Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.153.100.128. Please contact the publisher to request reinstatement.
1.
Grace  AA.  Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.  Nat Rev Neurosci. 2016;17(8):524-532. doi:10.1038/nrn.2016.57PubMedGoogle ScholarCrossref
2.
Lodge  DJ, Grace  AA.  Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.  Trends Pharmacol Sci. 2011;32(9):507-513. doi:10.1016/j.tips.2011.05.001PubMedGoogle ScholarCrossref
3.
Schobel  SA, Chaudhury  NH, Khan  UA,  et al.  Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.  Neuron. 2013;78(1):81-93. doi:10.1016/j.neuron.2013.02.011PubMedGoogle ScholarCrossref
4.
Allen  P, Chaddock  CA, Egerton  A,  et al.  Resting hyperperfusion of the hippocampus, midbrain, and basal ganglia in people at high risk for psychosis.  Am J Psychiatry. 2016;173(4):392-399. doi:10.1176/appi.ajp.2015.15040485PubMedGoogle ScholarCrossref
5.
Allen  P, Seal  ML, Valli  I,  et al.  Altered prefrontal and hippocampal function during verbal encoding and recognition in people with prodromal symptoms of psychosis.  Schizophr Bull. 2011;37(4):746-756. doi:10.1093/schbul/sbp113PubMedGoogle ScholarCrossref
6.
Pantelis  C, Velakoulis  D, McGorry  PD,  et al.  Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison.  Lancet. 2003;361(9354):281-288. doi:10.1016/S0140-6736(03)12323-9PubMedGoogle ScholarCrossref
7.
Mechelli  A, Riecher-Rössler  A, Meisenzahl  EM,  et al.  Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study.  Arch Gen Psychiatry. 2011;68(5):489-495. doi:10.1001/archgenpsychiatry.2011.42PubMedGoogle ScholarCrossref
8.
Konradi  C, Heckers  S.  Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment.  Pharmacol Ther. 2003;97(2):153-179. doi:10.1016/S0163-7258(02)00328-5PubMedGoogle ScholarCrossref
9.
Moghaddam  B, Javitt  D.  From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment.  Neuropsychopharmacology. 2012;37(1):4-15. doi:10.1038/npp.2011.181PubMedGoogle ScholarCrossref
10.
Javitt  DC, Zukin  SR.  Recent advances in the phencyclidine model of schizophrenia.  Am J Psychiatry. 1991;148(10):1301-1308. doi:10.1176/ajp.148.10.1301PubMedGoogle ScholarCrossref
11.
Krystal  JH, Karper  LP, Seibyl  JP,  et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses.  Arch Gen Psychiatry. 1994;51(3):199-214. doi:10.1001/archpsyc.1994.03950030035004PubMedGoogle ScholarCrossref
12.
Lahti  AC, Koffel  B, LaPorte  D, Tamminga  CA.  Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.  Neuropsychopharmacology. 1995;13(1):9-19. doi:10.1016/0893-133X(94)00131-IPubMedGoogle ScholarCrossref
13.
Malhotra  AK, Pinals  DA, Adler  CM,  et al.  Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics.  Neuropsychopharmacology. 1997;17(3):141-150. doi:10.1016/S0893-133X(97)00036-5PubMedGoogle ScholarCrossref
14.
Pollak  TA, Beck  K, Irani  SR, Howes  OD, David  AS, McGuire  PK.  Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications.  Psychopharmacology (Berl). 2016;233(9):1605-1621. doi:10.1007/s00213-015-4156-yPubMedGoogle ScholarCrossref
15.
Lennox  BR, Palmer-Cooper  EC, Pollak  T,  et al; PPiP study team.  Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study.  Lancet Psychiatry. 2017;4(1):42-48. doi:10.1016/S2215-0366(16)30375-3PubMedGoogle ScholarCrossref
16.
Schizophrenia Working Group of the Psychiatric Genomics Consortium.  Biological insights from 108 schizophrenia-associated genetic loci.  Nature. 2014;511(7510):421-427. doi:10.1038/nature13595PubMedGoogle ScholarCrossref
17.
Merritt  K, Egerton  A, Kempton  MJ, Taylor  MJ, McGuire  PK.  Nature of glutamate alterations in schizophrenia: a meta-analysis of proton magnetic resonance spectroscopy studies.  JAMA Psychiatry. 2016;73(7):665-674. doi:10.1001/jamapsychiatry.2016.0442PubMedGoogle ScholarCrossref
