Download PDF
Fortschr Neurol Psychiatr 2001; 69(11): 503-509
DOI: 10.1055/s-2001-18379
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Antipsychotika und Phospholipidmetabolismus bei der Schizophrenie

Antipsychotics and Phospholipid Metabolism in SchizophreniaA.  Schmitt1 , A.  Maras1 , D.  F.  Braus1 , G.  Petroianu2 , A.  Jatzko1 , W.  F.  Gattaz3
  • 1 1Zentralinstitut für Seelische Gesundheit, Mannheim (Direktor: Prof. Dr. Dr. F. A. Henn)
  • 2 2Institut für Pharmakologie und Toxikologie, Mannheim (Direktor: Prof. Dr. B. Lemmer)
  • 3 3Department of Psychiatry, Faculty of Medicine, University of Sao Paulo/Brazil (Direktor: Prof. Dr. W. F. Gattaz)
Die Arbeit wurde unterstützt durch die Deutsche Forschungsgemeinschaft, SFB 258, S4.
Further Information

Publication History

Publication Date:
12 November 2001 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

An peripheren Zellen, in Post-mortem-Gehirnuntersuchungen und mittels der In-vivo-31P-Magnetresonanz-Spektroskopie (MRS) wurde wiederholt eine Beschleunigung des Phospholipidmetabolismus bei schizophrenen Patienten beschrieben. Die Spezifität der Ergebnisse für die Schizophrenie und der Einfluss antipsychotischer Medikation wurde bislang nicht hinreichend untersucht. In der vorliegenden Studie wurde die Zusammensetzung der Membranphospholipide an Thrombozyten bei 67 unbehandelten schizophrenen Patienten im Vergleich zu gesunden und psychiatrischen Kontrollen bestimmt. Bei einer Subgruppe der Patienten wurden die Effekte einer 6-monatigen antipsychotischen Behandlung auf den Phospholipidmetabolismus untersucht. Während bei unbehandelten Patienten die Hauptbestandteile der Membranphospholipide, Phosphatidylcholin und Phosphatidylethanolamin im Vergleich zu den Kontrollen erniedrigt und deren durch Aktivität der Phospholipase A2 entstandenes Abbauprodukt Lysophosphatidylcholin (LPC) erhöht war, sank LPC während einer 3-wöchigen, standardisierten Haloperidol-Therapie signifikant ab. Im Langzeitverlauf, bei Verwendung klassischer und atypischer Antipsychotika finden sich divergente Effekte. So blieb LPC unter kontinuierlicher Therapie mit typischen Neuroleptika weiterhin erniedrigt, während es bei denjenigen Patienten, die auf das Atypikum Zotepin umgestellt wurden, zu einem Anstieg von LPC kam. Unterschiedliche Wirkungen verschiedener Substanzklassen der Antipsychotika auf den Phospholipidmetabolismus können möglicherweise die divergenten Befunde der 31P-MRS bei medizierten schizophrenen Patienten erklären.

Abstract

To date numerous in-vivo 31P-MRS and in-vitro studies in schizophrenic patients have been able to demonstrate changes in their membrane phospholipid metabolism, which might be relevant for the cause and the therapeutic responsiveness of this disorder. Thus far, however, only limited studies exist regarding the specificity of these findings for schizophrenia and the effect of antipsychotic medication. The present study examined the composition of membrane phospholipids in platelets of 67 neuroleptic-free schizophrenic patients compared to healthy and psychiatric controls. In a subsample of the schizophrenic patients we determined the effect of antipsychotic treatment on the phospholipid metabolism during six-months follow up. While untreated patients showed a decrease in major membrane phospholipid components, i.e. phosphatidylcholine and phosphatidylethanolamine, when compared to control subjects, as well as an increase in their breakdown-product lysophosphatidylcholine (LPC), there was a significant reduction in LPC during three weeks of pharmacotherapy with haloperidol. After six months treatment with different antipsychotics some divergent effects on phospholipid metabolism in schizophrenic patients could be demonstrated. While in the long-term course LPC remained decreased under continuous therapy with typical neuroleptics, patients being treated with the atypical drug zotepine showed an increase in LPC compared to their baseline level before therapy. Thus, specific mechanisms of the different antipsychotic therapies on phospholipid metabolism might serve to explain the divergent findings of 31P-MRS in medicated patients.

