Experimental Approaches for Testing the Cholinergic-Noradrenergic Imbalance Hypothesis of Affective Disorders

  • M. Berger
  • P. Fleckenstein
  • D. Riemann
  • W. E. Müller


The hypothesis of a cholinergic-/aminergic transmitter imbalance as the cause of manic-depressive disorders, formulated by Janowsky and coworkers (Janowsky et al. 1972; Janowsky and Risch 1986), is based on the observation that biological systems, such as heart rate, blood pressure, body temperature, and extrapyramidal system, are regulated by at least two transmitter systems in reciprocal interaction. It seemed reasonable to extend the amine deficiency hypothesis of depression to an imbalance model between the aminergic and cholinergic central transmitter systems (Berger 1985, 1987).


Growth Hormone Growth Hormone Secretion Growth Hormone Response Growth Hormone Release Hormone Imbalance Model 
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  1. Ansseau M, Scheyvaerts M, Doumont A, Poirrier R, Legros JJ, Franck G (1984) Concurrent use of REM latency, dexamethasone suppression, clonidine, and apomorphine tests as biological markers of endogenous depression: a pilot study. Psychiatry Res 12: 261–272PubMedCrossRefGoogle Scholar
  2. Ansseau M, Frenckell R von, Cerfontaine JL, Papart P, Franck G, Timsit-Berthier M, Geenen V, Legros JJ (1987) Neuroendocrine evaluation in catecholaminergic neurotrans-mission in mania. Psychiatry Res 22: 193–206PubMedCrossRefGoogle Scholar
  3. Beersma DGM, Daan S, Hoofdakker RH van den (1984) Sleep structure in depression. Exp Brain Res 8: 285–296CrossRefGoogle Scholar
  4. Berger M (1985) Vergleichende psychobiologische Untersuchungen bei enogenen und neurotischen Depressionen. Thesis, University of MunichGoogle Scholar
  5. Berger M (1987) Schlaf-EEG Studien zum aminerg-cholinergen Imbalance-Modell depressiver Erkrankungen. In: Angst J, Gastpar M (eds) Depression - Schlaf - Traum. Panscientia, Hedingen, Zürich, pp 38–51Google Scholar
  6. Berger M, Doerr P, Lund R, Bronisch T, Zerssen D von (1982) Neuroendocrinological and neurophysiological studies in major depressive disorders: are there biological markers for the endogenous subtype? Biol Psychiatry 17: 1217–1242PubMedGoogle Scholar
  7. Berger M, Lund R, Bronisch T, Zerssen D von (1983) REM latency in neurotic and endogenous depression and the cholinergic REM induction test. Psychiatry Res 10:113– 123Google Scholar
  8. Berger M, Pirke KM, Doerr P, Krieg JC, Zerssen D von (1984) The limited utility of the dexamethasone suppression test for the diagnostic process in psychiatry. Br J Psychiatry 145: 372–382PubMedCrossRefGoogle Scholar
  9. Berger M, Riemann D, Höchli D, Spiegel R (1989) The cholinergic REM induction test with RS 86: state or trait marker of depression? Arch Gen Psychiatry 46: 421–428PubMedCrossRefGoogle Scholar
  10. Bunney WE Jr, Goodwin FK, Murphy DL, House GM, Gordon EK (1972) The “switch process” in manic-depressive illness. II. Relationship to catecholamines, REM sleep, and drugs. Arch Gen Psychiatry 27: 304–309Google Scholar
  11. Checkley SA, Slade AP, Shur E (1981) Growth hormone and other responses to Clonidine in patients with endogenous depression. Br J Psychiatry 138: 51–55PubMedCrossRefGoogle Scholar
  12. Delitala G, Maioli M, Pacifico A, Brianda S, Palermo M, Mannelli M (1983) Cholinergic receptor control mechanisms for L-dopa, apomorphine, and clonidine-induced growth hormone secretion in man. J Clin Endocrinol Metab 57: 1145–1149PubMedCrossRefGoogle Scholar
