hypothesis of schizophrenia making sense of it all

Dopamine hypothesis of schizophrenia: making sense of it all

Affiliation.

• 1 [email protected]
• PMID: 17880866
• DOI: 10.1007/s11920-007-0041-7

The dopamine (DA) hypothesis of schizophrenia has evolved over the last decade from the stage of circumstantial evidence related to clinical observations and empirical validation from antipsychotic treatment to finally reach more direct testing and validation from imaging studies. These have provided much information that allows us at this point to assemble all the pieces and attempt to synthesize them and integrate them with the other neurotransmitter alterations observed in this illness. Although clearly not sufficient to explain the complexity of this disorder, the DA dysregulation offers a direct relationship to symptoms and to their treatment. We will review here its history, validation, and implications for treatment.

Publication types

• Research Support, Non-U.S. Gov't
• Antipsychotic Agents / adverse effects
• Antipsychotic Agents / therapeutic use
• Brain / drug effects
• Brain / physiopathology*
• Corpus Striatum / drug effects
• Corpus Striatum / physiopathology
• Diagnostic Imaging
• Dopamine / physiology*
• Prefrontal Cortex / drug effects
• Prefrontal Cortex / physiopathology
• Receptors, Dopamine D2 / drug effects
• Receptors, Dopamine D2 / physiology
• Risk Factors
• Schizophrenia / drug therapy
• Schizophrenia / genetics
• Schizophrenia / physiopathology*
• Antipsychotic Agents
• Receptors, Dopamine D2

Europe PMC requires Javascript to function effectively.

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page.

Search life-sciences literature (44,009,535 articles, preprints and more)

• Available from publisher site using DOI. A subscription may be required. Full text
• Citations & impact
• Similar Articles

Dopamine hypothesis of schizophrenia: making sense of it all.

Author information, affiliations.

• All authors 1. [email protected]

Current Psychiatry Reports , 01 Aug 2007 , 9(4): 329-336 https://doi.org/10.1007/s11920-007-0041-7   PMID: 17880866 

Abstract 

Full text links .

Read article at publisher's site: https://doi.org/10.1007/s11920-007-0041-7

References 

Articles referenced by this article (96)

The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs.

van Rossum JM

Arch Int Pharmacodyn Ther, (2):492-494 1966

MED: 5954044

EFFECT OF CHLORPROMAZINE OR HALOPERIDOL ON FORMATION OF 3METHOXYTYRAMINE AND NORMETANEPHRINE IN MOUSE BRAIN.

CARLSSON A , LINDQVIST M

Acta Pharmacol Toxicol (Copenh), 140-144 1963

MED: 14060771

Brain receptors for antipsychotic drugs and dopamine: direct binding assays.

Seeman P , Chau-Wong M , Tedesco J , Wong K

Proc Natl Acad Sci U S A, (11):4376-4380 1975

MED: 1060115

Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs.

Creese I , Burt DR , Snyder SH

Science, (4238):481-483 1976

Provocative tests with psychostimulant drugs in schizophrenia.

Lieberman JA , Kane JM , Alvir J

Psychopharmacology (Berl), (4):415-433 1987

MED: 2884687

Angrist B, van Kammen DP: CNS stimulants as a tool in the study of schizophrenia. Trends Neurosci 1984, 7:388–390.

Dopamine, the prefrontal cortex and schizophrenia..

Knable MB , Weinberger DR

J Psychopharmacol, (2):123-131 1997

MED: 9208376

D(1) receptors in prefrontal cells and circuits.

Goldman-Rakic PS , Muly EC 3rd , Williams GV

Brain Res Brain Res Rev, (2-3):295-301 2000

MED: 10719156

Dopamine in schizophrenia: a review and reconceptualization.

Davis KL , Kahn RS , Ko G , Davidson M

Am J Psychiatry, (11):1474-1486 1991

MED: 1681750

Implications of normal brain development for the pathogenesis of schizophrenia.

Weinberger DR

Arch Gen Psychiatry, (7):660-669 1987

MED: 3606332

Citations & impact 

Impact metrics, citations of article over time, alternative metrics.

Article citations

Between neurons and networks: investigating mesoscale brain connectivity in neurological and psychiatric disorders..

Caznok Silveira AC , Antunes ASLM , Athié MCP , da Silva BF , Ribeiro Dos Santos JV , Canateli C , Fontoura MA , Pinto A , Pimentel-Silva LR , Avansini SH , de Carvalho M

Front Neurosci , 18:1340345, 20 Feb 2024

Cited by: 0 articles | PMID: 38445254

Genetic Susceptibility to Tardive Dyskinesia and Cognitive Impairments in Chinese Han Schizophrenia: Role of Oxidative Stress-Related and Adenosine Receptor Genes.

Jiang Q , Zhang X , Lu X , Li Y , Lu C , Chi J , Ma Y , Shi X , Wang L , Li S

Neuropsychiatr Dis Treat , 19:2499-2509, 20 Nov 2023

Cited by: 0 articles | PMID: 38029048 | PMCID: PMC10679515

Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility.

Casserly L , Garton DR , Montaño-Rodriguez A , Andressoo JO

Biomolecules , 13(9):1428, 21 Sep 2023

Cited by: 1 article | PMID: 37759827 | PMCID: PMC10526418

Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia.

Kidambi N , Elsayed OH , El-Mallakh RS

Neuropsychiatr Dis Treat , 19:1145-1151, 10 May 2023

Cited by: 0 articles | PMID: 37193547 | PMCID: PMC10183173

Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring.

Perez-Palomar B , Erdozain AM , Erkizia-Santamaría I , Ortega JE , Meana JJ

J Neuroimmune Pharmacol , 18(3):348-365, 20 May 2023

Cited by: 2 articles | PMID: 37208550 | PMCID: PMC10577104

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Schizophrenia: a computational reinforcement learning perspective.

Schizophr Bull , 34(6):1008-1011, 12 Sep 2008

Cited by: 22 articles | PMID: 18791075 | PMCID: PMC2632497

Free full text in Europe PMC

Occupancy of striatal dopamine D2 receptors.

Psychiatry Res , 61(4):285-287, 01 Nov 1995

Cited by: 0 articles | PMID: 8748471

Model-based parametric study of frontostriatal abnormalities in schizophrenia patients.

BMC Psychiatry , 10:17, 27 Feb 2010

Cited by: 4 articles | PMID: 20187970 | PMCID: PMC2848218

Antipsychotic drug mechanisms and neurotransmitter systems in schizophrenia.

Reynolds GP

Acta Psychiatr Scand Suppl , 380:36-40, 01 Jan 1994

Cited by: 7 articles | PMID: 7914046

Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action.

Sanyal S , Van Tol HH

J Psychiatr Res , 31(2):219-232, 01 Mar 1997

Cited by: 43 articles | PMID: 9278187

Europe PMC is part of the ELIXIR infrastructure

Dopamine hypothesis of schizophrenia: Making sense of it all

• Published: 11 July 2007
• Volume 9 , pages 329–336, ( 2007 )

Cite this article

• Mitsuru Toda BA &
• Anissa Abi-Dargham MD 1  

4962 Accesses

158 Citations

3 Altmetric

Explore all metrics

The dopamine (DA) hypothesis of schizophrenia has evolved over the last decade from the stage of circumstantial evidence related to clinical observations and empirical validation from antipsychotic treatment to finally reach more direct testing and validation from imaging studies. These have provided much information that allows us at this point to assemble all the pieces and attempt to synthesize them and integrate them with the other neurotransmitter alterations observed in this illness. Although clearly not sufficient to explain the complexity of this disorder, the DA dysregulation offers a direct relationship to symptoms and to their treatment. We will review here its history, validation, and implications for treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (Russian Federation)

Instant access to the full article PDF.

Rent this article via DeepDyve

Institutional subscriptions

Similar content being viewed by others

Schizophrenia: from neurochemistry to circuits, symptoms and treatments

The Dopamine Dysfunction in Schizophrenia Revisited: New Insights into Topography and Course

Dopamine and Response to Antipsychotic Medication

References and recommended reading.

Rossum V: The significance of dopamine receptor blockade for the mechanism of action of neuroleptic drugs . Arch Int Pharmacodyn Ther 1966, 160: 492–494.

PubMed   Google Scholar  

Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain . Acta Pharmacol Toxicol 1963, 20: 140–144.

Article   CAS   Google Scholar  

Seeman P, Chau-Wong M, Tedesco J, Wong K: Brain receptors for antipsychotic drugs and dopamine: direct binding assays . Proc Natl Acad Sci U S A 1975, 72: 4376–4380.

Article   PubMed   CAS   Google Scholar  

Creese I, Burt DR, Snyder SH: Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs . Science 1976, 19: 481–483.

Article   Google Scholar  

Lieberman JA, Kane JM, Alvir J: Provocative tests with psychostimulant drugs in schizophrenia . Psychopharmacology 1987, 91: 415–433.

Angrist B, van Kammen DP: CNS stimulants as a tool in the study of schizophrenia . Trends Neurosci 1984, 7: 388–390.

Knable MB, Weinberger DR: Dopamine, the prefrontal cortex and schizophrenia . J Psychopharmacol 1997, 11: 123–131.

Goldman-Rakic PS, Muly EC 3rd, Williams GV: D(1) receptors in prefrontal cells and circuits . Brain Res Brain Res Rev 2000, 31: 295–301.

Davis KL, Kahn RS, Ko G, Davidson M: Dopamine in schizophrenia: a review and reconceptualization . Am J Psychiatry 1991, 148: 1474–1486.

PubMed   CAS   Google Scholar  

Weinberger DR: Implications of the normal brain development for the pathogenesis of schizophrenia . Arch Gen Psychiatry 1987, 44: 660–669.

Pycock CJ, Kerwin RW, Carter CJ: Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats . Nature 1980, 286: 74–77.

Young D, Scoville WB: Paranoid psychosis in narcolepsy and the possible dangers of benzedrine treatment . Med Clin North Am 1938, 22: 637.

Google Scholar  

Connell PH: Amphetamine Psychosis . London: Chapman and Hill; 1958.

Griffith JJ, Oates J, Cavanaugh J: Paranoid episodes induced by drugs . J Am Med Assoc 1968, 205: 39.

Angrist BM, Gershon S: The phenomenology of experimentally induced amphetamine psychosis-preliminary observation . Biol Psychiatry 1970, 2: 95–107.

Bell DS: The experimental reproduction of amphetamine psychosis . Arch Gen Psychiatry 1973, 29: 35–40.

Ellinwood EH, Jr.: Amphetamine psychosis: I. Description of the individuals and process . J Nerv Ment Dis 1967, 144: 273–283.

Ellinwood EH, Sudilovsky A, Nelson LM: Evolving behavior in the clinical and experimental amphetamine model psychosis . Am J Psychiatry 1973, 130: 1088–1093.

Lieberman JA, Kane JM, Sarantakos S, et al.: Prediction of relapse in schizophrenia . Arch Gen Psychiatry 1987, 44: 597–603.

Delay J, Deniker P, Harl J: Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP) [in French] . Ann Med Psychol (Paris) 1952, 110: 112–117.

CAS   Google Scholar  

Talbot PS, Laruelle M: The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development . Eur Neuropsychopharmacol 2002, 12: 503–511.

Kapur S, Zipursky R, Jones C, et al.: Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia . Am J Psychiatry 2000, 157: 514–520.

Nordstrom AL, Farde L, Wiesel FA, et al.: Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients . Biol Psychiatry 1993, 33: 227–235.

Farde L, Nordstrom AL, Wiesel FA, et al.: Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects . Arch Gen Psychiatry 1992, 49: 538–544.

Weinberger D, Laruelle M: Neurochemical and neuropharmacological imaging in schizophrenia . In Neuropsychopharmacology—The Fifth Generation of Progress . Edited by Davis KL, Charney DS, Coyle J, et al. Philadelphia: Lippincott Williams & Wilkins; 2001 : 833–855.

Seeman P, Guan HC, Niznik HB: Endogenous dopamine lowers the dopamine D2 receptor density as measured by [3H]raclopride: implications for positron emission tomography of the human brain . Synapse 1989, 3: 96–97.

Seeman P: Brain dopamine receptors in schizophrenia: PET problems . Arch Gen Psychiatry 1988, 45: 598–600.

Hirvonen J, van Erp TG, Huttunen J, et al.: Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia . Arch Gen Psychiatry 2005, 62: 371–378.

Okubo Y, Suhara T, Suzuki K, et al.: Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET . Nature 1997, 385: 634–636.

Abi-Dargham A, Mawlawi O, Lombardo I, et al.: Prefrontal dopamine D1 receptors and working memory in schizophrenia . J Neurosci 2002, 22: 3708–3719.

Karlsson P, Farde L, Halldin C, Sedvall G: PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia . Am J Psychiatry 2002, 159: 761–767.

Article   PubMed   Google Scholar  

Laruelle M, Iyer RN, al-Tikriti MS, et al.: Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates . Synapse 1997, 25: 1–14.

Villemagne VL, Wong DF, Yokoi F, et al.: GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [(11)C]raclopride continuous infusion PET scans . Synapse 1999, 33: 268–273.

Breier A, Su TP, Saunders R, et al.: Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method . Proc Natl Acad Sci U S A 1997, 94: 2569–2574.

Laruelle M, Abi-Dargham A, van Dyck CH, et al.: Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects . Proc Natl Acad Sci U S A 1996, 93: 9235–9240.

Abi-Dargham A, Gil R, Krystal J, et al.: Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort . Am J Psychiatry 1998, 155: 761–767.

Laruelle M, Abi-Dargham A, Gil R, et al.: Increased dopamine transmission in schizophrenia: relationship to illness phases . Biol Psychiatry 1999, 46: 56–72.

Parsey RV, Oquendo MA, Zea-Ponce Y, et al.: Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression . Biol Psychiatry 2001, 50: 313–322.

Laruelle M, Abi-Dargham A, van Dyck C, et al.: Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [(123)I]beta-CIT . Biol Psychiatry 2000, 47: 371–379.

Laakso A, Vilkman H, Alakare B, et al.: Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography . Am J Psychiatry 2000, 157: 269–271.

Taylor SF, Koeppe RA, Tandon R, et al.: In vivo measurement of the vesicular monoamine transporter in schizophrenia . Neuropsychopharmacology 2000, 23: 667–675.

Laruelle M: Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review . J Cereb Blood Flow Metab 2000, 20: 423–451.

Laruelle M, D’souza CD, Baldwin RM, et al.: Imaging D2 receptor occupancy by endogenous dopamine in humans . Neuropsychopharmacology 1997, 17: 162–174.

Abi-Dargham A, Rodenhiser J, Printz D, et al.: Increased baseline occupancy of D2 receptors by dopamine in schizophrenia . Proc Natl Acad Sci U S A 2000, 97: 8104–8109.

Kegeles L, Frankle W, Gil R, et al.: Schizophrenia is associated with increased synaptic dopamine in associative rather than limbic regions of the striatum: implications for mechanisms of action of antipsychotic drugs . J Nucl Med 2006, 47: 139P.

Alexander GE, Delong MR, Stick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex . Ann Rev Neurosci 1986, 9: 357–381.

Hoover JE, Strick PL: Multiple output channels in the basal ganglia . Science 1993, 259: 819–821.

Ferry AT, Ongur D, An X, Price JL: Prefrontal cortical projections to the striatum in macaque monkeys: evidence for an organization related to prefrontal networks . J Comp Neurol 2000, 425: 447–470.

Joel D, Weiner I: The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum . Neuroscience 2000, 96: 451–474.

Parent A, Hazrati LN: Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop . Brain Res Brain Res Rev 1995, 20: 91–127.

Dao-Castellana MH, Paillere-Martinot ML, Hantraye P, et al.: Presynaptic dopaminergic function in the striatum of schizophrenic patients . Schizophr Res 1997, 23: 167–174.

Elkashef AM, Doudet D, Bryant T, et al.: 6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography . Psychiatry Res 2000, 100: 1–11.

Hietala J, Syvalahti E, Vilkman H, et al.: Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia . Schizophr Res 1999, 35: 41–50.

Hietala J, Syvalahti E, Vuorio K, et al.: Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients . Lancet 1995, 346: 1130–1131.

Lindstrom LH, Gefvert O, Hagberg G, et al.: Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET . Biol Psychiatry 1999, 46: 681–688.

McGowan S, Lawrence AD, Sales T, et al.: Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study . Arch Gen Psychiatry 2004, 61: 134–142.

Meyer-Lindenberg A, Miletich RS, Kohn PD, et al.: Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia . Nat Neurosci 2002, 5: 267–271.

Reith J, Benkelfat C, Sherwin A, et al.: Elevated dopa decarboxylase activity in living brain of patients with psychosis . Proc Natl Acad Sci U S A 1994, 91: 11651–11654.

Zhu M Y, Juorio AV, Paterson IA, Boulton AA: Regulation of striatal aromatic L-amino acid decarboxylase: effects of blockade or activation of dopamine receptors . Eur J Pharmacol 1993, 238: 157–164.

Cho S, Neff NH, Hadjiconstantinou M: Regulation of tyrosine hydroxylase and aromatic L-amino acid decarboxylase by dopaminergic drugs . Eur J Pharmacol 1997, 323: 149–157.

Danielsen EH, Smith D, Hermansen F, et al.: Acute neuroleptic stimulates DOPA decarboxylase in porcine brain in vivo . Synapse 2001, 41: 172–175.

Torstenson R, Hartvig P, Langstrom B, et al.: Effect of apomorphine infusion on dopamine synthesis rate relates to dopaminergic tone . Neuropharmacology 1998, 37: 989–995.

Grunder G, Vernaleken I, Muller MJ, et al.: Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo . Neuropsychopharmacology 2003, 28: 787–794.

Grace AA: Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia . Neuroscience 1991, 41: 1–24.

Goldman-Rakic P: Working memory dysfunction in schizophrenia . J Neuropsychiatry Clin Neurosci 1994, 6: 348.

Goldberg TE, Weinberger DR: Genes and the parsing of cognitive processes . Trends Cogn Sci 2004, 8: 325–335.

Weinberger DR, Berman KF, Chase TN: Mesocortical dopaminergic function and human cognition . Ann N Y Acad Sci 1988, 537: 330–338.

Kahn RS, Harvey PD, Davidson M, et al.: Neuropsychological correlates of central monoamine function in chronic schizophrenia: relationship between CSF metabolites and cognitive function . Schizophr Res 1994, 11: 217–224.

Daniel DG, Weinberger DR, Jones DW, et al.: The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia . J Neurosci 1991, 11: 1907–1917.

Dolan RJ, Fletcher P, Frith CD, et al.: Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia . Nature 1995, 378: 180–182.

Guo N, Hwang D, Abdellhadis S, et al.: The effect of chronic DA depletion on D1 ligand binding in rodent brain . Soc Neurosc Abst 2001, 27: 238.

Dumartin B, Jaber M, Gonon F, et al.: Dopamine tone regulates D1 receptor trafficking and delivery in striatal neurons in dopamine transporter-deficient mice . Proc Natl Acad Sci U S A 2000, 97: 1879–1884.

Scott L, Kruse MS, Forssberg H, et al.: Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation . Proc Natl Acad Sci U S A 2002, 99: 1661–1664.

Hirvonen J, van Erp TG, Huttunen J, et al.: Brain dopamine d1 receptors in twins discordant for schizophrenia . Am J Psychiatry 2006, 163: 1747–1753.

Lidow MS, Elsworth JD, Goldman-Rakic PS: Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs . J Pharmacol Exp Ther 1997, 281: 597–603.

Ekelund J, Slifstein M, Narendran R, et al.: In vivo DA D1 receptor selectivity of NNC 112 and SCH23390 . Mol Imaging Biol 2007, 9: 117–125.

Tuppurainen H, Kuikka J, Viinamaki H, et al.: Extrastriatal dopamine D 2/3 receptor density and distribution in drug-naive schizophrenic patients . Mol Psychiatry 2003, 8: 453–455.

Talvik M, Nordstrom A L, Okubo Y, et al.: Dopamine D(2) receptor binding in drug-naive patients with schizophrenia examined with raclopride-C11 and positron emission tomography . Psychiatry Res 2006, 148: 165–173.

Talvik M, Nordstrom A L, Olsson H, et al.: Decreased thalamic D2/D3 receptor binding in drug-naive patients with schizophrenia: a PET study with [11C]FLB 457 . Int J Neuropsychopharmacol 2003, 6: 361–370.

Suhara T, Okubo Y, Yasuno F, et al.: Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia . Arch Gen Psychiatry 2002, 59: 25–30.

Glenthoj BY, Mackeprang T, Svarer C, et al.: Frontal dopamine D(2/3) receptor binding in drug-naive first-episo de schizophrenic patients correlates with positive psychotic symptoms and gender . Biol Psychiatry 2006, 60: 621–629.

Agid O, Mamo D, Ginovart N, et al.: Striatal vs extrastriatal dopamine D(2) receptors in antipsychotic response-a double-blind PET study in schizophrenia . Neuropsychopharmacology 2007, 32: 1209–1215.

Gurevich EV, Bordelon Y, Shapiro RM, et al.: Mesolimbic dopamine D-3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study . Arch Gen Psychiatry 1997, 54: 225–232.

Murray AM, Hyde TM, Knable MB, et al.: Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia . J Neurosci 1995, 15: 2186–2191.

Sumiyoshi T, Stockmeier CA, Overholser JC, et al.: Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression . Brain Res 1995, 681: 109–116.

Marzella PL, Copolov D: [H-3]nemonapride binding in human caudate and putamen . Brain Res Bull 1997, 44: 167–170.

Lahti RA, Roberts RC, Conley RR, et al.: Dopamine D2, D3 and D4 receptors in human postmortem brain sections: comparison between normals and schizophrenics . Schizophr Res 1996, 18: 173.

Reynolds GP, Mason SL: Are striatal dopamine D-4 receptors increased in schizophrenia? J Neurochem 1994, 63: 1576–1577.

Lahti RA, Roberts RC, Cochrane EV, et al.: Direct determination of dopamine D-4 receptors in normal and schizophrenic postmortem brain tissue: a [H-3]NGD-94-1 study . Mol Psychiatry 1998, 3: 528–533.

Kramer MS, Last B, Getson A, Reines SA: The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group . Arch Gen Psychiatry 1997, 54: 567–572.

Narendran R, Frankle WG, Keefe R, et al.: Altered prefrontal dopaminergic function in chronic recreational ketamine users . Am J Psychiatry 2005, 162: 2352–2359.

Abi-Dargham A, Moore H: Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia . Neuroscientist 2003, 9: 404–416.

Kegeles LS, Abi-Dargham A, Zea-Ponce Y, et al.: Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia . Biol Psychiatry 2000, 48: 627–640.

Laruelle M, Kegeles LS, Abi-Dargham A: Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment . Ann N Y Acad Sci 2003, 1003: 138–158.

