Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial.

BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.

Verbal Memory Performance in Depressed Children and Adolescents: Associations with EPA but Not DHA and Depression Severity.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been described as positively associated with cognitive functioning. Current meta-analyses have identified eicosapentaenoic acid (EPA) as potentially more effective than docosahexaenoic acid (DHA). An especially vulnerable subgroup that might benefit from these beneficial effects are depressed youths. In this study, we examined associations between red blood cell (RBC) DHA and EPA levels and depression severity and verbal memory performance in a sample of 107 moderately (n = 63) and severely (n = 44) depressed youths. The findings showed that youths with high RBC EPA levels had steeper learning curves compared to those with moderate or low RBC EPA levels (Pillai's Trace = 0.195, p = 0.027, ηp2 = 0.097). No associations between RBC DHA levels or depression severity and verbal memory performance were observed. Our results further confirm previous findings indicating a more important role of EPA compared to DHA in relation to cognitive functioning. Future research should further investigate the differential role of EPA and DHA concerning cognitive functioning in depressed youths. Evidence supporting beneficial supplementation effects could potentially establish a recommendation for a natural and easily accessible intervention for cognitive improvement or remission.

Omega-3 and its domain-specific effects on cognitive test performance in youths: A meta-analysis.

Omega-3 fatty acids are vital for brain development. The aim of this meta-analysis was to broaden current knowledge of the effects of omega-3 supplementation on cognitive test performance in youths. Randomized controlled trials (RCTs) meeting selection criteria were identified through two independent literature searches on PubMed, Cochrane Library, PsycARTICLES and PsycINFO (last search June 2019). Twenty-nine out of 1126 studies assessing 4247 participants met all selection criteria. A meta-analysis using random-effects model was performed for eight different cognitive domains. This first analysis revealed no main effect of omega-3 fatty acid supplementation on domain-specific cognitive test performance in youths. Subgroup analyses identified beneficial effects of eicosapentaenoic acid (EPA)-rich but not docosahexaenoic acid (DHA)-rich formulations in the domains of long-term memory, working memory and problem solving and a tendency towards beneficial effects in clinical rather than non-clinical populations. Future research should investigate differential effects of EPA and DHA and consider their baseline levels, other nutritional components and interactions with gene variations as potential predictors of response.

Supplementation with the omega-3 long chain polyunsaturated fatty acids: Changes in the concentrations of omega-3 index, fatty acids and molecular phospholipids of people at ultra high risk of developing psychosis.

Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are necessary for optimum mental health, with recent studies showing low n-3 LCPUFA in people at ultra-high risk (UHR) of developing psychosis. Furthermore, people at UHR of psychosis had increased erythrocyte sphingomyelin (SM) and reduced phosphatidylethanolamine (PE) concentrations as well as 27 erythrocyte phospholipid species that differed when compared to erythrocytes from age matched people not at UHR of psychosis. The aim of this analysis was to evaluate the effect of n-3 supplementation on the different erythrocyte lipid species (including SM and PE concentrations) in people at UHR of psychosis. Participants were randomly assigned to fish oil (containing 840 mg EPA and 560 mg DHA per day) or placebo (paraffin oil) for 6 months. Fasted blood samples were taken at baseline and post intervention. Mass spectrometry was used to analyse the molecular phospholipids and fatty acid composition of erythrocytes for both groups. The n-3 index was significantly increased from 3.0% to 4.12% after 6 months of receiving n-3 capsules. Fish oil capsules increased the phospholipid molecular species containing n-3 LCPUFA, and concomitant decreases in n-6 LCPUFA species. SM species did not show any significant changes in n-3 LCPUFA group however, three SM species (SM 16:0, SM 18:0, SM 18:1) significantly increased after 6 months of supplementation with placebo. N-3 supplementation for 6 months led to higher n-3 incorporation into erythrocytes, at the expense of n-6 PUFA across all phospholipid classes analyzed and may have prevented the increase in SM seen in the placebo group.

The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youths at Ultra-High Risk for Psychosis.

