Current Psychosis and Therapeutics reports Vol. 4, Issue 4

 Evolutionary Epidemiology of Endophenotypes in the Bipolar Spectrum:

Evolved Neuropsychological Mechanisms of Social Rank

by Daniel R. Wilson, M.D., Ph.D. ¹ and John S. Price, D.M.²

(2,807 words in 15 pages, plus one table)

ABSTRACT (54 words): 

Medicine – until quite recently – has disregarded Darwin.  However, novel ethological perspectives of evolutionary epidemiology are beginning to shed light on both proximal and ultimate causes of human behavior in its boundaries with adaptive endophenotypes, disease and therapeutics.  Here we summarize how a Darwinian framework informs new insights concerning the spectrum from mania to depression. 

¹  Professor & Chairman of Psychiatry, Professor of Anthropology

   Creighton University, 3528 Dodge Street, Omaha, NE 68131 USA        

   wilson@creighton.edu          402.345.8828          402.345.8815 fax

² Department of Psychiatry, Brighton General Hospital, Brighton BN2 3EW UK
   johnscottprice@hotmail.com         00441273696100

Introduction

Niko Tinbergen – Dutch ethologist, Oxford professor, and Nobel laureate – said behavior requires four types of explanation [1].  Most usual are proximal explanations – “How?” epigenetic pathways operate from gene to behavior via neuroanatomy, neurophysiology and psychology.  As the molecular genetics of bipolar disorder encounters numerous barriers, the search is now for “endophenotypes” – recognizable, genetically distinct manifestations identifiable in relatives of probands [2-4].  Such endophenotypes include impairments of cognitive function [5-6], cyclothymia [7], dysmodulation of motivation and reward, and eye movement abnormalities [8].   Tinbergen also required ultimate explanations – “Why?” explaining how natural and sexual selection designed “evolved psychological mechanisms” that underlie all adaptive behavior, including attachment, reciprocal exchange, cheater detection, predator avoidance and social rank competition [9].  A third explanation is ontological – “What?” trait development is affected by life experience.  The final Tinbergian explanation is phylogenetic – “When?” delineating traits through prehistory.  Bipolar psychopathology is a malfunction of these evolved systems, with as yet unidentified endophenotypes [***10].  

Recognition that some psychopathologies are remnants of past adaptive behaviors is so new that little of this evolutionary neuroscience is yet systematized.  Several useful forays stand out: Darwin [***11]; Romanes [12]; Lloyd Morgan [13]; Huxley [14]; Price [15]; Gardner [**16]; Wenegrat [17]; Bailey [18]; Chance [19]; Gilbert [**20]; Glantz and Pearce [**21]; MacLean [***22]; Wilson [***23]; Williams and Nesse [**24]; Stevens and Price [***25]; McGuire and Troisi [**26], and Sherman [**27].

Meanwhile psychiatry, currently looking for endophenotypes underlying psychiatric conditions, would do well to recall that MacLean showed the basis for sociality to be evolved psychological mechanisms expressed via two opposing archetypal neuromental circuitries at three levels [MacLean 22]; malfunction in any aspect of which leads to disorder.   MacLean identified the first as R (reptilian)-complex, insofar as brain stem, midbrain, and part of forebrain became fully instantiated in ancestral reptilians 300 millions years ago.  The second level abuts R-complex as an assemblage of transitional mammals about 250 million years ago.  This Paleomammalian limbic system facilitates nursing of infants, parent-infant bonding, continuously interactive 'warm-blooded' social life and the emergence of play.  The third, a Neomammalian complex, from some 60 million years ago extends increasingly sophisticated domain-specific functions such as language, abstract thought, for greatly enhanced reciprocally interactive social life, including self-consciousness.

