Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms

Abstract

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, effect size 0.55) were not significant. A ≥30% change in total BPRS symptoms was observed in 7/28 (25%) among minocycline and 1/23 (4%) among placebo participants, respectively (p=0.044). Global cognitive function (MATRICS Consensus Cognitive Battery, MCCB) 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 SANS 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 to placebo. Conclusion Minocycline’s effect on the MCCB 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.

Microglia Activation and Schizophrenia: Lessons From the Effects of Minocycline on Postnatal Neurogenesis, Neuronal Survival and Synaptic Pruning

“…6 Subsequent clinical studies reported efficacy of minocycline especially in alleviating negative symptoms of schizophrenia when used as add-on therapy in combination with classical antipsychotics. [7][8][9] These findings are in line with antipsychotic-like effects of minocycline in animal models of schizophrenia, demonstrating, similar to haloperidol, improvement of the cognitive deficits induced by the NMDA receptor (NMDAR) antagonist MK-801. 10 Alleviation of protracted schizophrenia-like abnormalities (hyperlocomotion, sensorimotor gating, and social interaction deficits) by minocycline was described also in a mouse model of maternal immunization.…”

A pilot, open‐label, 8‐week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression

“…A meta‐analysis of four of the trials documented its superiority to placebo in mitigating negative but not positive symptoms of schizophrenia . Evidence from clinical trials in individuals with schizophrenia also provides support for the hypothesis that adjunctive minocycline may improve cognitive function in individuals with BD . The open‐label study herein aimed to provide ‘proof‐of‐concept’ evidence that mitigating inflammation with adjunctive minocycline alleviates symptoms of depression and improves cognitive function in individuals with BD.…”

“…Results from a 6‐week, open‐label study suggest that adjunctive minocycline mitigates depressive symptom severity in individuals with major depressive disorder who present with psychotic features . The potential benefit of adjunctive minocycline for individuals with BD is buttressed by five randomized, placebo‐controlled trials in individuals with schizophrenia . A meta‐analysis of four of the trials documented its superiority to placebo in mitigating negative but not positive symptoms of schizophrenia .…”

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

“…In cuprizone-fed C57BL/6 mice, minocycline reduced microglial activation and demyelination in the brain and prevented disturbances in motor coordination (Pasquini et al, 2007;Skripuletz et al, 2010;Tanaka et al, 2013). Furthermore, minocycline in combination with an antipsychotic such as risperidone, olanzapine, quetiapine, or clozapine significantly improved positive, negative, and cognitive symptoms in recent-onset or chronic schizophrenia patients (Levkovitz et al, 2010;Ghanizadeh et al, 2014;Chaves et al, 2015;Kelly et al, 2015). From these results, it is likely that application of minocycline can dampen M1 signaling, subsequently resulting in skewing of M2a microglia that reduce proinflammatory signaling and increase production of anti-inflammatory cytokines.…”