Molecular insights into schizophrenia

  • J. W. Pettegrew
  • N. J. Minshew
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 36)


A number of studies have demonstrated alterations in the structure and function of the frontal cortex in some schizophrenic patients. The possible etiology and pathogenesis of these abnormalities are unknown, but genetic and developmental causes are frequently mentioned. Recent in vivo 31P NMR studies of the dorsal prefrontal cortex have been conducted in eleven neuroleptic naive, first episode schizophrenic patients and corn-pared with normal controls of comparable age, educational level and parental educational level. The findings in the schizophrenic patients are different from those of normal IQ adult autistic patients of comparable age and Alzheimer’s patients but similar to normal elderly controls. These studies show decreased frontal lobe utilization of adenosine triphosphate in the schizophrenic patients which suggests a hypoactive dorsal prefrontal cortex. In addition, indices of membrane phospholipid metabolism are altered in the schizophrenic patients. However, the findings in the schizophrenic patients are quite similar to those observed in normal elderly controls and to those that normally occur to a lesser degree during adolescence. The phospholipid alterations observed in the schizophrenic patients are compatible with either premature aging or altered timing and exaggeration of the regressive events which occur during normal brain development. The changes in high-energy phosphate metabolism observed in the schizophrenic patients may prove to be state dependent, but the changes in membrane phospholipid metabolism could be related to molecular changes that precede the onset of clinical symptoms and brain structural changes in schizophrenia. These findings suggest new avenues of thinking about the pathogenesis and treatment of schizophrenia.


Nuclear Magnetic Resonance Schizophrenic Patient Nuclear Magnetic Resonance Spectroscopy Normal Elderly Control Occur Cell Death 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ackerman JH, Grove TH, Wong GG, Gadian DG, Radda GK (1980) Mapping of metabolites in whole animals by 31P nuclear magnetic resonance spectroscopy. Nature 283: 167–170CrossRefPubMedGoogle Scholar
  2. Andreasen NC (1988) Brain imaging: applications in psychiatry. Science 239: 1381–1388CrossRefPubMedGoogle Scholar
  3. Andreasen N, Nasrallah HA, Dunn V, Olson SC, Grove WM, Ehrhardt JC, Coffman JA, Crossett JHW (1986) Structural abnormalities the frontal system in schizophrenia. Arch Gen Psychiatry 43: 136–144CrossRefPubMedGoogle Scholar
  4. Barany M, Glonek T (1984) Identification of diseased states by phosphorus-31 NMR. In: Gorenstein DG (ed) Phosphorus-31 NMR, principles and applications. Academic Press, New York, pp 511–515Google Scholar
  5. Berman KF, Illowsky BP, Weinberger DR (1988) Physiological dysfunction of dorsolateral prefontal cortex in schizophrenia. Arch Gen Psychiatry 45: 616–622CrossRefPubMedGoogle Scholar
  6. Berridge MJ, Irvine RF (1984) Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315–321CrossRefPubMedGoogle Scholar
  7. Blass JP, Hanin I, Barclay L, Kopp U, Reding MJ (1985) Red blood cell abnormalities in Alzheimer’s disease. J Am Geriatr Soc 33: 401–405PubMedGoogle Scholar
  8. Brown GG, Levine SR, Gorell JM, Pettegrew JW, Gdowski JW, Bueri JA, Helpern JA, Welch KMA (1989) In vivo 31P NMR profiles of Alzheimer’s disease and multiple subcortical infarct dementia. Neurology 39: 1423–1427PubMedGoogle Scholar
  9. Buchsbaum MS (1987) Positron emission tomography in schizophrenia. In: Meltzer HY (ed) Psychopharmacology, the third generation of progress. Raven Press, New York, pp 783–792Google Scholar
