minocycline and Schizophrenia

Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.

Topics: Anti-Inflammatory Agents; Bipolar Disorder; Humans; Minocycline; Obsessive-Compulsive Disorder; Schizophrenia

The pharmacological treatment of schizophrenia is currently based on the employment of antipsychotic medications showing an antagonism of dopaminergic and serotoninergic inhibitors. 20-40% of patients are drug-resistant or residually symptomatic in the long-term antipsychotic treatment, and new strategies are needed for improving their functional and cognitive impairment.. This systematic review has summarized evidences from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, and Google Scholar.. The possible role of glutamate and its receptors as targets of the antipsychotic mechanism of action has been described. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. Results show an efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA- Receptor antagonist) for cognition and psychopathology. The putative antipsychotic effect of cannabidiol on positive symptoms and cognition will also be discussed. The action on serotoninergic and GABAergic receptors will be considered as a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown to induce improvements in cognitive symptoms in schizophrenia, as well as Erythropoietin. Oxytocin has been reported to have an antipsychotic-like effect; moreover, COX-2 inhibitors lead to a reduction in positive symptoms of psychosis, specifically in the first episode of illness.. This narrative report suggests a promising role of new agents in the treatment of Schizophrenia; however, more research is needed to approve their clinical employment.

Topics: Antipsychotic Agents; Cyclooxygenase 2 Inhibitors; Erythropoietin; Glutamic Acid; Heterocyclic Compounds, 4 or More Rings; Humans; Minocycline; Molecular Targeted Therapy; Oxytocin; Receptors, N-Methyl-D-Aspartate; Schizophrenia

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.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Humans; Microglia; Minocycline; Neurogenesis; Neuronal Plasticity; Neurons; Schizophrenia

This study aimed to conduct a meta-analysis of the efficacy and safety of adjunctive minocycline for schizophrenia. Randomized controlled trials (RCTs) comparing adjunctive minocycline with placebo in patients with schizophrenia were included in the meta-analysis. Two independent investigators extracted and synthesized data. Standard mean differences (SMDs), risk ratio (RR) ±95% confidence intervals (CIs) and the number-needed-to-harm (NNH) were calculated. Eight RCTs with 548 schizophrenia patient including 286 (52.2%) patients on minocycline (171.9±31.2mg/day) and 262 (47.8%) on placebo completed 18.5±13.4 weeks of treatment. Meta-analyses of Positive and Negative Syndrome Scale (PANSS) (7 RCTs with 8 treatment arms)/Brief Psychiatric Rating Scale (BPRS) (1 RCT) total score [SMD: -0.64, (95%CI: -1.02, -0.27), P=0.0008; I

Topics: Antipsychotic Agents; Databases, Bibliographic; Humans; Minocycline; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Schizophrenia

Our aim was to perform an updated systematic review and meta-analysis on the efficacy and safety of adjunctive minocycline as a treatment of schizophrenia.. We conducted a PubMed/Scopus database search from inception to 3 February 2016 for randomized, placebo-controlled trials (RCTs), open non-randomized studies, and case reports/series evaluating minocycline in patients with schizophrenia. Random-effects meta-analysis of positive, negative, depressive, and cognitive symptom rating scales, discontinuation and adverse effects rates calculating standardized mean difference (SMD), and risk ratios±95% confidence intervals (CI 95%) were calculated.. Six RCTs were eligible (minocycline n=215, placebo n=198) that demonstrated minocycline's superiority versus placebo for reducing endpoint Positive and Negative Syndrome Scale (PANSS) total scores (SMD=-0.59; CI 95%=[1.15, -0.03]; p=0.04), negative (SMD=-0.76; CI 95%=[-1.21, -0.31]; p=0.001); general subscale scores (SMD=-0.44; CI 95%=[-0.88, -0.00]; p=0.05), Clinical Global Impressions scores (SMD=-0.50; CI 95%=[-0.78, -0.22]; p<0.001); and executive functioning (SMD=0.22; CI 95%=[0.01, 0.44]; p=0.04). Endpoint PANSS positive symptom scores (p=0.13), depression rating scale scores (p=0.43), attention (p=0.47), memory (p=0.52), and motor speed processing (p=0.50) did not significantly differ from placebo, before execution of a trim-and-fill procedure. Minocycline did not differ compared to placebo on all-cause discontinuation (p=0.56), discontinuation due to inefficacy (p=0.99), and intolerability (p=0.51), and due to death (p=0.32). Data from one open-label study (N=22) and three case series (N=6) were consistent with the metaanalytic results.. Minocycline appears to be an effective adjunctive treatment option in schizophrenia, improving multiple relevant disease dimensions. Moreover, minocycline has an acceptable safety and tolerability profile. However, more methodologically sound and larger RCTs remain necessary to confirm and extend these results.

Topics: Anti-Bacterial Agents; Antipsychotic Agents; Humans; Minocycline; Randomized Controlled Trials as Topic; Schizophrenia

Although there has been more than 50 years of development, there remains a great need for better antipsychotic medications. This article looks at the recent advances in treatment of schizophrenia. New hypotheses have been suggested that may replace or complement the dopamine hypotheses. The article explores the different novel drugs that impact some of the key neurotransmitter systems currently. Phosphodiesterase 10A inhibitors and α-7 neuronal nicotinic acetylcholine receptor modulators constitute the majority. The marketing of these medications eventually may result in change about how schizophrenia is treated.

Topics: Antipsychotic Agents; Drug Approval; Excitatory Amino Acid Agents; Glycine Agents; Humans; Minocycline; Nicotinic Agonists; Phosphodiesterase Inhibitors; Piperazines; Piperidines; Schizophrenia

Altered antioxidant status has been implicated in schizophrenia. Microglia are major sources of free radicals such as superoxide in the brain, and play crucial roles in various brain diseases. Recent postmortem and imaging studies have indicated microglial activation in the brain of schizophrenia patients. Animal models that express some phenotypes of schizophrenia have revealed the underlying microglial pathology. In addition, minocycline, an antibiotic and the best known inhibitor of microglial activation, has therapeutic efficacy in schizophrenia. We have recently revealed that various antipsychotics directly affect microglia via proinflammatory reactions such as oxidative stress, by in vitro studies using rodent microglial cells. Based on these findings, we have suggested that microglia are crucial players in the brain in schizophrenia, and modulating microglia may be a novel therapeutic target. In this review paper, we introduce our hypothesis based on the above evidence. The technique of in vivo molecular redox imaging is expected to be a powerful tool to clarify this hypothesis.

