Borna Virus and Psychiatric Disorders
An introduction to the psychiatric aspects of Borna infection
1: Schizophr Res. 2002 Oct 1;57(2-3):303-5.
Borna disease virus and psychiatric disorders.
Lebain P, Vabret A, Freymuth F, Brazo P, Chabot B, Dollfus S, Henri B.
Publication Types:
Letter
PMID: 12223262 [PubMed - indexed for MEDLINE]
2: Mol Psychiatry. 2001 Jul;6(4):481-91.
Borna disease virus-specific circulating immune complexes, antigenemia, and free
antibodies--the key marker triplet determining infection and prevailing in
severe mood disorders.
Bode L, Reckwald P, Severus WE, Stoyloff R, Ferszt R, Dietrich DE, Ludwig H.
Project Bornavirus Infections, Robert Koch-Institut, Nordufer 20, 13353 Berlin,
Germany. bodel@rki.de
Borna disease virus (BDV), a unique genetically highly conserved RNA virus
(Bornaviridae; Mononegavirales), preferentially targets neurons of limbic
structures causing behavioral abnormalities in animals. Markers and virus in
patients with affective disorders and schizophrenia have raised worldwide
interest. A persistent infection was suggestive from follow-up studies, but
inconstant detectability weakened a possible linkage.This study for the first
time discloses that detection gaps are caused by BDV-specific circulating immune
complexes (CIC), and their interplay with free antibodies and plasma antigens
(p40/p24). Screening 3000 sera each from human and equine patients over the past
4 years by new enzyme immunoassays (EIAs) revealed that BDV-CICs indicate 10
times higher infection rates (up to 30% in controls, up to 100% in patients)
than did previous serology. Persistence of high amounts of CICs and plasma
antigens correlates with severity of depression. Even BDV RNA could be detected
in plasma samples with strong antigenemia. Our discovery not only explains the
course of persistent infection, but offers novel easy-to-use diagnostic tools by
which new insights into BDV-related etiopathogenesis of disease and epidemiology
are possible.
Publication Types:
Multicenter Study
PMID: 11443538 [PubMed - indexed for MEDLINE]
3: Bipolar Disord. 2000 Mar;2(1):65-70.
Amantadine in depressive patients with Borna disease virus (BDV) infection: an
open trial.
Dietrich DE, Bode L, Spannhuth CW, Lau T, Huber TJ, Brodhun B, Ludwig H, Emrich
HM.
Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover,
Germany. dietrich.detlef@mh-hannover.de
OBJECTIVE: Originally introduced into pharmacotherapy as an antiviral compound,
amantadine was shown to also have multiple pharmacological eftfects on the
central nervous system. In addition. only a few studies reported on certain
antidepressive properties of amantadine. This effect was highlighted by the
discovery of its antiviral effect on Borna disease virus (BDV), which is
hypothesized to be an etiopathogenetic factor to subtypes of affective
disorders. Therefore, the therapeutical use of amantadine in BDV-infected
depressive patients was investigated. METHODS: In this open trial, amantadine
was added to antidepressive and or mood-stabilizing compounds treating
BDV-infected depressed patients (n = 25) with bipolar or major depressive
disorders. Amantadine was given twice a day (100-300 mg/day) for a mean of 11
weeks. Antidepressive treatment response was measured on the Hamilton rating
scale for depression (HAM-D) and/or with an operationalized diagnostic criteria
system (OPCRIT: version 3.31). Virological response was measured by expression
of BDV infection parameters in blood samples. RESULTS: The overall response rate
of the amantadine augmentation in the BDV-infected patients with regard to
depressive symptoms was 68% after a mean of 2.9 weeks of treatment. Bipolar I
patients improved faster and did not show any following hypomania. In addition,
the decrease of depression tended to correspond with the decrease in viral
activity. CONCLUSION: Amantadine appears to show a remarkable antidepressive
efficacy in BDV-infected depressive patients. The antidepressive effect in this
open trial appeared to be comparable to standard antidepressives, possibly being
a result of its antiviral effect against BDV as a potentially relevant
etiopathogenetic factor in these disorders.
