                                                       831   These...
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Metabolic depression in hibernation and major depression                                                 833of black bears...
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Metabolic depression in hibernation and major depression                                                                  ...
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Metabolic depression in hibernation and major depression                                                                  ...
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Metabolic depression in hibernation and major depression: an explanatory theory and an animal model of depression


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Metabolic depression, an adaptive biological process for energy preservation, is responsible for torpor, hibernation and estivation. We propose that a form of metabolic depression, and not mitochondrial dysfunction, is the process underlying the observed hypometabolism, state-dependent neurobiological changes and vegetative symptoms of major depression in humans. The process of metabolic depression is reactivated via differential gene expression in response to perceived adverse stimuli in predisposed persons. Behavior inhibition by temperament, anxiety disorders, genetic vulnerabilities, and early traumatic experiences predispose persons to depression. The proposed theory is supported by similarities in the presentation and neurobiology of hibernation in bears and major depression and explains the yet unexplained neurobiological changes of depression. Although, gene expression is suppressed in other hibernators by deep hypothermia, bears were chosen because they hibernate with mild hypothermia. Pre-hibernation in bears and major depression with atypical features are both characterized by fat storage through overeating, oversleeping, and decreased mobility. Hibernation in bears and major depression with melancholic features are characterized by withdrawal from the environment, lack of energy, loss of weight from not eating and burning stored fat, changes in sleep pattern, and the following similar neurobiological findings: reversible subclinical hypothyroidism; increased concentration of serum cortisol; acute phase protein response; low respiratory quotient; oxidative stress response; decreased neurotransmitter levels; and changes in cyclic-adenosine monophosphate-binding activity. Signaling systems associated with protein phosphorylation, transcription factors, and gene expression are responsible for the metabolic depression process during pre-hibernation and hibernation. Antidepressants and mood stabilizers interfere with the hibernation process and produce their therapeutic effects by normalizing the fluctuation of activities in the different signaling systems, which are down-regulated during hibernation and depression and up-regulated during exodus from hibernation and the hypomanic or manic phase of mood disorders. The ways individuals cognitively perceive, understand, communicate, and react to the vegetative symptoms of depression, from downregulation in energy production, and in the absence of known medical causes, produce the other characteristics of depression including guilt, helplessness, hopelessness, suicidal phenomena, agitation, panic attacks, psychotic symptoms, and sudden switch to hypomanic or manic episodes. The presence of one or more of these characteristics depends on the person's neuropsychological function, its social status between the others, and the other's response to the person. Neurobiological changes associated with metabolic depression during entrance, maintenance, and exodus from hibernation in bears is suggested a

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Metabolic depression in hibernation and major depression: an explanatory theory and an animal model of depression

  1. 1. Medical Hypotheses (2005) 65, 829–840 depression in hibernation andmajor depression: An explanatory theory andan animal model of depressionJohn A. Tsiouris *George A. Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities,1050 Forest Hill Road, Staten Island, NY 10314, USAReceived 20 May 2005; accepted 23 May 2005Summary Metabolic depression, an adaptive biological process for energy preservation, is responsible for torpor,hibernation and estivation. We propose that a form of metabolic depression, and not mitochondrial dysfunction, is theprocess underlying the observed hypometabolism, state-dependent neurobiological changes and vegetative symptomsof major depression in humans. The process of metabolic depression is reactivated via differential gene expression inresponse to perceived adverse stimuli in predisposed persons. Behavior inhibition by temperament, anxiety disorders,genetic vulnerabilities, and early traumatic experiences predispose persons to depression. The proposed theory issupported by similarities in the presentation and neurobiology of hibernation in bears and major depression andexplains the yet unexplained neurobiological changes of depression. Although, gene expression is suppressed in otherhibernators by deep hypothermia, bears were chosen because they hibernate with mild hypothermia. Pre-hibernation in bears and major depression with atypical features are both characterized by fat storage throughovereating, oversleeping, and decreased mobility. Hibernation in bears and major depression with melancholic featuresare characterized by withdrawal from the environment, lack of energy, loss of weight from not eating and burning storedfat, changes in sleep pattern, and the following similar neurobiological findings: reversible subclinical hypothyroidism;increased concentration of serum cortisol; acute phase protein response; low respiratory quotient; oxidative stressresponse; decreased neurotransmitter levels; and changes in cyclic-adenosine monophosphate-binding activity. Signaling systems associated with protein phosphorylation, transcription