Current Psychosis & Therapeutics Reports

, Volume 2, Issue 4, pp 135–141

The status of the sensitization/kindling hypothesis of bipolar disorder

  • Robert M. Post


Kindling refers to repeated, intermittent, subthreshold stimulation that evokes increasingly widespread biochemical and physiologic manifestations culminating in a progression of behavioral abnormalities, and eventually full-blown seizures, which if sufficiently repeated, become spontaneous. Since Kraepelin initially observed that untreated bipolar illness tends to be progressive, and that initial episodes of mania and depression may be precipitated by stressors, but with repetition may occur more autonomously and with a shorter well interval, the basic tenets of the kindling hypothesis for the affective disorders have been largely validated. Not only is there evidence of stress sensitization (an increasing sensitivity to psychosocial stressors), but there is now also strong evidence of episode sensitization (the increased vulnerability to recurrence with shorter well intervals as a function of the number of prior episodes). However, with appropriate psychotherapeutic and pharmacotherapeutic intervention, episodes and episode progression can be prevented. Whether or not underlying illness progression can be prevented (which has not been definitively tested), the clinician and patient have nothing to lose if they act as if this were the case and engage in early effective pharmacoprophylaxis.


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References and Recommended Reading

  1. 1.
    Goddard GV, McIntyre DC, Leech CK:A permanent change in brain function resulting from daily electrical stimulation.Exp Neurol 1969,25:295–330.PubMedCrossRefGoogle Scholar
  2. 2.
    Racine RJ:Modification of seizure activity by electrical stimulation. II. Motor seizure.Electroencephalogr Clin Neurophysiol 1972,32:281–294.PubMedCrossRefGoogle Scholar
  3. 3.
    Racine RJ:Modification of seizure activity by electrical stimulation. I. After-discharge threshold.Electroencephalogr Clin Neurophysiol 1972,32:269–279.PubMedCrossRefGoogle Scholar
  4. 4.
    Racine R:Kindling: the first decade.Neurosurgery 1978,3:234–252.PubMedCrossRefGoogle Scholar
  5. 5.
    Pinel JP, Rovner LI:Experimental epileptogenesis: kindling-induced epilepsy in rats.Exp Neurol 1978,58:190–202.PubMedCrossRefGoogle Scholar
  6. 6.
    Wada JA, Sato M, Corcoran ME:Persistent seizure susceptibility and recurrent spontaneous seizures in kindled cats.Epilepsia 1974,15:465–478.PubMedGoogle Scholar
  7. 7.
    Weiss SR, Post RM:Caveats in the use of the kindling model of affective disorders.Toxicol Ind Health 1994,10:421–447.PubMedGoogle Scholar
  8. 8.
    Post RM, Ketter TA, Speer AM,et al.:Predictive validity of the sensitization and kindling hypotheses. InBipolar Disorders: Basic Mechanisms and Therapeutic Implications. Edited by Soares JC, Gershon S. New York: Marcel Dekker; 2000:387–432.Google Scholar
  9. 9.
    Goddard GV, Douglas RM:Does the engram of kindling model the engram of normal long term memory? Can J Neurol Sci 1975,2:385–394.PubMedGoogle Scholar
  10. 10.
    Post RM, Weiss SRB, Leverich GS,et al.:Sensitization and kindling-like phenomena in bipolar disorder: implications for psychopharmacology.Clin Neurosci Res 2001,1:69–81.CrossRefGoogle Scholar
  11. 11.
    Pinel JPJ:Effects of diazepam and diphenylhydantoin on elicited and spontaneous seizures in kindled rats: a double dissociation.Pharmacol Biochem Behav 1983,18:61–63.PubMedCrossRefGoogle Scholar
  12. 12.
    Post RM:Do the epilepsies, pain syndromes, and affective disorders share common kindling-like mechanisms? Epilepsy Res 2002,50:203–219.PubMedCrossRefGoogle Scholar
  13. 13.
