Zizkind-somerfeld research award 1992| Volume 32, ISSUE 6, P469-484, September 15, 1992

Endogenous biochemical abnormalities in affective illness: Therapeutic versus pathogenic

  • Robert M. Post
    Address reprint requests to Robert M. Post, M.D., Chief, Biological Psychiatry Branch, NIMH, Bldg. 10, Room 3N212, 9000 Rockville Pike, Bethesda, MD 20892.
    Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, USA
    Search for articles by this author
  • Susan R.B. Weiss
    Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, USA
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.


      Examination of the neurobiology of psychiatric illness in general, and of affective disorders in particular, reveals a variety of associated biochemical abnormalities. These have generally been assumed to be part of the pathological process or secondary to it, and thus deserving of therapeutic efforts aimed at reversal. However, recent clinical and preclinical data suggest that some alterations occurring in the affective disorders may be compensatory and adaptive; that is, part of an endogenous therapeutic mechanism rather than part of the evolving disease process. For example, the symptom of sleep loss in depression seems to fall under this rubric inasmuch as sleep deprivation induced mood improvement in depressed patients. Preclinical data are presented that another primary pathological process—the occurrence of kindled seizures—can evoke endogenous compensatory processes that are either anticonvulsant in their own right, or enable the anticonvulsant effects of a drug such as carbamazepine. It may be that some biochemical abnormalities occurring in affective illness are similarly adaptive. As one example, increased thyrotropin-releasing hormone (TRH) has been reported in the cerebrospinal fluid (CSF) of depressed patients. This elevation of TRH and the resulting neuroendocrine profile may be part of an endogenous counter-regulatory process aimed at mood improvement. Again, preclinical seizure models are supportive in that TRH not only is induced following repeated seizures, but also exerts anticonvulsant effects on these same seizures. In an analogous fashion, TRH elevations in depressed patients may also exert ameliorating effects on depressive symptomatology. This formulation presents directly testable hypotheses that could importantly impact on our understanding of the pathophysiology of affective disorders, and suggests novel therapeutic strategies through the enhancement of endogenous compensatory mechanisms.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Alkon D.L.
        Memory storage and neural systems.
        Sci Am. 1989; 261: 42-51
        • Arana G.W.
        • Forbes R.A.
        Dexamethasone for the treatment of depression: a preliminary report.
        J Clin Psychiatry. 1991; 52: 304-306
        • Arana G.W.
        • Mossman D.
        The dexamethasone suppression test and depression. Approaches to the use of a laboratory test in psychiatry.
        Neurol Clin. 1988; 6: 21-39
        • Arana G.W.
        • Baldessarini R.J.
        • Ornsteen M.
        The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Commentary and review.
        Arch Gen Psychiatry. 1985; 42: 1193-1204
        • Banki C.M.
        • Bissette G.
        • Arato M.
        • Nemeroff C.B.
        Elevation of immunoreactive CSF TRH in depressed patients.
        Am J Psychiatry. 1988; 145: 1526-1531
        • Bauer M.S.
        • Whybrow P.C.
        Thyroid hormones and the central nervous system in affective illness: Interactions that may have clinical significance.
        Integrat Psychiatry. 1988; 6: 75-85
        • Baumgartner A.
        • Graf K.-J.
        • Kurten I.
        • Meinhold H.
        The hypothalamic-pituitary-thyroid axis in psychiatric patients and healthy subjects: part 3: The TRH test and thyroid hormone determinations as predictors of therapeutic response and long-term outcome in major depression and schizophrenia.
        Psychiatry Res. 1988; 24: 271-332
        • Bunney Jr., W.E.
        • Hartmann E.L.
        Study of a patient with 48-hour manic-depressive cycles. Part I.
        Arch Gen Psychiatry. 1965; 12: 611-618
        • Burnham W.M.
        The GABA hypothesis of kindling: recent assay studies.
        Neurosci Biobehav Rev. 1989; 13: 281-288
        • Carroll B.J.
        • Feinberg M.
        • Greden J.F.
        • Tarika J.
