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Systematic review and meta-analysis of the efficacy and safety of minocycline in schizophrenia

  • Marco Solmi (a1) (a2) (a3), Nicola Veronese (a3) (a4), Nita Thapa (a5), Silvia Facchini (a4), Brendon Stubbs (a6) (a7), Michele Fornaro (a8), André F. Carvalho (a9) and Christoph U. Correll (a10) (a11) (a12) (a13)...

Our aim was to perform an updated systematic review and meta-analysis on the efficacy and safety of adjunctive minocycline as a treatment of schizophrenia.


We conducted a PubMed/Scopus database search from inception to 3 February 2016 for randomized, placebo-controlled trials (RCTs), open non-randomized studies, and case reports/series evaluating minocycline in patients with schizophrenia. Random-effects meta-analysis of positive, negative, depressive, and cognitive symptom rating scales, discontinuation and adverse effects rates calculating standardized mean difference (SMD), and risk ratios±95% confidence intervals (CI 95%) were calculated.


Six RCTs were eligible (minocycline n=215, placebo n=198) that demonstrated minocycline’s superiority versus placebo for reducing endpoint Positive and Negative Syndrome Scale (PANSS) total scores (SMD=–0.59; CI 95%=[1.15, –0.03]; p=0.04), negative (SMD=–0.76; CI 95%=[–1.21, –0.31]; p=0.001); general subscale scores (SMD=–0.44; CI 95%=[–0.88, –0.00]; p=0.05), Clinical Global Impressions scores (SMD=–0.50; CI 95%=[–0.78, –0.22]; p<0.001); and executive functioning (SMD=0.22; CI 95%=[0.01, 0.44]; p=0.04). Endpoint PANSS positive symptom scores (p=0.13), depression rating scale scores (p=0.43), attention (p=0.47), memory (p=0.52), and motor speed processing (p=0.50) did not significantly differ from placebo, before execution of a trim-and-fill procedure. Minocycline did not differ compared to placebo on all-cause discontinuation (p=0.56), discontinuation due to inefficacy (p=0.99), and intolerability (p=0.51), and due to death (p=0.32). Data from one open-label study (N=22) and three case series (N=6) were consistent with the metaanalytic results.


Minocycline appears to be an effective adjunctive treatment option in schizophrenia, improving multiple relevant disease dimensions. Moreover, minocycline has an acceptable safety and tolerability profile. However, more methodologically sound and larger RCTs remain necessary to confirm and extend these results.

Corresponding author
*Address correspondence to: Marco Solmi, Department of Neurosciences, University of Padua, Via Giustiniani, 2, 35128 Padova, Italy. (Email:
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No funding was directly involved in the preparation of this paper.