Literatur

  • 1 Pettegrew J W, Keshavan M S, Minshew N J. 31P nuclear magnetic resonance spectroscopy: neurodevelopment and schizophrenia.  Schizophr Bull. 1993;  19 35-53
    PubMedSearch in Google Scholar
  • 2 Riehemann S, Volz H P, Smesny S, Hubner G, Wenda B, Rössger G, Sauer H. Phosphor-Magnetresonanzspektroskopie in der Schizophrenieforschung.  Nervenarzt. 2000;  71 354-363
    CrossrefPubMedSearch in Google Scholar
  • 3 Keshavan M S, Stanley J A, Pettegrew J W. Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings - part II.  Biol Psychiatry. 2000;  48 369-380
    Search in Google Scholar
  • 4 Stanley J A, Williamson P C, Drost D J, Carr T J, Rylett R J, Malla A, Thompson R T. An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy.  Arch Gen Psychiatry. 1995;  52 399-406
    PubMedSearch in Google Scholar
  • 5 Fukuzako H, Fukuzako T, Hashiguchi T, Kodama S, Takigawa M, Fujimoto T. Changes in levels of phosphorus metabolites in temporal lobes of drug-naive schizophrenic patients.  Am J Psychiatry. 1999;  156 1205-1208
    PubMedSearch in Google Scholar
  • 6 Volz H P, Rossger G, Riehemann S, Hubner G, Maurer I, Wenda B, Rzanny R, Kaiser W A, Sauer H. Increase of phosphodiesters during neuroleptic treatment of schizophrenics: a longitudinal 31P-magnetic resonance spectroscopic study.  Biol Psychiatry. 1999;  45 1221-1225
    CrossrefPubMedSearch in Google Scholar
  • 7 Volz H R, Riehemann S, Maurer I, Smesny S, Sommer M, Rzanny R, Holstein W, Czekalla J, Sauer H. Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a (31)P chemical shift spectroscopic-imaging study.  Biol Psychiatry. 2000;  47 954-961
    CrossrefPubMedSearch in Google Scholar
  • 8 Keshavan M S, Pettegrew J W, Panchalingam K, Kaplan D. In vivo 31P NMR spectroscopy of the frontal lobe metabolism in neuroleptic naive first episode psychoses.  Schizophr Res. 1989;  1 122
    PubMedSearch in Google Scholar
  • 9 Deicken R F, Calabrese G, Merrin E L, Meyerhoff D J, Dillon W P, Weiner M W, Fein G. 31Phosphorus magnetic resonance spectroscopy of the frontal and parietal lobes in chronic schizophrenia.  Biol Psychiatry. 1994;  36 503-510
    CrossrefPubMedSearch in Google Scholar
  • 10 Stanley J A, Williamson P C, Drost D J, Carr T J, Rylett R J, Morrison-Stewart S, Thompson R T. Membrane phospholipid metabolism and schizophrenia: an in vivo 31P-MR spectroscopy study.  Schizophr Res. 1994;  13 209-215
    CrossrefPubMedSearch in Google Scholar
  • 11 Volz H P, Gaser C, Hager F, Rzanny R, Mentzel H J, Kreitschmann-Andermahr I, Kaiser W A, Sauer H. Brain activation during cognitive stimulation with the Wisconsin Card Sorting Test - a functional MRI study on healthy volunteers and schizophrenics.  Psychiatry Res. 1997;  75 145-157
    CrossrefPubMedSearch in Google Scholar
  • 12 Volz H P, Hubner G, Rzanny R, Rossger G, Preussler B, Eichhorn M, Kreitschmann-Andermahr I, Kaiser W A, Sauer H. High-energy phosphates in the frontal lobe correlate with Wisconsin Card Sort Test performance in controls, not in schizophrenics: a 31phosphorus magnetic resonance spectroscopic and neuropsychological investigation.  Schizophr Res. 1998;  31 37-47
