title: Haloperidol-induced extrapyramidal reaction: lack of protective effect by vitamin E N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis Adjunctive Taurine in First-Episode Psychosis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study. A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia A randomised trial of nutrient supplements to minimise psychological stress after a natural disaster The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial) Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study Inflammation as a Predictive Biomarker for Response to Omega-3 Fatty Acids in Major Depressive Disorder: A Proof of Concept Study Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment N-Acetylcysteine as an Adjunct to Risperidone for Treatment of Negative Symptoms in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. Oxidative stress reduction related to the efficacy of n-3 polyunsaturated fatty acids in first episode schizophrenia: Secondary outcome analysis of the OFFER randomized trial. Neuroprotective effects of ethyl-eicosapentaenoic acid in first episode psychosis: A longitudinal T2 relaxometry pilot study
abstract: Abstract Haloperidol treatment has been shown to produce oxidative stress in patients with acute psychosis . Oxidative stress has also been implicated in the extrapyramidal symptoms ( EPS ) produced by haloperidol . Supporting the oxidative stress hypothesis , vitamin E ( antioxidant ) has demonstrated therapeutic efficacy in idiopathic parkinsonism . The prophylactic efficacy of vitamin E ( antioxidant ) on haloperidol-induced EPS was examined in a r and omized controlled trial . The sample consisted of 24 acute psychotic patients hospitalized for a 2-week trial . All patients received oral haloperidol  10 mg/day . The sample was equally r and omized to receive either haloperidol alone or haloperidol + vitamin E ( 3200 IU/day ) . EPS was rated at recruitment , both live and with video records , and on days 3 , 7 , 10 and 14 . Psychopathology was rated at recruitment and weekly thereafter . Vitamin E had no prophylactic effect on drug-induced EPS , though it did not interfere with the therapeutic efficacy of haloperidol Abstract Biomarker-guided treatments are needed in psychiatry , and previous data suggest oxidative stress may be a target in schizophrenia . A previous add-on trial with the antioxidant N-acetylcysteine ( NAC ) led to negative symptom reductions in chronic patients . We aim to study NAC ’s impact on symptoms and neurocognition in early psychosis ( EP ) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment . In a double-blind , r and omized , placebo-controlled trial in 63 EP patients , we assessed the effect of NAC supplementation ( 2700 mg/day , 6 months ) on PANSS , neurocognition , and redox markers ( brain GSH [ GSHmPFC ] , blood cells GSH levels [ GSHBC ] , GSH peroxidase activity [ GPxBC ] ) . No changes in negative or positive symptoms or functional outcome were observed with NAC , but significant improvements were found in favor of NAC on neurocognition ( processing speed ) . NAC also led to increases of GSHmPFC by 23 % ( P = .005 ) and GSHBC by 19 % ( P = .05 ) . In patients with high-baseline GPxBC compared to low-baseline GPxBC , subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC . In conclusion , NAC supplementation in a limited sample of EP patients did not improve negative symptoms , which were at modest baseline levels . However , NAC led to some neurocognitive improvements and an increase in brain GSH levels , indicating good target engagement . Blood GPx activity , a redox peripheral index associated with brain GSH levels , could help identify a subgroup of patients who improve their positive symptoms with NAC . Thus , future trials with antioxidants in EP should consider biomarker-guided treatment OBJECTIVE Taurine is an inhibitory neuromodulatory amino acid in the central nervous system that activates the GABA- and glycine-insensitive chloride channel and inhibits the N-methyl-D-aspartate receptor . It also functions as a neuroprotective agent and has a role in neural development and neurogenesis . The aim of this study was to determine the efficacy of adjunctive taurine in improving symptomatology and cognition among patients with a DSM-IV first-episode psychotic disorder . METHODS 121 patients with first-episode psychosis , aged 18 - 25 years , attending early intervention services consented to participate in this r and omized , double-blind , placebo-controlled trial conducted from January 2007 to May 2009 . Patients taking low-dose antipsychotic medication were r and omly assigned to receive once-daily taurine 4 g or placebo for 12 weeks . The co primary outcomes were change in symptomatology ( measured by the Brief Psychiatric Rating Scale [ BPRS ] total score ) and change in cognition ( measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia [ MATRICS ] Consensus Cognitive Battery composite score ) at 12 weeks . Secondary outcomes included tolerability and safety and