BACKGROUND: NEURAPRO was a multicenter, placebo-controlled trial of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) in 304 individuals at ultra-high risk for psychotic disorders. The study failed to show benefits of n-3 PUFAs over placebo. Although the randomized controlled trial design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil randomized controlled trials, as not only is the test agent present in the intervention group, but also n-3 fats are present in the diet and the body tissue of all participants. METHODS: Analysis of biomarker data (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], n-3 index, EPA+DHA) collected as part of NEURAPRO was conducted on 218 participants with longitudinal biomarker data to determine if n-3 PUFAs measured in erythrocytes at baseline and month 6 predicted clinical outcomes. RESULTS: Increases of the n-3 index, EPA, and DHA predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio [95% confidence interval (CI)] = 1.79 [1.30-2.48]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.43 [1.16-1.76]) and at month 12 (n-3 index baseline: adjusted odds ratio [95% CI] = 2.60 [1.71-3.97]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.36 [1.06-1.74]). CONCLUSIONS: These data suggest that n-3 PUFAs can exert therapeutic effects in ultra-high-risk individuals. This finding has implications for early intervention and treatment guidelines, as n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services.

Validation of a Food Frequency Questionnaire to Assess Intake of n-3 Polyunsaturated Fatty Acids in Switzerland.

Population-based data suggest that high intake of omega-3 (n-3) polyunsaturated fatty acids (PUFA) may be beneficial in a variety of health conditions. It is likely that mainly those patients with preexisting n-3 deficiency are those that benefit most from n-3 fatty acid supplementation. Therefore, for targeted interventions, a fast and reliable screening tool for n-3 PUFA intake is necessary. Thus, the aim of this project was to adapt and validate a food frequency questionnaire (FFQ) for n-3 PUFA intake in Switzerland while using as references the following: (1) 7-day food records (FR), and (2) n-3 fatty acid composition of red blood cells (RBC). We recruited 46 healthy adults for the first part of the study and 152 for the second. We used the dietary software EBISpro for the analysis of n-3 PUFA intake. RBC fatty acid composition was determined by gas chromatography mass spectrometry (GC-MS). Using correlation analysis, we found a moderate significant association between FFQ and FR for α-linolenic acid (ALA), eicosapentanoic acid (EPA), docosahexanoic acid (DHA), and total n-3 fatty acids (all r between 0.523 and 0.586, all p < 0.001). Bland Altman analysis further showed good agreement between the two methods and no proportional bias. Correlations between FFQ and RBC fatty acid composition were also moderate for EPA and DHA (r = 0.430 and r = 0.605, p < 0.001), but weaker for ALA and total n-3 (r = 0.314 and r = 0.211, p < 0.01). The efficacy of the FFQ to classify individuals into the same or adjacent quartile of RBC PUFA content ranged between 70% and 87% for the different fatty acids. In conclusion, we showed that the Swiss n-3 PUFA FFQ is a valid tool to assess dietary n-3 PUFA intake, especially DHA and EPA, to determine population groups at risk for low intake.

The Vitamins in Psychosis Study: A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of Vitamins B12, B6, and Folic Acid on Symptoms and Neurocognition in First-Episode Psychosis.

BACKGROUND: Elevated homocysteine is observed in schizophrenia and associated with illness severity. The aim of this study was to determine whether vitamins B12, B6, and folic acid lower homocysteine and improve symptomatology and neurocognition in first-episode psychosis. Whether baseline homocysteine, genetic variation, sex, and diagnosis interact with B-vitamin treatment on outcomes was also examined. METHODS: A randomized, double-blind, placebo-controlled trial was used. A total of 120 patients with first-episode psychosis were randomized to an adjunctive B-vitamin supplement (containing folic acid [5 mg], B12 [0.4 mg], and B6 [50 mg]) or placebo, taken once daily for 12 weeks. Coprimary outcomes were change in total symptomatology (Positive and Negative Syndrome Scale) and composite neurocognition. Secondary outcomes included additional measures of symptoms, neurocognition, functioning, tolerability, and safety. RESULTS: B-vitamin supplementation reduced homocysteine levels (p = .003, effect size = -0.65). B-vitamin supplementation had no significant effects on Positive and Negative Syndrome Scale total (p = .749) or composite neurocognition (p = .785). There were no significant group differences in secondary symptom domains. A significant group difference in the attention/vigilance domain (p = .024, effect size = 0.49) showed that the B-vitamin group remained stable and the placebo group declined in performance. In addition, 14% of the sample had elevated baseline homocysteine levels, which was associated with greater improvements in one measure of attention/vigilance following B-vitamin supplementation. Being female and having affective psychosis was associated with improved neurocognition in select domains following B-vitamin supplementation. Genetic variation did not influence B-vitamin treatment response. CONCLUSIONS: While 12-week B-vitamin supplementation might not improve overall psychopathology and global neurocognition, it may have specific neuroprotective properties in attention/vigilance, particularly in patients with elevated homocysteine levels, patients with affective psychosis, and female patients. Results support a personalized medicine approach to vitamin supplementation in first-episode psychosis.

