Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions.

Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, we perform specialised transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.

Peripheral ProBDNF Delivered by an AAV Vector to the Muscle Triggers Depression-Like Behaviours in Mice.

Major depression is a leading cause of morbidity and disease burden in modern society. Current drug treatment is only effective in a fraction of patients as underlying mechanisms of depression are not fully understood. ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and its receptor p75NTR are highly upregulated in patients with major depression and in animal models of depression induced by chronic stress. Here, we hypothesise that proBDNF may be a pathogenic factor triggering depression. C57BL/6 mice were injected in the bilateral gluteus maximus muscle with AAV-proBDNF or AAV-EGFP. Four weeks after the injection, AAV-proBDNF injected animals developed depression-like behaviours, which were evident for 4-8 weeks and then returned to the control level after 12 weeks. In the second experiment, mice were divided into three groups; one group was treated with sheep anti-proBDNF antibody after AAV-proBDNF injection whereas the other two groups received PBS injection after the AAV-proBDNF or AAV-EGFP delivery. The group that was injected with AAV-proBDNF showed a time-dependent increase in immobility time in the tail suspension test and forced swim test, reduced sucrose consumption and decreased grooming time after sucrose spraying. Treatment with sheep anti-proBDNF antibody alleviated the depressive-like symptoms. Peripheral AAV-proBDNF delivery also resulted in a reduction of density and length of dendritic spines in the dentate gyrus and amygdala. Thus, we conclude that peripheral proBDNF is a primary pathogenic factor triggering depression-like behavioural changes in mice likely by reducing dendritic spine plasticity.

A model of human endogenous retrovirus (HERV) activation in mental health and illness.

Despite strong evidence for the heritability of major depressive disorder (MDD), efforts to identify causal genes have been disappointing. Furthermore, although there is strong support for life stress as a major predictor of MDD, there are also considerable individual differences in susceptibility and resilience that remain poorly understood. Efforts to identify specific gene-by-environment risk factors produced results that were initially encouraging, but that were not supported by later large-scale studies. Here I propose a novel mechanism that could address the "missing heritability" of MDD, the role of environmental risk factors, and individual differences in susceptibility and resilience. This mechanism focuses on a class of transposable elements, Human Endogenous Retroviruses (HERVs), which make up approximately 8% of the human genome as the result of ancient retroviral infections that entered mammalian germ lines throughout the course of evolution. My primary hypothesis is that exposure to either exogenous viruses or traumatic experiences can activate HERVs in the brain to cause depressive (and possibly other psychiatric) symptoms. My secondary hypothesis is that individual differences in vulnerability or resilience result from the balance of activated HERVs with pathogenic versus protective functions in the brain. Future research can test these hypotheses by analysis of postmortem human brain tissue from donors with known viral or trauma histories; animal studies manipulating HERV expression; cell culture studies examining regulatory mechanisms of HERV expression; and from brain imaging studies of individuals with known HERV-expression. Such research may reveal novel functions of HERVs in neural tissue and may lead to a new generation of psychiatric interventions designed to target aberrant HERV activation.

Co-infection with HIV associated with reduced vulnerability to symptoms of depression during antiviral treatment for hepatitis C.

In this prospective study, we examined new-onset major depressive disorder (MDD) and the differential expression of depressive symptoms in a sample of 132 HCV mono-infected and 40 HIV/HCV co-infected patients initiating pegylated interferon-based treatment, including protease inhibitor therapy. The semi-structured clinical interview (SCID-I) was used to assess MDD. Severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Of the total sample, 60 patients (34.9%) developed SCID-I defined MDD during antiviral treatment. The proportion of HCV mono- and HIV/HCV patients developing MDD during treatment was not significantly different (37.9% vs. 25%; p=0.185). In both groups, there was a significant increase in HAMD total score from baseline to week 4, and a significant decrease between week 24 and 6 months post-treatment cessation. The greatest increase was observed in the symptoms of the neurovegetative syndrome. HCV mono-infected patients reported higher scores than co-infected patients, particularly impaired activity and somatic symptoms, but the differences were only significant at week 12. The finding that co-infected patients appear less vulnerable to the development of depressive symptoms during HCV treatment than HCV mono-infected patients warrants further exploration, including a thorough analysis of the biological and psychosocial factors associated with this emergence.

