minocycline and Depressive-Disorder

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.. 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.. 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.. 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.

Topics: Adult; Antidepressive Agents; Depressive Disorder; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Psychotic Disorders; Treatment Outcome

Inflammasome activation and followed by the release of proinflammatory cytokines play a pivotal role in the development and progression of depression. However, the involvement of gasdermin D (GSDMD)-mediated pyroptosis in inflammasome-associated depression has not been studied. The present study aimed to determine the involvement of pyroptosis in the development of depression.. The rat depressive model was established by the administration of monosodium glutamate (MSG) in postnatal rats. Minocycline (an anti-inflammatory agent) and VX-765 (a specific inhibitor of caspase-1) were given as intervention treatments when rats were two-month-old. Rat depressive behaviors were evaluated by behavioral tests, including open field test, sucrose preference test, and forced swim test. Rat hippocampi were collected for western blotting and immunofluorescence examination.. MSG administration induced depressive-like behavior in rats. MSG upregulated protein presences of caspase-1, GSDMD, interleukin-1β (IL-1β), interleukin-18 (IL-18), NLR pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), high mobility group box 1 protein (HMGB1), and the receptor for advanced glycation end products (RAGE) in the hippocampus. Protein presences of HMGB1, NLRP3 and GSDMD were upregulated in Olig2+ oligodendrocytes in the hippocampus. The data suggest that both HMGB1/RAGE/NLRP3 signalings and GSDMD-dependent pyroptosis were activated. Both minocycline and VX-765 treatments improved depressive-like behaviors. Minocycline treatment significantly reduced both HMGB1/RAGE/NLRP3 inflammasome signalings and GSDMD-dependent pyroptosis. VX-765 downregulated GSDMD-dependent pyroptosis, but not HMGB1/RAGE signalings, indicating that GSDMD-dependent pyroptosis is a key player in the progress of depression.. In rats hippocampus, NLRP3 inflammasome activates GSDMD mediated-pyroptosis in the hippocampus of MSG-induced depressive rats.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antidepressive Agents; Depressive Disorder; Disease Models, Animal; Inflammasomes; Male; Minocycline; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Rats; Rats, Sprague-Dawley; Sodium Glutamate

Neuroinflammation induced by stress results in aberrant neurotransmission and dyslipidemia, which can trigger depression- and anxiety-like behaviors. Gamma-aminobutyric acid (GABA) and cholesterol play a crucial role in anxiety-like states, including self-grooming - a common stress-evoked rodent behavior. However, the interaction between neuroinflammation, GABA and cholesterol under stress, and their effects on grooming, remain unclear. Here, we utilize the chronic unpredictable mild stress (CUMS) rat cohort used previously in our Zhang et al. (2019) study, to examine whether CUMS affects grooming behavior, and whether minocycline, a microglia antagonist, can correct these behavioral deficits, accompanied by altering hippocampal neuroinflammation, GABA and serum cholesterol levels. Female Sprague-Dawley rats underwent a 6-week CUMS and received daily minocycline (40 mg/kg, i.p.) during this period, followed by behavioral testing in the open field test. Serum cholesterol, inflammatory cytokines and GABA levels in hippocampus were assayed by ELISA. CUMS significantly decreased locomotion, rearing, central zone entries and time spent in the open field center compared to unstressed controls. CUMS also strongly affected self-grooming behaviors, increasing the frequency of grooming episodes, the number of transitions, interruptions and individual elements of various grooming phases. However, these CUMS-induced behavioral abnormalities were corrected by minocycline. Likewise, CUMS elevated total serum cholesterol and lowered serum high-density lipoprotein cholesterol, whereas minocycline ameliorated these responses. CUMS also lowered hippocampal GABA, whereas minocycline normalized CUMS-induced GABA in the hippocampus. We also found significant correlations between neuroinflammation and GABA, neuroinflammation and cholesterol, GABA and grooming, as well as cholesterol and grooming measures, further implicating stress-evoked neuroinflammation, GABA and cholesterol in the regulation of complex rodent behaviors. In summary, minocycline ameliorated CUMS-induced aberrant self-grooming behaviors in rats by altering hippocampal neuroinflammation, GABA and serum cholesterol levels.

