title: Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. Adjunctive Taurine in First-Episode Psychosis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study. Utilization of the PICO framework to improve searching PubMed for clinical questions Efficacy of Zinc Sulfate as an Add-on Therapy to Risperidone Versus Risperidone Alone in Patients With Schizophrenia: A Double-Blind Randomized Placebo-Controlled Trial A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial. Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses. Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia Folate supplementation in schizophrenia: A possible role for MTHFR genotype Vitamin E in the treatment of tardive dyskinesia: the possible involvement of free radical mechanisms. Vitamin B6 treatment in acute neuroleptic-induced akathisia: a randomized, double-blind, placebo-controlled study. Vitamin E in the treatment of tardive dyskinesia: a replication study. Vitamin B6 Versus Mianserin and Placebo in Acute Neuroleptic-induced Akathisia: A Randomized, Double-blind, Controlled Study The effect of vitamin E addition to acute neuroleptic treatment on the emergence of extrapyramidal side effects in schizophrenic patients: An open label study Lack of effect of inositol treatment in chronic schizophrenia The impact of omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol: an open-label pilot study. CSF inositol in schizophrenia and high-dose inositol treatment of schizophrenia 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.
abstract: BACKGROUND Vitamin B6 , or pyridoxine , plays an intrinsic role in the synthesis of certain neurotransmitters that take part in development of psychotic states . Several reports indicate that vitamin B6 may be a factor in a number of psychiatric disorders and related conditions , such as autism , Alzheimer 's disease , hyperactivity , learning disability , anxiety disorder , and depression . Moreover , there are anecdotal reports of a reduction in psychotic symptoms after vitamin B6 supplementation of psychopharmacologic treatment of patients suffering from schizophrenia or organic mental disorder . The aim of this study was to examine whether vitamin B6 therapy influences psychotic symptoms in patients suffering from schizophrenia and schizoaffective disorder . METHOD The effects of the supplementation of vitamin B6 to antipsychotic treatment on positive and negative symptoms in 15 schizophrenic and schizoaffective patients ( DSM-IV criteria ) were examined in a double-blind , placebo-controlled , crossover study spanning 9 weeks . All patients had stable psychopathology for at least 1 month before entry into the study and were maintained on treatment with their pre study  psychoactive and antiparkinsonian medications  throughout the study . All patients were assessed using the Positive and Negative Syndrome Scale ( PANSS ) for schizophrenia on a weekly basis . Patients r and omly received placebo or vitamin B6 , starting at 100 mg/day in the first week and increasing to 400 mg/day in the fourth week by 100-mg increments each week . RESULTS PANSS scores revealed no differences between vitamin B6- and placebo-treated patients in amelioration of their mental state . CONCLUSION Further studies with larger population s and shorter duration of illness are needed to clarify the question of the possible efficacy of vitamin B6 in treatment of psychotic symptoms in schizophrenia 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 , r and omized , 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 Out patients 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 r and omized 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 484 T 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 clinical trials.gov Identifier : NCT00611806 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 Supporting 21st century health care and the practice of evidence -based medicine ( EBM ) requires ubiquitous access to clinical information and to knowledge-based re sources to answer clinical questions . Many questions go unanswered , however , due to lack of skills in formulating questions , crafting effective search strategies , and accessing data bases to identify best levels of evidence . Methods This r and omized trial was design ed as a pilot study to measure the relevancy of search results using three different interfaces for the PubMed search system . Two of the search interfaces utilized a specific framework called PICO , which was design ed to focus clinical questions and to prompt for publication type or type of question asked . The third interface was the st and ard PubMed interface readily available on the Web . Study subjects were recruited from interns and residents on an inpatient general medicine rotation at an academic medical center in the US . Thirty-one subjects were r and omized to one of the three interfaces , given 3 clinical questions , and asked to search PubMed for a set of relevant articles that would provide an answer for each question . The success of the search results was determined by a precision score , which compared the number of relevant or gold st and ard articles retrieved in a result set to the total number of articles retrieved in that set . Results Participants using the PICO templates ( Protocol A or Protocol B ) had higher precision scores for each question than the participants who used Protocol C , the st and ard PubMed Web interface . ( Question 1 : A = 