Lewis DA, Gonzalez-Burgos G: Pathophysiologically based treatment interventions in schizophrenia . Nat Med 2006, 12: 1016–1022.

Hsiao MC, Lin KJ, Liu C Y, et al.: Dopamine transporter change in drug-naive schizophrenia: an imaging study with 99mTc-TRODAT-1 . Schizophr Res 2003, 65: 39–46.

Download references

Author information

Authors and affiliations.

1051 Riverside Drive, Box 31, New York, NY, 10032, USA

Anissa Abi-Dargham MD

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Anissa Abi-Dargham MD .

Rights and permissions

Reprints and permissions

About this article

Toda, M., Abi-Dargham, A. Dopamine hypothesis of schizophrenia: Making sense of it all. Curr Psychiatry Rep 9 , 329–336 (2007). https://doi.org/10.1007/s11920-007-0041-7

Download citation

Published : 11 July 2007

Issue Date : August 2007

DOI : https://doi.org/10.1007/s11920-007-0041-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Nemonapride
• Opamine Receptor
• Find a journal
• Publish with us
• Track your research

Psych Scene Hub

The Dopamine Hypothesis of Schizophrenia – Advances in Neurobiology and Clinical Application

The dopamine hypothesis stems from early research carried out in the 1960’s and 1970’s when studies involved the use of amphetamine (increases dopamine levels) which increased psychotic symptoms while reserpine which depletes dopamine levels reduced psychotic symptoms.

The original dopamine hypothesis was put forward by Van Rossum in 1967 that stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms. [1]

DOPAMINE PRODUCTION AND METABOLISM

Dopamine is synthesised from the amino acid tyrosine. Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.

DOPA is converted into dopamine (DA) by the enzyme DOPA decarboxylase (DOPADC).

This dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse.

Dopamine Receptors:

When dopamine is released during neurotransmission, it acts on 5 types of postsynaptic receptors (D1-D5).

A negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron.

Dopamine Breakdown

Any excess dopamine is also ‘mopped up’ from the synapse by Dopamine transporter (DAT) and stored in the vesicles via VMAT2.

Dopamine is broken down by monoamine oxidase A (MAO-A), MAO-B and catechol-o-methyltransferase (COMT).

Learning points:

• Tyrosine hydroxylase is the rate-limiting step in the production of dopamine. Its expression is significantly increased in the substantia nigra of schizophrenia patients when compared to normal healthy subjects. [2]
• Carbidopa is a peripheral DOPA-decarboxylase inhibitor co-administered with levodopa. Carbidopa prevents the conversion of levodopa to dopamine in the periphery, thus allowing more levodopa to pass the blood-brain barrier to be converted into dopamine for its therapeutic effect.
• Methamphetamine increases extracellular dopamine by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT).
• Valbenazine a highly selective VMAT2 inhibitor has been approved by the FDA for the treatment of tardive dyskinesia.
• There is compelling evidence that presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. Furthermore, dopamine synthesis capacity has also been shown to steadily increase with the onset of severe psychotic symptoms. [3] , [Howes & Shatalina, 2022]

• Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors , and D1 dysfunction has been linked to cognitive impairment and negative symptoms of schizophrenia . [4]

THE 4 DOPAMINE PATHWAYS IN THE BRAIN

1.The Mesolimbic Pathway

• The pathway projects from the ventral tegmental area (VTA) to the nucleus accumbens in the limbic system.
• Hyperactivity of dopamine in the mesolimbic pathway mediates positive psychotic symptoms. The pathway may also mediate aggression.
• The mesolimbic pathway is also the site of the rewards pathway and mediates pleasure and reward. Antipsychotics can block D2 receptors in this pathway reducing pleasure effects. This may be one explanation as to why individuals with schizophrenia have a higher incidence of smoking as nicotine enhances dopamine in the reward pathway (self-medication hypothesis)
• Antagonism of D2 receptors in the mesolimbic pathway treats positive psychotic symptoms.
• There is an occupancy requirement with the minimum threshold at 65% occupancy for treatment to be effective. Observations support this relationship between D2-receptor occupancy and clinical response that 80% of responders have D2-receptor occupancy above this threshold after treatment. [5]

2.The Mesocortical Pathway

• Projects from the VTA to the prefrontal cortex.
• Projections to the dorsolateral prefrontal cortex regulate cognition and executive functioning.
• Projections into the ventromedial prefrontal cortex regulate emotions and affect.
• Decreased dopamine in the mesocortical projection to the dorsolateral prefrontal cortex is postulated to be responsible for negative and depressive symptoms of schizophrenia.
• Nicotine releases dopamine in the mesocortical pathways alleviating negative symptoms (self-medication hypothesis).

3.The Nigrostriatal Pathway

• Projects from the dopaminergic neurons in the substantia nigra to the basal ganglia or striatum.
• The nigrostriatal pathway mediates motor movements.
• Blockade of dopamine D2 receptors in this pathway can lead to dystonia, parkinsonian symptoms and akathisia.
• Hyperactivity of dopamine in the nigrostriatal pathway is the postulated mechanism in hyperkinetic movement disorders such as chorea, tics and dyskinesias.
• Long-standing D2 blockade in the nigrostriatal pathway can lead to tardive dyskinesia. 

4.The Tuberoinfundibular (TI) Pathway

• Projects from the hypothalamus to the anterior pituitary.
• The TI pathway inhibits prolactin release.
• Blockade of D2 receptors in this pathway can lead to hyperprolactinemia which clinically manifests as amenorrhoea, galactorrhoea and sexual dysfunction.
• Long-term hyperprolactinemia can be associated with osteoporosis.

Conceptualisation of Schizophrenia

Based on the above understanding, schizophrenia is best conceptualised as a complex entity which involves multiple pathways.

In clinical practice, there can be a disproportionate focus on positive psychotic symptoms.

It is however, important to recognise that affective (e.g depressive), negative and cognitive symptoms are a core part of schizophrenia and should be taken into account in treatment.

The aim of treatment, thus, is to modulate treatment creating a balance between effectiveness and reduction of side effects.

The balance is achieved by optimal dopamine blockade in the mesolimbic pathway while preserving (or enhancing) dopamine transmission in the other pathways.

DOPAMINE AND SCHIZOPHRENIA

The dopamine hypothesis of schizophrenia has moved from the dopamine receptor hypothesis (increased dopamine transmission at the postsynaptic receptors) to a focus on presynaptic striatal hyperdopaminergia.

According to Howes and Kapur-

This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia. In addition to funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. Schizophrenia is thus dopamine dysregulation in the context of a compromised brain. [6]

Read more on the molecular imaging of dopamine abnormalities in schizophrenia. 

Clinical Implications

The hypothesis that the final common pathway is presynaptic dopamine dysregulation has some important clinical implications. Firstly, it implies that current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis. This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects. [6]

Concept of Salience

Usually, dopamine’s role is to mediate motivational salience and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.

The salience network consists of the Anterior Cingulate Cortex (ACC), insula and the amygdala.

Schizophrenia is associated with an aberrant attribution of salience due to dysregulated striatal dopamine transmission.

Dysregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis for psychotic phenomena such as ideas of reference, where everyday occurrences may be layered with a with a heightened sense of bizarre significance.  Furthermore, this misattribution of salience can lead to paranoid behaviour and persecutory delusions. [7]

A stimulus, even if initially lacking inherent salience, once paired with dopaminergic activity, maintains the ability to evoke dopaminergic activity over time. This suggests that in psychosis, once an environmental stimulus has been highlighted by aberrant dopamine signalling, it may maintain its ability to trigger dopaminergic activity, potentially cementing its position in a delusional framework, even if the system subsequently returns to normal function. [McCutcheon, et al, 2019]

LIMITATIONS OF THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

Current research shows that one-third of individuals with schizophrenia do not respond to non-clozapine antipsychotics despite high levels of D2-receptor occupancy.

Furthermore, a study using tetrabenazine (used as augmentation) which depletes presynaptic dopamine was not found to be effective in augmenting a clinical response in schizophrenia. [8]

Therefore, for a significant number of patients with schizophrenia, the basis of their symptoms is either unrelated to dopaminergic dysfunction or is associated with something more than just dopamine excess.

Alternatively, this could also mean that for some patients with schizophrenia there might be a non-dopaminergic sub-type of schizophrenia.

The current dopamine hypothesis of schizophrenia does not adequately explain the cognitive and negative symptoms. Current treatments which modulate dopamine transmission have only modest effects in improving these symptoms.

It has taken two decades for the dopamine hypothesis to evolve and reach its current state. More recent evidence shows another neurotransmitter, glutamate playing an essential role in schizophrenia.

The future likely holds a lot more secrets about schizophrenia which should unravel with the advances in understanding the brain.

Learn more:

Simplified Guide to Mechanisms of Action of Oral Antipsychotics

RECOMMENDED BOOKS

Howes O, et al . Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. Brain . 2013

Howes OD, Shatalina E. Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance. Biol Psychiatry. 2022 Sep 15;92(6):501-513.

Howes, O., McCutcheon, R., & Stone, J. (2015). Glutamate and dopamine in schizophrenia: an update for the 21st century. Journal of psychopharmacology , 29 (2), 97-115.

Kapur S, et al . Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. American Journal of Psychiatry . 2000

Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet . 2014

McCutcheon, R. A., Abi-Dargham, A., & Howes, O. D. (2019). Schizophrenia, dopamine and the striatum: from biology to symptoms.  Trends in neurosciences ,  42 (3), 205-220

Module 11: Schizophrenia Spectrum and Other Psychotic Disorders

Perspectives on schizophrenia, learning objectives.

• Describe how various psychological perspectives view and explain schizophrenia

Psychodynamic Perspectives on Psychosis

Early psychoanalytic conceptions of psychosis explained psychotic symptoms as a manifestation of the conscious mind being invaded by the unconscious and by dreams (Federn, 1928/1952). More contemporary approaches underline the importance of early relationship patterns (e.g., Bion, 1962; Winnicott, 1991). Internal representations of experiences with significant others and current relationships are assumed to result in tension and psychotic symptoms are considered to be a constructive way of dealing with this tension (von Haebler & Freyberger, 2013). Psychodynamic therapy focuses on these processes and helps the patient to gain self-awareness and understanding of the influence of the past on present behavior, and it fosters new positive relationship experiences. An empathic, respectful, and supportive attitude allows re-enactment of internalized relational patterns in the therapist–patient interaction (Lempa, Montag, & von Haebler, 2013). Some early theories of psychoanalytic thought argued that psychosis could result from poor parenting behaviors (e.g., the schizophrenogenic mother stereotype) and the concept of double-bind communication, which refers to parental communication that is contradictory (rejecting while demanding affection), have not been supported in later research. [1] Additionally, studies have generally shown that insight-oriented forms of psychotherapy do not typically work well with most persons with schizophrenia because of their difficulty in self-reflection and abstract thinking due to thought disorder.

Humanistic Perspectives on Psychosis

In client-centered or humanistic therapy, unconditional positive regard, accurate empathy, and genuineness are assumed to help a patient to increase the congruence between the real self and the ideal self (Rogers, Gendlin, Kiesler, & Truax, 1967). Rogers and colleagues’ concept of actualizing tendency points to an inherent tendency to achieve personal growth and reach one’s full potential. In this framework, psychotic symptoms are understood as a distortion of this actualizing tendency. Client-centered therapy focuses on personal experiences whereas relieving specific symptoms is secondary. Thus, no specific therapeutic strategies have been established for psychosis. However, this perspective recommends therapists pay particular attention to understanding the client’s perspective, ensuring that the patient is being heard and emphasizing the personal relationship (Gendlin, 1962). [2]

The Cognitive Perspective of Schizophrenia

When we think of the core symptoms of psychotic disorders such as schizophrenia, we think of an individual who may hear voices, see visions, and have false beliefs about reality (i.e., delusions). However, problems in cognitive function are also a critical aspect of psychotic disorders and of schizophrenia in particular. This emphasis on cognition in schizophrenia is in part due to the growing body of research suggesting that cognitive problems in schizophrenia are a major source of disability and loss of functional capacity (Green, 2006; Nuechterlein et al., 2011). The cognitive deficits that are present in schizophrenia are widespread and can include problems with episodic memory (the ability to learn and retrieve new information or episodes in one’s life), working memory (the ability to maintain information over a short period of time, such as 30 seconds), and other tasks that require one to control or regulate one’s behavior (Barch & Ceaser, 2012; Bora, Yucel, & Pantelis, 2009a; Fioravanti, Carlone, Vitale, Cinti, & Clare, 2005; Forbes, Carrick, McIntosh, & Lawrie, 2009; Mesholam-Gately, Giuliano, Goff, Faraone, & Seidman, 2009). Individuals with schizophrenia also have difficulty with what is referred to as processing speed  and are frequently slower than healthy individuals on almost all tasks. Importantly, these cognitive deficits are present prior to the onset of the illness (Fusar-Poli et al., 2007) and are also present, albeit in a milder form, in the first-degree relatives of people with schizophrenia (Snitz, Macdonald, & Carter, 2006).

These findings suggest that cognitive impairments in schizophrenia reflect part of the risk for the development of psychosis, rather than only being an outcome of developing psychosis. Further, people with schizophrenia who have more severe cognitive problems also tend to have more severe negative symptoms and more disorganized speech and behavior (Barch, Carter, & Cohen, 2003; Barch et al., 1999; Dominguez Mde, Viechtbauer, Simons, van Os, & Krabbendam, 2009; Ventura, Hellemann, Thames, Koellner, & Nuechterlein, 2009; Ventura, Thames, Wood, Guzik, & Hellemann, 2010). In addition, people with more cognitive problems have worse functioning in everyday life (Bowie et al., 2008; Bowie, Reichenberg, Patterson, Heaton, & Harvey, 2006; Fett et al., 2011).

The Cognitive-Behavioral Perspective

Cognitive-behavioral interventions for psychosis (CBTp) build on the assumption that psychotic symptoms lie on a continuum with normal experiences. They are also informed by research suggesting that psychotic experiences result from normal, though exaggerated, mechanisms of perception and reasoning. This understanding has formed the basis for cognitive models of psychosis. As one of the most influential of these models, Garety, Kuipers, Fowler, Freeman, & Bebbington (2001) postulate that psychotic symptoms develop when stressors overload a person, causing them to have unusual experiences. According to this model, the unusual experience itself is not crucial, but its appraisal—how it is understood or evaluated by the person—is. Most descriptions within the cognitive-behavioral interventions for psychosis (CBTp) framework converge in stressing the importance of building a stable therapeutic relationship through the process of listening and validating, of taking a collaborative approach, and of working with an individual case formulation. The use of cognitive and behavioral interventions for working with psychotic symptoms as well as for changing dysfunctional beliefs and interventions to prevent relapse are also essential elements. [3]

Social Cognition

Some people with schizophrenia also show deficits in what is referred to as social cognition, though it is not clear whether such problems are separate from the cognitive problems described above or the result of them (Hoe, Nakagami, Green, & Brekke, 2012; Kerr & Neale, 1993; van Hooren et al., 2008). This deficit of social cognition includes problems with the recognition of emotional expressions on the faces of other individuals (Kohler, Walker, Martin, Healey, & Moberg, 2010) and problems inferring the intentions of other people (theory of mind) (Bora, Yucel, & Pantelis, 2009b). Individuals with schizophrenia who have more problems with social cognition also tend to have more negative and disorganized symptoms (Ventura, Wood, & Hellemann, 2011) as well as worse community function (Fett et al., 2011).

Diathesis-Stress Model

Figure 1 . We know that biological and genetic components play a large role in influencing the development of schizophrenia, although biological factors alone cannot explain why a person may develop the disorder.

The diathesis-stress model helps to settle the debate of nature versus nurture; it explains how the two have a bidirectional relationship and a dual influence on the development of many mental health illnesses, especially schizophrenia. The diathesis refers to the genetic predisposition or risk an individual has of developing a certain disorder. This predisposition comes from the individual’s unique genetic makeup as well as the increased risk if a first-degree blood relative such as parent or sibling has been diagnosed with a disorder. The diathesis is the nature component of the model, reflecting the biological vulnerability an individual possesses. An environmental  stressor can trigger the onset of a disorder, especially in those genetically vulnerable to developing the disorder. If an individual is greatly susceptible to developing a disorder, only a small level of stress is needed to catalyze the onset of the disorder. Extreme trauma or the use of a drug such as cannabis can serve as environmental stressors and aspects of nurture that influence the onset of schizophrenia and related disorders.

Childhood trauma has specifically been shown to be a predictor of adolescent and adult psychosis. Approximately 65% of individuals with psychotic symptoms have experienced childhood trauma (e.g., physical or sexual abuse and physical or emotional neglect). Increased individual vulnerability toward psychosis may interact with traumatic experiences promoting an onset of future psychotic symptoms, particularly during sensitive developmental periods. Importantly, the relationship between traumatic life events and psychotic symptoms appears to be dose-dependent, in which multiple traumatic life events accumulate, compounding symptom expression and severity. This relationship suggest trauma prevention and early intervention may be an important target for decreasing the incidence of psychotic disorders and ameliorating its effects.

Sociocultural Perspective

Figure 2. In some cultures, some of the symptoms of schizophrenia may not be considered abnormal.

There are also a number of environmental factors that are associated with an increased risk of developing schizophrenia. For example, problems during pregnancy such as increased stress, infection, malnutrition, and/or diabetes have been associated with increased risk of schizophrenia. In addition, complications that occur at the time of birth and cause hypoxia (lack of oxygen) are also associated with an increased risk for developing schizophrenia in the child (M. Cannon, Jones, & Murray, 2002; Miller et al., 2011). Children born to older fathers are also at a somewhat increased risk of developing schizophrenia. Further, using cannabis increases risk for developing psychosis, especially if when other risk factors are present (Casadio, Fernandes, Murray, & Di Forti, 2011; Luzi, Morrison, Powell, di Forti, & Murray, 2008). The likelihood of developing schizophrenia is also higher for kids who grow up in urban settings (March et al., 2008) and for some marginalized ethnic groups (Bourque, van der Ven, & Malla, 2011). Both of these factors may reflect higher social and environmental stress in these settings. Unfortunately, none of these risk factors is specific enough to be particularly useful in a clinical setting, and most people with these risk factors do not develop schizophrenia. However, together they are beginning to give us clues as the neurodevelopmental factors that may lead someone to be at an increased risk for developing this disorder.

Cross-Cultural Perspectives and Cultural Influences

Culture plays a role in the way we view mental health disorders and their corresponding features. There are cultures around the world, such as in Peru, who do not perceive features of schizophrenia like hearing voices (hallucinations) as abnormal. Rather, they may even be seen as special abilities and connections to the spirit realm, where the individual who hears voices could be the community Shaman, or medicine man. These individuals actually help to provide insight and healing to themselves and to others.

In Western societies, the same feature of hearing voices would be considered to be abnormal and a symptom of an underlying disease such as schizophrenia. An individual experiencing these symptoms would not be placed in a position of reverence or admiration, but would most likely be placed in a treatment facility or hospital for further care and treatment to manage and reduce the experienced symptoms. Even in Western society, however, there have been advocates, like Dorothea Dix and Philippe, who emphasized respecting and admiring those with mental disorders.

Cross-Cultural Studies

The International Pilot Study of Schizophrenia revealed some interesting data about how schizophrenia differs across cultures. Among all cultures, paranoid schizophrenia was the most common subtype (40% of persons diagnosed). The content and themes of delusions vary between the background experiences and beliefs of individuals with schizophrenia—religious delusions are more common in Christian societies, while magical religious delusions are more common in rural areas. In Islamic Pakistan, there were lower rates of religious delusions, grandiose delusions, and delusions of guilt, while these were more common in African countries.

Visual hallucinations are more common in African countries and non-European patients. Auditory hallucinations are common everywhere. Negative symptoms are also more common than positive symptoms, though there are differences between countries as to which types of negative symptoms are most distressing. [4]

Watch this video (starting at the 3:35 mark) to learn about various explanations for the etiology of schizophrenia.

You can view the transcript for “Tricky Topics: Causes of Schizophrenia” here (opens in new window) .

• Seeman M.V. (2016) Schizophrenogenic Mother. In: Lebow J., Chambers A., Breunlin D. (eds) Encyclopedia of Couple and Family Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-15877-8_482-1 ↵
• Lincoln, T. M., & Pedersen , A. (2019). An Overview of the Evidence for Psychological Interventions for Psychosis: Results From Meta-Analyses. Clinical Psychology in Europe, 1(1), 1-23. https://doi.org/10.32872/cpe.v1i1.31407 ↵
• Viswanath, B., & Chaturvedi, S. K. (2012). Cultural aspects of major mental disorders: a critical review from an Indian perspective. Indian journal of psychological medicine , 34(4), 306–312. https://doi.org/10.4103/0253-7176.108193 ↵
• Shaman. Authored by : Benjamin Alexander. Located at : https://pixabay.com/photos/shaman-peruvian-coca-leaf-ceremony-431960/ . License : Other . License Terms : Pixabay License
• Schizophrenia Spectrum Disorders. Authored by : Deanna M. Barch . Provided by : Washington University in St. Louis. Located at : https://nobaproject.com/modules/schizophrenia-spectrum-disorders . Project : The Noba Project. License : CC BY-NC-SA: Attribution-NonCommercial-ShareAlike
• Psychosis. Provided by : Wikipedia. Located at : https://en.wikipedia.org/wiki/Psychosis#Treatment . License : CC BY-SA: Attribution-ShareAlike
• An Overview of the Evidence for Psychological Interventions for Psychosis: Results From Meta-Analyses. Authored by : Tania M. Lincoln and Anya Pedersenb. Provided by : Institute of Psychology, Universitu00e4t Hamburg, Hamburg, Germany. Institute of Psychology, Christian-Albrechts-Universitu00e4t, Kiel, Germany. Located at : https://cpe.psychopen.eu/index.php/cpe/article/view/2365/1789 . Project : Clinical Psychology in Europe. License : CC BY-SA: Attribution-ShareAlike

• Search Menu
• Volume 27, Issue 4, April 2024
• Advance articles
• Author Guidelines
• Submission Site
• Open Access
• Why publish with IJNP?
• About the CINP
• Editorial Board
• Advertising and Corporate Services
• Journals Career Network
• Self-Archiving Policy
• Journals on Oxford Academic
• Books on Oxford Academic

Article Contents

Introduction, acknowledgments, making sense of: sensitization in schizophrenia.

Correspondence: Siegfried Kasper, MD, Department of Psychiatry and Psychotherapie, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria ( [email protected] ).