Natural selection depends on competition including getting food and avoiding disease and, fundamentally, reproduction.  Darwin [11] pointed out much competition is social, either intrasexual (between members of the same sex) or intersexual (mate choice).  Such social competition results in asymmetry in populations – some individuals succeed and others do not.  This asymmetry has existed since social competition began some 300 million years ago and mechanisms have evolved for managing asymmetry.  Inapt expressions of evolved selected mechanisms underlie mood disorders.  Mechanisms to accommodate failure underlie depressive personality disorder, those for change from success to non-success relate to depressive disorder, and those sub-serving change from non-success to success relate to elevated mood.  The secondary but important association with the attachment system arose as for over forty million years success in primate social competition has been largely due to alliances [28-32].  Mood elevation and depression in bipolar disorder are analogs of escalation/de-escalation strategies of agonistic behavior.  These evolved mechanisms regulate social competition and allocation of rank.  Partial replacement of more primitive agonistic competition by prestige competition has occurred in the human line but earlier repertoires can be activated especially in persons epigenetically prone to conscious or unconscious changes in self-esteem. 

It is helpful to review evolved changes in social competition organized relatively independently at three levels, both to emphasize the relation of mood disorders to social competition in the clinical setting and as a research avenue.

Social Competition

Animals compete not only for food and mates, but also for rank and territory with priority access to resources.  In virtually all vertebrates competition is ritualized agonistic behavior as two animals confront in “pair-wise contest”:  upon exchange of ritualized signals, one ends up dominant, the other subordinate.  In territorial species interactions are brief as the options are fight or flight:  fighters take territory, fleers must move elsewhere.   In group species, such as canids and primates, agonistic behavior differs subtly.  First, the option of submission is added to flight which usually, if it occurs at all, is temporary with early return of the defeated to the group via appeasement and reconciliation.  Second, agonistic encounters can greatly extend in time; for instance, change of rank in chimpanzees may take several months over a series of initially inconclusive “bouts”.  In the mammaloprimate line, fight or flight is replaced by escalation or de-escalation.  Escalation, behavior that increases chances of winning but also increases costs of losing, begins with agonism rising to more risky fighting (e.g., stags switching from parallel walking to locking horns) and recruiting allies.  De-escalation, behavior that reduces chances of winning but also reduces risks, consists of flight, submission and/or appeasement.

At some stage in primatohominoid evolution the basis for competition changed from agonism to prestige [33].  This was of profound importance.  Instead of contests decided by two contestants alone, group members adjudicate via approbation to one and disapprobation to the other – success is by charismatic attractiveness rather than intimidation, e.g., political speech, artistic expression, scientific innovation, or just being nice.  In prestige competition, escalation is self-assertive pursuit of goals likely to be esteemed by others.  De-escalation is more complex, because there is no one from whom to flee (nor, significantly, no one with whom to reconcile via submission or appeasement).  De-escalation is self-effacement, goal abandonment, and inactivity. 

Chimpanzees form both prestige and dominance hierarchies [34].  Thus prestige competition dates to our common ancestor some five million years ago, atop 300 million years of agonistically competitive neuromental evolution.  Humans retain agonistic impulses that are – generally – controlled by culture, except where societal norms are breached, such as prisons, school playgrounds, and dysfunctional homes.  However, neomammalian forebrain, the most sophisticated element in all of evolution, has incomplete control over the lower two levels, e.g., humans cannot simply will themselves to feel less angry or less depressed.  Nevertheless in recent human evolution, lineages with prestige competition out-competed agonistic groups in part because in prestige competition the group sets criteria, and so may select for altruism or other eusociality.   Conversely in agonistic competition, it is impossible to reward those who put group interests before their own concerns [20].

The Triune Brain

MacLean [22] noted that forebrain has three “central processing assemblies”, each relatively independent in dealing with environmental cues.  These evolved in distinct eras and are arranged rostral-caudally – Reptilian (approximately 300 million years ago), Paleomammalian (250 million years ago) and, Primatomammalian (60 million years ago).  This triune formulation has been criticized only in matters of detail [35].   Appeasement can operate at one or all three levels.   In its most primitive form as seen in contemporary reptiles, it is an all-or-nothing response such as total body color change – adult males pale and revert to dark muddy brown of immature animals (e.g., Anolis carolinensis) [36].  Such a lizard cannot appease an up-rival while dominating a down-rival.  ‘All-or-nothing’ is a mood strategy of the reptilian forebrain as both mood changes are pervasive in their effects but not subject to conscious modification.