    CrossrefPubMedSearch in Google Scholar
  • 13 Potwarka J J, Drost D J, Williamson P C, Carr T, Canaran G, Rylett W J, Neufeld R W. A 1H-decoupled 31P chemical shift imaging study of medicated schizophrenic patients and healthy controls.  Biol Psychiatry. 1999;  45 687-693
    CrossrefPubMedSearch in Google Scholar
  • 14 Fujimoto T, Nakano T, Takano T, Hokazono Y, Asakura T, Tsuji T. Study of chronic schizophrenics using 31P magnetic resonance chemical shift imaging.  Acta Psychiatr Scand. 1992;  86 455-462
    PubMedSearch in Google Scholar
  • 15 Fukuzako H, Fukuzako T, Takeuchi K, Ohbo Y, Ueyama K, Takigawa M, Fujimoto T. Phosphorus magnetic resonance spectroscopy in schizophrenia: correlation between membrane phospholipid metabolism in the temporal lobe and positive symptoms.  Prog Neuropsychopharmacol Biol Psychiatry. 1996;  20 629-640
    CrossrefPubMedSearch in Google Scholar
  • 16 Fukuzako H, Fukuzako T, Kodama S, Hashiguchi T, Takigawa M, Fujimoto T. Haloperidol improves membrane phospholipid abnormalities in temporal lobes of schizophrenic patients.  Neuropsychopharmacology. 1999;  21 542-549
    CrossrefPubMedSearch in Google Scholar
  • 17 Rotman A. Blood platelets in psychopharmacological research.  Prog Neuropsychopharmacol Biol Psychiatry. 1983;  7 135-151
    CrossrefPubMedSearch in Google Scholar
  • 18 Rotrosen J, Wolkin A. Phospholipid and prostaglandin hypotheses of schizophrenia.  In: Meltzer HY (Hrsg.). Psychopharmacology: The third generation of progress. New York: Raven Press 1987: 759-764
    Search in Google Scholar
  • 19 Pangerl A M, Steudle A, Jaroni H W, Rufer R, Gattaz W F. Increased platelet membrane lysophosphatidylcholine in schizophrenia.  Biol Psychiatry. 1991;  30 837-840
    CrossrefPubMedSearch in Google Scholar
  • 20 Chang J, Musser J H, McGregor H. Phospholipase A2: function and pharmacological regulation.  Biochem Pharmacol. 1987;  36 2429-2436
    CrossrefPubMedSearch in Google Scholar
  • 21 Gattaz W F, Schmitt A, Maras A. Increased platelet phospholipase A2 activity in schizophrenia.  Schizophr Res. 1995;  16 1-6
    CrossrefPubMedSearch in Google Scholar
  • 22 Smesny S, Volz H P, Riehemann S, Sauer H. Störungen im Phospholipidmetabolismus als mögliche pathogenetische Faktoren der Schizophrenie.  Fortschr Neurol Psychiatr. 2000;  68 301-312
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Noponen M, Sanfilipo M, Samanich K, Ryer H, Ko G, Angrist B, Wolkin A, Duncan E, Rotrosen J. Elevated PLA2 activity in schizophrenics and other psychiatric patients.  Biol Psychiatry. 1993;  34 641-649
    CrossrefPubMedSearch in Google Scholar
  • 24 Ross B M, Hudson C, Erlich J, Warsh J J, Kish S J. Increased phospholipid breakdown in schizophrenia. Evidence for the involvement of a calcium-independent phospholipase A2.  Arch Gen Psychiatry. 1997;  54 487-494
    PubMedSearch in Google Scholar
  • 25 Gattaz W F, Brunner J, Schmitt A, Maras A. Beschleunigter Abbau von Membranphospholipiden bei der Schizophrenie - Implikationen für die Hypofrontalitätshypothese.  Fortschr Neurol Psychiatr. 1994;  62 489-496