Publication Types:
Clinical Trial
PMID: 11254023 [PubMed - indexed for MEDLINE]
4: Eur Psychiatry. 2001 Feb;16(1):3-10.
Borna disease virus and psychiatry.
Taieb O, Baleyte JM, Mazet P, Fillet AM.
Department of Virology, CERVI, 47-83 Boulevard de l'Hopital, 75013 Paris,
France.
Borna disease virus (BDV), a noncytolytic neurotropic nonsegmented
negative-stranded RNA virus with a wide geographic distribution, infects several
vertebrate animal species and causes an immune-mediated central nervous system
(CNS) disease with various manifestations, depending on both host and viral
factors. In animal infections, BDV can persist in the CNS and induce alterations
in brain cell functions, neurodevelopmental abnormalities and behavioral
disturbances. An association between BDV and psychiatric disorders (essentially
schizophrenia and affective disorders) has been suggested by some serologic and
molecular studies but further investigations are required to substantiate the
possible contribution of this virus to the pathogenesis of these disorders.
Publication Types:
Review
Review, Tutorial
PMID: 11246286 [PubMed - indexed for MEDLINE]
5: Pharmacopsychiatry. 1999 Jul;32(4):142-7.
Amantadine revisited: an open trial of amantadinesulfate treatment in
chronically depressed patients with Borna disease virus infection.
Ferszt R, Kuhl KP, Bode L, Severus EW, Winzer B, Berghofer A, Beelitz G, Brodhun
B, Muller-Oerlinghausen B, Ludwig H.
Department of Gerontopsychiatry, Freie Universitat Berlin, Germany.
ferszt@zedat.fu-berlin.de
Amantadinesulfate is a well known substance which has proven useful in the
treatment and prophylaxis of viral infections, in treating symptoms of
Parkinson's disease, cocaine dependence, and apathy in multiple sclerosis. It
has also been reported as having mild antidepressive effects not sufficient to
warrant its use as an antidepressant. Striking antidepressive effects in some
patients have been attributed to its antiviral activity against human Borna
disease virus (BDV) infection which is frequently seen in patients with
depressive episodes. In this 8 to 12 week open study of oral amantadine in 30
depressed patients with various states of BDV infection we found a significant
antidepressive response in 19 of 30. Peripheral BDV antigen indicating acute
infection was cleared in both responders and non-responders, but only in
responders peripheral infection was significantly reduced.
Publication Types:
Clinical Trial
PMID: 10505484 [PubMed - indexed for MEDLINE]
6: Pharmacopsychiatry. 1999 May;32(3):93-8.
Activated Borna disease virus in affective disorders.
Ferszt R, Severus E, Bode L, Brehm M, Kuhl K-P, Berzewski H, Ludwig H.
Department of Gerontopsychiatry, Free University of Berlin, Germany.
ferszt@zedat.fu-berlin.de
BACKGROUND: Borna disease virus (BDV) is an animal pathogen that causes
behavioral changes in animals. Previous studies have found a high prevalence of
serum antibodies as well as Borna disease viral antigens (BDVAGs) and RNA in the
white blood cells of psychiatric patients, especially those with affective
disorders. The present study attempts to offer a better description of the BDVAG
cohort using clinical parameters. METHODS: The prevalence of BDVAG was examined
in the peripheral mononuclear leukocytes of patients with a major depressive
episode. A subgroup of patients underwent further clinical analysis. RESULTS: In
this pilot study, at least, there was a significant difference in the prevalence
of BDVAG between psychiatric inpatients with a major depressive episode and
control individuals. It also appeared that BDVAG is more frequent in patients
with recurrent major depression or bipolar disorder than in those with any other
psychiatric disorder studied. The number of previous depressive episodes, as
well as symptoms involving fatigue and concentration difficulties were
positively related to BDVAG. CONCLUSIONS: The high rate of BDVAG, especially in
fatigued patients with recurrent major depression or bipolar disorder, may be a
nonspecific aspect of immunosuppression. The question remains whether this
neurotropic virus may contribute to the pathogenesis of some types of affective
disorder.