    Post RM, Weiss SR, Pert A:Differential effects of carbamazepine and lithium on sensitization and kindling.Prog Neuropsychopharmacol Biol Psychiatry 1984,8:425–434.PubMedGoogle Scholar
  14. 14.
    Post RM, Weiss SR, Pert A:Cocaine-induced behavioral sensitization and kindling: implications for the emergence of psychopathology and seizures.Ann N Y Acad Sci 1988,537:292–308.PubMedCrossRefGoogle Scholar
  15. 15.
    Post RM, Weiss SR, Pert A:Implications of behavioral sensitization and kindling for stress- induced behavioral change.Adv Exp Med Biol 1988,245:441–463.PubMedGoogle Scholar
  16. 16.
    Weiss SR, Post RM, Pert A,et al.:Context-dependent cocaine sensitization: differential effect of haloperidol on development versus expression.Pharmacol Biochem Behav 1989,34:655–661.PubMedGoogle Scholar
  17. 17.
    Post RM, Weiss SR, Fontana D, Pert A:Conditioned sensitization to the psychomotor stimulant cocaine.Ann N Y Acad Sci 1992,654:386–399.PubMedCrossRefGoogle Scholar
  18. 18.
    Weiss SR, Clark M, Rosen JB,et al.:Contingent tolerance to the anticonvulsant effects of carbamazepine: relationship to loss of endogenous adaptive mechanisms.Brain Res Brain Res Rev 1995,20:305–325.PubMedCrossRefGoogle Scholar
  19. 19.
    Post RM, Weiss SRB:Kindling and stress sensitization. InBipolar Disorder: Biological Models and Their Clinical Application. Edited by Joffe RT, Young LT. New York: Marcel Dekker; 1997:93–126.Google Scholar
  20. 20.
    Childress AR, McLellan AT, Ehrman R, O’Brien CP:Classically conditioned responses in opioid and cocaine dependence: a role in relapse? NIDA Res Monogr 1988,84:25–43.PubMedGoogle Scholar
  21. 21.
    O’Brien CP, Childress AR, McLellan AT, Ehrman R:Classical conditioning in drug-dependent humans.Ann N Y Acad Sci 1992,654:400–415.PubMedCrossRefGoogle Scholar
  22. 22.
    Barnes SJ, Pinel JP:Conditioned effects of kindling.Neurosci Biobehav Rev 2001,25:745–751.PubMedCrossRefGoogle Scholar
  23. 23.
    Kendler KS, Thornton LM, Gardner CO:Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis.Am J Psychiatry 2000,157:1243–1251.PubMedCrossRefGoogle Scholar
  24. 24.
    Kendler KS, Thornton LM, Gardner CO:Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression.Am J Psychiatry 2001,158:582–586.PubMedCrossRefGoogle Scholar
  25. 25.
    Caspi A, Sugden K, Moffitt TE,et al.:Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.Science 2003,301:386–389.PubMedCrossRefGoogle Scholar
  26. 26.
    Leverich GS, McElroy SL, Suppes T,et al.:Early physical and sexual abuse associated with an adverse course of bipolar illness.Biol Psychiatry 2002,51:288–297.PubMedCrossRefGoogle Scholar
  27. 27.
    Hammen C, Gitlin M:Stress reactivity in bipolar patients and its relation to prior history of disorder.Am J Psychiatry 1997,154:856–857.PubMedGoogle Scholar
  28. 28.
    Hlastala SA, Frank E, Kowalski J,et al.:Stressful life events, bipolar disorder, and the “kindling model”.J Abnorm Psychol 2000,109:777–786.PubMedCrossRefGoogle Scholar
  29. 29.
    Kraepelin E:Manic-depressive Insanity and Paranoia. Edinburgh: ES Livingstone; 1921.Google Scholar
  30. 30.
    Cutler NR, Post RM:Life course of illness in untreated manic-depressive patients.Compr Psychiatry 1982,23:101–115.PubMedCrossRefGoogle Scholar
  31. 31.
