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Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms

Kelly, Deanna L. PharmD, BCPP*; Sullivan, Kelli M. MPH*; McEvoy, Joseph P. MD; McMahon, Robert P. PhD*; Wehring, Heidi J. PharmD, BCPP*; Gold, James M. PhD*; Liu, Fang MS*; Warfel, Dale RN*; Vyas, Gopal DO*; Richardson, Charles M. MD*; Fischer, Bernard A. MD*; Keller, William R. MD*; Koola, Maju Mathew MD; Feldman, Stephanie M. MSW*; Russ, Jessica C. BS§; Keefe, Richard S. E. PhD§; Osing, Jennifer MA*; Hubzin, Leeka MS*; August, Sharon MA*; Walker, Trina M. RN§; Buchanan, Robert W. MD*

Journal of Clinical Psychopharmacology: August 2015 - Volume 35 - Issue 4 - p 374–381
doi: 10.1097/JCP.0000000000000345
Original Contributions

Objective Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes.

Methods Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23).

Results Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo.

Conclusions Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

From the *Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD; †Department of Psychiatry, Georgia Regents University, Medical College of Georgia, Augusta, GA; ‡Department of Psychiatry, Clinical Research Program, Sheppard Pratt Health System and University of Maryland School of Medicine, Baltimore, MD; and §Department of Psychiatry, Psychology and Neuroscience, Duke University School of Medicine, Durham, NC.

Received October 29, 2014; accepted after revision March 31, 2015.

Reprints: Deanna L. Kelly, PharmD, BCPP, Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228 (e-mail:

This study was funded by NIMH R21MH091184-01A1 (D.L.K.; registration number: NCT#01433055).

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