additional clinical and functioning measures . RESULTS 86 participants ( n = 47 taurine ; n = 39 placebo ) were included in the final analysis . Taurine significantly improved symptomatology measured by the BPRS total score ( 95 % CI , 1.8 - 8.5 ; P = .004 ) and psychotic subscale ( 95 % CI , 0.1 - 1.5 ; P = .026 ) compared to placebo . Additionally , improvements were observed in the Calgary Depression Scale for Schizophrenia ( 95 % CI , 0.1 - 3.0 ; P = .047 ) and Global Assessment of Functioning ( 95 % CI , 0.3 - 8.8 ; P = .04 ) scores . There was no group difference in composite cognitive score ( 95 % CI , -1.7 to 1.0 ; P = .582 ) . A significant group difference was found on one safety and tolerability item ( psychic item 2 , asthenia/lassitude/increased fatigability ) of the Udvalg for Kliniske Undersogelser , with the taurine group showing a more favorable outcome ( P = .006 ) . CONCLUSIONS Adjunctive taurine did not improve cognition , but it appears to improve psychopathology in patients with first-episode psychosis . The use of taurine warrants further investigation in larger r and omized studies , particularly early in the course of psychosis . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00420823 BACKGROUND While antipsychotics are effective in the maintenance treatment of schizophrenia they have safety and tolerability risks . We investigated whether a combination of omega-3 polyunsaturated fatty acids ( ω-3 PUFAs ) and a metabolic antioxidant , alpha-lipoic acid ( α-LA ) , is effective in preventing relapse after antipsychotic discontinuation in subjects who were successfully treated for 2 - 3 years after a first-episode of schizophrenia , schizo-affective or schizophreniform disorder . METHODS In this r and omized , double-blind , placebo controlled study antipsychotic treatment was tapered and discontinued and participants received either ω-3 PUFAs ( eicosapentaenoic acid 2g/day and docosahexaenoic acid 1g/day)+α-LA 300 mg/day or placebo . Subjects were followed up for two years , or until relapse . RESULTS Recruitment was terminated prematurely due to the high relapse rates in both treatment groups as well as the severity of some of the relapse episodes . Of the 33 participants , 19/21(90 % ) r and omized to ω-3 PUFAs+α-LA  relapsed and one ( 5 % ) completed two years without relapse ( p=0.6 ) ; and 9/12 ( 75 % ) r and omized to placebo relapsed and none completed two years without relapse . Mean times to relapse were 39.8 ± 25.4 and 38.3 ± 26.6 weeks for the ω-3 PUFAs+α-LA and placebo groups , respectively ( p=0.9 ) . There were no significant differences between the groups in relapse symptom severity . CONCLUSIONS We found no evidence that ω-3 PUFAs+α-LA could be a suitable alternative to maintenance antipsychotic treatment in relapse prevention , in this small study . Antipsychotic discontinuation after a single episode of schizophrenia carries a very high risk of relapse , and treatment guidelines endorsing this practice should be revised After devastating flooding in southern Alberta in June 2013 , we attempted to replicate a New Zeal and r and omised trial that showed that micronutrient ( minerals , vitamins ) consumption after the earthquakes of 2010 - 11 result ed in improved mental health .  Residents of southern Alberta were invited to participate in a study on the potential benefit of nutrient supplements following a natural disaster . Fifty-six adults aged 23 - 66 were r and omised to receive a single nutrient ( vitamin D , n=17 ) , a few-nutrients formula ( B-Complex , n=21 ) , or a broad-spectrum mineral/vitamin formula ( BSMV , n=18 ) . Self-reported changes in depression , anxiety and stress were monitored for six weeks . Although all groups showed substantial decreases on all measures , those consuming the B-Complex and the BSMV formulas showed significantly greater improvement in stress and anxiety compared with those consuming the single nutrient , with large effect sizes ( Cohen 's d range 0.76 - 1.08 ) . There were no group differences between those consuming the B-Complex and BSMV . The use of nutrient formulas with multiple minerals and /or vitamins to minimise stress associated with natural disasters is now supported by three studies . Further research should be carried out to evaluate the potential population benefit that might accrue if such formulas were distributed as a post-disaster public health measure Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Long-chain omega-3 polyunsaturated fatty acids ( PUFAs ) are essential for neural development and function . As key components of brain tissue , omega-3 PUFAs play critical roles in brain development and function , and a lack of these fatty acids has been implicated in a number of mental health conditions over the lifespan , including schizophrenia . We have previously shown that a 12-week intervention with omega-3 PUFAs reduced the risk of progression to psychotic disorder in young people with subthreshold psychotic states for a 12-month period compared with placebo . We have now completed a longer-term follow-up of this r and omized , double-blind , placebo-controlled trial , at a median of 6.7 years . Here we show that brief intervention with omega-3 PUFAs reduced both the risk of progression to psychotic disorder and psychiatric morbidity in general in this study . The majority of the individuals from the omega-3 group did not show severe functional impairment and no longer experienced attenuated psychotic symptoms at follow-up BACKGROUND Brain glutathione levels are decreased in schizophrenia , a disorder that often is chronic and refractory to treatment . N-acetyl cysteine ( NAC ) increases brain glutathione in rodents . This study was conducted to evaluate the safety and effectiveness of oral NAC ( 1 g orally twice daily [ b.i.d . ] ) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period . METHODS A r and omized , multicenter , double-blind , placebo-controlled study . The primary readout was change from baseline on the Positive and Negative Symptoms Scale ( PANSS ) and its components . Secondary readouts included the Clinical Global Impression ( CGI ) Severity and Improvement scales , as well as general functioning and extrapyramidal rating scales . Changes following a 4-week treatment discontinuation were evaluated . One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were r and omized ; 84 completed treatment . RESULTS Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [ -5.97 ( -10.44 , -1.51 ) , p = .009 ] , PANSS negative [ mean difference -1.83 ( 95 % confidence interval : -3.33 , -.32 ) , p = .018 ] , and PANSS general [ -2.79 ( -5.38 , -.20 ) , p = .035 ] , CGI-Severity ( CGI-S ) [ -.26 ( -.44 , -.08 ) , p = .004 ] , and CGI-Improvement ( CGI-I ) [ -.22 ( -.41 , -.03 ) , p = .025 ] scores . No significant change on the PANSS positive subscale was seen . N-acetyl cysteine treatment also was associated with an improvement in akathisia ( p = .022 ) . Effect sizes at end point were consistent with moderate benefits . CONCLUSIONS These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia OBJECTIVE To investigate if ethyl-eicosapentaenoic acid ( E-EPA ) augmentation improves antipsychotic efficacy and tolerability in first-episode psychosis ( FEP ) . METHOD We performed a 12-week , r and omized , double-blind , placebo-controlled trial of 2-g E-EPA augmentation in 80 FEP patients . Sixty-nine patients were eligible for analysis ; a post hoc analysis was computed for a subgroup of nonaffective FEP patients ( N = 53 ) . The first participant was included in November 2000 and the last participant completed the trial in August 2003 . Primary outcome measures were symptom change scores and time to first response , while tolerability measures and cumulative antipsychotic dose were secondary outcome measures . RESULTS Analysis of covariance controlling for baseline symptoms found no significant mean difference between E-EPA and placebo at week 12 for symptom change scores . Cox regression analysis revealed a significant treatment by diagnosis interaction ( p = .024 ) for time to first response favoring E-EPA in nonaffective psychosis . Post hoc analysis for cumulative response rates further confirmed a higher response rate at week 6 ( 42.9 % [ 15/35 ] vs. 17.6 % [ 6/34 ] for all participants , p = .036 ; 54.2 % [ 13/24 ] vs. 17.2 % [ 5/29 ] for the nonaffective psychosis subset , p = .008 ) ; however , the difference at week 12 was no longer significant . Analysis of secondary outcome measures revealed that E-EPA-augmented participants needed 20 % less antipsychotic medication between weeks 4 through 6 ( p = .03 ) , had less extrapyramidal side effects in the initial 9 weeks ( p < .05 for all participants and for all timepoints ) , and reported less constipation ( p = .011 ) and fewer sexual side effects ( p = .016 ) than those treated with antipsychotic medication alone . CONCLUSION The findings suggest that E-EPA may accelerate treatment response and improve the tolerability of antipsychotic medications . However , it was not possible to demonstrate a sustained symptomatic benefit of E-EPA in early psychosis , possibly due to a ceiling effect , since a high proportion of first-episode patients already achieve symptomatic remission with antipsychotic medication alone . Further controlled trials in nonaffective early psychosis seem warranted . TRIAL REGISTRATION Australian Clinical Trials Registry identifier 12605000267651 ( http://actr.org.au ) Background The possible therapeutic impact of dietary changes on existing mental illness is largely unknown . Using a r and omised controlled trial design , we aim ed to investigate the efficacy of a dietary improvement program for the treatment of  major depressive episodes .  