    Ghaemi SN, Boiman EE, Goodwin FK:Kindling and second messengers: an approach to the neurobiology of recurrence in bipolar disorder.Biol Psychiatry 1999,45:137–144.PubMedCrossRefGoogle Scholar
  32. 32.
    Grof P, Angst J, Haines T:The clinical course of depression: Practical issues. InClassification and Prediction of Outcome of Depression/Symposium Schloss Reinhartshausen/Rhein, September 23–26, 1973. Edited by Angst J. Stuttgart: FK Schattauer Verlag; 1974:141–148.Google Scholar
  33. 33.
    Roy-Byrne P, Post RM, Uhde TW,et al.:The longitudinal course of recurrent affective illness: life chart data from research patients at the NIMH.Acta Psychiatr Scand Suppl 1985,71:1–34.CrossRefGoogle Scholar
  34. 34.
    Angst J, Sellaro R:Historical perspectives and natural history of bipolar disorder.Biol Psychiatry 2000,48:445–457.PubMedCrossRefGoogle Scholar
  35. 35.
    Turvey CL, Coryell WH, Solomon DA,et al.:Long-term prognosis of bipolar I disorder.Acta Psychiatr Scand 1999,99:110–119.PubMedGoogle Scholar
  36. 36.
    Kessing LV, Andersen PK, Mortensen PB, Bolwig TG:Recurrence in affective disorder. I. Case register study.Br J Psychiatry 1998,172:23–28.PubMedGoogle Scholar
  37. 37.
    Kessing LV, Mortensen PB, Bolwig TG:Clinical consequences of sensitisation in affective disorder: a case register study.J Affect Disord 1998,47:41–47.PubMedCrossRefGoogle Scholar
  38. 38.
    Kessing LV, Hansen MG, Andersen PK, Angst J:The predictive effect of episodes on the risk of recurrence in depressive and bipolar disorders — a life-long perspective.Acta Psychiatr Scand 2004,109:339–344.PubMedCrossRefGoogle Scholar
  39. 39.
    Solomon DA, Keller MB, Leon AC,et al.:Multiple recurrences of major depressive disorder.Am J Psychiatry 2000,157:229–233.PubMedCrossRefGoogle Scholar
  40. 40.
    Post RM, Weiss SIR:Ziskind-Somerfeld Research Award 1992. Endogenous biochemical abnormalities in affective illness: therapeutic versus pathogenic.Biol Psychiatry 1992,32:469–484.PubMedCrossRefGoogle Scholar
  41. 41.
    Post RM, Weiss SRB:A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures.Mol Neurobiol 1996,13:33–60.PubMedGoogle Scholar
  42. 42.
    Goodwin FK, Jamison KR:Manic-depressive illness. New York: Oxford University Press, 1990.Google Scholar
  43. 43.
    Kupka RW, Luckenbaugh DA, Post RM,et al.:A comparative study of rapid and non-rapid cycling bipolar disorder using daily mood ratings in 539 outpatients.Am J Psychiatry 2004, in press.Google Scholar
  44. 44.
    Nolen WA, Luckenbaugh DA, Altshuler LL,et al.:Correlates of 1-year prospective outcome in bipolar disorder: results from the Stanley Foundation Bipolar Network.Am J Psychiatry 2004,161:1447–1454.PubMedCrossRefGoogle Scholar
  45. 45.
    Post RM, Denicoff KD, Leverich GS,et al.:Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH Life Chart Method.J Clin Psychiatry 2003,64:680–690.PubMedCrossRefGoogle Scholar
  46. 46.
    Leverich GS, Altshuler LL, Frye MA,et al.:Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network.J Clin Psychiatry 2003,64:506–515.PubMedCrossRefGoogle Scholar
  47. 47.
    Martinez-Aran A, Vieta E, Colom F,et al.:Neuropsychological performance in depressed and euthymic bipolar patients.Neuropsychobiology 2002,46 Suppl 1:16–21.PubMedCrossRefGoogle Scholar
  48. 48.
    Ferrier IN, Stanton BR, Kelly TP, Scott J:Neuropsychological function in euthymic patients with bipolar disorder.Br J Psychiatry 1999,175:246–251.PubMedCrossRefGoogle Scholar
  49. 49.