• Article contents
• Figures & tables
• Supplementary Data

Ana Weidenauer, Martin Bauer, Ulrich Sauerzopf, Lucie Bartova, Nicole Praschak-Rieder, Harald H. Sitte, Siegfried Kasper, Matthäus Willeit, Making Sense of: Sensitization in Schizophrenia, International Journal of Neuropsychopharmacology , Volume 20, Issue 1, 1 January 2017, Pages 1–10, https://doi.org/10.1093/ijnp/pyw081

• Permissions Icon Permissions

Sensitization is defined as a process whereby repeated intermittent exposure to a given stimulus results in an enhanced response at subsequent exposures. Next to robust findings of an increased dopamine synthesis capacity in schizophrenia, empirical data and neuroimaging studies support the notion that the mesolimbic dopamine system of patients with schizophrenia is more reactive compared with healthy controls. These studies led to the conceptualization of schizophrenia as a state of endogenous sensitization, as stronger behavioral response and increased dopamine release after amphetamine administration or exposure to stress have been observed in patients with schizophrenia. These findings have also been integrated into the neurodevelopmental model of the disorder, which assumes that vulnerable neuronal circuits undergo progressive changes during puberty and young adulthood that lead to manifest psychosis. Rodent and human studies have made an attempt to identify the exact mechanisms of sensitization of the dopaminergic system and its association with psychosis. Doing so, several epigenetic and molecular alterations associated with dopamine release, neuroplasticity, and cellular energy metabolism have been discovered. Future research aims at targeting these key proteins associated with sensitization in schizophrenia to enhance the knowledge of the pathophysiology of the illness and pave the way for an improved treatment or even prevention of this severe psychiatric disorder.

Sensitization denotes a neuro-behavioral process where repeated exposure to a stimulus leads to a progressive enhancement in the response to this stimulus. The underlying neurobiological processes are essential for reinforcement learning in animals and humans. However, sensitization occurs also with many drugs of abuse. The neurotransmitter dopamine plays a key role in mediating the amplification of neuronal and behavioural responses to environmental stimuli and drugs of abuse. Amphetamines increase the release of dopamine in the brain, a mechanism that is essential for inducing addictive behaviour. However, release of dopamine also induces psychotic symptoms in patients with schizophrenia. Patients with schizophrenia are particularly sensitive to amphetamines even if they have never before consumed the drug. Thus, schizophrenia is believed to be associated with a state of ‘natural sensitization’ towards amphetamines. This review highlights the importance of understanding sensitization for better understanding and treating schizophrenia.

The Concept of Sensitization

Sensitization denotes a nonassociative learning process in which repeated exposure to a stimulus leads to a progressive amplification in the behavioral and neurochemical response. In a pharmacological context, sensitization is defined as an amplified response to a constant dose of a substance after repeated administration. Sensitization has been described for most drugs of abuse associated with addictive behavior, including amphetamines, cocaine, opiates, nicotine, Δ 9 -tetrahydrocannabinol, and alcohol. Sensitization is, so to say, the opposite of the more familiar concept of drug tolerance, the diminishing effect of a drug resulting from repeated administration. Sensitization is thus often referred to as reverse tolerance (see Figure 1 ). In animals, sensitization to cocaine or d-amphetamine typically presents as an increase in locomotor responses or stereotypies ( Robinson and Becker, 1986 ). Humans sensitized with low-dose amphetamine report an increase in alertness, euphoria, or focus after amphetamine administration ( Strakowski et al., 2001 ; Boileau et al., 2006 ).

Sensitization leads to an increase in drug effects. The dose of a drug producing half-maximal response (ED50) decreases with sensitization, so that a lower dose is needed to produce half-maximal drug effects (ED50S). Alternatively, the original ED50 will cause larger effects in the sensitized state. The opposite is found in tolerance, where the efficiency of a drug decreases and a higher dose (ED50T) is now needed to produce half-maximal effects, or where the original ED50 will now induce smaller effects.

A common mechanism of action of substances also serving as drugs of abuse is that they elicit a direct or indirect increase in brain extracellular dopamine levels immediately after drug administration. A release of dopamine is also a central element in the neurochemistry of behavioral learning ( Keiflin and Janak, 2015 ), as dopamine release and specific patterns of activity in dopaminergic neurons are detected during conditioned (or Pavlovian) learning paradigms. In conditioned learning paradigms, a previously neutral environmental cue (the conditioned stimulus) is repeatedly presented in close temporal and spatial proximity to a primary or unconditioned stimulus such as food, sex, or an aversive pain stimulus. An animal’s learning rate in conditioning paradigms can be influenced by manipulating brain dopamine transmission: Higher levels of extracellular dopamine are associated with an increased response to the conditioned stimulus (better “learning”), and lower levels are associated with a decreased conditioned response. The connection between dopamine release induced by drugs of abuse and conditioned (or “cue”) learning is found across species using a broad variety of research methods, and it forms something like the core of the dopamine theory of addiction. As outlined later in this manuscript, there is substantial evidence that sensitization to psychostimulants is associated with a progressive increase in the amount of dopamine released in response to a given dose of the drug. As reflected in the term “drug learning” sometimes used when referring to psychostimulant sensitization, release of brain dopamine is a neurochemical mechanism common to learning and sensitization to psychostimulant drugs.

Amphetamines

Amphetamines constitute a group of chemically related synthetic derivatives of phenethylamine, a so-called trace amine that is naturally produced in catecholaminergic neurons by decarboxylation of the essential amino acid phenylalanine ( Sitte and Freissmuth, 2015 ). Amphetamine itself is a synthetic compound first synthesized in 1887 ( Edeleano, 1887 ) and is not known to occur naturally in any animals or plants. The main somatic effects of amphetamine include an increase in the activity of the sympathetic nervous system leading to mydriasis, bronchodilatation, and increased blood pressure and heart rate. The main psychophysiological effects are an increase in attention and vigilance, slight euphoria, increased drive, and an improvement in psychomotor speed and some cognitive domains related to attention and vigilance. However, amphetamine also increases errors in memory retrieval ( Ballard et al., 2014 ). At higher doses, amphetamine induces stereotypies in animals and psychotic symptoms in humans.

The main sites of action of amphetamines are presynaptic monoamine-transmembrane transporters (the dopamine, norepinephrine, and serotonin reuptake transporters DAT, NET, and SERT) and the vesicular monoamine transporter 2 (VMAT2; Sulzer et al., 2005 ). The main physiological role of monoamine transporters is reuptake of monoamines into the presynaptic neuron immediately after they have been released into the synaptic cleft. Thereby, monoamine transporters regulate temporal and spatial spread of the monoamine signal. In contrast to pure transporter blockers such as cocaine or methylphenidate, amphetamines are also substrates of DAT, NET, and SERT and are thus transported in an ion gradient-dependent way into the neuron ( Sitte and Freissmuth, 2015 ). There, amphetamines lead to neurotransmitter release from storage vesicles into the cytosol. Most importantly, however, amphetamines reverse the transport direction of monoamine transporters ( Sitte and Freissmuth, 2015 ). By binding to the transporter from on the inside of the cell, amphetamines switch monoamine transporters from a reluctant to a willing state to perform outward transport and thus lead to a massive outflow of neurotransmitter into the synapse and surrounding extracellular space ( Robertson et al., 2009 ).

Various amphetamines differ in their respective affinity to the 3 major monoamine transporters and have thus a distinct neuropharmacological profile. d-Amphetamine, the compound used in most animal and human studies, acts primarily at DAT and NET, and administration of d-amphetamine was shown to increase extracellular dopamine levels by several hundred percent over physiologic baseline levels ( Zetterstrom et al., 1983 ; Laruelle et al., 1995 ; Breier et al., 1997 ).

Sensitization in Schizophrenia

Schizophrenia is a disorder with heterogeneous clinical manifestations characterized by a large variety of so-called positive (hallucinations, delusions, thought disorder, and motor symptoms) and negative symptoms (poverty of speech, apathy, social withdrawal). The presence of pronounced positive symptoms is what marks an acute psychotic episode of the illness, and generally, positive symptoms respond better to antipsychotic treatment. Negative symptoms are frequently found also outside of acute psychotic episodes and present a major therapeutic challenge in the treatment of schizophrenia ( APA, 2013 ). The good responsiveness of positive symptoms to antipsychotic dopamine D 2/3 receptor-blocking drugs is one of the reasons why psychosis has been associated with a hyper-dopaminergic state. Several complex genetic and environmental factors (birth in the winter months, urban upbringing, parental age, and others) have been shown to increase the risk for schizophrenia ( Collip et al., 2008 ; van Winkel et al., 2008 ). As of yet it is unknown how these risk factors are related to each other and in which way they increase the illness risk. However, according to current interpretations ( Laruelle, 2000 ; Kapur, 2003 ; Collip et al., 2008 ; van Winkel et al., 2008 ; Howes and Kapur, 2009 ; van Os and Kapur, 2009 ) of the dopamine theory of schizophrenia ( van Rossum, 1966 ), all known risk factors seem to converge in a common final pathway, a hyper-dopaminergic state that causes psychotic symptoms in schizophrenia.

While sensitization is a concept that has substantial face value for explaining many behavioral patterns observed in patients with substance use disorders, its relationship to the phenomenologically diverse schizophrenia syndrome is not as self-evident. However, first descriptions of newly emerging psychotic states related to amphetamine intake date back to the first half of the last century ( Young and Scoville, 1938 ). Since then, a link between amphetamine intake and psychotic symptoms has been described in many studies, some of them using escalating doses of amphetamine for prospective induction of psychotic symptoms in healthy volunteers ( Ellinwood et al., 1973 ). Low doses of amphetamine induce mild euphoria, sometimes an increased sense of purpose, subjects feel awakened and notice an increase in the ability to focus their attention. In a plastic description, N. Richtand ( Richtand 2006 ) notes that with increasing dose and frequency of intake, “symptoms following repetitive stimulant drug use evolve gradually from intense curiosity, progressing to intense exploration of the environment, which may be displayed in repetitive stereotyped searching, sorting, and examining behaviors. This curious ‘suspiciousness’ of the environment later evolves into paranoia and psychotic thought.” Moreover, experimentally administered amphetamine induces hallucination and classical Schneiderian first rank symptoms in healthy subjects ( Janowsky and Risch, 1979 ). In these studies, symptoms usually resolved within hours after discontinuation of stimulant intake. In addition to positive symptoms of schizophrenia, an analysis of subjects suffering from methamphetamine-induced psychosis ( Srisurapanont et al., 2011 ) showed considerable frequency and severity of negative symptoms. In summary, amphetamine is able to induce a reversible clinical picture resembling psychosis in schizophrenia in many aspects. However, to do so, amphetamines need to be consumed repeatedly and at high doses. Although studies specifically designed to measure behavioral and neurochemical effects of sensitization in humans used low amphetamine doses only, there is no reason to assume that neurochemical mechanisms of sensitization to higher stimulant doses differ completely from those to lower doses. In fact, as further discussed below, neurochemical findings in regular abusers of stimulants are in good agreement to what is found in prospectively sensitized animals.

Administering psychostimulants to patients with schizophrenia is one of the most frequently used challenge tests in psychiatric research. A classic 1987 review by Lieberman and colleagues (1987) lists 36 studies on the use of amphetamines or methylphenidate in patients with schizophrenia. Despite considerable heterogeneity of methods and design, the studies show that patients with schizophrenia exhibit greater responsiveness to psychostimulants than healthy subjects or patients with nonpsychotic illness. Generally, patients with full-blown psychosis showed larger changes in psychopathology upon psychostimulant administration, while patients with prominent negative symptoms showed no or little response. As described later in this review, today it is safe to say that hyper-responsiveness to stimulants in schizophrenia is due to an increased amount of dopamine released in response to the drug.

Competition and Blocking Experiments in Schizophrenia

So-called competition, displacement, or blocking paradigms use a decrease in dopamine D 2/3 receptor radioligand binding after administration of a dopamine-releasing agent such as d-amphetamine as a proxy for the amount of dopamine released into the extracellular space ( Laruelle, 2000 ; Ginovart, 2005 ). The effects of amphetamine-induced dopamine release on D 2/3 radioligand binding have also been repeatedly studied in patients with schizophrenia. Using [ 123 I]IBZM and single photon emission tomography, enhanced radioligand displacement in patients with schizophrenia and a positive correlation between displacement and the emergence or worsening of positive psychotic symptoms has been found ( Laruelle et al., 1996 ). A study using [ 11 C]raclopride and positron emission tomography (PET) ( Breier et al., 1997 ) confirmed the finding in patients with schizophrenia and showed a clear relationship between amphetamine-induced displacement and the amount of dopamine released into the extracellular space in a cohort of nonhuman primates undergoing PET and in vivo microdialysis. Further studies confirmed and extended the finding by adding a dopamine-depletion paradigm that also elicited larger changes in radioligand binding in psychotic patients ( Abi-Dargham et al., 1998 ; Abi-Dargham et al., 2009 ).

Presynaptic Dopamine Precursor Uptake and Storage in Schizophrenia

An increase in uptake and storage of the radiolabelled dopamine precursor [ 18 F]FDOPA into the striatum is a robust and well-replicated finding in patients with schizophrenia ( Fusar-Poli and Meyer-Lindenberg, 2013 ). The uptake of [ 18 F]FDOPA shows a positive correlation with the severity of positive symptoms ( Meyer-Lindenberg et al., 2002 ; McGowan et al., 2004 ; Kumakura and Cumming, 2009 ). This, together with evidence from the aforementioned competition studies where positive symptoms correlated with d-amphetamine-induced dopamine release, supports the close relationship between high dopamine levels and psychotic symptoms in schizophrenia. However, to our knowledge, there is no study directly relating increased uptake of [ 18 F]FDOPA to enhanced d-amphetamine-induced dopamine release in sensitization or schizophrenia. A recently described key finding is that increased [ 18 F]FDOPA uptake already occurs in prodromal stages of schizophrenia, where patients show no or almost no psychotic symptoms ( Howes et al., 2009 ). This shows that dopamine overactivity predates the onset of full-blown psychosis and suggests that dopamine is causally involved in the pathogenesis of the illness.

In summary, several studies support a close link between the mechanism of action of psychostimulant drugs and psychotic symptoms in schizophrenia. The behavioral super-sensitivity of patients with schizophrenia towards substances increasing brain extracellular dopamine levels, together with an enhanced d-amphetamine-induced dopamine release suggest that schizophrenia is associated with a state of “natural sensitization” towards dopamine-releasing agents. We will further discuss below how the mechanisms of d-amphetamine sensitization might relate to the enhanced dopamine synthesis and storage capacity shown by [ 18 F]FDOPA PET studies in schizophrenia.

The Neuropharmacology of Sensitization

Findings in humans.

On a neurochemical level, sensitization to amphetamines manifests as lasting hyper-responsiveness of mesencephalic dopaminergic pathways, paralleled by an increase in the amount of extracellular dopamine released from presynaptic terminals to a given dose of d-amphetamine in animals ( Kalivas and Duffy, 1993 ; Wolf et al., 1993 ; Paulson and Robinson, 1995 ; Pierce and Kalivas, 1995 ; Robinson and Badiani, 1998 ; Robinson et al., 1998 ) and humans ( Boileau et al., 2006 ; Booij et al., 2016 ). The literature reports only on a limited number of studies where humans were prospectively sensitized to stimulants ( Strakowski et al., 2001 ; Farre et al., 2004 ; Boileau et al., 2006 , 2016 ; O’Daly et al., 2011 , 2014a , 2014b ). An increase in d-amphetamine-induced reductions in striatal binding of the D 2/3 receptor radioligand [ 11 C]raclopride after repeated administration of a constant dose of d-amphetamine shows a progressive increase in the amount of dopamine released into the extracellular space in the striatum of sensitized individuals ( Boileau et al., 2006 ; Booij et al., 2016 ). This increase is paralleled by an enhancement in behavioral measures, for example the eye-blink rate, ratings of alertness, euphoria or focus, and by enhanced amphetamine-induced plasma cortisol secretion ( Strakowski et al., 2001 ; Farre et al., 2004 ).

Interestingly, dopamine release after a single amphetamine or ethanol administration seems to be greater in males ( Munro et al., 2006 ; Urban et al., 2010 ), while behavioral effects of sensitization in animals have been found to be stronger in females ( Becker et al., 2001 ; Strakowski et al., 2001 ; Cope et al., 2010 ; Chen et al., 2014 ). Sex differences are frequently attributed to the action of gonadal steroid hormones either during an early organizational period or in adulthood ( Gillies et al., 2014 ). Castration of male rats facilitated the behavioral sensitization produced by either repeated amphetamine treatment or repeated restraint stress. In contrast, ovarectomy in female rats was without effect ( Camp and Robinson, 1988 ). Neurochemical effects of sensitization to amphetamines in humans have so far been studied in males only ( Boileau et al., 2006 ). Since schizophrenia, substance use disorders, and many other dopamine-related psychiatric disorders show a robust sexual dimorphism, there is a clear need for studies filling the gaps in our knowledge on the effects of sex on sensitization and its neurochemistry in humans.

Findings in Animals

Sensitization in research animals has been induced using several different protocols of repeated substance administration. The strength of sensitization is influenced by various factors, such as number and interval between treatments, dose, sex, age, and genetics ( Post and Contel, 1983 ). Behavioral sensitization has been reported to occur in response to cocaine, amphetamine, morphine, ethanol, nicotine, and tetrahydrocannabinol ( Joyce and Iversen, 1979 ; Robinson and Becker, 1986 ; Benwell and Balfour, 1992 ; Cunningham and Noble, 1992 ; Post et al., 1992 ; Cadoni et al., 2001 ). An important finding of several studies is the occurrence of cross-sensitization of the behavioral response between drugs. Cross-sensitization has been shown for amphetamine to morphine ( Vezina and Stewart, 1989 ), amphetamine to cocaine ( Santos et al., 2009 ), ethanol to cocaine and vice versa ( Itzhak and Martin, 1999 ), and Δ9-tetrahydrocannabinol to morphine ( Cadoni et al., 2001 ).

Molecular Mechanisms of Sensitization

As of yet, molecular mechanisms of sensitization of the dopamine system are only partially understood. Apparently, sensitization occurs in 2 stages, first by changes in VTA dopamine receptors, followed by a so-called expression phase, in which dopamine release is enhanced in the nucleus accumbens ( Marinelli et al., 2003 ). Among others, a transient subsensitivity of dopamine autoreceptors in the ventral tegmental area has been suggested to play a role in the induction of sensitization ( Wolf et al., 1993 ; Paulson and Robinson, 1995 ; Pierce and Kalivas, 1995 ; Calipari et al., 2015 ), as this change has been associated with increased basal activity of dopamine neurons ( White and Wang, 1984 ; Henry et al., 1989 ). Long-lasting sensitization might also be accompanied by increases in the sensitivity of D 1 dopamine receptors in the nucleus accumbens ( Henry and White, 1991 ). This is supported by findings of blunted locomotor sensitization in D 1 -deficient mice ( El-Ghundi et al., 2010 ) and the prevention of pertussis toxin-induced sensitization by D 1 antagonists ( Narayanan et al., 1996 ). For D 2/3 autoreceptors, animal work points to decreased intracellular signal transmission via intracellular G-proteins after repeated amphetamine transmission ( Sharpe et al., 2015 ) and changes of regulatory proteins of intracellular G-proteins such as Rgs9 (regulator of G-protein signalling) ( Maple et al., 2007 ). These changes may occur already after a single stimulant administration specifically in the ventral tegmental area ( Arora et al., 2011 ; Padgett et al., 2012 ).

Other cellular mechanisms involved in sensitization include altered activation of VMAT2, as a recent publication discovered that argon blocks sensitization by its antagonistic properties at the VMAT2. Chen et al. (2014) on the other hand found an important role of AKT1, a protein directly downstream of dopamine D 2/3 receptors that interacts with beta-arrestin complex, a regulator of dopamine signalling cascades. Interestingly, male AKT1 knockout animals were less sensitive to methamphetamine-induced hyperlocomotion during methamphetamine challenge compared with wild-type controls and AKT1 knockout females ( Chen et al., 2014 ). Another protein, the calmodulin kinase IIα (αCaMKII) is a transporter-interacting protein, which was found to regulate amphetamine-triggered reverse DAT transport. αCaMKII has been associated with development of sensitization, as mice depleted of this kinase showed blunted sensitization effects following repeated amphetamine exposure ( Steinkellner et al., 2014 ). Furthermore, the authors speculate that subtle variations in the relative expression levels of DAT and of αCaMKII may contribute to inter-individual differences in the susceptibility to amphetamine addiction ( Steinkellner et al., 2014 ).

A recent proteomics study ( Wearne et al., 2015 ) examined brain protein expression in rats sensitized to methamphetamine. Expression of proteins previously implicated in the pathophysiology of schizophrenia was significantly altered in the prefrontal cortex of sensitized rats. These proteins are involved in mitochondrial function, cellular architecture, cell signalling, and synaptic plasticity, which, in turn, are tightly related to stress mechanisms on a cellular level. In accordance, cell adhesion molecules assessed peripherally were found to be altered in patients with schizophrenia and correlated with prefrontal grey matter volume ( Piras et al., 2015 ).

The Role of Dopamine D 3 Receptors

Cocaine- or methamphetamine-dependent subjects can safely be assumed to be sensitized to the action of psychostimulant drugs. Studies using the dopamine D 2/3 receptor agonist PET radioligand [ 11 C]-(+)-PHNO ( Wilson et al., 2005 ) in humans addicted to cocaine or methamphetamine have consistently shown an increase in [ 11 C]-(+)-PHNO binding in the substantia nigra/ventral tegmental area ( Boileau et al., 2012 ; Matuskey et al., 2014 ; Payer et al., 2014 ). In these brain regions, the signal measured with [ 11 C]-(+)-PHNO is predominantly due to binding to dopamine D 3 receptors (see Figure 2 ; Graff-Guerrero et al., 2010 ). An increase in dopamine D 3 receptor expression is also found in postmortem studies of cocaine addicted subjects ( Staley and Mash, 1996 ; Segal et al., 1997 ). In view of these findings, dopamine D 3 receptor antagonists have been proposed as a possible treatment for stimulant addiction. This notion is supported by rodent studies administering D 3 -preferring agonists, such as pramipexole, which enhanced opioid-conditioned reinforcement ( Bertz et al., 2015 ). Vice versa, D 3 -preferring antagonists inhibited related rewarding effects of cocaine- and drug-seeking behavior ( Xi et al., 2006 ; Song et al., 2012 ; John et al., 2015 ; Galaj et al., 2016 ).

Adjacent transversal slices of a positron-emission tomography image using the dopamine D 2/3 receptor agonist radioligand [ 11 C]-(+)-PHNO. Bright areas show binding to dopamine D 2/3 receptors in the human striatum and brainstem substantia nigra/ventral tegmental area.

