NeuRA Essential fatty acids August 2016

Transcription

1 Introduction One important group of compounds that have been suggested as an adjunctive therapy are the essential fatty acids (EFAs). A supplementary, or adjunctive, treatment is administered in conjunction with a patient s ongoing antipsychotic therapy, in an attempt to treat symptoms or improve functions that are not addressed by the antipsychotic alone. The two main EFAs are omega-3 and omega-6. They are important compounds for brain function, as they have impact on membrane receptors, ion channels and synapse function, as well as neuronal development. 1, 2 However, they are not made in the body and must be sourced from the diet. People with schizophrenia have shown to have lower levels of these essential compounds and their products, including omega-3 products docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), its esther, ethyleicosapentaenoic acid (E-EPA), omega-6 product arachidonic acid (AA), and their metabolites including prostaglandins (PGE). 1 It has been suggested that supplementing essential fatty acid levels may have some benefit for improving the outcome or reducing illness burden for people with schizophrenia. Method We have included only systematic reviews (systematic literature search, detailed methodology with inclusion/exclusion criteria) published in full text, in English, from the year 2000 that report results separately for people with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder or first episode schizophrenia. Reviews were identified by searching the databases MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO and the Cochrane library. Hand searching reference lists of identified reviews was also conducted. When multiple copies of reviews were found, only the most recent version was included. Reviews with pooled data are prioritised for inclusion. Review reporting assessment was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, which describes a preferred way to present a meta-analysis 3. Reviews rated as having less than 50% of items checked have been excluded from the library. The PRISMA flow diagram is a suggested way of providing information about studies included and excluded with reasons for exclusion. Where no flow diagram has been presented by individual reviews, but identified studies have been described in the text, reviews have been checked for this item. Note that early reviews may have been guided by less stringent reporting checklists than the PRISMA, and that some reviews may have been limited by journal guidelines. Evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group approach where high quality evidence such as that gained from randomised controlled trials (RCTs) may be downgraded to moderate or low if review and study quality is limited, if there is inconsistency in results, indirect comparisons, imprecise or sparse data and high probability of reporting bias. It may also be downgraded if risks associated with the intervention or other matter under review are high. Conversely, low quality evidence such as that gained from observational studies may be upgraded if effect sizes are large or if there is a dose dependent response. We have also taken into account sample size and whether results are consistent, precise and direct with low associated risks (see end of table for an explanation of these terms) 4. The resulting table represents an objective summary of the available evidence, although the conclusions are solely the opinion Page 1

2 of staff of NeuRA (Neuroscience Research Australia). Results We found nine systematic reviews that met our inclusion criteria. 1, 5-12 High quality evidence suggests no effect of adjunctive low-dose omega-3 EPA or DHA (2-3g daily) for reducing overall symptom severity. Moderate to low quality evidence suggests some benefit of higher dose adjunctive omega-3 EPA or DHA (up to 10g daily) for improving symptoms, particularly negative symptoms and movement effects (tardive dyskinesia). Moderate to low quality evidence suggests limited benefit of omega-6 supplementation for improving global state, and evidence is unclear about benefit for movement effects (tardive dyskinesia). Moderate quality evidence suggests no significant benefit of supplementation PGE1 for schizophrenia symptoms. Low quality evidence is unclear as to any difference in effect between EPA and DHA omega-3 supplementation for mental state and study retention. Page 2

3 Fenton WS, Hibbeln J, Knable M Essential Fatty Acids, Lipid Membrane Abnormalities, and the Diagnosis and Treatment of Schizophrenia Biological Psychiatry 2000; 47: 8-21 Comparison Effectiveness of essential fatty acid supplementation in people with schizophrenia vs. healthy controls. Moderate to low quality evidence (RCTs, small samples, direct, unable to assess precision or consistency) suggests omega-3 may be associated with improvements in symptoms, with no benefits after omega-6 or PGE1 administration. Omega-3 5 RCTs, N = 76, treatment period ranged from 6 weeks to 6 months. 5/5 studies reported positive results, with significant improvement in PANSS or SAPS/SANS scores. Results were significantly associated with red blood cell membrane n-3 concentration. Omega-6 4 RCTs, N = 95, treatment period ranged from 6 weeks to 8 months. 3/4 studies yielded negative results, with no significant difference between treatment and control groups in tardive dyskinesia, BPRS, or CPRS scores. PGE1 One small trial reported 4/7 patients had transient improvements in symptoms. ness of results No significant side effects were reported for any treatments, and no long term side effects were reported. No measure of consistency is reported. No confidence intervals are reported. Page 3