Topics: Animals; Anxiety; Anxiety Disorders; Behavior, Animal; Cholesterol; Depression; Depressive Disorder; Disease Models, Animal; Female; gamma-Aminobutyric Acid; Grooming; Hippocampus; Minocycline; Neuroimmunomodulation; Rats; Rats, Sprague-Dawley; Stress, Psychological

Exposure to early adversity increases vulnerability to psychiatric disorders in later life. Microglia-mediated inflammation has been linked to psychopathology, so such inflammation may be a target for treating depression. Using a model of depression involving adolescent male C57BL/6J mice subjected to maternal separation, we explored whether using minocycline to mitigate inflammation can alleviate depression-like behaviors. Between postnatal days 1 and 14, male mice were separated from their mothers for 3 h per day. Minocycline (20 mg/kg) was administered intraperitoneally once daily for 2 weeks starting one week after weaning. Then the male mice were subjected to a second stress for 2 weeks. Results from the sucrose preference test, forced swimming test, and open field test showed that maternal separation did not obviously alter behavior of the male mice, but it did increase the risk of depression-like behaviors following a second stress. This increased risk disappeared if minocycline was given preemptively before the second stress. Maternal separation and second stress up-regulated pro-inflammatory markers and down-regulated anti-inflammatory markers in the hippocampus, and they activated microglia and promoted pro-inflammatory transitions in microglia. All these effects were reversed by minocycline. These changes in inflammatory processes correlated with changes in neurogenesis and BDNF expression in the hippocampus. Our results in this mouse model suggest the potential of minocycline for treating psychiatric disorders induced by early adversity.

Topics: Animals; Brain; Depression; Depressive Disorder; Disease Models, Animal; Hippocampus; Inflammation; Inflammation Mediators; Male; Maternal Deprivation; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Neurogenesis; Stress, Psychological

The aim of the current study was to analyse the augmentation of minocycline with bupropion in treating depression. 'Saline' (10 ml/kg), 'minocycline per se' (25 mg/kg), 'minocycline per se' (50 mg/kg), 'bupropion per se' (5 mg/kg), 'bupropion per se' (10 mg/kg) and 'bupropion + minocycline' (5 mg/kg + 25 mg/kg each) were administered to mice via the intraperitoneal route. In the forced swim and tail suspension test, the immobility period was analysed after 30 min of the treatment. Monoamines like dopamine, norepinephrine and serotonin levels were analysed in brain areas such as the whole brain, hippocampus and cerebral cortex using an HPLC-fluorescence detector. Euthanasia of mice was performed 1 h after treatment. Comparison between the control group and combination therapy and other standard drug groups showed a significant decrease in immobility in both antidepressant animal models. The combination of bupropion and minocycline showed greater benefits with respect to a reduction in the immobility time period and enhancement of dopamine, serotonin, and norepinephrine levels in the cerebral cortex, hippocampus and the whole brain when compared to the monotherapy treated groups. Hence, the side effects may be reduced drastically through this combination by a reduction in the bupropion/minocycline dosage.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; Bupropion; Depression; Depressive Disorder; Dopamine; Male; Mice; Minocycline; Motor Activity; Serotonin

Neurological melioidosis, an extremely rare condition, is caused by the gram-negative bacterium Burkholderia pseudomallei. If treatment is suboptimal or delayed, this infection can produce diverse clinical symptoms and result in death.. A healthy 65-year-old female who had been treated with antipsychotic medication for neurotic depression for over 2 years presented with acute-onset fever, headache, lead-pipe rigidity of all limbs, and delirium.. Melioidosis meningitis was diagnosed by performing blood examinations and cerebrospinal fluid analysis and cultures.. Intravenous ceftazidime (2 g/8 h for 3 weeks) was administered in-hospital and 240 mg trimethoprim/1200 mg sulfamethoxazole and 100 mg minocycline twice daily administered out-hospital.. The patient fully recovered after antibiotic therapy without cognitive deficits and associated neurological complications.. Because melioidosis is endemic in Southern Taiwan and the use of antipsychotics might mask the symptoms, physicians dealing with patients from endemic areas with a medical history of antipsychotics should always consider the possibility of neurological melioidosis and provide prompt empirical management to suspicious cases.