Predictors of depression recovery in HIV-infected individuals managed through measurement-based care in infectious disease clinics.

BACKGROUND: Treatment of comorbid chronic disease, such as depression, in people living with HIV/AIDS (PLWHA) increasingly falls to HIV treatment providers. Guidance in who will best respond to depression treatment and which patient-centered symptoms are best to target is limited. METHODS: Bivariable analyses were used to calculate hazard ratios for associations between baseline demographic, mental health-related, and HIV-related factors on time to first depression remission among PLWHA enrolled in a randomized trial of measurement-based antidepressant management. Time-updated factors also were analyzed at time of antidepressant (AD) initiation/adjustment and 8 weeks post AD initiation/adjustment. RESULTS: Baseline comorbid depression and anxiety; comorbid depression, anxiety and substance abuse; and generalized anxiety disorder predicted a slower time to first remission. Being on ART but non-adherent, having panic disorder, having a history of a major depressive episode, or having been in HIV care for >10 years prior to study initiation predicted a faster time to first remission. Sleep difficulty or fatigue at the time of AD initiation/adjustment predicted a slower time to remission. In non-remitters at 8 weeks post AD initiation/adjustment, sleep difficulty, anxiety, and fatigue each predicted a slower time to remission. LIMITATIONS: Remission was determined by PHQ-9 scores, not diagnostic criteria. The results may apply only to depression recovery in this particular model of treatment. We conducted only exploratory analyses to determine magnitude of effects. CONCLUSIONS: Baseline comorbid anxiety with or without substance abuse predicts slower time to depression remission among PLWHA treated in HIV clinics. Targeting anxiety or fatigue at the time of AD initiation/adjustment or sleep difficulty, anxiety, and fatigue at 8 weeks post AD initiation/adjustment could shorten time to depression remission in this model.

The role of depression chronicity and recurrence on neurocognitive dysfunctions in HIV-infected adults.

Research assessing whether major depressive disorders (MDD) impacts neurocognitive functions in HIV+ persons has yielded inconsistent results. However, none have considered the role of MDD remission, chronicity, and stability on treatment. Ninety-five HIV+ adults clinically stable on combined antiretroviral treatment completed a psychiatric interview, a depression scale, a neuropsychological, daily living, and cognitive complaints assessments at baseline and 18 months. Participants were screened for current (within 12 months of study entry) alcohol and/or substance use disorder. History of alcohol and/or substance abuse disorder prior to the 12 months entry screen and MDD treatments were recorded. Participants were grouped into two psychiatric nomenclatures: (1) lifetime: no MD episode (MDE), single MDE life-event treated and fully remitted, chronic MDD treated and stable, chronic MDD treated and unstable, and baseline untreated MDE; (2) recent: last 2 years MDE (yes or no). We found that lifetime and recent psychiatric history were more strongly associated with decreased in independence in daily living and cognitive complaints than with baseline neuropsychological performance. However, lack of full remission, instability on treatment in chronic MDD, and severity of symptoms in current MDE were factors in whether MDD impacted baseline neuropsychological performance. Depressive symptoms improved at follow-up in those with baseline moderate-severe symptoms, and MDD was not associated with neurocognitive change at 18 months. A history of alcohol and/or substance abuse disorder was significantly more frequent in those with treated and unstable chronic MDD but it was not associated with neuropsychological performance. MDD recurrence, chronicity profiles, and associated comorbidities are keys factors to understand any potential impact on neurocognitive abilities in HIV infection. More comprehensive consideration of these complex effects could serve at constructively updating the HAND diagnostic criteria.

The risk of new onset depression in association with influenza--A population-based observational study.