  10. Buchsbaum MS, Ingvar DH, Kessler R, Waters RN, Cappelette J, van Kammen DP, King C, Johnson JL, Manning RB, Flynn RW, Mann LS, Bunney WE, Sokoloff L (1982) Cerebral glucography with positron tomography. Arch Gen Psychiatry 39: 251–259CrossRefPubMedGoogle Scholar
  11. Butterfield DA, Markesbery WR (1980) Specificity of biophysical and biochemical alterations in erythrocyte membranes with neurological disorders. J Neurol Sci 97: 261–271CrossRefGoogle Scholar
  12. Butterfield DA, Oeswein JW, Markesbery WR (1977) Electron spin resonance study of membrane protein alterations in erythrocytes in Huntington’s disease (letter). Nature 267: 453–455CrossRefPubMedGoogle Scholar
  13. Butterfield DA, Oeswein JW, Prunty ME, Hisle KC, Markesbery WR (1978) Increased sodium plus potassium adenosine triphosphatase activity in erythrocyte membranes in Huntington’s disease. Ann Neurol 4: 60–62CrossRefPubMedGoogle Scholar
  14. Butterfield DA, Nicholas MM, Markesbery WR (1985) Evidence for an increased rate of choline efflux across erythrocyte membranes in Alzheimer’s disease. Neurochem Res 10: 909–918CrossRefPubMedGoogle Scholar
  15. Cady EB, Dawson MJ, Hope PL, Tofts PS, Costello AM, Delpy DT, Reynolds EOR, Wilkie DR (1983) Non-invasive investigation of cerebral metabolism in newborn infants by phosphorus nuclear magnetic resonance spectroscopy. Lancet is 1059–1062Google Scholar
  16. Carruthers A, Helgerson AL, Herbert DN, Tefft RE Jr, Naderi S, Melchior DL (1989) Effects of calcium, ATP and lipids on human erythrocyte sugar transport. Ann NY Acad Sci 568: 52–67Google Scholar
  17. Chance B, Nakase Y, Bond M, Leigh JS Jr, McDonald G (1978) Detection of 31P nuclear magnetic resonance signals in brain by in vivo and freeze trapped assays. Proc Natl Acad Sci USA 75: 4925–4929CrossRefPubMedGoogle Scholar
  18. Clarke PG (1985) Neuronal death in the development of the vertebrate nervous system. Trends Neurosci 8: 345–349CrossRefGoogle Scholar
  19. Cohen MM, Pettegrew JW, Kopp SJ, Minshew N, Glonek T (1984) P-31 nuclear magnetic resonance analysis of brain: normoxic and anoxic brain slices. Neurochem Res 9: 785–801CrossRefPubMedGoogle Scholar
  20. Cowan WM, Fawcett JW, OLeary DD, Stanfield BB (1984) Regressive events in neurogenesis. Science 225: 1258–1265CrossRefPubMedGoogle Scholar
  21. Demisch L, Gerbaldo H, Heinz K, Kirsten R (1987) Transmembranal signalling in schizophrenic and affective disorders: studies on arachidonic acid and phospholipids. Schizophr Res 22: 275–282Google Scholar
  22. Diamond JM, Matsuyama SS, Meier K, Jarvik LF (1983) Elevation of erythrocyte countertransport rates in Alzheimer’s dementia (letter). N Engl J Med 309: 1061–1062PubMedGoogle Scholar
  23. DSM-III-R Diagnostic and Statistical Manual of Mental Disorders, 3rd edn (1987)Google Scholar
  24. American Psychiatric Association. Workgroup to revise DSM-III, Washington, DC Endicott J, Spitzer RL (1978) A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35: 837–844CrossRefGoogle Scholar
  25. Essali MA, Das I, deBelleroche J, Hirsch SR (1989) The platelet polyphosphoinositide system in schizophrenia: pathological and pharmacological implications. Schizophr Res 2: 148CrossRefGoogle Scholar
  26. Falkai P, Bogerts B, Rozumek M (1988) Cell loss and volume reduction in the entorhinal cortex of schizophrenics. Eur Arch Psychiatry Neurol Sci 24: 515–521Google Scholar
  27. Farde L, Wiesel FA, Hall H, Halldin C, Stone-Elander S, Sedvall G (1987) No D2 receptor increase in PET study of schizophrenia (letter). Arch Gen Psychiatry 44: 671— 672Google Scholar
  28. Feinberg I (1982) Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 17 [Suppl] 4: 319–334Google Scholar
