Inflammation and immunity in schizophrenia: Implications for pathophysiology and treatment

The Lancet Psychiatry

Volumn 2, Issue 3, 2015, Pages 258-270

  Khandaker, Golam M ^a,b,c   Cousins, Lesley ^a,b,c   Deakin, Julia ^a,b,c   Lennox, Belinda R ^d   Yolken, Robert ^e   Jones, Peter B ^a,b,c  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b National Institute for Health Research Cambridge Biomedical Research Centre ^*  (United Kingdom)

^c CAMBRIDGESHIRE AND PETERBOROUGH NHS FOUNDATION TRUST   (United Kingdom)

^d UNIVERSITY OF OXFORD   (United Kingdom)

^e JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; AUTOANTIBODY; BENZODIAZEPINE DERIVATIVE; CYTOKINE; NEUROTRANSMITTER;

ADAPTIVE IMMUNITY; BLOOD BRAIN BARRIER; BRAIN; CELL SURFACE; CLINICAL TRIAL (TOPIC); COGNITION; HUMAN; IMMUNE DYSREGULATION; IMMUNE SYSTEM; IMMUNITY; INFECTION; INFLAMMATION; INNATE IMMUNITY; MENTAL DISEASE; MICROBIOME; MICROGLIA; MOOD; NERVE CELL DIFFERENTIATION; NERVE DEGENERATION; PATHOPHYSIOLOGY; PHYSICIAN; PSYCHOSIS; REVIEW; SCHIZOPHRENIA; T LYMPHOCYTE; IMMUNOLOGY; RANDOMIZED CONTROLLED TRIAL (TOPIC);

HUMANS; IMMUNE SYSTEM; INFLAMMATION; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SCHIZOPHRENIA;

EID: 84923302342     PISSN: 22150366     EISSN: 22150374     Source Type: Journal    
DOI: 10.1016/S2215-0366(14)00122-9     Document Type: Review

References (129)

1. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008, 9:46-56.
2. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB Association of serum interleukin-6 and c-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitdunal study. JAMA Psychiatry 2014, 71:1121-1128.
3. McFarland HF, Martin R Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 2007, 8:913-919.
4. Dantzer R Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 2004, 500:399-411.
5. Miller AH, Maletic V, Raison CL Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009, 65:732-741.
6. Zandi MS, Irani SR, Lang B, et al. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol 2011, 258:686-688.
7. Neurophysiology 2002, Hodder Arnold, London. 4th edn. R.H.S. Carpenter (Ed.).
8. Immunobiology: the immune system in health and disease 2001, Garland Science, New York. 5th edn. C.A. Janeway, P. Travers, M. Walport, M.J. Shlomchik (Eds.).
9. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC CNS immune privilege: hiding in plain sight. Immunol Rev 2006, 213:48-65.
10. Hanisch UK, Kettenmann H Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10:1387-1394.
11. Kirkbride JB, Errazuriz A, Croudace TJ, et al. Incidence of schizophrenia and other psychoses in England, 1950-2009: a systematic review and meta-analyses. PloS One 2012, 7:e31660.
12. Khandaker GM, Clarke M, Cannon M, Jones PB Life course approach to specific mental disorders: schizophrenia and related psychosis. Life course epidemiology of mental disorders 2014, 61-75. Oxford University Press, New York, NY. 1st edn. K. Koenen, S. Rudenstine, E. Susser, S. Galeo (Eds.).
13. Brown AS, Derkits EJ Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 2010, 167:261-280.
14. Khandaker GM, Zimbron J, Dalman C, Lewis G, Jones PB Childhood infection and adult schizophrenia: a meta-analysis of population-based studies. Schizophr Res 2012, 139:161-168.
15. 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, 43:239-257.
16. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011, 70:663-671.
17. Canetta S, Sourander A, Surcel HM, et al. Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. Am J Psychiatry 2014, 171:960-968.
18. Gardner RM, Dalman C, Wicks S, Lee BK, Karlsson H Neonatal levels of acute phase proteins and later risk of non-affective psychosis. Transl Psychiatry 2013, 3:e228.
19. Khandaker GM, Stochl J, Zammit S, Lewis G, Jones PB Childhood Epstein-Barr Virus infection and subsequent risk of psychotic experiences in adolescence: A population-based prospective serological study. Schizophr Res 2014, 158:19-24.
20. Torrey EF, Bartko JJ, Yolken RH Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull (Bp) 2012, 38:642-647.
21. Khandaker GM, Zammit S, Lewis G, Jones PB A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophr Res 2014, 152:139-145.
22. Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry 2011, 168:1303-1310.
23. Eaton WW, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006, 163:521-528.
24. Engelhardt B, Sorokin L The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 2009, 31:497-511.
25. Shi J, Levinson DF, Duan J, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009, 460:753-757.
26. Stefansson H, Ophoff RA, Steinberg S, et al. Common variants conferring risk of schizophrenia. Nature 2009, 460:744-747.
27. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014, 511:421-427. Schizophrenia Working Group of the Psychiatric Genomics Consortium.
28. Andreassen OA, Harbo HF, Wang Y, et al. Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. Mol Psychiatry 2014, published online Jan 28. http://dx.doi.org/10.1038/mp.2013.195.
29. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 2008, 63:801-808.
30. Upthegrove R, Manzanares-Teson N, Barnes NM Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res 2014, 155:101-108.
31. Wium-Andersen MK, Orsted DD, Nordestgaard BG Elevated C-reactive protein associated with late- and very-late-onset schizophrenia in the general population: a prospective study. Schizophr Bull (Bp) 2014, 40:1117-1127.
32. Ganguli R, Brar JS, Chengappa KN, Yang ZW, Nimgaonkar VL, Rabin BS Autoimmunity in schizophrenia: a review of recent findings. Ann Med 1993, 25:489-496.
33. Garver DL, Tamas RL, Holcomb JA Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. Neuropsychopharmacology 2003, 28:1515-1520.
34. Hayes LN, Severance EG, Leek JT, et al. Inflammatory molecular signature associated with infectious agents in psychosis. Schizophr Bull (Bp) 2014, 40:963-972.
35. Stojanovic A, Martorell L, Montalvo I, et al. Increased serum interleukin-6 levels in early stages of psychosis: associations with at-risk mental states and the severity of psychotic symptoms. Psychoneuroendocrinology 2014, 41:23-32.
36. de Witte L, Tomasik J, Schwarz E, et al. Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophr Res 2014, 154:23-29.
37. Maes M, Meltzer HY, Bosmans E Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine. Acta Psychiatr Scand 1994, 89:346-351.
38. Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res 1995, 29:141-152.
39. Maes M, Bosmans E, Kenis G, De Jong R, Smith RS, Meltzer HY In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr Res 1997, 26:221-225.
40. Yirmiya R, Goshen I Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011, 25:181-213.
41. Harrison NA, Doeller CF, Voon V, Burgess N, Critchley HD Peripheral Inflammation Acutely Impairs Human Spatial Memory via Actions on Medial Temporal Lobe Glucose Metabolism. Biol Psychiatry 2014, 76:585-593.