Topics: Aged; Anti-Bacterial Agents; Antipsychotic Agents; Burkholderia pseudomallei; Ceftazidime; Cerebrospinal Fluid; Depressive Disorder; Diagnosis, Differential; Female; Humans; Melioidosis; Meningitis, Bacterial; Minocycline; Neuroleptic Malignant Syndrome; Trimethoprim, Sulfamethoxazole Drug Combination

Anxiety disorders are chronic, disabling conditions across the world, and bring a great burden to individuals and society. Although advances have been made in understanding of the pathophysiology of these diseases, no mechanistically new drugs for anxiety disorders have reached the market in the past two decades. Some evidence indicates that stress increases neuroinflammatory signaling, which is related to the development of anxiety and depression. Minocycline, a broad-spectrum tetracycline-antibiotic, has been reported to suppress microglia activation-mediated brain endogenous inflammation. However, it is still unknown whether minocycline can be developed to treat stress-induced anxiety disorders and what is the underlying mechanisms. We chose the anxiety model induced by repeated stress consisting of 2 h of restraint on each of 7 consecutive days. The behavioral test results showed that chronic minocycline treatment, not acute minocycline treatment, increased the time spent in the center area in the open field test and the number of open arm entries and time spent in open arms in the elevated plus maze test, which were comparable with the effect of buspirone. Further mechanism studies demonstrated that chronic minocycline treatment inhibited the microglia activation and decreased the levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). In addition, peroxisome proliferator-activated receptor gamma/ nuclear factor kappa B (PPAR-γ/NF-κB) signaling pathway was also modulated by chronic minocycline treatment. In conclusion, our findings support the hypothesis that immune dysregulation plays an important role in stress-induced anxiety disorders, and minocycline can be developed to be used in these diseases.

Topics: Amygdala; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior, Animal; Depression; Depressive Disorder; Disease Models, Animal; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Neuroimmunomodulation; NF-kappa B; PPAR gamma; Signal Transduction; Stress, Psychological; Tumor Necrosis Factor-alpha

A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN.

Topics: Analgesics; Animals; Antidepressive Agents; Cold Temperature; Depressive Disorder; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Hyperalgesia; Hypoglycemic Agents; Male; Minocycline; Random Allocation; Rats, Wistar; Touch

Neonatal infection is associated with increased lifetime risk for neuropsychiatric disorders including anxiety and depression, with evidence showing that dysregulation of the hypothalamic-pituitary-adrenal-(HPA)-axis system may be partly responsible. Preclinical and clinical studies demonstrate that minocycline exhibits antidepressant effects through inhibition of microglial activation and anti-inflammatory actions, and of interest is that recent studies suggest that minocycline alleviates the behavioral abnormalities induced by early-life insults. The current study was designed to determine if developmental minocycline treatment attenuates the neonatal immune activation-induced anxiety- and depression-like symptoms and HPA-axis-dysregulation later in life. To this end, neonatal mice were treated to either lipopolysaccharide or saline on postnatal days (PND) 3-5, then dams during lactation (PND 6-20) and male offspring during adolescence (PND 21-40) received oral administration of minocycline or water via regular drinking bottles. Anxiety- and depression-like behaviors, HPA-axis-reactivity (corticosterone), and hippocampal inflammation (TNF-α and IL-1β) after exposure to stress were evaluated. The results indicated that neonatal immune activation resulted in increased anxiety and depression-like symptoms, HPA-axis-hyperactivity, and elevated the levels of TNF-α and IL-1β in the hippocampus in response to stress in adulthood. Interestingly, developmental minocycline treatment significantly reduced the abnormalities induced by neonatal inflammation in adult mice. In addition, minocycline, regardless of postnatal inflammation, did not have any detrimental effects on the above measured parameters. Considering that minocycline is currently under exploration as an alternative or adjunctive therapy for reducing the symptoms of neurological disorders, our findings suggest that minocycline during development can decrease the behavioral abnormalities induced by early life inflammation in adulthood.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Anxiety Disorders; Depressive Disorder; Disease Models, Animal; Female; Hippocampus; Hypothalamo-Hypophyseal System; Inflammation; Lactation; Lipopolysaccharides; Male; Mice; Minocycline; Pituitary-Adrenal System

Minocycline is a broad-spectrum tetracycline antibiotic with multiple actions, including anti-inflammatory and neuroprotective effects, that was proposed as novel treatment for several psychiatric disorders including schizophrenia and depression. However, there are contradictory results regarding antidepressant effects of minocycline in rodent models. Additionally, the possible anxiolytic effect of minocycline is still poorly investigated. Therefore, we aimed to clarify in the present study the influence of minocycline on behavioral correlates of mood disorders in standard tests for depression and anxiety, the Porsolt Forced Swim Test (FST), Elevated O-Maze, Dark-Light Box Test and Openfield Test in adult C57BL/6 mice. We found, unexpectedly, that mice treated with minocycline (20-40mg/kg, i.p.) did not display antidepressant- or anxiolytic-like behavioral changes in contrast to mice treated with diazepam (0.5mg/kg, anxiety tests) or imipramine (20mg/kg, depressive-like behavior). These results are relevant for future studies, considering that C57BL/6 mice, the most widely used strain in pharmacological and genetic animal models, did not react as expected to the treatment regime applied.