Topics: Animals; Antipsychotic Agents; Brain; Disease Models, Animal; Free Radicals; Humans; Microglia; Minocycline; Molecular Targeted Therapy; Oxidation-Reduction; Oxidative Stress; Schizophrenia; Superoxides

To provide a systematic review of the literature regarding the efficacy of anti-inflammatory drugs in three major mental disorders [major depressive disorder (MDD), schizophrenia and bipolar disorders].. Four databases were explored, without any year or language restrictions. The baseline search paradigm was limited to open-labelled clinical and randomized controlled trials (RCTs).. Four major classes of anti-inflammatory drugs were identified, namely polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, anti-TNFalpha and minocycline. Effectiveness and benefit/risk ratio of each class in MDD, bipolar disorders and schizophrenia was detailed when data were available. Several meta-analyses indicated effectiveness of PUFAs in MDD with a good tolerance profile. One meta-analysis indicated that COX-2 specific inhibitors showed effectiveness in schizophrenia. Anti-TNFalpha showed important effectiveness in resistant MDD with blood inflammatory abnormalities. Minocycline showed effectiveness in schizophrenia.. Polyunsaturated fatty acids seem to have the best benefit/risk ratio profile but proved their effectiveness only in MDD. A number of anti-inflammatory drugs are available as adjunct treatment for treatment-resistant patients with MDD, schizophrenia and bipolar disorder. If used with caution regarding their possible side-effects, they may be reasonable therapeutic alternatives for resistant symptomatology.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Bipolar Disorder; Cyclooxygenase Inhibitors; Depressive Disorder, Major; Fatty Acids, Unsaturated; Humans; Minocycline; Schizophrenia; Tumor Necrosis Factor-alpha

The tetracyclic antibiotic minocycline appears to have positive results when added to the the treatment prescribed for persistent symptoms of schizophrenia.. To provide an overview of the literature on minocycline and schizophrenia.. PubMed, up to September 2013, was scanned for articles relating to minocycline and schizophrenia.. We found seven case reports with regard to the use of minocycline as an additive in the treatment of persistent schizophrenia. Furthermore, an open-label study and two randomised placebo-controlled studies regarding this addition were published. Using minocycline may add to the improvement of negative symptoms and cognition in patients with schizophrenia.. It is concluded, albeit somewhat cautiously, that minocycline may be helpful in treating negative and cognitive symptoms in schizophrenia.

Topics: Antipsychotic Agents; Cognition; Humans; Minocycline; Schizophrenia; Schizophrenic Psychology

This study aimed to perform a comprehensive meta-analysis of minocycline augmentation therapy in patients with schizophrenia receiving antipsychotic agents.. Data published up to 2 June 2014 were obtained from the PubMed, PsycINFO, Google Scholar, and Cochrane Library databases.We conducted a systematic review and meta-analysis of patient data from randomized controlled trials (RCTs) comparing minocycline with placebo. Relative risk (RR), standardized mean difference (SMD), and 95% confidence intervals were calculated.. We included four RCTs. The total sample included 330 patients. Minocycline was superior to placebo for decreasing Positive and Negative Syndrome Scale (PANSS) total scores (SMD=0.70), PANSS negative subscale scores (SMD=0.86), and PANSS general subscale scores (SMD=-0.50) but was not different from placebo for PANSS positive subscale scores (SMD=0.26) and depressive symptoms (SMD=0.28). Minocycline was equivalent to placebo for all-cause discontinuation (RR=1.10), discontinuation due to inefficacy (RR=0.42), discontinuation due to adverse events (RR = 1.56), and discontinuation due to death (RR = 3.18). Minocycline was superior to placebo for extrapyramidal side-effect scores (SMD=0.32).. Minocycline may improve the psychopathology of schizophrenia, especially the negative symptoms, and seems to be well tolerated.

Topics: Antipsychotic Agents; Drug Therapy, Combination; Humans; Minocycline; Randomized Controlled Trials as Topic; Schizophrenia

Accumulating evidence suggests a role of inflammation in the pathophysiology of a number of neuropsychiatric diseases. The second generation antibiotic drug minocycline has potent neuroprotective and anti-inflammatory effects. We reported that minocycline could attenuate behavioral abnormalities and dopaminergic neurotoxicity in mice after administration of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Furthermore, we reported that minocycline was effective in the animal models of schizophrenia. Moreover, a double-blind, placebo-control, cross-over study showed that minocycline was effective in the rewarding effects in healthy human subjects. In this article, we would like to discuss minocycline as a potential therapeutic drug for methamphetamine-related disorders.

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Humans; Methamphetamine; Minocycline; Schizophrenia; Substance-Related Disorders

Schizophrenia is a chronic debilitating mental disorder that affects about 1% of the US population. The pathophysiology and etiology remain unknown, thus new treatment targets have been challenging and few novel treatments with new mechanisms of action have come to market in the past few decades. Increasing attention has been paid to the role of inflammation in schizophrenia and new data suggests that decreasing inflammation and inflammatory biomarkers may play some role in schizophrenia treatment. This review summarizes the clinical trial literature regarding medications that possess anti-inflammatory properties that have been tested for schizophrenia symptoms and covers such medications as non-steroidal anti-inflammatory agents, such as the cyclo-oxygenase-2 (COX-2) inhibitors and aspirin, omega-3 fatty acids, neurosteroids and minocycline. Overall, there is accumulating evidence, albeit mostly adjunctive treatments, that agents working on inflammatory pathways have some benefits in people with schizophrenia. In the next few years the field will begin to see data on many treatments with anti-inflammatory properties that are currently under study. Hopefully advancements in understanding inflammation and effective treatments having anti-inflammatory properties may help revolutionize our understanding and provide new targets for prevention and treatment in schizophrenia.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Dietary Supplements; Evidence-Based Medicine; Fatty Acids, Omega-3; Humans; Minocycline; Neurotransmitter Agents; Schizophrenia

The pharmacologic treatment of schizophrenia and bipolar disorder leaves much to be desired. Repurposed drugs, which are approved for other medical conditions, represent an underutilized therapeutic resource for patients who have not responded to other drugs. Using experience gained from a decade of repurposed drug studies by the Stanley Medical Research Institute and search of the literature, we have identified nine such drugs for which there is some evidence of efficacy for schizophrenia and/or bipolar disorder. These include: aspirin; celecoxib; estrogen/raloxifene; folate; minocycline; mirtazapine; omega-3 fatty acids; pramipexole; and, pregnenolone. The evidence of efficacy is reviewed for each drug. Because there is little or no financial incentive for pharmaceutical companies to promote such drugs, there is a paucity of definitive trials, and these drugs are less widely known than they deserve to be. Biomarker studies should also be carried out to identify subgroups of patients who do respond to these drugs.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Aspirin; Benzothiazoles; Bipolar Disorder; Celecoxib; Chemotherapy, Adjuvant; Cyclooxygenase 2 Inhibitors; Dopamine Agonists; Estrogens; Fatty Acids, Omega-3; Folic Acid; Humans; Mianserin; Minocycline; Mirtazapine; Pramipexole; Pregnenolone; Pyrazoles; Randomized Controlled Trials as Topic; Schizophrenia; Sulfonamides; Treatment Outcome; Vitamin B Complex

Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA) transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R). This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Brain; Clinical Trials as Topic; Glycine Agents; Humans; Minocycline; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Signal Transduction

Topics: Antipsychotic Agents; Humans; Microglia; Minocycline; Schizophrenia

Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to various clinical trials. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline as an open-label adjunct to antipsychotic medication to patients with schizophrenia. The results of this trial suggested that minocycline might be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia. The present review summarizes the available data supporting the clinical testing of minocycline for patients with schizophrenia. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antipsychotic Agents; Apoptosis; Humans; Microglia; Minocycline; Nerve Degeneration; Neuroprotective Agents; Schizophrenia; Treatment Outcome

Use of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) is an extremely serious and growing problem throughout the world, including Japan. Antipsychotic drugs have been used for psychotic symptoms associated with these abused drugs. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with these abused drugs. Recently, we reported that the second generation antibiotic drug minocycline can attenuate behavioral abnormalities and neurotoxicity in the brain after administration of methamphetamine or MDMA. In this review, we discuss minocycline as a new potential therapeutic drug for schizophrenia as well as psychosis associated with these abused drugs.