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1. Chaves, C, Marque, CR, Trzesniak, C, et al. Glutamate-N-methyl-d-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update. Braz J Med Biol Res. 2009; 42(11): 10021014. Accessed January 13, 2017.
2. Monte, 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(11): 10321043. Epub ahead of print Sep 17. Accessed January 13, 2017.
3. Hashimoto, K. Abnormality of cerebral perfusion in the posterior cingulate gyrus of a refractory patient with schizophrenia and minocycline treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2010; 34(6): 1132; author reply 1133–1134. Epub ahead of print Apr 28.
4. Hashimoto, K, Ishima, T, Fujita, Y, Zhang, L. Antibiotic drug minocycline: a potential therapeutic drug for methamphetamine-related disorders [in Japanese]. Nihon Arukoru Yakubutsu Igakkai Zasshi. 2013; 48(2): 118125.
5. Zhang, L, Shirayama, Y, Iyo, M, Hashimoto, K. Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology. 2007; 32(9): 20042010. Epub ahead of print Jan 17. Accessed January 13, 2017.
6. Macdonald, H, Kelly, RG, Allen, ES, Noble, JF, Kanegis, LA. Pharmacokinetic studies on minocycline in man. Clin Pharmacol Ther. 1973; 14(5): 852861.
7. Hanson, E, Healey, K, Wolf, D, Kohler, C. Assessment of pharmacotherapy for negative symptoms of schizophrenia. Curr Psychiatry Rep. 2010; 12(6): 563571.
8. Liaury, K, Miyaoka, T, Tsumori, T, et al. Minocycline improves recognition memory and attenuates microglial activation in Gunn rat: a possible hyperbilirubinemia-induced animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 50: 184190. Epub ahead of print Jan 2.
9. Seki, 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(1–3): 2028. Epub ahead of print Oct 4.
10. Zhang, W, Narayanan, M, Friedlander, RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003; 53(2): 267270.
11. Yrjanheikki, J, Tikka, T, Keinanen, R, Goldsteins, G, Chan, PH, Koistinaho, J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999; 96(23): 1349613500. Accessed January 13, 2017.
12. Davis, J, Moylan, S, Harvey, BH, Maes, M, Berk, M. Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014; 48(6): 512529. Epub ahead of print May 6. Accessed January 13, 2017.
13. Muller, N, Weidinger, E, Leitner, B, Schwarz, MJ. The role of inflammation in schizophrenia. Front Neurosci. 2015; 9: 372. Accessed January 13, 2017.
14. Hu, W, MacDonald, ML, Elswick, DE, Sweet, RA. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci. 2015; 1338: 3857. Epub ahead of print Oct 14, 2014. Accessed January 13, 2017.
15. Zink, M, Correll, CU. Glutamatergic agents for schizophrenia: current evidence and perspectives. Expert Rev Clin Pharmacol. 2015; 8(3): 335352.
16. Reus, GZ, Fries, GR, Stertz, L, et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience. 2015; 300: 141154. Epub ahead of print May 14.
17. Shim, S, Shuman, M, Duncan, E. An emerging role of cGMP in the treatment of schizophrenia: a review. Schizophr Res. 2015; 170(1): 226231. Epub ahead of print Dec 22.
18. Fillman, SG, Weickert, TW, Lenroot, RK, et al. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol Psychiatry. 2015; 21(8): 10901098. Epub ahead of print Jul 21. Accessed January 13, 2017.
19. Xiu, MH, Yang, GG, Tan, YL, et al. Decreased interleukin-10 serum levels in first-episode drug-naive schizophrenia: relationship to psychopathology. Schizophr Res. 2014; 156(1): 914. Epub ahead of print Apr 22.
20. Tuominen, HJ, Tiihonen, J, Wahlbeck, K. Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2005; 72(2–3): 225234.
21. Ventura, J, Subotnik, KL, Gitlin, MJ, et al. Negative symptoms and functioning during the first year after a recent onset of schizophrenia and 8 years later. Schizophr Res. 2015; 161(2–3): 407413. Epub ahead of print Dec 8, 2014. Accessed January 13, 2017.
22. Remberk, B, Bazynska, AK, Bronowska, Z, et al. Which aspects of long-term outcome are predicted by positive and negative symptoms in early-onset psychosis? An exploratory eight-year follow-up study. Psychopathology. 2015; 48(1): 4755. Epub ahead of print Dec 2, 2014.
23. Marchesi, C, Affaticati, A, Monici, A, De Panfilis, C, Ossola, P, Tonna, M. Severity of core symptoms in first episode schizophrenia and long-term remission. Psychiatry Res. 2015; 225(1–2): 129132. Epub ahead of print Nov 11, 2014.
