<b>Importance: </b>More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation.<b>OBJECTIVES: </b>To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response.<b>DESIGN: </b>Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12.<b>SETTING: </b>Three community mental health centers affiliated with academic medical centers in the United States.<b>Participants: </b>Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale.<b>Intervention: </b>One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo.<b>MAIN OUTCOME MEASURES: </b>Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale).<b>RESULTS: </b>Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups.<b>CONCLUSIONS: </b>Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms.<b>Trial Registration: </b>clinicaltrials.gov Identifier: NCT00611806.
Membrane lipid metabolism and redox regulation may be disturbed in schizophrenia. We examined the clinical effect of adding an omega-3 fatty acid and/or vitamins E+C to antipsychotics. It was hypothesized that lower baseline levels of polyunsaturated fatty acids (PUFAs) would predict more benefit from the add-on treatment. The trial had a multicenter, randomized, double-blind, placebo-controlled 2 × 2 factorial design. Patients aged 18-39 years with schizophrenia or related psychoses were consecutively included at admission to psychiatric departments in Norway. They received active or placebo ethyl-eicosapentaenoate (EPA) 2 g day⁻¹ and active or placebo vitamin E 364 mg day⁻¹+vitamin C 1000 mg day⁻¹ (vitamins) for 16 weeks. The main outcome measures were Positive and Negative Syndrome Scale (PANSS) total and subscales scores, analyzed by linear mixed models. Ninety-nine patients were included. At baseline, erythrocyte PUFA were measured in 97 subjects. Given separately, EPA and vitamins increased drop-out rates, whereas when combined they did not differ from placebo. In low PUFA patients, EPA alone impaired the course of total PANSS (Cohen's d=0.29; P=0.03) and psychotic symptoms (d=0.40; P=0.003), especially persecutory delusions (d=0.48; P=0.0004). Vitamins alone impaired the course of psychotic symptoms (d= 0.37; P=0.005), especially persecutory delusions (d=0.47; P=0.0005). Adding vitamins to EPA neutralized the detrimental effect on psychosis (interaction d=0.31; P=0.02). In high PUFA patients, there were no significant effects of trial drugs on PANSS scales. In conclusion, given separately during an acute episode, EPA and vitamins E+C induce psychotic symptoms in patients with low levels of PUFA. Combined, these agents seem safe.
<b>BACKGROUND: </b>Folate deficiency and the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism have been linked to negative symptoms in schizophrenia both independently and synergistically. This study examined the effect of folate supplementation on negative symptoms overall and in relation to MTHFR 677C>T genotype.<b>METHOD: </b>Forty-six stable adult schizophrenia outpatients were enrolled and 32 were randomised, double-blind, in a parallel-group, twelve week add-on trial of folate 2mg/d or matching placebo. The primary outcome measure was change from baseline to week 12 on the modified SANS total score using a mixed-model analysis. In addition, we measured the effect of MTHFR genotype on treatment effects and on changes in serum folate by grouping participants with T/T genotype together with C/T genotype and comparing their interactions to patients with C/C genotype.<b>RESULTS: </b>Twenty-eight participants completed the trial. Folate supplementation did not significantly affect negative symptoms compared to placebo across the entire cohort. However, there was a significant genotype×treatment effect on negative symptoms (F=7.13, df=1,39, p=0.01). In addition, MTHFR status significantly moderated the relationship between change in serum folate and change in negative symptoms: among participants with at least one copy of the T allele negative symptoms were more likely to improve with increased serum folate (p=0.03).<b>CONCLUSION: </b>We did not detect a therapeutic benefit of folate supplementation in a sample of patients with residual negative symptoms. However, a possible association between genotypes associated with reduced MTHFR activity and benefit from folate supplementation should be investigated further.
Classical antipsychotics like haloperidol are suggested to increase oxidative stress and oxidative cell injury in the brain. Pro-oxidant effect of haloperidol may influence the course and treatment outcomes of schizophrenia. Dietary supplementation of either antioxidants or omega-3 fatty acids was found to improve symptoms of schizophrenia. Thus we decided to assess the impact of combining omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol. Ongoing haloperidol treatment of 17 schizophrenia patients was supplemented with 1000 mg capsule of omega-3 fatty acids (180 mg EPA+120 mg DHA) bid, vitamin E 400 IU bid and vitamin C 1000 mg/day. Patients were assessed with Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) over a 4 month period. Gluthatione peroxidase, superoxide dismutase, malondialdehyde, vitamin E and C levels were also evaluated at baseline and at the end of study. BPRS, SANS, SAS and BARS scores obtained at follow-up visits were significantly lower compared to baseline. Superoxide dismutase level was significantly lower at the end of study. No significant differences were detected in other laboratory parameters. Our results support the beneficial effect of the supplementation on positive and negative symptoms of schizophrenia as well as the severity of side effects induced by haloperidol. The effect of supplementation on akathisia is especially noteworthy and it has not been investigated in previous studies.
