Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

World Psychiatry - Tập 19 Số 1 - Trang 15-33 - 2020
Robert A. McCutcheon1,2,3, John H. Krystal4,5,6, Oliver Howes1,2,3
1Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
2MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, UK
3South London and Maudsley Foundation NHS Trust, Maudsley Hospital, London, UK
4Department of Psychiatry; Yale University School of Medicine; New Haven CT USA
5Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
6VA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA

Tóm tắt

Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

Từ khóa


Tài liệu tham khảo

McCutcheon RA, Schizophrenia: an overview, JAMA Psychiatry

10.1016/S2215-0366(17)30078-0

Rossum JM, 1966, The significance of dopamine‐receptor blockade for the mechanism of action of neuroleptic drugs, Arch Int Pharmacodyn Thérapie, 160, 492

Kaar SJ, Antipsychotics: mechanisms underlying clinical response and side‐effects and novel treatment approaches based on pathophysiology, Neuropharmacology

10.1038/1801200a0

10.1016/j.pnpbp.2007.08.025

10.1016/j.neuron.2006.01.023

10.1038/s41537-019-0074-z

10.1016/j.biopsych.2015.11.007

10.1023/A:1021171129766

10.1001/archpsyc.1974.01760130034005

10.1016/0920-9964(94)90015-9

10.1016/0165-1781(83)90012-4

10.1016/0006-3223(85)90038-1

10.1016/0165-1781(85)90109-X

10.1007/BF00427323

10.1093/schbul/23.1.147

10.1016/0920-9964(91)90032-M

10.1001/archpsyc.1975.01760260127011

10.1016/0165-1781(83)90003-3

Robinson DG, 1999, Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder, Am J Psychiatry, 156, 544, 10.1176/ajp.156.4.544

10.1176/ajp.137.2.191

10.1016/S0920-9964(98)00041-3

10.1007/s002130000532

10.1523/JNEUROSCI.5416-06.2007

10.1016/j.molbrainres.2003.11.004

10.1007/BF02250926

10.1038/tp.2016.257

10.1007/s00406-013-0479-z

10.1126/science.aat8127

10.1126/science.1145194

10.1126/science.3854

10.1016/S0140-6736(19)31135-3

10.1136/bmj.1.5018.582

10.1001/archpsyc.1973.04200010020003

10.1176/ajp.135.6.669

10.1080/10826084.2018.1521430

10.1176/appi.ajp.158.9.1367

10.1073/pnas.1304308110

10.1101/lm.1112209

10.1073/pnas.1109625108

10.1016/0304-3940(80)90178-0

10.1016/S0920-9964(97)00079-0

10.1093/schbul/sbw221

10.1111/nyas.12547

10.1176/ajp.148.10.1301

10.1007/s00213-013-3354-8

10.1016/j.psychres.2016.01.023

10.1073/pnas.1807983116

10.1007/s00213-011-2543-6

10.1001/jamapsychiatry.2015.2196

10.1001/archgenpsychiatry.2012.169

10.1016/j.biopsych.2008.12.007

10.1001/archgenpsychiatry.2010.10

10.1093/ijnp/pyx063

10.1016/j.biopsych.2011.10.009

10.1016/j.biopsych.2017.11.032

10.1016/j.biopsych.2018.02.015

10.1038/npp.2009.189

10.1124/mol.63.2.456

Brugger SP, Heterogeneity of striatal dopamine function in schizophrenia: meta‐analysis of variance, Biol Psychiatry

10.1093/ijnp/pyz017

10.1192/bjp.bp.113.132308

10.1523/JNEUROSCI.22-09-03708.2002

10.1177/0269881111409265

10.1016/j.lfs.2010.03.018

10.1176/ajp.2006.163.10.1747

10.1038/385634a0

10.1176/appi.ajp.159.5.761

10.1007/s00213-013-3026-8

10.1038/sj.npp.1300224

10.1007/s11307-007-0077-4

Lidow MS, 1997, Down‐regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs, J Pharmacol Exp Ther, 281, 597