Topics: Animals; Anti-Bacterial Agents; Brain; Disease Models, Animal; Humans; Methamphetamine; Minocycline; N-Methyl-3,4-methylenedioxyamphetamine; Positron-Emission Tomography; Psychoses, Substance-Induced; Schizophrenia; Substance-Related Disorders

Immune dysfunction has been implicated in negative symptoms of schizophrenia and also in depression. These disorders are frequently co-morbid, with some symptoms such as anhedonia and apathy common to both. The anti-inflammatory agent minocycline may be ineffective in schizophrenia, but more positive effects have been seen in depression. Our aim was to investigate the role of immune dysfunction in depression and sub-domains of negative symptoms in schizophrenia by investigating their intercorrelation and the influence of treatment with minocycline.. We analysed longitudinal data from 207 patients within 5 years of onset of schizophrenia, from the randomised double-blind, placebo-controlled trial of minocycline (BeneMin). Symptom ratings and circulating IL-6, C-reactive protein (CRP) and TNF-α concentrations were collected at baseline and repeated over twelve months. The sample was not stratified by CRP prior to randomisation. Positive and Negative Syndrome Scale composite ratings of avolition-apathy and diminished expression, Calgary Depression Scale total scores, and immune markers were examined cross-sectionally using Spearman's rank, and longitudinally by linear mixed effect models that included body mass index and minocycline. Additionally, post hoc analysis of the sample stratified by elevated CRP (>1 mg/l and <10 mg/l at baseline) was carried out to assess whether minocycline had any effect on specific symptoms in an immune active sub-group of patients.. Depression and avolition-apathy were significantly positively related, and depression correlated weakly with IL-6 at baseline. Diminished expression was associated with increased TNF-α both cross-sectionally and longitudinally. CRP was unrelated to any symptom domain. Minocycline did not affect any individual symptom or sub-domain in the full sample or in the immune active sub-group.. IL-6 may have some specificity to depression in early schizophrenia. TNF-α may be an indicator of immune dysfunction relevant to negative symptoms, and our longitudinal findings add to this evidence. However, minocycline continues to show very little promise as a treatment for any symptom dimension of early schizophrenia.

Topics: Anhedonia; Depression; Double-Blind Method; Humans; Minocycline; Schizophrenia

Cognitive deficits of schizophrenia are predictors of poor function, but antipsychotic medication has limited efficacy for cognitive deficits. These deficits in learning and memory may result from activity of pro-inflammatory cytokines, which microglia produce. The microglia inhibitor minocycline might arrest this cytokine damage to the hippocampus and reverse the cognitive deficits of schizophrenia.. A double-blind, placebo-controlled study involved 75 patients with schizophrenia who randomly received low dose (100 mg/day) or high dose minocycline (200 mg/day) or placebo added to risperidone. MATRICS Consensus Cognitive Battery (MCCB) was used to assess the cognitive functioning, and serum levels of Interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were assessed.. Minocycline. Minocycline adjunctive treatment was effective in improving cognitive deficits of patients with schizophrenia. The beneficial effect of minocycline may be related to reducing pro-inflammatory cytokines through microglia inhibition.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Antipsychotic Agents; Cognitive Dysfunction; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Male; Microglia; Middle Aged; Minocycline; Risperidone; Schizophrenia; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

Studies have hypothesized that immunological abnormalities might contribute to schizophrenia, and basic science studies, as well as several clinical trials suggest that minocycline could be efficacious in ameliorating both positive and negative symptoms of schizophrenia. In this study we examined the effect of minocycline on schizophrenia in a large randomized controlled trial.. We performed a 16-week, multi-center, double-blind, randomized, placebo-controlled study on 200 subjects with schizophrenia or schizoaffective disorder randomized to receive either minocycline (200 mg/day, n = 100), or placebo (n = 100) as an add-on to anti-psychotic treatment. The primary outcome measure was the PANSS total score.. Mixed models for repeated measures showed no significant difference between minocycline and placebo for total PANSS (p = 0.862), PANSS subscales, CGI or BACS.. Minocycline did not improve symptoms or cognition in schizophrenia.

Topics: Adult; Anti-Bacterial Agents; Antipsychotic Agents; Cognition; Double-Blind Method; Female; Humans; Male; Middle Aged; Minocycline; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Neuroprotective Agents; Schizophrenia

This study examined the effect of adjunctive minocycline on body metabolism in risperidone-treated patients with schizophrenia.. Each subject had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia and had been on stable dose of risperidone for at least 4 weeks. In a 16-week randomized, double-blind, placebo-controlled study, subjects received either minocycline (200 mg/d) or placebo. Various metabolic parameters, including weight, waist circumference, fasting insulin, glucose, and lipids, were measured at baseline and week 16.. A total of 63 subjects with schizophrenia were enrolled in the study. Fifty-five patients completed week-16 assessments (27 in the minocycline group, 28 in the placebo group). There were no significant differences between the 2 groups in week 16 changes for body weight, body mass index, waist circumference, fasting insulin, glucose, and lipids (P's > 0.300).. In the present study, adjunctive treatment of minocycline did not seem to improve body metabolism in patients with schizophrenia receiving risperidone. The implications for future studies were discussed.

Topics: Adult; Anti-Inflammatory Agents; Antipsychotic Agents; Double-Blind Method; Female; Humans; Inflammation; Male; Minocycline; Outcome Assessment, Health Care; Risperidone; Schizophrenia; Young Adult

This study examined the effect of adjunctive minocycline on psychopathology and possibly relevant biomarkers in patients with schizophrenia.. In a 16-week randomized, double-blind, placebo-controlled study, subjects received either minocycline (200mg per day) or placebo. Psychopathology was assessed using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS) at baseline and week 16. Plasma levels of tumor necrosis factor α (TNFα), interleukin-1 β (IL-1β) and nitric oxide metabolites were assessed at both time points.. Fifty-five patients completed the study (27 in the minocycline group, 28 in the placebo group). The minocycline group had significant decreases in the SANS total sore, the PANSS total score and the PANSS negative symptoms score at week 16 compared to the placebo group. In addition, the minocycline group had a significant decrease in plasma levels of nitric oxide metabolites, but no significant difference in changes in plasma levels of IL-1β or TNF-α, compared to the placebo group at week 16. Further, the more decrease in plasma levels of nitric oxide metabolites was associated with less improvement in negative symptoms.. The beneficial effect of adjunctive minocycline treatment on negative symptoms might be through mechanisms other than the nitric oxide pathway. The implications for future studies were discussed.