Still, this concept is somewhat at odds with a solid body of evidence showing that an increase in dopamine D 3 receptor signalling in the ventral tegmental area actually acts as a brake on dopamine release in the striatum and reduces psychostimulant-induced behaviors in rodents ( Damsma et al., 1993 ; Ahlenius and Salmi, 1994 ; Pugsley et al., 1995 ; Caine et al., 1997 ; Richtand et al., 2001 ). A pilot study on the administration of the D 3 -preferring agonist pramipexole to patients with schizophrenia ( Kasper et al., 1997 ) showed beneficial effects against negative and positive symptoms. Since positive symptoms in schizophrenia correlate directly with amphetamine-induced dopamine release in the striatum of patients with schizophrenia, D 3 agonism, although not directly shown in this or other studies so far, may have reduced striatal dopamine release in this collective.

There are various possible reasons for the discrepant findings. One is that most D 2 or D 3 receptor-preferring compounds are not entirely selective for either subtype. Therefore, it is hard to distinguish via which receptor behavioral or neurochemical effects are exerted, especially when opposing roles are suggested ( Ellinwood et al., 2000 ). Another aspect is that D 3 -preferring compounds may act in a species-dependent way, and that their action may depend on the administration paradigm (cocaine self-administration vs conditioning/reinforcement) ( Keck et al., 2015 ). Furthermore, studies suggest that individual D 3 availability and the resulting occupancy or alternative D 3 gene splicing might lead to differential effects when D 3 ligands bind ( Richtand, 2006 ; Mugnaini et al., 2013 ; Kim et al., 2014 ; John et al., 2015 ). Interestingly, brain-derived neurotrophic factor might influence the expression of D 3 receptors and seems to be necessary for behavioral sensitization and co-occurring D 3 overexpression ( Guillin et al., 2001 ).

Although it would be intuitive to state that sensitization leads to increased D 3 receptor expression and therefore that D 3 should be antagonized in order to prevent sensitization, increased expression of D 3 in its role as a regulator of DA release might be a compensatory mechanism in the development of sensitization, which, however, fails to fulfil its purpose.

In summary, the differential impact of dopamine D 2 autoreceptors and D 3 receptors in the substantia nigra/ventral tegmental area on induction and expression of sensitization appears insufficiently understood as of yet. An intriguing concept though is that sensitization to amphetamine, together with an increase in amphetamine-induced dopamine release into the striatum, are a consequence of tolerance in inhibitory systems induced by repeated exposure of brainstem dopamine receptors to high levels of dopamine itself ( Richtand, 2006 ).

Stress, Sensitization, and Neurodevelopment

Several studies on the relationship between stress and psychostimulants in rodents were able to show cross-sensitization between repeated stress and repeated exposure to amphetamine ( Antelman et al., 1980 ; Kalivas et al., 1986 ; Hamamura and Fibiger, 1993 ; Febo and Pira, 2011 ; Booij et al., 2016 ). It is known that stress preferentially stimulates dopamine release in mesolimbic projection ( Horger and Roth, 1996 ) and frontal areas ( Lataster et al., 2011 ) and that glucocorticoids modulate the sensitivity of mesencephalic dopaminergic neurons to drugs of abuse ( Sorg and Kalivas, 1991 ; Deroche et al., 1995 ). In good agreement with animal studies, it was shown that exposure to stress is able to induce recurrence of psychotic symptoms in remitted patients with methamphetamine-induced psychosis ( Yui et al., 2002 ). Patients with schizophrenia exhibit distinct alterations in the hypothalamic-pituitary-adrenal axis ( Borges et al., 2013 ), and an increase in dopamine release and behavioral reactivity in response to stress has been observed in healthy subjects sensitized to amphetamine, in patients with schizophrenia ( Mizrahi et al., 2012 ; Lataster et al., 2013 ), and in subjects at high risk for psychosis ( Soliman et al., 2008 ; Mizrahi et al., 2014 ).

Lieberman and colleagues (1997) have proposed a framework extending the classical stress vulnerability model of psychosis to integrate the neurodevelopmental model of schizophrenia with findings linking stress to altered dopamine signalling: in early development, neuronal circuits are being formed which then experience neuroplastic changes during early adolescence ( Feinberg, 1982 ; Keshavan et al., 1994 ). There, stress-related activity of mesolimbic dopamine neurons sets the vulnerability for sensitization. Sensitization finally leads to excessive dopamine release and progressive development of psychosis ( Laruelle, 2000 ; Seeman 2011 ). Importantly, the view of schizophrenia as a degenerative disease has been substituted by the view of a disorder in which deficits in regenerative capacity are present ( Falkai et al., 2015 ). These deficits may include the previously mentioned alterations of cell architecture and metabolism, higher oxidative stress, and the consequent changes of synaptic formations ( Flatow et al., 2013 ; Wearne et al., 2015 ). In addition, as the prefrontal cortex is hypothesized to act as a brake on striatal dopamine release ( Carlsson et al., 2001 ), a dysregulation of inhibitory feedback mechanisms involved in the regulation of ventral tegmental neuronal activity may result in a pathological potentiation of impulse-dependent phasic dopamine release. The association of frontal cortical thickness with amphetamine-induced dopamine release corroborates this notion ( Casey et al., 2013 ). As of yet, the question is unresolved whether it is increased striatal dopamine transmission to cause altered activation of cortical networks (bottom-up) or whether insufficient frontal-cortical control of striatal neurons is leading to alterations in presynaptic dopamine release in psychosis (top-down).

Sensitization in Cells

In an in vitro examination, rat pheochromocytoma cells (PC-12), which are capable of dopamine release upon pharmacological stimulation but possess no dopamine receptors, were sensitized successfully by intermittent treatment with amphetamine for 5 consecutive days followed by a >6-day, drug-free interval. Sensitization of PC12 cells was marked by significantly increased dopamine release upon amphetamine stimulation in sensitized when compared with nonsensitized cells. This was not accompanied by increase in [H 3 ]-dopamine uptake ( Kantor et al., 2002 ). Intermittent amphetamine treatment also led to increased neurite outgrowth in PC-12 cells after an interval of more than 3 drug-free days ( Park et al., 2002 ). Increased dopamine release and neurite outgrowth were dependent on protein kinase C and MAP kinase in vitro ( Park et al., 2003 ). The fact that it is possible to sensitize cells to amphetamine holds the promise that it may be possible to identify drug targets enabling to target alterations in dopamine release already in presynaptic neurons.

What Can We Learn for Schizophrenia Research?

The observation of alterations in the dopaminergic system has led to the question how this effect might be related to clinical symptoms of schizophrenia. Notably, the dopaminergic changes are dependent on the illness phase ( Laruelle et al., 1999 ), and the correlation of radioligand uptake and positive symptom severity ( Meyer-Lindenberg et al., 2002 ; McGowan et al., 2004 ; Kumakura et al., 2007 ) suggests that the method does indeed capture a biologically meaningful signal closely connected to the pathogenesis of schizophrenia. There seems to be a differential effect of amphetamine on positive and negative symptoms of schizophrenia: positive symptoms and thought disorder intensify temporarily, while negative symptoms tend to improve. This suggests that, although positive and negative symptoms are likely to differ in their pathogenesis, dopamine plays a major role in both symptom groups. Patients in remission show comparably small responses to amphetamine ( Lieberman et al., 1987 ), and amphetamine-induced dopamine release is larger during the acute phase of the illness ( Laruelle, 2000 ). Although some authors consider the processes predisposing to psychosis in schizophrenia to be irreversible, especially those hypothesized to have a neurodevelopemental origin, and although the disorder has a progressive course in a considerable proportion of the patients, findings from imaging studies suggest that at least part of the dopamine-related pathogenetic alterations are reversible. In this context, antipsychotic medication has been proposed to contribute to the reversibility of sensitization by D 2/3 blockade, although the exact mechanism is yet unknown. On the other hand, some observations suggest that chronic blockade of dopamine D 2/3 receptors rather induces supersensitivity of postsynaptic receptor systems, leading to increased vulnerability for relapse once antipsychotic medication is discontinued. However, the possibly life-long persistence of a predisposition of the dopamine system to sensitize supports the necessity of long-term proactive measures to prevent psychosis in many patients.

In sum, an increase in amphetamine-induced dopamine release is common to amphetamine-induced sensitization in animals and humans, and the natural sensitization of the dopamine system observed in patients with schizophrenia is associated with increased amphetamine-induced dopamine release as well. The exact mechanisms and the association with increased dopamine synthesis observed in schizophrenia and preceding phases of the illness have yet to be elucidated, and amphetamine-induced sensitization might provide a suitable model for this purpose. Nevertheless, sensitization of the dopamine system is probably only one small part of the bigger picture of neurobiological changes occurring in schizophrenia. Different molecular changes are under intense investigation and might shed light on the development of sensitization in schizophrenia. Antipsychotics might reverse sensitization and restore the flow of information from frontal areas to cortico-striatal-thalamo-cortical loops, thereby leading to symptom relief. As of yet, schizophrenia is a disorder often associated with nonresponse or partial response to treatment, leading to high disability. Sensitization to amphetamine is a narrowly defined pharmaco-behavioral construct. Its neurochemical signature can be readily studied in humans and animals. One day, translational research on amphetamine-sensitization will hopefully help to identify new molecular drug targets allowing for improved therapeutic strategies in schizophrenia.

Increased response after repeated exposure to a stable dose of a substance

Cross-sensitization with stress described for most sensitizing substances

Close relationship to dopamine-mediated learning (e.g. conditioned learning)

Increased release of dopamine in response to a stable dose of amphetamine, cocaine, opiates, or methylphenidate

Increased release of dopamine in sensitized animals and humans

Behavioral sensitization towards amphetamines and methylphenidate in schizophrenia

Sensitization is believed to underlie habit-formation in addiction

Blunted dopamine release in substance use disorders

Increased presynaptic release of dopamine

Increased quantal size

Increase in markers of dopamine synthesis

Increase in postsynaptic dopamine-D 2/3 function

Sub-sensitivity of inhibitory auto-receptors

Altered dopamine D 3 receptor binding and function

This work was supported in part by funds of the Austrian Science Fund P23585B09, the Oesterreichische Nationalbank (Oesterreichische Nationalbank, Anniversary Fund OENB16723), and the Vienna Science and Technology Fund CS15-033.

Abi-Dargham A Gil R Krystal J Baldwin RM Seibyl JP Bowers M van Dyck CH Charney DS Innis RB Laruelle M ( 1998 ) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort . The American journal of psychiatry 155 : 761 – 767 .

Google Scholar

Abi-Dargham A van de Giessen E Slifstein M Kegeles LS Laruelle M ( 2009 ) Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects . Biological psychiatry 65 : 1091 – 1093 .

Ahlenius S Salmi P ( 1994 ) Behavioral and biochemical effects of the dopamine D3 receptor-selective ligand, 7-OH-DPAT, in the normal and the reserpine-treated rat . Eur J Pharmacol 260 : 177 – 181 .

Antelman SM Eichler AJ Black CA Kocan D ( 1980 ) Interchangeability of stress and amphetamine in sensitization . Science 207 : 329 – 331 .

APA ( 2013 ) Diagnostic and statistical manual of mental disorders: DSM-5 , Fifth Edition Edition: American Psychiatric Association .

Google Preview

Arora D Hearing M Haluk DM Mirkovic K Fajardo-Serrano A Wessendorf MW Watanabe M Lujan R Wickman K ( 2011 ) Acute cocaine exposure weakens GABA(B) receptor-dependent G-protein-gated inwardly rectifying K+ signaling in dopamine neurons of the ventral tegmental area . The Journal of neuroscience: the official journal of the Society for Neuroscience 31 : 12251 – 12257 .

Ballard ME Gallo DA de Wit H ( 2014 ) Amphetamine increases errors during episodic memory retrieval . J Clin Psychopharmacol 34 : 85 – 92 .

Becker JB Molenda H Hummer DL ( 2001 ) Gender differences in the behavioral responses to cocaine and amphetamine. Implications for mechanisms mediating gender differences in drug abuse . Annals of the New York Academy of Sciences 937 : 172 – 187 .

Benwell ME Balfour DJ ( 1992 ) The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity . Br J Pharmacol 105 : 849 – 856 .

Bertz JW Chen J Woods JH ( 2015 ) Effects of pramipexole on the acquisition of responding with opioid-conditioned reinforcement in the rat . Psychopharmacology (Berl) 232 : 209 – 221 .

Boileau I Dagher A Leyton M Gunn RN Baker GB Diksic M Benkelfat C ( 2006 ) Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men . Archives of general psychiatry 63 : 1386 – 1395 .

Boileau I Payer D Houle S Behzadi A Rusjan PM Tong J Wilkins D Selby P George TP Zack M Furukawa Y McCluskey T Wilson AA Kish SJ ( 2012 ) Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study . The Journal of neuroscience: the official journal of the Society for Neuroscience 32 : 1353 – 1359 .

Booij L Welfeld K Leyton M Dagher A Boileau I Sibon I Baker GB Diksic M Soucy JP Pruessner JC Cawley-Fiset E Casey KF Benkelfat C ( 2016 ) Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers . Transl Psychiatry 6 : e740 .

Borges S Gayer-Anderson C Mondelli V ( 2013 ) A systematic review of the activity of the hypothalamic-pituitary-adrenal axis in first episode psychosis . Psychoneuroendocrinology 38 : 603 – 611 .

Breier A Su TP Saunders R Carson RE Kolachana BS de Bartolomeis A Weinberger DR Weisenfeld N Malhotra AK Eckelman WC Pickar D ( 1997 ) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method . Proceedings of the National Academy of Sciences of the United States of America 94 : 2569 – 2574 .

Cadoni C Pisanu A Solinas M Acquas E Di Chiara G ( 2001 ) Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine . Psychopharmacology (Berl) 158 : 259 – 266 .

Caine SB Koob GF Parsons LH Everitt BJ Schwartz JC Sokoloff P ( 1997 ) D3 receptor test in vitro predicts decreased cocaine self-administration in rats . Neuroreport 8 : 2373 – 2377 .

Calipari ES Siciliano CA Zimmer BA Jones SR ( 2015 ) Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 40 : 728 – 735 .

Camp DM Robinson TE ( 1988 ) Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic D-amphetamine treatment on locomotion, stereotyped behavior and brain monoamines . Behav Brain Res 30 : 55 – 68 .

Carlsson A Waters N Holm-Waters S Tedroff J Nilsson M Carlsson ML ( 2001 ) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence . Annual review of pharmacology and toxicology 41 : 237 – 260 .

Casey KF Cherkasova MV Larcher K Evans AC Baker GB Dagher A Benkelfat C Leyton M ( 2013 ) Individual differences in frontal cortical thickness correlate with the d-amphetamine-induced striatal dopamine response in humans . The Journal of neuroscience: the official journal of the Society for Neuroscience 33 : 15285 – 15294 .

Chen YW Kao HY Min MY Lai WS ( 2014 ) A sex- and region-specific role of Akt1 in the modulation of methamphetamine-induced hyperlocomotion and striatal neuronal activity: implications in schizophrenia and methamphetamine-induced psychosis . Schizophr Bull 40 : 388 – 398 .

Collip D Myin-Germeys I Van Os J ( 2008 ) Does the concept of “sensitization” provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr Bull 34 : 220 – 225 .

Cope ZA Huggins KN Sheppard AB Noel DM Roane DS Brown RW ( 2010 ) Neonatal quinpirole treatment enhances locomotor activation and dopamine release in the nucleus accumbens core in response to amphetamine treatment in adulthood . Synapse 64 : 289 – 300 .

Cunningham CL Noble D ( 1992 ) Conditioned activation induced by ethanol: role in sensitization and conditioned place preference . Pharmacol Biochem Behav 43 : 307 – 313 .

Damsma G Bottema T Westerink BH Tepper PG Dijkstra D Pugsley TA MacKenzie RG Heffner TG Wikstrom H ( 1993 ) Pharmacological aspects of R-(+)-7-OH-DPAT, a putative dopamine D3 receptor ligand . Eur J Pharmacol 249 : R9 – 10 .

Deroche V Marinelli M Maccari S Le Moal M Simon H Piazza PV ( 1995 ) Stress-induced sensitization and glucocorticoids. I. Sensitization of dopamine-dependent locomotor effects of amphetamine and morphine depends on stress-induced corticosterone secretion . The Journal of neuroscience: the official journal of the Society for Neuroscience 15 : 7181 – 7188 .

Edeleano L ( 1887 ) Über einige Derivate der Phenylmethacrylsäure und der Phenylisobuttersäure .

El-Ghundi MB Fan T Karasinska JM Yeung J Zhou M O’Dowd BF George SR ( 2010 ) Restoration of amphetamine-induced locomotor sensitization in dopamine D1 receptor-deficient mice . Psychopharmacology (Berl) 207 : 599 – 618 .

Ellinwood EH Jr Sudilovsky A Nelson LM ( 1973 ) Evolving behavior in the clinical and experimental amphetamine (model) psychosis . The American journal of psychiatry 130 : 1088 – 1093 .

Ellinwood EH King GR Davidson C Lee TH ( 2000 ) The dopamine D2/D3 antagonist DS121 potentiates the effect of cocaine on locomotion and reduces tolerance in cocaine tolerant rats . Behav Brain Res 116 : 169 – 175 .

Falkai P Rossner MJ Schulze TG Hasan A Brzozka MM Malchow B Honer WG Schmitt A ( 2015 ) Kraepelin revisited: schizophrenia from degeneration to failed regeneration . Mol Psychiatry 20 : 671 – 676 .

Farre M de la Torre R Mathuna BO Roset PN Peiro AM Torrens M Ortuno J Pujadas M Cami J ( 2004 ) Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics . Psychopharmacology (Berl) 173 : 364 – 375 .

Febo M Pira AS ( 2011 ) Increased BOLD activation to predator stressor in subiculum and midbrain of amphetamine-sensitized maternal rats . Brain research 1382 : 118 – 127 .

Feinberg I ( 1982 ) Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 17 : 319 – 334 .

Flatow J Buckley P Miller BJ ( 2013 ) Meta-analysis of oxidative stress in schizophrenia . Biological psychiatry 74 : 400 – 409 .

Fusar-Poli P Meyer-Lindenberg A ( 2013 ) Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies . Schizophr Bull 39 : 33 – 42 .

Galaj E Haynes J Nisanov R Ananthan S Ranaldi R ( 2016 ) The dopamine D3 receptor antagonist, SR 21502, facilitates extinction of cocaine conditioned place preference . Drug Alcohol Depend 159 : 263 – 266 .

Gillies GE Virdee K McArthur S Dalley JW ( 2014 ) Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: a molecular, cellular and behavioral analysis . Neuroscience 282C : 69 – 85 .

Ginovart N ( 2005 ) Imaging the dopamine system with in vivo [11c]raclopride displacement studies: understanding the true mechanism . Mol Imaging Biol 7 : 45 – 52 .

Graff-Guerrero A Redden L Abi-Saab W Katz DA Houle S Barsoum P Bhathena A Palaparthy R Saltarelli MD Kapur S ( 2010 ) Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925 . Int J Neuropsychopharmacol 13 : 273 – 287 .

Guillin O Diaz J Carroll P Griffon N Schwartz JC Sokoloff P ( 2001 ) BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization . Nature 411 : 86 – 89 .

Hamamura T Fibiger HC ( 1993 ) Enhanced stress-induced dopamine release in the prefrontal cortex of amphetamine-sensitized rats . Eur J Pharmacol 237 : 65 – 71 .

Henry DJ Greene MA White FJ ( 1989 ) Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration . J Pharmacol Exp Ther 251 : 833 – 839 .

Henry DJ White FJ ( 1991 ) Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens . J Pharmacol Exp Ther 258 : 882 – 890 .

Horger BA Roth RH ( 1996 ) The role of mesoprefrontal dopamine neurons in stress . Crit Rev Neurobiol 10 : 395 – 418 .

Howes OD Kapur S ( 2009 ) The dopamine hypothesis of schizophrenia: version III--the final common pathway . Schizophr Bull 35 : 549 – 562 .

Howes OD Montgomery AJ Asselin MC Murray RM Valli I Tabraham P Bramon-Bosch E Valmaggia L Johns L Broome M McGuire PK Grasby PM ( 2009 ) Elevated striatal dopamine function linked to prodromal signs of schizophrenia . Archives of general psychiatry 66 : 13 – 20 .

Itzhak Y Martin JL ( 1999 ) Effects of cocaine, nicotine, dizocipline and alcohol on mice locomotor activity: cocaine-alcohol cross-sensitization involves upregulation of striatal dopamine transporter binding sites . Brain research 818 : 204 – 211 .

Janowsky DS Risch C ( 1979 ) Amphetamine psychosis and psychotic symptoms . Psychopharmacology (Berl) 65 : 73 – 77 .

John WS Newman AH Nader MA ( 2015 ) Differential effects of the dopamine D3 receptor antagonist PG01037 on cocaine and methamphetamine self-administration in rhesus monkeys . Neuropharmacology 92 : 34 – 43 .

Joyce EM Iversen SD ( 1979 ) The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat . Neurosci Lett 14 : 207 – 212 .

Kalivas PW Duffy P ( 1993 ) Time course of extracellular dopamine and behavioral sensitization to cocaine. II. Dopamine perikarya . The Journal of neuroscience: the official journal of the Society for Neuroscience 13 : 276 – 284 .

Kalivas PW Richardson-Carlson R Van Orden G ( 1986 ) Cross-sensitization between foot shock stress and enkephalin-induced motor activity . Biological psychiatry 21 : 939 – 950 .

Kantor L Park YH Wang KK Gnegy M ( 2002 ) Enhanced amphetamine-mediated dopamine release develops in PC12 cells after repeated amphetamine treatment . Eur J Pharmacol 451 : 27 – 35 .

Kapur S ( 2003 ) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia . The American journal of psychiatry 160 : 13 – 23 .

Kasper S Barnas C Heiden A Volz HP Laakmann G Zeit H Pfolz H ( 1997 ) Pramipexole as adjunct to haloperidol in schizophrenia. Safety and efficacy . Eur Neuropsychopharmacol 7 : 65 – 70 .

Keck TM John WS Czoty PW Nader MA Newman AH ( 2015 ) Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis . Journal of medicinal chemistry 58 : 5361 – 5380 .

Keiflin R Janak PH ( 2015 ) Dopamine Prediction Errors in Reward Learning and Addiction: From Theory to Neural Circuitry . Neuron 88 : 247 – 263 .

Keshavan MS Anderson S Pettegrew JW ( 1994 ) Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited . J Psychiatr Res 28 : 239 – 265 .

Kim SW Fowler JS Skolnick P Muench L Kang Y Shea C Logan J Kim D Carter P King P Alexoff D Volkow ND ( 2014 ) Therapeutic doses of buspirone block D3 receptors in the living primate brain . Int J Neuropsychopharmacol 17 : 1257 – 1267 .

Kumakura Y Cumming P ( 2009 ) PET studies of cerebral levodopa metabolism: a review of clinical findings and modeling approaches . Neuroscientist 15 : 635 – 650 .