10.1093/schbul/sbw192

10.1016/j.jpsychires.2009.04.009

10.1016/S0893-133X(00)00165-2

10.1016/S0006-3223(00)00981-1

10.1016/S0924-977X(02)00041-X

10.1016/j.neubiorev.2009.05.005

10.1002/syn.890070409

10.1177/1073858409338217

10.22237/jmasm/1257035100

10.1093/schbul/sbx180

10.1176/appi.ajp.2012.12010144

10.1176/ajp.155.11.1550

10.1001/jamapsychiatry.2017.2943

10.1016/S0920-9964(98)00113-3

10.1093/brain/awz093

10.1016/j.neuroimage.2009.12.058

10.1093/brain/awt264

10.1523/JNEUROSCI.0805-07.2007

10.1016/S0925-4927(00)00064-0

10.1038/sj.npp.1380111

10.1016/j.neuroimage.2015.06.057

10.1001/jamapsychiatry.2014.2414

10.1093/brain/awy133

10.1093/schbul/sby076

10.1038/tp.2015.37

10.1093/schbul/sbx042

10.1016/j.biopsych.2004.01.018

10.1001/archgenpsychiatry.2008.514

10.1016/j.biopsych.2012.11.017

Howes OD, Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi‐modal PET‐magnetic resonance brain imaging study, Neuropsychopharmacology

10.1176/appi.ajp.2011.11010160

10.1093/schbul/sbr195

10.1017/S0033291711000341

10.1016/j.euroneuro.2018.03.005

10.1016/j.biopsych.2007.04.017

10.1073/pnas.91.24.11651

10.1016/j.pscychresns.2017.11.014

10.1016/j.pscychresns.2009.10.002

10.1111/j.1600-0447.2008.01223.x

10.1016/j.pscychresns.2005.10.004

10.1037/h0077500

10.1126/science.275.5306.1593

10.1016/j.cell.2015.07.014

10.7554/eLife.21886

10.1038/s41593-018-0222-1

10.1038/s41593-018-0174-5

10.1038/nature08028

10.1016/0306-9877(76)90040-2

10.1176/appi.ajp.160.1.13

10.1016/j.tins.2018.12.004

10.1016/j.biopsych.2018.05.015

10.3389/neuro.09.012.2009

10.1126/science.aan3458

10.1016/j.cub.2017.12.059

10.1073/pnas.1809298115

10.1016/j.schres.2018.12.011

10.1038/nrn3857

10.1016/j.neuron.2013.06.027

10.1007/s00429-010-0262-0

10.1126/sciadv.1501672

Braun U, 2019, Brain state stability during working memory is explained by network control theory, modulated by dopamine D1/D2 receptor function, and diminished in schizophrenia, bioRxiv, 679670

10.1016/j.biopsych.2018.09.010

10.1038/nn.2723

10.1016/j.biopsych.2017.01.004

10.1152/jn.1998.80.1.1

10.1016/j.biopsych.2016.05.021

10.1016/j.biopsych.2010.10.015

10.1001/archgenpsychiatry.2011.1269

10.1007/BF03033360

10.1001/2013.jamapsychiatry.43

10.1093/schbul/sbm046

10.1002/wps.20624

10.1016/j.nbd.2018.12.013

10.1016/S1364-6613(98)01240-6

10.1016/j.neuron.2013.02.011

10.1038/mp.2017.249

10.1038/npp.2011.181

10.1016/S0893-133X(97)00036-5

10.1016/S2215-0366(19)30001-X

10.1001/archpsyc.1994.03950030035004

10.1177/0269881113494107

10.1016/j.schres.2018.02.049

10.1038/mp.2013.136

10.1111/j.1471-4159.2006.03913.x

10.1002/jnr.21444

Merritt K, 2016, Nature of glutamate alterations in schizophrenia, JAMA Psychiatry, 52, 998

10.1093/schbul/sbx190

10.1001/jamapsychiatry.2018.3637

Kumar J, Glutathione and glutamate in schizophrenia: a 7T MRS study, Mol Psychiatry

10.1016/j.nicl.2014.10.005

10.1016/j.bpsc.2017.04.003

10.1016/j.schres.2016.02.017

10.1038/npjschz.2015.28

10.1177/0269881117747579

10.1093/schbul/sbx133

10.1016/j.schres.2016.11.008

10.1021/acs.jmedchem.8b00714

10.1111/j.1471-4159.2006.04200.x

10.1038/s41386-018-0136-3

10.1073/pnas.95.1.316

10.1038/nm.2615

10.1038/mp.2016.258

Modinos G, 2018, Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis, Neuropsychopharmacology, 43, 262