Topics: Adult; Antipsychotic Agents; Biomarkers; Double-Blind Method; Female; Humans; Male; Minocycline; Nitric Oxide; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

We attempted to replicate the efficacy of minocycline, a second-generation tetracycline, as adjunctive therapy for the negative symptoms of schizophrenia, and to investigate its association with pro-inflammatory cytokine levels.. Seventy-five schizophrenia patients with negative symptoms entered a 3-month, double blind, randomized, placebo-controlled clinical trial. Subjects were assigned low dose (100 mg per day) or high dose minocycline (200 mg per day) or placebo combined with risperidone. The outcomes used the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS)-negative subscale. We assessed three pro-inflammatory cytokines in serum: interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).. Subjects receiving high dose minocycline not only had greater improvements on the SANS total scores and PANSS negative subscale scores (P < 0.01), but also had greater reductions in IL-1β and IL-6 serum levels (P < 0.01) when compared with those receiving low dose minocycline or placebo. The improvement in negative symptoms with minocycline was significantly correlated with the reduction of IL-1β and IL-6 serum levels (P < 0.05).. Schizophrenia patients showed a significant improvement in negative symptoms with the addition of minocycline to risperidone. Reducing pro-inflammatory cytokines may play an important role in the potential mechanism for efficacy.

Topics: Adult; Antipsychotic Agents; Biomarkers; Cytokines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Minocycline; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The at-risk mental state (ARMS) describes individuals at high risk of developing schizophrenia or psychosis. The use of antipsychotics in this population is not supported, because most individuals with ARMS are unlikely to develop psychosis. Anti-inflammatory treatments and polyunsaturated fatty acids (PUFAs) may have some beneficial effects in the treatment of ARMS. There have been no controlled clinical trials in which researchers have investigated the use of minocycline for ARMS and no trials involving PUFAs in combination with other proposed treatments. There is a need to find effective, tolerable and inexpensive interventions for individuals with ARMS that are available in high-, low- and middle-income countries.. A 6-month intervention study of minocycline and/or omega-3 fatty acids added to treatment as usual (TAU) in patients with ARMS will be conducted in Pakistan using a randomised, placebo-controlled, double-blind factorial design. A total of 320 consenting patients with capacity will be recruited from the community, general practitioner clinics and psychiatric units. Allowing for a 25% dropout rate, we will recruit 59 completing participants into each study arm, and in total 236 will complete the study. We will determine whether the addition of minocycline and/or omega-3 fatty acids to TAU attenuates the rate of transition from ARMS to first-episode psychosis and improves symptoms and/or level of functioning in ARMS. We will also investigate whether any candidate risk factors, such as negative symptoms, influence treatment response in the ARMS group. The primary efficacy endpoint is conversion to psychotic disorder at 12 months after study entry. Analysis will be done according to the intention to treat principle using analysis of variance, chi-square tests and adjusted ORs to assess between-group differences. Cox regression analysis will be used to evaluate potential between-group differences in time to onset of psychosis.. The outcomes of this trial will provide evidence of the potential benefits of minocycline and PUFAs in the treatment of ARMS. Both minocycline and PUFAs are inexpensive, are readily available in low-/middle-income countries such as Pakistan, and if proven, may be safe and effective for treating individuals with ARMS.. ClinicalTrials.gov, NCT02569307 . Registered on 3 October 2015.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Chi-Square Distribution; Clinical Protocols; Dietary Supplements; Double-Blind Method; Fatty Acids, Omega-3; Female; Humans; Intention to Treat Analysis; Male; Mental Health; Minocycline; Pakistan; Proportional Hazards Models; Psychotic Disorders; Research Design; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome; Young Adult

Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12months of a randomized double-blind, placebo-controlled clinical trial of minocycline add-on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12months of adjuvant treatment with minocycline (200mg/d) or placebo. MRI (1.5T) and [(99m)Tc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel-based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.

Topics: Adult; Antipsychotic Agents; Brain; Cerebrovascular Circulation; Cysteine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Magnetic Resonance Imaging; Male; Minocycline; Organ Size; Organotechnetium Compounds; Psychiatric Status Rating Scales; Radiopharmaceuticals; Schizophrenia; Signal Processing, Computer-Assisted; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Young Adult

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.. 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).. Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) 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 Scale for the Assessment of Negative Symptoms 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 with placebo.. Minocycline's effect on the MATRICS Consensus Cognitive Battery 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.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The objective of this study was to assess the efficacy and tolerability of minocycline add-on to risperidone in treatment of negative symptoms of patients with chronic schizophrenia. In a randomized double-blind placebo-controlled study, 40 patients with chronic schizophrenia who were stabilized on risperidone for a minimum duration of eight weeks were recruited. The patients were randomly assigned to minocycline (titrated up to 200 mg/day) or placebo in addition to risperidone (maximum dose of 6 mg/day) for eight weeks. Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, and Extrapyramidal Syndrome Rating Scale were used. Thirty-eight patients completed the study. Significant time × treatment interaction for negative [F(2.254,85.638)=59.046, P<0.001] general psychopathology [F(1.703,64.700)=6.819, P=0.001], and positive subscales [F(1.655,62.878)=5.193, P=0.012] as well as total PANSS scores [F(1.677,63.720)=28.420, P<0.001] were observed. The strongest predictors for change in negative symptoms were the treatment group (β=-0.94, t=-10.59, P<0.001) followed by the change in PANSS positive subscale (β=-0.185, t=-2.075, P=0.045). Side effect profiles of the two treatment regimens were not significantly different. Minocycline seems to be an efficacious and tolerable short-term add-on to risperidone for treatment of negative and general psychopathology symptoms of schizophrenia.

Topics: Adult; Anti-Bacterial Agents; Antipsychotic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

It is difficult to improve negative symptoms and cognitive impairments in schizophrenia. A previous pilot study has shown that minocycline, a semi-synthetic second-generation tetracycline, is effective in treating for negative and/or cognitive symptoms in schizophrenia.. The present study was designed to examine the efficacy and safety of minocycline for the treatment of negative symptoms and cognitive impairments in patients with schizophrenia.. Ninety-two patients with early stage schizophrenia treated with risperidone entered this 16-week, double blind, randomized, placebo-controlled clinical trial. Subjects were randomly assigned to receive minocycline (200mg per day) or the placebo. The primary outcome was evaluated using the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the response rate of SANS, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI), and cognitive tests.. Subjects receiving minocycline had greater improvements on SANS total scores and PANSS negative subscale scores (P<0.001) when compared with those receiving the placebo. Rates of treatment response (43.6%) in the minocycline group were significantly higher than those in the placebo group (10.0%) after 16weeks of treatment. There was no significant difference between the seven cognitive domains (P>0.05), except for the attention domain (P=0.044).. The addition of minocycline to atypical antipsychotic drugs in early schizophrenia had significant efficacy on negative symptoms but had a slight effect on the attention domains of patients with schizophrenia. It may be considered as a new adjunct treatment for negative symptoms of schizophrenia. Clinical trials.gov identifier: NCT01493622.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Cognition Disorders; Double-Blind Method; Female; Follow-Up Studies; Humans; Hyperkinesis; Male; Minocycline; Neuropsychological Tests; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Young Adult

There are contradictory reports about the efficacy of minocycline for treating schizophrenia. This is a randomized, placebo-controlled clinical trial investigating the effectiveness of minocycline for treating schizophrenia. Forty three patients with schizophrenia diagnosed according to DSM-IV were randomly allocated into minocycline (200mg/d) + risperidone group (n = 21) or placebo + risperidone group (n = 22). Scale for Assessment of Negative Symptoms (SANS), Positive and Negative Syndrome Scale for schizophrenia (PANSS), Beck's Depression inventory, and Abnormal Involuntary Movement Scale (AIMS) were used. Assessments occurred at baseline, week 4 and week 8. Thirty five patients completed the trial. The changes of SANS total score from baseline to week 4 were not statistically different between the two groups. However, at week 8, there was a statistically significant difference between the two groups. SANS score decreased in the minocycline group more than that of the placebo group (12.2(7.9) versus 6.8(8.6), respectively). The decline of PANSS Negative score from baseline to week 8 in the minocycline group was more than placebo group (4.3(4.2) versus 3.2(3.3). However, the difference was not statistically significant. No one dropped out due to adverse effects. This trial supports the effectiveness of minocycline as an adjuvant treatment with risperidone for treating negative symptoms of patients with schizophrenia. Some patents on the use of tetracycline for the treatment of schizophrenia are also outlined.