FUNDAMENTO: Varios investigadores implicados función de la patología mediada por radicales libres en la esquizofrenia. Ningún estudio ha examinado nunca el efecto de la vitamina C con antipsicóticos atípicos en el tratamiento de la esquizofrenia.
OBJETIVO: El objetivo de este estudio fue examinar el efecto de la vitamina C oral con antipsicóticos atípicos en suero de malondialdehído (MDA), los niveles de ácido ascórbico en plasma, y una breve escala de calificación psiquiátrica (BPRS) Puntuación en pacientes esquizofrénicos.
MÉTODO: Cuarenta pacientes esquizofrénicos participaron en un estudio prospectivo, doble ciego, controlado con placebo, noncrossover, de 8 semanas de estudio. Los pacientes con esquizofrenia se dividieron aleatoriamente en placebo y vitamina grupo C de 20 cada uno. El suero ácido ascórbico y MDA en plasma se estimaron por métodos de Nischal y Aye, respectivamente.
Resultados: El aumento de suero de MDA y la disminución de los niveles de ácido ascórbico en plasma fueron encontrados en pacientes esquizofrénicos. Estos niveles se invirtieron significativamente después del tratamiento con vitamina C junto con los antipsicóticos atípicos en comparación con el placebo con antipsicóticos atípicos. BPRS puntuaciones de cambio a las 8 semanas mejoraron estadísticamente significativa con la vitamina C en comparación con el placebo.
Conclusión: La suplementación oral de la vitamina C con antipsicótico atípico revierte los niveles de ácido ascórbico, reduce el estrés oxidativo, y mejora la BPRS puntuación, por lo tanto, tanto los fármacos en combinación se pueden utilizar en el tratamiento de la esquizofrenia.
Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs), namely, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acids (DHAs), and their association with psychopathology have been consistently reported in both chronic-medicated schizophrenic patients as well as in never-medicated patients soon after the first episode of psychosis. Past supplementation studies with either omega-6 or omega-3 or both EPUFAs generally in chronic-medicated-older patients have reported varying degrees of therapeutic effects, and have suggested that supplementation with primarily omega-3 EPUFAs (EPA>DHA) may be preferable. We report the supplementation with a mixture of EPA/DHA (180:120 mg) and antioxidants (vitamin E/C, 400 IU:500 mg) orally morning and evening to schizophrenic patients (N=33) for 4 months. The red blood cell (RBC) membrane fatty acid levels, plasma lipid peroxides and clinical measures were carried out by established procedures at pretreatment, posttreatment and after 4 months of postsupplementation period to determine the stability of treatment effects within patients. Levels of fatty acids and lipid peroxides were compared with their levels in normal controls (NC) (N=45).Posttreatment levels of RBC EPUFAs were significantly higher than pretreatment levels as well as levels in normal controls without any significant increase in plasma peroxides. Concomitantly, there was significant reduction in psychopathology based on reduction in individual total scores for brief psychiatric rating scale (BPRS) and positive and negative syndrome scale (PANSS), general psychopathology-PANSS and increase in Henrich's Quality of Life (QOL) Scale. The EPUFA levels returned to pretreatment levels after 4 months of supplementation washout. However, the clinical improvement was significantly retained. Future studies need be done in placebo-controlled trials and also with a comparison group supplemented with fatty acids alone in a larger number of patients, both chronic as well as never medicated, and for a longer duration of treatment while the dietary intake is monitored. This may establish the EPUFA supplementation a very effective treatment to improve the outcome for an extended period of time.
OBJETIVO: Este estudio investigó la eficacia y la tolerabilidad de etil-eicosapentaenoico (E-EPA) como tratamiento complementario en la esquizofrenia crónica, severa.
Método: Se realizó un estudio aleatorizado, de grupos paralelos, doble ciego, controlado con placebo, de dosis fija, complemento estudio se realizó durante 12 semanas. Cuarenta pacientes con síntomas persistentes después de al menos 6 meses de tratamiento antipsicótico estable recibido E-EPA o placebo, además del tratamiento existente.
RESULTADOS: A las 12 semanas, el grupo E-EPA tuvo una reducción significativamente mayor de las puntuaciones de síntomas positivos y negativos totales de las puntuaciones de la escala y discinesia que en el grupo placebo.
CONCLUSIONES: La EPA puede ser un medio eficaz y bien tolerado tratamiento complementario en la esquizofrenia.