18.
Nenadic  I, Maitra  R, Basu  S,  et al.  Associations of hippocampal metabolism and regional brain grey matter in neuroleptic-naive ultra-high-risk subjects and first-episode schizophrenia.  Eur Neuropsychopharmacol. 2015;25(10):1661-1668. doi:10.1016/j.euroneuro.2015.05.005PubMedGoogle ScholarCrossref
19.
Stone  JM, Day  F, Tsagaraki  H,  et al; OASIS.  Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume.  Biol Psychiatry. 2009;66(6):533-539. doi:10.1016/j.biopsych.2009.05.006PubMedGoogle ScholarCrossref
20.
Wood  SJ, Kennedy  D, Phillips  LJ,  et al.  Hippocampal pathology in individuals at ultra-high risk for psychosis: a multi-modal magnetic resonance study.  Neuroimage. 2010;52(1):62-68. doi:10.1016/j.neuroimage.2010.04.012PubMedGoogle ScholarCrossref
21.
de la Fuente-Sandoval  C, León-Ortiz  P, Azcárraga  M, Favila  R, Stephano  S, Graff-Guerrero  A.  Striatal glutamate and the conversion to psychosis: a prospective 1H-MRS imaging study.  Int J Neuropsychopharmacol. 2013;16(2):471-475. doi:10.1017/S1461145712000314PubMedGoogle ScholarCrossref
22.
Allen  P, Chaddock  CA, Egerton  A,  et al.  Functional outcome in people at high risk for psychosis predicted by thalamic glutamate levels and prefronto-striatal activation.  Schizophr Bull. 2015;41(2):429-439. doi:10.1093/schbul/sbu115PubMedGoogle ScholarCrossref
23.
Egerton  A, Stone  JM, Chaddock  CA,  et al.  Relationship between brain glutamate levels and clinical outcome in individuals at ultra high risk of psychosis.  Neuropsychopharmacology. 2014;39(12):2891-2899. doi:10.1038/npp.2014.143PubMedGoogle ScholarCrossref
24.
Fusar-Poli  P, Byrne  M, Badger  S, Valmaggia  LR, McGuire  PK.  Outreach and support in south London (OASIS), 2001-2011: ten years of early diagnosis and treatment for young individuals at high clinical risk for psychosis.  Eur Psychiatry. 2013;28(5):315-326. doi:10.1016/j.eurpsy.2012.08.002PubMedGoogle ScholarCrossref
25.
Yung  AR, Phillips  LJ, McGorry  PD,  et al.  Prediction of psychosis. A step towards indicated prevention of schizophrenia.  Br J Psychiatry Suppl. 1998;172(33):14-20. doi:10.1192/S0007125000297602PubMedGoogle ScholarCrossref
26.
Hall  RC.  Global assessment of functioning: a modified scale.  Psychosomatics. 1995;36(3):267-275. doi:10.1016/S0033-3182(95)71666-8PubMedGoogle ScholarCrossref
27.
Hamilton  M.  The assessment of anxiety states by rating.  Br J Med Psychol. 1959;32(1):50-55. doi:10.1111/j.2044-8341.1959.tb00467.xPubMedGoogle ScholarCrossref
28.
Hamilton  M.  A rating scale for depression.  J Neurol Neurosurg Psychiatry. 1960;23:56-62. doi:10.1136/jnnp.23.1.56PubMedGoogle ScholarCrossref
29.
Nelson  HE, O’Connell  A.  Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test.  Cortex. 1978;14(2):234-244. doi:10.1016/S0010-9452(78)80049-5PubMedGoogle ScholarCrossref
30.
Annett  M.  A classification of hand preference by association analysis.  Br J Psychol. 1970;61(3):303-321. doi:10.1111/j.2044-8295.1970.tb01248.xPubMedGoogle ScholarCrossref
31.
Provencher  SW.  Estimation of metabolite concentrations from localized in vivo proton NMR spectra.  Magn Reson Med. 1993;30(6):672-679. doi:10.1002/mrm.1910300604PubMedGoogle ScholarCrossref
32.
LCModel manual. (http://s-provencher.com/pub/LCModel/manual/manual.pdf). Accessed September 23, 2018.
33.
Kaiser  LG, Schuff  N, Cashdollar  N, Weiner  MW.  Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T.  Neurobiol Aging. 2005;26(5):665-672. doi:10.1016/j.neurobiolaging.2004.07.001PubMedGoogle ScholarCrossref
34.
Gallinat  J, Lang  UE, Jacobsen  LK,  et al.  Abnormal hippocampal neurochemistry in smokers: evidence from proton magnetic resonance spectroscopy at 3 T.  J Clin Psychopharmacol. 2007;27(1):80-84. doi:10.1097/JCP.0b013e31802dffdePubMedGoogle ScholarCrossref
35.