The middle level involves limbic system Paleomammalian emotionality.  Subordinate rodents, canids or primates feel fear and chastening by dominants.  Such mammalian emotions are distinct from reptilian moods.  Mammalian emotion is not pervasive, but context dependent – most mammals rank mid-hierarchically and may be chastened from above, yet able to aggress upon and elicit appeasement from subordinates.  ‘Looking up’ generates anxiety whereas ‘looking down’ generates irritability.  Rational, voluntary, conscious appeasement at the Primatomammalian level requires considerable social skill, as in flowery speech of submission.

                                    (Table 1 about here)

Table 1 shows behavioral manifestations and other correlates of escalation and de-escalation at three brain levels.  Note that manifestations differ for the upper two levels (mammalian and primate), but are the same in reptilian brain. 

Implications for Research

Much work has been done on agonistic behavior, especially the rodent resident/intruder paradigm wherein the resident typically wins with the intruder enduring domination.  Early on this research was to do with cardiovascular and gastrointestinal disease, but eventually it was also noted dominated animals suffered depression while appeasement entailed changes in brain chemistry and anatomy [37].  This valid animal modelling of depression began with mammals but is extending in current studies on cynomolgus monkeys [38], tree shrews [39], rats [40-44], mice [45], fish [46, 47] and invertebrates [48].  Studies of reptiles are crucial, as capacity for mood elevation and depression first evolved in reptilian forebrain.

Implications for Treatment

Rank stress (threats to social position or anticipation of defeat) activates reptilian agonistic strategies with either escalation (elevated mood) or de-escalation (depressed mood).  Removal of rank stress allows recovery, although chronic escalation or de-escalation tend to habituation.  Rank stress is ended by reconciliation, negotiation, training, reframing, removal (from the physical or psychological situation), and other ways more the province of philosophy and religion [49].  De-escalation is of particular evolutionary importance in highly competitive species whose peaceable kinship bands or other social groups require considerable submission, appeasement and/or subordination.  Thus humans are exquisitely sensitive to put-down behavior, especially from dominants as well as friends and loved ones such as parents and children.  What is not generally realized is that even minor threats to self-esteem can cause severe episodes of escalation and de-escalation. 

Conclusion

Symptomatic elevation and depression of mood are maladaptive activations of ancient strategies evolved to regulate social competition.  Some patients are too prone to activate; others excessively escalate and de-escalate.  In some, activation is from within, independent of life events.  In others, early bipolar episodes may be event-related, yet later episodes may occur spontaneously via habituation.   In reaction to mismatch with contemporary developmental environs, persons with polymorphisms for enhanced eusocial endophenotyes are increasingly prone to pathophenotypy [10, 14, 15, 16, 18, 20, 23, 27].  Study of such endophenotypy in the context of evolved psychological mechanisms related to social competition is a promising avenue for advances in clinical neuroscience and molecular psychiatry.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as:

**   Of importance

*** Of major importance

1. Tinbergen, N: On aims and methods of ethology.  Zietschrift fur Tierpsychologie 1963, 20:410-433.

2. Gottesman II, Gould TD:  The endophenotype concept in psychiatry:  etymology and strategic intentions.  Am J Psychiatry 2003, 160:636-645.

3. Gould TD, Gottesman II:  Psychiatric endophenotypes and the development of valid animal models.  Genes, Brain and Behavior 2006, 5:113-119.

4. Hasler G, Drevets WC, Gould TD, et al: Toward constructing an endophenotype strategy for bipolar disorders.  Biol Psychiatry 2006, in press.

5. Christensen MV, Kyvick KO, Kessing LV:  Cognitive function in unaffected twins discordant for affective disorder.  Psychol Med 2006, in press.

6. Savitz JB, Solms M, Ramesar RS:  Neurocognitive function as an endophenotype for genetic studies of bipolar disorder.  Neuromolecular Med 2005, 7:275-286.

