Minocycline for negative symptoms of schizophrenia and possible mechanistic actions: the BeneMin RCT

Research output: Contribution to journalArticlepeer-review

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Minocycline for negative symptoms of schizophrenia and possible mechanistic actions : the BeneMin RCT. / Deakin, Bill; Suckling, John; Dazzan, Paola; Joyce, Eileen; Lawrie, Stephen M; Upthegrove, Rachel; Husain, Nusrat; Chaudhry, Imran B; Dunn, Graham; Jones, Peter B; Lisiecka-ford, Danuta; Lewis, Shôn; Barnes, Thomas Re; Williams, Steven Cr; Pariante, Carmine M; Knox, Emma; Drake, Richard J; Smallman, Richard; Barnes, Nicholas M.

In: Efficacy and Mechanism Evaluation, Vol. 6, No. 7, 01.08.2019, p. 1-66.

Research output: Contribution to journalArticlepeer-review

Harvard

Deakin, B, Suckling, J, Dazzan, P, Joyce, E, Lawrie, SM, Upthegrove, R, Husain, N, Chaudhry, IB, Dunn, G, Jones, PB, Lisiecka-ford, D, Lewis, S, Barnes, TR, Williams, SC, Pariante, CM, Knox, E, Drake, RJ, Smallman, R & Barnes, NM 2019, 'Minocycline for negative symptoms of schizophrenia and possible mechanistic actions: the BeneMin RCT', Efficacy and Mechanism Evaluation, vol. 6, no. 7, pp. 1-66. https://doi.org/10.3310/eme06070

APA

Deakin, B., Suckling, J., Dazzan, P., Joyce, E., Lawrie, S. M., Upthegrove, R., Husain, N., Chaudhry, I. B., Dunn, G., Jones, P. B., Lisiecka-ford, D., Lewis, S., Barnes, T. R., Williams, S. C., Pariante, C. M., Knox, E., Drake, R. J., Smallman, R., & Barnes, N. M. (2019). Minocycline for negative symptoms of schizophrenia and possible mechanistic actions: the BeneMin RCT. Efficacy and Mechanism Evaluation, 6(7), 1-66. https://doi.org/10.3310/eme06070

Vancouver

Author

Deakin, Bill ; Suckling, John ; Dazzan, Paola ; Joyce, Eileen ; Lawrie, Stephen M ; Upthegrove, Rachel ; Husain, Nusrat ; Chaudhry, Imran B ; Dunn, Graham ; Jones, Peter B ; Lisiecka-ford, Danuta ; Lewis, Shôn ; Barnes, Thomas Re ; Williams, Steven Cr ; Pariante, Carmine M ; Knox, Emma ; Drake, Richard J ; Smallman, Richard ; Barnes, Nicholas M. / Minocycline for negative symptoms of schizophrenia and possible mechanistic actions : the BeneMin RCT. In: Efficacy and Mechanism Evaluation. 2019 ; Vol. 6, No. 7. pp. 1-66.

