1.Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder
2.Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner
3.THE UNDERDIAGNOSIS OF NEUROPSYCHIATRIC LYME DISEASE IN CHILDREN AND ADULTS
4.Minocycline as a treatment for schizophrenia: is the discussion truly finished?
5. Infectious Agents in Schizophrenia and Bipolar Disorder
lyme Disease
Biological Psychiatry
Volume 45, Issue 6, 15 March 1999, Page 795
Biological Psychiatry
Case Reports
Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder
Author links open overlay panelAlexanderHessaJohannesBuchmannbUwe KlausZettlaSveaHenschelcDetlefSchlaefkecGabrieleGraudReinerBeneckea
a
Department of Neurology (AH, UKZ, RB), Germany
b
Department of Child and Adolescent Neuropsychiatry/Psychotherapy (JB), Germany
c
Department of Psychiatry/Psychotherapy (SH, DS), Germany
d
Department of Diagnostical and Interventional Radiology (GG), University of Rostock, Rostock, Germany
Abstract
Background: We report on a 42-year-old female patient who presented with a schizophreniform disorder and complete relief of symptoms after specific therapy.
Methods: Cerebrospinal fluid and magnetic resonance imaging findings led to the diagnosis of Lyme disease.
Results: To our knowledge this is the first reported case with an exclusive psychiatric manifestation of Lyme disease.
Conclusions: In case of first manifestation of psychotic disorder, although neurological symptoms are lacking, Lyme disease should be considered and be excluded by cerebrospinal fluid analysis.Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder - ScienceDirect
https://www.sciencedirect.com/science/article/abs/pii/S0006322398002777
Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner
Anna K. Schmidtner, David A. Slattery, Joachim Gläsner, Andreas Hiergeist, Katharina Gryksa, Victoria A. Malik, Julian Hellmann-Regen, Isabella Heuser, Thomas C. Baghai, André Gessner, Rainer Rupprecht, Barbara Di Benedetto & Inga D. Neumann
Translational Psychiatry volume 9, Article number: 223 (2019) Cite this article
Abstract
Major depressive disorder is the main cause of disability worldwide with imperfect treatment options. However, novel therapeutic approaches are currently discussed, from augmentation strategies to novel treatments targeting the immune system or the microbiome-gut-brain axis. Therefore, we examined the potential beneficial effects of minocycline, a tetracycline antibiotic with pleiotropic, immunomodulatory action, alone or as augmentation of escitalopram on behavior, prefrontal microglial density, and the gut microbiome in rats selectively bred for high anxiety-like behavior (HAB).We show that concomitant with their high innate anxiety and depression, HABs have lower microglial numbers in the infralimbic and prelimbic prefrontal cortex and an altered gut microbiota composition compared with controls.
Three weeks of minocycline treatment alleviated the depressive-like phenotype, further reduced microglial density, exclusively in male HAB rats, and reduced plasma concentrations of pro-inflammatory cytokines.
However, coadministration of escitalopram, which had no effect alone, prevented these minocycline-induced effects. Moreover, minocycline led to a robust shift in cecal microbial composition in both HABs and rats non-selected for anxiety-like behavior. Minocycline markedly increased relative abundance of Lachnospiraceae and Clostridiales Family XIII, families known for their butyrate production, with a corresponding increase and positive correlation in plasma 3-OH-butyrate levels in a trait-dependent manner. Thus, our data suggest that the antidepressant effect of minocycline is sex- and trait-dependent, associated with a reduced microglial number in the prefrontal cortex, and with changes in microbial composition and their metabolites. These results further support the microbiome-gut–brain axis as potential target in the treatment of depression.
Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner | Translational Psychiatry
https://www.nature.com/articles/s41398-019-0556-9
Psychiatric Clinics of North America
Volume 21, Issue 3, 1 September 1998, Pages 693-703
Psychiatric Clinics of North America
THE UNDERDIAGNOSIS OF NEUROPSYCHIATRIC LYME DISEASE IN CHILDREN AND ADULTS
Author links open overlay panelBrian A.FallonMD, MPHaJanice M.KochevarNPbAndreaGaitoMDcJenifer A.NieldsMDd
a
Department of Psychiatry, Columbia University Medical Center and the Lyme Disease Research Program, New York, New York (BAF)
b
private practice, Armonk, New York (JMK)
c
Department of Medicine, Seton Hall University, and private practice, Basking Ridge, New Jersey (AG)
d
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (JAN)
Available online 29 June 2005.
Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi. Reported throughout the United States, the greatest incidence of Lyme disease occurs in certain areas, such as the Northeast, the upper Midwest, and the Pacific Coastal states. It has been dubbed “The New Great Imitator” because, like another spirochetal illness neurosyphilis—the original Great Imitator, Lyme disease has a vast array of multisystem manifestations, including neuropsychiatric ones.18 Failure to recognize Lyme disease early in its course can result in the development of a chronic illness that is only temporarily or partially responsive to antibiotic therapy. The goal of this article is to present the typical and atypical manifestations of Lyme disease in children and adults in order to help the clinician more rapidly unmask the correct diagnosis behind the puzzling presentations of some patients.THE UNDERDIAGNOSIS OF NEUROPSYCHIATRIC LYME DISEASE IN CHILDREN AND ADULTS - ScienceDirect
https://www.sciencedirect.com/science/article/abs/pii/S0193953X05700320
Minocycline as a treatment for schizophrenia: is the discussion truly finished?
Taishiro Kishimoto
Toshiro Horigome
Akihiro Takamiya
Open AccessPublished:October 12, 2018DOI:https://doi.org/10.1016/S2215-0366(18)30389-4
The improvement of negative symptoms and cognitive function is an unresolved and important concern surrounding schizophrenia treatment. Dysfunctional glutaminergic, inflammatory, and oxidative stress pathways are considered the pathophysiology of schizophrenia, especially in relation to negative and cognitive symptoms.1, 2Minocycline, a second-generation tetracycline, is expected to have neuroprotective effects through the above-mentioned actions,3, 4 on the basis of findings from studies on both animals and humans. In fact, an effect of minocycline on negative symptoms and on some cognitive domains has been shown in multiple, although relatively small, clinical trials.5, 6, 7, 8, 9
In The Lancet Psychiatry, Bill Deakin and colleagues10 report findings from BeneMin, a randomised controlled trial of 207 participants that compared minocycline with placebo as an adjunctive treatment to usual antipsychotic treatment. The BeneMin study was unique because not only did it examine the effect of minocycline on clinical symptoms, but it also explored its potential function through brain imaging (grey-matter volume and blood-oxygen-level-dependent response in the dorsolateral-prefrontal cortex) and serum inflammatory markers (circulating interleukin 6 [IL-6] and high-sensitivity C-reactive protein [hs-CRP] concentrations). Contrary to expectations, the results were negative: there was no difference in clinical symptoms, including negative symptoms (treatment effect difference −0·19, 95% CI −1·23 to 0·85; p=0·73), or in imaging and inflammatory markers. Furthermore, the authors did not find an increase in circulating hs-CRP and IL-6 concentrations in their samples.