  13. Doerr P, Berger M (1983) Physostigmine induced escape from dexamethasone suppression in normal adults. Biol Psychiatry 18: 261–267PubMedGoogle Scholar
  14. Doerr P, von Zerssen D, Fischler M, Schulz H (1979) Relationship between mood changes and adrenal cortical activity in a patient with a 48-hour unipolar depressive cycle. J Affective Disord 1: 93–104CrossRefGoogle Scholar
  15. Gilbert P (1984) Depression: from psychology to brain state. Lawrence Erlbaum, HillsdaleGoogle Scholar
  16. Hobson JA, Steriade M (1986) Neuronal basis of behavioural state control. In: Mountcastle VB, Bloom FE, Geiger SR (eds) Intrinsic regulatory systems of the brain. American Physiological Society Bethesda, pp 701-823 (Handbook of physiology, vol 4 )Google Scholar
  17. Hobson JA, McCarley RW, McKenna TM (1976) Cellular evidence bearing on the pontine brainstem hypothesis of desynchronized sleep control. Prog Neurobiol 6: 280–285Google Scholar
  18. Hoehe M, Valido G, Matussek, N (1988) Growth hormone, noradrenaline, blood pressure and Cortisol responses to Clonidine in healthy male volunteers: dose-response relations and reproducibility. Psychoneuroendocrinology 13: 409–418PubMedCrossRefGoogle Scholar
  19. Hudson JI, Lipinski JF, Frankenburg FR, Grochocinski VJ, Kupfer DJ (1989) Electroen- cephalographic sleep in mania. Arch Gen Psychiatry 45: 267–273CrossRefGoogle Scholar
  20. Janowsky DS, Risch SC (1986) Adrenergic-cholinergic balance and affective disorders. In: Rush AJ, Altshuler KZ (eds) Depression - basic mechanisms, diagnosis, and treatment. Guilford, New York, pp 84–101Google Scholar
  21. Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ (1972) A cholinergic noradrenergic hypothesis of mania and depression. Lancet 2: 632–635PubMedCrossRefGoogle Scholar
  22. Janowsky DS, Risch SC, Jedd LL, Parker DC, Kalin NH, Huey LJ (1983) Behavioral and neuroendocrine effects of physostigmine in affective disorder patients. In: Clayton PJ, Barret JE (eds) Treatment of depression: old controversies and new approaches. Raven, New York, pp 61–74Google Scholar
  23. Krieg JC, Berger M (1986) Cholinergic influence on manic symptoms. Clin Neuropharmacol 9: 544–546PubMedGoogle Scholar
  24. Krieg JC, Bossert S, Pirke KM, Zerssen D von, Berger M (1987) The influence of the muscarinic agonist RS 86 on the Cortisol system. Biol Psychiatry 2: 573–582CrossRefGoogle Scholar
  25. Kupfer DJ, Henninger GR (1972) REM activity as a correlate of mood changes throughout the night. Arch Gen Psychiat 27: 368–373PubMedCrossRefGoogle Scholar
  26. Lauer C, Zulley J, Krieg JC, Riemann D, Berger M (1988) EEG sleep and the cholinergic REM induction test in anorexia and bulimic patients. Psychiatry Res 26: 171–181PubMedCrossRefGoogle Scholar
  27. Matussek N (1988) Catecholamines and mood: neuroendocrine aspects. In: Granten D, Pfaff D, Fuxe K (eds) Current topics in neuroendocrinology, vol 8, pp 141–182, Springer, Berlin Heidelberg New YorkGoogle Scholar
  28. Matussek N, Ackenheil M, Hippius H, Müller F, Schröder HT, Schultes H, Wasilewski B (1980) Effect of Clonidine on growth hormone release in psychiatric patients and controls. Psychiatry Res 2: 25–36PubMedCrossRefGoogle Scholar
  29. McCarley RW (1982) REM sleep and depression: common neurobiological control mechanisms. Am J Psychiatry 139:565–570Google Scholar