El objetivo era poner a prueba los efectos de etilo eicosapentaenoato (EE) en persistentes síntomas en curso en pacientes que reciben diferentes tipos de fármacos anti-esquizofrénicos, antipsicóticos típicos, nuevos antipsicóticos atípicos y la clozapina. 115 pacientes con esquizofrenia del DSM-IV-definidos fueron estudiados, 31 en la clozapina, 48 sobre nuevos fármacos atípicos y 36 sobre los antipsicóticos típicos. Placebo o 1, 2 o 4 g / día de EE fue dada durante 12 semanas, además de la medicación de fondo. La evaluación principal fue el cambio desde el inicio hasta 12 semanas en la PANSS y sus subescalas. No hubo tratamiento relacionados con los efectos secundarios o adversos efectos bioquímicos o hematológicos. Los pacientes tratados con 2 y 4 g / EE día mostraron una reducción significativa de los niveles de triglicéridos, que había sido elevada por la clozapina. En los pacientes que recibieron 2 g / EE día hubo mejoras en la PANSS y sus subescalas, pero también hubo un gran efecto placebo en pacientes con antipsicóticos típicos y atípicos nuevo y no hay diferencia entre el tratamiento activo y el placebo. En los pacientes con clozapina, en cambio, no hubo respuesta placebo poco, pero un efecto clínicamente importante y estadísticamente significativa de la EA en todas las escalas de calificación. Este efecto fue mayor a 2 g / día. Se encontró una relación positiva entre la mejora en las escalas de calificación y el aumento en la concentración de glóbulos rojos ácido araquidónico.
Evidencia de que el metabolismo de los fosfolípidos y ácidos grasos poliinsaturados (PUFA) es anormal en la esquizofrenia proporcionaron el fundamento para los estudios de intervención con suplementos de AGPI. Un primer estudio de etiqueta abierta que indica la eficacia de n-3 PUFA en la esquizofrenia condujo a dos pequeños estudios piloto doble ciego. El primer estudio fue diseñado para distinguir entre los posibles efectos de dos diferentes PUFA n-3: el ácido eicosapentaenoico (EPA) y ácido docohexanoico (DHA). Cuarenta y cinco pacientes esquizofrénicos con medicación antipsicótica estable que aún se encontraban sintomáticos fueron tratados con EPA, DHA o placebo durante 3 meses. Mejora de la EPA medido por la Escala de Síntomas Positivos y Negativos (PANSS) fue estadísticamente superior a placebo DHA y uso de los cambios en las puntuaciones porcentuales en la PANSS total. EPA fue significativamente superior al DHA para los síntomas positivos usando ANOVA para medidas repetidas. En el segundo estudio controlado con placebo, la EPA se utiliza como tratamiento único, aunque el uso de fármacos antipsicóticos se permitió aún si esto era clínicamente imperativo. Al final del estudio, todos los 12 pacientes tratados con placebo, pero sólo ocho de 14 pacientes en EPA, estaban tomando fármacos antipsicóticos. A pesar de esto, los pacientes que toman EPA tenían puntuaciones significativamente más bajas en la escala de puntuación PANSS por el final del estudio. Se concluye que la EPA puede representar un nuevo enfoque de tratamiento para la esquizofrenia, y esto requiere una investigación a gran escala controlados con placebo.
OBJETIVO: Este estudio determinó si el aumento de los neurolépticos con 3 g / día de etil ácido eicosapentaenoico (EPA) mejora los síntomas y la cognición en pacientes con esquizofrenia o trastorno esquizoafectivo.
MÉTODO: Ochenta y siete pacientes que cumplían criterios para la esquizofrenia o trastorno esquizoafectivo que presentaban síntomas residuales pese al tratamiento neuroléptico se les asignó aleatoriamente para recibir 3 g / día de etil-EPA (N = 43) o placebo (N = 44) en una de 16 semanas , doble ciego y suplementos de juicio. Las evaluaciones se realizaron al inicio del estudio y en las semanas 1, 2, 4, 8, 12 y 16; una batería cognitiva se administró al inicio del estudio y en la semana 16.
RESULTADOS: No se encontraron diferencias entre los grupos en los síntomas positivos o negativos, la cognición estado de ánimo, o clasificaciones globales de impresión. Los resultados fueron similares a la intención de tratar (N = 87) y los grupos de terminadores (n = 75).
CONCLUSIONES: En pacientes con esquizofrenia tratados con 3 g / día de etil-EPA, mejora en los síntomas residuales y el deterioro cognitivo no fue mayor que para los pacientes con esquizofrenia tratados con placebo.
Importance: More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation.
OBJECTIVES:
To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response.
DESIGN:
Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12.
SETTING:
Three community mental health centers affiliated with academic medical centers in the United States.Participants: Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale.Intervention: One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo.
MAIN OUTCOME MEASURES:
Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale).
RESULTS:
Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups.
CONCLUSIONS:
Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms.Trial Registration: clinicaltrials.gov Identifier: NCT00611806.