7. Hantouche EG, Akiskal HS: Toward a definition of a cyclothymic behavioural phenotype: which traits tap the familial diathesis for bipolar 11 disorder? J Affect Dis, in press.

8. Kathmann N, Hochrein A, Uwer R, Bondy B: Deficits in gain of smooth pursuit eye movements in schizophrenia and affective disorder patients and their unaffected relatives.  Am J Psychiatry 2003, 160:696-702.

9. Bowlby, J. Attachment and Loss. Vol. 3: Loss: Sadness and Depression.  London: Hogarth Press; 1980.

10. *** Wilson D, Cory G. The Evolutionary Epidemiology of Mania and Depression. New York: Mellen Press; in press.

Remarkable as the first contribution in evolutionary psychology generally that attends systematically to both genes and brains, with special attention to the bipolar spectrum.

11. *** Darwin C. The Origin of Species: By Means of Natural Selection, or the Preservation of Favored Races in the Stuggle for Life.  London: John Murray, 1859.  See also, The Descent of Man and Selection in Relation to Sex. London: John Murray, 1871.  Together the ne plus ultra of references.

12.  Romanes, GJ. Mental Evolution in Animals. London: Keegan, Paul, Trench & Co, 1884

13. Lloyd-Morgan, C:  Mental factors in evolution. In Darwin and Modern Science.  

Edited by Seward AC. Cambridge: Cambridge University Press; 1909

14. Huxley, J; Mayr, E; Osmond, H; Hoffer, A:  Schizophrenia as a genetic morphism.

Nature, 1964, 204:220-221.

15.  **Price, JS:  The dominance hierarchy and the evolution of mental illness. Lancet, 1967, 2:243.

A landmark presaging a resurgence of interest in Darwinian medicine and psychiatry.

16. **Gardner, RJ:  Mechanisms in manic-depressive disorder: An evolutionary model. Arch Gen Psychiatry, 1982, 39:1436-1441.

The first paper to directly link psychopathology to leadership traits.

17. Wenegrat, B:  Sociobiology and Mental Disorder: A New View. Menlo Park, CA:               Addison Wesley, 1984

18. Bailey, K:  Human Paleopsychology: Applications to Aggression and Pathological

Processes. Hillsdale, NJ: Lawrence Erlbaum; 1987

19. Chance, MRA:  A systems synthesis of sociality. In Social Fabrics of the Mind. Edited by M Chance. London: Lawrence Erlbaum; 1988

20. **Gilbert, P:  Depression: The Evolution of Powerlessness. London: Lawrence

Erlbaum, 1992

An exceptionally well detailed work explaining adaptive aspects of depression.

21. **Glantz, K; Pearce, J:  Exiles from Eden: Psychotherapy from and Evolutionary Perspective. New York: Norton, 1989

An early contribution to the resurgence of Darwinian thinking in psychopathology with excellent clinical vignettes.

22. *** MacLean, PD.  The Triune Brain in Evolution. New York: Plenum Press; 1990. The essential book on neuroethology.

23. *** Wilson, DR. Evolutionary epidemiology and manic-depression. British Journal of Medical Psychology, 1998; V71, 4/12: 375-396.

The first paper to operationalize evolutionary epidemiology.

24. **Williams, GC; Nesse, R:  The dawn of Darwinian medicine. Quarterly Review of Biology 1991, 66:1-22.

A classic description of Darwinian consequences in medicine as a whole.

25. **Maguire, M & Troisi, A.  Darwinian Psychiatry.  New York: Oxford University Press; 1998

A reinterpretation of social psychology in evolutionary terms.

26. *** Stevens A, Price J. Evolutionary Psychiatry: A New Beginning. Second edition. London: Routledge; 2000.   

An excellent overview of evolutionary psychiatry with clinical emphasis.

27. Sherman, JA: Evolutionary origin of bipolar disorder.  Psycoloquy 2001, 12 (028).

28. Price J, Sloman L, Gardner R, Gilbert P, Rohde P: The social competition hypothesis of depression. British Journal of Psychiatry 1994, 164, 309-315.