    Butters MA, Whyte EM, Nebes RD,et al.:The nature and determinants of neuropsychological functioning in late-life depression.Arch Gen Psychiatry 2004,61:587–595.PubMedCrossRefGoogle Scholar
  50. 50.
    Post RM, Speer AM, Hough CJ, Xing G:Neurobiology of bipolar illness: implications for future study and therapeutics.Ann Clin Psychiatry 2003,15:85–94.PubMedCrossRefGoogle Scholar
  51. 51.
    Luby ED, Singareddy RK:Long-term therapy with lithium in a private practice clinic: a naturalistic study.Bipolar Disord 2003,5:62–68.PubMedCrossRefGoogle Scholar
  52. 52.
    Grunze H:Lithium in the acute treatment of bipolar disorders-a stocktaking.Eur Arch Psychiatry Clin Neurosci 2003,253:115–119.PubMedCrossRefGoogle Scholar
  53. 53.
    Baldessarini RJ, Tondo L, Hennen J:Lithium treatment and suicide risk in major affective disorders: update and new findings.J Clin Psychiatry 2003,64(Suppl 5):44–52.PubMedGoogle Scholar
  54. 54.
    Ahrens B, Muller-Oerlinghausen B, Schou M,et al.:Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium prophylaxis.J Affect Disord 1995,33:67–75.PubMedCrossRefGoogle Scholar
  55. 55.
    Chen G, Zeng WZ, Yuan PX,et al.:The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS.J Neurochem 1999,72:879–882.PubMedCrossRefGoogle Scholar
  56. 56.
    Chen RW, Chuang DM:Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity.J Biol Chem 1999,274:6039–6042.PubMedCrossRefGoogle Scholar
  57. 57.
    Manji HK, Quiroz JA, Sporn J,et al Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression.Biol Psychiatry 2003,53:707–742.PubMedCrossRefGoogle Scholar
  58. 58.
    RoweMK, ChuangDM:Lithium neuroprotection: molecular mechanisms and clinical implications.Expert Rev Mol Med 2004,6: in press.Google Scholar
  59. 59.
    Nibuya M, Morinobu S, Duman RS:Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.J Neurosci 1995,15:7539–7547.PubMedGoogle Scholar
  60. 60.
    Malberg JE, Eisch AJ, Nestler EJ, Duman RS:Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.J Neurosci 2000,20:9104–9110.PubMedGoogle Scholar
  61. 61.
    Smith MA, Makino S, Kvetnansky R, Post RM:Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus.J Neurosci 1995,15:1768–1777.PubMedGoogle Scholar
  62. 62.
    Smith MA, Makino S, Altemus M,et al.:Stress and antidepressants differentially regulate neurotrophin 3 mRNA expression in the locus coeruleus.Proc Natl Acad Sci U S A 1995,92:8788–8792.PubMedCrossRefGoogle Scholar
  63. 63.
    Duman RS:Synaptic plasticity and mood disorders.Mol Psychiatry 2002,7(Suppl 1):S29-S34.PubMedCrossRefGoogle Scholar
  64. 64.
    Sheline YI, Gado MH, Kraemer HC:Untreated depression and hippocampal volume loss.Am J Psychiatry 2003,160:1516–1518.PubMedCrossRefGoogle Scholar
  65. 65.
    Egan MF, Kojima M, Callicott JH,et al.:The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.Cell 2003,112:257–269.PubMedCrossRefGoogle Scholar
  66. 66.
    Neves-Pereira M, Mundo E, Muglia P,et al.:The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study.Am J Hum Genet 2002,71:651–655.PubMedCrossRefGoogle Scholar
  67. 67.
    Sklar P, Gabriel SB, McInnis MG,et al.:Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor.Mol Psychiatry 2002,7:579–593.PubMedCrossRefGoogle Scholar
  68. 68.
    Lohoff FW, Sander T, Gallinat J, Berrettini WH:Conformation of association between the Val66Met variation in the BDNF gene and bipolar disorder.Biol Psychiatry 2004,55:10S.Google Scholar
  69. 69.