Topics: Animals; Anti-Anxiety Agents; Anti-Bacterial Agents; Antidepressive Agents; Anxiety Disorders; Depressive Disorder; Diazepam; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Imipramine; Male; Mice, Inbred C57BL; Minocycline; Neuropsychological Tests

There is a paucity of data on the role of microglia and neuroinflammatory processes in the association between chronic pain and depression. The current study examined the effect of the microglial inhibitor minocycline on depressive-like behaviour, spinal nerve ligation (SNL)-induced mechanical and cold allodynia and associated changes in the expression of genes encoding microglial markers (M1 vs. M2 polarisation) and inflammatory mediators in the prefrontal cortex in the olfactory bulbectomised (OB) rat model of depression. Acute minocycline administration did not alter OB-induced depressive-like behaviour but prevented SNL-induced mechanical allodynia in both OB and sham rats. In comparison, chronic minocycline attenuated OB-induced depressive-like behaviour and prevented the development of SNL-induced mechanical allodynia in OB, but not sham, rats. Further analysis revealed that SNL-induced mechanical allodynia in OB rats was attenuated by chronic minocycline at almost all time-points over a 2week testing period, an effect observed only from day 10 post-SNL in sham rats. Chronic administration of minocycline reduced the expression of CD11b, a marker of microglial activation, and the M1 pro-inflammatory cytokine IL-1β, in the prefrontal cortex of sham-SNL animals. In comparison, the expression of the M2 microglia marker (MRC2) and anti-inflammatory cytokine IL-10 was increased, as were IL-1β, IL-6 and SOCS3, in the prefrontal cortex of OB-SNL animals following chronic minocycline. Thus, chronic minocycline attenuates neuropathic pain behaviour and modulates microglial activation and the central expression of inflammatory mediators in a manner dependent on the presence or absence of a depressive-like phenotype.

Topics: Analgesics; Animals; Behavior, Animal; Cerebral Cortex; Depressive Disorder; Disease Models, Animal; Gene Expression; Hyperalgesia; Male; Microglia; Minocycline; Motor Activity; Neuralgia; Pain Measurement; Rats; Rats, Sprague-Dawley

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.

Topics: Animals; Anti-Bacterial Agents; Antidepressive Agents; Behavior, Animal; Depressive Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Exercise Test; Exploratory Behavior; Locomotion; Male; Minocycline; Motor Activity; Quinolines; Rats; Rats, Wistar; Swimming

Isotretinoin is indicated for the treatment of severe, recalcitrant nodular acne. Spontaneous reports have suggested a possible association between isotretinoin and depression that has not been supported by prior studies. Depression has been reported in patients with acne and is common among adolescents.. The objective of this study was to investigate whether there is an association between isotretinoin use and onset of depression.. A large retrospective database study was performed through a review of pharmacy claims to evaluate the order of first-recorded isotretinoin and antidepressant dispensings in incident users. The study included 2821 patients, aged 12 to 49 years, who filled isotretinoin prescriptions between June 1, 1999, and March 31, 2000. The ratio of the number of patients who filled isotretinoin prescription first versus second was computed, with adjustment for variations in physician prescribing patterns; a ratio significantly greater than 1.0 indicates a depression-invoking relationship. Similar analyses of minocycline were performed.. Adjusted ratios for all antidepressants and by class were not significantly greater than 1.0. Similar results were found for minocycline.. The results do not support an association between the use of isotretinoin and the onset of depression.

Topics: Acne Vulgaris; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Age Distribution; Antidepressive Agents; Child; Cohort Studies; Confidence Intervals; Depressive Disorder; Dermatologic Agents; Drug Prescriptions; Drug Therapy; Drug Utilization; Female; Humans; Incidence; Isotretinoin; Male; Middle Aged; Minocycline; Probability; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Distribution