Methods ‘ SMILES ’ was a 12-week , parallel-group , single blind , r and omised controlled trial of an adjunctive dietary intervention in the treatment of moderate to severe depression . The intervention consisted of seven individual nutritional consulting sessions delivered by a clinical dietician . The control condition comprised a social support protocol to the same visit schedule and length . Depression symptomatology was the primary endpoint , assessed using the Montgomery – Åsberg Depression Rating Scale ( MADRS ) at 12 weeks . Secondary outcomes included remission and change of symptoms , mood and anxiety . Analyses utilised a likelihood-based mixed-effects model repeated measures ( MMRM ) approach . The robustness of estimates was investigated through sensitivity analyses . Results We assessed 166 individuals for eligibility , of whom 67 were enrolled ( diet intervention , n = 33 ; control , n = 34 ) . Of these , 55 were utilising some form of therapy : 21 were using psychotherapy and pharmacotherapy combined ; 9 were using exclusively psychotherapy ;  and 25 were using only pharmacotherapy . There were 31 in the diet support group and 25 in the social support control group who had complete data at 12 weeks . The dietary support group demonstrated significantly greater improvement between baseline and 12 weeks on the MADRS than the social support control group , t(60.7 ) = 4.38 , p < 0.001 , Cohen ’s d = –1.16 . Remission , defined as a MADRS score < 10 , was achieved for 32.3 % ( n = 10 ) and 8.0 % ( n = 2 ) of the intervention and control groups , respectively ( χ2 ( 1 ) = 4.84 , p = 0.028 ) ; number needed to treat ( NNT ) based on remission scores was 4.1 ( 95 % CI of NNT 2.3–27.8 ) . A sensitivity analysis , testing departures from the missing at r and om ( MAR ) assumption for dropouts , indicated that the impact of the intervention was robust to violations of MAR assumptions . Conclusions These results indicate that dietary improvement may provide an efficacious and accessible treatment strategy for the management of this highly prevalent mental disorder , the benefits of which could extend to the management of common co-morbidities . Trial registration Australia and New Zeal and Clinical Trials Register ( ANZCTR ) : ACTRN12612000251820 . Registered on 29 February 2012 OBJECTIVE Based on clues from epidemiology and animal experiments , low vitamin D during early life has been proposed as a risk factor for schizophrenia . The aim of this study was to explore the association between the use of vitamin D supplements during the first year of life and risk of developing schizophrenia . METHOD Subjects were drawn from the Northern Finl and 1966 Birth Cohort ( n=9,114 ) . During the first year of life , data were collected about the frequency and dose of vitamin D supplementation . Our primary outcome measures were schizophrenia , psychotic disorders other than schizophrenia , and nonpsychotic disorders as diagnosed by age 31 years . Males and females were examined separately . RESULTS In males , the use of either irregular or regular vitamin D supplements was associated with a reduced risk of schizophrenia ( Risk ratio (RR)=0.08 , 95 % CI 0.01 - 0.95 ; RR=0.12 , 95 % CI 0.02 - 0.90 , respectively ) compared with no supplementation . In males , the use of at least 2000 IU of vitamin D was associated with a reduced risk of schizophrenia ( RR=0.23 , 95 % CI 0.06 - 0.95 ) compared to those on lower doses . There were no significant associations between either the frequency or dose of vitamin D supplements  and ( a ) schizophrenia in females , nor with ( b ) nonpsychotic disorder or psychotic disorders other than schizophrenia in either males or females . CONCLUSION Vitamin D supplementation during the first year of life is associated with a reduced risk of schizophrenia  in males . Preventing hypovitaminosis D during early life may reduce the incidence of schizophrenia This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 ( n-3 ) fatty acids in subjects with major depressive disorder ( MDD ) . One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders , 4th Edition ( DSM-IV ) MDD , a baseline 17-item Hamilton Depression Rating Scale ( HAM-D-17 ) score ⩾15 and baseline biomarker data ( interleukin (IL)-1ra , IL-6 , high-sensitivity C-reactive protein ( hs-CRP ) , leptin and adiponectin ) were r and omized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day−1 , docosahexaenoic acid (DHA)-enriched n-3 900 mg day−1 or placebo . Outcomes were determined using mixed model repeated measures analysis for ‘ high ’ and ‘ low ’ inflammation groups based on individual and combined biomarkers . Results are presented in terms of st and ardized treatment effect size ( ES ) for change in HAM-D-17 from baseline to treatment week 8 . Although overall treatment group differences were negligible ( ES=−0.13 to + 0.04 ) , subjects with any ‘ high ’ inflammation improved more on EPA than placebo ( ES=−0.39 ) or DHA ( ES=−0.60 ) and less on DHA than placebo ( ES=+0.21 ) ; furthermore , EPA-placebo separation increased with increasing numbers of markers of high inflammation . Subjects r and omized to EPA with ‘ high ’ IL-1ra or hs-CRP or low adiponectin ( ‘ high ’ inflammation ) had medium ES decreases in HAM-D-17 scores vs subjects ‘ low ’ on these biomarkers . Subjects with ‘ high ’ hs-CRP , IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers ( medium to large ES differences ) . Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort . Studies are needed to replicate and extend this proof-of-concept work The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy , emotional blunting , and social withdrawal . Such ‘ negative ’ symptoms are unaffected by current antipsychotic therapies . There is evidence that the antibiotic minocycline has neuroprotective properties . We investigated whether the addition of minocycline to treatment as usual ( TAU ) for 1 year in early psychosis would reduce negative symptoms compared with placebo . In total , 144 participants within 5 years of first onset in Brazil and Pakistan were r and omised to receive TAU plus placebo or minocycline .  The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale .  Some 94 patients completed the trial . The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7 , an adjusted difference of 3.53 ( s.e . 1.01 ) 95 % CI : 1.55 , 5.51 ; p < 0.001 in the intention-to-treat population . The effect was present in both countries . The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms . Whether this is mediated by neuroprotective , anti-inflammatory or others actions is under investigation Rationale Several investigators implicated role of free radical-mediated pathology in schizophrenia . No study has ever examined the effect of vitamin C with atypical antipsychotics in the treatment of schizophrenia . Objective The aim of this study was to examine the effect of oral vitamin C with atypical antipsychotics on serum malondialdehyde ( MDA ) , plasma ascorbic acid levels , and brief psychiatric rating scale ( BPRS ) score in schizophrenic patients . Method Forty schizophrenic patients participated in a prospect i ve , double-blind , placebo-controlled , noncrossover , 8-week study . The patients with schizophrenia were divided r and omly into placebo and vitamin C group of 20 each . Serum MDA and plasma ascorbic acid were estimated by methods of Nischal and Aye , respectively . Result Increased serum MDA and decreased plasma ascorbic acid levels were found in schizophrenic patients . These levels were reversed significantly after treatment with vitamin C along with atypical antipsychotics compared to placebo with atypical antipsychotics .  BPRS change scores at 8 weeks improved statistically significant with vitamin C as compared to placebo . Conclusion Oral supplementation of vitamin C with atypical antipsychotic reverses ascorbic acid levels , reduces oxidative stress , and improves BPRS score , hence both the drugs in combination can be used in the treatment of schizophrenia A r and omized trial ( VITACOG ) in people with mild cognitive impairment ( MCI ) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline . We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment . 266 participants with MCI aged ≥70 years were r and omized to B vitamins ( folic acid , vitamins B6 and B12 ) or placebo for 2 years . Baseline cognitive test performance , clinical dementia rating ( CDR ) scale , and plasma concentrations of total homocysteine , total docosahexaenoic and eicosapentaenoic acids ( omega-3 fatty acids ) were measured . Final scores for verbal delayed recall , global cognition , and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids , whereas scores in the placebo group were similar across these concentrations . Among those with good omega-3 status , 33 % of those on B vitamin treatment had global CDR scores > 0 compared with 59 % among those on placebo . For all three outcome measures , higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins , while eicosapentaenoic acid appeared less effective . When omega-3 fatty acid concentrations are low , B vitamin treatment has no effect on cognitive decline in MCI , but when omega-3 levels are in the upper normal range , B vitamins interact to slow cognitive decline . A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD Objectives Despite the burden of negative symptoms on quality of life in schizophrenic patients , no completely effective treatment has been developed to address such symptoms yet . Abnormalities in oxidative stress pathways have been recently demonstrated to be involved in the pathophysiology of schizophrenia , and a growing interest in antioxidant agents is emerging for targeting negative symptoms of schizophrenia . N-Acetylcysteine ( NAC ) is a potent antioxidant with neuroprotective properties . This study aim ed to evaluate the possible effects of NAC as an adjunct to risperidone in treating negative symptoms of schizophrenia . Material s and Methods In this r and omized , double-blind , placebo-controlled , parallel-group study , 42 patients with chronic schizophrenia and a score of 20 or greater on the negative subscale of positive and negative syndrome scale ( PANSS ) were enrolled in the active phase of their illness . The participants were equally r and omized to receive NAC ( up to 2 g/d ) or placebo , in addition to risperidone ( up to 6 mg/d ) for 8 weeks . The participants were rated using PANSS every 2 weeks , and the decrease of PANSS negative subscale score was considered as our primary outcome . Results By the study end point , NAC-treated patients showed significantly greater improvement in the PANSS total ( P = 0.006 ) and negative subscale ( P < 0.001 ) scores than that in the placebo group , but this difference was not significant for positive and general psychopathology subscales . There was no significant difference between the 2 groups in the frequency of adverse effects .  