Should we give up our expectations for minocycline, or should we even deny the inflammatory hypothesis of schizophrenia? Scrutinising the results of this negative study is important in determining the direction of future research. As the authors of the BeneMin study discussed, early influences on negative symptoms might have occurred before the introduction of minocycline. Although the investigators recruited patients in the early stage of their illness (ie, within 5 years of a schizophrenia diagnosis), systemic inflammation could have happened when the patients were acutely ill. Related to this point, patients in the BeneMin study had less severe disease compared with previous randomised controlled trials that showed a significant effect from minocycline on clinical symptoms. Patients were taking antipsychotics and it might have caused the effect of minocycline to be undetectable, or in some cases made the negative symptoms worse. The BeneMin study did not standardise antipsychotic treatment, which made it easier to do the study but made it more difficult to clearly understand the effect of minocycline. It is also important to take into consideration the effect of relapse on outcomes. A large proportion of patients are reported to experience relapse after their first episode.11 It should be remembered that only the group effect is apparent in randomised controlled trials, and they do not necessarily reflect specific patients' trajectories. Relapses should have a large effect on psychopathology scores, as well as inflammatory markers. The authors examined the effect of minocycline on patients who did not experience relapse, finding no alteration in results, but conversely an effect might have been seen for patients who might have had relapse before or during a study. Assessment of negative symptoms can be very difficult to do with equal quality across all study sites. Other limitations of this study include some inherent difficulties of randomised controlled trials, such as selection bias, poor adherence to the study medication, and high rates of dropouts in long-term studies such as BeneMin.
Clearly, studies with an identical design should not be repeated in the future and it might be better to target patients who are even more early phase or acutely ill than those in BeneMin. Identifying patients with an active inflammatory process might be the best approach, but such identification is difficult. The BeneMin authors discuss the potential of using translocator protein (TSPO)-PET for such purposes, but it is known whether TSPO-PET highlights pro-inflammatory or anti-inflammatory microglia.12 The development of new tools to assess neuroinflammation, such as serum biomarkers and PET tracers, is warranted. There is growing evidence indicating that the microbiome might influence the immune system, and it could play some role as a regulator in neuroinflammation, too. Although there are difficulties, further studies targeting inflammation-associated patients with such new tools and approaches should deepen our understanding of the pathophysiology of the disease and lead to the development of new treatments.
Figure thumbnail fx1https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(18)30389-4/fulltext
Infectious Agents in Schizophrenia and Bipolar Disorder
Robert H. Yolken, MDE. Fuller Torrey, MDdirector of the Stanley Division of Developmental Neurovirology and professor, department of pediatrics, The Johns Hopkins University School of Medicine, Baltimore. Dr Torrey is associate director for laboratory research, The Stanley Medical Research Institute, and professor of psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Md.
June 1, 2006
Volume: 23Issue: 7
Bipolar Disorder, Schizophrenia, Schizophrenia Psychotic Features, Alcohol Abuse
The idea that schizophrenia and bipolar disorder might be caused by infection is not new. This was a prominent hypothesis in the early years of the last century. For example, an article entitled, Is insanity due to a microbe? was published in Scientific American as early as 1896. Research to test this hypothesis by identifying causative viruses was already being conducted by the 1930s, when data were reported from experiments in which cerebrospinal fluid (CSF) from patients with schizophrenia was injected into rabbit brains.1
New research in the field continues, aided increasingly by impressive technologic advances in microbiology and virology. As recently as the past decade, reports documented the presence of influenza virus, rubella virus, bovine disease virus, and other infectious agents in patients with schizophrenia and bipolar disorder, as well as the presence of other infectious agents in childhood pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) and obsessive-compulsive disorder.
In this article, we briefly highlight the background of such research; discuss our own research on Toxoplasma gondii, herpes simplex virus (HSV), Cytomegalovirus (CMV), and endogenous retroviruses; and consider the future implications of such research for psychiatric clinicians.
Background and rationale
Why should we look for infectious agents in schizophrenia and bipolar disorder? Such a hypothesis is consistent with the known genetic contributions to these disorders. Indeed, a genetic predisposition is well established for most chronic infectious diseases, including tuberculosis, malaria, polio, AIDS, and peptic ulcers caused by Helicobacter pylori.2 The hypothesis is consistent with the role of neurotransmitter abnormalities in schizophrenia and bipolar disorder, because specific infectious agents have been shown to alter dopamine, serotonin, glutamate, γ-aminobutyric acid, and acetylcholine in animal models. The hypothesis is also consistent with neurodevelopmental models of schizophrenia and bipolar disorder. Pearce3 and others developed animal models that show how exposure to specific infectious agents during neurodevelopment correlates with later behavioral alterations in animals.