PMID: 10463375 [PubMed - indexed for MEDLINE]
7: Pharmacopsychiatry. 1999 Mar;32(2):47-55.
Possible use of amantadine in depression.
Huber TJ, Dietrich DE, Emrich HM.
Department of Clinical Psychiatry, Medical School of Hanover, Germany.
Amantadine, originally used in the treatment and prophylaxis of influenza
infection, has also proved beneficial in drug-induced Parkinsonism, Parkinson's
disease, traumatic head injury, dementia, multiple sclerosis and cocaine
withdrawal. Amantadine appears to act through several pharmacological
mechanisms, none of which has been identified as the one chief mode of action.
It is a dopaminergic, noradrenergic and serotonergic substance, blocks
monoaminoxidase A and NMDA receptors, and seems to raise
beta-endorphin/beta-lipotropin levels. However, it is still uncertain which of
these actions are relevant in therapeutic doses. One new aspect is the antiviral
effect of amantadine on Borna disease virus, which it is suspected may possibly
play a role in affective disorders. All of these actions could constitute an
antidepressant property, and it is suggested that amantadine might work as an
antidepressant not through one, but through several mechanisms thought to be
related to antidepressant activity. Effects of amantadine on symptoms of
affective disorders have been demonstrated in several trials administering it
for varying purposes. Additionally, animal studies as well as clinical trials in
humans have hinted at an antidepressant activity of amantadine. We present here
an overview of the current data. However, only a limited body of evidence is
available, and further studies are needed to investigate the efficacy of
amantadine as well as its modes of action in depression.
Publication Types:
Review
Review, Academic
PMID: 10333162 [PubMed - indexed for MEDLINE]
8: J Neurovirol. 1999 Apr;5(2):196-9.
Failure to demonstrate Borna disease virus genome in peripheral blood
mononuclear cells from psychiatric patients in Korea.
Kim YK, Kim SH, Choi SH, Ko YH, Kim L, Lee MS, Suh KY, Kwak DI, Song KJ, Lee YJ,
Yanagihara R, Song JW.
Department of Psychiatry, College of Medicine, Korea University, Seoul.
RNA, extracted from peripheral blood mononuclear cells (PBMC) obtained from 81
Korean psychiatric patients (39 with schizophrenia, 33 with bipolar affective
disorders and nine with major depression), was analyzed for a 391-nucleotide,
highly conserved region of the p24 protein-encoding ORF II of Borna disease
virus (BDV), using nested reverse transcription-polymerase chain reaction
(RT-PCR). BDV genomic RNA was not detected in PBMC from any of the 81 Korean
psychiatric patients. These data do not support an etiologic association between
BDV infection and neuropsychiatric disorders in humans.
PMID: 10321984 [PubMed - indexed for MEDLINE]
9: Lancet. 1998 Dec 5;352(9143):1828-9.
Borna disease virus proteins in cerebrospinal fluid of patients with recurrent
depression and multiple sclerosis.
Deuschle M, Bode L, Heuser I, Schmider J, Ludwig H.
Publication Types:
Letter
PMID: 9851390 [PubMed - indexed for MEDLINE]
10: Pharmacopsychiatry. 1998 May;31(3):77-82.
Comment in:
Pharmacopsychiatry. 1998 May;31(3):75-6.
Pharmacopsychiatry. 1999 Jan;32(1):44-6.
A viro-psycho-immunological disease-model of a subtype affective disorder.
Dietrich DE, Schedlowski M, Bode L, Ludwig H, Emrich HM.
Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover,
Germany.