Conclusions NAC add-on therapy showed to be a safe and effective augmentative strategy for alleviating negative symptoms of schizophrenia Short-term clinical trials of omega-3 polyunsaturated fatty acids ( n-3 PUFA ) as add-on therapy in patients with schizophrenia revealed mixed results . The majority of these studies used an 8- to 12-week intervention based on ethyl-eicosapentaenoic acid . A r and omized placebo-controlled trial was design ed to compare the efficacy of 26-week intervention , composed of either 2.2 g/day of n-3 PUFA , or olive oil placebo , with regard to symptom severity in first-episode schizophrenia patients . Seventy-one patients ( aged 16 - 35 ) were enrolled in the study and r and omly assigned to the study arms . The primary outcome measure of the clinical evaluation was schizophrenia symptom severity change measured by the Positive and Negative Syndrome Scale ( PANSS ) . Mixed models repeated measures analysis revealed significant differences between the study arms regarding total PANSS score change favouring n-3 PUFA ( p = 0.016 ; effect size ( ES ) = 0.29 ) . A fifty-percent improvement in symptom severity was achieved significantly more frequently in the n-3 PUFA group than in the placebo group ( 69.4 vs 40.0 % ; p = 0.017 ) . N-3 PUFA intervention was also associated with an improvement in general psychopathology , measured by means of PANSS ( p = 0.009 ; ES = 0.32 ) , depressive symptoms ( p = 0.006 ; ES = 0.34 ) , the level of functioning ( p = 0.01 ; ES = 0.31 ) and clinical global impression ( p = 0.046 ; ES = 0.29 ) . The findings suggest that 6-month intervention with n-3 PUFA may be a valuable add-on therapy able to decrease the intensity of symptoms and improve the level of functioning in first-episode schizophrenia patients Intervention studies of n-3 polyunsaturated fatty acids ( n-3 PUFA ) as add-on therapy in patients with schizophrenia have not examined changes in oxidative stress . A r and omized placebo-controlled trial of a 26-week intervention composed of 2.2g/day of n-3 PUFA was found to reduce symptom severity in first-episode schizophrenia patients . The present study is an extension of our previous report , whose secondary aim was to assess the association between the clinical effect of n-3 PUFA and changes in oxidative stress indices . Seventy-one patients aged 16 - 35 were enrolled in the study and r and omly assigned to the study arms . Total plasma antioxidant capacity and 8-epi-isoprostane F2α content were assessed at baseline and at weeks 8 and 26 of the study as secondary outcome measures . Significant changes in oxidative stress indices favouring the intervention group were observed : decreases in 8-isoprostane F2α ( p<0.001 ) and increases in total plasma antioxidant capacity ( p<0.001 ) . Significant correlations between changes in clinical scores relevant to symptom severity and changes in oxidative indices were observed . The results of the present study hence suggest that the efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to improvement in oxidative stress indices We used magnetic resonance imaging to examine the effect of ethyl-eicosapentaenoic acid ( E-EPA ) on hippocampal T(2 ) relaxation time in first episode psychosis patients at baseline and after 12 weeks of follow-up . There was an increase in T(2 ) in the placebo group but not in the E-EPA group , suggesting a neuroprotective effect of E-EPA treatment . In addition , the smaller the increase in T(2 ) , the greater the improvement in negative symptoms
target: However , mechanistic studies found significant improvements in hippocampal neuronal health and brain glutathione .
  CONCLUSION There is preliminary evidence that taurine improves outcomes in FEP , whereas effects of omega-3 and antioxidant vitamins/amino-acids are inconsistent ; perhaps mainly benefitting patients with high levels of oxidative stress .
background: AIM The effects of nutrient-based treatments , including adjunctive vitamin or antioxidant supplementation , have been explored extensively in long-term schizophrenia .
  However , no systematic evaluation of trials in " first-episode psychosis " ( FEP ) has been conducted , despite the potential benefits of using these treatments during the early stages of illness .
  Therefore , we aim ed to review all studies examining efficacy , tolerability and the biological mechanisms of action , of nutrient supplementation in FEP .