A Double-Blind, Randomized Study of Minocycline for the Treatment of Negative and Cognitive Symptoms in Early-Phase Schizophrenia

Levkovitz, Yechiel; Mendlovich, Shlomo; Riwkes, Sharon; Braw, Yoram; Levkovitch-Verbin, Hani; Gal, Gilad; Fennig, Shmuel; Treves, Ilan; Kron, Shmuel

doi:10.4088/jcp.08m04666yel

Cited by 356 publications

(301 citation statements)

References 114 publications

(118 reference statements)

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“…Since minocycline had no effect on the TNFR2 expression levels in the NPCs derived from the hippocampi of NaCl offspring per se, we propose that the mode of action of minocycline is promoted through the regulation of microglial derived TNF-α and IL-1β. In human patients minocycline had beneficial effects at a similar dosage as we have used in our study (Levkovitz et al, 2010). In a recent in vitro study it was shown that minocycline inhibited the production of TNF-α from IFN-γ-activated microglia (Seki et al 2013).…”

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confidence: 54%

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Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

Mattei

Djodari-Irani

Hadar³

et al. 2014

Brain, Behavior, and Immunity

163

130

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Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia.We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1β and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1β production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.3

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confidence: 54%

“…With an average of 5ml water intake per 250g rat per day, the animals received an average daily dosage of 3mg/kg over the course of approximately 70 days. The daily dosage was adapted from treatments in schizophrenic patients (Levkovitz et al, 2010). Water bottles were changed every second day to ensure minocycline stability.…”

Section: Minocycline Treatmentmentioning

confidence: 99%

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

Mattei

Djodari-Irani

Hadar³

et al. 2014

Brain, Behavior, and Immunity

163

130

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“…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.…”

Section: Pharmacological Approach To Neuroinflammation In Asd and Schmentioning

confidence: 96%

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

Nakagawa¹,

Chiba²

2016

Journal of Pharmacology and Experimental Therapeutics

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Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset.

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“…Therefore, our study provides insight into why immune-and glutamate-modulating therapies may be helpful for acutely ill suicidal patients suffering from depression. Potential candidate drugs include the tetracycline antibiotic minocycline, which inhibits microglial activation by blocking NF-kappa B nuclear translocation [39][40][41][42] or antiinflammatory inhibitors of cyclooxygenase-2 [43,44]. Furthermore, severely depressed suicidal patients may Figure 3 Illustration of QUIN-immunopositive cell densities.…”

Section: Discussionmentioning

confidence: 99%

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Steiner

Walter

Gos

et al. 2012

Neurology, Psychiatry and Brain Research

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Background: Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described. Methods: Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects. Results: Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD.

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A Double-Blind, Randomized Study of Minocycline for the Treatment of Negative and Cognitive Symptoms in Early-Phase Schizophrenia

Abstract: clinicaltrials.gov Identifier: NCT00733057.

Cited by 356 publications

References 114 publications

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

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

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

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