        • Albala A.A.
        • Haskett R.F.
        • James N.M.
        • Kronfol Z.
        • Lohr N.
        • Steiner M.
        • de Vigne J.P.
        • Young E.
        A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility.
        Arch Gen Psychiatry. 1981; 38: 15-22
        • Clark M.
        • Post R.M.
        • Weiss S.R.B.
        • Cain C.J.
        • Nakajima T.
        Regional expression of c-fos mRNA in rat brain during the evolution of amygdala kindled seizures.
        Mol Br Res. 1991; 11: 55-64
        • Costa E.
        • Guidotti A.
        Diazepam binding inhibitor (DBI): A peptide and multiple biological actions.
        Life Sci. 1991; 49: 325-344
        • Cutler N.R.
        • Post R.M.
        Life course of illness in untreated manic-depressive patients.
        Compr Psychiatry. 1982; 23: 101-115
        • DeMontigny C.
        Is the serotonin system still a promising target for the future of pharmacotherapy of affective disorders?.
        in: Presentation, Yale Symposium on Neurobiology of Affective Disorders, October 25–26, 19911991
        • Dragunow M.
        Endogenous anticonvulsant substances.
        Neurosci Biobehav Rev. 1986; 10: 229-244
        • Ehlers C.L.
        • Henriksen S.J.
        • Wang M.
        • Rivier J.
        • Vale W.
        • Bloom F.E.
        Corticotropin-releasing factor produces increases in brain excitability and convulsive seizures in rats.
        Brain Res. 1983; 278: 332-336
        • Ehlers C.L.
        • Reed T.K.
        • Henriksen S.J.
        Effects of corticotropin-releasing factor and growth-releasing factor on sleep and activity in rats.
        Neuroendocrinology. 1986; 42: 467-474
        • Engel Jr., J.
        • Bandler R.
        • Griffith N.C.
        • Caldecott-Hazard S.
        Neurobiological evidence foe epilepsy-induced interictal disturbances.
        in: Advances in Neurology, vol 55, Neurobehavioral Problems in Epilepsy. Raven, New York1991: 97-111
        • Fawcett J.
        • Maas J.W.
        • Dekirmenjian H.
        Depression and MHPG excretion.
        Arch Gen Psychiatry. 1972; 26: 246-251
        • Gallager D.W.
        • Jacobs A.A.
        • Craig J.S.
        • During M.J.
        • Hernandez T.D.
        Chronic treatments that produce reversible and irreversible changes in gamma-aminobutyric acid.
        in: Transmitter Amino Acid Receptors: Structures, Transduction and Models for Drug Development. Fidia Research Foundation Symposium Series. Vol. 6. Thieme Medical Publisher, New York1991: 113-128
        • Glanzman D.L.
        • Kandel E.R.
        • Schacher S.
        Target-dependent structural changes accompanying long-term synaptic facilitation in Aplysia neurons.
        Science. 1990; 249: 799-802
        • Goddard G.V.
        • McIntyre D.C.
        • Leech C.K.
        A permanent change in brain function resulting from daily electrical stimulation.
        Exp Neurol. 1969; 25: 295-330
        • Gold P.W.
        • Chrousos G.
        • Kellner C.
        • et al.
        Psychiatric implications of basic and clinical studies with corticotropin-releasing factor.
        Am J Psychiatry. 1984; 141: 619-627
        • Guidotti A.
        • Alho H.
        • Berkovich A.
        • et al.
        DBI processing: allosteric modulation at different GABA/benzodiazepine receptor subtypes.
        in: Barnard E.A. Costa E. Allosteric Modulation of Amino Acid Receptors: Therapeutic Implications. Raven, New York1991: 109-123
        • Havlicek V.
        • Friesen H.G.
        Comparison of behavioral effects of somatostatin and beta-endorphin in animals.
        in: Collu E. Ducharme J.R. Barbeau A. Rochefort S.G. Central Nervous System Effect of Hypothalamic Hormones and Other Peptides. Raven, New York1979: 381-402
        • Higuchi T.