An additional important reason to look for infectious agents in schizophrenia and bipolar disorder is that CNS infection by specific pathogens frequently mimics the clinical symptoms of primary psychiatric diseases. For example, Caroff and colleagues4 reviewed 108 cases of psychiatric disorders resulting from suspected or confirmed CNS viral infections; in 62 cases, a specific virus was implicated, including HIV, HSV-1, HSV-2, Epstein-Barr, and CMV; and measles, mumps, coxsackie, and influenza viruses. Among bacteria, the fact that the spirochete of syphilis can cause the symptoms of schizophrenia was well known to psychiatric clinicians of an earlier era. More recently, infection with the spirochetal organism Borrelia burgdorferi has also been associated with schizophrenia-like symptoms in some persons.5
Another reason to look for infectious agents in schizophrenia and bipolar disorder is the well-established association between the risk of these disorders and winter-spring seasonal birth.6 There have been more than 200 studies of this phenomenon, and it remains one of the most highly replicated findings of these diseases. Because many infectious diseases occur seasonally, with a peak in the winter or spring, it is reasonable to postulate that fetal or newborn infection could contribute to subsequent mental illness.7
Current research
At the present time, we are focusing our research on 4 infectious agents as possible causes of schizophrenia and bipolar disorder. These are T gondii, HSV-1 and HSV-2, CMV, and endogenous retroviruses.
Toxoplasma gondii
T gondii is a protozoan parasite whose definitive host is the cat family. Humans become infected by ingesting oocysts shed in the feces of infected cats or by eating undercooked meat from an animal that came into contact with infected cat feces. T gondii is one of the most widespread human parasites; 10% to 20% of Americans test seropositive by adulthood. Exposure to T gondii during early pregnancy can cause severe fetal CNS abnormalities. Exposure during late pregnancy was never considered a problem until recently, when animal data showed that late exposure to the organism causes behavioral changes, neurologic symptoms, and stillbirths.8,9
Since 1956, more than 20 studies have compared antibodies to T gondii in adults with and without schizophrenia.10 An overall analysis of the studies indicates that serologic evidence of Toxoplasma infection is almost 3 times more common in persons with schizophrenia than in controls living in the same geographic region.Two additional studies reported an increased level of T gondii antibodies in the late-pregnancy serum of women giving birth to infants in whom schizophrenia later developed. 11,12 Other studies have reported greater childhood exposure to cats among persons with schizophrenia than among controls.13,14 Our research is focusing on the timing of Toxoplasma infections in relation to development, as well as on possible differences in T gondii strains and human genetic susceptibility.
Herpes simplex viruses
Like Toxoplasma, HSV-1 and HSV-2 are common causes of infection in humans. HSV-1 may be spread by either sexual or nonsexual contact with infected persons, while HSV-2 is primarily spread through sexual contact. Both of these viruses are known to cause encephalitis and to be highly neurotropic. Traditionally, however, these viruses have been regarded as relatively benign in the majority of asymptomatic patients who carry them. Recent data suggest that this may not be true. One study evaluated the mothers of patients in whom schizophrenia or bipolar disorder developed. These women had increased levels of HSV-2 serum antibodies just before parturition.15
Comparison studies of persons with and without schizophrenia or bipolar disorder show that HSV-1 infection significantly increases cognitive dysfunction—especially recent memory deficits—in persons with schizophrenia or bipolar disorder.16,17 This did not occur in persons infected with other viruses in the herpes family and also did not occur in persons without schizophrenia or bipolar disorder who were infected with HSV-1.