35 % , B = 28 % , C = 20 % ; Question 2 : A = 5 % , B = 6 % , C = 4 % ; Question 3 : A = 1 % , B = 0 % , C = 0 % ) 95 % confidence intervals were calculated for the precision for each question using a lower boundary of zero . However , the 95 % confidence limits were overlapping , suggesting no statistical difference between the groups . Conclusion Due to the small number of search es for each arm , this pilot study could not demonstrate a statistically significant difference between the search protocol s. However there was a trend towards higher precision that needs to be investigated in a larger study to determine if PICO can improve the relevancy of search results Background : Zinc can modulate fast-excitatory transmission , facilitate the release of amino butyric acid and potentiate nicotinic acetylcholine receptors . There are also emerging evidence s discussing the implication of these neurotransmitters in pathophysiology of schizophrenia . Objectives : The purpose of this study was to evaluate the efficacy of Zn sulfate as an add-on therapy in the treatment of schizophrenia in a 6-week , double-blind and placebo-controlled trial . Patients and Methods : Eligible participants were 30 in patients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , Text Revision criteria . Patients were r and omly allocated into two equal groups ; one group of patients received risperidone 6 mg/day plus capsules of Zn sulfate ( each containing 50 mg elemental Zn ) three times a day and another group received risperidone 6 mg/day plus placebo . The Positive and Negative Syndrome Scale ( PANSS ) was applied to assess the psychotic symptoms and aggression risk at baseline , week 2 , 4 , and 6 of the study . Results : The results of this study showed that both protocol s significantly decreased the scores on all subscales of the PANSS and supplemental aggression risk subscale as well as PANSS total score over the study . However , this improvement was significantly higher in Zn sulfate receiving group compared to the placebo group . No major clinical side-effects were detected . Conclusions : It may be concluded that Zn is an effective adjuvant agent in the management of patients with schizophrenia 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 , r and omized , 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 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 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 BACKGROUND There is evidence that offenders consume diets lacking in essential nutrients and this could adversely affect their behaviour . AIMS To test empirically if physiologically adequate intakes of vitamins , minerals and essential fatty acids cause a reduction in antisocial behaviour . METHOD Experimental , double-blind , placebo-controlled , r and omised trial of nutritional supplements on 231 young adult prisoners , comparing disciplinary offences before and during supplementation . RESULTS Compared with placebos , those receiving the active capsules committed an average of 26.3 % ( 95 % CI 8.3 - 44.33 % ) fewer offences ( P=0.03 , two-tailed ) . Compared to baseline , the effect on those taking active supplements for a minimum of 2 weeks ( n=172 ) was an average 35.1 % ( 95 % CI 16.3 - 53.9 % ) reduction of offences ( P<0.001 , two-tailed ) , whereas placebos remained within st and ard error . CONCLUSIONS Antisocial behaviour in prisons , including violence , are reduced by vitamins , minerals and essential fatty acids with similar implication s for those eating poor diets in the community OBJECTIVE To compare two micronutrient ( vitamins and minerals ) formulas ( Berocca ™ and CNE ™ ) and assess their impact on emotions and stress related to the 6.3 earthquake on February 22(nd ) 2011 in Christchurch , New Zeal and . METHODS 91 adults experiencing heightened anxiety or stress 2 - 3 months following the earthquake were r and omized to Berocca ™ , CNE ™ low dose ( CNE4 ) , or CNE ™ high dose ( CNE8 )  , for 28 days and monitored weekly via on-line question naires and followed 1 month post-trial . A nonr and omized control group ( n = 25 ) completed question naires at baseline and 4 weeks . RESULTS All treatment groups experienced significant declines in psychological symptoms ( p < .001 ) . CNE ™ groups experienced greater reduction in intrusive thoughts as compared with Berocca ™ ( p = .05 ) , with no group differences on other measures of psychological symptoms . However , CNE8 group reported greater improvement in mood , anxiety , and energy ( p < .05 ) with twice as many reporting being " much " to " very much " improved and five times more likely to continue taking CNE ™ post-trial than Berocca ™ group . Treated participants had better outcomes on most measures over 4 weeks as compared to controls . CONCLUSIONS This study supports micronutrients as an inexpensive and practical treatment for acute stress following a natural disaster with a slight advantage to higher doses ACTRN 12611000460909 BACKGROUND The role of nutrition in the treatment of  attention-deficit hyperactivity disorder ( ADHD )  is gaining international attention ; however , treatments have generally focused only on diet restriction or supplementing with one nutrient at a time . AIMS To investigate the efficacy and safety of a broad-based micronutrient formula consisting mainly of vitamins and minerals , without omega fatty acids , in the treatment of ADHD in adults . METHOD This double-blind r and omised