Minocycline for Schizophrenia: A critical review


Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestoractive or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington’s disease, amyotrophic lateral sclerosis and Parkinson’s disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to the launching of various clinical trials. Previously, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline as an open-label adjunct to antipsychotic medication to patients with schizophrenia. The results of this trial suggested that minocycline might be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for “boosting” antipsychotic efficacy and for treating schizophrenia. Recently, in randomized double-blind placebo-controlled clinical trials, the addition of minocycline to treatment as usual early in the course of schizophrenia predominantly improves negative symptoms. The present review summarizes the available data supporting the clinical testing of minocycline for patients with schizophrenia. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.

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Miyaoka, T. (2012) Minocycline for Schizophrenia: A critical review. Open Journal of Psychiatry, 2, 399-406. doi: 10.4236/ojpsych.2012.224056.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Yong, V.W., Wells, J., Giuliani, F., Casha, S., Power, C. and Metz, L.M. (2004) The promise of minocycline in neurology. The Lancet Neurology, 3, 744-751. doi:10.1016/S1474-4422(04)00937-8
[2] Conley, R.R. and Buchanan, R.V. (1997) Evaluation of treatment-resistant schizophrenia. Schizophrenia Bulletin, 23, 663-674. doi:10.1093/schbul/23.4.663
[3] Miyaoka, T., Yasukawa, R., Yasuda, H., Hayashida, M., Inagaki, T. and Horiguchi, J. (2007) Possible antipsychotic effects of minocycline in patients with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 31, 304-307. doi:10.1016/j.pnpbp.2006.08.013
[4] Miyaoka, T., Yasukawa, R., Yasuda, H., Hayashida, M., Inagaki, T. and Horiguchi, J. (2008) Minocycline as adjunctive therapy for schizophrenia: An open-label study. Clinical Neuropharmacology, 31, 287-292.
[5] Levkovitz, Y., Mendlovich, S., Riwkes, S., Braw, Y., Levkovitch-Verbin, H., Gal, G., Fenning, S., Treves, I. and Kron, S. (2010) A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in ealy-phase schizophrenia. Journal of Clinical Psychiatry, 71, 138-149. doi:10.4088/JCP.08m04666yel
[6] Chaudhry, I.B., Hallak, J., Husain, N., Minhas, F.A., Stirling, J., Richardson, P., Dursun, S., Dunn, G. and Deakin, B. (2012) Minocycline benefits negative symptoms in early schizophrenia: A randomized double-blind placebo-controlled clinical trial in patients on standard treatment. Journal of Psychopharmacology (in press). doi:10.1177/0269881112444941
[7] Good, M.L. and Hussey, D.L. (2003) Minocycline: Stain devil? British Journal of Dermatology, 149, 237-239. doi:10.1046/j.1365-2133.2003.05497.x
[8] Colovic, M. and Caccia, S. (2003) Liquid chromatographic determination of minocycline in brain-to-plasma distribution studies in the rat. Journal of Chromatography B, 791, 337-343. doi:10.1016/S1570-0232(03)00247-2
[9] Bonelli, R.M., Heuberger, C. and Reisecker, F. (2003) Minocycline for Huntington’s disease: An open label study. Neurology, 60, 883-884. doi:10.1212/01.WNL.0000049936.85487.7A
[10] Shapiro, L.E., Knowles, S.R. and Shear, N.H. (1997) Comparative safety of tetracycline, minocycline, and doxycycline. Archives of Dermatology, 133, 1224-1230. doi:10.1001/archderm.1997.03890460044005
[11] Gottlieb, A. (1997) Safety of minocycline for acne. Lancet, 349, 374. doi:10.1016/S0140-6736(97)80006-2
[12] Dommeguess, M.A., Plaisant, F., Vermey, C. and Gressens, O. (2003) Early microglial activation following neonatal excitoxic brain damage in mice: a potential target for neuroprotection. Neuroscience, 121, 619-628. doi:10.1016/S0306-4522(03)00558-X
[13] Yrjanheikki, J., Keinanen, R., Pellika, M., Hokfelt, T. and Hoistinaho, J. (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proceedings of the National Academy of Sciences, 95, 15769-15774. doi:10.1073/pnas.95.26.15769
[14] Yrjanheikki, J.,Tikka, T., Keinanen, R., Goldstein, G., Chan, P.H. and Koistinaho, J. (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proceedings of the National Academy of Sciences, 96, 13496-13500. doi:10.1073/pnas.96.23.13496
[15] Tikka, T., Fiebich, B.L., Goldsteins, G., Keinnanen, R. and Koistinaho, J. (2001) Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. The Journal of Neuroscience, 21, 2580-2588.