In a follow-up study, Dickerson and associates18 showed that a polymorphism on the COMT gene (COMT Val 158 Met polymorphism) also increases cognitive dysfunction; this suggests a synergistic effect between HSV infection and the gene. This kind of interaction may be a model for future research that integrates multiple factors in the development of schizophrenia and bipolar disorder.Cytomegalovirus
CMV is another member of the herpes family of viruses. Infection is widespread and is known to occasionally cause encephalitis, primarily in patients with immunosuppression.
In contrast to older studies, recent studies report significantly more CMV antibodies in persons with schizophrenia than in controls. In a study by Leweke and colleagues,19 for example, 36 treatment-naive schizophrenic patients had significantly more antibodies in their sera (P P 20 Another recent study reports that serum antibodies to CMV are particularly high in schizophrenic persons who have predominantly negative symptoms (the so-called deficit syndrome).21
Finally, a recent treatment trial showed significant symptomatic improvement in schizophrenic patients who were treated with valacyclovir, an antiviral agent effective against herpes viruses.22
Endogenous retroviruses
Endogenous retroviruses are DNA elements that have become part of the human genome through infection and integration into germ line cells of humans and nonhuman primate progenitors. Retroviruses lie dormant most of the time. When activated, however, they can influence the transcription of genes above or below the site of their chromosomal integration. Genetic polymorphisms of endogenous retroviruses have been linked with an alteration in immune response and increased susceptibility to autoimmune disorders.23
Endogenous retroviruses share properties of both genes and infectious agents, and are thus potential links between the two.24 Of particular interest is the fact that endogenous retroviruses may be activated by infections with herpesviruses or protozoan organisms such as Toxoplasma, providing a potential link between infectious agents and genetic elements as causative factors in human psychiatric diseases. Increased retroviral transcription in the CSF and blood of persons with recentonset psychosis supports a possible role for human endogenous retrovirus in the development of schizophrenia.25,26
Implications for clinicians
Proving a causative role for infectious agents in schizophrenia and bipolar disorder would open the door to new treatments and disease prevention strategies. With the support of The Stanley Medical Research Institute, we are conducting several double-blind treatment trials that involve the use of adjunctive antibiotics and antiviral medications in persons with schizophrenia and bipolar illness. To date, these medications show some promise in patients with recent-onset disease. The results are less remarkable in persons with long-standing illness. In the future, it might even be possible to develop a vaccine to protect children against possible infections that contribute to these 2 mental illnesses.
Even with what is known today, in clinical settings, some patients who present initially with symptoms suggestive of schizophrenia or bipolar disorder could instead be in the initial stages of viral encephalitis. Some physicians would argue that patients with first-admission psychosis should have a lumbar puncture and CSF analysis, adding other studies as appropriate if indicated by an increase in CSF protein or lymphocytes. A small sample of the CSF could be frozen and stored for future analysis. With further advances in research at the interface between psychiatry and infectious disease, these samples may eventually provide the key to proving the connection between infection and mental disturbance, and pave the way for pharmacologic treatment specifically targeted to that causative infectious organism.
Dr Yolken is director of the Stanley Division of Developmental Neurovirology and professor, department of pediatrics, The Johns Hopkins University School of Medicine, Baltimore. Dr Torrey is associate director for laboratory research, The Stanley Medical Research Institute, and professor of psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Md.Infectious Agents in Schizophrenia and Bipolar Disorder: Page 2 of 2 | Psychiatric Times
https://www.psychiatrictimes.com/bipolar-disorder/infectious-agents-schizophrenia-and-bipolar-disorder/page/0/1
米诺环素（Minocycline），又称二甲胺四环素或美满环素，是一种广谱抗菌的四环素类抗生素。能与tRNA结合，达到抑菌的效果。米诺环素比同类药物具有更广的抗菌谱，具有抑菌活性。抗菌谱与四环素相近，对革兰阳性菌包括耐四环素的金黄色葡萄球菌、链球菌和革兰阴性菌中的淋病奈瑟球菌均有很强的作用；对革兰阴性杆菌的作用一般较弱；对沙眼衣原体和溶脲支原体亦有较好的抑制作用。