Double blind trial of adjunctive valacyclovir in individuals with schizophrenia who are seropositive for cytomegalovirus.

OBJECTIVE: To investigate if adjunctive valacyclovir, an antiviral medication, reduces symptoms of persistent schizophrenia in individuals who are seropositive for cytomegalovirus (CMV). METHOD: N=47 CMV seropositive schizophrenia outpatients were randomly assigned to receive valacyclovir 1 g twice daily (n=24) or placebo (n=23) for 16 weeks after a 2-week placebo run-in. Symptoms were assessed biweekly. RESULTS: There was no significant difference in the change of positive, negative, general, or total PANSS symptoms between the valacyclovir vs. the placebo group. CONCLUSIONS: The study did not demonstrate benefit of adjunctive valacyclovir for schizophrenia individuals with persistent symptoms who are CMV seropositive.

Predictors of occupational status six months after hospitalization in persons with a recent onset of psychosis.

Participation in work or school activity is an important aspect of social functioning in individuals with a recent onset of psychosis. We measured the predictors of occupational status 6 months following hospitalization in a sample of 71 adults with recent onset affective or non-affective psychosis. At baseline, participants were evaluated with cognitive measures including the Wisconsin Card Sorting Test, symptom rating scales, the Modified Vocational Index to assess occupational status, and other clinical and demographic measures. At follow-up, occupational status was re-assessed and categorized as whether or not the patient had any current work or school activity. Results of a backwards stepwise logistic regression examining occupational status at follow-up yielded a significant model with the following independent predictors: a higher baseline level of cognitive functioning as measured by performance on the Wisconsin Card Sorting Test lower level of baseline depression as measured by the Calgary Depression Scale; and better socioeconomic status as measured by level of maternal education. Cognitive functioning, but not psychosis severity, is a significant independent predictor of occupational status early in the course of psychotic illness.

The catechol O-methyltransferase Val158Met polymorphism is not associated with broad-based cognitive functioning in schizophrenia.

BACKGROUND: A valine/methionine polymorphism of the catechol O-methyltransferase gene at the nucleotide which encodes amino acid val or met at position 158 in the protein (COMT Val158Met polymorphism) has been associated with deficits in executive functioning in schizophrenia in some studies. The association between the COMT polymorphism and other cognitive domains has been the focus of only limited investigation. METHODS: We measured COMT Val158Met genotypes in N=364 individuals with schizophrenia. Cognitive functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We employed univariate and multivariate analyses of variance to determine the association between COMT genotypes and the RBANS index and individual test scores. RESULTS: There was no significant association between the COMT Val158Met genotypes and any of the RBANS index or individual test scores measured in either univariate or multivariate analyses (all p>.3). CONCLUSION: Based on the results in our sample, the catechol O-methyltransferase Val158Met polymorphism is not associated with broad-based cognitive functioning in schizophrenia.

The association between cognitive functioning and occupational status in persons with a recent onset of psychosis.

The ability to engage in occupational activity is an important aspect of functioning in individuals with recent onset psychosis. We measured the determinants of occupational status in a sample of n = 86 adults with a recent onset of affective or nonaffective psychosis. Participants were evaluated with the Repeatable Battery of Neuropsychological Status, the Wisconsin Card Sorting Test, symptom rating scales, and other clinical and demographic measures. Results of a discriminant function analysis indicated that the most significant differences between those who worked or attended school and those who did not could be attributed to better immediate verbal memory (F = 13.16, p < .0005) and the absence of substance abuse (F = 5.17, p = .026). Occupational activity was not significantly associated with age, gender, race, or symptom severity in this population. Cognitive assessments may prove useful to identify recent onset patients who are most at risk for occupational impairment and who could most benefit from therapeutic interventions.

C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia.

OBJECTIVES: We investigated the association between serum levels of C-reactive protein (CRP), a marker of inflammation, and the severity of psychopathology and cognitive impairment in schizophrenia. METHODS: We measured the levels of CRP in N=413 individuals with schizophrenia. Symptom severity was evaluated with the Positive and Negative Syndrome Scale (PANSS) and cognitive functioning with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: The individuals with CRP >or=5.0 mg/microl had significantly lower RBANS cognitive scores than those with CRP <5.0 mg/microl (F=8.07, p<.005). However the CRP groups did not differ in the severity of positive, negative, or general PANSS symptoms (all p>.2). CONCLUSIONS: Elevated serum levels of C-reactive protein in schizophrenia are associated with the severity of cognitive impairment but not of psychiatric symptoms. The long term consequences of elevated levels of CRP require further investigation.

Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder.