Bibtex

@article{e95e1bc9797c4437846b33c216117dc0,
title = "Minocycline for negative symptoms of schizophrenia and possible mechanistic actions: the BeneMin RCT",
abstract = "Background: In a previous trial we reported that the neuroprotective, anti-inflammatory antibiotic minocycline lessened the negative symptoms of schizophrenia compared with placebo over 1 year. The BeneMin study aimed to replicate this benefit and to determine whether or not there was associated preservation of grey matter, reduction in circulating inflammatory cytokines and enhancement of cognition.Objectives: To determine the efficacy of minocycline on the negative symptoms of schizophrenia and the mechanistic role of neuroprotective, anti-inflammatory and cognitive enhancing actions.Methods: Two hundred and seven patients with a current research diagnosis of schizophrenia within 5 years of onset were randomised by a permuted blocks algorithm to minocycline (300 mg/day) or matching placebo as an adjunct to their continuing treatment. The primary efficacy outcome variable was the negative symptom subscale score from the Positive and Negative Syndrome Scales at 2, 6, 9 and 12 months. The primary mechanistic (biomarker) variables were (1) medial prefrontal grey matter volume (GMV), (2) circulating cytokine interleukin (IL) 6 concentration and (3) dorsolateral prefrontal cortex functional magnetic resonance imaging (fMRI) activations during performance of the N-back task. Movement disorder, side effects and treatment adherence were monitored throughout the study.Results: Compared with placebo, the addition of minocycline had no effect on the severity of negative symptoms [treatment effect difference –0.186, 95% confidence interval (CI) –1.225 to 0.854] across the 2-, 6-, 9- and 12-month follow-up visits. None of the mechanistic biomarkers was influenced by minocycline: left GMV –91.2 (95% CI –303.8 to 121.4), IL-6 0.072 (95% CI –0.118 to 0.262) and N-back fMRI 0.66 (95% CI –1.53 to 0.20). There were no statistically significant treatment effects on any of the secondary outcomes and no group differences at baseline. Most measures were stable over the 12 months. Twenty-five out of the 29 serious adverse events were hospital admission for worsening psychiatric state, which affected 10 minocycline-treated participants and six placebo-treated participants.Main outcome measures: The addition of minocycline to standard treatment had no benefit on the symptoms of schizophrenia in this early phase sample. There was no evidence of a progressive neuropathic or inflammatory process affecting GMV.Limitations: Although recruitment to target was achieved on time, only 43% (n = 89) of the 207 randomised patients completed 12 months of the study. However, 83% of those who started treatment remained on it and were assessed over 6 months. By contrast, no follow-up data were available for the cognitive and imaging markers in those who dropped out before the final 12-month assessments, and this reduced the power to detect treatment effects on these mechanistic variables. Patients were not selected for the presence of negative symptoms, and their initial overall psychopathology was, at most, moderate and, therefore, less likely to show treatment effects.Conclusions: The results of the study do not support the use of adjunctive minocycline for the treatment of negative or other symptoms of schizophrenia within 2–5 years of onset. More secure evidence of central inflammation is needed before further trials are conducted at other stages of psychosis.Trial registration: Current Controlled Trials ISRCTN49141214.Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research partnership. The study was sponsored by Greater Manchester Mental Health NHS Foundation Trust and supported by the UK Clinical Research Network.",
author = "Bill Deakin and John Suckling and Paola Dazzan and Eileen Joyce and Lawrie, {Stephen M} and Rachel Upthegrove and Nusrat Husain and Chaudhry, {Imran B} and Graham Dunn and Jones, {Peter B} and Danuta Lisiecka-ford and Sh{\^o}n Lewis and Barnes, {Thomas Re} and Williams, {Steven Cr} and Pariante, {Carmine M} and Emma Knox and Drake, {Richard J} and Richard Smallman and Barnes, {Nicholas M}",
year = "2019",
month = aug,
day = "1",
doi = "10.3310/eme06070",
language = "English",
volume = "6",
pages = "1--66",
journal = "Efficacy and Mechanism Evaluation",
issn = "2050-4365",
publisher = "Prepress Projects Ltd",
number = "7",

}

RIS

TY - JOUR

T1 - Minocycline for negative symptoms of schizophrenia and possible mechanistic actions

T2 - the BeneMin RCT

AU - Deakin, Bill

AU - Suckling, John

AU - Dazzan, Paola

AU - Joyce, Eileen

AU - Lawrie, Stephen M

AU - Upthegrove, Rachel

AU - Husain, Nusrat

AU - Chaudhry, Imran B

AU - Dunn, Graham

AU - Jones, Peter B

AU - Lisiecka-ford, Danuta

AU - Lewis, Shôn

AU - Barnes, Thomas Re

AU - Williams, Steven Cr

AU - Pariante, Carmine M

AU - Knox, Emma

AU - Drake, Richard J

AU - Smallman, Richard

AU - Barnes, Nicholas M

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Background: In a previous trial we reported that the neuroprotective, anti-inflammatory antibiotic minocycline lessened the negative symptoms of schizophrenia compared with placebo over 1 year. The BeneMin study aimed to replicate this benefit and to determine whether or not there was associated preservation of grey matter, reduction in circulating inflammatory cytokines and enhancement of cognition.Objectives: To determine the efficacy of minocycline on the negative symptoms of schizophrenia and the mechanistic role of neuroprotective, anti-inflammatory and cognitive enhancing actions.Methods: Two hundred and seven patients with a current research diagnosis of schizophrenia within 5 years of onset were randomised by a permuted blocks algorithm to minocycline (300 mg/day) or matching placebo as an adjunct to their continuing treatment. The primary efficacy outcome variable was the negative symptom subscale score from the Positive and Negative Syndrome Scales at 2, 6, 9 and 12 months. The primary mechanistic (biomarker) variables were (1) medial prefrontal grey matter volume (GMV), (2) circulating cytokine interleukin (IL) 6 concentration and (3) dorsolateral prefrontal cortex functional magnetic resonance imaging (fMRI) activations during performance of the N-back task. Movement disorder, side effects and treatment adherence were monitored throughout the study.Results: Compared with placebo, the addition of minocycline had no effect on the severity of negative symptoms [treatment effect difference –0.186, 95% confidence interval (CI) –1.225 to 0.854] across the 2-, 6-, 9- and 12-month follow-up visits. None of the mechanistic biomarkers was influenced by minocycline: left GMV –91.2 (95% CI –303.8 to 121.4), IL-6 0.072 (95% CI –0.118 to 0.262) and N-back fMRI 0.66 (95% CI –1.53 to 0.20). There were no statistically significant treatment effects on any of the secondary outcomes and no group differences at baseline. Most measures were stable over the 12 months. Twenty-five out of the 29 serious adverse events were hospital admission for worsening psychiatric state, which affected 10 minocycline-treated participants and six placebo-treated participants.Main outcome measures: The addition of minocycline to standard treatment had no benefit on the symptoms of schizophrenia in this early phase sample. There was no evidence of a progressive neuropathic or inflammatory process affecting GMV.Limitations: Although recruitment to target was achieved on time, only 43% (n = 89) of the 207 randomised patients completed 12 months of the study. However, 83% of those who started treatment remained on it and were assessed over 6 months. By contrast, no follow-up data were available for the cognitive and imaging markers in those who dropped out before the final 12-month assessments, and this reduced the power to detect treatment effects on these mechanistic variables. Patients were not selected for the presence of negative symptoms, and their initial overall psychopathology was, at most, moderate and, therefore, less likely to show treatment effects.Conclusions: The results of the study do not support the use of adjunctive minocycline for the treatment of negative or other symptoms of schizophrenia within 2–5 years of onset. More secure evidence of central inflammation is needed before further trials are conducted at other stages of psychosis.Trial registration: Current Controlled Trials ISRCTN49141214.Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research partnership. The study was sponsored by Greater Manchester Mental Health NHS Foundation Trust and supported by the UK Clinical Research Network.

