Table 1.
Double-blind randomized placebo-controlled trials of omega-3 fatty acids in mental illness.
| Authors | Participants | Daily dosage | Length of trial | Measures | Outcomes* |
|---|---|---|---|---|---|
| Voigt et al. (2001) [53] | N = 54; 6-12 year old (78% boys); idiopathic ADHD diagnosis; were being treated successfully with medication | 345 mg DHA (algae-derived) or undefined placebo | 16 weeks | CPRS; CBC; TOVA; CCT | Treatment = placebo on all measures |
| Stevens et al. (2003) [59] | N = 50; 6-13 year old (78% boys); ADHD diagnosis; high FADSl; some on medication (equally allocated to conditions) | 96 mg GLA, 40 mg AA, 80 mg EPA, 480 mg DHA, 24 mg Vit E or olive oil placebo | 16 weeks | DBD; ASQ; CPT; WJPEB-R; FADS | Treatment > placebo: DBD-Conduct (parents); DBD-Attention (teachers). Other 14 outcome measures non-significant |
| Hirayama et al. (2004) [55] | N = 40; 6-12 year old (80% boys); ADHD diagnosis; 15% medicated; 82% comorbid conditions | 100 mg EPA, 514 mg DHA or olive oil placebo (supplied in soymilk & bread) | 8 weeks | ADHD DSM-IV; DTVP; STM; CPT; Other | Treatment = placebo on all measures (except that placebo > treatment on CPT and STM) |
| Richardson & Puri (2002) [58] | N = 29; 8-12 year old (62% boys); normal IQ; low reading ability; above average ADHD scores on Conners’ Index; no participants in treatment for ADHD | 864 mg LA, 42 mg AA, 96 mg ALA, 186 mg EPA, 480 mg DHA, 60 iµ Vit E or olive oil placebo | 12 weeks | CPRS | Treatment > placebo: CPRS; Cognitive problems/inattention; Anxious/shy; Conners’ global index; DSM inattention; DSM hyperactive/impulsive; Conners’ ADHD Index |
| Richardson & Montgomery (2005) [60] | N = 117; 5-12 year old (77% boys); Developmental Coordination Disorder, 1/3 with ADHD symptoms in clinical range, not in treatment; IQ > 70; | 60 mg AA, 10 mg GLA, 558 mg EPA, 174 mg DHA, 9.6 mg Vit E or olive oil placebo | 12 weeks active vs. placebo; one-way crossover to active treatment for 12 weeks | MABC; WORD; CTRS | Treatment > placebo: WORD; CTRS Oppositional behaviour; Cognitive problems/inattention; Hyperactivity; Anxious/shy; Perfectionism; Social problems; Conners’ index; DSM-IV inattention, hyperactive/impulsive |
| Treatment = placebo: MABC | |||||
| Sinn et al. (2007; 2008) [61,62] | N = 132 (questionnaire data available for 104); 7-12 year old (74% boys); ADHD symptoms in clinical range; unmedicated | 60 mg AA, 10 mg GLA, 558 mg EPA, 174 mg DHA, 9.6 mg Vit E, or palm oil placebo | 15 weeks active vs. placebo; one-way crossover to active treatment for 15 weeks | CPRS, CTRS Vocabulary, subtests from WISC-III & TEA-ch, Stroop | Treatment > placebo CPRS: Cognitive problems/inattention; Hyperactivity; ADHD Index; Restless/Impulsive; DSM-IV Hyperactive/Impulsive; Oppositional. Treatment = placebo on other subscales and CTRS. |
| Treatment > placebo on Creature Counting & vocabulary. Treatment = placebo on other cognitive tests | |||||
| Johnson et al. (2008) [64] | N = 75, 8-18 year old children with diagnosed ADHD, unmedicated (85% males) | 60 mg AA, 10 mg GLA, 558 mg EPA, 174 mg DHA, 9.6 mg Vit E or olive oil placebo | 3 months active vs. placebo; one-way crossover to active treatment for 3 months | Investigator-rated ADHD Rating Scale-IV; CGI | Treatment = placebo overall Treatment > placebo in subgroups with inattentive subtype & comorbid neurodevelopmental disorders |