IMPORTANCE: Case-reports provided evidence that influenza infections, particularly severe episodes, may exert neuronal damage in the CNS and thereby increase the risk of depression. OBJECTIVE: It was the aim of this study to analyse the association between influenza infections and the risk of developing incident depression. DESIGN: We conducted a case-control analysis between 2000 and 2013 using the large UK-based primary care database Clinical Practice Research Datalink (CPRD). SETTING: This database contains anonymous longitudinal data from primary care. At present, it contains over 100 million person-years of data from some 10 million active patients. PARTICIPANTS: We encompassed 103307 patients below the age of 80 years with an incident major depression diagnosis between 2000 and 2013, and matched each case to one control patient on age, sex, general practice, number of medical encounters, and years of history in the CPRD prior to the index date. EXPOSURE: Major depression diagnosis was identified by READ-codes based on ICD-10 codes (F32), with a minimum of three prescriptions for antidepressant drugs recorded after the diagnosis. MAIN OUTCOME: We calculated relative risk estimates of developing depression in association with previous influenza infections, stratified by the number, timing and severity of such events, and we adjusted for a variety of comorbidities, smoking status, alcohol intake, body mass index, use of oral corticosteroids, and benzodiazepines. RESULTS: Patients with a previous influenza infection had an increased risk of developing depression (OR 1.30, 95%CI 1.25-1.34) compared to patients with no history of influenza infections. A recent influenza infection recorded within 30-180 days prior to the index date yielded an adjusted 1.57 (95%CI 1.36-1.81), and an increasing number of previous influenza infections was associated with increasing odds ratios (⩾ 3 recorded influenza infections, adjusted OR 1.48, 95%CI 1.22-1.81). CONCLUSION: This study suggests that influenza infections are associated with a moderately increased risk of developing depression.

Health care professionals at risk of infection with Borna disease virus - evidence from a large hospital in China (Chongqing).

BACKGROUND: Human Borna disease virus (BDV) infections have recently been reported in China. BDV causes cognitive and behavioural disturbances in animals. The impact on human mental disorders is subject to debate, but previous studies worldwide have found neuropsychiatric patients more frequently infected than healthy controls. A few isolates were recovered from severely depressed patients, but contagiousness of BDV strain remains unknown. METHOD: We addressed the risk of infection in health care settings at the first affiliated hospital of Chongqing Medical University (CQMU), located in downtown Chongqing, a megacity in Southwest China. Between February 2012 and March 2013, we enrolled 1529 participants, of whom 534 were outpatients with major depressive disorder (MDD), 615 were hospital personnel, and 380 were healthy controls who underwent a health check. Infection was determined through BDV-specific circulating immune complexes (CIC), RNA, and selective antibodies (blood). RESULTS: One-fifth of the hospital staff (21.8%) were found to be infected (CIC positive), with the highest prevalence among psychiatry and oncology personnel, which is twice as many as were detected in the healthy control group (11.1%), and exceeds the prevalence detected in MDD patients (18.2%). CONCLUSION: BDV circulates unnoticed in hospital settings in China, putting medical staff at risk and warranting clarification of infection modes and introduction of prevention measures.

Herpesviruses, inflammatory markers and incident depression in a longitudinal study of Detroit residents.

BACKGROUND: Depression is predicted to become the leading cause of disability worldwide by 2030 and moreover, socioeconomic inequalities in depression persist. Herpesviruses, which are more prevalent among socioeconomically disadvantaged populations, subject to stress-induced reactivation and are associated with increased levels of pro-inflammatory cytokines implicated in the etiology of depression, may serve as novel risk factors for depression onset. METHODS: Data are from individuals in the Detroit Neighborhood Health Study tested for herpes simplex virus-1 (HSV-1) and cytomegalovirus (CMV) seropositivity/immunoglobulin G (IgG) antibody levels (N=263) as well as interleukin-6 (IL-6) (N=245) and C-reactive protein (CRP) (N=236) levels and assessed for incident depression via the Patient Health Questionnaire-9. Linear and logistic regression models were used to examine associations between pathogen seropositivity/IgG antibody levels, pro-inflammatory markers and incident depression over approximately one-year of follow-up. RESULTS: For every one unit increase in CMV IgG antibody level, the odds of incident depression increased by 26% and individuals with IgG antibody levels in the highest quartile had over three times greater odds of incident depression (odds ratio 3.87, 95% confidence interval 1.47, 10.19), compared to those in the lower three quartiles. Neither CMV or HSV-1 seropositivity nor HSV-1 IgG antibody level were associated with IL-6 or CRP levels at Wave 1, nor were IL-6 or CRP levels associated with incident depression at Wave 2. CONCLUSIONS: Further examination of the biological pathways linking CMV and depression are warranted.

Varicella zoster virus-specific immune responses to a herpes zoster vaccine in elderly recipients with major depression and the impact of antidepressant medications.