AB - Background: In a previous trial we reported that the neuroprotective, anti-inflammatory antibiotic minocycline lessened the negative symptoms of schizophrenia compared with placebo over 1 year. The BeneMin study aimed to replicate this benefit and to determine whether or not there was associated preservation of grey matter, reduction in circulating inflammatory cytokines and enhancement of cognition.Objectives: To determine the efficacy of minocycline on the negative symptoms of schizophrenia and the mechanistic role of neuroprotective, anti-inflammatory and cognitive enhancing actions.Methods: Two hundred and seven patients with a current research diagnosis of schizophrenia within 5 years of onset were randomised by a permuted blocks algorithm to minocycline (300 mg/day) or matching placebo as an adjunct to their continuing treatment. The primary efficacy outcome variable was the negative symptom subscale score from the Positive and Negative Syndrome Scales at 2, 6, 9 and 12 months. The primary mechanistic (biomarker) variables were (1) medial prefrontal grey matter volume (GMV), (2) circulating cytokine interleukin (IL) 6 concentration and (3) dorsolateral prefrontal cortex functional magnetic resonance imaging (fMRI) activations during performance of the N-back task. Movement disorder, side effects and treatment adherence were monitored throughout the study.Results: Compared with placebo, the addition of minocycline had no effect on the severity of negative symptoms [treatment effect difference –0.186, 95% confidence interval (CI) –1.225 to 0.854] across the 2-, 6-, 9- and 12-month follow-up visits. None of the mechanistic biomarkers was influenced by minocycline: left GMV –91.2 (95% CI –303.8 to 121.4), IL-6 0.072 (95% CI –0.118 to 0.262) and N-back fMRI 0.66 (95% CI –1.53 to 0.20). There were no statistically significant treatment effects on any of the secondary outcomes and no group differences at baseline. Most measures were stable over the 12 months. Twenty-five out of the 29 serious adverse events were hospital admission for worsening psychiatric state, which affected 10 minocycline-treated participants and six placebo-treated participants.Main outcome measures: The addition of minocycline to standard treatment had no benefit on the symptoms of schizophrenia in this early phase sample. There was no evidence of a progressive neuropathic or inflammatory process affecting GMV.Limitations: Although recruitment to target was achieved on time, only 43% (n = 89) of the 207 randomised patients completed 12 months of the study. However, 83% of those who started treatment remained on it and were assessed over 6 months. By contrast, no follow-up data were available for the cognitive and imaging markers in those who dropped out before the final 12-month assessments, and this reduced the power to detect treatment effects on these mechanistic variables. Patients were not selected for the presence of negative symptoms, and their initial overall psychopathology was, at most, moderate and, therefore, less likely to show treatment effects.Conclusions: The results of the study do not support the use of adjunctive minocycline for the treatment of negative or other symptoms of schizophrenia within 2–5 years of onset. More secure evidence of central inflammation is needed before further trials are conducted at other stages of psychosis.Trial registration: Current Controlled Trials ISRCTN49141214.Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research partnership. The study was sponsored by Greater Manchester Mental Health NHS Foundation Trust and supported by the UK Clinical Research Network.

U2 - 10.3310/eme06070

DO - 10.3310/eme06070

M3 - Article

VL - 6

SP - 1

EP - 66

JO - Efficacy and Mechanism Evaluation

JF - Efficacy and Mechanism Evaluation

SN - 2050-4365

IS - 7

ER -