  29. Gattaz W (1987) Increased plasma phospholipase A2 activity in schizophrenic patients: reduction in schizophrenia. Biol Psychiatry 22: 421CrossRefPubMedGoogle Scholar
  30. Glonek T, Kopp SJ, Kot E, Pettegrew JW, Harrison WH, Cohen MM (1982) P-31 nuclear magnetic resonance analysis of brain: the perchloric acid extract spectrum. J Neurochem 39: 1210–1219CrossRefPubMedGoogle Scholar
  31. Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41: 1–24CrossRefPubMedGoogle Scholar
  32. Henn F (1980) Biological concepts of schizophrenia. In: Baxter C, Melnachuk T (eds )Google Scholar
  33. Perspectives in schizophrenia research. Raven Press, New York, pp 209–223 Hitzemann R, Hirschwitz D, Garver D (1984) Membrane abnormalities in the psychoses and affective disorders. J Psychiatr Res 18: 319–326CrossRefGoogle Scholar
  34. Huttenlocher PR (1979) Synaptic density in human frontal cortex. Developmental changes and effects of aging. Brain Res 163: 195–205CrossRefPubMedGoogle Scholar
  35. Huttenlocher PR, deCourten C, Garey U, Van Der Loos H (1982) Synaptogenesis in human visual cortex-evidence for synapse elimination during normal development. Neurosci Lett 33: 247–252CrossRefPubMedGoogle Scholar
  36. Ingvar DH, Franzen G (1974) Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenics. Acta Psychiatr Scand 50: 425–462CrossRefPubMedGoogle Scholar
  37. Jaskiw G, Kleinman J (1988) Postmortem neurochemistry studies in schizophrenia. In: Schulz SC, Tamminga HK (eds) Schizophrenia: a scientific focus. Oxford University Press, New York, pp 264–273Google Scholar
  38. Kaiya H, Takeuchi K, Namba M, Imai A, Nakashima S, Nozawa Y (1984) Abnormal phosphatidylinositol-cycle of platelet membrane in schizophrenia — a preliminary study. Folia Psychiat Neurol Jpn 38: 437–444PubMedGoogle Scholar
  39. Kornhuber J, Riederer P, Reynolds GP, Beckmann H, Jellinger K, Gabriel E (1989) 3H-spiperone binding sites in post-mortem brains from schizophrenia patients: relationship to neuroleptic drug treatment, abnormal movements, and positive symptoms. J Neural Transm 75: 1–10Google Scholar
  40. Kraepelin E (1919) Dementia praecox and paraphrenia. Churchill Livingstone, EdinburghGoogle Scholar
  41. Majerus PW, Connolly TM, Deckmyn H, Ross TS, Bross TE, Ishii H, Bansal VS, Wilson DB (1986) The metabolism of phosphoinositide-derived messenger molecules. Science 234: 1519–1526CrossRefPubMedGoogle Scholar
  42. Maris JM, Evans AE, McLaughlin AC, D’Angio GJ, Bolinger L, Manos H, Chance B (1985) 31P nuclear magnetic resonance spectroscopic investigation of human neuroblastoma in situ. N Engl J Med 312: 1500–1505Google Scholar
  43. Markesbery WR, Leung PK, Butterfield DA (1980) Spin label and biochemical studiesGoogle Scholar
  44. of erythrocyte membranes in Alzheimer’s disease. J Neurol Sci 45: 323–330 Mcllwain H, Bachelard HS (1985) Biochemistry and the central nervous system, 5th edn. Churchill Livingstone, New York, pp 41–43Google Scholar
  45. Miller BL, Jenden D, Tang C, Read S (1989) Choline and choline-bound phospholipids in aging and Alzheimer’s disease (abstract). Neurology 39 [Suppl] 1: 254Google Scholar
  46. Minshew NJ, Pettegrew JW, Panchalingam K (1990) Membrane phospholipid alterations observed in Alzheimer’s disease are not present in Down’s syndrome (abstract). Biol Psychiatry 27 (9A): 123A - 124AGoogle Scholar
  47. Morel BA (1860) Traitement des maladies mentales. Masson, ParisGoogle Scholar
  48. Oppenheim RW (1985) Naturally occurring cell death during neural development. Trends Neurosci 8: 487–493CrossRefGoogle Scholar
  49. Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Rep 10: 799– 812Google Scholar