Kumakura Y Cumming P Vernaleken I Buchholz HG Siessmeier T Heinz A Kienast T Bartenstein P Grunder G ( 2007 ) Elevated [18F]fluorodopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study . The Journal of neuroscience: the official journal of the Society for Neuroscience 27 : 8080 – 8087 .

Laruelle M ( 2000 ) The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies . Brain research Brain research reviews 31 : 371 – 384 .

Laruelle M Abi-Dargham A Gil R Kegeles L Innis R ( 1999 ) Increased dopamine transmission in schizophrenia: relationship to illness phases . Biological psychiatry 46 : 56 – 72 .

Laruelle M Abi-Dargham A van Dyck CH Gil R D’Souza CD Erdos J McCance E Rosenblatt W Fingado C Zoghbi SS Baldwin RM Seibyl JP Krystal JH Charney DS Innis RB ( 1996 ) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects . Proceedings of the National Academy of Sciences of the United States of America 93 : 9235 – 9240 .

Laruelle M Abi-Dargham A van Dyck CH Rosenblatt W Zea-Ponce Y Zoghbi SS Baldwin RM Charney DS Hoffer PB Kung HF et al.  . ( 1995 ) SPECT imaging of striatal dopamine release after amphetamine challenge . Journal of nuclear medicine: official publication, Society of Nuclear Medicine 36 : 1182 – 1190 .

Lataster J Collip D Ceccarini J Haas D Booij L van Os J Pruessner J Van Laere K Myin-Germeys I ( 2011 ) Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: a positron emission tomography study using [(1)(8)F]fallypride . Neuroimage 58 : 1081 – 1089 .

Lataster T Valmaggia L Lardinois M van Os J Myin-Germeys I ( 2013 ) Increased stress reactivity: a mechanism specifically associated with the positive symptoms of psychotic disorder . Psychol Med 43 : 1389 – 1400 .

Lieberman JA Kane JM Alvir J ( 1987 ) Provocative tests with psychostimulant drugs in schizophrenia . Psychopharmacology (Berl) 91 : 415 – 433 .

Lieberman JA Sheitman BB Kinon BJ ( 1997 ) Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 17 : 205 – 229 .

Maple AM Perna MK Parlaman JP Stanwood GD Brown RW ( 2007 ) Ontogenetic quinpirole treatment produces long-lasting decreases in the expression of Rgs9, but increases Rgs17 in the striatum, nucleus accumbens and frontal cortex . Eur J Neurosci 26 : 2532 – 2538 .

Marinelli M Cooper DC Baker LK White FJ ( 2003 ) Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior . Psychopharmacology (Berl) 168 : 84 – 98 .

Matuskey D Gallezot JD Pittman B Williams W Wanyiri J Gaiser E Lee DE Hannestad J Lim K Zheng MQ Lin SF Labaree D Potenza MN Carson RE Malison RT Ding YS ( 2014 ) Dopamine D(3) receptor alterations in cocaine-dependent humans imaged with [(1)(1)C](+)PHNO . Drug Alcohol Depend 139 : 100 – 105 .

McGowan S Lawrence AD Sales T Quested D Grasby P ( 2004 ) Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study . Archives of general psychiatry 61 : 134 – 142 .

Meyer-Lindenberg A Miletich RS Kohn PD Esposito G Carson RE Quarantelli M Weinberger DR Berman KF ( 2002 ) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia . Nature neuroscience 5 : 267 – 271 .

Mizrahi R Addington J Rusjan PM Suridjan I Ng A Boileau I Pruessner JC Remington G Houle S Wilson AA ( 2012 ) Increased stress-induced dopamine release in psychosis . Biological psychiatry 71 : 561 – 567 .

Mizrahi R Kenk M Suridjan I Boileau I George TP McKenzie K Wilson AA Houle S Rusjan P ( 2014 ) Stress-induced dopamine response in subjects at clinical high risk for schizophrenia with and without concurrent cannabis use . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 39 : 1479 – 1489 .

Mugnaini M Iavarone L Cavallini P Griffante C Oliosi B Savoia C Beaver J Rabiner EA Micheli F Heidbreder C Andorn A Merlo Pich E Bani M ( 2013 ) Occupancy of brain dopamine D3 receptors and drug craving: a translational approach . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 38 : 302 – 312 .

Munro CA McCaul ME Wong DF Oswald LM Zhou Y Brasic J Kuwabara H Kumar A Alexander M Ye W Wand GS ( 2006 ) Sex differences in striatal dopamine release in healthy adults . Biological psychiatry 59 : 966 – 974 .

Narayanan S Wallace L Uretsky N ( 1996 ) Spontaneous and drug-stimulated locomotor activity after the administration of pertussis toxin into the ventral tegmental area . J Psychiatry Neurosci 21 : 172 – 180 .

O’Daly OG Joyce D Stephan KE Murray RM Shergill SS ( 2011 ) Functional magnetic resonance imaging investigation of the amphetamine sensitization model of schizophrenia in healthy male volunteers . Archives of general psychiatry 68 : 545 – 554 .

O’Daly OG Joyce D Tracy DK Stephan KE Murray RM Shergill S ( 2014 a) Amphetamine sensitisation and memory in healthy human volunteers: a functional magnetic resonance imaging study . J Psychopharmacol 28 : 857 – 865 .

O’Daly OG Joyce D Tracy DK Azim A Stephan KE Murray RM Shergill SS ( 2014 b) Amphetamine sensitization alters reward processing in the human striatum and amygdala . PloS one 9 : e93955 .

Padgett CL Lalive AL Tan KR Terunuma M Munoz MB Pangalos MN Martinez-Hernandez J Watanabe M Moss SJ Lujan R Luscher C Slesinger PA ( 2012 ) Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA . Neuron 73 : 978 – 989 .

Park YH Kantor L Wang KK Gnegy ME ( 2002 ) Repeated, intermittent treatment with amphetamine induces neurite outgrowth in rat pheochromocytoma cells (PC12 cells) . Brain research 951 : 43 – 52 .

Park YH Kantor L Guptaroy B Zhang M Wang KK Gnegy ME ( 2003 ) Repeated amphetamine treatment induces neurite outgrowth and enhanced amphetamine-stimulated dopamine release in rat pheochromocytoma cells (PC12 cells) via a protein kinase C- and mitogen activated protein kinase-dependent mechanism . J Neurochem 87 : 1546 – 1557 .

Paulson PE Robinson TE ( 1995 ) Amphetamine-induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: a microdialysis study in behaving rats . Synapse 19 : 56 – 65 .

Payer DE Behzadi A Kish SJ Houle S Wilson AA Rusjan PM Tong J Selby P George TP McCluskey T Boileau I ( 2014 ) Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 39 : 311 – 318 .

Pierce RC Kalivas PW ( 1995 ) Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine . J Pharmacol Exp Ther 275 : 1019 – 1029 .

Piras F Schiff M Chiapponi C Bossu P Muhlenhoff M Caltagirone C Gerardy-Schahn R Hildebrandt H Spalletta G ( 2015 ) Brain structure, cognition and negative symptoms in schizophrenia are associated with serum levels of polysialic acid-modified NCAM . Transl Psychiatry 5 : e658 .

Post R Contel N ( 1983 ) Human and animal studies of cocaine: Implications for development of behavioral pathology . In: Stimulants: Neurochemical, Behavioral and Clinical Perspectives . ( I C , ed), pp 169 – 203 . New York : Raven Press ;.

Post RM Weiss SR Fontana D Pert A ( 1992 ) Conditioned sensitization to the psychomotor stimulant cocaine . Annals of the New York Academy of Sciences 654 : 386 – 399 .

Pugsley TA Davis MD Akunne HC MacKenzie RG Shih YH Damsma G Wikstrom H Whetzel SZ Georgic LM Cooke LW et al.  . ( 1995 ) Neurochemical and functional characterization of the preferentially selective dopamine D3 agonist PD 128907 . J Pharmacol Exp Ther 275 : 1355 – 1366 .

Richtand NM ( 2006 ) Behavioral sensitization, alternative splicing, and d3 dopamine receptor-mediated inhibitory function . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 31 : 2368 – 2375 .

Richtand NM Woods SC Berger SP Strakowski SM ( 2001 ) D3 dopamine receptor, behavioral sensitization, and psychosis . Neurosci Biobehav Rev 25 : 427 – 443 .

Robertson SD Matthies HJ Galli A ( 2009 ) A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters . Mol Neurobiol 39 : 73 – 80 .

Robinson TE Badiani A ( 1998 ) Drug-induced adaptations in catecholamine systems: on the inevitability of sensitization . Adv Pharmacol 42 : 987 – 990 .

Robinson TE Becker JB ( 1986 ) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis . Brain research 396 : 157 – 198 .

Robinson TE Browman KE Crombag HS Badiani A ( 1998 ) Modulation of the induction or expression of psychostimulant sensitization by the circumstances surrounding drug administration . Neurosci Biobehav Rev 22 : 347 – 354 .

Santos GC Marin MT Cruz FC Delucia R Planeta CS ( 2009 ) Amphetamine- and nicotine-induced cross-sensitization in adolescent rats persists until adulthood . Addict Biol 14 : 270 – 275 .

Seeman P ( 2011 ) All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors . CNS neuroscience & therapeutics 17 : 118 – 132 .

Segal DM Moraes CT Mash DC ( 1997 ) Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities . Brain Res Mol Brain Res 45 : 335 – 339 .

Sharpe AL Varela E Bettinger L Beckstead MJ ( 2015 ) Methamphetamine self-administration in mice decreases GIRK channel-mediated currents in midbrain dopamine neurons . Int J Neuropsychopharmacol 18 .

Sitte HH Freissmuth M ( 2015 ) Amphetamines, new psychoactive drugs and the monoamine transporter cycle . Trends Pharmacol Sci 36 : 41 – 50 .

Soliman A O’Driscoll GA Pruessner J Holahan AL Boileau I Gagnon D Dagher A ( 2008 ) Stress-induced dopamine release in humans at risk of psychosis: a [11C]raclopride PET study . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 33 : 2033 – 2041 .

Song R Yang RF Wu N Su RB Li J Peng XQ Li X Gaal J Xi ZX Gardner EL ( 2012 ) YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice . Addict Biol 17 : 259 – 273 .

Sorg BA Kalivas PW ( 1991 ) Effects of cocaine and footshock stress on extracellular dopamine levels in the ventral striatum . Brain research 559 : 29 – 36 .

Srisurapanont M Arunpongpaisal S Wada K Marsden J Ali R Kongsakon R ( 2011 ) Comparisons of methamphetamine psychotic and schizophrenic symptoms: a differential item functioning analysis . Prog Neuropsychopharmacol Biol Psychiatry 35 : 959 – 964 .

Staley JK Mash DC ( 1996 ) Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities . The Journal of neuroscience: the official journal of the Society for Neuroscience 16 : 6100 – 6106 .

Steinkellner T Mus L Eisenrauch B Constantinescu A Leo D Konrad L Rickhag M Sorensen G Efimova EV Kong E Willeit M Sotnikova TD Kudlacek O Gether U Freissmuth M Pollak DD Gainetdinov RR Sitte HH ( 2014 ) In vivo amphetamine action is contingent on alphaCaMKII . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 39 : 2681 – 2693 .

Strakowski SM Sax KW Rosenberg HL DelBello MP Adler CM ( 2001 ) Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 25 : 548 – 554 .

Sulzer D Sonders MS Poulsen NW Galli A ( 2005 ) Mechanisms of neurotransmitter release by amphetamines: a review . Prog Neurobiol 75 : 406 – 433 .

Urban NB Kegeles LS Slifstein M Xu X Martinez D Sakr E Castillo F Moadel T O’Malley SS Krystal JH Abi-Dargham A ( 2010 ) Sex differences in striatal dopamine release in young adults after oral alcohol challenge: a positron emission tomography imaging study with [(1)(1)C]raclopride . Biological psychiatry 68 : 689 – 696 .

van Os J Kapur S ( 2009 ) Schizophrenia . Lancet 374 : 635 – 645 .

van Rossum JM ( 1966 ) The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs . Archives internationales de pharmacodynamie et de therapie 160 : 492 – 494 .

van Winkel R Stefanis NC Myin-Germeys I ( 2008 ) Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction . Schizophr Bull 34 : 1095 – 1105 .

Vezina P Stewart J ( 1989 ) The effect of dopamine receptor blockade on the development of sensitization to the locomotor activating effects of amphetamine and morphine . Brain research 499 : 108 – 120 .

Wearne TA Mirzaei M Franklin JL Goodchild AK Haynes PA Cornish JL ( 2015 ) Methamphetamine-induced sensitization is associated with alterations to the proteome of the prefrontal cortex: implications for the maintenance of psychotic disorders . J Proteome Res 14 : 397 – 410 .

White FJ Wang RY ( 1984 ) Interactions of cholecystokinin octapeptide and dopamine on nucleus accumbens neurons . Brain research 300 : 161 – 166 .

Wilson AA McCormick P Kapur S Willeit M Garcia A Hussey D Houle S Seeman P Ginovart N ( 2005 ) Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography . Journal of medicinal chemistry 48 : 4153 – 4160 .

Wolf ME White FJ Nassar R Brooderson RJ Khansa MR ( 1993 ) Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization . J Pharmacol Exp Ther 264 : 249 – 255 .

Xi ZX Newman AH Gilbert JG Pak AC Peng XQ Ashby CR Jr Gitajn L Gardner EL ( 2006 ) The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine’s rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats . Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 31 : 1393 – 1405 .

Young D Scoville W ( 1938 ) Paranoid psychosis in narcolepsy and the possible danger of benzedrine treatment . Med Clin North Am 22 : 637 – 646 .

Yui K Ikemoto S Goto K ( 2002 ) Factors for susceptibility to episode recurrence in spontaneous recurrence of methamphetamine psychosis . Annals of the New York Academy of Sciences 965 : 292 – 304 .

Zetterstrom T Sharp T Marsden CA Ungerstedt U ( 1983 ) In vivo measurement of dopamine and its metabolites by intracerebral dialysis: changes after d-amphetamine . J Neurochem 41 : 1769 – 1773 .

Author notes

• amphetamine
• schizophrenia
• sensitization

Email alerts

Citing articles via, affiliations.

• Online ISSN 1469-5111
• Copyright © 2024 Collegium Internationale Neuro-Psychopharmacologicum
• About Oxford Academic
• Publish journals with us
• University press partners
• What we publish
• New features  
• Open access
• Institutional account management
• Rights and permissions
• Get help with access
• Accessibility
• Advertising
• Media enquiries
• Oxford University Press
• Oxford Languages
• University of Oxford

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide

• Copyright © 2024 Oxford University Press
• Cookie settings
• Cookie policy
• Privacy policy
• Legal notice

This Feature Is Available To Subscribers Only

Sign In or Create an Account

This PDF is available to Subscribers Only

For full access to this pdf, sign in to an existing account, or purchase an annual subscription.

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.

Springer Medicine

Dopamine hypothesis of schizophrenia: Making sense of it all

Authors: Mitsuru Toda, BA, Anissa Abi-Dargham, MD

Published in: Current Psychiatry Reports | Issue 4/2007

Please log in to get access to this content

Other articles of this issue 4/2007.

OriginalPaper

A systematic review of the quality of information on the treatment of anxiety disorders on the internet

Schizophrenia: from brain morphology to psychopathology.

Invited Commentary

Antipsychotic treatment of schizophrenia: Two steps forward, one step back

Antiepileptic drugs for the treatment of post-traumatic stress disorder, reducing variation in the pharmacologic treatment of schizophrenia: defining acceptable standards of treatment, self-help interventions for anxiety disorders: an overview.

• Medical Journals
• Webcasts & Webinars
• CME & eLearning
• Newsletters
• ESMO Congress 2023
• 2023 ERS Congress
• ESC Congress 2023
• EHA2023 Hybrid Congress
• 2023 ASCO Annual Meeting Coverage
• Advances in Alzheimer’s
• About Springer Medicine
• Diabetology
• Endocrinology
• Gastroenterology
• Geriatrics and Gerontology
• Gynecology and Obstetrics
• Infectious Disease
• Internal Medicine
• Respiratory Medicine
• Rheumatology

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• My Account Login
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Review Article
• Open access
• Published: 11 April 2023

The synaptic hypothesis of schizophrenia version III: a master mechanism

• Oliver D. Howes   ORCID: orcid.org/0000-0002-2928-1972 1 , 2 , 3 &
• Ellis Chika Onwordi 1 , 2 , 3 , 4  

Molecular Psychiatry volume  28 ,  pages 1843–1856 ( 2023 ) Cite this article

9455 Accesses

20 Citations

13 Altmetric

Metrics details

• Neuroscience
• Schizophrenia

The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there has been a step-change in the evidence available, and some tenets of earlier versions are not supported by recent findings. Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. We then consider the mechanism that could underlie synaptic changes and update the hypothesis. Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss. Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. Based on this evidence, we propose version III of the synaptic hypothesis. This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. It accounts for the typical onset of schizophrenia in adolescence/early adulthood, its major risk factors, and symptoms, and identifies potential synaptic, microglial and immune targets for treatment.

Similar content being viewed by others

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility

Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications

Introduction.

Schizophrenia is generally a severe mental illness with a lifetime prevalence of about 1% of the population worldwide [ 1 ], and a major cause of global disease burden [ 2 ]. Symptoms typically begin in late adolescence or early adulthood, and can be separated into three domains: (1) positive (e.g., hallucinations, delusions, paranoia and thought disorder), (2) negative (e.g., anhedonia, avolition, social withdrawal and thought poverty) and (3) cognitive (e.g., dysfunction in attention, working memory and executive function) [ 3 ]. The onset of the first psychotic episode is commonly preceded by a prodrome generally of 1–5 years and characterised by sub-clinical negative, cognitive and psychotic symptoms [ 4 , 5 ].

In up to 20% of patients with schizophrenia, their illness shows a limited response to adequate trials of two different anti-psychotic drugs and clozapine [ 6 ] and treatments for negative symptoms and cognitive deficits remain an unmet clinical need [ 7 ]. Thus, there is a need to understand the pathoaetiology of schizophrenia to help identify new treatment targets.

In 1982, Irwin Feinberg first proposed that a fault in synaptic elimination in adolescence is causal to schizophrenia [ 8 ]. The hypothesis was subsequently revised to propose that a combination of excessive pruning of cortical synapses in prefrontal circuits and insufficient pruning of subcortical synapses underlies the onset of schizophrenia [ 9 ]. Judged by the number of citations on the theme, the synaptic hypothesis of schizophrenia has stimulated substantial interest, particularly in the last few years (see Fig.  1 ).

The first arrow indicates the year Feinberg’s hypothesis was published. The second arrow indicates the year Keshavan et al.’s hypothesis was published.

However, since these iterations of the synaptic hypothesis of schizophrenia, new data from novel methods, such as induced pluripotent stem cell (iPSC) and genome-wide association studies (GWAS) and in vivo synaptic imaging, have emerged. Here, we update the synaptic hypothesis in light of this new evidence.

The synaptic hypothesis version I

Feinberg proposed arguably the earliest version of the synaptic hypothesis of schizophrenia, stating that ‘too many, too few, or the wrong synapses are eliminated’ [ 8 ]. He speculated that this led to impaired neuronal integration, which resulted in auditory hallucinations, thought interference and the loss of self-boundaries observed in schizophrenia [ 8 , 10 ].

Feinberg referred to ‘reduced synaptic density’ as an umbrella term for qualitative changes in synapses, such as reorganisation, as well as a quantitative reduction in the number of synapses. He cited four main lines of evidence in support of a role for synaptic alterations in schizophrenia. First, Feinberg observed that EEG wave amplitudes markedly increase in infancy, and decline substantially in adolescence, with little variation in adulthood. Second, brain metabolic rate, as measured by CMRO 2 uptake, peaks in the first decade of life, declining rapidly through adolescence and early adulthood, before declining more slowly through the remaining adulthood [ 11 ]. Third, the degree of neuroanatomical plasticity observed in childhood, whereby the brain is capable of functional recovery from injury, is lost by adolescence. Fourth, Feinberg speculated that cognitive performance (termed ‘functional power’) peaks in adolescence. Feinberg observed that these electrophysiological, metabolic, anatomical and cognitive trajectories track trajectories for synaptic density, which peaks in childhood, before rapidly declining in late childhood and early adolescence [ 12 ]. He also observed that schizophrenia typically emerges in adolescence or early adulthood, thereby correlating temporally with the period of marked synaptic elimination. In addition, he noted that markers tracking synaptic trajectories (EEG wave amplitude and cognitive performance) are altered in schizophrenia.

Much of the evidence concerning synapses cited in version I of the hypothesis was indirect in nature, for instance, that cortical glucose metabolism is lower in schizophrenia than in controls. However, whilst lower glucose could reflect lower synaptic density, approximately 30% of cortical glucose metabolism supports non-signaling processes, unrelated to synaptic levels or activity [ 13 ]. This highlighted the need for more direct evidence of synaptic levels in schizophrenia.

The synaptic hypothesis version II

In 1994, Keshavan et al. updated the synaptic hypothesis with new evidence for structural and metabolic abnormalities in schizophrenia, and revised it to propose excessive cortical pruning and insufficient subcortical pruning [ 9 ]. They also highlighted that there could be a failure to form synapses in the first place, excessive synaptic elimination later in neurodevelopment, excess synaptic production early in development, or a combination of these processes.

Keshavan et al. synthesised new evidence regarding normal neurodevelopment, by drawing on non-human primate and human data, which indicated a peak in cortical synaptic density in normal early postnatal development, followed by a sharp decline in synaptic density through puberty, and a slower decline in adulthood [ 14 , 15 , 16 , 17 ]. Keshavan et al. noted that these trajectories were consistent with Feinberg’s hypothesised synaptic trajectory in normal human neurodevelopment. However, they noted that the locus of synaptic elimination (both spatial, in relation to synapse type, laminar location, and regional variation, and temporal) had yet to be established.

Keshavan et al. built on the neurostructural foundations of Feinberg’s hypothesis, by incorporating new evidence from CT studies indicating that grey-white matter ratios reduce from childhood during normal development. They also incorporated new evidence for neurostructural alterations in schizophrenia, including post-mortem studies showing reduced brain volume, cortical thinning and sulcal enlargement [ 18 , 19 ] and early MRI studies showing reduced frontal lobe volume [ 20 , 21 ], greater frontal sulcal size [ 22 ], and reduced cortical grey matter volume [ 23 , 24 ] in schizophrenia patients relative to healthy controls. The data were not all consistent, however, with other MRI studies failing to find significant differences in frontal or cerebral volume [ 25 ].