BACKGROUND: The Depression Substudy of the Shingles Prevention Study (SPS) was designed to evaluate the association between major depression and immune responses to a high-titer live attenuated varicella zoster virus (VZV) vaccine (zoster vaccine), which boosts cell-mediated immunity (CMI) to VZV and decreases the incidence and severity of herpes zoster (HZ). The Depression Substudy was a 2-year longitudinal cohort study in 92 community-dwelling adults≥60 years of age who were enrolled in the SPS, a large, double-blind, placebo-controlled Veterans Affairs Cooperative zoster vaccine efficacy study. METHODS: Forty subjects with major depressive disorder, stratified by use of antidepressant medications, and 52 age- and sex-matched controls with no history of depression or other mental illness had their VZV-CMI measured prior to vaccination with zoster vaccine or placebo and at 6 weeks, 1 year, and 2 years postvaccination. RESULTS: Depressed subjects who were not treated with antidepressant medications had lower levels of VZV-CMI following administration of zoster vaccine than nondepressed controls or depressed subjects receiving antidepressants even when antidepressant medications failed to alter depressive symptom severity (P<.005). Similar results were obtained taking into account the time-varying status of depression and use of antidepressant medications, as well as changes in depressive symptoms, during the postvaccination period. CONCLUSIONS: Depressed patients have diminished VZV-CMI responses to zoster vaccine, and treatment with antidepressant medication is associated with normalization of these responses. Because higher levels of VZV-CMI correlate with lower risk and severity of HZ, untreated depression may increase the risk and severity of HZ and reduce the efficacy of zoster vaccine.

Major depressive disorder, cognitive symptoms, and neuropsychological performance among ethnically diverse HIV+ men and women.

Major depressive disorder (MDD), cognitive symptoms, and mild cognitive deficits commonly occur in HIV-infected individuals, despite highly active antiretroviral therapies. In this study, we compared neuropsychological performance and cognitive symptoms of 191 HIV-infected participants. Results indicated that participants with a formal diagnosis of current MDD performed significantly worse than participants without MDD in all seven neuropsychological domains evaluated, with the largest effect sizes in information processing speed, learning, and memory. In addition, a brief assessment of cognitive symptoms, derived from a comprehensive neuromedical interview, correlated significantly with neurocognitive functioning. Participants with MDD reported more cognitive symptoms and showed greater neurocognitive deficits than participants without MDD. These findings indicate that HIV-infected adults with MDD have more cognitive symptoms and worse neuropsychological performance than HIV-infected individuals without MDD. The results of this study have important implications for the diagnosis of HIV-associated neurocognitive disorders (HAND).

Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts.

BACKGROUND: Anecdotal reports of mood disorder following infection with common respiratory viruses with neurotropic potential have been in existence since the last century. Nevertheless, systematic studies on the association between these viruses and mood disorders are lacking. METHODS: Influenza A, B and coronavirus antibody titers were measured in 257 subjects with recurrent unipolar and bipolar disorder and healthy controls, by SCID. Pearson's χ² tests and logistic regression models were used to analyze associations between seropositivity for coronaviruses, influenza A and B viruses and the following: a) history of recurrent mood disorders b) having attempted suicide in the past c) uni- vs. bi-polarity and d) presence of psychotic symptoms during mood episodes. RESULTS: Seropositivity for influenza A (p=0.004), B (p<0.0001) and coronaviruses (p<0.0001) were associated with history of mood disorders but not with the specific diagnosis of unipolar or bipolar depression. Seropositivity for influenza B was significantly associated with a history of suicide attempt (p=0.001) and history of psychotic symptoms (p=0.005). LIMITATIONS: The design was cross-sectional. Socioeconomic factors, inflammatory markers, and axis II psychopathology were not assessed. CONCLUSIONS: The association of seropositivity for influenza and coronaviruses with a history of mood disorders, and influenza B with suicidal behavior require replication in larger longitudinal samples. The need for these studies is additionally supported by the high incidence of these viral infections, the high prevalence of mood disorders, and resilience of suicide epidemics.

Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus-infected individuals.

