Neurotoxicity Research

, Volume 18, Issue 3–4, pp 256–271

Mechanisms of Illness Progression in the Recurrent Affective Disorders



Along with genetic vulnerability, multiple environmental factors convey liability to illness progression, including: (1) distal and proximal stressors; (2) recurrence of episodes; and (3) comorbid cocaine abuse. Recurrence of each of these can increase responsivity (sensitize) to themselves and cross-sensitize to the two other factors and drive illness progression as seen clinically in increases in cycle acceleration, severity or duration of episodes, treatment refractoriness, disability, cognitive dysfunction, and premature death. Some mechanisms appear common to all three types of sensitization, such as decreases of brain-derived neuroprotective factor (BDNF) in hippocampus and blood, as well as increases in BDNF in the nucleus accumbens, suggesting the possibility that single treatments could ameliorate several of these factors at once. A potential example is N-acetylcysteine (NAC), which decreases bipolar affective illness severity (Berk et al. Biol Psychiatry 64:468–475, 2008) and cocaine reinstatement and craving (Baker et al. Ann N Y Acad Sci 1003:349–351, 2003; LaRowe et al. Am J Addict 15:105–110, 2006). Mechanisms of illness progression also involve epigenetic changes and add further rationale to the existing empirical clinical evidence of the importance of early recognition, treatment, and prevention of affective episodes. Adequate treatment could prevent or ameliorate both the increases in pathological factors and erosion of adaptive factors that propel illness exacerbation and treatment resistance. This view of the sensitization and cross-sensitization among stressors, episodes, and abused substances should lead to a fundamental re-conceptualization of the recurrent affective disorders not as benign, isolated episodes of “mental” illness, but as severe, potentially progressive and lethal medical disorders of brain and body that deserve careful life-long monitoring and treatment.


Kindling Sensitization Depression Bipolar disorder Brain-derived neurotrophic factor (BDNF) Stress Epigenetics Cocaine 


  1. Andreazza AC, Kauer-Sant’anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, Yatham LN (2008) Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord 111:135–144CrossRefPubMedGoogle Scholar
  2. Andreazza AC, Kapczinski F, Kauer-Sant’Anna M, Walz JC, Bond DJ, Goncalves CA, Young LT, Yatham LN (2009) 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci 34:263–271PubMedGoogle Scholar
  3. Antelman S (1988) Stressor-induced sensitization to subsequent stress: implications for the development and treatment of clinical disorders. In: Kalivas P, Barnes C (eds) Sensitization in the nervous system. Telford Press, Caldwell, NJ, pp 227–254Google Scholar
  4. Baker DA, McFarland K, Lake RW, Shen H, Toda S, Kalivas PW (2003) N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci 1003:349–351CrossRefPubMedGoogle Scholar
  5. Bearden CE, Thompson PM, Dalwani M, Hayashi KM, Lee AD, Nicoletti M, Trakhtenbroit M, Glahn DC, Brambilla P, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Soares JC (2007) Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry 62:7–16CrossRefPubMedGoogle Scholar
  6. Benson B (2009) Interregional cerebral metabolic associativity in unipolar and bipolar disorder. Part II. Differential alterations in bipolar and unipolar disorders. Psychiatry Res 164:30–47Google Scholar
  7. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI (2008) N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry 64:468–475CrossRefPubMedGoogle Scholar
  8. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868CrossRefPubMedGoogle Scholar
  9. Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14:268–276CrossRefPubMedGoogle Scholar
  10. Champagne FA, Meaney MJ (2006) Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. Biol Psychiatry 59:1227–1235CrossRefPubMedGoogle Scholar
  11. Clark M, Post RM, Weiss SR, Cain CJ, Nakajima T (1991) Regional expression of c-fos mRNA in rat brain during the evolution of amygdala kindled seizures. Brain Res Mol Brain Res 11:55–64CrossRefPubMedGoogle Scholar
  12. Coe CL, Kramer M, Czeh B, Gould E, Reeves AJ, Kirschbaum C, Fuchs E (2003) Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol Psychiatry 54:1025–1034CrossRefPubMedGoogle Scholar