OBJECTIVES: We investigated the association between serum levels of C-reactive protein (CRP), a marker of inflammation, and the severity of psychopathology in outpatients with bipolar disorder. We also compared the levels of CRP in the bipolar disorder individuals with those of a non-psychiatric control group. METHODS: We measured the level of CRP in N=122 outpatients with bipolar disorder and N=165 control individuals and evaluated the symptom severity of the bipolar disorder patients with the Young Mania Rating Scale (YMRS) and the Hamilton Depression Scale (Ham-D). RESULTS: Within the bipolar disorder sample, CRP was significantly associated with the YMRS score (r=.306, p<.006), age of onset, gender, and race. CRP was not significantly associated with the Ham-D score or other clinical or demographic variables. In a multivariate analysis of covariance, CRP was the only independent predictor of YMRS score (F=11.7, p=.0009). The CRP levels of the n=41 individuals with YMRS >6 were significantly greater than the levels of the n=81 individuals with YMRS 6 were also significantly greater than the levels of the control group (p=.033) while the CRP levels of the group with YMRS .05). CONCLUSIONS: Our results suggest that outpatients with bipolar disorder with mania symptoms have increased levels of CRP as compared to those without mania symptoms and compared to individuals without psychiatric disorders. The long-term consequences of CRP in bipolar disorder should be the subject of future studies.

Toxoplasma gondii in individuals with schizophrenia: association with clinical and demographic factors and with mortality.

BACKGROUND: Increased rates of exposure to Toxoplasma gondii have been found in individuals with schizophrenia as compared with control groups, but the correlates of Toxoplasma exposure in schizophrenia have not been defined. METHODS: We measured IgG class antibodies to Toxoplasma gondii in 358 individuals with schizophrenia. We correlated Toxoplasma antibody status with clinical and demographic variables and examined the effect of Toxoplasma seropositivity on mortality in a follow-up period of up to 5 years. RESULTS: Individuals with schizophrenia who had serological evidence of Toxoplasma infection were more likely to be female but did not differ in age, race, total symptom score, or other demographic or clinical characteristics. However, we found that serological evidence of Toxoplasma was associated with a significantly increased risk of dying of natural causes during the follow-up period (Cox proportional hazard ratio of 4.70; 95% confidence interval, 1.27-17.31, P = .020) adjusted for age, gender, and other clinical and demographic variables. CONCLUSIONS: Toxoplasma infection may confer an increased risk for mortality from natural causes in schizophrenia. An understanding of the pathogenesis of Toxoplasma infections in individuals with schizophrenia might lead to new approaches to the management of this disorder.

The lymphotoxin Cys13Arg polymorphism and cognitive functioning in individuals with schizophrenia.

Genetic factors that modulate the immune response have been implicated as risk factors for schizophrenia and cognitive impairment. We assessed the correlation between cognitive functioning and the LTA Cys13Arg polymorphism in 351 individuals with schizophrenia, 122 with bipolar disorder, and 160 controls. There was a significant association between cognitive functioning and the LTA Cys13Arg polymorphism within the schizophrenia (p<0.008) but not the other diagnostic groups. There was no association between cognitive functioning and the two other polymorphisms in the same gene complex. The LTA Cys13Arg polymorphism may represent a risk factor for cognitive impairment in individuals with schizophrenia.

The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder.

BACKGROUND: Bipolar disorder is associated with deficits in cognitive functioning. The etiology of cognitive impairment in bipolar disorder may relate to both genetic and environmental factors. A valine/methionine polymorphism of the catechol O-methyltransferase gene at amino acid 158 (COMT Val158Met polymorphism) has been identified as a risk factor for cognitive impairment in schizophrenia. Serological evidence of infection with herpes simplex virus type 1 (HSV-1) has also been identified as a risk factor for cognitive impairment in bipolar disorder. METHODS: We used Taqman technology to measure COMT Val158Met alleles in 107 individuals with bipolar disorder and in 95 controls. We also measured antibodies to HSV-1 in sera obtained from the same individuals. Cognitive functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and the Letter-Number Sequencing Test. The effects of the COMT Val158Met polymorphism and antibodies to HSV-1 on cognitive functioning were analyzed with multinomial logistic regressions. RESULTS: The COMT Val158Val genotype and serological evidence of infection with HSV-1 are independent risk factors for cognitive impairment in individuals with bipolar disorder, particularly in the domains of immediate and delayed memory. Individuals with bipolar disorder with the COMT158 Val/Val genotype and serological evidence of HSV-1 infection were more than 85 times more likely to be in the lowest quintile of cognitive functioning when compared with the highest quintile when controlling for potential confounding variables such as symptom severity and education. Control individuals did not display this association. CONCLUSION: Both the COMT Val158Met polymorphism and serological evidence of HSV-1 infection affect cognitive functioning in individuals with bipolar disorder.

