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.

Minocycline differentially modulates human spatial memory systems

“…However, it remains unclear whether minocycline confers beneficial or deleterious effects in healthy animals. Furthermore, studies of the therapeutic effects of minocycline across a range of human disorders including HIV-associated cognitive impairment [23], Schizophrenia [24] and mild Alzheimer's disease [25] have been disappointing. In Motor Neuron Disease, minocycline has even been associated with accelerated functional decline [26].…”

The effect of first- and second-generation antipsychotics on brain morphology in schizophrenia: A systematic review of longitudinal magnetic resonance studies with a randomized allocation to treatment arms

“…The PRISMA stages are shown in Figure 1. Eventually, seven studies were selected for final evaluation (Breier et al, 2018; Chaves et al, 2015; Crespo-Facorro et al, 2008; Deakin et al, 2019; Garver et al, 2005; Lieberman et al, 2005; Lyall et al, 2021), of whom only three met the criteria (Crespo-Facorro et al, 2008; Garver et al, 2005; Lieberman et al, 2005). Of note is the fact that this means that no new studies of interest were published since the meta-analysis of Vita et al (2015).…”

“…Some authors suggest that after controlling for possible confounders, there is a clear correlation between exposure to medications and brain volume loss (Fusar-Poli et al, 2013;Haijma et al, 2013;Ho et al, 2011;Navari and Dazzan, 2009;Radua et al, 2012;Smieskova et al, 2009;Torres et al, 2013;Vita et al, 2015), and this could be unrelated to the outcome (Emsley et al, 2017). Others suggest correlations with increased or less decreased brain volume (Boonstra et al, 2011;Garver et al, 2005;Van Haren et al, 2007), but some studies did not find any relationship at all (Ahmed et al, 2015;Breier et al, 2018;Deakin et al, 2019;Goff et al, 2018). Unfortunately, the results of many studies are difficult to interpret because they were essentially exploratory and might lose their strength after proper correction for multiple comparisons (Andreasen et al, 2013;Boonstra et al, 2011;Crespo-Facorro et al, 2008;Ho et al, 2007;Lieberman et al, 2001Lieberman et al, , 2005Tian et al, 2013;Toulopoulou et al, 2004;Veijola et al, 2014).…”

Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia

“…Controversial data have been found for the use of minocycline in SZ as well. Whereas some studies do not support a therapeutic role of minocycline in SZ [ 161 ], others cautiously report that minocycline may be helpful in treating negative and cognitive symptoms in SZ [ 162 ]. Minocycline administration has been associated with an amelioration of cognitive deficits and correlated with the remission of negative symptoms and reduction of inflammatory parameters [ 163 ].…”