Major depressive disorder (MDD) is a significant cause of morbidity in people living with the human immunodeficiency virus (HIV). FKBP5 is a candidate gene with single-nucleotide polymorphisms (SNPs) rs1360780 and rs3800373 associated with MDD. This gene product and its relative, FKBP4, physically associate with the glucocorticoid receptor whose function is implicated in MDD pathophysiology. Because these genes are expressed in blood and brain and elevated in HIV infection, we explored the relationship between gene expression, genotype, and MDD symptoms. Longitudinally followed subjects (N = 57) as part of the CNS HIV AntiRetroviral Effects Research study, with diagnosed MDD and who donated blood for genotyping and gene expression analysis, were assessed. Subjects donated blood on adjacent visits with and without meeting criteria for MDD episode. Changes in clinical parameters were compared changes in gene expression. Change in FKBP5 expression correlated with change in Beck Depression Inventory (BDI) for MDD → euthymic comparison in GG genotype of rs3800373 (P = .013) and TT carriers of rs1360780 (P = .02). In euthymic → MDD comparison, GG homozygous, FKBP5 expression correlated with more severe change in BDI. Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373.

No association between prenatal viral infection and depression in later life--a long-term cohort study of 6152 subjects.

OBJECTIVE: Previous studies have suggested a role for prenatal viral infections in the etiology of schizophrenia; however, little is known about depression. We examined whether in-utero viral infections result in increased risk of depression in later life. METHOD: We identified a cohort (n = 3076) born between 1946 and 1980, whose mothers suffered known viral infections in pregnancy. Subjects were individually matched by birthdate, sex, and area of birth to another cohort (n = 3076) from the UK National Health Service Central Register (NHSCR). These 2 cohorts, one exposed to viruses prenatally, the other not known to have been exposed, were then followed-up to June 1996 by sending a morbidity questionnaire to their primary care physicians. This included specific items on affective disorders, schizophrenia, mental handicap (mental retardation), epilepsy, as well as other central nervous system disorders and specified physical illness, all coded according to the International Classification of Diseases, Ninth Edition. Death certificates were supplied by the NHSCR. A method for matched-pair cohort data calculated the relative risk and 95% confidence intervals for depression in the exposed and unexposed cohorts by varying type of viral exposure. RESULTS: The response to the questionnaire was high (85%). There was no overall increased risk for depression associated with viral exposure; a narrow confidence interval surrounded unity (RR = 1.0, 95% CI 0.8 to 1.2); effects for individual viral exposures were all scattered around unity. CONCLUSIONS: The results provide no support for the hypothesis that in-utero exposure to viral infection is associated with risk of subsequent nonpsychotic affective disorder. Further analyses on schizophrenia, bipolar disorder, and mental illness other than depression are required.

Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.

BACKGROUND: Whether antidepressants prevent depression during interferon-alpha/ribavirin treatment for hepatitis C virus infection has yet to be established. AIM: To investigate the use of paroxetine in a prospective, double-blind, placebo-controlled study for this indication. METHODS: Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: Rates of major depression during the study were low (17%) and did not differ between groups. Nevertheless, using published MADRS cut-off scores, the percent of subjects who met criteria for mild, moderate or severe depression during interferon-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher's exact test). Assignment to paroxetine was also associated with significantly reduced depressive symptom severity. This effect was largely accounted for by participants with depression scores above the median (MADRS > 3) at baseline in whom paroxetine was associated with a maximal reduction in MADRS scores of 10.3 (95% CI: 2.1-18.5) compared with placebo at 20 weeks (P < 0.01). Study limitations included a small sample size and high drop-out rate. CONCLUSION: This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.

[Hepatitis C viral infection and depression]. / Hepatitis C vírusfertozés és depresszió.

About 170 million individuals can be found with chronic hepatitis C viral infection all over the world. The occurrence of depression is more frequent among the persons than in the healthy population, this depression can be found in 58 per cent of patients with chronic hepatitis C. On the basis of the literature the authors review the aetiology of depression in liver diseases, examining the neuropathogenic effect of HCV. They demonstrate the scientific results which are evidences of hepatitis C viral infection for the alterations in the central nerve system. The depression is one of the side effects of the alpha-interferon treatment used in the therapy of HCV. The authors demonstrate the biological basis, development, consequences of depression produced by interferon and they give a review of the protocol in the diagnostic procedure of a patient with depression. They summarize the steps of psychiatric drug therapy in chronic liver diseases. That is also important whether the chronic HCV infected patient with depression can be treated with interferon. The loss of interferon treatment can lead to the fatal outcome of liver disease. In order to have the correct decision a collaboration between internist and psychiatric specialist is necessary.