| Milte et al. (in preparation) [65] | N = 54 (45 with bloods), 7-12 year old (79% male) with ADHD/ADHD symptoms (50% diagnosed) ACTRN012607000332426 | 1g EPA-rich oil, 1g DHA rich oil or sunflower oil placebo | 3 x 3 crossover (4 months on each treatment) | CPRS, reading, writing, vocabulary, TEA-ch | Treatment = placebo in 12-month crossover. |
| Over 4 months erythrocyte DHA increases associated with improvements on CPRS - oppositional behaviour, anxiety/shyness – divided attention & reading. In subgroup with learning difficulties (n = 16 with blood) also on CPRS hyperactivity/impulsivity and spelling. | |||||
| Amminger et al. (2007) [80] | N = 13 (5-17 years) with Autistic Disorder (81.9% male) | 1.5g/d n-3 PUFA (0.84g EPA, 0.7g DHA), Vit E ; or coconut oil placebo | 6 weeks parallel design | Aberrant Behavior Checklist (ABC) | Treatment > placebo for stereotypy & hyperactivity (trends with large effect sizes) |
| Treatment = placebo on 3 other subscales | |||||
| Peet & Horrobin (2002) [103] | N = 70 (18-70 years), depressed (>15 on HDRS), medicated | Ethyl-EPA – 1, 2 or 4 g/day or placebo | 12 week parallel design, adjunctive therapy | HDRS, MADRS, BDI | Treatment > placebo on all 3 rating scales with 1g/day EPA – strong effects for core depressive symptoms. Treatment = placebo on 2g and 4g/day (non-significant trends) |
| Nemets et al. (2002) [104] | N = 20 (28-73 years), diagnosed major depression disorder (85% women) HDRS score > 18 | 2g ethyl-EPA (96% from fish oil) or placebo, Vit E | 4 weeks parallel design, adjunctive therapy | HDRS | Treatment > placebo at weeks 2, 3 and 4 on HDRS score and on core depressive symptom subscales. |
| Su et al. (2003) [106] | N = 22 (18-60 years), outpatients with major depressive disorder; HDRS score > 18, medicated | 3.3g/day n-3 PUFA (2.2g DHA, 1.1g EPA) | 8 weeks parallel design, adjunctive therapy | HDRS | Treatment > placebo on HDRS |
| Marangell et al. (2003) [111] | N = 35 (18-65 years), major depressive disorder diagnosis; HDRS score > 16 (80% female) | 2g/day DHA or placebo | 6 weeks parallel | MADRS, HDRS, GAFS | Treatment = placebo on outcome measures |
| Silvers et al. (2005) [112] | N =77 (18-65 yrs recruited, mean age 38), being treated for current depressive episode (53% female) | 3g/day n-3 PUFA (2.4g DHA ; 0.6g EPA) + Vit E or olive oil placebo | 12 weeks parallel, adjunctive therapy | HDRS short form, BDI | Treatment = placebo on outcome measures (improvements in both groups at week 2) |
| Nemets et al. (2006) [105] | N = 20 (6-12 year old; 25% girls); children with major depressive disorder | 400mg EPA + 200mg DHA/day or safflower oil/olive oil placebos | 16 weeks, parallel (5 children medicated) | aCDRS, CDI, CGI | Treatment > placebo on outcome measures |
| Grenyer et al. (2007) [113, 114] | N = 83(18-72 years, M = 45), outpatients with major depression diagnosis | 3g/day n-3 PUFA (2.2g DHA, 0.6g EPA) + Vit E or olive oil placebo | 4 month parallel design, adjunctive therapy | HDRS, BDI, GAFS | Treatment = placebo on outcome measures (improvements in both groups) |
| Su et al. (2008) [109] | N = 24 (18-40 years); with major depressive disorder during pregnancy | 2.2g EPA + 1.2g DHA or placebo, both with tocopherols & orange flavor | 8 weeks, parallel design | HDRS, EPDS, GDI | Treatment > placebo on outcome measures |