  50. Panchalingam K, Post JFM, Pettegrew JW (1987) Evidence for increased aluminum binding ligands in Alzheimer’s disease (abstract). Neurology 37 [Suppl] 1: 331Google Scholar
  51. Panchalingam K, Pettegrew JW, Strychor S, Tretta M (1990) Effect of normal aging on membrane phospholipid metabolism by 31P in vivo NMR spectroscopy (abstract). Soc Neurosci Abstr 16: 843Google Scholar
  52. Petroff OAC, Prichard JW, Behar KL, Alger JR, den Hollander JA, Shulman RG (1985) Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy. Neurology 35: 781–788PubMedGoogle Scholar
  53. Molecular insights 39Google Scholar
  54. Pettegrew JW, Nichols JS, Stewart RM (1979a) Studies of the fluorescence of fibroblasts from Huntington’s disease: evidence of a membrane abnormality. N Engl J Med 300: 678PubMedGoogle Scholar
  55. Pettegrew JW, Nichols JS, Stewart RM (1979b) Fluorescence spectroscopy on Huntington’s fibroblasts. J Neurochem 33: 905–911CrossRefPubMedGoogle Scholar
  56. Pettegrew JW, Glonek T, Baskin F, Rosenberg RN (1979c) Phosphorus-31 NMR of neuroblastoma clonal lines: effect of cell confluency state and dibutyryl cyclic AMP. Neurochem Res 4: 795–801CrossRefPubMedGoogle Scholar
  57. Pettegrew JW, Nichols JS, Stewart RM (1981) Membrane studies in Huntington’s disease: steady-state and time-dependent fluorescence spectroscopy of intact lymphocytes. J Neurochem 36: 1966–1976CrossRefPubMedGoogle Scholar
  58. Pettegrew JW, Nichols JS, Minshew NJ, Rush AJ, Stewart RM (1982) Membrane biophysical studies of lymphocytes and erythrocytes in manic-depressive illness. J Affective Disord 4: 237–247CrossRefGoogle Scholar
  59. Pettegrew JW, Minshew NJ, Stewart RM (1983a) Dynamic membrane studies in individuals at risk for Huntington’s disease. Life Sci 32: 1207–1212CrossRefPubMedGoogle Scholar
  60. Pettegrew JW, Minshew NJ, Diehl J, Smith T, Kopp SJ, Glonek T (1983b) Anatomical considerations for interpreting topical P-31 NMR. Lancet ii: 913Google Scholar
  61. Pettegrew JW, Minshew NJ, Cohen MM, Kopp SJ, Glonek T (1984) P-31 NMR changes in Alzheimer’s and Huntington’s disease brain (abstract). Neurology 34 [Suppl] 1: 281Google Scholar
  62. Pettegrew JW, Kopp SJ, Dadok J, Minshew SJ, Feliksik JM, Glonek T, Cohen MM (1986) Chemical characterization of a prominent phosphomonoester resonance from mammalian brain: 31P and 1H NMR analysis at 4.7 and 14.1 tesla. J Magn Reson 67: 443–450Google Scholar
  63. Pettegrew JW, Kopp SJ, Minshew NJ, Glonek T, Feliksik JM, Tow JP, Cohen MM (1987a) 31P nuclear magnetic resonance studies of phosphoglyceride metabolism in developing and degenerating brain: preliminary observations. J Neuropathol Exp Neurol 46: 419–430Google Scholar
  64. Pettegrew JW, Withers G, Panchalingam K, Post JF (1987b) 31P nuclear magnetic resonance ( NMR) spectroscopy of brain in aging and Alzheimer’s disease. J Neural Transm [Suppl] 24: 261–268Google Scholar
  65. Pettegrew JW, Withers G, Panchalingam K, Post JFM (1988a) Considerations for brain pH assessment by 31P NMR. Magn Reson Imaging 6: 135–142CrossRefPubMedGoogle Scholar
  66. Pettegrew JW, Moossy J, Withers G, McKeag D, Panchalingam K (1988b) 31P Nuclear magnetic resonance study of the brain in Alzheimer’s disease. J Neuropathol Exp Neurol 47: 235–248Google Scholar
  67. Pettegrew JW, Panchalingam K, Moossy J, Martinez J, Rao G, Boller F (1988c) Correlation of phosphorus-31 magnetic resonance spectroscopy and morphologic findings in Alzheimer’s disease. Arch Neurol 45: 1093–1096CrossRefPubMedGoogle Scholar
  68. Pettegrew JW, Minshew NJ, Payton JB (1989) 31P NMR in normal IQ adult autistics (abstract). Biol Psychiatry 25: 182Google Scholar
