Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: A double blind, randomized, controlled trial

Liu, Fang; Guo, Xiaofeng; Wu, Rengrong; Ou, Jianjun; Zheng, Yingjun; Zhang, Bingkui; Xie, Liqin; Zhang, Limei; Yang, Li; Yang, Shuyun; Yang, Junwei; Ruan, Ye Chun; Zeng, Yong; Xu, Xiufeng; Zhao, Jingping

doi:10.1016/j.schres.2014.01.011

Cited by 120 publications

(100 citation statements)

References 43 publications

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“…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.…”

supporting

confidence: 66%

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

Inta

Lang

Borgwardt

et al. 2016

SCHBUL

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The implication of neuroinflammation in schizophrenia, sustained by recent genetic evidence, represents one of the most exciting topics in schizophrenia research. Drugs which inhibit microglia activation, especially the classical tetracycline antibiotic minocycline are currently under investigation as alternative antipsychotics. However, recent studies demonstrated that microglia activation is not only a hallmark of neuroinflammation, but plays important roles during brain development. Inhibition of microglia activation by minocycline was shown to induce extensive neuronal cell death and to impair subventricular zone (SVZ) neurogenesis and synaptic pruning in the early postnatal and adolescent rodent brain, respectively. These deleterious effects contrast with the neuroprotective actions of minocycline at adult stages. They are of potential importance for schizophrenia, since minocycline triggers similar pro-apoptotic effects in the developing brain as NMDA receptor (NMDAR) antagonists, known to induce long-term schizophrenia-like abnormalities. Moreover, altered postnatal neurogenesis, recently described in the human striatum, was proposed to induce striatal dopamine dysregulation associated with schizophrenia. Finally, the effect of minocycline on synapse remodeling is of interest considering the recently reported strong genetic association of the pruning-regulating complement factor gene C4A with schizophrenia. This raises the exciting possibility that in conditions of hyperactive synaptic pruning, as supposed in schizophrenia, the inhibitory action of minocycline turns into a beneficial effect, with relevance for early therapeutic interventions. Altogether, these data support a differential view on microglia activation and its inhibition. Further studies are needed to clarify the relevance of these results for the pathogenesis of schizophrenia and the use of minocycline as antipsychotic drug.Key words: minocycline/apoptosis/postnatal neurogenesis/subventricular zone/synaptic pruning/early therapy More than 30 years ago signs of low-grade inflammation had been found post-mortem in brains of patients with schizophrenia.

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supporting

confidence: 66%

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

Inta

Lang

Borgwardt

et al. 2016

SCHBUL

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“…65 Several animal and human studies have suggested that minocycline might also have a potential therapeutic effect on cognitive dysfunction in schizophrenia. [66][67][68] In summary, multiple studies, notably those that used unbiased approaches, support a link between MMP-9 and schizophrenia. Unknown, however, is whether increased or decreased MMP-9 levels contribute to the disease.…”

Section: Discussionmentioning

confidence: 96%

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

Lepeta¹,

Kaczmarek²

2015

SCHBUL

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Recent findings implicate alterations in glutamate signaling, leading to aberrant synaptic plasticity, in schizophrenia. Matrix metalloproteinase-9 (MMP-9) has been shown to regulate glutamate receptors, be regulated by glutamate at excitatory synapses, and modulate physiological and morphological synaptic plasticity. By means of functional gene polymorphism, gene responsiveness to antipsychotics and blood plasma levels MMP-9 has recently been implicated in schizophrenia. This commentary critically reviews these findings based on the hypothesis that MMP-9 contributes to pathological synaptic plasticity in schizophrenia.Key words: synaptic plasticity/glutamate/extracellular matrix Matrix Metalloproteinase-9 in Animal Studies Matrix Metalloproteinase-9 Expression and Activity in the BrainMatrix metalloproteinase-9 (MMP-9) belongs to a family of zinc-dependent proteases, mostly secreted as inactive pro-enzymes, activated outside the cell upon proteolytic cleavage. MMPs degrade extracellular matrix constituents, other proteases, growth factors, and extracellular domains of transmembrane proteins, such as cell adhesion molecules and receptors. As a result, MMPs participate in remodeling the pericellular microenvironment and cell-signaling via either the release or processing (to reveal their binding domains) of cell-surface receptor ligands.

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“…Chaudhry et al [35] was a two-site study with adjunct treatment of minocycline to treatment as usual in patients in the first five years of their illness but with both positive and negative symptoms as the primary outcomes. Liu et al [33] studied adjunct minocycline to risperidone in patients in the first five years of illness but with negative symptoms as the primary outcome. Lastly, Khodaie-Ardakanie et al [34] also added minocycline to risperidone and with negative symptoms as the primary outcome, but in a chronic population.…”

Section: Discussionmentioning

confidence: 99%

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms

Kelly¹,

Sullivan²,

McEvoy³

et al. 2015

Journal of Clinical Psychopharmacology

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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.

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Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: A double blind, randomized, controlled trial

Cited by 120 publications

References 43 publications

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

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

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms

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