42. Eraly SA, Nievergelt CM, Maihofer AX, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 2014, 71:423-431.
43. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 2008, 65:409-415.
44. Walker AK, Budac DP, Bisulco S, et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 2013, 38:1609-1616.
45. Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001, 58:445-452.
46. Santambrogio L, Belyanskaya SL, Fischer FR, et al. Developmental plasticity of CNS microglia. Proc Natl Acad Sci USA 2001, 98:6295-6300.
47. Ransohoff RM, Perry VH Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 2009, 27:119-145.
48. Perry VH, Nicoll JA, Holmes C Microglia in neurodegenerative disease. Nat Rev Neurol 2010, 6:193-201.
49. van Berckel BN, Bossong MG, Boellaard R, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008, 64:820-822.
50. Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 2009, 50:1801-1807.
51. Schroder K, Sweet MJ, Hume DA Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology 2006, 211:511-524.
52. Brennand KJ, Simone A, Jou J, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011, 473:221-225.
53. Lehmann-Facius H Über die Liquordiagnose der Schizophrenien. Klinische Wochenschrift 1937, 16:1646-1648. (in German).
54. Lachance LR, McKenzie K Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis. Schizophr Res 2014, 152:521-527.
55. Rothermundt M, Arolt V, Bayer TA Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun 2001, 15:319-339.
56. Deakin J, Lennox BR, Zandi MS Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis. Biol Psychiatry 2014, 75:284-291.
57. Lennox BR, Vincent A Antibody-mediated encephalitis: a treatable cause of schizophrenia?. Br J Psychiatry 2012, 200:92-94.
58. Parthasarathi UD, Harrower T, Tempest M, et al. Psychiatric presentation of voltage-gated potassium channel antibody-associated encephalopathy. Case report. Br J Psychiatry 2006, 189:182-183.
59. Steiner J, Walter M, Glanz W, et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 2013, 70:271-278.
60. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011, 10:63-74.
61. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013, 12:157-165.
62. Pearlman DM, Najjar S Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder. Schizophr Res 2014, 157:249-258.
63. Pomarol-Clotet E, Honey GD, Murray GK, et al. Psychological effects of ketamine in healthy volunteers. Phenomenological study. Br J Psychiatry 2006, 189:173-179.
64. Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014, 506:179-184.
65. Nikkila HV, Muller K, Ahokas A, Rimon R, Andersson LC Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 2001, 49:99-105.
66. Nikkila H, Muller K, Ahokas A, Miettinen K, Andersson LC, Rimon R Abnormal distributions of T-lymphocyte subsets in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 1995, 14:215-221.
67. Busse S, Busse M, Schiltz K, et al. Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations?. Brain Behav Immun 2012, 26:1273-1279.
68. Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2013, 73:993-999.
69. Meyer U, Feldon J Neural basis of psychosis-related behaviour in the infection model of schizophrenia. Behav Brain Res 2009, 204:322-334.
70. Carlsson M, Carlsson A Schizophrenia: a subcortical neurotransmitter imbalance syndrome?. Schizophr Bull (Bp) 1990, 16:425-432.
71. Schwarcz R, Pellicciari R Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 2002, 303:1-10.
72. Stone TW Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 1993, 45:309-379.
73. Schwieler L, Erhardt S, Erhardt C, Engberg G Prostaglandin-mediated control of rat brain kynurenic acid synthesis-opposite actions by COX-1 and COX-2 isoforms. J Neural Transm 2005, 112:863-872.
74. Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res 2007, 90:179-185.
75. Muller N, Krause D, Dehning S, et al. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res 2010, 121:118-124.
76. Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S The immunoregulatory role of dopamine: an update. Brain Behav Immun 2010, 24:525-528.
77. Besser MJ, Ganor Y, Levite M Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFalpha or both. J Neuroimmunol 2005, 169:161-171.
78. Levite M, Chowers Y, Ganor Y, Besser M, Hershkovits R, Cahalon L Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates beta1 integrin function. Eur J Immunol 2001, 31:3504-3512.
79. Ilani T, Ben-Shachar D, Strous RD, et al. A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes. Proc Natl Acad Sci USA 2001, 98:625-628.
80. Nagai Y, Ueno S, Saeki Y, Soga F, Hirano M, Yanagihara T Decrease of the D3 dopamine receptor mRNA expression in lymphocytes from patients with Parkinson's disease. Neurology 1996, 46:791-795.
81. Woods BT Is schizophrenia a Progressive Neurodevelopmental Disorder? Toward a Unitary Pathogenetic Mechanism. Am J Psychiatry 1998, 155:1661-1670.
82. Harrison PJ The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999, 122:593-624.
83. Veijola J, Guo JY, Moilanen JS, et al. Longitudinal changes in total brain volume in schizophrenia: relation to symptom severity, cognition and antipsychotic medication. PloS One 2014, 9:e101689.
84. Flatow J, Buckley P, Miller BJ Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry 2013, 74:400-409.
85. Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain 2012, 135:2809-2816.
