Abstract
Several lines of evidence from post-mortem, brain imaging, and genetic studies in schizophrenia patients suggest that Gamma-amino butyric acid (GABA) deficits may contribute to the pathophysiology of schizophrenia. Pharmacological induction of a transient GABA-deficit state has been shown to enhance vulnerability of healthy subjects to the psychotomimetic effects of various drugs. Exacerbating or creating a GABA deficit was hypothesized to induce or unmask psychosis in schizophrenia patients, but not in healthy controls. To test this hypothesis, a transient GABA deficit was pharmacologically induced in schizophrenia patients and healthy controls using iomazenil, an antagonist and partial inverse agonist of the benzodiazepine receptor. In a double-blind, randomized, placebo-controlled study, clinically stable chronic schizophrenia patients (n=13) received iomazenil (3.7 μg administered intravenously over 10 min). Psychosis was measured using the Brief Psychiatric Rating Scale and perceptual alterations were measured using the Clinician Administered Dissociative Symptoms Scale before and after iomazenil administration. These data were compared with the effects of iomazenil in healthy subjects (n=20). Iomazenil produced increases in psychotic symptoms and perceptual alterations in schizophrenia patients, but not in healthy controls. The greater vulnerability of schizophrenia patients to the effects of iomazenil relative to controls provides further support for the GABA-deficit hypothesis of schizophrenia.
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References
Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M et al (1998). Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155: 761–767.
Ball S, Busatto GF, David AS, Jones SH, Hemsley DR, Pilowsky LS et al (1998). Cognitive functioning and GABAA/benzodiazepine receptor binding in schizophrenia: a 123I-iomazenil SPET study. Biol Psychiatry 43: 107–117.
Beer HF, Blauenstein PA, Hasler PH, Delaloye B, Riccabona G, Bangerl I et al (1990). In vitro and in vivo evaluation of iodine-123-Ro 16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors. J Nucl Med 31: 1007–1014.
Benes FM (2000). Emerging principles of altered neural circuitry in schizophrenia. Brain Res Brain Res Rev 31: 251–269.
Benes FM, Berretta S (2001). GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25: 1–27.
Benes FM, Vincent SL, Marie A, Khan Y (1996). Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 75: 1021–1031.
Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS et al (1998). Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Traumatic Stress 11: 125–136.
Busatto GF, Pilowsky LS, Costa DC, Ell PJ, David AS, Lucey JV et al (1997). Correlation between reduced in vivo benzodiazepine receptor binding and severity of psychotic symptoms in schizophrenia. Am J Psychiatry 154: 56–63.
Charych EI, Liu F, Moss SJ, Brandon NJ (2009). GABA(A) receptors and their associated proteins: implications in the etiology and treatment of schizophrenia and related disorders. Neuropharmacology 57: 481–495.
Cruz DA, Weaver CL, Lovallo EM, Melchitzky DS, Lewis DA (2009). Selective alterations in postsynaptic markers of chandelier cell inputs to cortical pyramidal neurons in subjects with schizophrenia. Neuropsychopharmacology 34: 2112–2124.
D’Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G et al (2005). Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry 57: 594–608.
D’Souza DC, Gil RB, Zuzarte E, MacDougall LM, Donahue L, Ebersole JS et al (2006). Gamma-aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation. Biol Psychiatry 59: 128–137.
D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT et al (2004). The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29: 1558–1572.
Engel AK, Singer W (2001). Temporal binding and the neural correlates of awareness. Trends Cogn Sci 5: 16–25.
Fritschy JM, Mohler H (1995). GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol 359: 154–194.
Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z et al (2003). Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 23: 6315–6326.
Hunkeler W, Mohler H, Pieri L, Polc P, Bonetti EP, Cumin R et al (1981). Selective antagonists of benzodiazepines. Nature 290: 514–516.
Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG et al (1998). A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA 95: 15718–15723.
Iqbal N, Asnis GM, Wetzler S, Kahn RS, Kay SR, van Praag HM (1991). The MCPP challenge test in schizophrenia: hormonal and behavioral responses. Biol Psychiatry 30: 770–778.
Johnson EW, Woods SW, Zoghbi S, McBride BJ, Baldwin RM, Innis RB (1990). Receptor binding characterization of the benzodiazepine radioligand 125I-Ro16-0154: potential probe for SPECT brain imaging. Life Sci 47: 1535–1546.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humansPsychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51: 199–214.
Krystal JH, Seibyl JP, Price LH, Woods SW, Heninger GR, Aghajanian GK et al (1993). m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia. Arch Gen Psychiatry 50: 624–635.
Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995). Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13: 9–19.
Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R (1999). Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 46: 56–72.
Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J et al (1996). Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93: 9235–9240.
