possible treatment-research into antibiotic and schizophrenia

Hello
I thought the following articles from reputable journals, academics etc. may be of interest


The Independent (newspaper)

article by Jeremy Laurance in dated 02/03/12


Scientists shocked to find antibiotics alleviate symptoms of schizophrenia

Chance discovery of link between acne drug and psychosis may unlock secrets of mental illness


Also


Psychiatry Weekly: Use of The Antibiotic Minocycline To Treat Catatonic Schizophrenia

Psychiatry weekly
Jan 15th 2007
Use of The Antibiotic Minocycline To Treat Catatonic Schizophrenia
Dr.David L Ginsberg
[U]Part of the article by Dr Ginsberg is printed below

January 15, 2007
David L. Ginsberg, MD



Director of Outpatient Services, Tisch Hospital’s Department of Psychiatry, New York University Medical Center



Minocycline is a semisynthetic second-generation tetracycline which exerts anti-inflammatory effects that are separate and distinct from its anti-microbial action (MacDonald et al. 1973). One of the more brain-penetrable tetracyclines, minocycline has been shown to have neuroprotective effects in models of ischemic injury (Yrianheikki et al. 1999) and the 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine model of Parkinson’s disease (Du et al. 2001). While direct neuroprotective effects have been observed some of its actions result from indirect effects in inhibiting glial (astrocytic;/microglial) caspase 1 and iNOS activity (Amin et al. 1996; Yong et al. 2004). Recent reports indicate that minocycline delays mortality or disease progression in mouse models of Huntington’s disease (Chen et al. 2000; Berger 2000) and amyotrophic lateral sclerosis (Zhang et al. 2003). There is also a case report in humans of possible antidepressant effects of minocycline, which has been attributed mechanistically to the inhibition of noradrenaline-sensitive adenylate cyclase (Levine et al. 1996). Now comes a report of 2 cases of acute schizophrenia with predominant catatonic symptoms that responded well to minocycline (Miyaoka et al. 2007).

In the first case, a 23 year-old man, college graduate employed by a company, with no prior neurologic or psychiatric history developed insomnia and anxiety. Further, he became agitated and talked incoherently with persecutory delusions and paranoid ideation. He was admitted to a Japanese hospital. Examination of his mental state revealed auditory hallucinations, persecutory delusions, psychomotor excitement, catatonic stupor, and deterioration in the level of social functioning. Physical and neurologic examinations were normal. Complete work-up including laboratory testing of serum and urine, electroencephalography (EEG), computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were all normal. Diagnosed with catatonic schizophrenia, the patient was started on haloperidol, titrated to 20 mg/day. One week later, his psychomotor excitement, auditory hallucinations, persecutory delusions, and catatonic stupor persisted. In addition, his symptoms were complicated by severe pneumonia. Serum creatine kinase and renal parameters were normal. Minocycline 150 mg/day was initiated to treat the pneumonia. Two weeks later, the pneumonia and psychiatric symptoms resolved. Minocycline was discontinued for one week; subsequently the psychiatric symptoms significantly worsened. As a result, minocycline 150 mg bid was resumed. Within 3 days, a noticeable clinical improvement was observed. The patient continued minocycline 150 mg/day and haloperidol 20 mg/day. Twenty-four days later, the patient became practically symptom-free. On the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), his score declined from approximately 38 to 12. His haloperidol was reduced to 10 mg/day, then over the next 2 and ½ weeks to 2 mg/day. Minocycline was maintained at 150 mg/day. At last follow-up two years later, the patient continued to do well with no worsening of psychiatric symptoms.

The second case involved a 61 year-old man with schizophrenia since the age of 20 and five prior psychiatric hospitalizations. During his last admission, he deteriorated and became autistic, and so remained in the hospital for 4 years. He was treated with haloperidol 10 mg/day and risperidone 2 mg/day. Routine laboratory testing including blood, urine, and feces were within normal limits. Electroencephalography (EEG), computed tomography (CT), and magnetic resonance imaging (MRI) of the brain were all negative. One year prior, the patient had developed psychomotor excitement, catatonic stupor, and negativism. In addition, a large decubitus formed on his left hip. Minocycline 150 mg/day was initiated. Haloperidol and risperidone were continued at their previous doses. Two weeks later, the decubitus healed. Minocycline was discontinued for one week. This was followed by a significant worsening of his psychiatric symptoms; his PANSS score which had declined from 25 to 10, now increased to 40. As a result, minocycline was resumed at a dose of 150 mg bid. Within 3 days, noticeable clinical improvement was observed (PANSS = 10). Minocycline was reduced back to 150 mg/day while his antipsychotics were continued at their previous dosages. After another 13 days, the patient became practically symptom-free. Haloperidol was descreased to 3 mg/day while risperidone was discontinued. Of note, throughout his course, the patient did not have fever or receives benzodiazepines. At last follow-up one year later, the patient continued to do well with no worsening of psychiatric symptoms.