In addition, Feinberg speculated that synaptic elimination in adolescence may underlie reductions in cerebral metabolism and, when faulty, the onset of schizophrenia. This would suggest alterations in cerebral metabolism in schizophrenia. Keshavan et al.’s second version of the synaptic hypothesis of schizophrenia incorporated emerging evidence for frontal lobe hypometabolism, including positron emission tomography (PET), single-photon emission computed tomography, 133 Xe inhalation, 31 P-magnetic resonance spectroscopy, and cerebral blood flow studies indicating frontal hypometabolism [ 26 , 27 , 28 ], although again, these data were not unequivocal, with some studies failing to find evidence for hypofrontality [ 29 ].

Feinberg’s hypothesis lacked specificity in terms of the precise location of suspected synaptic alterations in schizophrenia. This was refined in the second synaptic hypothesis, which proposed excessive cortical pruning and insufficient subcortical pruning. The evidence for a failure of subcortical synaptic pruning was derived from individual MRI studies, which reported greater lenticular nucleus and left caudate volume in patients with schizophrenia [ 30 , 31 ]. However, this could be an effect of anti-psychotic treatment and meta-analysis of these and subsequent studies have not found consistent evidence for subcortical alterations in anti-psychotic-free patients [ 32 ].

Critically, neither this nor version I proposed a mechanism for faulty synaptic elimination, or how this is linked to genetic or environmental risk factors. To address this, we review new lines of evidence and propose an updated version of the hypothesis.

Evidence for synaptic changes in normal brain development

Multiple lines of evidence indicate that synapses undergo dramatic reorganisation through the course of life. Preclinical studies have found that normal development shows an early phase of net synaptic production followed by a phase of net synaptic elimination, and then comparatively balanced elimination and production leading to relatively stable synaptic levels in adulthood [ 15 , 16 , 33 ]. Consistent with this, human post-mortem studies show the greatest synapse density in early childhood, followed by intermediate levels during adolescence and early adulthood and lower, stable levels in adulthood (Fig.  2 ) [ 34 ]. Synaptic density reduces by approximately 40% from childhood through adolescence, with elimination particularly affecting glutamatergic synapses [ 9 , 15 , 16 ]. There was limited longitudinal in vivo imaging evidence for brain changes during human development when versions I and II of the hypothesis were proposed, but there have been a number of large studies since then. These show that cortical grey matter volumes increase and peak early in development [ 35 ], before undergoing a monotonic decrease into early adulthood [ 36 , 37 , 38 ]. Although beyond the scope of this review, it is important to recognise that findings from longitudinal imaging studies vary according to region, volumetric measure and developmental windows studied (see review [ 38 ]). The timing of these structural changes is broadly in line with the timing of synaptic changes seen in the preclinical and human post-mortem data on synaptic changes [ 36 , 39 ], although this temporal association does not mean they are causally related (discussed further in the section on evidence for structural alterations in schizophrenia).

Adapted from post-mortem data reported by Petanjek et al. for basal dendritic spine density of pyramidal cells from layer IIIc [ 34 ].

The mechanisms governing synaptic elimination

Microglia are histiocytes that play a central role in synaptic elimination during normal brain maturation [ 40 , 41 ]. During neurodevelopment, redundant synapses are tagged by complement proteins such as C1q (the cascade-initiating protein) and other complement proteins including C3 and C4, in a process which triggers the phagocytosis of the synapse by microglia (Fig.  3 ) [ 41 , 42 ].

Complement component C1q interacting with binding partners triggers cleavage of the complement components C2 and C4, thereby promoting the generation of activated C3. Activated C3 induces synaptic phagocytosis by microglia. Other complement signalling pathways can also trigger phagocytosis.

Adult mice overexpressing human C4 show increased microglial engulfment of synapses and reduced synapse density in the medial prefrontal cortex [ 43 ]. Similarly, C4-overexpressing mice show reduced spine number, and decreased spine turnover in juvenile mice, as well as abnormalities in glutamatergic cells [ 44 ]. In contrast, complement-dependent pruning is reduced by repeated firing of a synapse [ 42 ]. Thus, taken together, these lines of evidence show synaptic pruning is activity dependent and can be altered by genetic variants affecting the complement system.

In addition, astrocytes play both indirect and direct roles in synaptic elimination [ 45 ]. For example, C1q mRNA expression is dependent on factors secreted by astrocytes [ 42 ]. Moreover, astrocytes directly engulf synapses through the activation of phagocytic pathways necessary for normal neural circuit refinement [ 46 ].

Non-glial-related mechanisms also play a role in the elimination of synapses. For example, activation of the transcription factor myocyte enhancer factor 2 leads to ubiquitination of post-synaptic density protein 95 (PSD-95), which is then targeted for proteasomal degradation [ 47 ]. Stimulated synapses release molecules that change the actin skeleton in neighbouring dendritic spines, ultimately leading to their elimination [ 48 ]. Other molecules, such as semaphorin 7A, are released post-synaptically, and act in a retrograde manner to promote the elimination of pre-synaptic elements [ 49 ].

Genetic and environmental risk factors for schizophrenia implicate synapses

There has been a massive expansion in the power of genetic association studies since earlier versions of the hypothesis. The latest genome wide association study (GWAS) includes 76,755 schizophrenia patients and 243,649 controls, and identified 287 common variant loci associated with schizophrenia. These associations implicate genes involved in synaptic organisation, differentiation and transmission, and post-synaptic terms, with additional enrichment of genes playing roles in synaptic transmission and signalling [ 50 ].

The most significant GWAS signal for schizophrenia in a sample predominantly of European origin lies in the major histocompatibility complex (MHC) and has been shown to link to complement expression, in particular to higher C4A brain expression levels [ 51 , 52 ]. Complement-dependent pruning is reduced by repeated firing of a synapse and increased calcium signalling, as shown in the mouse visual cortex [ 42 ]. This suggests that the refinement of neural circuits via synapses could be altered by a genetic predisposition to impairments in the complement system and/or in glutamatergic signalling. However, it should be noted that a recent GWAS in people predominantly of East Asian ancestry did not find this association [ 53 ]. This highlights the need for more genetic studies in ethnically diverse groups to test the generalisability of findings [ 54 ]. Notwithstanding this, other risk factors for schizophrenia, such as stress, affect synaptic pruning (see summary in synaptic hypothesis version III section), and may account for aberrant synaptic pruning independent of genetic effects.

Brain co-expression network analyses coupled with gene ontogeny analyses have revealed that C4A expression levels are inversely associated with expression levels of synaptic genes, and that schizophrenia risk loci occur in synaptic pathways [ 52 ]. In addition, numerous other genetic loci associated with schizophrenia are linked to genes encoding proteins that mediate synaptogenesis [ 55 ], synaptic plasticity [ 56 ], spine formation and those involved in mechanisms of refining circuitry [ 55 ]. Animal models of some of these genetic risk factors have shown that they lead to lower synaptic marker levels [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].

Genetic loci linked to increased risk for schizophrenia are also involved in synaptic pathways during development. These include VRK2 , encoding vaccinia-associated kinase 2, which is involved in neurodevelopmental microglia-mediated synaptic elimination [ 56 ], CUL3 , encoding Culin-3, which is involved in neural development, glutamate receptor turnover and maintenance of excitation-inhibition balance [ 56 , 67 , 68 ], KALRN , encoding kalirin, which mediates dendritic spine formation [ 67 , 68 ] and CLSTN3 , encoding Calsyntenin-3, which promotes inhibitory and excitatory synaptic development [ 67 , 68 ].

Early environmental insults, such as maternal infection, are risk factors for schizophrenia [ 69 , 70 ], and animal models of antenatal infection or immune challenge show that these affect synaptic development, with some effects enduring into adulthood [ 71 , 72 , 73 ]. These seem to particularly affect synaptic development in glutamatergic neurons [ 72 , 73 ].

Preclinical models of a number of other environmental risk factors for schizophrenia also show lower levels of synaptic markers. For example, studies of social isolation have identified that rats weaned on postnatal day 21 and subsequently reared in isolation for 8 weeks show lower medial prefrontal cortical and hippocampal dendritic spine density in adulthood (postnatal day 77) compared to controls reared in social groups [ 74 ]. Similarly, rats aged 28–32 days subsequently reared in individual caged environments for 30 days showed lower dorsolateral striatal dendritic spine density in adulthood compared to controls reared in complex environments containing social groups and objects [ 75 ]. A model of chronic social defeat stress has found that mice aged 8–10 weeks introduced to and attacked by unfamiliar resident mice show lower levels of prefrontal cortical pyramidal neuron apical dendritic spine density 30 days following the stress procedure compared to controls [ 76 ]. Numerous studies have identified that rodents subjected to chronic stress show changes in dendritic arborisation, with effects varying according to the brain regions studied [ 77 , 78 , 79 , 80 ]. Furthermore, studies of maternal immune activation models, which expose pregnant rodents to lipopolysaccharide [ 81 ] or polyribocytidylic acid (poly I:C) [ 82 ] on gestational day 9.5, have found lower levels of both pre-synaptic and post-synaptic markers in cortical brain regions as adults. This includes lower levels of pre-synaptic proteins such as synaptophysin, syntaxin-1 and synaptobrevin, and lower levels of post-synaptic proteins, including PSD-95 and SH3 and multiple ankyrin repeat domains proteins 1, 2 and 3, at postnatal days 52–54 [ 81 ], and also lower dendritic spine density at postnatal day 80 [ 82 ] compared to controls. These models show that risk factors acting at various developmental stages can lead to loss of synaptic markers. Similarly, lifetime stress has been linked to lower levels of dendritic spine density post-mortem in human cortical tissue [ 83 ]. It should be recognised that a range of brain and behavioural alterations are seen in these preclinical models, and it remains to be established that the synaptic changes are primary rather than secondary to other alterations. Furthermore, the effects of stress on dendritic spine density may show specificity in terms of brain region, spine type and timing of stressful events [ 76 ]. Nevertheless, taken together with the genetic studies, these findings indicate that a range of risk factors for schizophrenia affect synaptic levels to potentially increase vulnerability to the disorder.

The link between complement expression and brain structure and function has begun to be investigated. A recent imaging genetics study of a mixed sample of healthy control subjects ( n  = 46), patients with psychosis ( n  = 40) and individuals at clinical high risk for psychosis ( n  = 43) showed that levels of genotype-predicted brain C4A expression were positively associated with brain levels of translocator protein (TSPO, a marker expressed by glia), and negatively associated with hippocampal surface area [ 84 ]. However, there was no significant effect of clinical group on these relationships, indicating it is most likely a common mechanism. Further work in a large UK Biobank sample (n > 27,000) which excluded individuals with diagnoses of neurological or mental disorders identified that predicted C4A expression levels are negatively associated with cortical thickness in a number of brain regions implicated in schizophrenia pathogenesis, including the parahippocampal, insula, entorhinal, medial orbitofrontal and parts of the cingulate cortices [ 85 ]. Other work has investigated the relationship between complement markers and phosphorous magnetic resonance spectroscopy, which enables the quantification of membrane phospholipid precursors and catabolites [ 86 ] that are considered as proxies for the degree of neuropil contraction [ 87 ]. Higher C4A gene copy number has been shown to be directly associated with higher levels of catabolites in the inferior frontal cortex, and lower levels of precursors in the inferior parietal lobule, suggestive of greater neuropil contraction in these regions, in patients with schizophrenia [ 87 ]. In addition, higher C4A expression levels have been negatively associated with middle temporal cortex activation in healthy controls during an functional MRI (fMRI) visual processing task, and with episodic memory performance in healthy controls and patients with schizophrenia [ 88 ]. The findings discussed in this section thus show associations between diminished cortical volumes and thickness and altered brain activation and complement levels, consistent with a model that higher complement levels could underlie brain structural and functional changes in schizophrenia, although, importantly, it remains to be established if complement leads to the changes. It should also be recognised that there are inconsistencies in the relationship between C4A and brain imaging measures [ 85 , 87 ]. Thus, further work is needed to investigate if complement expression underlies brain structural and functional changes, and to test if there is a link between complement expression and in vivo synaptic marker levels in patients with schizophrenia.

Post-mortem synaptic markers in schizophrenia

Since earlier iterations of the synaptic hypothesis of schizophrenia, a wealth of post-mortem evidence for lower levels of markers of synaptic density in schizophrenia has accumulated.

Post-mortem studies have reported lower levels of a number of pre-synaptic markers in schizophrenia relative to controls, with moderate-to-large effect size lower levels of synaptophysin in the frontal cortex, cingulate cortex and hippocampus on meta-analysis [ 89 ]. Furthermore, a meta-analysis of post-mortem studies found lower levels of post-synaptic elements (comprising dendritic spine density, post-synaptic density and post-synaptic density (PSD) protein expression levels) in people with schizophrenia, with a moderate effect size in cortical tissues [ 90 ]. Subgroup analysis demonstrated that levels of post-synaptic elements were lower in cortical but not subcortical tissues [ 90 ]. Thus, findings of lower pre-synaptic and post-synaptic markers in separate meta-analyses of post-mortem studies are highly suggestive of cortical synaptic alterations in schizophrenia. These findings are supported by electron microscopy studies, which provide the gold standard means for directly measuring synaptic density, showing lower levels of axospinous [ 91 ] and axodendritic [ 92 ] synaptic density in the anterior cingulate cortex, perforated (principally glutamatergic) synapses in the striatum [ 93 ], and lower total synaptic density in the substantia nigra, particularly affecting symmetric (inhibitory) synapses [ 94 ] in tissue from patients with schizophrenia compared to controls. However, there are inconsistencies in the findings, potentially relating to differences in methodological approaches and the specific markers used [ 95 ]. Post-mortem studies in schizophrenia are also subject to a number of potentially confounding factors, such as differences in lifetime anti-psychotic exposure, differences in cause of death and post-mortem interval [ 95 ]. Moreover, post-mortem studies are highly labour intensive, therefore limiting the number of subjects and regions investigated in the individual studies. These issues limit the generalisability of findings. Critically, they cannot provide conclusive evidence of synaptic density changes in the living brain, or when they occur in the illness.

Findings from neuronal cultures derived using induced pluripotent stem cells (iPSC) from patients

A significant technological advance since the earlier versions of the synaptic hypothesis has been the ability to use stem cells from patients to derive neuronal cultures. This enables neuronal development to be studied in brain tissue with the same genetic background as patients [ 96 ]. As seen in Table  1 , studies implementing these methods show evidence for both pre- and post-synaptic deficits, such as lower synaptic vesicle 2 (SV2) and synapsin I puncta density and synaptic vesicle release, and lower levels of post-synaptic markers including PSD-95 protein levels and dendritic spine density. They also show functional alterations in synaptic signalling in neurons derived from people with schizophrenia compared to controls (Table  1 ).

Importantly, recent iPSC models investigating synapse-glia interactions in vitro have demonstrated elevated, complement-dependent elimination of synaptic structures [ 97 ], highlighting a potential mechanism for excessive synaptic pruning by glia in schizophrenia [ 98 , 99 ], summarised in Fig.  4 . Thus, the evidence from patient-derived neural cultures indicates a failure to form and/or preserve synapses in early neurodevelopment in schizophrenia. Whilst beyond the scope of our review, it should be noted that in addition to synaptic alterations, iPSC models also show evidence for alterations in other aspects of neuronal development [ 100 ]. The role of these in the synaptic alterations remains to be determined.

Left: potential model of glia-mediated elimination of synapses in schizophrenia. This could affect glutamatergic synapses, including dendritic spines and collaterals that synapse onto inhibitory interneurons, as well as inhibitory synapses onto pyramidal neurons. Right: loss of synapses on pyramidal neurons and inhibitory interneurons, which could disrupt pyramidal neuron function and lead to negative and cognitive symptoms.

It is also important to appreciate the limitations of evidence obtained through patient-derived neuronal lines. As these neural cells are cultured in vitro, they do not adequately reflect the impact of environmental factors on neurobiology in schizophrenia [ 101 ]. Furthermore, the limited maturity of derived neural cells, methodological variability in processes for cellular reprogramming and brain cell generation, and genetic background variations may affect findings [ 96 ]. These considerations highlight the need for in vivo studies with other techniques in patients.

Evidence for altered brain structure in schizophrenia

There has been a step-change in the in vivo imaging evidence for altered brain structure in schizophrenia since versions I and II of the synaptic hypothesis were elaborated with, now, well over a hundred studies across brain regions and phases of illness [ 32 , 102 ]. Meta-analyses of findings in patients show well-replicated evidence for lower cortical grey matter volumes (Hedges g ~0.26–0.66 [ 32 ], Cohen’s d ~0.31–1.09 [ 102 ]), and lower or unaltered subcortical volumes (Hedges g  = ~0.11–0.46 [ 32 ], Cohen’s d  = 0.18 [ 102 ]) relative to healthy controls across illness phases from the first episode. Moreover, there is now substantial evidence for similar patterns of lower grey matter volumes and cortical thinning in people at clinical high risk for schizophrenia, and that this is particularly marked in those who go on to develop the disorder [ 103 , 104 ]. Meta-analysis also indicates that cortical thickness in fronto-temporal brain regions is lower in schizophrenia from the onset of the disorder ( z ~1.94–3.25) and in clinical high-risk subjects ( z ~1.01) [ 105 ].

In addition, studies have compared age-related brain structure in patients with controls. Cross-sectional imaging studies suggest that there is an accelerated age-related decline of grey matter volume in schizophrenia patients compared with controls [ 106 ]. This has been directly tested in longitudinal imaging studies, with meta-analyses of these indicating greater grey matter loss over time in patients compared to controls [ 107 , 108 ]. Furthermore, cross-sectional imaging has identified that these deficits start early in disorder [ 106 ], and longitudinal studies have demonstrated that elevated rates of cortical grey matter loss are associated with conversion from clinical high risk to a psychotic illness [ 104 , 109 ]. Moreover, there is an inverse relationship between cerebral volume and symptom severity in schizophrenia [ 110 , 111 , 112 ]. These observations implicate neurostructural alteration in the development of schizophrenia, raising the question as to the cellular and molecular basis of these changes.

A key question is, thus, whether structural MR imaging changes could be due to synaptic loss. Kassem et al. addressed this key question by combining structural MRI and confocal microscopy [ 113 ]. They observed grey matter volume loss on MRI in the anterior cingulate cortex and hippocampus of stressed mice, and reduced dendritic volume and spine density, in the absence of changes in the number or volumes of neuronal soma, astrocytes or oligodendrocytes. Moreover, there was a strong linear relationship ( R 2  > 0.9) between dendritic volume loss and MRI-estimated grey matter volume loss [ 113 ]. Similarly, Keifer et al. deployed voxel-based morphometry and confocal microscopy to investigate the effects of an auditory fear conditioning paradigm in mice. They found increased grey matter voxel intensity in the conditioned mice relative to the controls in the auditory cortex, amygdala and insula; concurrent increases in dendritic spine density in the auditory cortex; a positive relationship between dendritic spine density and grey matter voxel intensity; no change in neuronal nuclei density; and no relationship between nuclei density and grey matter voxel intensity [ 114 ]. These data show that synaptic changes can lead to changes in grey matter volumes measured by MRI, and indicate that stress can contribute to this. It should be noted, however, that Keifer et al. did not identify a significant change in auditory cortical thickness, suggesting dendritic spine density is less strongly linked to cortical thickness than to grey matter density.

Whilst cortical neuronal number remains largely unchanged in schizophrenia [ 115 ], post-mortem evidence shows lower cortical neuropil [ 116 ], cortical dendritic spine density [ 90 , 117 , 118 , 119 , 120 ], spine plasticity markers and synaptic vesicle protein levels relative to controls (as discussed above; also see [ 89 , 121 , 122 , 123 , 124 ]). Thus, taken together, this preclinical and post-mortem evidence indicates that synaptic changes could contribute to the neurostructural alterations seen in schizophrenia, although it does not prove it.

There are limitations to interpreting structural MRI findings as indicative of synaptic alterations in schizophrenia. Neuronal and glial number and size, and vasculature, as well as synaptic elements, may contribute to the grey matter signal ([ 114 , 125 ], and as discussed in [ 126 ]). Factors such as anti-psychotic treatment and movement artefacts could also confound case–control differences [ 126 , 127 ]. Thus, alterations in non-synaptic factors may contribute to or even account for structural MRI findings in schizophrenia, and so there has been a pressing need to develop in vivo imaging measures that are specific to synapses. This is reviewed in the next section.

In vivo evidence for lower synaptic markers in schizophrenia

A major limitation of the synaptic hypothesis was the lack of evidence for synaptic alterations in patients with schizophrenia in vivo. However, investigating synaptic density in the living human brain has recently been made possible by the development of PET radioligands, such as [ 11 C]UCB-J, that are specific for synaptic vesicle glycoprotein 2A (SV2A) [ 128 ]. SV2A is ubiquitously expressed in pre-synaptic terminals, and is a marker of synaptic terminal density [ 128 ]. Non-human primate studies demonstrate a strong positive relationship between [ 11 C]UCB-J volumes of distribution and in vitro SV2A levels measured using western blots ( r  > 0.8) and binding assays ( r  > 0.9) [ 128 ]. Displacement studies using levetiracetam [ 128 , 129 ], a drug which binds selectively to SV2A [ 130 ], show the [ 11 C]UCB-J signal is largely blocked, indicating high specificity of [ 11 C]UCB-J to SV2A. This evidence indicates that [ 11 C]UCB-J is a specific marker of SV2A levels. SV2A, one of three isoforms of SV2, is expressed throughout the brain and is present in GABAergic and glutamatergic pre-synaptic nerve terminals [ 131 ]. Furthermore, SV2A levels are strongly, positively correlated with synaptophysin levels in the brain ( r  > 0.95) [ 128 ], which is reduced in disorders associated with synaptic loss, and is widely used as a marker of synaptic density [ 132 ]. Moreover, SV2 shows lower variability in terms of copy number per synaptic vesicle than synaptophysin [ 133 ]. [ 11 C]UCB-J PET has demonstrated sensitivity to synaptic reductions in temporal lobe epilepsy and Alzheimer’s disease [ 128 , 134 ], showing it is able to detect alterations in disorders in which loss of synaptic density is expected.

The first [ 11 C]UCB-J PET study in patients with schizophrenia found that [ 11 C]UCB-J volume of distribution was lower in patients compared to healthy volunteers in the frontal and anterior cingulate cortices with large effect sizes, and possibly lower in the hippocampus as well [ 135 ]. This study also found evidence for lower synaptic density in subcortical regions in patients with schizophrenia, in contrast to the prediction from version II of the synaptic hypothesis. These findings have since been independently replicated [ 136 ]. To our knowledge, SV2A levels have not been studied post-mortem in schizophrenia in the frontal or anterior cingulate cortices or hippocampus, although a post-mortem study found lower SV2A transcript levels in the cerebellar cortex in schizophrenia compared to controls [ 137 ]. Both PET studies were in patients with chronic illnesses who were taking anti-psychotic drugs. However, neither study found a relationship between anti-psychotic exposure and [ 11 C]UCB-J binding, and a rodent study showed anti-psychotic drug exposure had no effect on SV2A protein or SV2A radioligand binding levels, indicating anti-psychotic treatment is unlikely to explain lower SV2A levels in schizophrenia [ 135 ].