        • Sikand G.S.
        • Kato M.
        Profound suppression of kindled seizures by cysteamine: Possible role of somatostatin to kindled seizures.
        Brain Res. 1983; 288: 359-362
        • Holsboer F.
        Psychiatric implications of altered limbic-hypothalamic-pituitary-adrenocortical activity.
        Eur Arch Psychiatry Neurol Sci. 1989; 238: 302-322
        • Hughes J.
        • Hunter J.C.
        • Woodruff G.N.
        Neurochemical actions of CCK underlying the therapeutic potential of CCK-B antagonists.
        Neuropeptides. 1991; 19 ([suppl]): 85-89
        • Iadarola M.J.
        • Shin C.
        • McNamara J.O.
        • Yang J.F.
        Changes in dynorphin, enkephalin and cholecystokinin content of hippocampus and substantia nigra after amygdala kindling.
        Brain Res. 1986; 365: 185-191
        • Isaac L.
        • Swanger J.
        Alteration of anticonvulsant threshold by cerebrospinal fluid from cats tolerant to anticonvulsant shock.
        Life Sci. 1983; 33: 2301-2304
        • Kamphuis W.
        • Gorter J.A.
        • da Silva F.L.
        A long-lasting decrease in the inhibitory effect of GABA on glutamate responses of hippocampal pyramidal neurons induced by kindling epileptogenesis.
        Neuroscience. 1991; 41: 425-431
        • Kato N.
        • Higuchi T.
        • Friesen H.G.
        Changes of immunoreactive somatostatin and beta-endorphin content in rat brain after amygdala kindling.
        Life Sci. 1983; 32: 2415-2422
        • Kirkegaard C.
        • Faber J.
        • Hummer L.
        • Rogowski P.
        Increased levels of TRH in cerebrospinal fluid from patients with endogenous depression.
        Psychoneuroendocrinology. 1979; 4: 227-235
        • Kubek M.J.
        • Fuson K.S.
        • Aydelotte M.R.
        • Knoblach S.M.
        Kindling increases neuronal production of thyrotropin-releasing hormone mRNA in seizure foci as determined by in situ hybridization histochemistry.
        Epilepsia. 1990; 31: 663
        • Kuhs H.
        • Tolle R.
        Sleep deprivation therapy.
        Biol Psychiatry. 1991; 29: 1129-1148
        • Lee P.H.
        • Zhao D.
        • Xie C.W.
        • McGinty J.F.
        • Mitchell C.L.
        • Hong J.S.
        Changes of proenkephalin and prodynorphin mRNAs and related peptides in rat brain during the development of deep prepyriform cortex kindling.
        Brain Res Mol Brain Res. 1989; 6: 263-273
        • Loosen P.T.
        The TRH-induced TSH response in psychiatric patients: a possible neuroendocrine marker.
        Psychoneuroendocrinology. 1985; 10: 237-260
        • Loosen P.T.
        • Prange Jr., A.J.
        Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: A review.
        Am J Psychiatry. 1982; 139: 405-416
        • Lynch G.S.
        Long-term potentiation and serial memory processing in the olfactory hippocampal circuit.
        in: Abstracts, AAAS Annual Meeting. 1991
        • Marley R.J.
        • Witkin J.M.
        • Goldberg S.R.
        Genetic factors influence changes in sensitivity to the convulsant properties of cocaine following chronic treatment.
        Brain Res. 1991; 542: 1-7
        • McEwen B.S.
        • Angulo J.
        • Cameron H.
        • Chao H.M.
        • Daniels D.
        • Gannon M.N.
        • Gould E.
        • Mendelson M.
        • Sakai R.
        • Spencer R.
        Paradoxical effects of adrenal steroids on the brain: protection versus degeneration.
        Biol Psychiatry. 1992; 31: 177-199
        • Meyerhoff J.L.
        • Bates V.E.
        • Kubek M.J.
        Elevated TRH levels in pyriform cortex after partial and fully generalized kindled seizures.
        Brain Res. 1990; 525: 144-148
        • Morgan J.I.