| Rogers et al. (2008) [117] | N = 190 (18-70 years recruited, mean age = 38); people from GP surgeries or public with mild-moderate depression (77% female) | 630mg EPA, 850mg DHA, 870mg olive oil, or olive oil placebo (both with tocopherols & orange oil) | 12 weeks parallel design | DASS, BDI, STAEI, mood using diary and visual probe task, cognitive function | Treatment = placebo on outcome measures (improvements in both groups) |
| Van de Rest et al. (2008) [118] | N = 302 (> 65 years, M = 70; 55% male) non-depressed community dwelling adults. NCT00124852 | 1.8g/day EPA + DHA, 400mg/day EPA + DHA or placebo | 26 weeks parallel design | CES-D, MADRS, GDS-15, HADQ, [POMS short form (n = 104)] | Treatment = placebo on outcome measures |
| Freund-Levi et al. (2008) [115] | N = 204 (mean age 73 years); people with AD living in own homes, on stable treatment with acetylcholine esterase inhibitors. NCT00211159 | 1.72g DHA + 600mg EPA/day or corn oil placebo | 6 months parallel + one-way crossover to fish oil for 6 months | NPI, MADRS, CGB, DAD | Treatment = placebo on outcome measures. Treatment > placebo on MADRS in non-apoE-4 carriers and agitation in apoE-4 carriers |
| Lucas et al. (2009) [108] | N = 120 (recruited 40-55 yrs; mean age 49) post-menopausal women with psychological distress & depressive symptoms | 1.5g ethyl-EPA, 0.5g ethyl-DHA | 8 weeks parallel design | PGWB, HSCL-D-20, HDRS | Treatment = placebo on all measures (improvements in both groups). Treatment > placebo in women without MDE (major depressive episode diagnosis) |
| Carney et al. (2009) [116] | N = 122; major depression + coronary heart disease NCT00116857 | 930mg ethyl-EPA + 750mg ethyl DHA/day or corn oil placebo | 10 weeks parallel design, adjunctive therapy | BDI-II; HDRS | Treatment = placebo on outcome measures (improvements in both groups) |
| Stoll et al. (1999) [120] | N = 30 (18-65 years); inpatients with bipolar disorder | 9.6g/day n-3 PUFA (6.2g EPA, 3.4g DHA) or olive oil esther placebo | 4 month parallel design; adjunctive therapy | HDRS, YMRS, CGI-S, GAS | Treatment > placebo on GAS, HDRS and CGI; Treatment = placebo on YMRS |
| Keck et al. (2006) [123] | N = 116 (n= 57 bipolar depressed; n = 59 rapid cycling), mean age: 45; 51% male | 6g/day ethyl-EPA or liquid paraffin placebo | 4 month parallel design; adjunctive therapy | IDS, YMRS, CGI-BP (bipolar disorder) | Treatment = placebo on outcome measures |
| Frangou et al. (2006) [124] | N = 75 (mean age: 47); outpatients with bipolar depression + scores > 17 on HDRS (76% female) | 1g/day ethyl EPA (n = 24) ; 2g/day ethyl EPA (n = 25) or paraffin placebo | 12 week parallel design, adjunctive therapy | HDRS, YMRS, CGI | Treatment > placebo on HDRS & CGI on 1g and 2g/day. Treatment = placebo on YMRS |
| Hallahan et al. (2007) [127] | N = 49 (16-64 years, M = 30); presenting after act of repeated self-harm (65% women) | 1.2g/day EPA + 0.9g DHA or corn oil placebo (with 1% EPA/DHA) | 12 weeks parallel design in addition to standard care | BDI, HDRS, OAS-M, IMT/DMT, PSS, DHUS | Treatment > placebo on BDI, HDRS, PSS, DHUS. Treatment = placebo on OAS-M & IMT/DMT (hostility/aggression, memory) |