  13. Colton CW, Manderscheid RW (2006) Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis 3:A42PubMedGoogle Scholar
  14. Dienes KA, Hammen C, Henry RM, Cohen AN, Daley SE (2006) The stress sensitization hypothesis: understanding the course of bipolar disorder. J Affect Disord 95:43–49CrossRefPubMedGoogle Scholar
  15. Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127CrossRefPubMedGoogle Scholar
  16. Franchini L, Zanardi R, Smeraldi E, Gasperini M (1999) Early onset of lithium prophylaxis as a predictor of good long-term outcome. Eur Arch Psychiatry Clin Neurosci 249:227–230CrossRefPubMedGoogle Scholar
  17. Gildengers AG, Mulsant BH, Begley A, Mazumdar S, Hyams AV, Reynolds Iii CF, Kupfer DJ, Butters MA (2009) The longitudinal course of cognition in older adults with bipolar disorder. Bipolar Disord 11:744–752CrossRefPubMedGoogle Scholar
  18. Goddard GV, McIntyre DC, Leech CK (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25:295–330CrossRefPubMedGoogle Scholar
  19. Gomez-Pinilla F, Vaynman S (2005) A “deficient environment” in prenatal life may compromise systems important for cognitive function by affecting BDNF in the hippocampus. Exp Neurol 192:235–243CrossRefPubMedGoogle Scholar
  20. Kalivas PW (2008) Addiction as a pathology in prefrontal cortical regulation of corticostriatal habit circuitry. Neurotox Res 14:185–189CrossRefPubMedGoogle Scholar
  21. Kalivas PW, O’Brien C (2008) Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33:166–180CrossRefPubMedGoogle Scholar
  22. Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16:223–244CrossRefPubMedGoogle Scholar
  23. Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413CrossRefPubMedGoogle Scholar
  24. Kapczinski F, Frey BN, Kauer-Sant’Anna M, Grassi-Oliveira R (2008a) Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. Expert Rev Neurother 8:1101–1113CrossRefPubMedGoogle Scholar
  25. Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, Kauer-Sant’anna M, Grassi-Oliveira R, Post RM (2008b) Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 32:675–692CrossRefPubMedGoogle Scholar
  26. Kauer-Sant’Anna M, Tramontina J, Andreazza AC, Cereser K, da Costa S, Santin A, Yatham LN, Kapczinski F (2007) Traumatic life events in bipolar disorder: impact on BDNF levels and psychopathology. Bipolar Disord 9(Suppl 1):128–135CrossRefPubMedGoogle Scholar
  27. Kauer-Sant’Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT, Yatham LN (2009) Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol 12:447–458CrossRefPubMedGoogle Scholar
  28. Kendler KS, Thornton LM, Gardner CO (2000) Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry 157:1243–1251CrossRefPubMedGoogle Scholar
  29. Kendler KS, Thornton LM, Gardner CO (2001) Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry 158:582–586CrossRefPubMedGoogle Scholar
  30. Kessing LV (2008) Severity of depressive episodes during the course of depressive disorder. Br J Psychiatry 192:290–293CrossRefPubMedGoogle Scholar
  31. Kessing LV, Andersen PK (2004) Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry 75:1662–1666CrossRefPubMedGoogle Scholar
  32. Kessing LV, Andersen PK (2005) Predictive effects of previous episodes on the risk of recurrence in depressive and bipolar disorders. Curr Psychiatry Rep 7:413–420CrossRefPubMedGoogle Scholar
  33. Kessing LV, Andersen PK, Mortensen PB, Bolwig TG (1998) Recurrence in affective disorder. I. Case register study. Br J Psychiatry 172:23–28CrossRefPubMedGoogle Scholar
  34. Kessing LV, Sondergard L, Forman JL, Andersen PK (2008) Lithium treatment and risk of dementia. Arch Gen Psychiatry 65:1331–1335CrossRefPubMedGoogle Scholar
  35. Kim YK, Jung HG, Myint AM, Kim H, Park SH (2007) Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord 104:91–95CrossRefPubMedGoogle Scholar
  36. Kraepelin E (1921) Manic-depressive insanity and paranoia. E.S. Livingston, EdinburghGoogle Scholar
  37. Krishnan V, Graham A, Mazei-Robison MS, Lagace DC, Kim KS, Birnbaum S, Eisch AJ, Han PL, Storm DR, Zachariou V, Nestler EJ (2008) Calcium-sensitive adenylyl cyclases in depression and anxiety: behavioral and biochemical consequences of isoform targeting. Biol Psychiatry 64:336–343CrossRefPubMedGoogle Scholar
  38. Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, Russo SJ, Laplant Q, Sasaki TS, Whistler KN, Neve RL, Self DW, Nestler EJ (2005) Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48:303–314CrossRefPubMedGoogle Scholar