4 Fusar-Poli P, Berger G Eicosapentaenoic Acid Interventions in Schizophrenia. Meta-Analysis of Randomized, Placebo-Controlled Studies Journal of Clinical Psychopharmacology 2012; 32: Comparison Effectiveness of essential fatty acid supplementation (omega-3: EPA, average 2g daily for 12 to 16 weeks) in schizophrenia vs. placebo. High quality evidence (consistent, precise, direct) suggests no benefit of adjunctive low-dose EPA over placebo. Symptoms No significant effect for improving symptoms; 7 RCTs, N = 335, g = 0.242, 95%CI to 0.512, p > 0.05, Q = 9.06, p = 0.170, I 2 = There were no significant effects of age, sex, and dose. ness of results Not reported Consistent Precise Haag M and the brain Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 2003; 48(3): Comparison Effectiveness of essential fatty acid supplementation (omega-3: EPA or DHA) in chronic, neuroleptic treated schizophrenia vs. placebo. Page 4

5 Moderate to low quality evidence (double blind trials, direct, unable to assess consistency or precision) suggests some benefit of higher dose omega-3 supplementation for improving symptom severity and movement effects. However, the influence of antipsychotic medication in this effect cannot be ruled out. Symptoms and movement effects 6 open label or double blind trials report on the effectiveness of omega-3 supplementation (either EPA or DHA) in chronic schizophrenia. N not reported, treatment period or dosage not reported for all trials. 4 trials (up to 10g daily dosage) reported positive results of omega-3 supplementation for symptom severity and movement effects (tardive dyskinesia), including PANSS and AIMS scores. However, two lower dose (2-3g daily) trials reported no effect of EPA on all outcomes measured, One of these showed an effect only in the presence of clozapine. ness of results Not reported No measure of consistency is reported. No confidence intervals are reported. Irving CB, Mumby-Croft R, Joy LA Polyunsaturated fatty acid supplementation for schizophrenia Cochrane Database of Systematic Reviews 2006; Issue 3: Art. No CD Comparison 1 Effectiveness of essential fatty acid supplementation (omega-3: E-EPA or EPA, any dosage) in chronic, neuroleptic treated schizophrenia vs. placebo. Page 5

6 Moderate to low quality evidence (mostly imprecise and unable to assess consistency, direct, mostly single trials with small sample sizes) suggests omega-3 supplementation did not provide significant benefit over placebo for global state, but did improve mental state in the short term only. No difference was reported for adverse movement effects or for study retention. Global state No difference was reported in overall global state, as measured by CGI, compared to placebo; 1 trial, N = 87, MD = 0.00, 95%CI to 0.29, p not reported No difference in symptomatic response was reported in all patients compared to placebo at 12 weeks; 1 trial, N = 69, RR = 0.90, 95%CI 0.50 to 1.63, p = 0.73 No effect was reported when this analysis was restricted to people with non-affective psychosis; 1 trial, N = 53, RR = 0.56, 95%CI 0.25 to 1.24, p = 0.15 Mental state Patients supplemented with omega-3 showed a higher level of improvements in PANSS score compared to placebo (trend significance); 1 trial, N = 29, RR = 0.62, 95%CI 0.37 to 1.05, p = By the end of the trial, patients supplemented with omega-3 also reported lower endpoint PANSS score in the short term, N = 26 (borderline significance); MD = , to -0.45, p = Another trial reported no difference on PANSS endpoint score between omega-3 and placebo in the medium term; N = 87, MD = -1.00, 95%CI to 6.15, p = Leaving the study early No significant difference in attrition rate was reported between omega-3 and placebo overall; 6 trials, N = 679, RR = 0.85, 95%CI 0.51 to 1.40, p = 0.52, Q = 1.19, p = 0.95, I 2 = 0% One trial, N = 77, reported no difference between omega-3 and placebo for average time until the first tardive dyskinesia response; MD = -0.40, 95%CI to 1.14, p = 0.61 Not applicable for all outcomes except leaving the study early consistent. Page 6