Topics: Adult; Anti-Bacterial Agents; Antipsychotic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Minocycline; Patents as Topic; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Young Adult

Schizophrenia is understood to be a heterogeneous brain condition with overlapping symptom dimensions. The negative symptom dimension, with its protean cognitive manifestations, responds poorly to treatment, which can be a particular challenge in countries where clozapine therapy is not available. Preliminary data indicate that minocycline may be beneficial adjunct in the treatment of schizophrenia: positive, negative, and cognitive symptoms.In this study we aim to assess the efficacy of adjunctive minocycline to alleviate symptoms of schizophrenia in patients who have failed to respond to a therapeutic trial of antipsychotic medications.. The study is a parallel group, double-blind, randomized, placebo-controlled trial. Participants will be adults (aged 18 years and above) with first episode or relapse episode of schizophrenia of under 5 years' duration. Patients who failed to show adequate therapeutic response to at least one antipsychotic medication given for a minimum of 4 weeks will be recruited from a psychiatry hospital in Addis Ababa and a psychiatry clinic in Butajira, Ethiopia. A total of 150 participants (75 in each arm) will be required to detect a five-point mean difference between the intervention arms adjusting for baseline symptom severity, at 90% power and 95% confidence. Patients in the intervention arm will receive minocycline (200 mg/day orally) added on to the regular antipsychotic medications participants are already on. Those in the placebo arm will receive an inactive compound identical in physical appearance to minocycline. Intervention will be offered for 12 weeks. Diagnosis will be established using the operational criteria for research (OPCRIT). Primary outcome measure will be a change in symptom severity measured using the positive and the negative syndrome scale for schizophrenia (PANSS). Secondary outcome measures will include changes in severity of negative symptoms, proportion achieving remission, and level of functioning. Whether changes are maintained post intervention will also be measured (PANSS). Key assessment for the primary outcome will be conducted at the end of trial (week 12). One post-intervention assessment will be conducted 4 weeks after the end of intervention (week 16) to determine sustainability of change.. Clinicaltrials.gov identifier: NCT01809158.

Topics: Adolescent; Adult; Clinical Protocols; Double-Blind Method; Follow-Up Studies; Humans; Middle Aged; Minocycline; Neurodegenerative Diseases; Sample Size; Schizophrenia

The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy, emotional blunting, and social withdrawal. Such 'negative' symptoms are unaffected by current antipsychotic therapies. There is evidence that the antibiotic minocycline has neuroprotective properties. We investigated whether the addition of minocycline to treatment as usual (TAU) for 1 year in early psychosis would reduce negative symptoms compared with placebo. In total, 144 participants within 5 years of first onset in Brazil and Pakistan were randomised to receive TAU plus placebo or minocycline. The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale. Some 94 patients completed the trial. The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7, an adjusted difference of 3.53 (s.e. 1.01) 95% CI: 1.55, 5.51; p < 0.001 in the intention-to-treat population. The effect was present in both countries. The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antipsychotic Agents; Brazil; Cognition Disorders; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Minocycline; Neuroprotective Agents; Neurotoxicity Syndromes; Pakistan; Patient Dropouts; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Young Adult

Current antipsychotics have only a limited effect on 2 core aspects of schizophrenia: negative symptoms and cognitive deficits. Minocycline is a second-generation tetracycline that has a beneficial effect in various neurologic disorders. Recent findings in animal models and human case reports suggest its potential for the treatment of schizophrenia. These findings may be linked to the effect of minocycline on the glutamatergic system, through inhibition of nitric oxide synthase and blocking of nitric oxide-induced neurotoxicity. Other proposed mechanisms of action include effects of minocycline on the dopaminergic system and its inhibition of microglial activation.. To examine the efficacy of minocycline as an add-on treatment for alleviating negative and cognitive symptoms in early-phase schizophrenia.. A longitudinal double-blind, randomized, placebo-controlled design was used, and patients were followed for 6 months from August 2003 to March 2007. Seventy early-phase schizophrenia patients (according to DSM-IV) were recruited and 54 were randomly allocated in a 2:1 ratio to minocycline 200 mg/d. All patients had been initiated on treatment with an atypical antipsychotic < or = 14 days prior to study entry (risperidone, olanzapine, quetiapine, or clozapine; 200-600 mg/d chlorpromazine-equivalent doses). Clinical, cognitive, and functional assessments were conducted, with the Scale for the Assessment of Negative Symptoms (SANS) as the primary outcome measure.. Minocycline was well tolerated, with few adverse events. It showed a beneficial effect on negative symptoms and general outcome (evident in SANS, Clinical Global Impressions scale). A similar pattern was found for cognitive functioning, mainly in executive functions (working memory, cognitive shifting, and cognitive planning).. Minocycline treatment was associated with improvement in negative symptoms and executive functioning, both related to frontal-lobe activity. Overall, the findings support the beneficial effect of minocycline add-on therapy in early-phase schizophrenia.. clinicaltrials.gov Identifier: NCT00733057.

Topics: Adolescent; Adult; Antipsychotic Agents; Cognition; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Minocycline; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Doxycycline and minocycline are brain-penetrant tetracycline antibiotics, which recently gained interest because of their immunomodulatory and neuroprotective properties. Observational studies have suggested that exposure to these drugs may decrease the risk to develop schizophrenia, but results are inconsistent. The aim of this study was to investigate the potential association between doxycycline use and later onset of schizophrenia.. We used data from 1 647 298 individuals born between 1980 and 2006 available through Danish population registers. 79 078 of those individuals were exposed to doxycycline, defined as redemption of at least 1 prescription. Survival analysis models stratified for sex with time-varying covariates were constructed to assess incidence rate ratios (IRRs) for schizophrenia (ICD-10 code F20.xx), with adjustment for age, calendar year, parental psychiatric status, and educational level.. In the non-stratified analysis, there was no association between doxycycline exposure and schizophrenia risk. However, men who redeemed doxycycline had a significantly lower incidence rate for schizophrenia onset compared to men that did not (IRR 0.70; 95% CI 0.57-0.86). By contrast, women had a significantly higher incidence rate for schizophrenia onset, compared to women that did not redeem doxycycline prescriptions (IRR 1.23; 95% CI 1.08, 1.40). The effects were not found for other tetracycline antibiotics (IRR 1.00; 95% CI 0.91, 1.09).. Doxycycline exposure is associated with a sex-dependent effect on schizophrenia risk. The next steps are replication of the results in independent well-characterized population cohorts, as well as preclinical studies to investigate sex-specific effects of doxycycline on biological mechanisms implicated in schizophrenia.

