Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial.

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.

Mercury-reactive lymphocytes in peripheral blood are not a marker for dental amalgam associated disease.

OBJECTIVES: The popular press and publications associated with alternative medicine increasingly report that chronic ill health, particularly myalgic encephalitis like conditions, are associated with mercury amalgam fillings. There are no scientifically proven definitive tests to support these claims. One of the more scientific tests in vogue is to assess the level of blood-borne mercury-reactive lymphocytes and to conclude that patients with high levels have developed a hypersensitivity reaction to mercury. The objective of this study was to determine the diagnostic value of this test. METHODS: This study represents an open comparison of mercury-reactive lymphocyte levels in healthy control individuals with those in patients complaining of symptoms associated with adverse effects of dental metal amalgam fillings. The healthy control group consisted of 51 male and female individuals, aged between 12 and 82 years, with and without dental amalgam fillings. The patient group consisted of 70 male and female individuals, aged between 12 and 87 years, and with the exception of one patient, with three or more mercury amalgam fillings of more than 1 year's duration. In vitro lymphocyte responses to mercury, and to nickel, as an example of a metal commonly associated with hypersensitivity reactions, and to more conventional protein antigens were determined. RESULTS: In the blood of patients and controls, there were similar levels of specifically reactive lymphocytes to all of the in vitro stimulating agents, but there were significantly higher numbers of sub-normal and non-responders within the patient group. CONCLUSIONS: The incidence and quantity of mercury-reactive lymphocytes in the blood are not pathogenic markers of illness associated with dental metal amalgams, but may rather reflect exposure to mercury. The clinical relevance of the decreased in vitro lymphocyte responses in the patient group needs further investigation.

Immunological markers of frequently recurrent genital herpes simplex virus and their response to hypnotherapy: a pilot study.

Patients were recruited for hypnotherapy from a clinic for patients with frequently recurrent genital herpes simplex virus (rgHSV). Psychological and immunological parameters were measured 6 weeks prior to hypnotherapy and 6 weeks afterwards, during which time each patient kept a diary of symptoms of rgHSV. Following hypnotherapy there was a significant overall reduction in the number of reported episodes of rgHSV, accompanied by an increase in the numbers of CD3 and CD8 lymphocytes, which may represent a non specific effect of hypnosis. The improvers showed significant rises in natural killer (NK) cell counts, HSV specific lymphokine activated killer (LAK) activity, and reduced levels of anxiety when compared to non-improvers. NK cell numbers and HSV specific LAK activity may therefore be important in the reduction in rgHSV following hypnotherapy.

Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects.

OBJECTIVE: The authors' goal was to study the relationship between smoking status and clinical characteristics in schizophrenic patients. METHOD: Seventy-eight schizophrenic outpatients were assessed by a single rater using the Brief Psychiatric Rating Scale (BPRS), the Abnormal Involuntary Movement Scale, and the Simpson-Angus Scale for extrapyramidal symptoms. Current smokers (N = 58) were compared with nonsmokers (N = 20) on clinical variables by independent t tests and chi-square tests. Differences in outcome variables were tested by multiple analysis of covariance (ANCOVA) with smoking status and gender as factors and age, neuroleptic dose, and caffeine consumption as covariates. RESULTS: Seventy-four percent of patients were current smokers and reported a mean of 19 cigarettes smoked per day. Compared to nonsmokers, current smokers were significantly more likely to be men, to be younger, and to have had an earlier age at onset and a greater number of previous hospitalizations. Current smokers and nonsmokers received mean neuroleptic doses of 1160 and 542 mg/day (chlorpromazine equivalents); the difference was significant. Current smokers also displayed significantly less parkinsonism and more akathisia and had higher total scores on the BPRS. Overall multiple ANCOVA demonstrated a significant main effect for smoking status but not gender or the interaction between gender and smoking status. Univariate ANCOVAs demonstrated a significant main effect of smoking status only for the Simpson-Angus Scale score. CONCLUSIONS: Cigarette smokers receive significantly higher neuroleptic doses, in part because of a smoking-induced increase in neuroleptic metabolism. Smoking is also associated with significant reduction in levels of parkinsonism. Smoking status is a significant factor that should be considered in assessment of neuroleptic dose requirements and neuroleptic side effects.