7 ness of results Comparison 2 Unable to assess continuous outcomes, imprecise for all dichotomous outcomes. Effectiveness of essential fatty acid supplementation (omega-3: E-EPA or EPA, specific dosages) in chronic, neuroleptic treated schizophrenia vs. placebo. Moderate to low quality evidence (unable to assess consistency, mostly imprecise, direct, small sample) suggests low dose E- EPA (<1g/day) had no effect for improving global state or mental state. Doses ranging from 1-4g/day did not increase study retention compared to placebo. There was no clear difference across all doses in rate of adverse effects compared to placebo. Global state Clinical global impression with E-EPA dose <1 g/day No difference was reported in overall global state, as measured by CGI, compared to placebo; 1 trial, N = 87, MD = 0.00, 95%CI to 0.29, p = 1.0 Mental state Symptom severity with E-EPA dose <1 g/day No difference was reported in PANSS endpoint, compared to placebo; 1 trial, N = 87, MD = -1.00, 95%CI to 6.15, p = 0.78 Leaving the study early No significant differences between groups with E-EPA dose <1 g/day; 2 trials, N = 150, RR = 1.61, 95%CI 0.71 to 3.67, p = 0.25, Q = 1.59, p = 0.21, I 2 = 37% For 2g/day dosage of E-EPA, there were also no differences; 3 trials, N = 307, RR = 1.17, 95%CI 0.54 to 2.55, p = 0.69, Q = 2.48, p = 0.29, I 2 = 20% For 4g/day dosage of E-EPA, there were also no differences; 1 trial, N = 58, RR = 2.30, 95%CI 0.22 to 23.94, p = 0.49 One trial, reported no difference in rate of adverse events for E-EPA omega-3 and placebo, for any dose (<1g/day: N = 63, RR = 0.97, 95%CI 0.60 to 1.58, p = 0.90; 2g/day: N = 63, RR = 0.67, 95%CI 0.37 to 1.20, p = 0.18; 4g/day: N = 58, RR = 1.15, 95%CI to 1.82, p = 0.56). Page 7

8 No clear or significant differences across doses were reported between E-EPA and placebo for gastrointestinal effects, liver and biliary tract problems, metabolic and nutritional difficulties, musculoskeletal, psychiatric, reproductive, or skin problems, respiratory difficulty, or vision effects. Not applicable for all outcomes except leaving the study early consistent. ness of results Comparison 3 Unable to assess continuous outcomes, imprecise for all dichotomous outcomes. Effectiveness of essential fatty acid supplementation (omega-6: GLA, any dosage) in chronic, neuroleptic treated schizophrenia vs. placebo. Low quality evidence (one trial, very small sample, unable to assess consistency, imprecise) is unclear as to the effect of omega-6 supplementation for study retention or tardive dyskinesia adverse effects. Leaving the study early No difference in attrition rate was reported between omega-6 and placebo in the short-term; 1 trial, N = 16, RR = 1.00, 95%CI 0.28 to 3.54, p = 1.0 ness of results Comparison 4 One trial, N = 16 favoured placebo over omega-6 for lower levels of tardive dyskinesia (average AIMS score) by the end of the trial; MD = 1.30, 95%CI to 4.56, p = Unable to assess, one trial per outcome. Imprecise for attrition, unable to assess for risks. Effectiveness of essential fatty acid supplementation (omega-3: E-EPA or EPA, any dosage) in chronic, neuroleptic treated schizophrenia vs. fatty acid supplementation (omega-3: DHA, any dosage). Low quality evidence (one trial, very small sample, unable to assess consistency, imprecise) is unclear as to any difference in effect between EPA and DHA omega-3 supplementation for mental state and study retention. Page 8