24. Galderisi, S, Bucci, P, Mucci, A, et al. Categorical and dimensional approaches to negative symptoms of schizophrenia: focus on long-term stability and functional outcome. Schizophr Res. 2013; 147(1): 157162. Epub ahead of print Apr 19.
25. Agid, O, Siu, CO, Pappadopulos, E, Vanderburg, D, Remington, G.. Early prediction of clinical and functional outcome in schizophrenia. Eur Neuropsychopharmacol. 2013; 23(8): 842851. Epub ahead of print Nov 7, 2012.
26. Hofer, A, Baumgartner, S, Bodner, T, et al. Patient outcomes in schizophrenia, II: the impact of cognition. Eur Psychiatry. 2005; 20(5–6): 395402.
27. Zhang, L, Zhao, J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat. 2014; 10: 11031111. Accessed January 13, 2017.
28. Monji, A, Kato, TA, Mizoguchi, Y, et al. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 42: 115121. Epub ahead of print Dec 13, 2011.
29. Glantz, LA, Gilmore, JH, Lieberman, JA, Jarskog, LF. Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res. 2006; 81(1): 4763. Epub ahead of print Oct 14, 2005.
30. Sertan Copoglu, U, Virit, O, Hanifi Kokacya, M, et al. Increased oxidative stress and oxidative DNA damage in non-remission schizophrenia patients. Psychiatry Res. 2015; 229(1–2): 200205. Epub ahead of print Jul 15.
31. Howes, O, McCutcheon, R, Stone, J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015; 29(2): 97115. Epub ahead of print Jan 13. Accessed January 13, 2017.
32. Xu, S, Gullapalli, RP, Frost, DO. Olanzapine antipsychotic treatment of adolescent rats causes long-term changes in glutamate and GABA levels in the nucleus accumbens. Schizophr Res. 2015; 161(2–3): 452457. Epub ahead of print Dec 5, 2014. Accessed January 13, 2017.
33. Goldstein, ME, Anderson, VM, Pillai, A, Kydd, RR, Russell, BR. Glutamatergic neurometabolites in clozapine-responsive and -resistant schizophrenia. Int J Neuropsychopharmacol. 2015; 18(6): pii: pyu117. Accessed January 13, 2017.
34. Koprivica, V, Regardie, K, Wolff, C, et al. Aripiprazole protects cortical neurons from glutamate toxicity. Eur J Pharmacol. 2011; 651(1–3): 7376. Epub ahead of print Nov 18, 2010.
35. Millan, MJ, Fone, K, Steckler, T, Horan, WP. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol. 2014; 24(5): 645692. Epub ahead of print Apr 4. Accessed January 13, 2017.
36. Millan, MJ, Agid, Y, Brune, M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012; 11(2): 141168.
37. Oya, K, Kishi, T, Iwata, N. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol. 2014; 29(5): 483491. Accessed January 13, 2017.
38. Iwata, Y, Nakajima, S, Suzuki, T, et al. Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. Mol Psychiatry. 2015; 20(10): 11511160. Epub ahead of print Jun 16.
39. Kay, SR, Fiszbein, A, Opler, LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13(2): 261276. Accessed January 13, 2017.
40. Andreasen, NC. Negative symptoms in schizophrenia: definition and reliability. Arch Gen Psychiatry. 1982; 39(7): 784788.
41. Guy, W. ECDEU (Early Clinical Drug Evaluation) Assessment Manual for Psychopharmacology. Washington, DC: U.S. Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration; 1976. Accessed January 13, 2017.
42. Ghanizadeh, 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(3): 211215.
43. Kelly, DL, Sullivan, KM, McEvoy, JP, et al. Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms. J Clin Psychopharmacol. 2015; 35(4): 374381. Accessed January 13, 2017.
44. Moher, D, Liberati, A, Tetzlaff, J, Altman, DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010; 8(5): 336341. Epub ahead of print Feb 18. Accessed January 13, 2017.
45. Overall, JE, Gorham, DR. The brief psychiatric rating scale. Psychol Rep. 1962; 10: 799812. Accessed January 13, 2017.
46. Lancon, C, Auquier, P, Reine, G, Bernard, D, Toumi, M. Study of the concurrent validity of the Calgary Depression Scale for Schizophrenics (CDSS). J Affect Disord. 2000; 58(2): 107115.
47. Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23: 5662. Accessed January 13, 2017.
48. Beck, AT, Alford, BA. Depression: Causes and Treatment, 2nd ed. Philadelphia: University of Pennsylvania Press; 2009.
49. Nuechterlein, KH, Green, MF, Kern, RS, et al. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008; 165(2): 203213. Epub ahead of print Jan 2. Accessed January 13, 2017.
50. Green, MF, Nuechterlein, KH. The MATRICS initiative: developing a consensus cognitive battery for clinical trials. Schizophr Res. 2004; 72(1): 13.