    PubMedSearch in Google Scholar
  • 26 Mombour W, Kockott G, Fliege K. The use of the brief psychiatric rating scale (BPRS) by overall and gorham for the diagnosis of acute paranoid psychoses: evaluation of a german translation of the BPRS.  Pharmakopsychiatr Neuropsychopharmakol. 1975;  8 279-288
    PubMedSearch in Google Scholar
  • 27 Biehl H, Maurer K, Jung E, Krumm B. The WHO Psychological Impairments Rating Schedule (WHO/PIRS). II. Impairments in Schizophrenics in cross-sectional and longitudinal perspective - the Mannheim experience in two independent samples.  Br J Psychiatry. 1989;  Suppl 71-77
    PubMedSearch in Google Scholar
  • 28 Biehl H, Maurer K, Jablensky A, Cooper J E, Tomov T. The WHO Psychological Impairments Rating Schedule (WHO/PIRS). I. Introducing a new instrument for rating observed behaviour and the rationale of the psychological impairment concept.  Br J Psychiatry. 1989;  Suppl 68-70
    PubMedSearch in Google Scholar
  • 29 Wing J K, Cooper J E, Sartorius N. Present state examination (PSE). Cambridge: Cambridge University Press 1973
    Search in Google Scholar
  • 30 Ishigooka J, Shizu Y, Wakatabe H, Tanaka K, Miura S. Different effects of centrally acting drugs on rabbit platelet aggregation: with special reference to selective inhibitory effects of antipsychotics and antidepressants.  Biol Psychiatry. 1985;  20 866-873
    CrossrefPubMedSearch in Google Scholar
  • 31 Singh S P, Shankar R. Effect of haloperidol on phospholipid biosynthesis in rat brain.  Indian J Exp Biol. 1996;  34 111-114
    PubMedSearch in Google Scholar
  • 32 Essali M A, Das I, de Belleroche J, Hirsch S R. The platelet polyphosphoinositide system in schizophrenia: the effects of neuroleptic treatment.  Biol Psychiatry. 1990;  28 475-487
    CrossrefPubMedSearch in Google Scholar
  • 33 Hudson C J, Lin A, Horrobin D F. Phospholipases: in search of a genetic base of schizophrenia.  Prostaglandins Leukot Essent Fatty Acids. 1996;  55 119-122
    CrossrefPubMedSearch in Google Scholar
  • 34 Hudson C, Gotowiec A, Seeman M, Warsh J, Ross B M. Clinical subtyping reveals significant differences in calcium-dependent phospholipase A2 activity in schizophrenia.  Biol Psychiatry. 1999;  46 401-405
    CrossrefPubMedSearch in Google Scholar
  • 35 Ross B M, Turenne S, Moszczynska A, Warsh J J, Kish S J. Differential alteration of phospholipase A2 activities in brain of patients with schizophrenia.  Brain Res. 1999;  821 407-413
    CrossrefPubMedSearch in Google Scholar
  • 36 Yao J K, Leonard S, Reddy R D. Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients.  Schizophr Res. 2000;  42 7-17
    CrossrefPubMedSearch in Google Scholar
  • 37 Trzeciak H I, Kalacinski W, Malecki A, Kokot D. Effect of neuroleptics on phospholipase A2 activity in the brain of rats.  Eur Arch Psychiatry Clin Neurosci. 1995;  245 179-182
    PubMedSearch in Google Scholar
  • 38 Kornhuber J, Schultz A, Wiltfang J, Meineke I, Gleiter C H, Zochling R, Boissl K W, Leblhuber F, Riederer P. Persistence of haloperidol in human brain tissue.  Am J Psychiatry. 1999;  156 885-890