Topics: Anti-Bacterial Agents; Denmark; Doxycycline; Female; Humans; Male; Minocycline; Registries; Risk Factors; Schizophrenia

The examination of post-mortem brain tissue suggests synaptic loss as a central pathological hallmark of schizophrenia spectrum (SCZ), which is potentially related to activated microglia and increased inflammation. Induced pluripotent stem cells serve as a source for neurons and microglia-like cells to address neuron-microglia interactions. Here, we present a co-culture model of neurons and microglia, both of human origin, to show increased susceptibility of neurons to microglia-like cells derived from SCZ patients. Analysis of IBA-1 expression, NFκB signaling, transcription of inflammasome-related genes, and caspase-1 activation shows that enhanced, intrinsic inflammasome activation in patient-derived microglia exacerbates neuronal deficits such as synaptic loss in SCZ. Anti-inflammatory pretreatment of microglia with minocycline specifically rescued aberrant synapse loss in SCZ and reduced microglial activation. These findings open up possibilities for further research in larger cohorts, focused clinical work and longitudinal studies that could facilitate earlier therapeutic intervention.

Topics: Humans; Inflammasomes; Microglia; Minocycline; Neurons; Schizophrenia

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

Topics: Cytokines; Humans; Inflammation; Interleukin-6; Minocycline; Schizophrenia; Tumor Necrosis Factor-alpha

Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model.. On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.. MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen).. MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Behavior, Animal; Brain Diseases, Metabolic; Disease Models, Animal; Female; Magnetic Resonance Imaging; Male; Minocycline; Nervous System Malformations; Neurodevelopmental Disorders; Oxidative Stress; Positron-Emission Tomography; Pregnancy; Prenatal Exposure Delayed Effects; Prepulse Inhibition; Rats; Rats, Wistar; Schizophrenia

Recent studies suggest that the tetracycline antibiotic minocycline, or its cousins, hold therapeutic potential for affective and psychotic disorders. This is proposed on the basis of a direct effect on microglia-mediated frontocortical synaptic pruning (FSP) during adolescence, perhaps in genetically susceptible individuals harboring risk alleles in the complement component cascade that is involved in this normal process of CNS circuit refinement. In reviewing this field, it is argued that minocycline is actually probing and modulating a deeply evolved and intricate system wherein psychosocial stimuli sculpt the circuitry of the "social brain" underlying adult behavior and personality. Furthermore, this system can generate psychiatric morbidity that is not dependent on genetic variation. This view has important ramifications for understanding "pathologies" of human social behavior and cognition as well as providing long-sought potential mechanistic links between social experience and susceptibility to mental and physical disease.

Topics: Adolescent; Adult; Brain; Humans; Minocycline; Neuronal Plasticity; Personality; Schizophrenia

Antipsychotic medication is the primary treatment for schizophrenia, which is effective on ameliorating positive symptoms and can reduce the risk of recurrence, but it has limited efficacy for negative symptoms and cognitive dysfunction. The negative symptoms and cognitive dysfunction seriously affects the life quality and social function for the patients with schizophrenia. Currently, there is plenty evidence that antipsychotic drugs combined with adjuvant therapy drugs can effectively improve the negative symptoms and cognitive dysfunction. These drugs include anti-oxidants, nicotinic acetylcholine receptors and neuro-inflammatory drugs (anti-inflammatory drugs, minocycline), which show potential clinical effects.. 抗精神病药物是治疗精神分裂症的主要方法，可有效缓解阳性症状和减少复发风险，但对阴性症状和认知功能障碍的临床疗效有限，而阴性症状和认知功能障碍严重影响精神分裂症患者的社会功能和生活质量。目前有较多的研究支持抗精神病药物联合辅助治疗药物可有效改善阴性症状和认知功能障碍。其中，作用于氧化应激、烟碱能乙酰胆碱受体和神经炎症的药物(抗炎药、米诺环素)有潜在的临床疗效。.

Topics: Anti-Inflammatory Agents; Antipsychotic Agents; Cognitive Dysfunction; Humans; Minocycline; Schizophrenia

Topics: Double-Blind Method; Humans; Minocycline; Psychotic Disorders; Schizophrenia

Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Cells, Cultured; Humans; Induced Pluripotent Stem Cells; Male; Microglia; Middle Aged; Minocycline; Neural Stem Cells; Neuronal Plasticity; Risk Factors; Schizophrenia; Synapses; Young Adult

Preclinical evidence shows that the minocycline and N-acetylcysteine (NAC) combination synergistically improved cognition. Meta-analyses of randomized controlled trials (RCTs) with minocycline and NAC have shown some efficacy signal for positive, cognitive, and negative symptoms of schizophrenia. Hence, the combination may be more effective than either medication alone. The objective of this article is to highlight the potential role of the minocycline-NAC combination for the treatment of schizophrenia. The antipsychotic-minocycline-NAC combination is promising and has the potential to concurrently treat positive, cognitive, and primary negative symptoms. RCTs are warranted with the minocycline-NAC combination to address the unmet clinical need in schizophrenia.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Antipsychotic Agents; Drug Therapy, Combination; Free Radical Scavengers; Humans; Minocycline; Schizophrenia

Topics: Double-Blind Method; Humans; Minocycline; Psychotic Disorders; Schizophrenia

Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer's disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.

Topics: Adult Children; Alzheimer Disease; Animals; Anti-Bacterial Agents; Behavior, Animal; Disease Models, Animal; Female; Humans; Immune System Phenomena; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Phagocytosis; Pregnancy; Schizophrenia; Synaptic Transmission; Transcriptome

In this study, we investigated whether minocycline, a second-generation tetracycline proposed as an add-on to antipsychotics in treatment-resistant schizophrenia (TRS), may affect the expression of Homer and Arc postsynaptic density (PSD) transcripts, implicated in synaptic regulation. Minocycline was administered alone or with haloperidol in rats exposed or not to ketamine, mimicking acute glutamatergic psychosis or naturalistic conditions, respectively. Arc expression was significantly reduced by minocycline compared with controls. Minocycline in combination with haloperidol also significantly reduced Arc expression compared with both controls and haloperidol alone. Moreover, haloperidol/minocycline combination significantly affected Arc expression in cortical regions, while haloperidol alone was ineffective on cortical gene expression. These results suggest that minocycline may strongly affect the expression of Arc as mediated by haloperidol, both in terms of quantitative levels and of topography of haloperidol-related expression. It is noteworthy that no significant pre-treatment effect was found, suggesting that pre-exposure to ketamine did not grossly affect gene expression. Minocycline was not found to significantly affect haloperidol-related Homer1a expression. No significant changes in Homer1b/c expression were observed. These results are consistent with previous observations that minocycline may modulate postsynaptic glutamatergic transmission, affecting distinct downstream pathways initiated by N-methyl-D-aspartate (NMDA) receptor modulation, i.e. Arc-mediated but not Homer1a-mediated pathways.