  69. Pettegrew JW, Panchalingam K, Withers G, McKeag D, Strychor S (1990) Changes in brain energy and phospholipid metabolism during development and aging in the Fischer 344 rat. J Neuropathol Exp Neurol 49: 237–249CrossRefPubMedGoogle Scholar
  70. Pettegrew JW, Keshauan MS, Panchalingam K, Strychor S, Kaplan DB,Tretta MG, Allen M (1991) Alterations in brain high-energy phosphate and membrane phospholipid metabolism on first-episode, drug-naive schizophrenics. Arch Gen Psychiatry 48: 563–568Google Scholar
  71. Pittman R, Oppenheim RW (1979) Cell death of motoneurons in the chick embryo spinal cord. IV. Evidence that a functional neuromuscular interaction is involved in the regulation of naturally occurring cell death and the stabilization of synapses. J Comp Neurol 187: 425–446Google Scholar
  72. Purves D, Lichtman JW (1980) Elimination of synapses in the developing nervous system. Science 210: 153–157CrossRefPubMedGoogle Scholar
  73. Rakic P, Riley KP (1983) Overproduction and elimination of retinal axons in the fetal rhesus monkey. Science 219: 1441–1444CrossRefPubMedGoogle Scholar
  74. Rotrosen J, Wolkin A (1987) Phospholipid and prostaglandin hypothesis in schizophrenia. In: Meltzer HY (ed) Psychopharmacology. The third generation of progress. Raven Press, New York, pp 759–764Google Scholar
  75. Rumsey JM, Duara R, Grady C, Rapoport JL, Margolin RA, Rapoport SI, Cutler NR (1985) Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography. Arch Gen Psychiatry 42: 448–455Google Scholar
  76. Seeman P, Ulpian C, Bergeron C, Riederer P, Jellinger K, Gabriel E, Reynolds GP, Tourtellotte WW (1984) Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science 225: 728–731CrossRefPubMedGoogle Scholar
  77. Sherman KA, Gibson SE, Blass JP (1986) Human red blood cell choline uptake with age and Alzheimer’s disease. Neurobiol Aging 7: 205–209CrossRefPubMedGoogle Scholar
  78. Spitzer RL, Endicott J, Robins E (1990) Research diagnostic criteria (RDC) for a selected group of function disorders, 3rd edn. New York State Psychiatric Hospital, New YorkGoogle Scholar
  79. Stevens JD (1972) The distribution of phospholipid fractions in the red cell membrane of schizophrenics. Schizophr Bull 6: 60–61Google Scholar
  80. Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR (1990) Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 322: 789–794CrossRefPubMedGoogle Scholar
  81. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44: 660–669CrossRefPubMedGoogle Scholar
  82. Weinberger DR, Berman KF, Zec DF (1986) Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia. Arch Gen Psychiatry 43: 114–124CrossRefPubMedGoogle Scholar
  83. Wong DF, Wagner HN, Tune LE, Dannals RF, Pearlson GD, Links JM, Tamminga CA, Broussolle EP, Ravert HT, Wilson AA, Toung JKT, Malat J, Williams JA, Lorcan A, O’Tuama O, Snyder SH, Kuhar MJ, Gjedde A (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234: 1558–1563CrossRefPubMedGoogle Scholar
  84. Zubenko GS, Cohen BM, Reynolds CF, Boller F, Malinakova I, Keefe MA (1987) Platelet membrane fluidity in Alzheimer’s disease and major depression. Am J Psychiatry 144: 860–868PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • J. W. Pettegrew
    • 1
    • 2
  • N. J. Minshew
    • 3
  1. 1.Neurophysics Laboratory, Center for Membrane Studies, Laboratory of Neurophysics, Department of Psychiatry, Western Psychiatric Institute and Clinic, School of MedicineUniversity of PittsburghPittsburghUSA
  2. 2.Western Psychiatric Institute and Clinicc/o The Graduate School of Public HealthPittsburghUSA
  3. 3.Autism and Social Disabilities Program, Center for Membrane Studies, Laboratory of Neurophysics, Department of Psychiatry, Western Psychiatric Institute and Clinic, School of MedicineUniversity of PittsburghPittsburghUSA

Personalised recommendations