factors, and gene expression are responsiblefor the metabolic depression process during pre-hibernation and hibernation. Antidepressants and mood stabilizersinterfere with the hibernation process and produce their therapeutic effects by normalizing the fluctuation of activitiesin the different signaling systems, which are down-regulated during hibernation and depression and up-regulated duringexodus from hibernation and the hypomanic or manic phase of mood disorders. The ways individuals cognitively perceive, understand, communicate, and react to the vegetative symptoms ofdepression, from downregulation in energy production, and in the absence of known medical causes, produce the othercharacteristics of depression including guilt, helplessness, hopelessness, suicidal phenomena, agitation, panic attacks,psychotic symptoms, and sudden switch to hypomanic or manic episodes. The presence of one or more of thesecharacteristics depends on the person’s neuropsychological function, its social status between the others, and theother’s response to the person. * Tel.: +1 718 494 5237; fax: +1 718 494 2258. E-mail address: 0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.mehy.2005.05.044
  2. 2. 830 Tsiouris Neurobiological changes associated with metabolic depression during entrance, maintenance, and exodus fromhibernation in bears is suggested as a natural animal model of human depression and mood disorders.c 2005 Elsevier Ltd. All rights reserved.Introduction ities [2,3] including the observed brain metabolic changes [15], except the ones associated with cer-Hippocrates introduced the terms melancholia and tain temperamental characteristics [13]. What hasmania 2400 years ago, yet his description of melan- not yet been identified is the mechanism that pro-cholia and mania is still clinically valid today. He duces the neurobiological findings observed inwas the first to attribute the origin of melancholia depressive disorders in the vulnerable individualsto natural causes, the excess generation of black above in response to environmental stressors.bile in the spleen. The high prevalence of depressive disorders at Theories explaining many aspects of depressive all ages and both sexes in humans [16] and the datadisorders have been proposed since then, espe- accumulated up to date suggest that depressivecially in the last 100 years. To date, no clear expla- disorders result from the expression of an old adap-nation has been offered for the signs, symptoms, tive pattern from our phylogeny for energy preser-and state-dependent neurobiological abnormalities vation, which in the past had survival value. It hasobserved in depressive disorders [1]. been proposed that a form of metabolic depression Treatment of depressive disorders with psycho- homologous to the metabolic depression observedtropics; the effects of antidepressants in animal during mammalian hibernation is the underlyingmodels of depression; and studies in the blood, old adaptive process responsible for the neurobio-cerebrospinal fluid, brains, and brain tissue of logical changes and the core somatic signs anddepressed patients versus normal controls have symptoms of depressive disorders in humans [17].generated many etiological hypotheses to explain I have proposed [18] that the process of meta-the accumulated data. Many of these hypotheses bolic depression in different forms is activateddescribe the effects of psychotropics with antide- via differential gene expression of existing normalpressant qualities on the physiology and neuro- genes, in individuals with behavior inhibition bychemistry of the brain at different levels or have temperament [7], anxiety disorders, and overalldocumented state-dependent abnormalities, but genetic vulnerabilities [11–13], or early traumaticthey do not explain the neurobiology of depressive experiences [10] in response to adverse externaldisorders [2–4]. or internal stimuli [6,19]. It is postulated that these Many common environmental stressors that can adverse external or internal stimuli (environmentalprecipitate depressive disorders in predisposed stressors or signs and symptoms of medical illness)individuals have been identified [5,6]. Behavior are perceived by the individuals predisposed toinhibition by temperament in children predisposes depression [7,10–13] as a threat to their psycho-to anxiety disorders later in life [7]. High comorbid- logical or somatic survival.ity has been reported between anxiety, neuroti- Metabolic depression is defined as a drop in stan-cism, female sex, and depressive disorders [8] or dard metabolic rates, to less than the normal valuebipolar disorders [9]. Also, early traumatic experi- [20]. Hibernation, torpor and estivation are adap-ences have been reported to contribute to the tive states of organisms, whose basic mechanismpathophysiology of anxiety and affective disorders is probably plesiomorphic (= ancestral/primitive)[10]. in evolutionary terms [21], and involves metabolic Current research has identified the genetic vul- depression, with energy-saving benefits that havenerabilities of women predisposed to depression well-known survival value for the organism exhibit-[11] as variations in cyclic adenosine monophos- ing them in response to life-threatening environ-phate (cAMP) response element-binding protein mental stressors [22–25].(CREB 1) [12]. In addition, a polymorphism in the If metabolic depression, the underlying process5-HTT gene was found to predispose both sexes of hibernation, is also responsible for the neurobio-to anxiety and especially to depression in response logical findings and the core somatic symptoms ofto life stressors [13,14]. major depression, as has been proposed [17,18], It has become evident after much investigation predictable similarities would be expected in thethat the abnormal neurobiological findings ob- presentation and neurobiological findings at differ-served during the depressive or manic phase of ent levels between hibernation in bears and majoraffective disorders are state-dependent abnormal- depression in humans.