  39. LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K, Saladin M, McRae A, Brady K (2006) Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 15:105–110CrossRefPubMedGoogle Scholar
  40. Leverich GS, Post RM, Keck PE Jr, Altshuler LL, Frye MA, Kupka RW, Nolen WA, Suppes T, McElroy SL, Grunze H, Denicoff K, Moravec MK, Luckenbaugh D (2007) The poor prognosis of childhood-onset bipolar disorder. J Pediatr 150:485–490CrossRefPubMedGoogle Scholar
  41. Levine AA, Guan Z, Barco A, Xu S, Kandel ER, Schwartz JH (2005) CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc Natl Acad Sci USA 102:19186–19191CrossRefPubMedGoogle Scholar
  42. Martinowich K, Manji H, Lu B (2007) New insights into BDNF function in depression and anxiety. Nat Neurosci 10:1089–1093CrossRefPubMedGoogle Scholar
  43. McElroy SL, Altshuler LL, Suppes T, Keck PE Jr, Frye MA, Denicoff KD, Nolen WA, Kupka RW, Leverich GS, Rochussen JR, Rush AJ, Post RM (2001) Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry 158:420–426CrossRefPubMedGoogle Scholar
  44. Mishkin M, Appenzeller T (1987) The anatomy of memory. Sci Am 256:80–89CrossRefPubMedGoogle Scholar
  45. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, Manji HK (2000) Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 48:1–8CrossRefPubMedGoogle Scholar
  46. Moorhead TW, McKirdy J, Sussmann JE, Hall J, Lawrie SM, Johnstone EC, McIntosh AM (2007) Progressive gray matter loss in patients with bipolar disorder. Biol Psychiatry 62:894–900CrossRefPubMedGoogle Scholar
  47. Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445–1449CrossRefPubMedGoogle Scholar
  48. Nestler EJ, Carlezon WA Jr (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59:1151–1159CrossRefPubMedGoogle Scholar
  49. Newcomer JW, Hennekens CH (2007) Severe mental illness and risk of cardiovascular disease. JAMA 298:1794–1796CrossRefPubMedGoogle Scholar
  50. Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11:851–876CrossRefPubMedGoogle Scholar
  51. Park SW, Lee CH, Lee JG, Lee SJ, Kim NR, Choi SM, Kim YH (2009) Differential effects of ziprasidone and haloperidol on immobilization stress-induced mRNA BDNF expression in the hippocampus and neocortex of rats. J Psychiatr Res 43:274–281CrossRefPubMedGoogle Scholar
  52. Perlis RH, Miyahara S, Marangell LB, Wisniewski SR, Ostacher M, DelBello MP, Bowden CL, Sachs GS, Nierenberg AA (2004) Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry 55:875–881CrossRefPubMedGoogle Scholar
  53. Pinel JP (1983) Effects of diazepam and diphenylhydantoin on elicited and spontaneous seizures in kindled rats: a double dissociation. Pharmacol Biochem Behav 18:61–63CrossRefPubMedGoogle Scholar
  54. Post RM (1992) Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999–1010PubMedGoogle Scholar
  55. Post RM (2004) The status of the sensitization/kindling hypothesis of bipolar disorder. Curr Psychos Ther Rep 2:135–141CrossRefGoogle Scholar
  56. Post RM (2007a) Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci Biobehav Rev 31:858–873CrossRefPubMedGoogle Scholar
  57. Post RM (2007b) Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J Psychiatr Res 41:979–990CrossRefPubMedGoogle Scholar
  58. Post RM (2008) Animal models of mood disorders: kindling as model of affective illness progression. In: Schachter S, Holmes G, Trenite D (eds) Behavioral aspects of epilepsy: principles, practice. Demos, New York, pp 19–27Google Scholar
  59. Post RM, Leverich GS, Kupka R, Keck R, McElroy S, Altshuler L, Frye M, Luckebaugh DA, Rowe M, Grunze H, Suppes T, Nolen W (2010) Early onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry, in pressGoogle Scholar
  60. Post RM, Kauer-Sant’Anna M (2010) An introduction to the neurobiology of bipolar illness onset, recurrence, and progression. In: Yatham LN, Maj M (eds) Bipolar disorder: clinical and neurological foundations. John Wiley & Sons, LtdGoogle Scholar
  61. Post RM, Kowatch RA (2006) The health care crisis of childhood-onset bipolar illness: some recommendations for its amelioration. J Clin Psychiatry 67:115–125CrossRefPubMedGoogle Scholar
  62. Post RM, Leverich GS (2008) Treatment of bipolar illness: a case book for clinicians and patients: WW Norton, Inc, New YorkGoogle Scholar
  63. Post RM, Miklowitz D (2010) The role of stress in the onset, course, and progression of bipolar illness and its comorbidites: implications for therapeutics. In: Miklowitz D, Cicchetti D (eds) Bipolar disorder: a developmental psychopathology approach. Guilford, New YorkGoogle Scholar