controlled trial assigned 80 adults with ADHD in a 1:1 ratio to either micronutrients  ( n = 42 ) or  placebo ( n = 38 ) for 8 weeks ( trial registered with the Australian New Zeal and Clinical Trials Registry : ACTRN12609000308291 ) . RESULTS Intent-to-treat analyses showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales . However , clinicians rated those receiving micronutrients as more improved than those on placebo both globally and on ADHD symptoms . Post hoc analyses showed that for those with moderate/severe depression  at baseline , there was a greater change in mood favouring active treatment over placebo . There were no group differences in adverse events . CONCLUSIONS This study provides preliminary evidence of efficacy for micronutrients in the treatment of  ADHD symptoms in adults , with a reassuring safety profile 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 BACKGROUND 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 . METHOD Forty-six stable adult schizophrenia out patients were enrolled and 32 were r and omised , 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 . RESULTS 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 ) . CONCLUSION 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 One of the major problems associated with long-term neuroleptic treatment is persistent tardive dyskinesia ( TD ) , for which there is no satisfactory treatment . We have recently proposed that some cases of TD are associated with neuronal dysfunction result ing from excess free radical production occurring during catecholamine metabolism . We therefore decided to assess the efficacy of a powerful free radical scavenging agent , alpha-tocopherol ( vitamin E ) , on the clinical signs of TD . We treated 15 patients with persistent TD with alpha-tocopherol and matched placebo in a r and omized crossover design . Patients demonstrated a significant overall reduction in scores on the Abnormal Involuntary Movements Scale ( AIMS ) after treatment with alpha-tocopherol , but not after placebo . The mean reduction in the AIMS score with alpha-tocopherol was 43 percent , with seven patients showing a greater than 50 percent reduction in their dyskinesia . There was also a trend for a decrease in scores on the Brief Psychiatric Rating Scale , but no change was observed in scores on the Simpson-Angus Scale for Extrapyramidal Side Effects . Our findings are consistent with the possibility that alpha-tocopherol is beneficial in the treatment of some patients with TD , but further research is necessary to establish the efficacy of this agent BACKGROUND Treatment strategies for acute neuroleptic-induced akathisia ( NIA ) contain anticholinergic ( antimuscarinic ) agents , dopamine agonists , gamma-aminobutyric acid (GABA)-ergic agents , beta-blockers , benzodiazepines , and serotonin antagonists . Nevertheless , many patients who suffer from acute akathisia fail to respond to treatment . In earlier studies , vitamin B6 was found to be effective in the treatment of neuroleptic-induced movement disorders . The purpose of this study was to evaluate the efficacy of vitamin B6 in the treatment of acute NIA . This is the first report of B6 as a treatment for NIA . METHOD This study was conducted in 2 mental health centers from February 2003 to November 2003 . Twenty schizophrenia and schizoaffective in patients with a DSM-IV diagnosis of NIA were r and omly divided to receive vitamin B6 600 mg/day b.i.d . ( N = 10 ) or placebo ( N = 10 ) twice a day for 5 days in a double-blind design . The Barnes Akathisia Scale ( BAS ) , the Brief Psychiatric Rating Scale ( BPRS ) , and the Clinical Global Impressions scale ( CGI ) were used to assess the severity of NIA and psychotic symptoms . The BAS assessment was made at baseline and every day during the study . The BPRS and CGI were completed at baseline and at the end of the study . RESULTS The vitamin B6-treated patients in comparison with the placebo group showed a significant improvement on the subjective-awareness of restlessness ( p = .0004 ) , subjective-distress ( p = .01 ) , and global ( p = .004 ) subscales of the BAS . The objective subscale did not demonstrate significant positive results ( p = .079 ) , but there was a trend of symptom amelioration in the vitamin B6 group . A reduction of at least 2 points on the BAS global subscale was noted in 8 patients in the vitamin B6 group ( 80 % ) , and in only 3 patients in the placebo group ( 30 % ) ( p = .037 ) . CONCLUSION Our preliminary results indicate that high doses of vitamin B6 may be useful additions to the available treatments for NIA , perhaps due to its combined effects on various neurotransmitter systems The aim of our study was to provide further information as to the efficacy of vitamin E for the management of tardive dyskinesia Abstract : Treatment strategies against acute neuroleptic-induced akathisia ( NIA ) include anticholinergic ( antimuscarinic ) agents , dopamine agonists , GABAergic agents , & bgr;-blockers , benzodiazepines , and serotonin antagonists . However , many patients who have acute akathisia fail to respond . In previous studies , mianserin and vitamin B6 were found to be effective in the treatment of acute akathisia . The purpose of this study was to compare the efficacy of B6 , mianserin and placebo in the treatment of acute NIA . Sixty schizophrenia and schizoaffective in patients who have NIA were r and omly divided to receive vitamin B6 1200 mg/d , mianserin 