Borna Disease Virus (BDV) infections are widespread in animal species. This
neurotropic, negative and single-stranded enveloped RNA virus spreads via axonal
and transsynaptic pathways quite specifically into olfactoric and limbic
structures. The symptoms in BDV-infected animals range from unapparent or subtle
clinical manifestations to fatal neurological disorders. The severe and
fulminant course of the infection, which is often accompanied by neurobehavioral
and "emotional" disturbances, occurs sporadically and, at least in
experimentally infected animals (rats), is thought to be mediated by
immunopathology. Increases in serum-BDV antibodies have also been detected in
neuropsychiatric patients. In addition, viral antigen and viral RNA have been
observed in acutely ill major depressive patients, leading to the conclusion
that BDV was causally related to psychiatric disorders, in particular to
affective disorders. A number of studies have meanwhile furnished evidence of
abnormal immune functions in mentally ill patients. In addition, stress has been
shown to decrease immune responses to viral infections. On the basis of these
findings it is hypothesized that human BDV infection represents a co-factor in
the development or course of psychiatric diseases. Stress may cause
immunosuppression and thus induce activation of persisting BDV in the limbic
system, resulting in an inflammatory reaction of these structures. These
neuropathological changes might influence the serotonergic or dopaminergic
neurotransmitter systems. In addition, a specific affinity of BDV structural
elements for aspartate and glutamate receptors in the hippocampal formation
might directly induce an imbalance of these transmitter system interactions,
causing affective and behavioral disturbances. The possible interactions between
stress-induced immunosuppression, BDV infection and affective disorders in
humans, and the theoretical and clinical aspects of this concept are discussed.
Publication Types:
Review
Review, Tutorial
PMID: 9657234 [PubMed - indexed for MEDLINE]
11: Arch Virol Suppl. 1997;13:167-82.
Clinical similarities and close genetic relationship of human and animal Borna
disease virus.
Bode L, Ludwig H.
Department of Virology, Robert Koch-Institut, Berlin, Federal Republic of
Germany.
Borna disease virus (BDV) is the prototype genus of a new family, Bornaviridae,
within the order Mononegavirales. BDV naturally infects animals and man. The
symptomatology in animals ranges from subclinical infection to rare cases of
encephalitis. Asymptomatic infection seemed more frequent than expected, based
on antibody data from 100 healthy horses derived from different stables with a
history of diseased cases (30-40% carriers). Likewise, phasic episodes of a
neurobehavioral syndrome followed by recovery were much more common than fatal
neurologic disease. They were paralleled by expression of BDV antigens
(N-protein p40, P-protein p24) and RNA transcripts in peripheral blood
mononuclear cells, indicating viral activation. Representative longitudinal
studies showed that episodes of depressive illness in humans as well as
apathetic phases in infected horses were accompanied by antigen expression and
followed a similar clinical course. After recovery, BDV antigen disappeared.
This temporal congruence, together with the recent isolation of infectious BDV
from such patients, points to a contributory role of this virus in human
affective disorders. Successful amelioration of BDV-induced neurobehavioral
disease in horses with antidepressants applied in psychiatry, supported a common
viral pathomechanism, involving reversible disturbances of the neurotransmitter
network in the limbic system. Sequences of genetic material amplified from
infected animal tissue and human PBMCs revealed a close interspecies
relationship and high sequence conservation of the BDV genome. In human BDV
isolates, however, single unique mutations were prominent in four genes. This
finding supports the hypothesis that despite of high genomic conservation,
species-specific genotypes may be definable, provided the sequences are derived
from RNA of infectious virus.
PMID: 9413536 [PubMed - indexed for MEDLINE]
12: Lancet. 1997 Jun 21;349(9068):1813-4.
Comment in:
Lancet. 1997 Aug 23;350(9077):592-3.
Lancet. 1997 Aug 23;350(9077):593.