29. Price JS, Gardner R, Erickson M:  Can depression, anxiety and somatisation be understood as appeasement displays?  Journal of Affective Disorders 2004 79, 1-11.

30. Gilbert P: Evolution and depression: issues and implications.  Psychological Medicine 2006, 36:287-297.

31. Gilbert, P.  Depression: A biopsychosocial, integrative and evolutionary approach. In Mood Disorders: A Handbook of Science and Practice. Edited by M. Power. Chichester: J. Wiley & Sons, in press.

32. De Waal FBM, Harcourt AH. Coalitions and alliances: a history of ethological research.  In Coalitions and Alliances in Humans and Other Animals. Edited by Harcourt AH, de Waal FBM. Oxford: Oxford University Press; 1992.

33. Sloman L, Farvolden P, Gilbert P, Price J: The interactive functioning of anxiety and depression in agonistic encounters and reconciliation.  Journal of Affective Disorders, 2006, 90, 93-99.

34. de Waal, F. Chimpanzee Politics.  London: Jonathan Cape; 1982.

35. Cory GA:  Reappraising MacLean’s triune brain concept.  In The Evolutionary Neuroethology of Paul MacLean: Convergences and Frontiers.  Edited by Cory GA & Gardner, R. Westport CT: Praeger; 2002: 9-30.

36. Greenberg, N., Crews, D.  Physiological ethology of aggression in amphibians and reptiles. In Hormones and Aggressive Behavior. Edited by Svare BB. New York: Plenum Press; 1983:469-506.

37. Davidson RL, Pizzagalli D, Nitschke JB, Putnam K:  Depression: Perspectives from affective neuroscience. Annual Review of Psychology 2002, 53:545-57

38. Shively CA, Friedman DP, Gage HD:  Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys. Arch Gen Psychiatry 2006, Apr; 63(4):396-403.

39. Fuchs E:  Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder. CNS Spectrums 2005, Mar;10(3):182-90.

40. Mitchell PJ, Redfern PH: Animal models of depressive illness: the importance of chronic drug treatment. Curr Pharm Dis 2005;11(2):171-203.

41. Rygula R, Abumaria N, Flugge G, et al:  Anhedonia and motivational deficits in rats: Impact of chronic social stress.  Behavioral Brain Research 2005, 162:127-134.

42. Marrow LP, Overton PG, Brain PF:  A re-evaluation of social defeat as an animal model of depression. J Psychopharmacol 1999; 13(2):115-21.

43. Malatynska E, Knapp RJ:  Dominant-submissive behavior as models of mania and depression.  Neurosci Biobehav Rev 2005; 29(4-5):715-37.

44. Nikulina EM, Miczek KA, Hammer RP:  Prolonged effects of repeated social defeat stress on mRNA expression and function of mu-opioid receptors in the ventral tegmental area of rats. Neuropsychopharmacology 2005, Jun;30(6):1096-103.

45. Beitia G, Garmendia L, Azpiroz A, et al:  Time-dependent behavioral, neurochemical, and immune consequences of repeated experiences of social defeat stress in male mice and the ameliorative effects of fluoxetine. Brain Behav Immun 2005, Nov; 19(6):530-9.

46. Overli O, Korzan WJ, Hoglund E, et al:  Stress coping style predicts aggression and social dominance in rainbow trout. Horm Behav 2004, Apr; 45(4):235-41.

47. Fernald RD:  Social regulation of the brain: sex, size and status.  Novartis Foundation Symposium 2002, London, 244:169-186

48. Dyakonova VE, Schurmann F, Sakharov DA:  Effects of serotonergic and opioidergic drugs on escape behaviors and social status of male crickets. Naturwissenschaften 1999, Sep; 86(9):435-7.

49. Stevens, A.  An Intelligent Person's Guide to Psychotherapy.  London: Duckworth; 1998.

Table 1.