15 mg/d , or placebo for 5 days , in a double-blind design . The Barnes Akathisia Rating Scale , Brief Psychiatric Rating Scale , and Clinical Global Impression were used to assess the severity of NIA and psychotic symptoms . The assessment was made at baseline and daily for the duration of the study . Compared with the placebo group , the vitamin B6-treated and mianserin-treated patients showed a significant improvement in the subjective ( P < 0.0001 ) , subjective distress ( P < 0.0001 ) , and global ( P < 0.0001 ) subscales . The objective subscale did not show significant positive results ( P = 0.056 ) , but there was a trend toward symptom amelioration in both groups . A reduction of at least 2 points on the Barnes Akathisia Rating Scale global subscale was noted in the vitamin B6 group ( 13/23 , 56 % ) as well as in the mianserin groups ( 13/20 , 65 % ) , and in only one patient in the placebo group ( 1/17 , 6 % ; P < 0.0005 ) . Our results indicate that high doses of B6 and a low dose of mianserin may be a useful addition to current treatments of NIA . The efficacy of vitamin B6 and mianserin suggests that the pathophysiology of acute NIA is heterogeneous with the various subtypes of acute NIA responding differently to the various pharmacological approaches The anti-oxidant vitamin E has been reported to be effective in the treatment of tardive dyskinesia . The present open label study examined the effect of supplemental therapy with vitamin E on acute extrapyramidal symptoms and cell enzymes in patients receiving neuroleptic drugs . Thirty-nine hospitalized schizophrenic patients were r and omly assigned to two groups : group 1 ( n = 20 ) was treated with neuroleptics , and group 2 ( n = 19 ) with neuroleptics combined with a fixed dose of vitamin E ( 600 IU/day ) , administered for two weeks . All patients were assessed with the Simpson-Angus Rating Scale ( Simpson and Angus , 1970 ) for neuroleptic induced Parkinsonism ( NIP ) , Barnes ' Akathisia Scale ( Barnes , 1989 ) , and Brief Psychiatric Rating Scale : laboratory parameters included serum creatine kinase ( CK ) activity , serum glutamate oxaloacetic transaminase ( SGOT ) and white blood cell count ( WBC ) . The addition of vitamin E to neuroleptic agents was associated with a trend ( p = 0.08 ) towards prevention of the emergence of NIP compared to neuroleptic treatment alone . Addition of vitamin E to neuroleptics may reduce the severity of acute NIP in schizophrenic patients The phosphatidylinositol ( PI ) cycle represents a key signal-transduction system for many neurotransmitters in the brain ( Berridge et al 1982 ) . Inositol is present in high concentration in brain tissue ( Sherman et al 1985 ) and reduction of inositol levels by lithium ( Li ) treatment may be related to Ll 's mechanism of action ( Berridge et al 1982 ) . Indeed , addition of inositol to Ll-treated rats reverses several of iithium 's behavioral effects in vivo ( Kofman and Belmaker 1990 ) as well as many of its biological effects in vitro ( Busa and Gimlich 1989 ) . As a second-messenger system for numerous neurotransmitters , the PI cycle may well be involved in psychiatric disorders other than manic-depressive illness ( Kaiya et al 1989 ) . Recently , we found that  inositol-lphosphatase  was elevated in red blood cells of chronic schizophrenic patients ( Zilberman-Kaufman et al 1992 ) . This suggested to us that inositol might be lacking in such patients and that the increased enzyme activity represented an attempted physiological compensation . We therefore decided on a clinical trial of inositol therapy in schizophrenia .  lnositol passes the blood-brain barrier poorly ( Spector 1988 ) . The behavioral effects noted in rats were done with intracerebroventricular ( ICV ) inositol ( Kofman and Belmaker 1990 ) . However , Belmaker et al ( 1992 ) showed that large doses of inositol IP reversed Ll-pilocarpine seizures as effectively as small doses given ICV . As in the history of L-Dopa therapy ( Marks 1974 ) , it may be that simple compounds can have psychoactive effects only when given at high doses 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 Inositol is a key metabolite in the phosphatidylinositol cycle , which is a second messenger system for serotonin-2 receptors that have been implicated in the pathophysiology of schizophrenia . Cerebrospinal fluid inositol levels were measured in 20 schizophrenic patients and 19 age- and sex-matched controls and no difference was found . However , the patients were all neuroleptic-treated . A controlled double-blind crossover trial of 12 g daily of inositol for a month in 12 anergic schizophrenic patients , twice the dose given before in schizophrenia , did not show any beneficial effects . However , the number of patients studied was small and the length of time of inositol administration may not have been sufficient 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
target: There were no overall effects from antioxidant vitamins , inositol or dietary minerals on psychiatric symptoms .
  There is preliminary evidence that certain vitamin and mineral supplements may reduce psychiatric symptoms in some people with schizophrenia .
background: BACKGROUND When used as an adjunctive with antipsychotics , certain vitamins and minerals may be effective for improving symptomatic outcomes of schizophrenia , by restoring nutritional deficits , reducing oxidative stress , or modulating neurological pathways .