    PubMedSearch in Google Scholar
  • 39 Pettegrew J W, Keshavan M S, Panchalingam K, Strychor S, Kaplan D B, Tretta M G, Allen M. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy.  Arch Gen Psychiatry. 1991;  48 563-568
    PubMedSearch in Google Scholar
  • 40 Williamson P, Drost D, Stanley J, Carr T, Morrison S, Merskey H. Localized phosphorus 31 magnetic resonance spectroscopy in chronic schizophrenic patients and normal controls.  Arch Gen Psychiatry. 1991;  48 578
    PubMedSearch in Google Scholar
  • 41 Shioiri T, Kato T, Inubushi T, Murashita J, Takahashi S. Correlations of phosphomonoesters measured by phosphorus-31 magnetic resonance spectroscopy in the frontal lobes and negative symptoms in schizophrenia.  Psychiatry Res. 1994;  55 223-235
    PubMedSearch in Google Scholar
  • 42 Kato T, Shioiri T, Murashita J, Hamakawa H, Takahashi Y, Inubushi T, Takahashi S. Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase- encoded 31P-MRS.  Psychol Med. 1995;  25 557-566
    PubMedSearch in Google Scholar
  • 43 Hinsberger A D, Williamson P C, Carr T J, Stanley J A, Drost D J, Densmore M, MacFabe G C, Montemurro D G. Magnetic resonance imaging volumetric and phosphorus 31 magnetic resonance spectroscopy measurements in schizophrenia.  J Psychiatry Neurosci. 1997;  22 111-117
    PubMedSearch in Google Scholar
  • 44 Shioiri T, Hamakawa H, Kato T, Fujii K, Murashita J, Inubishi T, Someya T. Frontal lobe membrane phospholipid metabolism and ventricle to brain ratio in schizophrenia: preliminary 31P-MRS and CT studies.  European archiveness of Psychiatry and clinical neuroscience. 2000;  250 169-174
    PubMedSearch in Google Scholar
  • 45 O’Callaghan E, Redmond O, Ennis R, Stack J, Kinsella A, Ennis J T, Larkin C, Waddington J L. Initial investigation of the left temporoparietal region in schizophrenia by 31P magnetic resonance spectroscopy.  Biol Psychiatry. 1991;  29 1149-1152
    CrossrefPubMedSearch in Google Scholar
  • 46 Calabrese G, Deicken R F, Fein G, Merrin E L, Schoenfeld F, Weiner M W. 31Phosphorus magnetic resonance spectroscopy of the temporal lobes in schizophrenia.  Biol Psychiatry. 1992;  32 26-32
    CrossrefPubMedSearch in Google Scholar
  • 47 Deicken R F, Calabrese G, Merrin E L, Vinogradov S, Fein G, Weiner M W. Asymmetry of temporal lobe phosphorous metabolism in schizophrenia: a 31phosphorous magnetic resonance spectroscopic imaging study.  Biol Psychiatry. 1995;  38 279-286
    CrossrefPubMedSearch in Google Scholar
  • 48 Deicken R F, Calabrese G, Merrin E L, Fein G, Weiner M W. Basal ganglia phosphorous metabolism in chronic schizophrenia.  Am J Psychiatry. 1995;  152 126-129
    PubMedSearch in Google Scholar
  • 49 Bluml S, Tan J, Harris K, Adatia N, Karme A, Sproull T, Ross B. Quantitative proton-decoupled 31P MRS of the schizophrenic brain in vivo.  J Comput Assist Tomogr. 1999;  23 272-275
    CrossrefPubMedSearch in Google Scholar

Dr. med. A. Schmitt

Zentralinstitut für Seelische Gesundheit, J5

68159 Mannheim

Email: schmitt@as200.zi-mannheim.de