Neuroethological evolutionary epidemiology: Dual strategies at three brain levels                       

THREE BRAIN LEVELS

                                                                    TWO SOCIAL STRATEGIES

                                                            Escalate                                    De-Escalate

LEVEL                                                                                                                                   

PRIMATOMAMMALIAN

Cortex (SAHP)                                    Attractive                                 Avoidant

Cognition > Affect > Instinct                 Manic/sociopathic                     Depressed/obsessed

Rational sociotropic cognitive    Optimistic, charming                 Pessimistic, ashamed

Prestige > Agonistic competition

Prestige – actions                      Adopt new goals                      Give up goals

Self assert                                 Self efface

Agonistic – feelings                   Stubborn                                  Submissive

Courageousness                       Escapist

Advanced hormones & peptides

S2 > S1 ∼D3, D4 > D1                         S2, D3, 4 & NE High               S2 Low, D3, 4 & NE?

PALEOMAMMALIAN

Limbic (RHP)                                       Fighting                                    Fleeing

Affect > cognition                                 Aggressive/sadistic                    Morbid/masochistic

Emotional acquisitive                          Confident, likely to win             Unsure, likely to lose

Agonistic > Prestige competition

Prestige – action                       Exhilarated                               Shamed & guilty

Enthusiastic                               Sense of failure

Agonistic – feelings                Angry or hostile               Inferiority & anxiety

                                                Aroused emotions                     Depressed emotions

Primitive hormones and peptides

S1 > S2, D2, 3, 4 > D1, +EPS             S1, D3, 4 & NE High               S1, D3, 4 & NE Low

REPTILIAN

Midbrain (RAB)                                  

Instinctive territorial                               Strident, strong                         Cowering, weak

Instinct > affect > cognition                   Violent, solipsistic                     Frightful, abulic

Ritualized agonistic competition Autonomic dominance  Autonomic meekness 

                                                            Elevated mood             Depressed mood

Few neurohormones and peptides

S1 >> S2 << D1 >> D2, D3, D4         D1 and NE High, S?                 D1 and NE Low, S?

________________________________________________________________________

Key:   S: serotonin, with subtypes                      SAHP: Social Attention Holding Potential

D: dopamine, with subtypes                  RHP:  Resource Holding Potential

NE: norepinephrine                               RAB: Ritualized Agonistic Behavior

EPS: extrapyramidal symptoms

Table 1 Note:

Unique evolutionarily stable strategies evolved in serial assemblages at three levels. They entail diverse neurobiological, cognition and behaviour correlates with varying ratios of instinctive, emotive, and rational repertoires. They began with primitive ritualized agonistic behavior (RAB) of reptilian midbrain, moved on to resource holding potential (RHP) in the paleomammalian paleolimbic system, and then social-attention holding potential (SAHP) in primatomammalian, neolimbic and neocortex. The levels exhibit unique phylogenies of peptidergic and neurotransmitter receptor subtypes, normative and pathological expressions, and other heuristics for evolutionary selective attainment.  

Table 2.

Lexicon                                                                                                                        .

Agonism                      Individuals striving against one another

Canids                         Dogs, or dog-like species

Darwinian                   Phylogeny via natural selection

De-escalation              Neurobehavioral algorithms to abate competition

Dysmodulation            Perturbations from modal norms

Endophenotyes            Genetic core mechanisms for epigenetic expression

Escalation                   Neurobehavioral algorithms to raise competition

Ethologist                    One who studies the neuromental science of behavior

Eusociality                  Characteristic (behaviour) of highly social species

Hominoid                    Post-anthropoids in the human line

Intersexual                  Characteristic (behaviour) of competition between sexes

Intrasexual                  Characteristic (behaviour) of competition  within a sex

Mammaloprimate       Characteristic (behaviour) of both mammals and primates

Neomammalian           Characteristic (behaviour) of late mammals

Neuromental               Characteristic (behaviour) derived from brain and mind

Paleomammalian        Characteristic (behaviour) of early mammals

Pathophenotypy          Epigenetic expression of disease

Phylogenetic               Epigenetic expression of heredity

Primatomammalian    Characteristic (behaviour) of both mammals and primates

Primatohominoid        Characteristic (behaviour) of both primates and hominoids

Tinbergian                   Behavioral analyses in line with those of Niko Tinbergen