Immunogenicity in guinea pigs and tolerance in grass pollen-sensitive volunteers of enteric-coated grass pollen allergens.

An acid-insoluble, methacrylic acid, methyl methacrylate copolymer (Eudragit L-100) was used to give an enteric coating to a grass pollen extract in order to protect it against gastric degradation. Substantial protection against the degradative effects of simulated gastric secretion was demonstrated using this preparation which was well tolerated by grass pollen-allergic volunteers. The enteric-coated allergen induced a greater secondary antibody response than did an aqueous presentation when administered orally to guinea pigs which had been primed previously by subcutaneous injection. This result indicates that an effective hyposensitisation regimen could consist of a short series of initial parenteral injections, followed by an oral course of the protected allergen.

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. IV. Suppressive activities in established IgE model systems.

Conjugates of poly-N-methylglycine (polysarcosine) and grass pollen extracts, previously found to be capable of suppressing immature IgE antibody responses in mice, were shown to be highly effective at inhibiting the capacity of immune splenocytes to produce a secondary response in sub-lethally irradiated recipient animals. Anamnestic IgE responses in mice primed without adjuvant were also suppressed, but the effects were modest and of short duration. The predictive value of murine models for selecting clinically appropriate specific IgE suppressive agents and treatment schedules that might be successfully employed for clinical use are discussed.

Antibody responses of mice to intragastric and parenterally administered aeroallergens.

Intragastric administration of aeroallergens (pollen extract)-primed mice to produce transient serum IgE antibody responses following subsequent parenteral stimulation while the same initial dose of extract, given parenterally, did not have this effect. In previously immunized animals, intragastric administration of pollen extract was found to enhance systemic antibody production. These observations indicate that exposure of gut-associated lymphoid tissue to aeroallergens can have a profound effect on subsequent reaginic antibody production. This procedure provides a useful model for studying IgE responses to allergens without the complication of an initial injection with adjuvant. A combination of parenteral immunization with oral administration may therefore offer a convenient immunotherapeutic manoeuvre for patients with seasonal rhinitis/asthma.

Differential suppressive influence of intranasal application of rye grass pollen extract on IgE antibody production in the mouse.

Serum antibody responses to a ubiquitous aero-allergen, rye grass pollen extract, have been monitored in BALB/c and BD1 mice following intranasal and parenteral administration. Parenteral treatments were shown to trigger antibody production while topical administration of low doses of allergen extract preferentially suppressed reaginic antibody production. However, higher doses of extract administered to the respiratory tract were found to induce the formation of IgE antibody. Thus in mice antigen administered intranasally can influence the immune response in a qualitatively different manner to parenteral exposure.

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. II. Suppressive activities in adjuvant-induced IgE responses.

Treatment with conjugates of polysarcosine and grass pollen allergen extracts efficiently suppressed the induction of IgE responses in mice. The suppressive activity was shown to be allergen-specific and required covalent linking of the polysarcosine. Inhibitory effects could be overcome by booster injections of native allergen when these were given 3-4 weeks after treatment with conjugates. Administration of conjugates had only marginal effects on established IgE responses. The variance of these results with those of other studies on IgE suppression and the suitability of murine models for investigating reaginic antibody suppression are discussed.

Antibody response profiles to components of rye grass pollen extract in various strains of mice.

Using a combination of immunoprecipitation and polyacrylamide gel electrophoresis techniques, patterns of antibody responses to a number of components in rye pollen extract have been studied in hyperimmune mouse sera. Common laboratory strains of mice were investigated, including AKR, C3H/He, SwR, Ist, Asn, Balb/c, C57BL10, DBA2 and BD1:F1 hybrids. All strains responded vigorously to the immunisation protocol used (rye pollen extract/alum followed by a booster dose in aqueous media) when tested with non-discriminating assay procedures such as haemagglutination or passive cutaneous anaphylaxis directed against the whole rye pollen extract. However, markedly variable antibody responses were observed between strains and between murine and human sera when considered in relation to individual rye extract components. Particularly noteworthy was the relatively poor response of all mice to the low molecular weight rye antigen component (11,000 daltons). This material was readily detected by human sera derived from pollenosis patients. Notable also was the fact that no single rye component was detected by all mice sera. These results illustrate the complex serological response induced by heterogeneous antigen mixtures, such as grass pollen extracts.