Lewis DA, Hashimoto T (2007). Deciphering the disease process of schizophrenia: the contribution of cortical gaba neurons. Int Rev Neurobiol 78: 109–131.
Lewis DA, Hashimoto T, Volk DW (2005). Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6: 312–324.
Lieberman JA, Kane JM, Sarantakos S, Gadaleta D, Woerner M, Alvir J et al (1987). Prediction of relapse in schizophrenia. Arch Gen Psychiatry 44: 597–603.
Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D et al (1997). Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17: 141–150.
Murphy BL, Arnsten AF, Goldman-Rakic PS, Roth RH (1996). Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci USA 93: 1325–1329.
Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC (1999). Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression. Neuroscience 93: 441–448.
Overall JE, Gorham DR (1962). Brief psychiatric rating scale. Psychological Reports 10: 799–812.
Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000). GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101: 815–850.
Roche . Iomazenil data on file.
Schroder J, Bubeck B, Demisch S, Sauer H (1997). Benzodiazepine receptor distribution and diazepam binding in schizophrenia: an exploratory study. Psychiatry Res 68: 125–131.
Schubiger P, Hasler P (1989). Iomazenil and other brain receptor tracers for SPECT. In: SPaHP (ed). Proceedings of the sixth Bottstein Colloquium. Wurenlingen/Villigen: Switzerland.
Singer W (1999). Neuronal synchrony: a versatile code for the definition of relations? Neuron 24: 49–65.
Singer W, Gray CM (1995). Visual feature integration and the temporal correlation hypothesis. Annu Rev of Neurosci 18: 555–586.
Tallman JF, Gallager DW (1985). The GABA-ergic system: a locus of benzodiazepine action. Ann Rev Neurosci 8: 21–44.
Tallon-Baudry C (2003). Oscillatory synchrony and human visual cognition. J Physiol Paris 97: 355–363.
Uhlhaas PJ, Singer W (2010). Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci 11: 100–113.
Varela F, Lachaux JP, Rodriguez E, Martinerie J (2001). The brainweb: phase synchronization and large-scale integration. Nat Rev Neurosci 2: 229–239.
Varela FJ (1995). Resonant cell assemblies: a new approach to cognitive functions and neuronal synchrony. Biol Res 28: 81–95.
Verhoeff NP, Soares JC, D’Souza CD, Gil R, Degen K, Abi-Dargham A et al (1999). [123I]Iomazenil SPECT benzodiazepine receptor imaging in schizophrenia. Psychiatry Res 91: 163–173.
Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA (2000). Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 57: 237–245.
Volk DW, Lewis DA (2002). Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction. Physiol Behav 77: 501–505.
Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA (2002). Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex 12: 1063–1070.
Waldvogel HJ, Baer K, Gai WP, Gilbert RT, Rees MI, Mohler H et al (2008). Differential localization of GABAA receptor subunits within the substantia nigra of the human brain: an immunohistochemical study. J Comp Neurol 506: 912–929.
Woerner MG, Mannuzza S, Kane JM (1988). Anchoring the BPRS: an aid to improved reliability. Psychopharmacol Bull 24: 112–117.
Wolkowitz OM, Pickar D (1991). Benzodiazepines in the treatment of schizophrenia: a review and reappraisal. Am J Psychiatry 148: 714–726.
Woo TU, Whitehead RE, Melchitzky DS, Lewis DA (1998). A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci USA 95: 5341–5346.
Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD et al (2010). GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 30: 3777–3781.
Acknowledgements
We acknowledge the critical contributions of the Neurobiological Studies Unit, VA Connecticut Healthcare System including Elizabeth O’Donnell, R.N; Angelina Genovese, R.N; and Robert Sturwold, RPh. We also acknowledge the contributions of John Krystal, MD, for his role in providing the impetus in conducting the study. This study was supported by the Department of Veterans Affairs Schizophrenia Biological Research Center.
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Roberto Gil, Richard Andrew Sewell, and Kyuengheup Ahn declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the last 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. John Seibyl receives research support from Eli Lilly, Bristol-Meyer-Squibb, Genentech, Neurologica, Roche, Avid Radiopharmaceuticals, Seaside, Abbott and Sepracor. John Seibyl holds equity in Molecular Neuroimaging and he also serves as a consultant to GE Healthcare and Bayer Healthcare. Deepak Cyril D’Souza currently receives or has received research support in the last 3 years from Eli Lilly, Organon—Schering Plough, Abbott, Sanofi Aventis, Pfizer, Cephalon, and Astra Zeneca, administered through Yale University School of Medicine.
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Ahn, K., Gil, R., Seibyl, J. et al. Probing GABA Receptor Function in Schizophrenia with Iomazenil. Neuropsychopharmacol 36, 677–683 (2011). https://doi.org/10.1038/npp.2010.198
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DOI: https://doi.org/10.1038/npp.2010.198
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