  3. 3. Metabolic depression in hibernation and major depression 831 These similarities will be outlined in the rest of this Major depression with atypical features or sea-paper. The non-active state bears fall into from the sonal affective disorder (SAD) is characterized bymiddle of October to the end of March has been la- overeating, craving for carbohydrates, weight gain,beled winter sleep or dormancy and not true hiberna- oversleeping, a special type of fatigue called lea-tion [26–28], but it has now been confirmed that den paralysis (e.g., heavy, leaden feeling in armsbears are the largest animals that hibernate [29–33]. and legs), and low energy expenditure; [39,45]. Hibernation in bears has been chosen as an ani- Similar characteristics have been observed in bearsmal model for major depression because: during their preparation for hibernation (pre-hiber- nation state) [46]. (a) Major depression is not associated with Differences have been observed in immune re- hypothermia; sponse between pre-hibernation and hibernation (b) Bears are the only animals that do not become states in bears [18,47,48] and between major hypothermic during hibernation, except for a depression with atypical features, or SAD and ma- drop of 2–4 °C in body temperature jor depression with melancholic features [49,50]. [27,34,35]. The literature also suggests that there are major (c) Deep hypothermia during hibernation of other differences in many neurobiological findings be- organisms suppresses gene expression and the tween the above two types of depression [1]. translation and transcriptional machinery of many proteins [27,36,37]. Direct metabolic depression process The process of metabolic depression during indicatorshibernation in bears as a natural animal model forunderstanding the neurobiology of depression is In bears during hibernation, metabolic rate (MR)being designed and discussed according to the five decreases by about 50% [51], oxygen consumptionsteps proposed by Sackett and Gould [38]. decreases by about 50% [52,53], and red blood cell The following similarities between hibernation (RBC) oxidative stress increases [54]. The lowin bears and major depression in humans are sup- respiratory quotient (RQ) of 0.6–0.73 observed inportive evidence for the metabolic depression the- bears during hibernation [34,41] represents pureory of major depression. fat combustion [55]. In humans, no studies have di- Where data are not available from studies in rectly evaluated the metabolic depression processbears, similarities between findings in major during major depression, but in one study, low RQdepression and torpor, hibernation, or estivation (0.71) was reported in treatment-resistant de-from other organisms will be cited. pressed patients versus controls [56]. This low RQ was thought to be clinically insignificant, but it demonstrated for the first time that oxygen wasPresentation – signs and symptoms used for oxidation of ‘‘other than carbohydrate substances’’ [56], mainly fat, in the depressed pa-According to the DSM IV [39], the core characteris- tients, as observed in mammals during hibernation.tics of major depression (unipolar or bipolar type), Metabolic depression in non-depressed humans hasespecially with melancholic and catatonic fea- been observed in the absence of hypothermia [57]tures, are insomnia, loss of appetite, weight loss, and in the presence of hypothermia after acciden-lack of interest in the environment, fatigue or loss tal exposure to the cold [58], suggesting that theof energy, and psychomotor retardation with occa- ability of the human organism to undergo meta-sional immobility. Psychomotor retardation is a bolic depression has not been lost.central psychobiological feature of depression[40]. Similarly, during hibernation, bears withdrawinto their den and are mostly immobile. They do Acute phase protein responsenot eat or drink, and they lose 25% of their bodyweight [41–43]. Bears appear to sleep constantly, Elevated levels of mRNA a2macroglobulin (a2M),but sleep EEG studies that would determine this without acute phase protein response, were ob-definitively have not been done on bears. Studies served in the liver of hibernating squirrels [59]. In-in other animals, however, revealed that during creased levels of haptoglobin were reported inhibernation, they are sleep-deprived and spend hibernating brown bears [47], and a2M levels weremany calories through gluconeogenesis to reach found to be elevated in black bears during hiberna-euthermic states to have rapid eye movement tion [48], but with an acute phase response [18].(REM) sleep [44]. Hypothermia suppresses the acute phase response
