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Minocycline For Depression: A Systematic Review And Meta-analysis Of Clinical Trials

Discussion in 'Scientific Studies' started by Logan-, Nov 29, 2018.

  1. Logan-

    Logan- Member

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    Journal of Affective Disorders
    Volume 227, February 2018, Pages 219-225
    [​IMG]
    Review article
    Efficacy and tolerability of minocycline for depression: A systematic review and meta-analysis of clinical trials

    Joshua D.Rosenblat Roger S.McIntyre

    Highlights


    A large antidepressant effect was observed for minocycline compared to placebo.


    Minocycline had good tolerability with low rates of adverse effects and discontinuation.


    Future larger RCTs of minocycline for depression are merited.


    Future studies should also identify subgroups more likely to benefit from minocycline.

    Abstract
    Background
    Minocycline has been identified as a potential novel treatment for depression. The objective of the current review is to determine the overall antidepressant efficacy and tolerability of minocycline.

    Methods
    Completed and ongoing clinical trials of minocycline for depression (both bipolar and unipolar) published prior to September 12, 2017 were identified through searching relevant databases. Using a random-effects model, data from randomized controlled trials (RCTs) were pooled to determine the antidepressant effect size of minocycline compared to placebo. Relative risk of all-cause discontinuation was determined to assess overall tolerability.

    Results
    Eighteen clinical studies (including published and unpublished RCTs, open label studies, ongoing clinical trials and a case report) were identified for inclusion in the qualitative synthesis. Only three RCTs (n = 158) met inclusion criteria for quantitative synthesis. The overall antidepressant effect size of minocycline compared to placebo was − 0.78 [95% confidence interval − 0.4 to − 1.33 (P = 0.005)], indicative of a large and statistically significant antidepressant effect. Heterogeneity of the pooled sample was moderate (I2 = 62%). There was no statistically significant difference in reported adverse effects or all-cause discontinuation in the minocycline group compared to placebo (p = 0.16).

    Limitations
    The small number of published RCTs, small sample sizes, heterogeneity of included studies, and potential publication bias were significant limitations.

    Conclusions
    Overall, a large antidepressant effect was observed for minocycline compared to placebo with good tolerability. The current analysis provides a proof-of-concept for the antidepressant effects of minocycline and provides impetus for future larger RCTs as well as identification of subgroups more likely to benefit from this intervention.

    https://www.sciencedirect.com/science/article/pii/S0165032717319985
     
  2. OP
    Logan-

    Logan- Member

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  3. OP
    Logan-

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    Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial

    Olivia M Dean, Buranee Kanchanatawan, Melanie Ashton, ...
    First Published June 3, 2017 Research Article
    https://doi.org/10.1177/0004867417709357
    Article information


    Abstract
    Objective:

    Conventional antidepressant treatments result in symptom remission in 30% of those treated for major depressive disorder, raising the need for effective adjunctive therapies. Inflammation has an established role in the pathophysiology of major depressive disorder, and minocycline has been shown to modify the immune-inflammatory processes and also reduce oxidative stress and promote neuronal growth. This double-blind, randomised, placebo-controlled trial examined adjunctive minocycline (200 mg/day, in addition to treatment as usual) for major depressive disorder. This double-blind, randomised, placebo-controlled trial investigated 200 mg/day adjunctive minocycline (in addition to treatment as usual) for major depressive disorder.

    Methods:
    A total of 71 adults with major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) were randomised to this 12-week trial. Outcome measures included the Montgomery–Asberg Depression Rating Scale (primary outcome), Clinical Global Impression–Improvement and Clinical Global Impression–Severity, Hamilton Anxiety Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool. The study was registered on the Australian and New Zealand Clinical Trials Register: www.anzctr.org.au, #ACTRN12612000283875.

    Results:
    Based on mixed-methods repeated measures analysis of variance at week 12, there was no significant difference in Montgomery–Asberg Depression Rating Scale scores between groups. However, there were significant differences, favouring the minocycline group at week 12 for Clinical Global Impression–Improvement score – effect size (95% confidence interval) = −0.62 [−1.8, −0.3], p = 0.02; Quality of Life Enjoyment and Satisfaction Questionnaire score – effect size (confidence interval) = −0.12 [0.0, 0.2], p < 0.001; and Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool score – 0.79 [−4.5, −1.4], p < 0.001. These effects remained at follow-up (week 16), and Patient Global Impression also became significant, effect size (confidence interval) = 0.57 [−1.7, −0.4], p = 0.017.

    Conclusion:
    While the primary outcome was not significant, the improvements in other comprehensive clinical measures suggest that minocycline may be a useful adjunct to improve global experience, functioning and quality of life in people with major depressive disorder. Further studies are warranted to confirm the potential of this accessible agent to optimise treatment outcomes.
     
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    Logan-

    Logan- Member

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    Minocycline Provides Neuroprotection Against N-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia
    Tiina M. Tikka and Jari E. Koistinaho
    J Immunol June 15, 2001, 166 (12) 7527-7533; DOI: Minocycline Provides Neuroprotection Against N-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia


    Abstract

    Glutamate excitotoxicity to a large extent is mediated through activation of the N-methyl-d-aspartate (NMDA)-gated ion channels in several neurodegenerative diseases and ischemic stroke. Minocycline, a tetracycline derivative with antiinflammatory effects, inhibits IL-1β-converting enzyme and inducible nitric oxide synthase up-regulation in animal models of ischemic stroke and Huntington’s disease and is therapeutic in these disease animal models. Here we report that nanomolar concentrations of minocycline protect neurons in mixed spinal cord cultures against NMDA excitotoxicity. NMDA treatment alone induced microglial proliferation, which preceded neuronal death, and administration of extra microglial cells on top of these cultures enhanced the NMDA neurotoxicity. Minocycline inhibited all these responses to NMDA. Minocycline also prevented the NMDA-induced proliferation of microglial cells and the increased release of IL-1β and nitric oxide in pure microglia cultures. Finally, minocycline inhibited the NMDA-induced activation of p38 mitogen-activated protein kinase (MAPK) in microglial cells, and a specific p38 MAPK inhibitor, but not a p44/42 MAPK inhibitor, reduced the NMDA toxicity. Together, these results suggest that microglial activation contributes to NMDA excitotoxicity and that minocycline, a tetracycline derivative, represents a potential therapeutic agent for brain diseases.

    Activation of the N-methyl-d-aspartate (NMDA)3 receptors to a large extent mediates the glutamate excitotoxicity and neuronal death in several neurodegenerative diseases and ischemic stroke (1, 2, 3). Subsequent to activation of NMDA receptors occurs toxic calcium influx, which activates numerous enzymes, including neuronal NO synthase (NOS). NO is able to further increase the excitotoxicity by enhancing glutamate release from presynaptic neurons (4, 5) and inhibiting glial glutamate transporters (6, 7).

    Several studies have suggested that inflammation, involving nonneuronal cells such as infiltrating leukocytes and parenchymal microglia, contributes to the delayed enlargement of ischemic brain injury (1, 2, 8), amyloid-induced neurotoxicity in Alzheimer’s disease (9, 10), and demyelination in multiple sclerosis (11, 12). The key players in inflammation are glial cells, both astrocytes and microglia, which are activated in these brain diseases and in response to glutamate excitotoxicity (13, 14, 15). Activated microglia release a large variety of neurotoxins, including the free radicals hydrogen peroxide, superoxide, and NO, that also is able to nitrate proteins; glutamate and quinolinic acid; extracellular proteases; eicosanoids; and cytokines, such as TNF-α and IL-1β, which further increase microglial proliferation and activation, thereby increasing the release of microglial toxins (8, 13, 14, 16, 17). Importantly, several studies have shown that the neurotoxicity of microglial toxins is mediated through the NMDA receptor (NMDAR), involving either glutamate and quinolinic acid or a still uncharacterized NMDAR binding molecule (18, 19, 20, 21). Because inflammation is a delayed and prolonged response to brain injury, it is regarded as a tempting pharmacological target with a potentially wide therapeutic window, unlike NMDAR antagonists that must be delivered immediately after a brain insult and have strong side effects (2, 22, 23).

    We have previously shown that minocycline, a semisynthetic tetracycline derivative, is able to provide neuroprotection against global ischemia in gerbils and focal brain ischemia in rats (24, 25). In addition, minocycline delays mortality in a transgenic mouse model of Huntington’s disease (26). In all these studies, the protective effect of minocycline was associated with reduced activation of inducible NOS and IL-1β-converting enzyme, which are mainly expressed by microglia. In addition, ischemia-induced proliferation of microglia was inhibited by minocycline. In the present study, we show that NMDA-induced neuronal death involves proliferation and activation of microglial cells and that minocycline prevents completely the NMDA toxicity and the preceding activation and proliferation of microglial cells. These results support the notion that microglial activation contributes to excitotoxic neuronal death, which can be inhibited by antiinflammatory compounds, such as minocycline.
     
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    Logan-

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    Logan-

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  7. James b

    James b Member

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    Very interesting. Known people to use antibiotics daily for years? Wondering the safety of that, do you have any thoughts? Ray mentions toxicity of most antibiotics in high doses, which is why he recoemmends say 30-40mg of penicillin for ~4 days....so 365 days a year would worry me based on that. What're your thoughts?
     
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    Logan-

    Logan- Member

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    I don't know.
     
  9. OP
    Logan-

    Logan- Member

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  10. OP
    Logan-

    Logan- Member

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  11. OP
    Logan-

    Logan- Member

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    I too would like to learn about the questions you asked.
     
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