        • Curran T.
        Stimulus-transcription coupling in the nervous system: involvement of inducible proto oncogenes fos and jun.
        Annual Rev Neurosci. 1991; 14: 421-451
        • Morrow A.L.
        • Pace J.R.
        • Purdy R.H.
        • Paul S.M.
        Characterization of steroid interactions with gamma-aminobutyric acid receptor-gated chloride ion channels: Evidence for multiple steroid recognition sites.
        Mol Pharmacol. 1990; 37: 263-270
        • Munck A.
        • Guyre P.M.
        • Holbrook N.J.
        Physiological functions of glucocorticoids in stress and their relation to pharmacological actions.
        Endocr Rev. 1984; 5: 25-44
        • Murphy B.E.
        • Dhar V.
        • Ghadirian A.M.
        • Chouinard G.
        • Keller R.
        Response to steroid suppression in major depression resistant to antidepressant therapy.
        J Clin Psychopharmacol. 1991; 11: 121-126
        • Nadi N.S.
        • Pless M.
        • Pintor M.
        The levels of somatostatin in eight brain regions of the rat during the development of kindling.
        Abstracts, Society for Neuroscience. 1989; 15 (Abs#310.16): 779
        • Nakajima T.
        • Post R.M.
        • Weiss S.R.B.
        • Pert A.
        • Ketter T.
        Perspectives on the mechanism of action of electroconvulsive therapy: anticonvulsant, dopaminergic, and c-fos oncogene effects.
        Conv Ther. 1989; 5: 274-295
        • Nemeroff C.B.
        • Widerlov E.
        • Bissette G.
        Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.
        Science. 1984; 226: 1342-1344
        • Pinel J.P.J.
        Kindling-induced experimental epilepsy in rats: cortical stimulation.
        Exp Neurol. 1981; 72: 559-569
        • Pinel J.P.J.
        • Rovner L.I.
        Experimental epileptogenesis: kindling-induced epilepsy in rats.
        Exp Neurol. 1978; 58: 190-202
        • Post R.M.
        Alternatives to lithium for bipolar affective illness.
        in: Review of Psychiatry. vol 9. American Psychiatric Press, Washington, DC1990: 170-202
        • Post R.M.
        ECT: The anticonvulsant connection.
        Neuropsychopharmacology. 1990; 3: 89-92
        • Post R.M.
        The transduction of psychosocial stress into the neurobiology of recurrent affective disorder.
        Am J Psychiatry. 1992; 149: 999-1010
      1. Post R.M. Ballenger J.C. Neurobiology of Mood Disorders. Williams & Wilkins, Baltimore1984
        • Post R.M.
        • Weiss S.R.B.
        Kindling and manic-depressive illness.
        in: Trimble M. Bolwig T.G. The Clinical Relevance of Kindling. Wiley, Chichester, England1989: 209-230
        • Post R.M.
        • Kopanda R.T.
        • Lee A.
        Progressive behavioral changes during chronic lidocaine administration: Relationship to kindling.
        Life Sci. 1975; 17: 943-950
        • Post R.M.
        • Kennedy C.
        • Shinohara M.
        • et al.
        Metabolic and behavioral consequences of lidocaine-kindled seizures.
        Brain Res. 1984; 324: 295-303
        • Post R.M.
        • Putnam F.W.
        • Contel N.R.
        • Goldman B.
        Electroconvulsive seizures inhibit amygdala kindling: Implications for mechanisms of action in affective illness.
        Epilepsia. 1984; 25: 234-239
        • Post R.M.
        • Rubinow D.R.
        • Ballenger J.C.
        Conditioning, sensitization, and kindling: Implications for the course of affective illness.
        in: Post R.M. Ballenger J.C. Neurobiology of Mood Disorders. Williams and Wilkins, Baltimore1984: 432-466
        • Post R.M.
        • Putnam F.
        • Uhde T.W.
        • Weiss S.R.B.