Deficit schizophrenia: association with serum antibodies to cytomegalovirus.

BACKGROUND: Patients with deficit schizophrenia differ from nondeficit patients with schizophrenia relative to several neurobiological correlates and relative to the risk factors of family history and season of birth. Exposure to human herpesviruses is a possible risk factor for schizophrenia. We hypothesized that there would be deficit/nondeficit difference in the prevalence of serum antibodies to human herpesviruses. METHODS: In deficit (N = 88) and nondeficit (N = 235) schizophrenia patients, we measured IgG class antibodies to the 6 known human herpesviruses: herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, Epstein-Barr virus, human herpes virus 6, and varicella-zoster virus. RESULTS: Deficit categorization was associated with the presence of serum antibodies to cytomegalovirus (odds ratio = 2.01, p = .006). This association remained significant after covarying for positive psychotic symptoms and demographic features known to be associated with cytomegalovirus seropositivity and after correcting for multiple comparisons. An association between herpes simplex virus type 1 and deficit status was not significant after covarying for potentially confounding variables. No other human herpesvirus was significantly associated with deficit versus nondeficit categorization. CONCLUSIONS: The association between deficit schizophrenia and cytomegalovirus antibody seropositivity provides further evidence for differences in etiopathophysiology between deficit and nondeficit schizophrenia.

Cognitive functioning in schizophrenia and bipolar disorder: comparison of performance on the Repeatable Battery for the Assessment of Neuropsychological Status.

Cognitive dysfunction is an important feature of schizophrenia and bipolar disorder. There is uncertainty about the relative magnitude of cognitive deficits in these disorders. We evaluated a total of 446 individuals: 229 with schizophrenia, 117 with bipolar disorder, and 100 controls without a history of psychiatric disorder. All participants were administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a cognitive screening battery that evaluated immediate verbal memory, visuospatial/constructional abilities, attention, language, and delayed memory. A comparison of the three groups showed significant differences on the RBANS total score and all of the measured domains. In all of the comparisons, the schizophrenia group obtained the lowest scores, followed by the bipolar disorder group, and then the individuals without psychiatric disorder. In an analysis of covariance of RBANS total scores with the patient samples, the difference between schizophrenia and bipolar disorder remained significant after controlling for a range of demographic and clinical variables. Both schizophrenia and bipolar disorder are associated with significant cognitive impairments, but those in schizophrenia are more severe. Cognitive deficits may be an appropriate target of treatment interventions in these disorders.

Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder.

BACKGROUND: In a previous investigation, we found an association between reduced cognitive functioning and the prevalence of antibodies to herpes simplex virus type 1 in individuals with schizophrenia. The current study was undertaken to determine if this association also occurs in individuals with bipolar disorder. METHODS: Cognitive functioning and serologic evidence of infection with potentially neurotropic herpesviruses were measured in 117 individuals with bipolar disorder and in 100 individuals without a history of psychiatric disorder. Cognitive functioning was evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status. For each patient, serologic evidence of infection was ascertained by the measurement of serum immunoglobulin G class antibodies with specificities for six potentially neurotropic human herpesviruses. The association between serologic evidence of herpesvirus infection and cognitive functioning was analyzed by univariate analyses, as well as multivariate analyses that included demographic and clinical factors associated with cognitive functioning. RESULTS: Serologic evidence of infection with herpes simplex virus type 1 was an independent predictor of decreased cognitive functioning in the individuals with bipolar disorder (F = 20.5, p <.0001). Discriminant function analysis indicated that most of the difference in cognitive functioning between individuals who were antibody positive and antibody negative for herpes simplex virus type 1 could be attributed to immediate verbal memory (F = 12.07, p <.001). There was no significant association between cognitive functioning and the other human herpesviruses. No association between antibodies to herpesviruses and cognitive functioning was found in the control individuals without a history of psychiatric disorder. CONCLUSIONS: Serologic evidence of herpes simplex virus type 1 infection is associated with cognitive impairment in individuals with bipolar disorder.

Association between cognitive functioning and employment status of persons with bipolar disorder.

OBJECTIVE: The purpose of this study was to identify variables associated with employment status among persons with bipolar disorder, including cognitive functioning, severity of symptoms, demographic variables, and variables related to course of illness. METHODS: The authors assessed the current employment status of 117 persons with bipolar disorder. Study participants' cognitive functioning was evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status, the information and letter-number sequencing subtests of the Wechsler Adult Intelligence Scale III, and part A of the Trail Making Test. Symptoms were rated by using the Brief Psychiatric Rating Scale, the Hamilton Depression Scale, and the Young Mania Rating Scale. A stepwise multivariate logistic regression analysis was used to predict employment status. RESULTS: Fifty-one percent of the study participants had no current work activity, 21 percent worked part-time or as volunteers, and 27 percent had full-time competitive employment. Current employment status was significantly associated with cognitive performance, especially immediate verbal memory, total symptom severity, history of psychiatric hospitalization, and maternal education. No association was found between employment status and history of psychotic symptoms, number of years of education, or age at onset of illness. CONCLUSIONS: Vocational programs for persons with bipolar disorder would benefit from inclusion of a formal cognitive assessment to better assess work potential and to study the predictors of work-related outcomes.