In healthy volunteers, [ 11 C]UCB-J binding and glutamate levels are directly associated in the anterior cingulate cortex and hippocampus, consistent with the high proportion of glutamatergic synapses there [ 138 ]. However, no significant relationship is seen between [ 11 C]UCB-J and glutamate measures in schizophrenia, suggesting a loss of glutamatergic synapses and/or a lower ratio of glutamatergic to GABAergic synapses in the disorder [ 138 ].

There are a number of considerations in interpreting the [ 11 C]UCB-J signal as a marker of synaptic density. As a marker of SV2A levels, changes in [ 11 C]UCB-J binding could reflect altered SV2A levels, and/or synaptic vesicle numbers and/or pre-synaptic terminal density and/or synaptic density. However, as discussed earlier, there is post-mortem evidence showing lower levels of a number of pre- and post-synaptic elements in schizophrenia. This includes lower levels of synaptophysin and other synaptic vesicle proteins [ 89 , 121 , 122 , 123 , 124 ], lower transcript levels of SV2A [ 137 ], lower cortical dendritic spine density and other post-synaptic elements, [ 90 , 117 , 118 , 120 ] and lower spine plasticity [ 139 ], in the context of unaltered neuronal numbers in schizophrenia [ 115 ]. When this post-mortem evidence is taken with the [ 11 C]UCB-J findings, the most parsimonious explanation is, thus, that lower [ 11 C]UCB-J binding reflects lower synaptic density in schizophrenia.

Version III of the synaptic hypothesis of schizophrenia: a master mechanism

The evidence from the post-mortem and PET studies discussed above provides direct evidence for lower synaptic levels, particularly in frontal regions, in schizophrenia, whilst the iPSC studies show lower synaptic marker levels, synaptic signalling deficits and elevated microglial-mediated synaptic pruning in neurons derived from patients relative to controls. On top of this, the MRI imaging data in schizophrenia show a greater loss of grey matter than seen in normal neurodevelopment and functional dysconnectivity across brain regions, both starting early in the course of the disorder. A number of brain changes could account for these structural and functional imaging alterations. However, given the preclinical data indicating that synaptic loss can account for at least a proportion of grey matter volume reductions, and taken with the PET, iPSC and post-mortem findings, synaptic loss likely contributes to these structural and functional alterations.

Based on these lines of evidence, we propose a revised synaptic hypothesis, summarised in Fig.  5 . The GWAS data link schizophrenia to risk variants involved in synapse formation (see earlier discussion), and a variant complement protein associated with increased microglial-mediated synaptic pruning, whilst the iPSC data indicate genetic risk translates into elevated microglial-mediated pruning and aberrant signalling in neurons derived from patients with schizophrenia. Schizophrenia is also associated with a number of environmental risk factors that are immune activators, such as maternal infections and obstetric complications [ 140 ], which have been shown to activate microglia so that they show an enhanced response to subsequent activation by later stressors in a process termed priming [ 141 , 142 ]. These environmental and genetic risk factors may, thus, increase the vulnerability of the individual to an excessive response to subsequent microglial activation. Exposure to psychosocial stressors, such as physical or emotional abuse, bullying or other adverse life events, also increases the risk of schizophrenia [ 3 ]. Animal studies show that stressors that recapitulate aspects of these risk factors, such as repeated exposure to dominant animals, activate microglia and lead to synaptic pruning [ 76 , 143 , 144 , 145 , 146 ]. Thus, genetic vulnerability translates into the aberrant formation of synapses and higher levels of complement proteins that tag synapses for elimination by glia, whilst environmental risk factors for schizophrenia may prime glia early in development and reactivate them later to lead to aberrant pruning of synapses by glia. Thus, we propose a multi-hit model, with both early and late risk factors converging to lead to synapse dysfunction and aberrant glial-mediated synaptic pruning. As microglia show priming, exposure to early risk factors may affect the timing of illness onset by enhancing their response to subsequent risk factors, such as psychosocial stress. Priming could thus account for findings that people exposed to early developmental environmental risk factors, such as obstetric complications, may be at increased risk of early onset of schizophrenia [ 140 ] because primed glia show an enhanced response to subsequent activation by stress.

This is a multi-hit model in which genetic variants increase the vulnerability of synapses to elimination, and subsequent environmental risk factors such as stress, then induce aberrant glial-mediated pruning. Aberrant synaptic pruning leads to cortical excitation-inhibition imbalance, resulting in cognitive impairment and negative symptoms, and dysregulated projections to the striatum and midbrain. This leads to dopaminergic neuron disinhibition, and impairments in predictive learning and processing of sensory stimuli, causing psychotic symptoms. The stress of psychosis feeds back on this system to lead to further aberrant pruning.

A key question is how aberrant synaptic function and pruning could contribute to cognitive and negative symptoms. Schizophrenia is associated with lower grey matter in cortical regions, such as the frontal cortex, that play key roles in goal-directed behaviours, working memory and other processes that underlie these symptoms [ 32 ]. A balance between excitation and inhibition is critical to ensure the optimal signal-to-noise ratio in cortical neuronal arrays [ 147 ]. We propose that aberrant synaptic pruning leads to excitation-inhibition imbalance in cortical arrays and a lower signal-to-noise ratio [ 148 ]. This would impair function in cortical regions, contributing to the cognitive impairments and negative symptoms seen in schizophrenia. It could also account for neurofunctional alterations, such as findings of frontal hypometabolism [ 149 ], or fMRI studies finding altered cortical function and connectivity in schizophrenia [ 150 , 151 , 152 , 153 , 154 , 155 , 156 ]. However, it is important to note that numerous factors contribute to fMRI measures of functional connectivity, including blood flow, blood volume and cerebral metabolic rate [ 157 ], and the extent to which synaptic factors contribute to fMRI connectivity measures and cerebral glucose metabolism remains undetermined. Moreover, it remains to be established whether aberrant synaptic pruning affects particular excitatory or inhibitory synapses.

Another central question is how aberrant synaptic function and pruning could contribute to psychotic symptoms. Multiple lines of evidence indicate that overactivity in mesostriatal dopamine neurons underlies the development of psychotic symptoms by dysregulating their role in predictive learning and the assignment of confidence to the detection of sensory stimuli [ 158 ]. Preclinical evidence indicates that disrupting cortical excitation-inhibition balance, for example, using ketamine, can lead to mesostriatal dopamine overactivity [ 159 , 160 , 161 ] and result in elevated striatal dopamine synthesis capacity, as seen in patients with schizophrenia [ 161 , 162 ]. Moreover, activating inhibitory interneurons in cortical brain regions may prevent hyperdopaminergia in a sub-chronic ketamine rodent model [ 161 ]. Thus, we propose that cortical excitation-inhibition imbalance due to aberrant synaptic function and/or pruning in turn may contribute to the dysregulation of neurons that project to the striatum and midbrain to disinhibit dopaminergic neurons in these regions, impairing predictive learning and processing of sensory stimuli to lead psychotic symptoms (for review see [ 163 ]). It should also be recognised that psychosis is, itself, intensely stressful, which may feedback on the system to cause further glial-mediated synaptic pruning and, in turn, worsen symptoms; setting up a vicious cycle (Fig.  5 ). Supporting this potential effect of psychosis, there is some evidence that greater duration of untreated psychosis is associated with larger grey matter reductions, albeit this does not directly show synaptic changes and further work is needed to test this association further [ 164 , 165 ].

This model could explain why schizophrenia is rare in childhood: during this period, the net production of synapses provides a buffer against overactive pruning and synaptic dysfunction. However, the normal developmental switch to net synaptic elimination in adolescence/early adulthood makes the system much more vulnerable to overactive pruning, unmasking the vulnerability to schizophrenia, and explaining its peak onset during this period.

Version III builds on the earlier versions, and we acknowledge a great debt to the many contributors to these. It extends them by incorporating new evidence to propose a mechanism that links risk factors to synaptic changes and then to symptoms. The new hypothesis is also a multi-hit model whereby genetics increase the vulnerability of synapses to elimination, and environmental risk factors act later on this vulnerable system to cause aberrant synapse-microglia interactions, resulting in synaptic dysfunction and excess microglia-mediated pruning, contributing to symptoms in disorder. This could be considered a master mechanism, as multiple risk factors may converge to lead to synaptic dysfunction and aberrant synaptic elimination which, in turn, has the potential to underlie many other pathophysiological findings in schizophrenia, including structural and functional brain imaging findings, and dopaminergic dysfunction. The hypothesis is falsifiable by, for example, showing that synaptic alterations are not associated with the worsening of symptoms.

The evidence outlined above has implications for developing new treatments. As synaptic elimination is a dynamic process governed by the complement system and glial activity, these could be novel treatment targets to restore normal synaptic organisation by, for example, reducing the activation of microglia.

Gaps in the evidence and future directions

A key evidence gap is whether there are synaptic alterations at the first episode, or earlier in the development of schizophrenia. PET studies in clinical high risk and unmedicated, first-episode schizophrenia would be invaluable in testing this. The finding of an altered relationship between an SV2A marker and glutamate measures in patients requires replication and the development of more specific imaging probes of glutamatergic synapses to enable it to be directly tested. An evidential gap is thus the link between synaptic loss and excitation-inhibition imbalance, and whether the synaptic loss particularly affects specific synapses, such as glutamatergic synapses. This could be tested using multi-modal imaging in patients and in studies of neurons derived from patients. Furthermore, developing organoid models would permit the investigation of neurodevelopmental stages later than those captured by 2D iPSC models.

We have drawn on evidence from preclinical and clinical studies using a variety of markers related to synapses, including pre-synaptic elements, post-synaptic structures and dendritic spine densities, and considered these as indicative of synaptic levels. However, whilst changes in these could be consistent with altered synaptic levels, we cannot exclude that some could be altered in the absence of synaptic changes. This highlights the value of future studies including measures of both pre- and post-synaptic elements to confirm that differences reflect synaptic loss. A related consideration is that some lines of evidence, such as post-mortem findings of lower dendritic spine density in schizophrenia relative to controls, could be due to a failure to form synapses instead of, or in addition to, aberrant synaptic pruning. Longitudinal studies would help disambiguate these possibilities.

To our knowledge, there have not been post-mortem studies of SV2A protein levels in schizophrenia, and the study of SV2A transcript levels was in the cerebellar cortex so it remains unclear if there are SV2A protein alterations post-mortem in the regions where changes are seen in vivo [ 137 ]. Conducting post-mortem studies of SV2A would be useful to corroborate the PET findings, and to investigate the relationship between levels of SV2A and those of other pre-, as well as post-synaptic proteins. Moreover, synaptic loss alone is highly unlikely to account for all the grey matter volume changes in schizophrenia and changes in related structures, such as dendritic spine density, likely contribute as well (see [ 126 ] for discussion). Another gap in knowledge is, thus, the degree to which synaptic loss accounts for the structural and functional imaging findings in schizophrenia. Multi-modal imaging studies combining synaptic marker measures, such as [ 11 C]UCB-J, and other modalities would be invaluable in assessing this.

The hypothesis proposes that glia are activated by environmental risk factors, such as stress. There is evidence for higher levels of markers associated with an activated glial phenotype in schizophrenia relative to controls from post-mortem studies (effect size ~0.7 on meta-analysis) [ 166 ], and that greater PET signal for TSPO, a protein expressed by activated glia, is associated with greater predicted complement levels in patients [ 84 ]. However, there are inconsistencies in the TSPO PET findings in schizophrenia (reviewed in [ 167 ]). Whilst the inconsistencies could be due to methodological issues [ 167 , 168 ], inconsistencies could also be due to the timing of the scans in relation to glial activation. Supporting the latter, a mouse study found social defeat increased TSPO PET signal in cortical regions in a time-specific manner [ 169 ]. Studies using TSPO PET imaging and synaptic markers in preclinical models of schizophrenia risk factors would be useful to further test these links, whilst the development of new tools to image glia is needed to provide greater sensitivity and specificity [ 170 ].

We have highlighted a potential role of C4, and this is now supported by recent evidence that cerebrospinal fluid concentrations of C4A are elevated in two separate cohorts of people with schizophrenia, and inversely related to levels of a synaptic marker [ 171 ]. However, it is important to recognise that this is only one potential pathway and other immune pathways or alternative mechanisms may also be involved. Indeed, there may be several pathways to the abnormal synaptic formation and/or pruning and the relative importance of C4 in this is unknown. These issues need further investigation. It should also be recognised that the GWAS studies are predominantly in European samples, and a recent GWAS in a population from East Asia did not find an association between schizophrenia and the major histocompatability locus linked to C4 variants [ 53 ]. There is thus a need for studies to include more diverse populations to test generalisability. Moreover, schizophrenia shows heterogeneity in its clinical and other features [ 32 , 172 , 173 ], and may show pathophysiologically based sub-types associated with distinct clinical phenotypes, such as late onset, treatment resistance and substance dependence, and variable illness trajectories, including some that show recovery after one episode [ 174 , 175 , 176 ]. It is unlikely that anyone neurobiological hypothesis can account for all sub-types of schizophrenia. For this reason, it is a potential master mechanism, but may not be the only one. Thus, it is important to determine if the synaptic loss is seen in sub-types of schizophrenia as well as typical presentations. By the same token, studies comparing synaptic markers in patients with neurodevelopmental disorders that share some genetic and other risk factors, such as schizophrenia and bipolar disorder, would be useful to determine if they share a common underlying mechanism. Finally, the proposed relationship between synaptic alterations and striatal dopamine dysregulation remains to be tested in vivo. This aspect of the hypothesis could be falsified by showing there is no association between cortical synaptic indices and striatal dopaminergic measures.

A considerable body of new evidence for synaptic loss in patients has grown over the four decades since Feinberg first proposed the synaptic hypothesis of schizophrenia. Crucially, there is now in vivo evidence for lower synaptic terminal levels in patients, a mechanism mediated by microglia that accounts for genetic and environmental risk factors for the disorder, and new understanding on how synaptic loss could contribute to symptoms. We have revised the hypothesis to account for these new data. We call it version III, as we anticipate elements may need revision as further evidence accumulates. Notwithstanding this, it has the potential to explain a number of key aspects of the epidemiology and clinical expression of schizophrenia, including the peak age of onset and symptoms, and identifies mechanisms and new potential targets for treatment.

The views expressed are those of the authors and not necessarily those of the National Health Services, the National Institute of Health Research, or the Department of Health and Social Care of the United Kingdom.

Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2:e141.

Article   PubMed   PubMed Central   Google Scholar  

McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia – an overview. JAMA Psychiatry. 2020;77:201–10.

Article   PubMed   Google Scholar  

Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;383:1677–87.

Cannon TD, Cadenhead K, Cornblatt B, Woods SW, Addington J, Walker E, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65:28–37.

Yung AR, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull. 1996;22:353–70.

Article   CAS   PubMed   Google Scholar  

Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62:772–7.

Kaar SJ, Natesan S, McCutcheon R, Howes OD. Antipsychotics: mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 2020;172:107704.

Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res. 1982;17:319–34.

Keshavan MS, Anderson S, Pettergrew JW. Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. J Psychiatr Res. 1994;28:239–65.

Feinberg I. Efference copy and corollary discharge: implications for thinking and its disorders. Schizophr Bull. 1978;4:636–40.

Kety SS. Human cerebral blood flow and oxygen consumption as related to aging. J Chronic Dis. 1956;3:478–86.

Huttenlocher PR. Synaptic density in human frontal cortex – developmental changes and effects of aging. Brain Res. 1979;163:195–205.

Yu Y, Herman P, Rothman DL, Agarwal D, Hyder F. Evaluating the gray and white matter energy budgets of human brain function. J Cereb Blood Flow Metab. 2018;38:1339–53.

Rakic P, Bourgeois JP, Eckenhoff MF, Zecevic N, Goldman-Rakic PS. Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science. 1986;232:232–5.

Bourgeois JP, Rakic P. Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage. J Neurosci. 1993;13:2801–20.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Zecevic N, Bourgeois J-P, Rakic P. Changes in synaptic density in motor cortex of rhesus monkey during fetal and postnatal life. Brain Res Dev Brain Res. 1989;50:11–32.

Huttenlocher PR, de Courten C. The development of synapses in striate cortex of man. Hum Neurobiol. 1987;6:1–9.

CAS   PubMed   Google Scholar  

Brown R, Colter N, Corsellis JA, Crow TJ, Frith CD, Jagoe R, et al. Postmortem evidence of structural brain changes in schizophrenia. Differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder. Arch Gen Psychiatry. 1986;43:36–42.

Pakkenberg B. Post-mortem study of chronic schizophrenic brains. Br J Psychiatry. 1987;151:744–52.

Andreasen N, Nasrallah HA, Dunn V, Olson SC, Grove WM, Ehrhardt JC, et al. Structural abnormalities in the frontal system in schizophrenia. A magnetic resonance imaging study. Arch Gen Psychiatry. 1986;43:136–44.

DeMyer MK, Gilmor RL, Hendrie HC, DeMyer WE, Augustyn GT, Jackson RK. Magnetic resonance brain images in schizophrenic and normal subjects: influence of diagnosis and education. Schizophr Bull. 1988;14:21–37.

Rubin P, Karle A, Moller-Madsen S, Hertel C, Povlsen UJ, Noring U, et al. Computerised tomography in newly diagnosed schizophrenia and schizophreniform disorder. A controlled blind study. Br J Psychiatry. 1993;163:604–12.

Zipursky RB, Lim KO, Sullivan EV, Brown BW, Pfefferbaum A. Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49:195–205.

Harvey I, Ron MA, Du Boulay G, Wicks D, Lewis SW, Murray RM. Reduction of cortical volume in schizophrenia on magnetic resonance imaging. Psychol Med. 1993;23:591–604.

Andreasen NC, Ehrhardt JC, Swayze VW II, Alliger RJ, Yuh WT, Cohen G, et al. Magnetic resonance imaging of the brain in schizophrenia. The pathophysiologic significance of structural abnormalities. Arch Gen Psychiatry. 1990;47:35–44.

Buchsbaum MS, Haier RJ. Functional and anatomical brain imaging: impact on schizophrenia research. Schizophr Bull. 1987;13:115–32.

Buchsbaum MS. The frontal lobes, basal ganglia, and temporal lobes as sites for schizophrenia. Schizophr Bull. 1990;16:379–89.

Buchsbaum MS, Haier RJ, Potkin SG, Nuechterlein K, Bracha HS, Katz M, et al. Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry. 1992;49:935–42.

Cleghorn JM, Garnett ES, Nahmias C, Firnau G, Brown GM, Kaplan R, et al. Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia. Psychiatry Res. 1989;28:119–33.

Jernigan TL, Zisook S, Heaton RK, Moranville JT, Hesselink JR, Braff DL. Magnetic resonance imaging abnormalities in lenticular nuclei and cerebral cortex in schizophrenia. Arch Gen Psychiatry. 1991;48:881–90.

Breier A, Buchanan RW, Elkashef A, Munson RC, Kirkpatrick B, Gellad F. Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch Gen Psychiatry. 1992;49:921–6.

Brugger SP, Howes OD. Heterogeneity and homogeneity of regional brain structure in schizophrenia: a meta-analysis. JAMA Psychiatry. 2017;74:1104–11.

Anderson SA, Classey JD, Conde F, Lund JS, Lewis DA. Synchronous development of pyramidal neuron dendritic spines and parvalbumin-immunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Neuroscience. 1995;67:7–22.

Petanjek Z, Judas M, Simic G, Rasin MR, Uylings HB, Rakic P, et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci USA. 2011;108:13281–6.

Lyall AE, Shi F, Geng X, Woolson S, Li G, Wang L, et al. Dynamic development of regional cortical thickness and surface area in early childhood. Cereb Cortex. 2015;25:2204–12.

Tamnes CK, Herting MM, Goddings AL, Meuwese R, Blakemore SJ, Dahl RE, et al. Development of the cerebral cortex across adolescence: a multisample study of inter-related longitudinal changes in cortical volume, surface area, and thickness. J Neurosci. 2017;37:3402–12.

Mills KL, Goddings AL, Herting MM, Meuwese R, Blakemore SJ, Crone EA, et al. Structural brain development between childhood and adulthood: convergence across four longitudinal samples. Neuroimage. 2016;141:273–81.

Norbom LB, Ferschmann L, Parker N, Agartz I, Andreassen OA, Paus T, et al. New insights into the dynamic development of the cerebral cortex in childhood and adolescence: integrating macro- and microstructural MRI findings. Prog Neurobiol. 2021;204:102109.

Bennett MR. Schizophrenia: susceptibility genes, dendritic-spine pathology and gray matter loss. Prog Neurobiol. 2011;95:275–300.

Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–8.

Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.

Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.

Yilmaz M, Yalcin E, Presumey J, Aw E, Ma M, Whelan CW, et al. Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat Neurosci. 2021;24:214–24.

Druart M, Nosten-Bertrand M, Poll S, Crux S, Nebeling F, Delhaye C, et al. Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes. Mol Psychiatry. 2021;26:3489–501.

Chung WS, Allen NJ, Eroglu C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harb Perspect Biol. 2015;7:a020370.

Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504:394–400.

Caroni P, Chowdhury A, Lahr M. Synapse rearrangements upon learning: from divergent-sparse connectivity to dedicated sub-circuits. Trends Neurosci. 2014;37:604–14.

Stein IS, Zito K. Dendritic spine elimination: molecular mechanisms and implications. Neuroscientist. 2019;25:27–47.

Uesaka N, Kano M. Presynaptic mechanisms mediating retrograde semaphorin signals for climbing fiber synapse elimination during postnatal cerebellar development. Cerebellum. 2018;17:17–22.

Trubetskoy V, Pardinas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604:502–8.

International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.

Article   PubMed Central   Google Scholar  

Kim M, Haney JR, Zhang P, Hernandez LM, Wang LK, Perez-Cano L, et al. Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia. Nat Neurosci. 2021;24:799–809.

Lam M, Chen CY, Li Z, Martin AR, Bryois J, Ma X, et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat Genet. 2019;51:1670–8.

Abdellaoui A, Dolan CV, Verweij KJH, Nivard MG. Gene-environment correlations across geographic regions affect genome-wide association studies. Nat Genet. 2022;54:1345–54.

Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell. 2019;179:1469–82.e11.

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005;7:1167–78.

Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci. 2009;32:485–95.

Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008;40:751–60.

Mukai J, Dhilla A, Drew LJ, Stark KL, Cao L, MacDermott AB, et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat Neurosci. 2008;11:1302–10.