Topics: Animals; Antipsychotic Agents; Cerebral Cortex; Drug Resistance; Gene Expression; Haloperidol; Homer Scaffolding Proteins; Intracellular Signaling Peptides and Proteins; Ketamine; Male; Membrane Proteins; Minocycline; Nerve Tissue Proteins; Post-Synaptic Density; Psychotic Disorders; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear.. In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment.. Attentional function in mice haploinsufficient for Map2k7 (Map2k7. Once stable performance had been achieved, Map2k7. Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

Topics: Animals; Attention; Choice Behavior; Cognition; Female; Haploinsufficiency; Humans; Male; MAP Kinase Kinase 7; Mice; Mice, Inbred C57BL; Mice, Knockout; Minocycline; Reaction Time; Risk Factors; Schizophrenia

In recent years schizophrenia has been recognized as a neurodevelopmental disorder likely involving a perinatal insult progressively affecting brain development. The poly I:C maternal immune activation (MIA) rodent model is considered as a neurodevelopmental model of schizophrenia. Using this model we and others demonstrated the association between neuroinflammation in the form of altered microglia and a schizophrenia-like endophenotype. Therapeutic intervention using the anti-inflammatory drug minocycline affected altered microglia activation and was successful in the adult offspring. However, less is known about the effect of preventive therapeutic strategies on microglia properties. Previously we found that deep brain stimulation of the medial prefrontal cortex applied pre-symptomatically to adolescence MIA rats prevented the manifestation of behavioral and structural deficits in adult rats. We here studied the effects of deep brain stimulation during adolescence on microglia properties in adulthood. We found that in the hippocampus and nucleus accumbens, but not in the medial prefrontal cortex, microglial density and soma size were increased in MIA rats. Pro-inflammatory cytokine mRNA was unchanged in all brain areas before and after implantation and stimulation. Stimulation of either the medial prefrontal cortex or the nucleus accumbens normalized microglia density and soma size in main projection areas including the hippocampus and in the area around the electrode implantation. We conclude that in parallel to an alleviation of the symptoms in the rat MIA model, deep brain stimulation has the potential to prevent the neuroinflammatory component in this disease.

Topics: Animals; Behavior, Animal; Brain; Deep Brain Stimulation; Disease Models, Animal; Female; Hippocampus; Microglia; Minocycline; Nucleus Accumbens; Poly I-C; Prefrontal Cortex; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Schizophrenia

Maternal immune activation can increase the vulnerability of the offspring to develop neuroimmune and behavioral abnormalities in response to stress in puberty. In offspring of immune-challenged mothers, stress-induced inflammatory processes precede the adult onset of multiple behavioral dysfunctions. Here, we explored whether an early anti-inflammatory intervention during peripubertal stress exposure might prevent the subsequent emergence of adult behavioral pathology. We used an environmental two-hit model in mice, in which prenatal maternal administration of the viral mimetic poly(I:C) served as the first hit, and exposure to sub-chronic unpredictable stress during peripubertal maturation as the second hit. Using this model, we examined the effectiveness of the tetracycline antibiotic minocycline (MINO) given during stress exposure to block stress-induced inflammatory responses and to prevent subsequent behavioral abnormalities. We found that combined exposure to prenatal immune activation and peripubertal stress caused significant deficits in prepulse inhibition and increased sensitivity to the psychotomimetic drugs amphetamine and dizocilpine in adulthood. MINO treatment during stress exposure prevented the emergence of these behavioral dysfunctions. In addition, the pharmacological intervention blocked hippocampal and prefrontal microglia activation and interleukin-1β expression in offspring exposed to prenatal infection and peripubertal stress. Together, these findings demonstrate that presymptomatic MINO treatment can prevent the subsequent emergence of multiple behavioral abnormalities relevant to human neuropsychiatric disorders with onset in early adulthood, including schizophrenia. Our epidemiologically informed two-hit model may thus encourage attempts to explore the use of anti-inflammatory agents in the early course of brain disorders that are characterized by signs of central nervous system inflammation during development.

Topics: Amphetamine; Animals; Anti-Inflammatory Agents; Central Nervous System Stimulants; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Hippocampus; Interferon Inducers; Interleukin-1beta; Mice; Microglia; Minocycline; Poly I-C; Prefrontal Cortex; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prepulse Inhibition; Psychoses, Substance-Induced; Schizophrenia; Stress, Psychological

Accumulating evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. We previously reported evidence of schizophrenia-like behaviors and microglial activation in Gunn rats. We concluded that the Gunn rat, which exhibits a high concentration of unconjugated bilirubin, may be useful as an animal model of schizophrenia. On the other hand, there have been numerous reports that minocycline is effective in treating schizophrenia.. In the present study, we investigated the effects of minocycline on performance of behavioral tests (prepulse inhibition (PPI) and novel object recognition test (NORT)) after animals received either 40mg/kg/d of minocycline or vehicle by intraperitoneal (i.p.) injection for 14 consecutive days. Furthermore, we examined the effects of minocycline on microglial activation in the hippocampal dentate gyrus of Gunn rats and Wistar rats.. We found that administration of minocycline for 14days significantly increased the exploratory preference in retention sessions and tended to improve the PPI deficits in Gunn rats. Immunohistochemistry analysis revealed that microglial cells in the minocycline-treated Gunn rat group showed less expression of CD11b compared to vehicle-treated Gunn and Wistar groups.. Our findings suggest that minocycline improves recognition memory and attenuates microglial activation in the hippocampal dentate gyrus of Gunn rats. Therefore, minocycline may be a potential therapeutic drug for schizophrenia.

Topics: Animals; Antipsychotic Agents; CD11b Antigen; Dentate Gyrus; Disease Models, Animal; Hyperbilirubinemia; Male; Microglia; Minocycline; Rats; Rats, Gunn; Rats, Wistar; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Sensory Gating

Some evidence has shown an increased number of activated microglial cells in patients with schizophrenia. It is hypothesized that activated microglia may contribute to the pathogenesis of schizophrenia. We injected saline or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) into the ventral hippocampus in adult Sprague-Dawley rats via micro-pump; at the same time, the rats were intragastrically administrated with saline or minocycline once a day for 14 consecutive days. Then, behavioral tests were examined and microglia were assessed using immunohistochemistry method. GM-CSF-injected group showed significant behavioral deficits (hyperlocomotion, social interaction deficits, prepulse inhibition (PPI) deficits). There was a dramatic increase of the number of activated microglial cells in the hippocampus and other brain regions such as cerebral cortex and thalamus compared with those in saline-injected group in immunohistochemistry. Minocycline was able to ameliorate deficits of social interaction and PPI but not hyperlocomotion. Minocycline was also able to inhibit the microglial activation. In conclusion, intrahippocampal administration of GM-CSF in adult rats may serve as a potential schizophrenia animal model, which may be related with the microglia hypothesis of schizophrenia.

Topics: Aging; Animals; Behavior, Animal; Disease Models, Animal; Granulocyte Colony-Stimulating Factor; Hippocampus; Immunohistochemistry; Male; Microglia; Minocycline; Motor Activity; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Schizophrenia

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.