Borna disease virus in brains of North American and European people with
schizophrenia and bipolar disorder. Bornavirus Study Group.
Salvatore M, Morzunov S, Schwemmle M, Lipkin WI.
Publication Types:
Letter
PMID: 9269221 [PubMed - indexed for MEDLINE]
13: Lancet. 1997 Mar 29;349(9056):958.
Comment on:
Lancet. 1997 Jan 18;349(9046):178-9.
Depression, Borna disease, and amantadine.
Lieb K, Hufert FT, Bechter K, Bauer J, Kornhuber J.
Publication Types:
Comment
Letter
PMID: 9093281 [PubMed - indexed for MEDLINE]
14: Lancet. 1997 Jan 18;349(9046):178-9.
Comment in:
Lancet. 1997 Mar 29;349(9056):958.
Amantadine and human Borna disease virus in vitro and in vivo in an infected
patient with bipolar depression.
Bode L, Dietrich DE, Stoyloff R, Emrich HM, Ludwig H.
Publication Types:
Letter
PMID: 9111548 [PubMed - indexed for MEDLINE]
15: Mol Psychiatry. 1996 Jul;1(3):200-12.
Comment in:
Mol Psychiatry. 1996 Jul;1(3):165-7.
First isolates of infectious human Borna disease virus from patients with mood
disorders.
Bode L, Durrwald R, Rantam FA, Ferszt R, Ludwig H.
Robert Koch-Institut, Federal Institute for Infectious and Non-Communicable
Diseases, Department of Virology, Berlin, Germany.
Borna disease virus (BDV), an unique type of non-segmented negative-stranded
enveloped RNA virus, is known as an animal pathogen that causes behavioral
diseases in higher vertebrates. Past studies have found antibodies to BDV as
well as BDV proteins and genomic transcripts in peripheral blood mononuclear
cells (PBMCs) of infected animals and human psychiatric patients. Here, we
present the first isolation of infectious BDV from such patients' PBMCs.
Isolation attempts were conducted with randomly collected PBMC samples from 33
psychiatric inpatients, by co-cultivation and long-term passaging with a human
cell line. BDV isolates were identified by infectivity, analysis of viral
antigens, sequencing of one viral gene, and successful infection of animals.
Three individual isolates could be recovered. They originated from two bipolar
patients with acute depression, and one patient with a chronic
obsessive-compulsive disorder. Rescue of human BDV required PBMC samples with
strong viral antigen expression, and at least 11 subcultures per sample. Genetic
and biological properties point to a close relationship of human and animal
strains, but also to the uniqueness of each human isolate. Isolation of BDV from
patients with major mood disorders at a time of acute depression strengthens the
possibility that BDV infection is one of the environmental factors that
contributes to recurrent depressive illnesses in man. These isolates represent
the first three defined strains of the infectious human BDV.
PMID: 9118344 [PubMed - indexed for MEDLINE]
16: J Affect Disord. 1993 Jan;27(1):61-8.
Detection of Borna disease virus-reactive antibodies from patients with
affective disorders by western immunoblot technique.
Fu ZF, Amsterdam JD, Kao M, Shankar V, Koprowski H, Dietzschold B.
Wistar Institute of Anatomy, Philadelphia, Pennsylvania.
Borna disease (BD) virus is a partially characterized neurotropic agent with a
predilection for neurons and astrocytes in the limbic system and cerebrum of
infected hosts. Although it usually causes a fatal encephalitis, some laboratory
animals which have been experimentally inoculated can develop a persistent
non-fatal infection characterized by a neuro-behavioral syndrome akin to human
manic-depression. Using immunofluorescent techniques, we previously observed BD
virus-specific antibodies in the sera of 4.5% of affectively ill patients, with
the highest titers present in bipolar patients. More recently, we have developed
a sensitive Western blot assay for the detection of anti-BD virus antibodies to
a 38/40 kDa and 24 kDa protein in human serum. In the present study, we screened
138 affectively ill patients and 117 healthy controls and observed a
significantly great proportion of patients with antibodies to the 38/40 kDa
protein (P < 0.0001), the 24 kDa protein (P < 0.05) and both the 38/40 kDa and
24 kDa proteins (P < 0.025). These data extend prior reports on the presence of
BD virus-specific antibodies in psychiatric patients, and suggest that a BD
virus-like agent may be associated with affective illness in humans.
