The effect of minocycline on symptoms in schizophrenia: Results from a randomized controlled trial

Weiser, Mark; Levi, Linda; Burshtein, Shimon; Chiriță, Roxana; Cirjaliu, Diana; Gonen, Ilan; Yolken, Robert H.; Davidson, Michael; Zamora, Daisy; Davis, John M.

doi:10.1016/j.schres.2018.10.023

Cited by 35 publications

(33 citation statements)

References 25 publications

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“…However, in a definitive follow-up UK study in 207 patients with recent onset psychosis, we found no benefit of minocycline after 8 or 52 weeks of treatment 9 . The reasons for the discrepant findings are not clear but another large study in 200 patients with established illness also reported no benefit of minocycline 10 . In the UK study, plasma cytokine levels did not predict outcome and did not change over the course of treatment.…”

Section: Introductionmentioning

confidence: 96%

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

et al. 2020

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NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (β = −2.5; [95% CI −4.7 to −0.4]), whereas negative symptoms were unaffected by treatment (β = −0.39; [95% CI −2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

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Section: Introductionmentioning

confidence: 96%

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

et al. 2020

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“…Minocycline is a broad-spectrum tetracycline antibiotic that has strong inhibitory effects on microglia cells and can easily cross the BBB (Watabe et al ., 2012). Ten studies assessed the effect of minocycline augmentation therapy for schizophrenia patients (Levkovitz et al ., 2010; Chaudhry et al ., 2012; Ghanizadeh et al ., 2014; Khodaie-Ardakani et al ., 2014; Liu et al ., 2014; Chaves et al ., 2015; Kelly et al ., 2015; Deakin et al ., 2018; Zhang et al ., 2018; Weiser et al ., 2019). The daily treatments doses varied from 100 to 300 mg, and the duration of treatment was relatively long, ranging from 2 to 12 months.…”

Section: Resultsmentioning

confidence: 99%

“…NAC (Sepehrmanesh et al ., 2018) improved attention, memory, and executive functions. However, other studies did not observe any beneficial effects on cognition for minocycline (Chaudhry et al ., 2012; Kelly et al ., 2015; Deakin et al ., 2018; Weiser et al ., 2019) and NAC (Breier et al ., 2018). For statins, only one study investigated the effects of pravastatin on cognition and did not observe any significant effects (Vincenzi et al ., 2014).…”

Section: Resultsmentioning

confidence: 99%

An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis

et al. 2019

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BackgroundAccumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs).MethodsPubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes.ResultsOur search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06–0.54], estrogens (ES: 0.78; n = 723; CI 0.36–1.19), minocycline (ES: 0.40; n = 946; CI 0.11–0.68), and NAC (ES: 1.00; n = 442; CI 0.60–1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect.ConclusionsSome, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.

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“…Also in this meta-analysis minocycline was superior to placebo in improving PANSS total, negative and general subscale, and here also for the positive subscale. However, two new RCTs do not find an effect of minocycline vs. placebo (115, 116). Deakin et al (116) randomized 207 people with schizophrenia-spectrum disorder with an illness duration < 5 years to minocycline or placebo, half and half.…”

Section: Drug Studies To Treat Immune Dysregulation or Inflammation Imentioning

confidence: 99%

“…No effect on the primary outcome PANSS negative subscale or other symptoms of schizophrenia was identified after 12 months treatment. Weiser et al (115) randomized 200 people with schizophrenia or schizoaffective disorder to 16 weeks treatment with minocycline or placebo as add-on to antipsychotic treatment. No effects on the primary outcome PANSS total or the secondary outcomes PANSS subscales, Clinical Global Impression Scale–Severity or–improvement scales, Brief Assessment of Cognition in Schizophrenia and drop out rates were identified.…”

Section: Drug Studies To Treat Immune Dysregulation or Inflammation Imentioning

confidence: 99%

Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics

et al. 2019

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Schizophrenia is considered a syndrome comprised by several disease phenotypes, covering a range of underlying pathologies. One of these disease mechanisms seems to involve immune dysregulation and neuroinflammation. While the current dopamine receptor-blocking antipsychotic drugs decrease psychotic symptoms and prevent relapse in the majority of patients with schizophrenia, there is a huge need to explore new treatment options that target other pathophysiological pathways. Such studies should aim at identifying robust biomarkers in order to diagnose and monitor the immune biophenotype in schizophrenia and develop better selection procedures for clinical trials with anti-inflammatory and immune-modulating drugs. In this focused review, we describe available methods to assess inflammatory status and immune disturbances in vivo. We also outline findings of immune disturbances and signs of inflammation at cellular, protein, and brain imaging levels in patients with schizophrenia. Furthermore, we summarize the results from studies with anti-inflammatory or other immune-modulating drugs, highlighting how such studies have dealt with participant selection. Finally, we propose a strategy to construct an immune signature that may be helpful in selecting and monitoring participants in studies with immune modulating drugs and also applicable in regular clinical work.

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The effect of minocycline on symptoms in schizophrenia: Results from a randomized controlled trial

Cited by 35 publications

References 25 publications

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis

Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics

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