Topics: Animals; Anti-Bacterial Agents; Brain; Cytokines; Disease Models, Animal; Male; Microglia; Minocycline; Neurogenesis; Poly I-C; Rats; Rats, Wistar; Schizophrenia; Sensory Gating

Treatment-resistant schizophrenia is a major health problem in the UK with the majority of patients treated with clozapine. In up to 70% of cases there is only a partial response to clozapine with continuing refractory symptoms. We describe two cases in a UK mental health service where minocycline was found to be useful and well tolerated as an augmentation agent with clozapine in the improvement of previously resistant positive and negative symptoms.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Humans; Male; Minocycline; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Various signs of activation of microglia have been reported in schizophrenia, and it is hypothesized that microglia activation is closely associated with the neuropathology of schizophrenia.. Neonatal intrahippocampal injection of lipopolysaccharide (LPS), an activator of microglia, was performed in rats at postnatal day 7 (P7), and they were separately given saline, risperidone (0.5 mg/kg), minocycline (40 mg/kg) or a combination of both of them at P42 for consecutive 14 days. Behavioral changes (locomotion activity, social interaction, novel object recognition and prepulse inhibition) were examined and the number of microglia was assessed by using immunohistochemistry in adulthood.. The adult rats in LPS-injected group showed obvious behavioral alteration (e. g. deficits in social interaction, novel object recognition and prepulse inhibition) and a dramatic increase of number of activated microglial cells in the hippocampus and other brain regions such as cerebral cortex and thalamus compared to those in saline-injected group. Interestingly, application of either minocycline, risperidone or both of them significantly rescued behavioral deficits and attenuated microglia activation.. Our results suggest that inhibition of microglia activation may be one of mechanisms underlying the antipsychotic effect of minocycline and risperidone.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Female; Hippocampus; Immunohistochemistry; Lipopolysaccharides; Locomotion; Microglia; Minocycline; Prepulse Inhibition; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Risperidone; Schizophrenia

Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. Activation of microglia is a key event in the reaction of the cerebral immune system to pathological changes. It can be hypothesized that microglia contribute to the neuropathology of schizophrenia. In this study, at embryonic day (ED) 9 pregnant mice were treated with intraperitoneal injection of polyriboinosinic-polyribocytidilic acid (Poly I:C) at a single dose of 20 mg/kg. At postnatal day 42, descendants were treated with minocycline (40 mg/kg) or saline for consecutive 14 days. Behavioral changes (locomotor activity, social interaction, and prepulse inhibition) were examined and the number of microglia was assessed after the treatment. The adult offspring exposed to Poly I:C at ED 9 showed behavioral changes (hyperlocomotion, deficits in social interaction and prepulse inhibition) and significant microglial activation in these brain areas (hippocampus, thalamus, and cerebral cortex) compared to those in saline-injected group. Moreover, minocycline attenuated the behavioral deficits and inhibited the activated microglia. These findings suggest that maternal infection may contribute to microglial activation in the offspring. In addition, the effect of minocycline in this immune model may be related to the inhibition of microglial activation.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Behavior, Animal; Brain; Cerebral Cortex; Disease Models, Animal; Female; Hippocampus; Humans; Injections, Intraperitoneal; Male; Mice; Microglia; Minocycline; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Prepulse Inhibition; Schizophrenia

Topics: Antipsychotic Agents; Cognition; Humans; Minocycline; Schizophrenia; Schizophrenic Psychology

Topics: Depression; Drug Evaluation, Preclinical; Drug Repositioning; Humans; Mental Disorders; Minocycline; Molecular Targeted Therapy; Psychiatry; Schizophrenia; Warfarin

Topics: Adult; Antipsychotic Agents; Humans; Male; Minocycline; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. This study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, animals received ketamine (20 mg/kg per day intraperitoneally or saline for 14 days, and minocycline (25 or 50 mg/kg daily), risperidone or vehicle treatment from days 8 to 14. In the prevention protocol, mice were pretreated with minocycline, risperidone or vehicle prior to ketamine. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite levels were measured in the prefrontal cortex, hippocampus and striatum. Minocycline and risperidone prevented and reversed ketamine-induced alterations in behavioral paradigms, oxidative markers (i.e. ketamine-induced decrease and increase in GSH levels and TBARS content, respectively) as well as nitrite levels in the striatum. These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitrergic systems.

Topics: Animals; Antioxidants; Antipsychotic Agents; Corpus Striatum; Drug Therapy, Combination; Glutathione; Hippocampus; Ketamine; Male; Maze Learning; Mice; Minocycline; Motor Activity; Nitric Oxide; Nitrites; Prefrontal Cortex; Risperidone; Schizophrenia; Schizophrenic Psychology; Sensory Gating; Social Behavior; Thiobarbituric Acid Reactive Substances

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Minocycline; Schizophrenia

Topics: Antipsychotic Agents; Brain; Cerebrovascular Circulation; Humans; Male; Minocycline; Schizophrenia; Tomography, Emission-Computed, Single-Photon; Young Adult

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Gyrus Cinguli; Humans; Minocycline; Schizophrenia

Topics: Animals; Humans; Mice; Minocycline; Receptors, AMPA; Schizophrenia

The N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP)-induced cognitive deficits have been used as an animal model for schizophrenia. This study was undertaken to determine whether the antibiotic drug minocycline could improve PCP-induced cognitive deficits in mice.. Saline (10 ml/kg/day, s.c., once daily on day 1-5, 8-12) or PCP (10 mg/kg/day, s.c., once daily on day 1-5, 8-12) were administered to mice for 10 days. Subsequently, vehicle (10 ml/kg/day, i.p.) or minocycline (4.0 or 40 mg/kg/day, i.p.) was injected for 14 consecutive days. One day after the final injection, a novel object recognition test was performed.. PCP-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of minocycline (40 mg/kg), but not minocycline (4.0 mg/kg).. This study suggests that minocycline could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Cognition Disorders; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Exploratory Behavior; Humans; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Minocycline; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology

Topics: Catatonia; Humans; Minocycline; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Minocycline is a second-generation tetracycline with a distinct neuroprotective profile. The current study assessed the effects of minocycline in an animal model of schizophrenia, the non-competitive NMDA antagonist (dizocilpine maleate; MK801). The effects of minocycline were compared to those of haloperidol, a dopamine antagonist used for the treatment of schizophrenia. The study protocol involved daily intraperitoneal injections of minocycline (35 mg/kg) for three consecutive days. On the fourth day, the rats were injected with MK801 and assessed for visual-spatial memory (Morris water maze) and sensorimotor gating (acoustic startle response, ASR, and the prepulse inhibition of the ASR). The findings indicate that MK801 caused cognitive visuo-spatial memory deficits and changes in sensorimotor gating, similar to those evident in schizophrenia. Minocycline reversed these cognitive effects of MK801 and this effect was similar to that of haloperidol. The results of this study suggest that minocycline may have protective properties against the cognitive effects of the MK801 animal model of schizophrenia. The discussion addresses potential mechanisms underlying the effects of minocycline and possible directions for future research.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Male; Maze Learning; Minocycline; Neural Inhibition; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex, Startle; Schizophrenia; Time Factors