| Peet et al. (2001) [139] | Study 1: N = 45 (mean age: 44 yrs); schizophrenic patients, PANSS score > 40 | 2g EPA, 2g DHA or placebo | 3 months parallel adjunctive therapy | PANSS | EPA treatment > placebo or DHA on positive PANSS score. Treatment = placebo on negative symptoms score |
| Study 2: N = 30 (mean age 35 years); diagnosed schizophrenia, untreated | 2g/day EPA or corn oil placebo | 3 months parallel, single therapy unless drugs needed | PANSS; need for antipsychotic medication | Treatment > placebo, particularly on positive subscale; 12/12 placebo and 8/14 EPA patients took medication | |
| Fenton et al. (2001) [141] | N = 87 (18-65 years, M = 40; 61% male) diagnosed schizophrenia or schizoaffective disorder | 3g/day ethyl EPA + Vit E or mineral oil + Vit E placebo | 16 week parallel design, adjunctive therapy | PANSS, CGI, MADRS, RBANS, AIMS, SARS | Treatment = placebo on outcome measures (some showed improvements in both groups) |
| Emsley et al. (2002) [138] | N = 40 (18-55 years, M = 45); schizophrenic, treatment resistant patients, PANSS score > 10 | 3g/day ethyl-EPA or liquid paraffin placebo | 12 weeks parallel design, adjunctive therapy | PANSS, ESRS | Treatment > placebo on PANSS and dykinesia subscale of ESRS. Treatment = placebo on other ESRS subscales |
| Peet & Horrobin (2002) [140] | N = 115 (20-62 years, M = 37; 66% male), treatment-resistant schizophrenia; PANSS > 50 | 1, 2 or 4g/day ethyl-EPA or liquid paraffin placebo | 12 weeks parallel design, adjunctive therapy | PANSS, LUNSERS, MADRS, AIMS, BAS, SARS | Treatment = placebo on all rating scales; 2g treatment > placebo for patients on clozapine (associated with ↑AA) |
| Berger et al. (2007) [144] | N = 69 (mean age 21 ± 4; 76% male) first episode psychosis patients | 2g/day ethyl-EPA or mineral oil placebo not absorbed by intestinal tract (both with Vitamin E) | 12 weeks parallel design, adjunctive therapy | BPRS, SANS, CDSS, CGI, GAF, SOFAS | Treatment = placebo on all outcome measures. |
| Treatment > placebo on CGI co-varying for duration of untreated psychosis; treatment > placebo at weeks 4-6 | |||||
| Amminger et al. (2010) [145] | N = 81 (13-25 years, M = 16 ± 2, 40% male), met defined risk factors for psychosis | ||||
| Hamazaki et al. (1996) [147] | N = 41 (19-30 years, 70% female); university students (study measured aggression and executive function) | 1.5-1.8g/day DHA or 97% soybean oil + 3% fish oil placebo capsules | 3 months parallel design | P-F Study; Stroop; Dementia-detecting test | Treatment > placebo on extragression (increased in placebo group during exam time); treatment = placebo on other measures |
| Gesch et al. (2002) [150] | N = 172 (male offenders > 18 years); prison inmates | Vitamin and mineral supplement + 80mg EPA, 44mg DHA, 1.26g ALA or veg oil placebo | 20 weeks, parallel design | No. disciplinary actions; GATB; ECQ; SAS; HADQ | Treatment > placebo on OAS-M & MADRS |
| Zanarini et al. (2003) [149] | N = 30 (18-40 years; M = 26); females with moderately severe borderline personality disorder | 1g/day ethyl-EPA or mineral oil placebo | 8 weeks parallel design | OAS-M; MADRS | Treatment > placebo no. disciplinary actions |
| Treatment = placebo on psychological measures | |||||
| Bradbury et al. (2004) [148] | Stressed university staff (PSS scores ≥ 17) ISRCTN22569553 | 1.5g DHA + 360mg EPA + Vit E, olive oil placebo, or no treatment control | 6 weeks parallel design | PSS | Treatment = placebo on PSS; treatment > no treatment control |