Reduction of symptoms by valacyclovir in cytomegalovirus-seropositive individuals with schizophrenia.

OBJECTIVE: The study was an investigation of the effect of the antiviral medication valacyclovir on the symptoms of outpatients with persistent schizophrenia. METHOD: Oral valacyclovir, 1 g twice daily, was administered to 65 outpatients over 16 weeks along with their usual psychiatric medications. Changes in psychiatric symptoms were measured with the Positive and Negative Syndrome Scale and were tested for correlations with antibodies to potentially neurotropic human herpesviruses, as measured by immunoassay before the start of the therapy. RESULTS: There was a significant improvement in the psychiatric symptoms of individuals who were seropositive for cytomegalovirus. Improvement was not associated with antibodies to other herpesviruses or to a range of demographic and clinical variables. CONCLUSIONS: The replication of cytomegalovirus may contribute to the symptoms of schizophrenia in some individuals.

Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia.

BACKGROUND: Cognitive deficits are a characteristic feature of schizophrenia and contribute to the profound disabilities associated with this illness. Some of the cognitive deficits that occur in individuals with schizophrenia are similar to those found in individuals who have recovered from central nervous system infections with human herpesviruses. METHODS: We measured cognitive functioning and serologic evidence of infection with human herpesviruses in 229 outpatients with schizophrenia. We evaluated cognitive functioning with the Repeatable Battery for the Assessment of Neuropsychological Status. For each patient, serum IgG class antibodies with specificities for the following potentially neurotropic human herpesviruses were measured by means of a solid-phase immunoassay: herpes simplex viruses 1 and 2, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and varicella-zoster virus. We determined the association between serologic evidence of herpesviruses infection and cognitive functioning by univariate and multivariate analyses, including demographic and clinical factors associated with cognitive functioning. RESULTS: We found that serologic evidence of infection with herpes simplex virus 1 is an independent predictor of cognitive dysfunction in individuals with schizophrenia. Discriminant function analysis indicated that much of the difference in cognitive functioning could be attributed to immediate memory. We found no significant association between cognitive dysfunction and serologic evidence of infection with other human herpesviruses. CONCLUSION: Serologic evidence of herpes simplex virus 1 infection is associated with cognitive impairment in schizophrenia.

Smoking, gender, and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder.

BACKGROUND: Prior reports of decreased levels of essential fatty acids among schizophrenic patients have generated several hypotheses proposing inherent abnormalities in phospholipid and fatty acid metabolism and have provided the basis for treatment trials; however, these essential fatty acid aberrations may be attributable to uncontrolled factors, such as smoking, rather than abnormalities inherent to schizophrenia. METHODS: Erythrocyte fatty acid compositions were quantified in 72 medicated schizophrenic or schizoaffective patients both at baseline and after 16 weeks of supplementation with 3 g/day of either ethyl-eicosapentaenoic acid or placebo. Current smoking status, gender, dietary survey, and Montgomery Asburg Depression Rating Scale, Repeatable Battery for the Assessment of Neuropsychological Status, Abnormal Involuntary Movement Scale, and Positive and Negative Syndrome Scale scores were assessed. RESULTS: Schizophrenic patients who smoked had lower baseline erythrocyte docosahexaenoic acid percent (2.98 +/-.7 vs. 3.59 +/- 1.2, p <.005) and eicosapentaenoic acid (EPA) percent (.39 +/-.13 vs. 47 +/-.22, p <.05), compared with nonsmokers, with a significant gender interaction (p <.01) in multivariate analyses of variance. Baseline arachidonic acid did not differ. Smokers reported lower dietary intake (percent total fat) of linolenic acid (F = 10.1, p <.003) compared with nonsmokers. Nonsmoking women reported greater dietary intake of EPA compared with smoking men or nonsmokers of either gender. CONCLUSIONS: Smoking status, gender, and dietary intake significantly predicted erythrocyte polyunsaturated fatty acid status among schizophrenic patients. No evidence was found for subgroups of schizophrenia or relationships to specific symptom severity on the basis of erythrocyte fatty acids. Prior reports of abnormalities of essential fatty acid metabolism among schizophrenic patients may have been an artifact of patients' smoking behavior and differences in dietary intake of omega-3 fatty acids.