  4. 4. 832 Tsiourisin other hibernating organisms [36,37], except the norepinephrine, suppresses the norepinephrinea2M [60], but not in bears [18,48], as their temper- neuron’s firing activity at the locus ceruleus (LC)ature drops only mildly (2–4 °C) during hibernation [84,85]. Norepinephrine injection also increases[27]. The theory of metabolic depression during thermogenesis through gluconeogenesis, promot-major depression [18] explains the previous finding ing exit from hibernation in ground squirrels [86].of acute phase response to depression [61–68] for Furthermore, depression is observed in humanswhich different hypotheses have been proposed secondary to psychostimulant withdrawal [2], and[69,70]. decreased secretion of norepinephrine from the During hibernation in bears and depression in hu- LC is noted during metabolic depression withoutmans, levels of the acute phase proteins increase, comorbid anxiety disorder [87,88].but modestly in comparison to the increase ob-served during inflammation, trauma, or surgery.Activation of the inflammatory response system Hormoneshas been suggested as an adaptive defense mecha- The reversible subclinical hypothyroidism of hypo-nism against the consequences of metabolic thalamic origin observed in black bears duringdepression and oxidative stress observed during hibernation [30,89] and in patients with majorhibernation [51]. The same mechanism has been depression [90] is caused by reduced stimulationproposed for the acute phase response observed of the hypothalamus by the LC [91]. In addition,during major depression [17,18]. In individuals the increased serum cortisol concentration duringwithout the predisposition to the adaptive process hibernation in captive and wild black bearsof metabolic depression or when the process of [92,93] and during depression in humans [94,95]metabolic depression is interrupted voluntarily or suggests similar hypothalamic-pituitary-adrenalinvoluntarily, in periods of acute and chronic (HPA) axis activation during hibernation in bears,stress, the elastase unchecked by a1antitrypsin as during depression in humans [96,97].can lead to extensive tissue damage [71]. Tissuedamage can cause autoimmune reactivity and pro-gress to autoimmune disorders, often associatedwith depressive disorder, if the acute phase pro- Second messengers and intracellularteins, especially the C-reactive protein (CRP), can- signalingnot fully regulate phagocytic leukocyte activities[72], remove the injured cells [73], and interact Current research on how antidepressants, lithium,with the nuclear antigens released from necrotic and mood stabilizers exercise their therapeutic ef-cells to prevent repositioning of these antigens in fects has focused on cyclic-adenosine monophos-tissue [74]. The role of elevated CRP levels in heart phate (cAMP), inositol 1,4,5 trisphosphate (IP3)attacks is currently under investigation [75,76]. and pathways associated with transcription factorsThe modest increase of CRP in individuals predis- and gene expression [4,98,99]. Levels of cAMPposed to heart attacks, similar to the increase ob- binding activity, IP3, protein kinase A (PKA), cAMPserved during depression, hibernation, and the response element binding (CREB), protein kinasestress of captivity in bears [18] suggests that CRP C (PKC), brain-derived neurotrophic factor (BDNF),is only an indicator of stress and depression, both glucogen synthase kinaseÀ3 (GSKÀ3), b-arrestin-1of which have been associated with heart attacks. [100–103] and other second messengers, which are associated with energy generation and preser- vation, were found to be decreased or altered dur-Neurotransmitters ing depression but to be increased or normalized after treatment with antidepressants or mood sta-At the neurotransmitter level, norepinephrine, bilizers [4,98,104,105].serotonin, and dopamine levels are decreased dur- cAMP and PKA play a role in the oxidative phos-ing mammalian [77] and reptilian [78] hibernation phorylation and regulation of enzymes involved inas well as during major depression in humans intermediate metabolism [106,107]. Reversible[56,79,80]. Drugs that increased the levels of the phosphorylation is considered one of the mainneurotransmitters above in the synapses reverse mechanisms initiating metabolic depression duringthe symptoms of depression in humans and disrupt hibernation [22], and selective changes of cAMPthe hibernation process [81–83]. Reversal of RQ in and IP3 were observed during estivation in thetreatment-resistant depressed patients after injec- hepatopancreas of otala lactae [108]. Also, de-tion of desipramine [56] can be explained by the creased levels of cAMP binding activity were mea-fact that systemic injection of desipramine, like sured during hibernation in the white blood cells