51. CANTAB. Cambridge: Cambridge Cognition Ltd. Accessed January 13, 2017.
52. Chouinard, G, Margolese, HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res. 2005; 76(2–3): 247265. Epub ahead of print Apr 18.
53. Higgins, JP, Altman, DG, Gotzsche, PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928. Accessed January 13, 2017.
54. RevMan 5. Accessed January 13, 2017.
55. DerSimonian, R, Kacker, R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007; 28(2): 105114. Epub ahead of print May 12, 2006.
56. DerSimonian, R, Laird, N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3): 177188.
57. Higgins, JP, Thompson, SG, Deeks, JJ, Altman, DG. Measuring inconsistency in meta-analyses. BMJ. 2003; 327(7414): 557560. Accessed January 13, 2017.
58. Comprehensive Meta-Analysis (CMA). Accessed January 13, 2017.
59. Egger, M, Davey Smith, G, Schneider, M, Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109): 629634. Accessed January 13, 2017.
60. Begg, CB, Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994; 50(4): 10881101.
61. Duval, S, Tweedie, R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000; 56(2): 455463.
62. Chaves, C, Marque, CR, Maia-de-Oliveira, JP, et al. Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia. Schizophr Res. 2015; 161(2–3): 439445. Epub ahead of print Dec 12, 2014.
63. Lisiecka, DM, Suckling, J, Barnes, TR, et al. The benefit of minocycline on negative symptoms in early-phase psychosis in addition to standard care—extent and mechanism (BeneMin): study protocol for a randomised controlled trial. Trials. 2015; 16: 71. Accessed January 13, 2017.
64. Fekadu, A, Mesfin, M, Medhin, G, et al. Adjuvant therapy with minocycline for schizophrenia (the MINOS Trial): study protocol for a double-blind randomized placebo-controlled trial. Trials. 2013; 14: 406. Accessed January 13, 2017.
65. 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. J Psychopharmacol. 2012; 26(9): 11851193. Epub ahead of print Apr 23. Accessed January 13, 2017.
66. Khodaie-Ardakani, MR, Mirshafiee, O, Farokhnia, M, et al. Minocycline add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. Psychiatry Res. 2014; 215(3): 540546. Epub ahead of print Jan 9.
67. Liu, 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(1–3): 169176. Epub ahead of print Feb 3.
68. 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. J Clin Psychiatry. 2010; 71(2): 138149. Epub ahead of print Nov 3, 2009.
69. Miyaoka, T, Yasukawa, R, Yasuda, H, Hayashida, M, Inagaki, T, Horiguchi, J. Minocycline as adjunctive therapy for schizophrenia: an open-label study. Clin Neuropharmacol. 2008; 31(5): 287292.
70. Kelly, DL, Vyas, G, Richardson, CM, et al. Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms. Schizophr Res. 2011; 133(1–3): 257258. Epub ahead of print Aug 26.
71. Jhamnani, K, Shivakumar, V, Kalmady, S, Rao, NP, Venkatasubramanian, G. Successful use of add-on minocycline for treatment of persistent negative symptoms in schizophrenia. J Neuropsychiatry Clin Neurosci. 2013; 25(1): E06E07. Accessed January 13, 2017.
72. Qurashi, I, Collins, J, Chaudhry, I, Husain, N. Promising use of minocycline augmentation with clozapine in treatment-resistant schizophrenia. J Psychopharmacol. 2014; 28(7): 707708. Epub ahead of print Mar 19. Accessed January 13, 2017.
73. Carbon, M, Correll, CU. Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr. 2014; 19(Suppl. 1): 3852; quiz 35–37, 53.
74. Carvalho, AF, Miskowiak, KK, Hyphantis, TN, et al. Cognitive dysfunction in depression: pathophysiology and novel targets. CNS Neurol Disord Drug Targets. 2014; 13(10): 18191835.
75. Kane, JM, Kishimoto, T, Correll, CU. Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry. 2013; 12(3): 216226. Accessed January 13, 2017.
76. Tehrani, R, Nash-Goelitz, A, Adams, E, Dahiya, M, Eilers, D. Minocycline-induced cutaneous polyarteritis nodosa. J Clin Rheumatol. 2007; 13(3): 146149.
77. Ramakrishna, J, Johnson, AR, Banner, BF. Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. J Clin Gastroenterol. 2009; 43(8): 787790.
78. Benjamin, RW, Calikoglu, AS. Hyperthyroidism and lupus-like syndrome in an adolescent treated with minocycline for acne vulgaris. Pediatr Dermatol. 2007; 24(3): 246249.
79. Ahmed, F, Kelsey, PR, Shariff, N. Lupus syndrome with neutropenia following minocycline therapy: a case report. Int J Lab Hematol. 2008; 30(6): 543545.
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