9 Mental state Patients supplemented with EPA omega-3 showed a higher level of improvements in PANSS score compared to DHA omega-3; 1 trial, N = 31, RR = 0.66, 95%CI 0.39 to 1.11, p not reported By the end of the trial, patients supplemented with EPA omega-3 also reported lower endpoint PANSS score compared to DHA omega-3 (trend significance); MD = -9.80, to 1.37, p = Leaving the study early No attrition was reported in the short term for either EPA or DHA omega-3 groups. ness of results Not reported Unable to assess, one trial only. Imprecise Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, Roukas DK Randomised controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review European Psychiatry 2005; 20: Comparison Ethyl-eicosapentanoic acid (E-EPA, dose range 1-4g/day) plus clozapine (dose unspecified). Treatment duration range weeks. Moderate to low quality evidence (small samples, direct, unable to assess precision) suggests some benefit of EPA for improving symptom severity in patients receiving clozapine, particularly at higher doses. Mental state Page 9

10 1 RCT (N = 87) compared adjunctive E-EPA with adjunctive placebo, and reported no significant difference in PANSS, CGI, MADRS, or cognitive tests following clozapine augmentation with EPA compared to placebo (statistics not reported). 1 RCT (N = 115) compared different doses of E-EPA compared to placebo or clozapine alone, and reported significantly better outcomes in the group receiving higher-dose EPA compared to all other groups, for PANSS positive and negative subscales. No difference between groups was reported for MADRS. 1 single-group study (N = 40) reported better positive outcomes in the EPA group (statistics not reported). ness of results Reported adverse effects included diarrhoea, respiratory infection, nausea, extrapyramidal and movement effects, reduced triglycerides. Statistics not reported. Not applicable 1 study. Unable to assess Maidment ID Are fish oils an effective therapy in mental illness- an analysis of the data Acta Psychiatrica Scandinavica 2000; 102(1): 3-11 Comparison Effectiveness of essential fatty acid supplementation (omega-3, omega-6, or prostaglandin) in neuroleptic treated schizophrenia vs. placebo. Moderate to low quality evidence (double blind trials, small sample, direct, unable to assess consistency or precision) suggests an overall benefit of fatty acid supplementation for improving negative symptoms, despite conflicting benefit of omega-3 for symptom severity, and limited benefit of omega-6 supplementation for global state. Omega-3 Page 10

11 Three trials investigated omega-3 fatty acid supplementation in chronic, treated schizophrenia. One study, N = 20, administered 10g daily of fish oil adjunct (containing omega-3 EPA and DHA) over 6 weeks, and reported fish oil supplementation was associated with improvements on PANSS (particularly negative symptoms) and AIMS. One open-label study, N = 10, administered 2g daily of EPA compared to placebo for 4 months. Reported significant reduction in PANSS rating of negative symptoms. One double-blind RCT, N = 45, administered 2g daily of either EPA or DHA compared to placebo for 4 months. Significant PANSS improvement in positive symptoms for EPA group only, compared to DHA or placebo, no effect for negative symptoms. Omega-6 One double-blind trial, N = 48, supplemented omega-6 in a sample of mostly schizophrenia. There was no reported improvement in AIMS, but significant improvement in Simpson and CPRS scales. ness of results Not reported No measure of consistency is reported. No confidence intervals are reported. Marshall M, Rathbone J Early Intervention for psychosis Cochrane Database of Systematic Reviews 2011; Issue 6. Art. No.: CD DOI: / CD pub3 Comparison 3 months of Ethyl-Eicosapentaenoic Acid oil (E-EPA dose 500 mg/twice a day) plus second generation antipsychotics vs. placebo plus second generation antipsychotics. Sample: First-episode psychosis Low quality evidence (1 RCT, direct, imprecise) suggests no differences between groups. Leaving the study early Page 11