This appears to be the first published report on the successful use of minocycline to treat psychosis and catatonia. While antipsychotics were also administered to these patients, the temporal sequence of events described is consistent with at least some of the benefit deriving from minocycline. Furthermore, benzodiazepines and/or electroconvulsive therapy (ECT) usually are needed for effective treatment of catatonia.

Typically used in the management of chronic conditions such as acne, rheumatoid arthritis, and rosacea, minocycline has an established safety record for long-term use (Thomas et al. 2003). If confirmed by further research, minocyline’s action in schizophrenia and other neurodegenerative diseases may result from its potent inhibition of microglial activation, a process normally associated with the production of neurotoxins and with apoptosis (Gehrmann et al. 1995). Additional study is indicated to more fully evaluate the safety and utility of minocycline in the treatment of catatonic schizophrenia.

Hello some of the research appears to be ongoing as with Manchester University and kings College London see: http://www.kcl.ac.uk/iop/depts/ps/research/clinicaltrials/Minocyclineandnegativesymptomsinschizophrenia.aspx

Minocycline and negative symptoms in schizophrenia

The benefit of minocycline on negative symptoms in schizophrenia: extent and mechanism

See also: http://clinicaltrials.gov/ct2/show/NCT01561742

Minocycline Augmentation in Schizophrenia



See also:http://www.ncbi.nlm.nih.gov/pubmed/18991666



Sponsor:

The University of Texas Health Science Center, Houston

Collaborator:

Stanley Medical Research Institute

Information provided by (Responsible Party):

Mujeeb Shad, The University of Texas Health Science Center, Houston



Why are we doing this research?

Patients with chronic schizophrenia have an impaired quality of life (QoL), with social isolation, self-neglect, unemployment and reduced activities of daily living, despite current treatments. Negative symptoms such as emotional and social withdrawal, anhedonia, lack of drive and deficiencies in emotional responsiveness persist, and along with cognitive impairment and a longer duration of untreated psychosis (DUP) consistently relate to impaired social functioning. The correlation between DUP and negative symptoms suggest that active psychosis may reflect a neuropathic process that results in negative symptoms and thus impaired QoL. This has led to interest in directly targeting neuroprotection in early treatment to prevent the development of or alleviate negative symptoms and cognitive decline and thus improve social function and quality of life. Although positive and disorganised symptoms usually respond to drug treatment, no antipsychotic drug (APD) treatment,not even clozapine, is unequivocally effective for negative symptoms.

What are we doing?

In this study we are using the recently developed PsyGrid infrastructure for UK-wide clinical and imaging research in first episode psychosis to determine whether negative symptoms can be lessened or prevented by minocycline treatment initiated early in the course of schizophrenia and to collect biomarker data to test hypotheses about how minocycline improves negative symptoms.

This is a multicentre, one-year, double-blind randomised placebo-controlled trial of minocycline versus placebo, added to standard antipsychotic drug (APD) treatment, for patients in an early episode of schizophrenia-related psychosis. We are exploring whether minocycline minimises later negative symptoms when administered during the acute phase of early psychosis. Furthermore, we are exploring how this occurs, and particularly whether minocycline acts by reducing the loss of grey matter associated with early psychosis; by interfering with inflammatory cytokine production; or by an action on glutamate systems to improve negative symptoms and cognitive function. We plan to recruit 170 patients with early psychosis over 22 months from 6 established PsyGrid centres in the UK, and conduct a longitudinal clinical, imaging, and inflammation evaluation.

Who is involved?

PIs for KCL London: Paola Dazzan, Steve Williams; Study Lead and Sponsor: William Deakin (University of Manchester); Co-PIs and Collaborators: Thomas Barnes (Imperial College, London), Imran Chaudhry (University of Manchester), Graham Dunn (University of Manchester), Nusrat Husain (University of Manchester), Peter Jones (University of Cambridge), Eileen Joyce (University College London), Stephen Lawrie (University of Edinburgh), Shon Lewis (University of Manchester), John Suckling (University of Cambridge), Stephen Hopkins (University of Manchester)

Who funds the study?

NIHR MRC Efficacy and Mechanism Evaluation programme

Contact

Dr Paola Dazzan



See also:http://www.ncbi.nlm.nih.gov/pubmed/18991666

Clinical potential of minocycline for schizophrenia.

Miyaoka T.


Source

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


Abstract


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.


PMID:18991666[PubMed - indexed for MEDLINE
And:http://www.ncbi.nlm.nih.gov/pubmed/22526685

Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment.

Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B.


Source

University of Manchester, Manchester, UK. ibchaudhry@btinternet.com


Abstract


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.


PMID:22526685[PubMed - indexed for MEDLINE]
also:http://www.ncbi.nlm.nih.gov/pubmed/22486246

Minocycline: therapeutic potential in psychiatry.

Dean OM, Data-Franco J, Giorlando F, Berk M.


Source

Deakin University, School of Medicine, Barwon Health, Geelong, VIC, Australia. oliviad@barwonhealth.org.au


Abstract


Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialled in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry.