        ECT as an anticonvulsant: Implications for its mechanism of action in affective illness.
        in: Electroconvulsive Therapy: Clinical and Basic Research Issues. Annals, NY Academy of Sciences. vol 462. NY Academy of Sciences, New York1986: 376-388
        • Post R.M.
        • Rubinow D.R.
        • Ballenger J.C.
        Conditioning and sensitization in the longitudinal course of affective illness.
        Br J Psychiatry. 1986; 149: 191-201
        • Post R.M.
        • Kramlinger K.G.
        • Joffe R.T.
        • Gold P.W.
        • Uhde T.W.
        Effects of carbamazepine on thyroid function.
        in: Sci Proc Am Psychiatr Assoc. 140. 1987: 190 (Abs#104D)
        • Post R.M.
        • Weiss S.R.B.
        • Clark M.
        • Nakajima T.
        • Pert A.
        Amygdala versus local anesthetic kindling: Differential anatomy, pharmacology, and clinical implications.
        in: Kindling. 4. Plenum Press, New York1990: 357-369
        • Post R.M.
        • Weiss S.R.B.
        • Nakajima T.
        • Clark M.
        • Pert A.
        Mechanism-based approaches to anticonvulsant therapy.
        in: Meldrum B.S. Williams M. Current and Future Trends in Anticonvulsant, Anxiety and Stroke Therapy. Wiley-Liss, New York1990: 45-90
        • Post R.M.
        • George M.S.
        • Ketter T.A.
        • Denicoff K.
        • Leverich G.
        • Mikalauskas K.
        Mechanisms underlying recurrence and cycle acceleration in affective disorders: implications for long-term treatment.
        in: Montgomery S. Psychopharmacology of Depression. Oxford University Press, London1992 (in press)
        • Post R.M.
        • Weiss S.R.B.
        • Uhde T.W.
        • Clark M.
        • Rosen J.B.
        Preclinical neuroscience advances pertinent to panic disorder: Implications of cocaine kindling, induction of the proto-oncogene c-fos, and contingent tolerance.
        in: Hoehn-Saric R. Biology of Anxiety Disorders: Recent Development. APA Press, Washington, DC1992 (in press)
        • Prange Jr., A.J.
        • Loosen P.T.
        • Wilson I.C.
        • Lipton M.A.
        The therapeutic use of hormones of the thyroid axis in depression.
        in: Post R.M. Ballenger J.C. Neurobiology of Mood Disorders. Williams and Wilkins, Baltimore1984: 311-322
        • Racine R.
        Kindling: the first decade.
        Neurosurgery. 1978; 3: 234-252
        • Risch S.c.
        • Lewine R.J.
        • Jewart R.D.
        • et al.
        The relationship between structural brain imaging, limbic HPA activity and CSF CRF and catecholamine metabolites in affective disorders and schizophrenia.
        Clin Neuropharmacol. 1990; 13: 601-602
        • Rose S.P.R.
        How chicks make memories: the cellular cascade from c-fos to dendritic remodeling.
        Trends Neurosci. 1991; 14: 390-397
        • Rosen J.B.
        • Cain C.J.
        • Weiss S.R.B.
        • Post R.M.
        Alterations in mRNA of enkephalin, dynorphin and thyrotropin releasing hormone during amygdala kindling: an in situ hybridization study.
        Mol Brain Res. 1992; (in press)
        • Roy-Byrne P.P.
        • Uhde T.W.
        • Post R.M.
        Antidepressant effects of one night's sleep deprivation: Clinical and theoretical implications.
        in: Post R.M. Ballenger J.C. Neurobiology of Mood Disorders. Williams & Wilkins, Baltimore1984: 817-835
        • Rubinow D.R.
        Cerebrospinal fluid somatostatin and psychiatric illness.
        Biol Psychiatry. 1986; 21: 341-365
        • Rubinow D.R.
        • Gold D.R.
        • Post R.M.
        Somatostatin in affective illness.
        Arch Gen Psychiatry. 1983; 40: 403-412
        • Rubinow D.R.
        • Gold P.W.
        • Post R.M.
        • Ballenger J.C.
        • Cowdry R.W.
