Minocycline as a treatment for schizophrenia: is the discussion truly finished?
Authors: Taishiro Kishimoto, Toshiro Horigome, Akihiro Takamiya
Journal: The Lancet Psychiatry (2018)

The improvement of negative symptoms and cognitive function is an unresolved and important concern surrounding schizophrenia treatment. Dysfunctional glutaminergic, inflammatory, and oxidative stress pathways are considered the pathophysiology of schizophrenia, especially in relation to negative and cognitive symptoms.1Müller N Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations.Schizophr Bull. 2018; 44: 973-982Crossref PubMed Scopus (127) Google Scholar, 2Solmi M Veronese N Thapa N et al.Systematic review and meta-analysis of the efficacy and safety of minocycline in schizophrenia.CNS Spectr. 2017; 22: 415-426Crossref PubMed Scopus (43) Google Scholar Minocycline, a second-generation tetracycline, is expected to have neuroprotective effects through the above-mentioned actions,3Seki Y Kato TA Monji A et al.Pretreatment of aripiprazole and minocycline, but not haloperidol, suppresses oligodendrocyte damage from interferon-γ-stimulated microglia in co-culture model.Schizophr Res. 2013; 151: 20-28Crossref PubMed Scopus (53) Google Scholar, 4Monte AS de Souza GC McIntyre RS et al.Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: possible involvement of antioxidant and nitrergic pathways.J Psychopharmacol. 2013; 27: 1032-1043Crossref PubMed Scopus (73) Google Scholar on the basis of findings from studies on both animals and humans. In fact, an effect of minocycline on negative symptoms and on some cognitive domains has been shown in multiple, although relatively small, clinical trials.5Levkovitz 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: 138-149Crossref PubMed Scopus (296) Google Scholar, 6Chaudhry 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: 1185-1193Crossref PubMed Scopus (203) Google Scholar, 7Liu F Guo X Wu R et al.Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: a double blind, randomized, controlled trial.Schizophr Res. 2014; 153: 169-176Crossref PubMed Scopus (86) Google Scholar, 8Kelly DL Sullivan KM McEvoy JP et al.Adjunctive minocycline in clozapine-treated schizophrenia patients with persistent symptoms.J Clin Psychopharmacol. 2015; 35: 374-381PubMed Google Scholar, 9Ghanizadeh A Dehbozorgi S OmraniSigaroodi M Rezaei Z Minocycline as add-on treatment decreases the negative symptoms of schizophrenia; a randomized placebo-controlled clinical trial.Recent Pat Inflamm Allergy Drug Discov. 2014; 8: 211-215Crossref PubMed Scopus (33) Google Scholar In The Lancet Psychiatry, Bill Deakin and colleagues10Deakin 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.Lancet Psychiatry. 2018; (published online Oct 12.)http://dx.doi.org/10.1016/S2215-0366(18)30345-6Summary Full Text Full Text PDF Scopus (59) Google Scholar report findings from BeneMin, a randomised controlled trial of 207 participants that compared minocycline with placebo as an adjunctive treatment to usual antipsychotic treatment. The BeneMin study was unique because not only did it examine the effect of minocycline on clinical symptoms, but it also explored its potential function through brain imaging (grey-matter volume and blood-oxygen-level-dependent response in the dorsolateral-prefrontal cortex) and serum inflammatory markers (circulating interleukin 6 [IL-6] and high-sensitivity C-reactive protein [hs-CRP] concentrations). Contrary to expectations, the results were negative: there was no difference in clinical symptoms, including negative symptoms (treatment effect difference −0·19, 95% CI −1·23 to 0·85; p=0·73), or in imaging and inflammatory markers. Furthermore, the authors did not find an increase in circulating hs-CRP and IL-6 concentrations in their samples. Should we give up our expectations for minocycline, or should we even deny the inflammatory hypothesis of schizophrenia? Scrutinising the results of this negative study is important in determining the direction of future research. As the authors of the BeneMin study discussed, early influences on negative symptoms might have occurred before the introduction of minocycline. Although the investigators recruited patients in the early stage of their illness (ie, within 5 years of a schizophrenia diagnosis), systemic inflammation could have happened when the patients were acutely ill. Related to this point, patients in the BeneMin study had less severe disease compared with previous randomised controlled trials that showed a significant effect from minocycline on clinical symptoms. Patients were taking antipsychotics and it might have caused the effect of minocycline to be undetectable, or in some cases made the negative symptoms worse. The BeneMin study did not standardise antipsychotic treatment, which made it easier to do the study but made it more difficult to clearly understand the effect of minocycline. It is also important to take into consideration the effect of relapse on outcomes. A large proportion of patients are reported to experience relapse after their first episode.11Robinson D Woerner MG Alvir JM et al.Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder.Arch Gen Psychiatry. 1999; 56: 241-247Crossref PubMed Scopus (978) Google Scholar It should be remembered that only the group effect is apparent in randomised controlled trials, and they do not necessarily reflect specific patients' trajectories. Relapses should have a large effect on psychopathology scores, as well as inflammatory markers. The authors examined the effect of minocycline on patients who did not experience relapse, finding no alteration in results, but conversely an effect might have been seen for patients who might have had relapse before or during a study. Assessment of negative symptoms can be very difficult to do with equal quality across all study sites. Other limitations of this study include some inherent difficulties of randomised controlled trials, such as selection bias, poor adherence to the study medication, and high rates of dropouts in long-term studies such as BeneMin. Clearly, studies with an identical design should not be repeated in the future and it might be better to target patients who are even more early phase or acutely ill than those in BeneMin. Identifying patients with an active inflammatory process might be the best approach, but such identification is difficult. The BeneMin authors discuss the potential of using translocator protein (TSPO)-PET for such purposes, but it is known whether TSPO-PET highlights pro-inflammatory or anti-inflammatory microglia.12Plavén-Sigray P Matheson GJ Collste K et al.Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data.Biol Psychiatry. 2018; 84: 433-442Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar The development of new tools to assess neuroinflammation, such as serum biomarkers and PET tracers, is warranted. There is growing evidence indicating that the microbiome might influence the immune system, and it could play some role as a regulator in neuroinflammation, too. Although there are difficulties, further studies targeting inflammation-associated patients with such new tools and approaches should deepen our understanding of the pathophysiology of the disease and lead to the development of new treatments. TK reports grants and personal fees from Otsuka, and personal fees from Janssen, Pfizer, Sumitomo Dainippon, Novartis, MSD, Eli Lilly, Meiji, and Astellas during the conduct of the study. TH and AT declare no competing interests. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trialMinocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. Full-Text PDF Open Access