  5. 5. Metabolic depression in hibernation and major depression 833of black bears versus the end of the hibernating depression [125] contributes the additional charac-state, but increased cAMP binding activity was teristics of depression, including feelings of worth-measured during the switch from prehibernating lessness; guilt; inability to concentrate; andto hibernating state [109]. This increase in cAMP suicidal ideations, threats, or attempts. Descrip-levels may be associated with the cAMP signaling tions, explanations, and treatment of depressivepathways involved in gene transcription when bears disorders through the years have been heavily influ-enter into the complete state of metabolic enced not only by medical knowledge of depressivedepression. disorders but also by society’s understanding and Depression of ion leakage and pumping (Na+ response to the presentation of depressive disor-pump) through changes in the lipid components of ders at given periods in different places of thethe membranes has been suggested as an energy- world.saving mechanism during hibernation [20]. Sodium Bipolar disorder was suggested by Lange to beinflux with voltage-gated sodium channels is regu- part of the same internal biological cyclical processlated by neuronal Na+/K+ATPase through significant as sleep and menses [126]. Hibernation was pro-ATP energy consumption [110]. Decreased activi- posed previously by others as a model for endoge-ties of Ca2+/Mg2+-ATPase and Na+/K+-ATPase, which nous depression [81,127] and SAD [128] butwere noted in the RBCs of hibernating black bears without reference to metabolic depression as the[54], confirm that energy-saving mechanisms are common underlying mechanism, which can explainin operation during hibernation in bears. Alterations the similarities in the presentation of hibernationin intracellular Ca2+ function [111–113] and de- and depression. The hibernation model of depres-creased Na+–Li+countertransport activity in RBC sion was abandoned, as it could not withstand themembranes have been reported in bipolar patients criticism that large animals do not hibernate[114,115]. The common mood-stabilizing mecha- [129], which has proven invalid [30,33,54]. Thenism of certain antiepileptics is voltage-dependent mitochondrial dysfunction hypothesis of depressionNa+channel inhibition [116,117] and lithium affects was proposed recently on the basis of (a) decreasedmood disorders by altering the transport kinetics of levels of phosphocreatine, which were observed inthe NA+À/L+ countertransport system [118] and Ca++ the left frontal lobes of patients with bipolarhomeostasis [119] . Lithium also suppresses hiber- depression by using magnetic resonance spectros-nation in the Turkish hamster [120], normalizes sys- copy (31P-MRS) [130] (b) decreased expression oftemic immune system activation associated with nuclear messenger-RNA, coding for mitochondrialdepression [66,67], stabilizes fluctuation in the proteins, in the hippocampus and frontal lobes ofactivities of different signaling systems through brains from subjects with bipolar disorders [131],multiple sites of action [121,122], and desynchro- (c) altered brain phospholipid abnormalities andnizes the oscillators [123] decoupling of which are their inhibitory effects on mitochondrial functionsassociated with disturbances of the body’s natural [6,132], and (d) other studies involving the intra-rhythms during mood disorders [124]. cellular process that regulates energy production. The proposed metabolic depression theory explains the above state-dependent phenomena that pro-Discussion duce ‘‘hypometabolism’’ during the depressive phase of bipolar disorder [130].Metabolic depression is a well-coordinated process It is proposed here that according to the meta-of different systems and pathways associated with bolic depression theory of depression, future stud-transcription factors and differential gene expres- ies would confirm ‘‘hypometabolism’’ during thesion. Initiated in response to stressors for energy depressed phase and ‘‘hypermetabolism’’ duringpreservation (conservation/savings) and survival the hypomanic/manic phase of mood disorders asof the organism, it is observed in organisms ranging cyclical, state-dependent phenomena. Polymor-from worms and otala lactae to bears and, accord- phisms in different genes will be identified, whiching to this theory, to humans during major depres- predispose individuals with a certain genotype orsion. It has been proposed [18] and further endophenotype to react to environmental stressorselaborated here that a form of metabolic depres- with ‘‘hypometabolism’’ [130], ‘‘functional shift’’sion is responsible for the lack of energy, fatigue, [133], ‘‘conservation-withdrawal’’ [134,135] andlack of interest in the environment, and sleep and alternating states between ‘‘hypermetabolism’’eating disturbances associated with major depres- (flight/fight) and ‘‘hypometabolism’’ (withdrawalsion. The way humans perceive cognitively, evalu- or freeze process) or mixed states.ate, describe, explain, and react to the above Major depression with atypical features may bevegetative signs and main characteristics of (a) a prodromal state to major depression with
  6. 6. 834 Tsiourismelancholic features, (b) a separate state influ- sion and to preserve the sense of well-being andenced by extremes in environmental temperatures ability to function.and sunlight or, (c) the type of depression towhich individuals with anxiety disorders aremostly predisposed. It appears that in such indi- Cortisol hypersecretion, metabolicviduals with certain temperamental and personal- depression, and psychotic processity characteristics, the metabolic depressionprocess is not fully coordinated or there is resis- Some individuals have high cortisol baseline secre-tance from the individual’s cognitive process to tion due to genetic factors and/or to stress during‘‘give up’’ or ‘‘let it go,’’ which at times triggers the pre/postnatal period of development. Shynessthe fear of dying and panic attacks, bringing the in young children was associated with elevatedperson to the emergency room for work-up for rates of baseline cortisol [140], which demon-different medical disorders. Treatment with anti- strated heritability and a relationship of cortisoldepressants and antianxiety medication at this levels with social stress and lack of social recogni-point or elimination of the environmental stress- tion [141]. Chronically high-average cortisol levelsors disrupts or reverses the process of metabolic were associated with anxiety and withdrawal indepression and reverses the symptoms of depres- adults with trait of anxiety and impaired socialsion, which could be considered another level of functioning [142,143]. High baseline morning corti-an adaptive process [136]. It has also been ob- sol is associated with a twofold increase in the riskserved that people with anxiety disorders and for onset of major depression within one year indepression with atypical features often develop adolescents identified as at high-risk for depressionbipolar disorder. Their bipolarity may be due to [144], and high evening cortisol levels in adoles-a vigorous attempt by the individual to prevent cents with depression have been found to predictentrance into major depression with melancholic chronic depression [145], recurrence of depres-features, by remaining in the state of major sion, and future suicide attempts [146]. Also, dexa-depression with atypical features and accumulat- methasone non-suppression has been associateding further weight (pre-hibernation) or escaping with both negative and cognitive symptoms in chil-from it by entering into a hypomanic/manic state dren with learning disabilities [147].(flight/fight response). It is worth noting that food Further increase of cortisol secretion secondaryavailability in a relatively warm environment dis- to metabolic depression during major depression inrupts the process of metabolic depression and en- such individuals can produce a trophic shift oftrance into deep hibernation in black and brown dopamine fibers away from pyramidal cells and intobears living in different parts of the world, keep- interneurons [148,149]. These individuals can being them in a state of pre-hibernation. vulnerable to developing reversible psychotic The underlying mechanism for panic attacks or symptoms during depressive and manic episodes.switching to hypomanic/manic state appears to The significant neurocognitive impairments acrossbe the following: Lack of energy due to the initia- a wide range of measures reported in bipolar pa-tion of the metabolic depression process and nega- tients [150] and the similarities that were observedtive cognitive evaluation of self-worth in in neuropsychological dysfunction between pa-individuals with anxiety disorders and other yet tients with psychotic depression and schizophreniaundefined temperamental and personality charac- [151] support this explanation.teristics invoke fear of annihilation and over-stim- The role of metabolic depression in schizophre-ulation of the central nucleus of the amygdala nia is unknown, but the prodromal symptoms of(CNA) and over-secretion of corticotropin-releasing schizophrenia (increased anxiety, impaired func-factor (CRF) [137,138]. This activation of CNA in tioning at different levels, withdrawal, lack of en-concert