        Somatostatin in patients with affective illness and normal volunteers.
        in: Post R.M. Ballenger J.C. Neurobiology of Mood Disorders. Williams and Wilkins, Baltimore1984: 369-387
        • Sapolsky R.M.
        • Pulsinelli W.A.
        Glucocorticoids potentiate ischemic injury to neurons: Therapeutic implications.
        Science. 1985; 229: 1397-1400
        • Sato M.
        Intractability of complex partial seizure with secondary generalization: Kindling studies in cats.
        Tohoku J Exp Med. 1990; 161 ([suppl]): 253-271
        • Sato M.
        • Morimoto K.
        • Wada J.A.
        Antiepileptic effects of thyrotropin-releasing hormone and its new derivative, DN-1417, examined in feline amygdaloid kindling preparation.
        Epilepsia. 1984; 25: 537-544
        • Shinoda H.
        • Schwartz J.P.
        • Nadi N.S.
        Amygdaloid kindling of rats increases preprosomatostatin mRNA and somatostatin without affecting glutamic acid decarboxylase (GAD) mRNA or GAD.
        Mol Brain Res. 1989; 5: 243-246
        • Smith M.
        • Weiss S.R.B.
        • Abedin T.
        • Post R.M.
        • Gold P.
        Effects of amygdala-kindling and electroconvulsive seizures on the expression of corticotropin releasing hormone (CRH) mRNA in the rat brain.
        Mol Cell Neurosci. 1991; 2: 103-116
        • Steiger A.
        • Pollmacher T.
        • Lauer C.
        • Holsboer F.
        Modulation of nocturnal sleep-EEG in humans by neuropeptides and adrenal steroids.
        Biol Psychiatry. 1991; 29: 52
        • Stone E.A.
        Problems with current catecholamine hypotheses of antidepressant agents: speculations toward a new hypothesis.
        Behav Brain Sci. 1983; 6: 535-577
        • Sutula T.
        • Xiao-Xian H.
        • Cavazos J.
        • Scott G.
        Synaptic reorganization in the hippocampus induced by abnormal functional activity.
        Science. 1988; 239: 1147-1150
        • Tortella F.C.
        • Long J.B.
        Characterization of opioid peptide-like anticonvulsant activity in rat cerebrospinal fluid.
        Brain Res. 1988; 456: 139-146
        • Vezzani A.
        • Serafini R.
        • Stasi M.A.
        • Samanin R.
        • Ferrarese C.
        Epileptogenic activity of two peptides derived from diazepam binding inhibitor after intrahippocampal injection in rats.
        Epilepsia. 1991; 32: 597-603
        • Wada J.A.
        • Sato M.
        • Corcoran M.E.
        Persistent seizure susceptibility and recurrent spontaneous seizures in kindled cats.
        Epilepsia. 1974; 15: 465-478
        • Weiss S.R.B.
        • Nierenberg J.
        • Lewis R.
        • Post R.M.
        Corticotropin-releasing hormone: potentiation of cocaine kindled seizures and lethality.
        Epilepsia. 1992; 33: 248-254
        • Weiss S.R.
        • Post R.M.
        • Gold P.W.
        • et al.
        CRF-induced seizures and behavior: interaction with amygdala kindling.
        Brain Res. 1986; 372: 345-351
        • Wu J.C.
        • Bunney Jr., W.E.
        The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis.
        Am J Psychiatry. 1990; 147: 14-21
        • Xie C.W.
        • Lee P.H.
        • Douglass J.
        • Crain B.
        • Hong J.S.
        Deep prepyriform cortex kindling differentially alters the levels of prodynorphin mRNA in rat hippocampus and striatum.
        Brain Res. 1989; 495: 156-160
        • Yeh G.C.
        • Bonhaus D.W.
        • Nadler J.V.
        • McNamara J.O.
        N-methyl-D-aspartate receptor plasticity in kindling: quantitative and qualitative alterations in the N-methyl-D-aspartate receptor-channel complex.
        in: Proc Natl Acad Sci USA. 86. 1989: 8157-8160