Neurocognition as a predictor of transition to psychotic disorder and functional outcomes in ultra-high risk participants: Findings from the NEURAPRO randomized clinical trial.

BACKGROUND: Neurocognitive impairments experienced by individuals at ultra-high risk (UHR) for psychosis are potential predictors of outcome within this population, however there is inconsistency regarding the specific neurocognitive domains implicated. This study aimed to examine whether baseline neurocognition predicted transition to psychosis, or functional outcomes, at medium-term (mean = 3.4 years) follow-up, while controlling for other clinical/treatment variables associated with transition to psychosis. METHOD: Analysis of data collected as part of a multi-centre RCT of omega-3 fatty acids and cognitive-behavioural case management (NEURAPRO) for UHR individuals was conducted on the 294 participants (134 males, 160 females) who completed neurocognitive assessment (Brief Assessment of Cognition for Schizophrenia) at baseline. Transition to psychosis was determined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functioning was measured with the Global Functioning: Social and Role Scales. RESULTS: Mean baseline z-scores indicated that UHR participants performed a quarter to half a standard deviation below normative means in all domains (range mean z = -0.24 to -0.47), except for executive functioning (mean z = 0.16). After adjusting for covariates, poorer Executive (p = .010) and Motor (p = .030) functions were predictive of transition to psychosis. Processing Speed and Verbal Fluency were significant predictors of role functioning at 12 months (p = .004), and social functioning at medium-term follow-up (p = .015), respectively. CONCLUSIONS: Neurocognitive abilities are independent predictors of both transition to psychosis and functional outcomes within the UHR population. Further research is needed to determine the best combination of risk variables in UHR individuals for prediction of psychosis transition, functioning and other psychopathology outcomes.

Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders: The NEURAPRO Randomized Clinical Trial.

IMPORTANCE: A promising treatment to prevent onset and improve outcomes in patients at ultrahigh risk for psychosis is dietary supplementation with long-chain ω-3 polyunsaturated fatty acids (PUFAs). OBJECTIVE: To determine whether treatment with ω-3 PUFAs in combination with a high-quality psychosocial intervention (cognitive behavioral case management [CBCM]) is more effective than placebo plus CBCM. DESIGN, SETTING, AND PARTICIPANTS: NEURAPRO, a double-blind, placebo-controlled, randomized clinical trial, was conducted from March 1, 2010, to September 30, 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. The primary analysis used the intention-to-treat approach. INTERVENTIONS: A daily dose of 1.4 g of ω-3 PUFAs or placebo (paraffin oil), plus 20 or fewer sessions of CBCM over the 6-month study period. MAIN OUTCOMES AND MEASURES: The primary outcome was transition to psychosis status at 6 months. The secondary outcomes were general levels of psychopathology and functioning, as assessed by the Brief Psychiatric Rating Scale (BPRS) (range, 24-168), Scale for the Assessment of Negative Symptoms (SANS) (range, 0-125), Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60), Young Mania Rating Scale (YMRS) (range, 0-44), Social and Occupational Functioning Assessment Scale (SOFAS) (range, 0-100), and the Global Functioning: Social and Role scale (range, 0-10). For SOFAS and Global Functioning: Social and Role scale, higher scores were better; for other measures, lower scores were better. RESULTS: In this study of 304 adults at ultrahigh risk for psychotic disorders, 153 (50.3%) received ω-3 PUFAs and 151 (49.7%) received placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The Kaplan-Meier-estimated 6-month transition rates were 5.1% (95% CI, 1.3%-8.7%) in the control group and 6.7% (95% CI, 2.3%-10.8%) in the ω-3 PUFA group. At 12 months, the rates were 11.2% (95% CI, 5.5%-16.7%) in the control group and 11.5% (95% CI, 5.8%-16.9%) in the ω-3 PUFA group. No significant difference was observed between the transition rates of both groups (hazard ratio, 1.1; 95% CI, 0.55-2.23; P = .76, stratified log-rank test). CONCLUSIONS AND RELEVANCE: This trial clearly failed to replicate the findings of the original single-center trial. The most likely explanation is that ω-3 PUFAs lack efficacy under these conditions. However, the lower-than-expected transition rate may have prevented a test of the main hypothesis. Given the substantial symptomatic and functional improvement in both groups, the other treatments received (ie, CBCM and antidepressants) likely produced a ceiling effect beyond which ω-3 PUFAs, even if effective, could not be shown to confer additional benefits. Nevertheless, the main conclusion is that ω-3 PUFAs are not effective under conditions where good quality, evidence-based psychosocial treatment is available. TRIAL REGISTRATION: anzctr.org.au Identifier: 12608000475347.