  64. Post RM, Post SLW (2004) Molecular and cellular developmental vulnerabilities to the onset of affective disorders in children and adolescents: some implications for therapeutics. In: Steiner H (ed) Handbook of mental health interventions in children and adolescents. Jossey-Bass, San FranciscoGoogle Scholar
  65. Post RM, Weiss SR (1992) Ziskind-Somerfeld Research Award 1992. Endogenous biochemical abnormalities in affective illness: therapeutic versus pathogenic. Biol Psychiatry 32:469–484CrossRefPubMedGoogle Scholar
  66. Post RM, Weiss SR (1996) A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures. Mol Neurobiol 13:33–60CrossRefPubMedGoogle Scholar
  67. Post RM, Weiss SR (1998) Sensitization and kindling phenomena in mood, anxiety, and obsessive-compulsive disorders: the role of serotonergic mechanisms in illness progression. Biol Psychiatry 44:193–206CrossRefPubMedGoogle Scholar
  68. Post RM, Kopanda RT, Lee A (1975) Progressive behavioral changes during chronic lidocaine administration: relationship to kindling. Life Sci 17:943–950CrossRefPubMedGoogle Scholar
  69. Post RM, Weiss S, Pert A, Uhde T (1987) Chronic cocaine administration: sensitization and kindling effects. In: Raskin A, Fisher S (eds) Cocaine: clinical, biobehavioral aspects. Oxford University Press, New York, pp 109–173Google Scholar
  70. Post RM, Speer AM, Hough CJ, Xing G (2003) Neurobiology of bipolar illness: implications for future study and therapeutics. Ann Clin Psychiatry 15:85–94PubMedGoogle Scholar
  71. Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294CrossRefPubMedGoogle Scholar
  72. Robinson LJ, Ferrier IN (2006) Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord 8:103–116CrossRefPubMedGoogle Scholar
  73. Robinson LJ, Thompson JM, Gallagher P, Goswami U, Young AH, Ferrier IN, Moore PB (2006) A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 93:105–115CrossRefPubMedGoogle Scholar
  74. Roceri M, Cirulli F, Pessina C, Peretto P, Racagni G, Riva MA (2004) Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol Psychiatry 55:708–714CrossRefPubMedGoogle Scholar
  75. Rosen JB, Cain CJ, Weiss SR, Post RM (1992) Alterations in mRNA of enkephalin, dynorphin and thyrotropin releasing hormone during amygdala kindling: an in situ hybridization study. Brain Res Mol Brain Res 15:247–255CrossRefPubMedGoogle Scholar
  76. Roth TL, Lubin FD, Funk AJ, Sweatt JD (2009) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 65:760–769CrossRefPubMedGoogle Scholar
  77. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, Chakravarty S, Peevey J, Oehrlein N, Birnbaum S, Vitaterna MH, Orsulak P, Takahashi JS, Nestler EJ, Carlezon WA Jr, McClung CA (2007) Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci USA 104:6406–6411CrossRefPubMedGoogle Scholar
  78. Sheline YI, Gado MH, Kraemer HC (2003) Untreated depression and hippocampal volume loss. Am J Psychiatry 160:1516–1518CrossRefPubMedGoogle Scholar
  79. Sonne SC, Brady KT, Morton WA (1994) Substance abuse and bipolar affective disorder. J Nerv Ment Dis 182:349–352CrossRefPubMedGoogle Scholar
  80. Torres IJ, Boudreau VG, Yatham LN (2007) Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr Scand Suppl 434:17–26Google Scholar
  81. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525CrossRefPubMedGoogle Scholar
  82. Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367CrossRefPubMedGoogle Scholar
  83. Weaver IC, Meaney MJ, Szyf M (2006) Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci USA 103:3480–3485CrossRefPubMedGoogle Scholar
  84. Weiss SR, Clark M, Rosen JB, Smith MA, Post RM (1995) Contingent tolerance to the anticonvulsant effects of carbamazepine: relationship to loss of endogenous adaptive mechanisms. Brain Res Brain Res Rev 20:305–325CrossRefPubMedGoogle Scholar
  85. Wilens TE, Biederman J, Kwon A, Ditterline J, Forkner P, Moore H, Swezey A, Snyder L, Henin A, Wozniak J, Faraone SV (2004) Risk of substance use disorders in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 43:1380–1386CrossRefPubMedGoogle Scholar
  86. Zhou W, Kalivas PW (2008) N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol Psychiatry 63:338–340CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Bipolar Collaborative NetworkBethesdaUSA

Personalised recommendations