12 No differences between groups at 12 weeks; 1 RCT, N = 80, RR = 0.83, 95%CI 0.28 to 2.51, p = 0.75 Global state Not responded to treatment by 12 weeks No differences between groups at 12 weeks; 1 RCT, N = 80, RR = 0.90, 95%CI 0.57 to 1.43, p = 0.65 ness of results None reported Not applicable, 1 RCT only Imprecise Ross BM, Seguin J, Sieswerda LE Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids in Health & Disease 2007; 6: 21 Comparison Effectiveness of essential fatty acid supplementation (omega-3, omega-6, or prostaglandin) in neuroleptic treated schizophrenia vs. placebo. Moderate to low quality evidence (double blind trials, small sample, direct, unable to assess consistency or precision) suggests conflicting benefit of omega-3 for symptom severity. Symptom severity Four double-blind trials have investigated omega-3 fatty acid supplementation (1-4g/day for 9-12 weeks) in treated schizophrenia. Two trials, N = 85, reported significant but small reductions in PANSS scores following up to 12 weeks of 2-3g/day omega-3 supplement. Two further trials, N = 202, reported no significant improvements for patients who received 1-4g/day Page 12

13 omega-3 supplement. ness of results Not reported No measure of consistency is reported. No confidence intervals are reported. Sommer IE, van Westrhenen R, Begemann M, de Witte L, Leucht S, Kahn RS Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update Schizophrenia Bulletin 2014; 40(1): Comparison Adjunctive omega-3 EPA or DHA; 2 to 3 g daily for 3 to 4 months vs. placebo. High quality evidence (consistent, precise, direct) suggests no effect of adjunctive EPA or DHA for reducing overall symptom severity. Symptom severity measured by PANSS, BPRS No effect of EPA or DHA; 7 RCTs, N = 338, g = 0.09, 95%CI 0.16 to 0.35, p = 0.47, I 2 = 26.6% ness of results Not reported Consistent Precise Page 13

14 Explanation of acronyms AIMS = Abnormal Involuntary Movement Scale, CI = Confidence Interval, d = Cohen s d and g = Hedges g = standardized mean differences (see below for interpretation of effect size) I² = the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance), N = number of participants, p = statistical probability of obtaining that result (p < 0.05 generally regarded as significant), PANSS = Positive and Negative Syndrome Scale, Q = Q statistic for the test of heterogeneity, vs = versus Page 14

15 Explanation of technical terms * Bias has the potential to affect reviews of both RCT and observational studies. Forms of bias include; reporting bias selective reporting of results; publication bias - trials that are not formally published tend to show less effect than published trials, further if there are statistically significant differences between groups in a trial, these trial results tend to get published before those of trials without significant differences; language bias only including English language reports; funding bias - source of funding for the primary research with selective reporting of results within primary studies; outcome variable selection bias; database bias - including reports from some databases and not others; citation bias - preferential citation of authors. Trials can also be subject to bias when evaluators are not blind to treatment condition and selection bias of participants if trial samples are small. 13 Different effect measures are reported by different reviews. Prevalence refers to how many existing cases there are at a particular point in time. Incidence refers to how many new cases there are per population in a specified time period. Incidence is usually reported as the number of new cases per 100,000 people per year. Alternatively some studies present the number of new cases that have accumulated over several years against a person-years denominator. This denominator is the sum of individual units of time that the persons in the population are at risk of becoming a case. It takes into account the size of the underlying population sample and its age structure over the duration of observation. Reliability and validity refers to how accurate the instrument is. Sensitivity is the proportion of actual positives that are correctly identified (100% sensitivity = correct identification of all actual positives) and specificity is the proportion of negatives that are correctly identified (100% specificity = not identifying anyone as positive if they are truly not). Weighted mean difference scores refer to mean differences between treatment and comparison groups after treatment (or occasionally pre to post treatment) and in a randomised trial there is an assumption that both groups are comparable on this measure prior to treatment. Standardised mean differences are divided by the pooled standard deviation (or the standard deviation of one group when groups are homogenous) which allows results from different scales to be combined and compared. Each study s mean difference is then given a weighting depending on the size of the sample and the variability in the data. 0.2 represents a small effect, 0.5 a medium effect, and 0.8 and over represents a large effect. 13 Odds ratio (OR) or relative risk (RR) refers to the probability of a reduction (< 1) or an increase (> 1) in a particular outcome in a treatment group, or a group exposed to a risk factor, relative to the comparison group. For example, a RR of 0.75 translates to a reduction in risk of an outcome of 25% relative to those not receiving the treatment or not exposed to the risk factor. Conversely, a RR of 1.25 translates to an increased risk of 25% relative to those not receiving treatment or not having been exposed to a risk factor. A RR or OR of 1.00 means there is no difference between groups. A medium effect is considered if RR > 2 or < 0.5 and a large effect if RR > 5 or < lnor stands for logarithmic OR where a lnor of 0 shows no difference between groups. Hazard ratios Page 15