Howes  OD, Bose  SK, Turkheimer  F,  et al.  Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.  Am J Psychiatry. 2011;168(12):1311-1317. doi:10.1176/appi.ajp.2011.11010160PubMedGoogle ScholarCrossref
36.
de la Fuente-Sandoval  C, León-Ortiz  P, Azcárraga  M,  et al.  Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a longitudinal proton magnetic resonance spectroscopy study.  JAMA Psychiatry. 2013;70(10):1057-1066. doi:10.1001/jamapsychiatry.2013.289PubMedGoogle ScholarCrossref
37.
Plitman  E, de la Fuente-Sandoval  C, Reyes-Madrigal  F,  et al.  Elevated myo-inositol, choline, and glutamate levels in the associative striatum of antipsychotic-naive patients with first-episode psychosis: a proton magnetic resonance spectroscopy study with implications for glial dysfunction.  Schizophr Bull. 2016;42(2):415-424. doi:10.1093/schbul/sbv118PubMedGoogle ScholarCrossref
38.
Chang  L, Munsaka  SM, Kraft-Terry  S, Ernst  T.  Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain.  J Neuroimmune Pharmacol. 2013;8(3):576-593. doi:10.1007/s11481-013-9460-xPubMedGoogle ScholarCrossref
39.
van Berckel  BN, Bossong  MG, Boellaard  R,  et al.  Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study.  Biol Psychiatry. 2008;64(9):820-822. doi:10.1016/j.biopsych.2008.04.025PubMedGoogle ScholarCrossref
40.
Doorduin  J, de Vries  EF, Willemsen  AT, de Groot  JC, Dierckx  RA, Klein  HC.  Neuroinflammation in schizophrenia-related psychosis: a PET study.  J Nucl Med. 2009;50(11):1801-1807. doi:10.2967/jnumed.109.066647PubMedGoogle ScholarCrossref
41.
Bloomfield  PS, Selvaraj  S, Veronese  M,  et al.  Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [(11)C]PBR28 PET brain imaging study.  Am J Psychiatry. 2016;173(1):44-52. doi:10.1176/appi.ajp.2015.14101358PubMedGoogle ScholarCrossref
42.
Maier  M, Ron  MA, Barker  GJ, Tofts  PS.  Proton magnetic resonance spectroscopy: an in vivo method of estimating hippocampal neuronal depletion in schizophrenia.  Psychol Med. 1995;25(6):1201-1209. doi:10.1017/S0033291700033171PubMedGoogle ScholarCrossref
43.
Lutkenhoff  ES, van Erp  TG, Thomas  MA,  et al.  Proton MRS in twin pairs discordant for schizophrenia.  Mol Psychiatry. 2010;15(3):308-318. doi:10.1038/mp.2008.87PubMedGoogle ScholarCrossref
44.
Hutcheson  NL, Reid  MA, White  DM,  et al.  Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging.  Schizophr Res. 2012;140(1-3):136-142. doi:10.1016/j.schres.2012.06.039PubMedGoogle ScholarCrossref
45.
Meyer  EJ, Kirov  II, Tal  A,  et al.  Metabolic abnormalities in the hippocampus of patients with schizophrenia: a 3D multivoxel MR spectroscopic imaging study at 3T.  AJNR Am J Neuroradiol. 2016;37(12):2273-2279. doi:10.3174/ajnr.A4886PubMedGoogle ScholarCrossref
46.
Marsman  A, van den Heuvel  MP, Klomp  DW, Kahn  RS, Luijten  PR, Hulshoff Pol  HE.  Glutamate in schizophrenia: a focused review and meta-analysis of 1H-MRS studies.  Schizophr Bull. 2013;39(1):120-129. doi:10.1093/schbul/sbr069PubMedGoogle ScholarCrossref
47.
Egerton  A, Broberg  BV, Van Haren  N,  et al.  Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE).  Mol Psychiatry. 2018. Epub ahead of print. doi:10.1038/s41380-018-0082-9PubMedGoogle Scholar
48.
Fusar-Poli  P, Rutigliano  G, Stahl  D,  et al.  Long-term validity of the At Risk Mental State (ARMS) for predicting psychotic and non-psychotic mental disorders.  Eur Psychiatry. 2017;42:49-54. doi:10.1016/j.eurpsy.2016.11.010PubMedGoogle ScholarCrossref
49.
Jelen  LA, King  S, Mullins  PG, Stone  JM.  Beyond static measures: a review of functional magnetic resonance spectroscopy and its potential to investigate dynamic glutamatergic abnormalities in schizophrenia.  J Psychopharmacol. 2018;32(5):497-508. doi:10.1177/0269881117747579PubMedGoogle ScholarCrossref
Original Investigation
November 14, 2018

Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis

Author Affiliations
  • 1Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
  • 2Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
  • 3Cambridge Early Onset service, Cambridgeshire and Peterborough Mental Health Partnership National Health Service Trust, Cambridge, United Kingdom
  • 4Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
  • 5Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
  • 6Department of Psychology, University of Roehampton, London, United Kingdom
JAMA Psychiatry. 2019;76(2):199-207. doi:10.1001/jamapsychiatry.2018.3252
Key Points

Question  What is the association between hippocampal glutamate levels and subsequent clinical outcomes in individuals at clinical high risk for psychosis?

Findings  In this cross-sectional study of 86 individuals from the United Kingdom, baseline hippocampal glutamate levels were significantly higher in clinical high-risk individuals who developed psychosis or had poor functional outcome at a mean clinical follow-up of 18.5 months.

Meaning  The association between adverse clinical outcomes in individuals at clinical high risk for psychosis and increased baseline hippocampal glutamate levels may suggest that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.

Abstract

Importance  Preclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum.

Objective  To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes.

Design, Setting, and Participants  This cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom.

Main Outcomes and Measures  Concentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale.

Results  Of 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high-risk individuals showed good overall functioning (Global Assessment of Function ≥65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function <65). Compared with clinical high-risk individuals who did not become psychotic, clinical high-risk individuals who developed psychosis showed higher hippocampal glutamate levels (mean [SD], 8.33 [1.48] vs 9.16 [1.28] glutamate levels; P = .048). The clinical high-risk individuals who developed psychosis also had higher myo-inositol levels (mean [SD], 7.60 [1.23] vs 6.24 [1.36] myo-inositol levels; P = .002) and higher creatine levels (mean [SD], 8.18 [0.74] vs 7.32 [1.09] creatine levels; P = .01) compared with clinical high-risk individuals who did not become psychotic, and higher myo-inositol levels compared with healthy controls (mean [SD], 7.60 [1.23] vs 6.19 [1.51] myo-inositol levels; P = .005). Higher hippocampal glutamate levels in clinical high-risk individuals were also associated with a poor functional outcome (mean [SD], 8.83 [1.43] vs 7.76 [1.40] glutamate levels; P = .02). In the logistic regression analyses, hippocampal glutamate levels were significantly associated with clinical outcome in terms of transition and nontransition to psychosis (β = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (β = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02).

Conclusions and Relevance  The findings indicate that adverse clinical outcomes in individuals at clinical high risk for psychosis may be associated with an increase in baseline hippocampal glutamate levels, as well as an increase in myo-inositol and creatine levels. This conclusion suggests that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.

×