10.1038/srep21873

10.1503/jpn.170201

10.1002/jmri.24123

10.1016/j.schres.2008.11.014

10.1046/j.1471-4159.2001.00026.x

10.3389/fpsyt.2013.00151

10.1038/mp.2008.87

10.1016/j.biopsych.2005.04.041

10.1016/j.neuron.2012.12.032

10.1038/nature12654

Buzsáki G, 2012, Brain rhythms and neural syntax: implications for efficient coding of cognitive content and neuropsychiatric disease, Dialogues Clin Neurosci, 14, 345, 10.31887/DCNS.2012.14.4/gbuzsaki

10.1038/nn.3660

10.1093/cercor/bhs370

10.1038/nrn2774

10.1016/j.tins.2011.10.004

10.1007/s10571-006-9062-8

10.1093/hmg/ddw007

10.1038/s41398-018-0114-x

10.1038/nature13595

10.1016/j.schres.2016.06.016

10.1016/j.pscychresns.2019.07.005

10.1093/hmg/ddy242

10.1016/j.neuron.2015.04.022

10.1001/jamapsychiatry.2013.1195

10.1038/mp.2014.22

10.1038/mp.2013.67

10.1016/j.stemcr.2014.08.001

10.1038/mp.2014.194

10.1038/nature09915

10.1038/nature13716

10.1016/j.stemcr.2014.01.009

10.1523/JNEUROSCI.3422-03.2004

10.1016/j.neubiorev.2015.07.008

Egerton A, 2017, Elevated striatal dopamine function in immigrants and their children: a risk mechanism for psychosis, Schizophr Bull, 43, 293

10.1016/j.schres.2016.06.005

10.1002/wps.20490

10.1002/wps.20655

10.1016/j.biopsych.2013.05.027

10.1038/npp.2012.232

10.1038/nrn3138

10.1016/j.nicl.2017.01.001

10.1016/j.neubiorev.2016.03.010

10.1038/s41398-018-0137-3

10.1038/s41386-018-0027-7

10.3389/fpsyt.2017.00066

10.1038/mp.2017.190

10.1007/s002130051049

10.1523/JNEUROSCI.0329-15.2015

10.1016/S2215-0366(18)30268-2

10.1016/j.biopsych.2010.05.034

10.3389/fphar.2012.00195

10.1126/science.1253895

10.1073/pnas.98.1.295

10.1176/appi.ajp.2016.16050503

10.1038/s41380-018-0042-4

10.1126/science.347574

10.1038/tp.2016.270

10.1073/pnas.1103029108

10.1016/j.neuron.2016.08.017

10.1176/appi.ajp.2008.06091591

10.1016/j.neubiorev.2018.02.007

10.1007/s00213-011-2436-8

10.1016/j.schres.2014.12.026

10.1016/j.scog.2017.02.001

10.2165/11586650-000000000-00000

10.4088/JCP.11m07031

10.1038/mp.2015.68

10.1007/s00213-016-4318-6

10.1001/jamapsychiatry.2014.257

10.1016/j.biopsych.2017.12.019

10.1016/j.coph.2014.12.004

10.1016/j.jpsychires.2017.04.004

10.1007/s12640-018-9952-9

10.3389/fpsyt.2013.00169

10.1016/j.tins.2015.06.002

10.1007/s00213-004-1982-8

10.1111/pcn.12823

10.1007/s00213-019-5188-5

10.1007/s00213-013-3261-z

10.1001/archpsyc.57.3.270

10.1016/j.schres.2009.01.002

10.1016/S2215-0366(15)00540-4

10.1038/s41380-018-0082-9

10.1016/j.biopsych.2013.06.011

10.1093/schbul/sbv151

10.1109/TMI.2005.861705

SongT‐A ChowdhurySR YangFet al. Super‐resolution PET imaging using convolutional neural networks. Submitted for publication.

McCutcheon R, The efficacy and heterogeneity of antipsychotic response in schizophrenia: a meta‐analysis, Mol Psychiatry

10.1001/jamapsychiatry.2017.3572

10.1016/j.biopsych.2019.05.015

10.1038/nn.4497

Thông tin
Thông tin xuất bản

World Psychiatry

Tập 19 Số 1

15-33

Thông tin tác giả