Davenport EC, Szulc BR, Drew J, Taylor J, Morgan T, Higgs NF, et al. Autism and schizophrenia-associated CYFIP1 regulates the balance of synaptic excitation and inhibition. Cell Rep. 2019;26:2037–51.e6.

De Rubeis S, Pasciuto E, Li KW, Fernandez E, Di Marino D, Buzzi A, et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron. 2013;79:1169–82.

Papaleo F, Yang F, Paterson C, Palumbo S, Carr GV, Wang Y, et al. Behavioral, neurophysiological, and synaptic impairment in a transgenic neuregulin1 (NRG1-IV) murine schizophrenia model. J Neurosci. 2016;36:4859–75.

Jia JM, Hu Z, Nordman J, Li Z. The schizophrenia susceptibility gene dysbindin regulates dendritic spine dynamics. J Neurosci. 2014;34:13725–36.

Liu WS, Pesold C, Rodriguez MA, Carboni G, Auta J, Lacor P, et al. Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse. Proc Natl Acad Sci USA. 2001;98:3477–82.

Jiang DY, Wu Z, Forsyth CT, Hu Y, Yee SP, Chen G. GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation. Mol Brain. 2018;11:31.

Li Z, Chen J, Yu H, He L, Xu Y, Zhang D, et al. Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nat Genet. 2017;49:1576–83.

Ikeda M, Takahashi A, Kamatani Y, Momozawa Y, Saito T, Kondo K, et al. Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect. Schizophr Bull. 2019;45:824–34.

Khandaker GM, Zimbron J, Lewis G, Jones PB. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med. 2013;43:239–57.

Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. Schizophrenia and influenza at the centenary of the 1918-1919 Spanish Influenza pandemic: mechanisms of psychosis risk. Front Psychiatry. 2020;11:72.

Mirabella F, Desiato G, Mancinelli S, Fossati G, Rasile M, Morini R, et al. Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring. Immunity. 2021;54:2611–31.e8.

Soumiya H, Fukumitsu H, Furukawa S. Prenatal immune challenge compromises development of upper-layer but not deeper-layer neurons of the mouse cerebral cortex. J Neurosci Res. 2011;89:1342–50.

Meyer U. Developmental neuroinflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:20–34.

Silva-Gómez AB, Rojas DX, Juárez I, Flores G. Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res. 2003;983:128–36.

Comery TA, Shah R, Greenough WT. Differential rearing alters spine density on medium-sized spiny neurons in the rat corpus striatum: evidence for association of morphological plasticity with early response gene expression. Neurobiol Learn Mem. 1995;63:217–9.

Colyn L, Venzala E, Marco S, Perez-Otano I, Tordera RM. Chronic social defeat stress induces sustained synaptic structural changes in the prefrontal cortex and amygdala. Behav Brain Res. 2019;373:112079.

Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002;22:6810–8.

Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4.

Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR, et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience. 2004;125:1–6.

Gilabert-Juan J, Bueno-Fernandez C, Castillo-Gomez E, Nacher J. Reduced interneuronal dendritic arborization in CA1 but not in CA3 region of mice subjected to chronic mild stress. Brain Behav. 2017;7:e00534.

Cieslik M, Gassowska-Dobrowolska M, Jesko H, Czapski GA, Wilkaniec A, Zawadzka A, et al. Maternal immune activation induces neuroinflammation and cortical synaptic deficits in the adolescent rat offspring. Int J Mol Sci. 2020;21:4097.

Li WY, Chang YC, Lee LJ, Lee LJ. Prenatal infection affects the neuronal architecture and cognitive function in adult mice. Dev Neurosci. 2014;36:359–70.

Kaul D, Smith CC, Stevens J, Frohlich AS, Binder EB, Mechawar N, et al. Severe childhood and adulthood stress associates with neocortical layer-specific reductions of mature spines in psychiatric disorders. Neurobiol Stress. 2020;13:100270.

Da Silva T, Guma E, Hafizi S, Koppel A, Rusjan P, Kennedy JL, et al. Genetically predicted brain C4A expression is associated with TSPO and hippocampal morphology. Biol Psychiatry. 2021;90:652–60.

O’Connell KS, Sonderby IE, Frei O, van der Meer D, Athanasiu L, Smeland OB, et al. Association between complement component 4A expression, cognitive performance and brain imaging measures in UK Biobank. Psychol Med. 2021;52:1–11.

PubMed   Google Scholar  

Stanley JA, Pettegrew JW, Keshavan MS. Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings–part I. Biol Psychiatry. 2000;48:357–68.

Prasad KM, Chowdari KV, D’Aiuto LA, Iyengar S, Stanley JA, Nimgaonkar VL. Neuropil contraction in relation to Complement C4 gene copy numbers in independent cohorts of adolescent-onset and young adult-onset schizophrenia patients-a pilot study. Transl Psychiatry. 2018;8:134.

Donohoe G, Holland J, Mothersill D, McCarthy-Jones S, Cosgrove D, Harold D, et al. Genetically predicted complement component 4A expression: effects on memory function and middle temporal lobe activation. Psychol Med. 2018;48:1608–15.

Osimo EF, Beck K, Reis Marques T, Howes OD. Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Mol Psychiatry. 2019;24:549–61.

Berdenis van Berlekom A, Muflihah CH, Snijders G, MacGillavry HD, Middeldorp J, Hol EM, et al. Synapse pathology in schizophrenia: a meta-analysis of postsynaptic elements in postmortem brain studies. Schizophr Bull. 2020;46:374–86.

Roberts RC, Barksdale KA, Roche JK, Lahti AC. Decreased synaptic and mitochondrial density in the postmortem anterior cingulate cortex in schizophrenia. Schizophr Res. 2015;168:543–53.

Aganova EA, Uranova NA. Morphometric analysis of synaptic contacts in the anterior limbic cortex in the endogenous psychoses. Neurosci Behav Physiol. 1992;22:59–65.

Kung L, Conley R, Chute DJ, Smialek J, Roberts RC. Synaptic changes in the striatum of schizophrenic cases: a controlled postmortem ultrastructural study. Synapse. 1998;28:125–39.

Mabry SJ, McCollum LA, Farmer CB, Bloom ES, Roberts RC. Evidence for altered excitatory and inhibitory tone in the post-mortem substantia nigra in schizophrenia. World J Biol Psychiatry. 2020;21:339–56.

McCullumsmith RE, Hammond JH, Shan D, Meador-Woodruff JH. Postmortem brain: an underutilized substrate for studying severe mental illness. Neuropsychopharmacology. 2014;39:65–87.

Wang M, Zhang L, Gage FH. Modeling neuropsychiatric disorders using human induced pluripotent stem cells. Protein Cell. 2020;11:45–59.

Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22:374–85.

Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.

Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, 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;173:44–52.

Noh H, Shao Z, Coyle JT, Chung S. Modeling schizophrenia pathogenesis using patient-derived induced pluripotent stem cells (iPSCs). Biochim Biophys Acta Mol Basis Dis. 2017;1863:2382–7.

Shen X, Yeung HT, Lai KO. Application of human-induced pluripotent stem cells (hiPSCs) to study synaptopathy of neurodevelopmental disorders. Dev Neurobiol. 2019;79:20–35.

Kuo SS, Pogue-Geile MF. Variation in fourteen brain structure volumes in schizophrenia: a comprehensive meta-analysis of 246 studies. Neurosci Biobehav Rev. 2019;98:85–94.

Enigma Clinical High Risk for Psychosis Working Group, Jalbrzikowski M, Hayes RA, Wood SJ, Nordholm D, Zhou JH, et al. Association of structural magnetic resonance imaging measures with psychosis onset in individuals at clinical high risk for developing psychosis: an ENIGMA Working Group mega-analysis. JAMA Psychiatry. 2021;78:753–66.

Article   Google Scholar  

Cannon TD, Chung Y, He G, Sun D, Jacobson A, van Erp TG, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry. 2015;77:147–57.

Zhao Y, Zhang Q, Shah C, Li Q, Sweeney JA, Li F, et al. Cortical thickness abnormalities at different stages of the illness course in schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry. 2022;79:560–70.

Cropley VL, Klauser P, Lenroot RK, Bruggemann J, Sundram S, Bousman C, et al. Accelerated gray and white matter deterioration with age in schizophrenia. Am J Psychiatry. 2017;174:286–95.

Vita A, De Peri L, Deste G, Sacchetti E. Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. Transl Psychiatry. 2012;2:e190.

Vita A, De Peri L, Deste G, Barlati S, Sacchetti E. The effect of antipsychotic treatment on cortical gray matter changes in schizophrenia: does the class matter? A meta-analysis and meta-regression of longitudinal magnetic resonance imaging studies. Biol Psychiatry. 2015;78:403–12.

Ziermans TB, Schothorst PF, Schnack HG, Koolschijn PC, Kahn RS, van Engeland H, et al. Progressive structural brain changes during development of psychosis. Schizophr Bull. 2012;38:519–30.

Padmanabhan JL, Tandon N, Haller CS, Mathew IT, Eack SM, Clementz BA, et al. Correlations between brain structure and symptom dimensions of psychosis in schizophrenia, schizoaffective, and psychotic bipolar I disorders. Schizophr Bull. 2015;41:154–62.

Lui S, Deng W, Huang XQ, Jiang LJ, Ma XH, Chen HF, et al. Association of cerebral deficits with clinical symptoms in antipsychotic-naive first-episode schizophrenia: an optimized voxel-based morphometry and resting state functional connectivity study. Am J Psychiatry. 2009;166:196–205.

Hulshoff Pol HE, Kahn RS. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull. 2008;34:354–66.

Kassem MS, Lagopoulos J, Stait-Gardner T, Price WS, Chohan TW, Arnold JC, et al. Stress-induced grey matter loss determined by MRI is primarily due to loss of dendrites and their synapses. Mol Neurobiol. 2013;47:645–61.

Keifer OP Jr., Hurt RC, Gutman DA, Keilholz SD, Gourley SL, Ressler KJ. Voxel-based morphometry predicts shifts in dendritic spine density and morphology with auditory fear conditioning. Nat Commun. 2015;6:7582.

Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40–68. image 5

Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry. 1999;45:17–25.

Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM, et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry. 1998;65:446–53.

Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000;57:65–73.

Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107.

MacDonald ML, Alhassan J, Newman JT, Richard M, Gu H, Kelly RM, et al. Selective loss of smaller spines in schizophrenia. Am J Psychiatry. 2017;174:586–94.

Davidsson P, Gottfries J, Bogdanovic N, Ekman R, Karlsson I, Gottfries C-G, et al. The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains. Schizophr Res. 1999;40:23–9.

Matosin N, Fernandez-Enright F, Lum JS, Engel M, Andrews JL, Gassen NC, et al. Molecular evidence of synaptic pathology in the CA1 region in schizophrenia. NPJ Schizophr. 2016;2:16022.

Eastwood SL, Harrison PJ. Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience. 1995;69:339–43.

Glantz LA, Lewis DA. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity. Arch Gen Psychiatry. 1997;54:660–9.

May A, Gaser C. Magnetic resonance-based morphometry: a window into structural plasticity of the brain. Curr Opin Neurol. 2006;19:407–11.

Howes OD, Cummings C, Chapman GE, Shatalina E. Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes. Neuropsychopharmacology. 2023;48:151–67.

Weinberger DR, Radulescu E. Structural magnetic resonance imaging all over again. JAMA Psychiatry. 2021;78:11–2.

Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8:348ra96.

Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, et al. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016;57:777–84.

Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA. 2004;101:9861–6.

Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci. 1994;14:5223–35.

Looney MR, Dohan FC Jr, Davies KG, Seidenberg M, Hermann BP, Schweitzer JB. Synaptophysin immunoreactivity in temporal lobe epilepsy-associated hippocampal sclerosis. Acta Neuropathol. 1999;98:179–85.

Mutch SA, Kensel-Hammes P, Gadd JC, Fujimoto BS, Allen RW, Schiro PG, et al. Protein quantification at the single vesicle level reveals that a subset of synaptic vesicle proteins are trafficked with high precision. J Neurosci. 2011;31:1461–70.

Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, et al. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018;75:1215–24.

Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel M-C, Wells L, et al. Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat Commun. 2020;11:246.

Radhakrishnan R, Skosnik PD, Ranganathan M, Naganawa M, Toyonaga T, Finnema S, et al. In vivo evidence of lower synaptic vesicle density in schizophrenia. Mol Psychiatry. 2021;26:7690–8.

Mudge J, Miller NA, Khrebtukova I, Lindquist IE, May GD, Huntley JJ, et al. Genomic convergence analysis of schizophrenia: mRNA sequencing reveals altered synaptic vesicular transport in post-mortem cerebellum. PLoS One. 2008;3:e3625.

Onwordi EC, Whitehurst T, Mansur A, Statton B, Berry A, Quinlan M, et al. The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study. Transl Psychiatry. 2021;11:393.

Moyer CE, Shelton MA, Sweet RA. Dendritic spine alterations in schizophrenia. Neurosci Lett. 2015;601:46–53.

Rosso IM, Cannon TD, Huttunen T, Huttunen MO, Lonnqvist J, Gasperoni TL. Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort. Am J Psychiatry. 2000;157:801–7.

Howes OD, McCutcheon R. Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization. Transl Psychiatry. 2017;7:e1024.

Giovanoli S, Engler H, Engler A, Richetto J, Voget M, Willi R, et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science. 2013;339:1095–9.

Tynan RJ, Naicker S, Hinwood M, Nalivaiko E, Buller KM, Pow DV, et al. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun. 2010;24:1058–68.

Hinwood M, Morandini J, Day TA, Walker FR. Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex. 2012;22:1442–54.

Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl). 2016;233:1637–50.

Wohleb ES, Fenn AM, Pacenta AM, Powell ND, Sheridan JF, Godbout JP. Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology. 2012;37:1491–505.

Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459:698–702.

Howes OD, Shatalina E. Integrating the neurodevelopmental and dopamine hypotheses of schizophrenia and the role of cortical excitation-inhibition balance. Biol Psychiatry. 2022;92:501–13.

Townsend L, Pillinger T, Selvaggi P, Veronese M, Turkheimer F, Howes O. Brain glucose metabolism in schizophrenia: a systematic review and meta-analysis of (18)FDG-PET studies in schizophrenia. Psychol Med. 2022:1–18.

Friston K, Brown HR, Siemerkus J, Stephan KE. The dysconnection hypothesis (2016). Schizophr Res. 2016;176:83–94.

Fornito A, Harrison BJ, Goodby E, Dean A, Ooi C, Nathan PJ, et al. Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis. JAMA Psychiatry. 2013;70:1143–51.

Cui LB, Liu K, Li C, Wang LX, Guo F, Tian P, et al. Putamen-related regional and network functional deficits in first-episode schizophrenia with auditory verbal hallucinations. Schizophr Res. 2016;173:13–22.

White TP, Wigton R, Joyce DW, Collier T, Fornito A, Shergill SS. Dysfunctional striatal systems in treatment-resistant schizophrenia. Neuropsychopharmacology. 2016;41:1274–85.

Shukla DK, Chiappelli JJ, Sampath H, Kochunov P, Hare SM, Wisner K, et al. Aberrant frontostriatal connectivity in negative symptoms of schizophrenia. Schizophr Bull. 2019;45:1051–9.

O’Neill A, Mechelli A, Bhattacharyya S. Dysconnectivity of large-scale functional networks in early psychosis: a meta-analysis. Schizophr Bull. 2019;45:579–90.

Lord LD, Allen P, Expert P, Howes O, Lambiotte R, McGuire P, et al. Characterization of the anterior cingulate’s role in the at-risk mental state using graph theory. Neuroimage. 2011;56:1531–9.

Zhang K, Huang D, Shah NJ. Comparison of resting-state brain activation detected by BOLD, blood volume and blood flow. Front Hum Neurosci. 2018;12:443.

McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry. 2020;19:15–33.

Quiroz C, Orru M, Rea W, Ciudad-Roberts A, Yepes G, Britt JP, et al. Local control of extracellular dopamine levels in the medial nucleus accumbens by a glutamatergic projection from the infralimbic cortex. J Neurosci. 2016;36:851–9.

Kim IH, Rossi MA, Aryal DK, Racz B, Kim N, Uezu A, et al. Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine. Nat Neurosci. 2015;18:883–91.

Kokkinou M, Irvine EE, Bonsall DR, Natesan S, Wells LA, Smith M, et al. Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine. Mol Psychiatry. 2021;26:2562–76.

D’Ambrosio E, Jauhar S, Kim S, Veronese M, Rogdaki M, Pepper F, et al. The relationship between grey matter volume and striatal dopamine function in psychosis: a multimodal (18)F-DOPA PET and voxel-based morphometry study. Mol Psychiatry. 2021;26:1332–45.

Howes OD, Hird EJ, Adams RA, Corlett PR, McGuire P. Aberrant salience, information processing, and dopaminergic signaling in people at clinical high risk for psychosis. Biol Psychiatry. 2020;88:304–14.

Cahn W, Rais M, Stigter FP, van Haren NE, Caspers E, Hulshoff Pol HE, et al. Psychosis and brain volume changes during the first five years of schizophrenia. Eur Neuropsychopharmacol. 2009;19:147–51.

Howes OD, Whitehurst T, Shatalina E, Townsend L, Onwordi EC, Mak TLA, et al. The clinical significance of duration of untreated psychosis: an umbrella review and random-effects meta-analysis. World Psychiatry. 2021;20:75–95.

van Kesteren CF, Gremmels H, de Witte LD, Hol EM, Van Gool AR, Falkai PG, et al. Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psychiatry. 2017;7:e1075.

Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P, et al. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med. 2019;49:2186–96.

Plaven-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD, et al. Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data. Biol Psychiatry. 2018;84:433–42.

Kopschina Feltes P, de Vries EF, Juarez-Orozco LE, Kurtys E, Dierckx RA, Moriguchi-Jeckel CM, et al. Repeated social defeat induces transient glial activation and brain hypometabolism: a positron emission tomography imaging study. J Cereb Blood Flow Metab. 2019;39:439–53.

McCluskey SP, Plisson C, Rabiner EA, Howes O. Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development. Eur J Nucl Med Mol Imaging. 2020;47:451–89.

Gracias J, Orhan F, Horbeck E, Holmen-Larsson J, Khanlarkani N, Malwade S, et al. Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia. Nat Commun. 2022;13:6427.

Wolfers T, Doan NT, Kaufmann T, Alnaes D, Moberget T, Agartz I, et al. Mapping the heterogeneous phenotype of schizophrenia and bipolar disorder using normative models. JAMA Psychiatry. 2018;75:1146–55.

Kane JM, Agid O, Baldwin ML, Howes O, Lindenmayer JP, Marder S, et al. Clinical guidance on the identification and management of treatment-resistant schizophrenia. J Clin Psychiatry. 2019;80:18com12123.

Jauhar S, Veronese M, Nour MM, Rogdaki M, Hathway P, Turkheimer FE, et al. Determinants of treatment response in first-episode psychosis: an (18)F-DOPA PET study. Mol Psychiatry. 2019;24:1502–12.

Veronese M, Santangelo B, Jauhar S, D’Ambrosio E, Demjaha A, Salimbeni H, et al. A potential biomarker for treatment stratification in psychosis: evaluation of an [(18)F] FDOPA PET imaging approach. Neuropsychopharmacology. 2021;46:1122–32.

Jaaskelainen E, Juola P, Hirvonen N, McGrath JJ, Saha S, Isohanni M, et al. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013;39:1296–306.

Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473:221–5.

Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515:414–8.

Shao Z, Noh H, Bin Kim W, Ni P, Nguyen C, Cote SE, et al. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia. Nat Neurosci. 2019;22:229–42.

Kathuria A, Lopez-Lengowski K, Watmuff B, McPhie D, Cohen BM, Karmacharya R. Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine. Transl Psychiatry. 2019;9:321.

Grunwald LM, Stock R, Haag K, Buckenmaier S, Eberle MC, Wildgruber D, et al. Comparative characterization of human induced pluripotent stem cells (hiPSC) derived from patients with schizophrenia and autism. Transl Psychiatry. 2019;9:179.

Download references

Acknowledgements

For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Figures were created with BioRender.com and Inkscape.

This study was funded by Medical Research Council-UK (no. MC_U120097115), Maudsley Charity (no. 666), and Wellcome Trust (no. 094849/Z/10/Z) grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. ECO acknowledges funding from NIHR. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Author information

Authors and affiliations.

Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, London, W12 0NN, UK

Oliver D. Howes & Ellis Chika Onwordi

Psychiatric Imaging Group, Medical Research Council, London Institute of Medical Sciences, Hammersmith Hospital, London, W12 0NN, UK

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, SE5 8AF, UK

Centre for Psychiatry and Mental Health, Wolfson Institute of Population Health, Queen Mary University of London, London, E1 2AB, UK

Ellis Chika Onwordi

You can also search for this author in PubMed   Google Scholar

Contributions

Conceptualisation, formal analysis, methodology, project administration, resources, supervision, validation and writing—review and editing: ODH and ECO. Funding acquisition: ODH and ECO. Data curation, investigation, software, visualisation and writing—original draft: ECO.

Corresponding authors

Correspondence to Oliver D. Howes or Ellis Chika Onwordi .

Ethics declarations

Competing interests.

ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angelini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/Mylan and was a part time employee of H Lundbeck A/s. ODH has a patent for the use of dopaminergic imaging. No other conflicts of interest were declared.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Howes, O.D., Onwordi, E.C. The synaptic hypothesis of schizophrenia version III: a master mechanism. Mol Psychiatry 28 , 1843–1856 (2023). https://doi.org/10.1038/s41380-023-02043-w

Download citation

Received : 30 June 2022

Revised : 16 March 2023

Accepted : 20 March 2023

Published : 11 April 2023

Issue Date : May 2023

DOI : https://doi.org/10.1038/s41380-023-02043-w

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Schizophrenia: from neurochemistry to circuits, symptoms and treatments.

• Oliver D. Howes
• Bernard R. Bukala
• Katherine Beck

Nature Reviews Neurology (2024)

Cortical gene expression architecture links healthy neurodevelopment to the imaging, transcriptomics and genetics of autism and schizophrenia

• Richard Dear
• Konrad Wagstyl
• Petra E. Vértes

Nature Neuroscience (2024)

Parkinson’s disease and schizophrenia interactomes contain temporally distinct gene clusters underlying comorbid mechanisms and unique disease processes

• Kalyani B. Karunakaran
• Sanjeev Jain
• Madhavi K. Ganapathiraju

Schizophrenia (2024)

Association study of the complement component C4 gene and suicide risk in schizophrenia

• Mahbod Ebrahimi
• Kowsar Teymouri
• James L. Kennedy

Psychosis and autism spectrum disorder: a special issue of Molecular Psychiatry

• Julio Licinio

Molecular Psychiatry (2023)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies