Re: SLS Minocycline evidence! » Slabicki

BMJ Open. 2012 Feb 22;2(1):e000643. Print 2012.
Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial.
Savitz J, Preskorn S, Teague TK, Drevets D, Yates W, Drevets W.
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INTRODUCTION: New medication classes are needed to improve treatment effectiveness in the depressed phase of bipolar disorder (BD). Extant evidence suggests that BD is characterised by neural changes such as dendritic remodelling and glial and neuronal cell loss. These changes have been hypothesised to result from chronic inflammation. The principal aims of the proposed research is to evaluate the antidepressant efficacy in bipolar depression of minocycline, a drug with neuroprotective and immune-modulating properties, and of aspirin, at doses expected to selectively inhibit cyclooxygenase 1 (COX-1). METHODS AND ANALYSIS: 120 outpatients between 18 and 55 years of age, who meet DSM-IV-TR criteria for BD (type I or II) and for a current major depressive episode will be recruited to take part in a randomised, double-blind, placebo-controlled, parallel-group, proof-of-concept clinical trial following a 2×2 design. As adjuncts to existing treatment, subjects will be randomised to receive one of the four treatment combinations: placebo-minocycline plus placebo-aspirin, active-minocycline plus placebo-aspirin, placebo-minocycline plus active-aspirin or active-minocycline plus active-aspirin. The dose of minocycline and aspirin is 100 mg twice daily and 81 mg twice daily, respectively. Antidepressant response will be evaluated by assessing changes in the Montgomery-Asberg Depression Rating Scale scores between baseline and the end of the 6-week trial. As secondary outcome measures, the anti-inflammatory effects of minocycline and aspirin will be tested by measuring pre-treatment and post-treatment levels of C reactive protein and inflammatory cytokines. ETHICS AND DISSEMINATION: Minocycline has been widely used as an antibiotic in doses up to 400 mg/day. Low-dose aspirin has been safely used on a worldwide scale for its role as an antithrombotic and thrombolytic. The study progress will be overseen by a Data, Safety and Monitoring Board, which will meet once every 6 months. Results of the study will be published in peer-reviewed publications. TRIAL REGISTRATION NUMBER: Clinical Trials.gov: NCT01429272.

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2.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jun 1;37(2):222-6. Epub 2012 Feb 10.
Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study.
Miyaoka T, Wake R, Furuya M, Liaury K, Ieda M, Kawakami K, Tsuchie K, Taki M, Ishihara K, Araki T, Horiguchi J.
Source

Department of Psychiatry, Shimane University School of Medicine, Izumo, Japan. miyanyan@med.shimane-u.ac.jp
Abstract
BACKGROUND:

Approximately 25% of patients admitted to a hospital as a result of depression are actually suffering from psychotic depression. Psychotic symptoms can be present in patients with either unipolar depression or bipolar depression and can be difficult to treat. It was reported the second-generation tetracycline may exert potential antidepressant effects through its robust neuroprotective activities, which include neurogenesis, antioxidation, and anti-glutamate excitotoxicity, and may direct regulation of pro-inflammatory agents.
METHODS:

This was a 6-week, open-label study to evaluate the efficacy and safety of minocycline in combination with antidepressants in adult inpatients (n=25) diagnosed with major depression with psychotic features (psychotic depression) according to DSM-IV-TR. The primary endpoint was the change from baseline in the Hamilton Depression Rating Scale (HAM-D-21) score from baseline to week 6. Secondary endpoints were changes in the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale scores from baseline to week 6. Spontaneously reported adverse events were recorded.
RESULTS:

The patients' average age was 46.9±10.2 years. Minocyline (150 mg/day) in combination with antidepressants (fulvoxamine, paroxetine, and sertraline) provided significant improvement in depression. Mean (± SD) HAM-D-21 was reduced to 6.7±1.9 at week 6 from a baseline value of 40.4±2.5. Significant improvement of psychotic symptoms (mean±SD) was indicated by the decrease in BPRS scores from baseline (63.3±8.7) to week 6 (4.6±2.4). No serious adverse events occurred.
CONCLUSIONS:

These preliminary data suggest that minocycline in combination with antidepressants is effective and well tolerated in the treatment of unipolar psychotic depression. Further studies using larger, double-blind, parallel-group design are warranted to confirm these findings.

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3.
Brain Res Rev. 2009 Oct;61(2):105-23. Epub 2009 May 28.
Emerging role of glutamate in the pathophysiology of major depressive disorder.
Hashimoto K.
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Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan. hashimoto@faculty.chiba-u.jp
Abstract

Major depressive disorder (MDD) is a common, chronic, recurrent mental illness that affects millions of individuals worldwide. To date, the monoaminergic systems (serotonin, norepinephrine, and dopamine) have received the most attention in the neurobiology of MDD, and all classes of antidepressants target these monoaminergic systems. Accumulating evidence suggests that the glutamatergic system plays an important role in the neurobiology and treatment of this disease. Some clinical studies have demonstrated that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant patients with MDD. Here, the author reviews the recent findings on the role of the glutamatergic system in the neurobiology of MDD and in new potential therapeutic targets (NMDA receptors, AMPA receptors, metabotropic glutamate receptors, ceftriaxone, minocycline, N-acetyl-L-cysteine) for MDD.

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4.
Biomed Pharmacother. 2008 Jun;62(5):308-11. Epub 2008 Jan 14.
Does minocycline have antidepressant effect?
Pae CU, Marks DM, Han C, Patkar AA.
Source

Department of Psychiatry, Kangnam St. Mary's Hospital, The Catholic University of Korea College of Medicine, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, South Korea. chiun.pae@duke.edu
Abstract

Only one-third of patients undergoing monotherapy with an antidepressant achieve remission of their depressive symptoms and gain functional recovery. Therefore, further exploration of antidepressant mechanisms of action is important in order to facilitate the development of antidepressants with new modes of action. Preclinical and clinical studies have demonstrated that major depression is associated with impaired inflammatory responses and deficient neuroprotection. In this regard, we propose that the second-generation tetracycline "minocycline" may hold a potential as a new treatment for major depression. Emerging findings in animal and human studies of minocycline reveal that it has antidepressant-like neuroprotective and anti-inflammatory actions, and minocycline has been shown to perform as an antidepressant in an accepted animal model (forced swimming test). Anecdotal evidence supports minocycline's efficacy for augmentation of antidepressants in major depressive disorder. The following review describes the evidence supporting the consideration of minocycline as a potential antidepressant. We suggest that minocycline may be particularly helpful in patients with depression and comorbid cognitive impairment, as well as depression associated with organic brain disease. We also describe the antinociceptive effect of minocycline and propose a role for minocycline in the treatment of patients with major depression and prominent somatic discomfort and somatoform spectrum disorders. The lack of clinical studies of minocycline for depression is noted. Further studies of the potential therapeutic mechanism of minocycline and its therapeutic implications for major depression are warranted, and may substantially contribute to the development of newer and more effective antidepressants.

5.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):380-6. Epub 2007 Sep 14.
Antidepressant-like actions of minocycline combined with several glutamate antagonists.
Molina-Hernández M, Tellez-Alcántara NP, Pérez-García J, Olivera-Lopez JI, Jaramillo-Jaimes MT.
Source

Laboratorio de Conducta, Instituto de Investigaciones Psicológicas, Universidad Veracruzana, Jalapa, Veracruz, México. mimolis@hotmail.com
Abstract

This study tested the potential antidepressant activity of minocycline alone or combined with two traditional antidepressant drugs or several glutamate receptor antagonists, using the time sampling method in the forced swimming test. Results showed that: desipramine (10.0 mg/kg, P<0.05; 15.0 mg/kg, P<0.05), minocycline (60.0 mg/kg, P<0.05; 80.0 mg/kg, P<0.05) and EMQMCM (1.5 mg/kg, P<0.05; 2.0 mg/kg, P<0.05), reduced immobility by increasing climbing. Fluoxetine (20.0 mg/kg, P<0.05; 25.0 mg/kg, P<0.05) reduced immobility by increasing swimming. MTEP (5.0 mg/kg, P<0.05; 10.0 mg/kg, P<0.05) and dizolcipine (1.0 mg/kg, P<0.05; 1.5 mg/kg, P<0.05) reduced immobility by increasing swimming and climbing. Combination experiments showed that a subthreshold dose of minocycline (50.0 mg/kg) synergized the antidepressant-like actions of subthreshold doses of: desipramine (5.0 mg/kg; P<0.05), EMQMCM (0.6 mg/kg; P<0.05), MTEP (2.5 mg/kg; P<0.05) and dizolcipine (0.5 mg/kg; P<0.05). In conclusion, minocycline produced antidepressant-like actions in the FST and subthreshold dose of minocycline combined with subthreshold dose of desipramine and several glutamate receptor antagonists and produced antidepressant-like actions.

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I dream of things that never were and ask why not.

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