Comments on Bozzatello et al. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. J. Clin. Med. 2016, 5, 67.

Paola Bozzatello et al. [1] have done a comprehensive qualitative review of the potential use of long-chain polyunsaturated fatty acids in the prevention and treatment of mental disorders.[...].

Polyunsaturated fatty acids in emerging psychosis: a safer alternative?

AIM: A promising approach of indicated prevention in individuals at increased risk of psychosis was based on the finding of potential neuroprotective properties of omega-3 polyunsaturated fatty acids (PUFAs). Considering the rising interest in omega-3 PUFA supplementation as preventive treatment strategy in young people at risk of psychosis, the question of safety issues must be addressed. METHODS: For this systematic review, a literature search for studies on omega-3 PUFAs for emerging psychosis with a focus on the safety profile was undertaken. Because limited data are available, information regarding potential side effects of omega-3 PUFAs was additionally derived from currently available data in psychotic disorders at different stages of the illness. Furthermore, helpful evidence from somatic disorders and healthy controls was used. RESULTS: In terms of safety issues, evidence from the randomized controlled trial in ultra-high-risk individuals and a variety of studies in schizophrenia patients strongly suggests that omega-3 PUFAs are safe and well tolerated even when used in relatively high doses. Most commonly occurring but clinically rarely significant are mild gastrointestinal symptoms; similarly, the slight risk of prolonged bleeding time has not been shown to be clinically relevant. Differential effects on metabolic parameters, most of which appear beneficial, have been reported. CONCLUSIONS: Taken together, one promising aspect of omega-3 PUFAs is that there seem to be no reports of relevant deleterious side effects in humans, even at high doses. The differential effects on lipid parameters and bleeding time are noteworthy and need further clarification.

Randomized controlled trial of interventions for young people at ultra high risk for psychosis: 6-month analysis.

OBJECTIVE: Cognitive therapy and/or low-dose antipsychotic administered during the prodromal phase of schizophrenia may prevent or delay the onset of full-blown illness. However, it is unclear which of these treatments are most effective, how long treatment should be given, and whether effects will be sustained over a prolonged period. METHOD: In order to examine these issues, we conducted a randomized controlled trial of cognitive therapy + risperidone; cognitive therapy + placebo; and supportive therapy + placebo in young people at ultra high risk for developing a psychotic disorder (that is, putatively prodromal). The main outcome was transition to psychotic disorder, with level of symptoms and functioning the secondary outcomes. This article reports the interim 6-month follow-up results. The study was conducted from August 2000 to May 2007. RESULTS: Of a possible 464 eligible ultra high risk individuals, 115 were recruited to the randomized controlled trial (cognitive therapy + risperidone, n = 43; cognitive therapy + placebo, n = 44; and supportive therapy + placebo, n = 28). An additional 78 individuals agreed to follow-up assessments but not to randomization ("monitoring group," n = 78). At 6 months, 8 of the 115 participants (7.0%) and 4 of the monitoring group (5.1%) had developed psychotic disorder. There were no significant differences between the 3 randomized groups (log rank test, P = .92) or between all 4 groups (log rank test, P = .93). There was also no difference between the 4 groups in secondary measures, with all groups showing a reduction in symptoms and increased functioning. CONCLUSIONS: Rates of transition to psychosis were lower than expected, particularly in the control supportive therapy + placebo group. This may have accounted for the negative finding, as the sample was therefore underpowered to find any difference between groups. Alternatively, it may be that all treatments were equally effective or equally ineffective at 6 months. TRIAL REGISTRATION: http://www.anzctr.org.au Identifier: ACTRN012605000247673.