with the bed nucleus of the stria termi- ergy, anhedonia, avolition, lack of interest in thenales (BNST), the principal regulator of the locus outside world, decreased communication, preoccu-ceruleus (LC) [139], through their excitatory pro- pation with body function and negative thoughts),jections which contain CRF, stimulates the LC to in- which are similar to the symptoms of major depres-crease norepinephrine production and reverses the sion [152] and the observed hypometabolism in firstprocess of metabolic depression. Panic attacks, episode psychosis and ultra high-risk individualspsychomotor agitation, or sudden switches from [153] suggest activation of the metabolic depres-depressed to hypomanic or manic phase can result sion process at the initial phase of schizophrenia.from such attempts of the affected individual to Elevated baseline levels of cortisol [154–156]resist or reverse the process of metabolic depres- and neurocognitive deficits [157] due to structural
  7. 7. Metabolic depression in hibernation and major depression 835brain abnormalities [158] have been associated states should elucidate the neurobiological processwith increased risk for conversion to Axis I psy- of affective and possibly psychotic disorders.chotic disorders. Psychosocial stress in vulnerable The hope is that understanding the etiology ofindividuals [159] is perceived by the amygdala as the neurological finding of major depression anda threat to survival of the organism due to the mood disorders in general, with or without psy-inability to respond with flight or fight from lack chotic features, will enhance the development ofof energy due to the metabolic depression process. new preventive and treatment strategies, whichThis threat for survival produces activation of the can be tested in the proposed animal model andcentral or the basolateral nucleus of the hippocam- possibly change the psychosocial aspects and thepus [160]. The activation of these hippocampus nu- stigma that is associated with these devastatingclei, combined with further increase of cortisol psychiatric disorders.secondary to metabolic depression, can lead to tro-phic shift of dopamine fibers into interneurons[148,149] and might culminate in an increased Acknowledgmentsexcitatory drive to individual GABA-ergic cells atthe anterior cingulated cortex [161]. Dopaminergic The author thanks Lawrence Black for referenceinhibitory input to these GABA-ergic cells increases assistance, Maureen Marlow for editorial com-[162] through this process, forcing the GABA-ergic ments/suggestions and Valerie Mazza for technicalcells to fail in their attempt to provide adequate assistance. This study was partially supported byinhibitory modulation to pyramidal neurons. This the New York State Office of Mental Retardationactivity possibly precipitates the development of and Developmental Disabilities.non-reversible psychotic symptoms in response tostressors in fully withdrawn, isolated and anxiousindividuals with severe neuropsychological dys- Referencesfunction, whose systems cannot tolerate the meta-bolic depression process and react to it differently [1] Flores BH, Musselman DL, DeBattista C, Garlow SJ,than those who develop major depression, unipolar Schatzberg AF, Nemeroff CB. Biology of mood disorders.or bipolar type. In: Schatzberg AF, Nemeroff CB, editors. Textbook of psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Press; 2004. p. 717–63. [2] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ,Summary Monteggia LM. Neurobiology of depression. Neuron 2002;34:13–25.The adaptive by phylogeny process of metabolic [3] Manji HK, Drevets WC, Charney DS. The cellular neurobi- ology of depression. Nat Med 2001;7:541–7.depression, which is activated in different forms, [4] Manji HK, Lenox RH. Ziskind-somerfeld research predisposed individuals in response to stressors, Protein kinase C signaling in the brain: molecular trans-can explain the presentation and most of the ob- duction of mood stabilization in the treatment of manic-served state-dependent neurobiological findings depressive illness. Biol Psychiatry 1999;46:1328–51.during major depression. Initiation of the meta- [5] Paykel ES, Myers JK, Dienelt MN, Klerman GL, Lindenthal JJ, Pepper MP. Life events and depression. A controlledbolic depression process in certain individuals with study. Arch Gen Psychiatry 1969;21:753–60.high baseline levels of cortisol, neuropsychological [6] Kessler RC. The effects of stressful life events ondysfunction, and personality vulnerabilities might depression. Annu Rev Psychol 1997;48:191–214.precipitate development of psychotic symptoms. [7] Kagan J, Snidman N. 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