PMID: 8432962 [PubMed - indexed for MEDLINE]
17: Arch Virol Suppl. 1993;7:159-67.
Borna disease virus infection and affective disorders in man.
Bode L, Ferszt R, Czech G.
Robert Koch-Institute, Department of Virology, Free University Berlin, Federal
Republic of Germany.
Borna Disease virus (BDV) can persistently infect the central nervous system of
a broad spectrum of animal species. The clinical course varies from slight
behavioral disturbances to a fatal neurological syndrome. In-vivo diagnosis is
based on the strong humoral immune response to BDV antigens. Since also human
infections could be confirmed by specific antibodies and increased
seroprevalence was found in patients with chronic neurologic or immunologic
disorders, the contribution of BDV or a BDV-like human variant to syndromes with
yet unknown etiology became of great interest. We presented the first data of a
current follow-up study on 70 psychiatric patients who were tested three times
each after hospitalization. In contrast to previously found low prevalence of
antibody carriers by screening (2-4%), we now found 20% positives by follow-up
testing. Furthermore, of the randomly selected patients with different
psychiatric diagnosis, the highest proportion of antibody carriers was detected
among patients with major depression (more than 30%), compared to only 8% among
patients with dysthymia (neurotic depression). This led us to hypothesize that
Bornavirus infection might contribute somehow to the syndrome of major
depressive illness by altering neuronal cells in the limbic system.
PMID: 8219801 [PubMed - indexed for MEDLINE]
18: Arch Gen Psychiatry. 1985 Nov;42(11):1093-6.
Borna disease virus. A possible etiologic factor in human affective disorders?
Amsterdam JD, Winokur A, Dyson W, Herzog S, Gonzalez F, Rott R, Koprowski H.
Borna disease virus is a unique neurotropic agent that appears to have a
predilection for the limbic area of the brain. In some animal species, it can
produce a behavioral syndrome characterized by aggressive and passive phases.
This syndrome has suggested an analogy to certain human affective disorders. In
this preliminary study, we examined the possible involvement of Borna disease
virus in the etiology of human mood disorders by assaying for virus-specific
antibodies in 265 patients with unipolar or bipolar depression and 105 normal,
healthy volunteers. Twelve patients (4.5%) and none of the healthy controls
demonstrated this antibody in their serum samples. It will be necessary to
replicate and extend these intriguing preliminary results to determine if Borna
disease virus is possibly involved in the pathogenesis of affective disorders in
humans.
PMID: 3931604 [PubMed - indexed for MEDLINE]
19: Science. 1985 May 10;228(4700):755-6.
Detection of serum antibodies to Borna disease virus in patients with
psychiatric disorders.
Rott R, Herzog S, Fleischer B, Winokur A, Amsterdam J, Dyson W, Koprowski H.
Borna disease virus causes a rare meningoencephalitis in horses and sheep and
has been shown to produce behavioral effects in some species. The possibility
that the Borna virus is associated with mental disorders in humans was evaluated
by examining serum samples from 979 psychiatric patients and 200 normal
volunteers for the presence of Borna virus-specific antibodies. Antibodies were
detected by the indirect immunofluorescence focus assay. Antibodies to the virus
were demonstrated in 16 of the patients but none of the normal volunteers. The
patients with the positive serum samples were characterized by having histories
of affective disorders, particularly of a cyclic nature. Further studies are
needed to define the possible involvement of Borna virus in human psychiatric
disturbances.
PMID: 3922055 [PubMed - indexed for MEDLINE]