Molecular Psychiatry (2014) 19, 20–29 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp REVIEW Imaging glutamate in schizophrenia: review of findings and implications for drug discovery EMP Poels1,2, LS Kegeles1,2, JT Kantrowitz1,2, M Slifstein1,2, DC Javitt1,2, JA Lieberman1,2, A Abi-Dargham1,2,3 and RR Girgis1,2 Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D2-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy (1H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed 1H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ. Molecular Psychiatry (2014) 19, 20–29; doi:10.1038/mp.2013.136; published online 29 October 2013 Keywords: glutamate; glutathione; magnetic resonance spectroscopy (MRS); NMDA; positron emission tomography (PET); schizophrenia INTRODUCTION emission tomography (PET)/single-photon emission computed At present, the antipsychotics (typical or atypical) are the only tomography (SPECT) investigations that have examined glutama- approved treatments for schizophrenia (SCZ). In many patients, tergic indices in SCZ, including those of modulatory compounds 1 psychotic symptoms are only partially responsive or completely such as glutathione (GSH) and glycine. We will also review H MRS/ unresponsive to antipsychotic drugs,1 and there are currently no PET/SPECT work that has been performed using the ketamine agents with proven efficacy for negative symptoms or persistent challenge model in healthy subjects and discuss their patho- neurocognitive dysfunction. Even for subjects who respond well physiological implications. Preclinical and clinical evidence sup- to treatments, existing medications are associated with significant porting a role for each particular component of the glutamatergic cognitive, motoric or metabolic side effects that limit compliance. system in SCZ will be reviewed, followed by summaries of the 1 Thus, newer treatments for SCZ are desperately required. relevant H MRS and/or PET/SPECT literature. We will conclude All current treatments for SCZ function primarily by blocking D2- with a discussion of how these neurochemical findings inform the type dopamine receptors.2 Alternative neurochemical theories glutamate hypothesis of SCZ and can enhance drug development focus on disturbances in brain glutamatergic pathways, including of glutamatergic agents in SCZ. impairments in signaling at synaptic N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs; Figure 1).3,4 Approaches for normalization of glutamatergic function are GLUTAMATE AND THE NMDA RECEPTOR currently under development. To date, promising results have Background: evidence for NMDA receptor dysfunction in SCZ been obtained with compounds such as glycine, D-serine, In initial studies with phencyclidine and ketamine in the early sarcosine5 and glycine transport inhibitors6 that target the 1960s, it was noted that both agents produced positive, negative glycine site of the NMDAR, and with N-acetylcysteine (NAC), a and cognitive symptoms of SCZ.8,9 These compounds induce precursor compound for the amino acid cysteine in brain.5 symptoms by blocking neurotransmission at the NMDAR, sug- However, the slow rate of therapeutic development has led a gesting an alternative model for pathogenesis in SCZ. Sympto- group of leading experts from academia, government and matic effects of NMDAR blockade were better classified starting in PHARMA7 to conclude that effectively translating findings from the early 1990s in a series of ketamine challenge studies genetics and basic science into therapies will require the conducted in both normal volunteers and SCZ patients.10–13 In development of robust biomarkers and assessment of target normal volunteers, positive, negative and cognitive symptoms engagement of experimental agents.7 were observed in similar proportions as in SCZ. NMDAR blockade The objective of this article is to review and synthesize the also reproduces both the severity and type of thought disorder proton magnetic resonance spectroscopy (1H MRS) and positron seen in SCZ with both, for example, being associated with high 1Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA; 2New York State Psychiatric Institute, New York, NY, USA and 3Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA. Correspondence: Dr RR Girgis, Department of Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 31, New York, NY 10032, USA. E-mail: [email protected] Received 23 March 2013; revised 25 August 2013; accepted 9 September 2013; published online 29 October 2013 Glutamate imaging in schizophrenia EMP Poels et al 21 levels of poverty of speech, circumstantiality and loss of goal, and relatively low levels of distractive or stilted speech or parapha- sias.11 These data and others suggest that reduction in NMDA functioning within the brain could serve as a single unifying feature to account for the otherwise complex pattern of deficits observed in SCZ (see review in Kantrowitz and Javitt4). The development of the glutamate hypothesis of SCZ, initially based in large part on the effects of phencyclidine, closely resembles the initial development of the dopamine hypothesis of SCZ, which was based in large part on observations of the psychotogenic effects of stimulant medications.14 PET and SPECT later supported this hypothesis by indicating increased dopamine synthesis,15–17 greater striatal amphetamine-stimulated dopamine release that is related to positive symptoms18–20 and increased baseline occupancy of striatal dopamine D2 receptors by dopa- mine that also predicts the response of positive symptoms to treatment with antipsychotic agents.21 The negative symptoms and cognitive deficits of SCZ are thought to be related, at least in part, to a cortical dopamine deficit, as originally proposed Figure 1. Schematic diagram of N-methyl-D-aspartate (NMDA) by Weinberger22 and Davis et al.23 based on preclinical and receptor showing D-serine and glutathione/redox-sensitive modula- tory sites (reprinted from Javitt Javitt DC, Int Rev Neurobiol, volume other indirect data. PET studies of cortical dopamine D1 24–27 78, Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspar- receptors reported inconsistent results, and more direct tate receptors, and dopamine-glutamate interactions, pages 69–108, examination of dopaminergic transmission in the cortex is Copyright 2007 with permission from Elsevier). currently underway. A point of convergence of the dopamine and NMDA models is In summary, PET and SPECT studies testing the effects of NMDA at the level of local regulation of presynaptic dopamine release. blockade on dopaminergic indices in healthy subjects using Within striatum and frontal cortex, presynaptic dopamine release ketamine alone found mixed results in striatum,29–33,35 but is under control of intrinsic inhibitory GABAergic neurons that, in significant effects in cortex, consistent with prior rodent data.37 turn, are activated by NMDAR. In striatum, regulation of dopamine However, strikingly similar results for amphetamine-induced release appears to be modulated by GABAB receptors localized to dopamine release in individuals with SCZ and healthy subjects presynaptic dopamine terminals. GABA release, in turn, is given acute ketamine35 provide initial support for the glutamate/ modulated by NMDAR located on GABA interneurons, with 28 NMDA hypothesis of SCZ. Nevertheless, direct, in vivo measure- stimulation leading to increased GABA release. Therefore, ments of glutamatergic indices are necessary to translate some of the initial imaging studies of the glutamatergic system preclinical and clinical findings into effective therapies. Although sought to further validate the glutamate/NMDA model of SCZ by the development of PET and SPECT imaging of the glutamate examining the effects of ketamine on dopamine transmission and system has lagged behind that of the dopamine system, MRS receptors in healthy control subjects. technologies have effectively been utilized to measure gluta- matergic indices in vivo. Glutamate and dopamine PET/SPECT 1 Several studies used the D2/D3 receptor PET/SPECT ligands Glutamatergic H MRS [11C]raclopride and [123]iodobenzamide ([123]IBZM) to measure Several studies have compared glutamatergic indices—namely the effects of ketamine infusion in healthy control subjects on glutamate (Glu), glutamine (Gln) or Glu þ Gln (Glx)—in the brains 1 D2/D3 receptor