Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-669899f699-ggqkh Total loading time: 0 Render date: 2025-05-04T10:49:51.481Z Has data issue: false hasContentIssue false

Chapter 6 - Effectiveness of Immunotherapies for Psychotic Disorders

Published online by Cambridge University Press:  02 September 2021

By
Rachel Upthegrove  and
Bill Deakin
Edited by
Golam Khandaker ,
Neil Harrison ,
Edward Bullmore  and
Robert Dantzer
Golam Khandaker
Affiliation:
University of Cambridge
Neil Harrison
Affiliation:
Cardiff University Brain Research Imaging Centre (CUBRIC)
Edward Bullmore
Affiliation:
University of Cambridge
Robert Dantzer
Affiliation:
University of Texas, MD Anderson Cancer Center
Get access

Summary

There is consistent evidence that psychosis is associated with a degree of peripheral immune activation. Many studies and meta-analyses report increased circulating concentrations of pro-inflammatory cytokines including IL-6, IL-1β and TNF-α together with acute phase proteins, such as CRP in patients with psychosis compared with controls. Meta-analysis confirms increased circulating IL-6 and other inflammatory markers in medication-naïve first-episode psychosis (FEP) (1), and in the CSF of schizophrenia patients compared with controls (2). Longitudinal studies show an association between elevated IL-6/CRP in childhood/adolescence and risk of psychotic symptoms or diagnosis of schizophrenia in adulthood (3,4). Genetic analysis shows that possession of a functional variant in the IL-6 R gene (Asp358Ala, rs2228145), which is known to reduce the activity of IL-6, is also associated with decreased risk of psychosis (5). This suggests that the association of raised IL-6 with psychosis may be causal and not due to reverse causality or residual confounding, i.e., the effect of a factor associated with psychosis that also by chance increases levels of this cytokine. However, Mendelian randomization analysis also suggests that elevated CRP levels may be protective for schizophrenia (6), in contrast to observational studies consistently reporting higher CRP levels in patients with the illness compared with controls (7). Divergent results for two known pro-inflammatory markers raises questions about potential mechanisms though which immune dysfunction may influence brain and behaviour to increase the risk of psychotic disorders. One explanation is that genetically predicted levels of low CRP may predispose to infections, which in turn, may increase schizophrenia risk through immune and non-immune mechanisms (6,8).

Type
Chapter
Information
Textbook of Immunopsychiatry , pp. 96 - 108
Publisher: Cambridge University Press
Print publication year: 2021