86. Iwashyna TJ, Ely EW, Smith DM, Langa KM Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010, 304:1787-1794.
87. Khandaker GM, Jones PB Cognitive and functional impairment after severe sepsis. JAMA 2011, 305:673-674.
88. Murray RM, Lewis SW Is schizophrenia a neurodevelopmental disorder?. BMJ (Clin Res Ed) 1987, 295:681-682.
89. Weinberger DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987, 44:660-669.
90. Meyer U, Feldon J Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol 2010, 90:285-326.
91. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007, 27:10695-10702.
92. Clarke MC, Tanskanen A, Huttunen M, Whittaker JC, Cannon M Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am J Psychiatry 2009, 166:1025-1030.
93. Nielsen PR, Laursen TM, Mortensen PB Association Between Parental Hospital-Treated Infection and the Risk of Schizophrenia in Adolescence and Early Adulthood. Schizophr Bull (Bp) 2013, 39:230-237.
94. Collins SM, Surette M, Bercik P The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012, 10:735-742.
95. Cryan JF, Dinan TG Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012, 13:701-712.
96. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013, 155:1451-1463.
97. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 2011, 108:16050-16055.
98. Severance EG, Alaedini A, Yang S, et al. Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res 2012, 138:48-53.
99. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 2010, 170:1179-1188.
100. O'Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005, 128:541-551.
101. Schwarz E, van Beveren NJ, Ramsey J, et al. Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathways. Schizophr Bull (Bp) 2014, 40:787-795.
102. Laan W, Selten JP, Grobbee DE, Smeets H, Kahn RS, Burger H Non-steroidal anti-inflammatory drugs and the risk of psychosis. Eur Neuropsychopharmacol 2007, 17:309-311.
103. Stolk P, Souverein PC, Leufkens HG, Weil JG, Egberts AC, Heerdink ER The association between exposure to COX-2 inhibitors and schizophrenia deterioration. A nested case-control study. Pharmacopsychiatry 2007, 40:111-115.
104. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2010, 71:520-527.
105. Baheti T, Nischal A, Nischal A, et al. A study to evaluate the effect of celecoxib as add-on to olanzapine therapy in schizophrenia. Schizophr Res 2013, 147:201-202.
106. Muller N, Riedel M, Scheppach C, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 2002, 159:1029-1034.
107. Muller N, Ulmschneider M, Scheppach C, et al. COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci 2004, 254:14-22.
108. Muller N, Riedel M, Schwarz MJ, Engel RR Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci 2005, 255:149-151.
109. Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry 2005, 57:1594-1596.
110. Bresee CJ, Delrahim K, Maddux RE, Dolnak D, Ahmadpour O, Rapaport MH The effects of celecoxib augmentation on cytokine levels in schizophrenia. Int J Neuropsychopharmacol 2006, 9:343-348.
111. Levkovitz Y, Mendlovich S, Riwkes S, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 2010, 71:138-149.
112. Chaudhry IB, Hallak J, Husain N, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 2012, 26:1185-1193.
113. Webb JR, Stubbe DE, Poncin YB Aspirin as an adjunctive treatment for childhood onset schizophrenia. J Child Adolesc Psychopharmacol 2013, 23:585-586.
114. Jhamnani K, Shivakumar V, Kalmady S, Rao NP, Venkatasubramanian G Successful use of add-on minocycline for treatment of persistent negative symptoms in schizophrenia. J Neuropsychiatry Clin Neurosci 2013, 25:E06-E07.
115. Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J Minocycline as adjunctive therapy for schizophrenia: an open-label study. Clin Neuropharmacol 2008, 31:287-292.
116. Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J Possible antipsychotic effects of minocycline in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31:304-307.
117. Chaves C, de Marque CR, Wichert-Ana L, et al. Functional neuroimaging of minocycline's effect in a patient with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2010, 34:550-552.
118. Kelly DL, Vyas G, Richardson CM, et al. Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms. Schizophr Res 2011, 133:257-258.
119. Sommer IE, de Witte L, Begemann M, Kahn RS Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry 2012, 73:414-419.
120. Mukherjee D, Nissen SE, Topol EJ Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001, 286:954-959.
121. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013, 70:31-41.
122. Carvalho LA, Torre JP, Papadopoulos AS, et al. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord 2013, 148:136-140.
123. Zunszain PA, Horowitz MA, Cattaneo A, Lupi MM, Pariante CM Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as underlying mechanisms of its antidepressant properties. Mol Psychiatry 2013, 18:1236-1241.
124. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006, 63:856-864.
125. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013, 170:1134-1142.
126. Zarate CA, Mathews D, Ibrahim L, et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 2013, 74:257-264.
127. Bullmore ET, Lynall ME Immunologic therapeutics and psychotic disorders. Biol Psychiatry 2014, 75:260-261.
128. Danesh J, Kaptoge S, Mann AG, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008, 5:e78.
129. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001, 286:327-334.