16 measure the effect of an explanatory variable on the hazard or risk of an event. Correlation coefficients (eg, r) indicate the strength of association or relationship between variables. They can provide an indirect indication of prediction, but do not confirm causality due to possible and often unforseen confounding variables. An r of 0.10 represents a weak association, 0.25 a medium association and 0.40 and over represents a strong association. Unstandardised (b) regression coefficients indicate the average change in the dependent variable associated with a 1 unit change in the independent variable, statistically controlling for the other independent variables. Standardised regression coefficients represent the change being in units of standard deviations to allow comparison across different scales. Inconsistency refers to differing estimates of effect across studies (i.e. heterogeneity or variability in results) that is not explained by subgroup analyses and therefore reduces confidence in the effect estimate. I² is the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) - 0% to 40%: heterogeneity might not be important, 30% to 60%: may represent moderate heterogeneity, 50% to 90%: may represent considerable heterogeneity and over this is considerable heterogeneity. I² can be calculated from Q (chi-square) for the test of heterogeneity with the following formula; 13 Imprecision refers to wide confidence intervals indicating a lack of confidence in the effect estimate. Based on GRADE recommendations, a result for continuous data (standardised mean differences, not weighted mean differences) is considered imprecise if the upper or lower confidence limit crosses an effect size of 0.5 in either direction, and for binary and correlation data, an effect size of GRADE also recommends downgrading the evidence when sample size is smaller than 300 (for binary data) and 400 (for continuous data), although for some topics, these criteria should be relaxed. 15 Indirectness of comparison occurs when a comparison of intervention A versus B is not available but A was compared with C and B was compared with C, which allows indirect comparisons of the magnitude of effect of A versus B. Indirectness of population, comparator and/or outcome can also occur when the available evidence regarding a particular population, intervention, comparator, or outcome is not available and is therefore inferred from available evidence. These inferred treatment effect sizes are of lower quality than those gained from head-tohead comparisons of A and B. Page 16

17 References 1. Fenton WS, Hibbeln J, Knable M. Essential Fatty Acids, Lipid Membrane Abnormalities, and the Diagnosis and Treatment of Schizophrenia. Biological Psychiatry. 2000; 47: Berger GE, Wood SJ, Pantelis C, Velakoulis D, Wellard RM, McGorry PD. Implications of lipid biology for the pathogenesis of schizophrenia. Australian & New Zealand Journal of Psychiatry. 2002; 36(3): Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMAGroup. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. British Medical Journal. 2009; 151(4): GRADEWorkingGroup. Grading quality of evidence and strength of recommendations. British Medical Journal. 2004; 328: Haag M. and the brain. Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie. 2003; 48(3): Irving CB, Mumby-Croft R, Joy LA. Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database of Systematic Reviews. 2006; (3). 7. Maidment ID. Are fish oils an effective therapy in mental illness--an analysis of the data. Acta Psychiatrica Scandinavica. 2000; 102(1): Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids in Health & Disease. 2007; 6: Fusar-Poli P, Berger G. Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. Journal of Clinical Psychopharmacology. 2012; 32(2): Marshall M, Rathbone J. Early intervention for psychosis. Cochrane Database of Systematic Reviews. 2011; (6): CD Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, Roukas DK. Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. European Psychiatry: the Journal of the Association of European Psychiatrists. 2005; 20(5-6): Sommer IE, van Westrhenen R, Begemann MJH, de Witte LD, Leucht S, Kahn RS. Efficacy of Antiinflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update. Schizophrenia Bulletin. 2014; 40(1): CochraneCollaboration. Cochrane Handbook for Systematic Reviews of Interventions. 2008: Accessed 24/06/ Rosenthal JA. Qualitative Descriptors of Strength of Association and Effect Size. Journal of Social Service Research. 1996; 21(4): GRADEpro. [Computer program]. Jan Brozek, Andrew Oxman, Holger Schünemann. Version 32 for Windows Page 17