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Upthegrove, RN, Manzanares-Teson, NM Barnes, NM. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophrenia Research. 2014;155(1–3):101–8.Google Scholar
Wang, AK, Miller, BJ. Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and depression. Schizophr Bull. 2018;44(1):75–83.Google Scholar
Khandaker, GM, Pearson, RM, Zammit, S, et al. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 2014;71(10):1121–8.CrossRefGoogle ScholarPubMed
Metcalf, SA, Jones, PB, Nordstrom, T, et al. Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study. Brain Behav Immun. 2017;59:253–9.Google Scholar
Khandaker, GM, Zammit, S, Burgess, S, et al. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain, Behavior, and Immunity. 2018;69:264–72.Google Scholar
Hartwig, FP, Borges, MC, Horta, BL, et al. Inflammatory biomarkers and risk of schizophrenia: a 2-sample Mendelian randomization study. JAMA Psychiatry. 2017;74(12):1226–33.Google Scholar
Miller, BJ Culpepper, N, Rapaport, MH. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin Schizophr Relat Psychoses. 2014;7(4):223–30.CrossRefGoogle ScholarPubMed
Khandaker, GM. Commentary: causal associations between inflammation, cardiometabolic markers and schizophrenia: the known unknowns. International Journal of Epidemiology. 2019;48(5)1735.CrossRefGoogle ScholarPubMed
Upthegrove, R, Barnes, NM. The immune system and schizophrenia: an update for clinicians. Advances in Psychiatric Treatment. 2014;20(2):83–91.CrossRefGoogle Scholar
Khandaker, GM, Dantzer, R. Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology (Berl). 2016;233(9):1559–73.Google Scholar
Notter, T, Coughlin, JM, Gschwind, T, et al. Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia. Molecular Psychiatry. 2018;23(2):323.Google Scholar
Das, TK, Javadzadeh, A, Dey, A, et al. Antioxidant defense in schizophrenia and bipolar disorder: a meta-analysis of MRS studies of anterior cingulate glutathione. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019;91:94–102.Google Scholar
Barnes, TR, Leeson, VC, Mutsatsa, SH, et al. Duration of untreated psychosis and social function: 1-year follow-up study of first-episode schizophrenia. The British Journal of Psychiatry. 2008;193(3):203–9.CrossRefGoogle ScholarPubMed
Boonstra, N, Klaassen, R, Sytema, S, et al. Duration of untreated psychosis and negative symptoms – a systematic review and meta-analysis of individual patient data. Schizophrenia Research. 2012;142(1–3):12–19.CrossRefGoogle ScholarPubMed
Chen, M, Ona, VO, Li, M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Medicine. 2000;6(7):797.CrossRefGoogle Scholar
Lampl, Y, Boaz, M, Gilad, R, et al. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology. 2007;69(14):1404–10.CrossRefGoogle ScholarPubMed
Gordon, PH, Moore, DH, Miller, RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. The Lancet Neurology. 2007;6(12):1045–53.CrossRefGoogle ScholarPubMed
Takahashi, T, Wood, SJ, Yung, AR, et al. Progressive gray matter reduction of the superior temporal gyrus during transition to psychosis. Archives of General Psychiatry. 2009;66(4):366–76.Google Scholar
Deakin, JW, Lees, J, McKie, S, et al. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco–magnetic resonance imaging study. Archives of General Psychiatry. 2008;65(2):154–64.CrossRefGoogle ScholarPubMed
Olney, JW, Farber, NB. Glutamate receptor dysfunction and schizophrenia. Archives of General Psychiatry. 1995;52(12):998–1007.CrossRefGoogle ScholarPubMed
Zhang, L, Shirayama, Y, Iyo, M, et al. Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology. 2007;32(9):2004.Google Scholar
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. Journal of Psychopharmacology. 2012;26(9):1185–93.Google Scholar
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. Journal of Clinical Psychiatry. 2010;71(2):138.Google Scholar
Deakin, B, Suckling, J, Barnes, TRE, et al. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. The Lancet Psychiatry. 2018;5(11):885–94.CrossRefGoogle ScholarPubMed
Zhang, L, Zheng, H, Wu, R, et al. Minocycline adjunctive treatment to risperidone for negative symptoms in schizophrenia: association with pro-inflammatory cytokine levels. Progress in Neuropsychopharmacology and Biological Psychiatry. 2018;85:69–76.CrossRefGoogle ScholarPubMed
Zhang, L, Zheng, H, Wu, R, et al. The effect of minocycline on amelioration of cognitive deficits and pro-inflammatory cytokines levels in patients with schizophrenia. Schizophrenia Research. 2019;212:92–8.Google Scholar
Scott, G, Zetterberg, H, Jolly, A, et al. Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. Brain. 2018;141(2):459–71.Google Scholar
Jones, R, Tait, C. Gastrointestinal side-effects of NSAIDs in the community. The British Journal of Clinical Practice. 1995;49(2):67–70.Google ScholarPubMed
Sommer, IE, van Westrhenen, R, Begemann, MJH, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophrenia Bulletin. 2013;40(1):181–91.Google Scholar
Attari, A, Mojdeh, A, Soltani, F, et al. Aspirin inclusion in antipsychotic treatment on severity of symptoms in schizophrenia: A randomized clinical trial. Iranian Journal of Psychiatry and Behavioral Sciences. 2017;11(1):e5848.Google Scholar
Akhondzadeh, S, Tabatabaee, M, Amini, H, et al. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophrenia Research. 2007;90(1–3):179–85.Google Scholar
Yokota, O, Terada, S, Ishihara, T, et al. Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia. Progress in Neuropsychopharmacology and Biological Psychiatry. 2004;28(4):715–21.CrossRefGoogle ScholarPubMed
Zheng, W, Cai, DB, Yang, XH, et al. Adjunctive celecoxib for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Journal of Psychiatric Research. 2017;92:139–46.Google Scholar
Marini, S, De Berardis, D, Vellante, F, et al. Celecoxib adjunctive treatment to antipsychotics in schizophrenia: a review of randomized clinical add-on trials. Mediators of Inflammation. 2016. https://doi.org/10.1155/2016/3476240CrossRefGoogle Scholar
Rapaport, MH, Delrahim, KK, Bresee, J, et al. Celecoxib augmentation of continuously ill patients with schizophrenia. Biological Psychiatry. 2005;57(12):1594–6.Google Scholar