  30. Palacios JM, Bollinger G, Closse A, Enz A, Gmelin G, Malanowski J (1986) The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro(4,5-decan- 1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist. Eur J Pharmacol 125: 45–62Google Scholar
  31. Post RM (1987) Mechanisms of action of carbamazepine and related anticonvulsants in affective illness. In: Meitzer HY (ed) Psychopharmacology: the third generation of progress. Raven, New York, pp 567–576Google Scholar
  32. Rechtschaffen A, Kales A (1968) Manual of standardized terminology techniques and scoring system for sleep stages of human subjects. National Institute of Health Publications 204. US Government Printing Office, Washington DCGoogle Scholar
  33. Riemann D, Berger M (1989) EEG sleep in depression and remission and the cholinergic REM induction response to RS 86. Neuropsychopharmacology 2: 145–152PubMedCrossRefGoogle Scholar
  34. Riemann D, Joy D, Höchli D, Lauer C, Zulley J, Berger M (1988) Influence of the cholinergic agonist RS 86 on normal sleep: sex and age effects. Psychiatry Res 24: 137–147PubMedCrossRefGoogle Scholar
  35. Siever LJ, Uhde TW (1984) New studies and perspectives on the noradrenergic receptor system in depression. Effects of the alpha2-adrenergic agonist Clonidine. Biol Psychiatry 19: 131–156PubMedGoogle Scholar
  36. Sitaram N, Moore AM, Gillin JC (1978 a) Experimental acceleration and slowing of REM sleep ultradian rhythm by cholinergic agonist and antagonist. Nature 274: 490–492Google Scholar
  37. Sitaram N, Moore AM, Gillin JC (1978 b) Induction and resetting of REM sleep rhythm in normal man by arecholine: blockade by scopolamine. Sleep 1: 83–90Google Scholar
  38. Sitaram N, Moore AM, Gillin JC (1979) Scopolamine induced muscarinic supersensitivity in normal man: changes in sleep. Psychiatry Res 1: 9–16PubMedCrossRefGoogle Scholar
  39. Sitaram N, Gillin JC, Bunney WE (1984) Cholinergic and catecholaminergic receptor sensitivity in affective illness: Strategy and theory. In: Post RM, Ballenger JC (eds) Neurobiology of mood disorders. Williams and Wilkins, Baltimore, pp 629–651Google Scholar
  40. Spiegel R (1984) Effects of RS 86, an orally active cholinergic agonist, on sleep in man. Psychiatry Res 11: 1–13PubMedCrossRefGoogle Scholar
  41. Van Loon GR (1973) Catecholamines and ACTH secretion. In: Ganong WF, Martin L (eds) Frontiers in neuroendocrinology. Oxford University Press, New York, pp 209–247Google Scholar
  42. Vogel GW, Vogel E, McAbee RS, Thurmond A J (1980) Improvement of depression by REM sleep deprivation. Arch Gen Psychiatry 37: 247–253PubMedCrossRefGoogle Scholar
  43. Zerssen D von (1986) Clinical self-rating scales (CSRS) of the Munich psychiatry information system (PSYCHIS München). In: Sartorius N, Ban T (eds) Assessment of depression. Springer, Berlin Heidelberg New YorkGoogle Scholar
  44. Zerssen D von, Lund R, Doerr P, Fischler M, Emrich HM, Ploog D (1979) 48-hour-cycles of depression and their biological concomitants with and without “Zeitgebers”. A case report. In: Saletu B, Berner P, Hollister L (eds) Neuropsychopharmacology. Pergamon, Oxford, pp 233–245Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • M. Berger
  • P. Fleckenstein
  • D. Riemann
  • W. E. Müller
    • 1
  1. 1.Zentralinstitut für Seelische GesundheitMannheimGermany

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