    Rybakowski JK, Borkowska A, Czerski PM,et al.:Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients.Bipolar Disord 2003,5:468–472.PubMedCrossRefGoogle Scholar
  70. 70.
    Hariri AR, Goldberg TE, Mattay VS,et al.:Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance.J Neurosci 2003,23:6690–6694.PubMedGoogle Scholar
  71. 71.
    Geller B, Badner JA, Tillman R,et al.:Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met poly-morphism in children with a prepubertal and early adolescent bipolar disorder phenotype.Am J Psychiatry 2004,161:1698–1700.PubMedCrossRefGoogle Scholar
  72. 72.
    He XP, Kotloski R, Nef S,et al.:Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model.Neuron 2004,43:31–42.PubMedCrossRefGoogle Scholar
  73. 73.
    Suppes T, Baldessarini RJ, Faedda GL, Tohen M:Risk of recurrence following discontinuation of lithium treatment in bipolar disorder.Arch Gen Psychiatry 1991,48:1082–1088.PubMedGoogle Scholar
  74. 74.
    Post RM, Leverich GS, Altshuler L, Mikalauskas K:Lithium-discontinuation-induced refractoriness: preliminary observations.Am J Psychiatry 1992,149:1727–1729.PubMedGoogle Scholar
  75. 75.
    Post RM, Leverich GS, Pazzaglia PJ,et al.:Lithium tolerance and discontinuation as pathways to refractoriness. InLithium in Medicine and Biology. Edited by Birch NJ, Padgham C, Hughes MS. Lancashire, UK: Marius Press; 1993:71–84.Google Scholar
  76. 76.
    Maj M, Pirozzi R, Magliano L:Nonresponse to reinstituted lithium prophylaxis in previously responsive bipolar patients: prevalence and predictors.Am J Psychiatry 1995,152:1810–1811.PubMedGoogle Scholar
  77. 77.
    Cavanagh J, Smyth R, Goodwin GM:Relapse into mania or depression following lithium discontinuation: a 7-year follow-up.Acta Psychiatr Scand 2004,109:91–95.PubMedCrossRefGoogle Scholar
  78. 78.
    Coryell W, Solomon D, Leon AC,et al.:Lithium discontinuation and subsequent effectiveness.Am J Psychiatry 1998,155:895–898.PubMedGoogle Scholar
  79. 79.
    Post RM:Neurobiology of seizures and behavioral abnormalities.Epilepsia 2004,45(Suppl 2):5–14.PubMedCrossRefGoogle Scholar
  80. 80.
    Malach M, Imperato PJ:Depression and acute myocardial infarction.Prev Cardiol 2004,7:83–90.PubMedCrossRefGoogle Scholar
  81. 81.
    Post RM, Speer AM, Leverich GS:Complex combination therapy: the evolution toward rational polypharmacy in lithium-resistant bipolar illness. In50 Years: The Psychopharmacology of Bipolar Ilness. Edited by Akiskal H, Tohen M. London: John Wiley & Sons; 2004: in press.Google Scholar
  82. 82.
    Post RM, Altshuler LL:Mood disorders: treatment of bipolar disorders. InKaplan & Sadock’s Comprehensive Textbook of Psychiatry, edn 8. Edited by Sadock BJ, Sadock VA. New York: Lippincott Williams & Wilkins; 2004: in press.Google Scholar
  83. 83.
    Post RM:Practical approaches to polypharmacy in the long-term management of bipolar disorder.Drug Benefit Trends 2004,16:329–342.Google Scholar
  84. 84.
    Post RM, Speer AM, Obrocea GV, Leverich GS:Acute and prophylactic effects of anticonvulsants in bipolar depression.Clin Neurosci Res 2002,2:228–251.CrossRefGoogle Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Robert M. Post
    • 1
  1. 1.Department of Health and Human Services, National Institutes of HealthNational Institute of Mental Health, Biological Psychiatry BranchBethesdaUSA

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