Kotecha, A, Upthegrove, R. Celecoxib plus standard care for people with schizophrenia. Cochrane Database of Systematic Reviews. 2018;(12):CD009205. doi:10.1002/14651858.CD009205.pub2Google Scholar
Suzuki, M, Kato, C, Kato, A. Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. Journal of Toxicologic Pathology. 2015;28(3):133–9.Google Scholar
Girgis, RR, Ciarleglio, A, Choo, T, et al. A randomized, double-blind, placebo-controlled clinical trial of tocilizumab, an interleukin-6 receptor antibody, for residual symptoms in schizophrenia. Neuropsychopharmacology. 2018;43(6):1317–23.CrossRefGoogle ScholarPubMed
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(1):31–41.Google Scholar
Khandaker, GM, Khandaker, GM, Oltean, BP, et al. Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. BMJ Open. 2018;8(9):e025333.Google Scholar
Cribbs, AP, Kennedy, A, Penn, H, et al. Methotrexate restores regulatory T cell function through demethylation of the FoxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis & Rheumatology. 2015;67(5):1182–92.Google Scholar
Cronstein, B. The antirheumatic agents sulphasalazine and methotrexate share an anti-inflammatory mechanism. Rheumatology. 1995;34(suppl_2):30–2.Google Scholar
Chaudhry, IB, Husain, N, ur Rahman, R, et al. A randomised double-blind placebo-controlled 12- week feasibility trial of methotrexate added to treatment as usual in early schizophrenia: study protocol for a randomised controlled trial. Trials. 2015;16(1):9.Google Scholar
Chaudhry, IH, Husain, MO, Khoso, AB, et al. A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis. Transl Psychiatry. (in press) 2020.Google Scholar
Miyaoka, T, Wake, R, Hashioka, S, et al. Remission of psychosis in treatment-resistant schizophrenia following bone marrow transplantation: a case report. Frontiers in Psychiatry. 2017;8:174.Google Scholar
Sommer, I, van Bekkum, DW, Klein, H, et al. Severe chronic psychosis after allogeneic SCT from a schizophrenic sibling. Bone Marrow Transplantation. 2015;50(1):153–4.Google Scholar
Levine, J, Gutman, J, Feraro, R, et al. Side effect profile of azathioprine in the treatment of chronic schizophrenic patients. Neuropsychobiology. 1997;36(4):172–6.CrossRefGoogle ScholarPubMed
Mahadik, SP, Evans, D, Lal, H. Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25(3):463–93.CrossRefGoogle ScholarPubMed
Berk, M, Copolov, D, Dean, O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial. Biological Psychiatry. 2008;64(5):361–8.Google ScholarPubMed
Farokhnia, M, Azarkolah, A, Adinehfar, F, et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clinical Neuropharmacology. 2013;36(6):185–92.CrossRefGoogle ScholarPubMed
Rossell, SL, Francis, PS, Galletly, C, et al. N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double-blind randomised placebo-controlled trial targeting negative symptoms. BMC Psychiatry. 2016;16(1):320.CrossRefGoogle ScholarPubMed
Fusar-Poli, P, Berger, G. Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. Journal of Clinical Psychopharmacology. 2012;32(2):179–85.Google Scholar
Bozzatello, P, Brignolo, E, Grandi, E, et al. Supplementation with omega-3 fatty acids in psychiatric disorders: a review of literature data. Journal of Clinical Medicine. 2016;5(8):67.Google Scholar
Berger, GE, Proffitt, TM, McConchie, M, et al. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. Journal of Clinical Psychiatry. 2007;68(12):1867–75.Google Scholar
Amminger, GP, Schäfer, MR, Papageorgiou, K, et al. Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Archives of General Psychiatry. 2010;67(2):146–54.CrossRefGoogle ScholarPubMed
Amminger, GP, Schäfer, MR, Schlögelhofer, M, et al. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nature Communications. 2015;6(1):1–7.Google Scholar
McGorry, PD, Nelson, B, Markulev, C, et al. Effect of ω-3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic disorders: the NEURAPRO randomized clinical trial. JAMA Psychiatry. 2017;74(1):19–27.Google Scholar
Jougasaki, M, Ichiki, T, Takenoshita, Y, et al. Statins suppress interleukin-6-induced monocyte chemo-attractant protein-1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells. British Journal of Pharmacology. 2010;159(6):1294–303.Google Scholar
Chataway, J., Schuerer, N, Alsanousi, A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. The Lancet. 2014;383(9936):2213–21.Google Scholar
Vincenzi, B, Stock, S, Borba, CP, et al. A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: effect on inflammation, psychopathology, cognition and lipid metabolism. Schizophrenia Research. 2014;159(2–3):395–403.Google Scholar
Ghanizadeh, A, Rezaee, Z, Dehbozorgi, S, et al. Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial. Psychiatry Research. 2014;219(3):431–5.Google Scholar
Chaudhry, IB, Husain, N, Drake, R, et al. Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: pilot study. Therapeutic Advances in Psychopharmacology. 2014;4(3):110–16.Google Scholar
Deakin, JF, Husain, N, Parker, AJ, et al. Efficacy of ondansetron and simvastatin on cognition and negative symptoms in established schizophrenia. Neuropsychopharmacology. 2014;39:S355–6.Google Scholar
Begemann, MJ, Schutte, MJ, Slot, MI, et al. Simvastatin augmentation for recent-onset psychotic disorder: A study protocol. BBA Clinical. 2015;4:52–8.Google Scholar
Blackburn, R, Osborn, D, Walters, K, et al. Statin prescribing for people with severe mental illnesses: a staggered cohort study of ‘real-world’ impacts. BMJ Open. 2017;7(3):e013154.Google Scholar
Perry, BI, Upthegrove, R, Thompson, A, et al. Dysglycaemia, inflammation and psychosis: findings from the UK ALSPAC birth cohort. Schizophrenia Bulletin. 2018;45(2):330–8.Google Scholar
Leucht, S, Winter-van Rossum, I, Heres, S, et al. The optimization of treatment and management of schizophrenia in Europe (OPTiMiSE) trial: rationale for its methodology and a review of the effectiveness of switching antipsychotics. Schizophrenia Bulletin. 2015;41(3):549–58.Google Scholar
Martinuzzi, E, Barbosa, S, Daoudlarian, D, et al. Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study. Translational Psychiatry. 2019;9(1):20.Google Scholar
Barnes, TR, Drake, R, Paton, C, et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology. 2020 Jan;34(1):3–78.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×