[16] Matsuki, S., Iuchi, Y., Ikeda, Y., Sasagawa, I., Tomita, Y. and Fujii, J. (2003) Suppression of cyctochrome c release and apoptosis in testes with heart stress by minocycline. Biochemical and Biophysical Research Communications, 312, 843-849. doi:10.1016/j.bbrc.2003.10.191
[17] Tikka, T.M. and Koistinaho, J.E. (2001) Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. The Journal of Immunology, 166, 7527-7533.
[18] Zhang, S.C., Goetz, B.D. and Duncan, I.D. (2003) Supression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors. Glia, 41, 191-198. doi:10.1002/glia.10172
[19] Ekdahl, C.T., Claasen, J.H., Bonde, S., Kokaia, Z. and Lindvall, O. (2003) Inflammation is detrimental for neurogenesis in adult brain. Proceedings of the National Academy of Sciences, 100, 13632-13637. doi:10.1073/pnas.2234031100
[20] Stiring, D.P., Khodarahmi, K., Liu, J., et al. (2004) Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. The Journal of Neuroscience, 24, 2182-2190. doi:10.1523/JNEUROSCI.5275-03.2004
[21] Arvin, K.L., Han, B.H., Du, Y., Lin, S.Z., Paul, S.M. and Holzman, D.M. (2002) Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Annals of Neurology, 52, 54-61. doi:10.1002/ana.10242
[22] Zhu, S., Stavrovskaya, I.G., Drozda, M., et al. (2002) Minocycline inhibits cytochrome c release and delayes progression of amyotrophic lateral sclerosis in mice. Nature, 417, 74-78. doi:10.1038/417074a
[23] Wang, X., Zhu, S., Drozda, M., et al. (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delayes mortality in a transgenic mouse model of Huntington disease, Nature Medicine, 6, 797-801. doi:10.1038/77528
[24] Wang, J., Wei, Q., Wang, C.Y., Hill, W.D., Hess, D.C. and Dong, Z. (2004) Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. The Journal of Biological Chemistry, 279, 19948-19954. doi:10.1074/jbc.M313629200
[25] Gabler, W.L., Amith, J. and Tsukuda, N. (1992) Comparison of deoxycycline and a chemically modified tetracycline inhibition of leukocyte functions. Research Communications in Chemical Pathology & Pharmacology, 78, 151-160.
[26] Amin, A.R., Attur, M.G., Thakker, G.D., et al. (1996) A novel mechanism of action of tetracyclines: Effect on nitric oxide synthases. Proceedings of the National Academy of Sciences, 93, 14014-14019. doi:10.1073/pnas.93.24.14014
[27] Young, V.W., Power, C., Forsyth, P. and Edwards, D.R. (2001) Metalloproteinases in biology and pathology of the nervous system. Nature Reviews Neuroscience, 2, 502-511. doi:10.1038/35081571
[28] Golub, L.M., Ramamurthy, N., McNamara, T.F., et al. (1984) Tetracyclines inhibit tissue collagenase activity. A new mechanism in the treatment of periodontal disease. Journal of Periodontal Research, 19, 651-655. doi:10.1111/j.1600-0765.1984.tb01334.x
[29] Paemen, L., Martens, E., Norga, K., et al. (1996) The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitiors. Biochemical Pharmacology, 52, 105-111. doi:10.1016/0006-2952(96)00168-2
[30] Power, C., Henry, S., Del Bigio, N.R., et al. (2003) Untracerebral hemorrhagew induces macrophage activation and matrix metalloproteinases. Annals of Neurology, 53, 731-742. doi:10.1002/ana.10553
[31] Kloppenburg, M., Verweij, C.L., Miltenburg, A.M., et al. (1995) The influence of tetracyclines on T cell activation. Clinical and Experimental Immunology, 102, 635-641. doi:10.1111/j.1365-2249.1995.tb03864.x
[32] Kloppenburg, M., Brinkman, B.M., de Rooji-Dijk, N.H., et al., (1996) The tetracycline derivate minocycline differentially affects cytokine production by monocytes and T lymphocytes. Antimicrobial Agents and Chemotherapy, 40, 934- 940.