Adhesio interthalamica in individuals at high-risk for developing psychosis and patients with psychotic disorders.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI) has been reported in psychotic disorders, but it is unknown whether individuals at risk for the disorder share the AI findings observed in patients with florid psychosis. Magnetic resonance imaging of 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, 135 individuals at ultra high-risk (UHR) of psychosis (of whom 39 later developed psychosis), and 87 healthy controls were used to investigate the length and prevalence of the AI. The relation of the AI length to lateral ventricular enlargement was also explored. The patients with FEP and chronic schizophrenia as well as UHR individuals had a shorter AI than the controls, but there was no difference in the AI findings between the UHR individuals who did and did not subsequently develop psychosis. There was a negative correlation between the AI length and lateral ventricular volume in all the diagnostic groups. The absence of the AI was more common in the chronic schizophrenia patients when compared with all other groups. These results support the notion that the AI absence or shorter length could be a neurodevelopmental marker related to vulnerability to psychopathology, but also suggest that schizophrenia patients may manifest progressive brain changes related to ongoing atrophy of the AI after the onset.

Pilot study evaluating the effect of massage therapy on stress, anxiety and aggression in a young adult psychiatric inpatient unit.

OBJECTIVE: The aim of the present pilot study was to examine the effectiveness of a relaxation massage therapy programme in reducing stress, anxiety and aggression on a young adult psychiatric inpatient unit. METHOD: This was a prospective, non-randomized intervention study comparing treatment as usual (TAU) with TAU plus massage therapy intervention (MT) over consecutive 7 week blocks (May-August 2006). MT consisted of a 20 min massage therapy session offered daily to patients during their period of hospitalization. The Kennedy Nurses' Observational Scale for Inpatient Evaluation (NOSIE), the Symptom Checklist-90-Revised (SCL-90-R), the State-Trait Anxiety Inventory (STAI) and stress hormone (saliva cortisol) levels were used to measure patient outcomes at admission and discharge from the unit. The Staff Observation Aggression Scale-Revised (SOAS-R) was used to monitor the frequency and severity of aggressive incidents on the unit. RESULTS: There was a significant reduction in self-reported anxiety (p < 0.001), resting heart rate (p < 0.05) and cortisol levels (p < 0.05) immediately following the initial and final massage therapy sessions. Significant improvements in hostility (p = 0.007) and depression scores (p < 0.001) on the SCL-90-R were observed in both treatment groups. There was no group x time interaction on any of the measures. Poor reliability of staff-reported incidents on the SOAS-R limited the validity of results in this domain. CONCLUSIONS: Massage therapy had immediate beneficial effects on anxiety-related measures and may be a useful de-escalating tool for reducing stress and anxiety in acutely hospitalized psychiatric patients. Study limitations preclude any definite conclusions on the effect of massage therapy on aggressive incidents in an acute psychiatric setting. Randomized controlled trials are warranted.

A 1H-MRS investigation of the medial temporal lobe in antipsychotic-naïve and early-treated first episode psychosis.

Schizophrenia is associated with significant brain abnormalities, including changes in brain metabolites as measured by proton magnetic resonance spectroscopy (MRS). What remains unclear is the extent to which these changes are a consequence of the emergence of psychotic disorders or the result of treatment with antipsychotic medication. We assessed 34 patients with first episode psychosis (15 antipsychotic naïve) and 19 age- and gender-matched controls using short-echo MRS in the medial temporal lobe bilaterally. Overall, there were no differences in any metabolite, regardless of treatment status. However, when the analysis was limited to patients with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder, significant elevations of creatine/phosphocreatine (Cr/PCr) and myo-inositol (mI) were found in the treated group. These data indicate a relative absence of temporal lobe metabolic abnormalities in first episode psychosis, but suggest that some treatment-related changes in mI might be apparent in patients with schizophrenia-spectrum diagnoses. Seemingly illness-related Cr/PCr elevations were also specific to the diagnosis of schizophrenia-spectrum disorder and seem worthy of future study.

Ethyl-eicosapentaenoic acid in first-episode psychosis. A 1H-MRS study.

Ethyl-eicosapentaenoic acid (E-EPA) is an omega-3 fatty acid that has been used in a range of neuropsychiatric conditions with some benefits. However, its mechanism of action is unknown. Here, we investigate its effects on in vivo brain metabolism in first-episode psychosis (FEP). Proton magnetic resonance spectroscopy at 3 T was performed in the temporal lobes of 24 FEP patients before and after 12 weeks of treatment in the context of a larger double-blind, placebo-controlled E-EPA augmentation study. Treatment group effects for glutathione (F1,12=6.1, p=0.03), and a hemisphere-by-group interaction for glutamine/glutamate (F1,20=4.4, p=0.049) were found. Glutathione increased bilaterally and glutamate/glutamine increased in the left hemisphere following E-EPA administration. Improvement in negative symptoms correlated with metabolic brain changes, particularly glutathione (r=-0.57). These results suggest that E-EPA augmentation alters glutathione availability and modulates the glutamine/glutamate cycle in early psychosis, with some of the metabolic brain changes being correlated with negative symptom improvement. Larger confirmatory studies of these postulated metabolic brain effects of E-EPA are warranted.