PMID:22486246[PubMed - indexed for MEDLINE]
Also:http://drmikespsychiatryblog.blogspot.co.uk/2009/05/adventures-with-mino

Thursday, May 28, 2009






Adventures with minocycline...in real time



I've added a link (on the left) to a really nice new blog by a fragile X parent who has just started her daughter on minocycline, and is blogging about the experience. I should say that I don't know these folks at all, other than getting permission to link. While they may well have gotten the idea to try minocycline from me and from this blog, I have no idea how it will all turn out---but check it out and follow the story.
Along the same lines, there is a recent paper from Japan suggesting that minocycline can act as a potent augmentation strategy for atypical antipsychotics (Risperdal, Abilify, etc.) in the treatment of schizophrenia:
Minocycline as adjunctive therapy for schizophrenia: an open-label study.
Clinical Neuropharmacology 2008 Sep-Oct;31(5):287-92.
Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J. Department of Psychiatry, Shimane University School of Medicine, Izumo, Japan. miyanyan@med.shimane-u.ac.jp
Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase, and has been shown to delay disease in a mouse model of neuropsychiatric disorders. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline (150 mg/d) for 4 weeks as an open-label adjunct to antipsychotic medication to 22 patients with schizophrenia. The Positive and Negative Syndrome Scale for schizophrenia showed statistically significant and robust clinical improvements with minocycline treatment, which were maintained at follow-up evaluation 4 weeks after the end of minocycline treatment. There were no adverse events. These results suggest that minocycline may 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.
This raises the interesting possibility that minocycline may (among many things) enhance the effectiveness of atypical antipsychotics. So far, I have seen fragile X patients respond to minocycline montherapy, but many of the most impressive responses have been in people taking atypical antipsychotics as well. This is oddly similar to the results obtained with Ampakines in clinical trials with schizophrenic subjects, and possibly in fragile X subjects as well (as suggested in Liz Berry-Kravis' CX 516 trial.)
This may also be a good time to address a question which I get asked a lot: will older people with fragile X respond to treatment with minocycline? Obviously, we are early in the game, so it is hard to say anything definitive at this point. However, I have seen some of the best responses to minocycline in adult patients, and some of the youngest patients I've seen treated have shown no observable effect. This may be related to co-administration of atypical antipsychotics, or other meds, as noted above, which tends to be more common in older individuals. Or, it may simply be that in younger patients minocycline is correcting synaptic defects before they can cause obvious behavioral problems, whereas older people with fragile X have had a longer time to form abnormal connections and develop symptoms, so correction (however partial) results in more apparent improvement. Generally speaking, I've seen impressive responses in most young adults (let's say 15-25), with a somewhat more gradual and prolonged response in older people. Some of the fragile X kids in the 5-8 age range have had little apparent benefit, and their parents have elected to discontinue, especially with the perceived risk of dental staining. We'll see if this observation amounts to anything, but it does contradict the general assumption that most drugs with a specific mechanism of action should work best in the youngest patients. In a way, this would be a favorable effect; if therapeutic effects are generally most easily observed in young adults with fragile X, this will make future trials with a wide range of agents much easier to conduct.

cyclinein-real-time.html

http://www.druglib.com/trial/55/NCT01433055.html

University of Maryland



see also:http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2009001100002

Below is part of study that deals with minocycline intervention, but please see website for full report.

Minocycline

To the best of our knowledge, the antipsychotic efficacy of minocycline was first observed in a patient with Huntington's disease (18). There is one case report (24) with addition of minocycline to the antipsychotic treatment as usual, using a dose of 150 mg/day in two cases of acute catatonic schizophrenia. Only the PANSS was used weekly for the evaluation of clinical efficacy, showing a marked reduction of positive, negative and cognitive symptoms. There were no considerable side effects, which were clinically evaluated, without using scales. The authors reported a considerable decrease of psychiatric symptoms, followed by a worsening of symptoms after discontinuation of minocycline. However, improvement was observed again after the reintroduction of minocycline. Both patients remained on minocycline co-treatment and were practically symptom-free after one year of follow-up, even though the dose of haloperidol was reduced.

Levkovitz et al. (23) examined the efficacy of minocycline as add-on treatment in a double-blind, randomized placebo-controlled study conducted on patients with early schizophrenia, who were treated with minocycline (N = 36) or placebo (N = 18). The patients were followed-up for 6 months with clinical evaluations by SANS and CGI. The cognitive assessment consisted of a computerized battery. This trial demonstrated improvement of negative symptoms and executive functioning. It is noteworthy that positive symptoms were not rated.

Miyaoka et al. (51) published an open-label study of minocycline as adjunctive therapy for schizophrenia. The researchers evaluated the addition of minocycline (150 mg/day) to second-generation antipsychotics in 22 patients with schizophrenia for a period of 4 weeks. The clinical ratings were performed using the PANSS, and the positive and negative symptom subscales were reduced to 40.4 and 44.0%, respectively, after 4 weeks of minocycline co-treatment. The PANSS general psychopathology subscale was reduced to 52.1%. All the improvements on the PANSS subscales were maintained when scored at the 4-week follow-up time.