[33] Hayashida, M., Miyaoka, T., Tsuchie, K., Yasuda, H., Wake, R., Nishida, A., Inagaki, T., Toga, T., Nagami, H., Oda, T. and Horiguchi, J. (2009) Hyperbilirubinemia-related behavioral and neuropathological changes in rats: A possible schizophrenia animal model. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 581-588. doi:10.1016/j.pnpbp.2009.02.013
[34] Liaury, K., Miyaoka, T., Tsumori, T., Furuya, M., Wake, R., Ieda, M., Tsuchie, K., Taki, M., Ishihara, K., Tanra, A.J. and Horiguchi, J. (2012) Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: A possible schizophrenia animal model. Journal of Neuroinflammation, 9, 56. doi:10.1186/1742-2094-9-56
[35] Levkovitz, Y., Levi, U., Braw, Y. and Cohen, H. (2007) Minocycline, a second-generation tetracycline, as a neuroprotective agent in an animal model of schizophrenia. Brain Research, 1154, 154-162.
[36] Zhang, L., Shirayama, Y., Iyo, M. and Hashimoto, K. (2007) Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology, 32, 2004-2010. doi:10.1038/sj.npp.1301313
[37] Mizoguchi, H., Takuma, K., Fukakusa, A., Ito, Y., Nakatani, A., Ibi, D., Kim, H.C. and Yamada, K. (2007) Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology, 196, 233-241. doi:10.1007/s00213-007-0955-0
[38] Kay, S.R., Fiszbein, A. and Opler, L.A. (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13: 261-276.
[39] American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 1994; 4th Edition, American Psychiatric Press, Washington DC.
[40] Weinberger, D.R. (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry, 44, 660-669. doi:10.1001/archpsyc.1987.01800190080012
[41] Waddington, J.L. (1993) Schizophrenia: Developmental neuroscience and pathology. Lancet, 341, 531-536. doi:10.1016/0140-6736(93)90288-R
[42] Arnold, S.E., Trojanowski, J.Q., Gur, R.E., Blackwell, P., Han, L.Y. and Choi, C. (1998) Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Archives of General Psychiatry, 55, 225-232.
[43] Harrison, P.J. and Weinberger, D.R. (2005) Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Molecular Psychiatry, 10, 40-68. doi:10.1038/sj.mp.4001558
[44] German, T.T., Tong, R.I., Gilmore, J.H., Lieberman, J.A. and Jarskog, L.F. (2004) Regulation of apoptosis by typical and atypical antipsychotics in rat frontal cortex. European Neuropsychopharmcology, 55, 214.
[45] Ahuja, N. and Carroll, B.T. (2007) Possible anti-catatonic effects of minocycline in patients with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 31, 968-969. doi:10.1016/j.pnpbp.2007.01.018
[46] Kempermann, G., Krebs, J. and Fabel, K. (2008) The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Current Opinion in Psychiatry, 21, 290-295. doi:10.1097/YCO.0b013e3282fad375
[47] Lei, G., Xia, Y. and Johnson, K.M. (2008) The role of Akt-GSK-3beta signaling and synaptic strength in phencyclidine-induced neurodegeneration. Neuropsychopharmacology, 33, 1343-1353. doi:10.1038/sj.npp.1301511
[48] Csernansky, J.G. (2007) Neurodegeneration in schizophrenia: evidence from in vivo neuroimaging studies. Scientific World Journal, 7, 135-143. doi:10.1100/tsw.2007.47
[49] Lieberman, et al. (2007) Neuroprotection: a therapeutic strategy to prevent deterioration associated with schizophrenia. CNS Spectrums, 3, 1-13.

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