Omega-3 fatty acids supplementation in children with autism: a double-blind randomized, placebo-controlled pilot study.

BACKGROUND: There is increasing evidence that fatty acid deficiencies or imbalances may contribute to childhood neurodevelopmental disorders. METHODS: We conducted a randomized, double-blind, placebo-controlled 6-week pilot trial investigating the effects of 1.5 g/d of omega-3 fatty acids (.84 g/d eicosapentaenoic acid, .7 g/d docosahexaenoic acid) supplementation in 13 children (aged 5 to 17 years) with autistic disorders accompanied by severe tantrums, aggression, or self-injurious behavior. The outcome measure was the Aberrant Behavior Checklist (ABC) at 6 weeks. RESULTS: We observed an advantage of omega-3 fatty acids compared with placebo for hyperactivity and stereotypy, each with a large effect size. Repeated-measures ANOVA indicated a trend toward superiority of omega-3 fatty acids over placebo for hyperactivity. No clinically relevant adverse effects were elicited in either group. CONCLUSIONS: The results of this study provide preliminary evidence that omega-3 fatty acids may be an effective treatment for children with autism.

Bioactive lipids in schizophrenia.

Bioactive lipids, in particular arachidonic acid (AA), are vital for monoaminergic neurotransmission, brain development and synaptic plasticity. Phospholipases A2 (PLA2) are key-enzymes in AA metabolism and are activated during monoaminergic neurotransmission. Reduced membrane AA levels, and an altered activity of PLA2 have been found in peripheral membranes of drug-naïve patients with schizophrenia with some conflicting results in more chronic patient populations. Furthermore, in vivo brain phosphorus-31 magnetic resonance spectroscopy suggests reduced lipid membrane precursors (phosphomonoesters) and increased membrane breakdown products (phosphodiesters) in drug-naïve or early treated first-episode schizophrenia patients compared to age-matched controls or chronic populations and these changes were correlated with peripheral red blood cell membrane AA levels. We postulate that processes modulating membrane lipid metabolism are associated with psychotic illnesses and might partially explain the mechanism of action of antipsychotic agents, as well as experimental agents such as purified ethyl-eicosapentaenoic acid (E-EPA). Recent supplementation trials suggest that E-EPA is a modestly effective augmentation treatment resulting in reduced doses of antipsychotic medication in acutely ill patients with schizophrenia (but not in residual-type schizophrenia). This review investigates the role of bioactive lipids in schizophrenia and its treatment, as well as its potential use in prevention.

Implications of lipid biology for the pathogenesis of schizophrenia.

OBJECTIVE: Preclinical and clinical data suggest that lipid biology is integral to brain development and neurodegeneration. Both aspects are proposed as being important in the pathogenesis of schizophrenia. The purpose of this paper is to examine the implications of lipid biology, in particular the role of essential fatty acids (EFA), for schizophrenia. METHODS: Medline databases were searched from 1966 to 2001 followed by the cross-checking of references. RESULTS: Most studies investigating lipids in schizophrenia described reduced EFA, altered glycerophospholipids and an increased activity of a calcium-independent phospholipase A2 in blood cells and in post-mortem brain tissue. Additionally, in vivo brain phosphorus-31 Magnetic Resonance Spectroscopy (31P-MRS) demonstrated lower phosphomonoesters (implying reduced membrane precursors) in first- and multi-episode patients. In contrast, phosphodiesters were elevated mainly in first-episode patients (implying increased membrane breakdown products), whereas inconclusive results were found in chronic patients. EFA supplementation trials in chronic patient populations with residual symptoms have demonstrated conflicting results. More consistent results were observed in the early and symptomatic stages of illness, especially if EFA with a high proportion of eicosapentaenoic acid was used. CONCLUSION: Peripheral blood cell, brain necropsy and 31P-MRS analysis reveal a disturbed lipid biology, suggesting generalized membrane alterations in schizophrenia. 31P-MRS data suggest increased membrane turnover at illness onset and persisting membrane abnormalities in established schizophrenia. Cellular processes regulating membrane lipid metabolism are potential new targets for antipsychotic drugs and might explain the mechanism of action of treatments such as eicosapentaenoic acid.