| Buydens-Branchey et al. (2008) [156] | N = 24 (mean age 51 years); patients with history of aggression | 2.5g EPA + 0.5g DHA/day + Vit E or soybean oil + Vit E placebo | 3 months parallel design, most taking medication | Anger score on POMS | Treatment > placebo on POMS anger scores |
| Yehuda et al. (1996) [168] | N = 100 (50-73 years; 21% females) AD patients | 0.5g ALA :LA, 1 :4 ratio (n = 60) or mineral oil placebo | 4 weeks parallel design, adjunctive therapy | 12-item quality of life questionnaire (caregiver), clinician interview | Treatment > placebo on 12-item QOL questionnaire. |
| Clinician interviews not reported. | |||||
| Terano et al. (1999) [169] | N = 20 (mean age 83) nursing home residents with mild-moderate vascular dementia | 4.32g/day DHA or ‘control’ | 12 months parallel design | MMSE; HDS-R; clinical evaluation | Treatment > placebo on outcome measures after 3 & 6 months, associated with DHA increases |
| Kotani et al. (2006) [171] | N = 21 (mean age 68; 57% male); outpatients with MCI | 240mg/day AA+DHA or olive oil placebo | 3 months parallel design | RBANS (Japanese version) | Treatment > placebo on immediate memory & attention. Treatment = placebo on other 10 sub-scales |
| Freund-Levi et al. (2006) [172] | N = 178 (mean age 74); mild-moderate AD patients NCT00211159 | 1.72g DHA + 600mg EPA/day or placebo | 6 months parallel design, adjunctive therapy | MMSE, ADAS-cog; global function on bCDRS | Treatment = placebo on outcome measures. Treatment > placebo on MMSE in mild MCI group (n = 27) |
| Chiu et al. (2008) [173] | N = 35 (mean age 74; 57% female); AD or MCI | 1.08g EPA + .72g DHA or olive oil placebo | 6 months | CIBIC-plus; ADAS-cog; MMSE; HDRS | Treatment > placebo on CIBIC-plus. Treatment = placebo on other measures. Treatment > placebo on ADAS-cog in MCI sub-group |
| van de Rest et al. (2008) [174] | N = 302 (mean age 70 years; 55% male) community non-demented dwelling adults NTR97; ISRCTN46249783 | 1.8g/day EPA+DHA; 400mg/day EPA + DHA; or sunflower oil placebo; tocopherol added | 26 weeks parallel design | Word Learning Task; Digit Span; Trail Making; Stroop; Verbal Fluency | Treatment = placebo on outcome measures; Treatment > placebo on attention for apoE-4 carriers and males |
Note: Trials are grouped according to subheadings in main text (e.g., ADHD, depression, etc.) *Positive treatment effects are presented in italic. AD = Alzheimer’s Disease; ADAS-cog = cognitive portion of the Alzheimer’s Disease Assessment Scale; ADHD = attention deficit hyperactivity disorder; AIMS = Abnormal Involuntary Movement Scale; ASQ = Conners’ Abbreviated Symptom Questionnaires; BDI = Beck Depression Inventory; BPRS = Brief Psychiatric Rating Scale; CBC = Child Behavior Checklist; CCT = Children’s Color Trails test; CDI = Childhood Depression Inventory; aCDRS = Childhood Depression Rating Scale; bCDRS = Clinical Dementia Rating Scale; CDSS = Calgary Depression Scale for Schizophrenia; CES-D = Centre for Epidemiologic Studies Depression Scale; CGB = Caregivers Burden Scale; CGI-S = Clinical Global Impression-Severity; CIBIC-plus = Clinician’s Interview-Based Impression of Change Scale; CPRS = Conners’ Parent Rating Scales; CPT = Conners’ Continuous Performance Test; CTRS = Conners’ Teacher Rating Scales; DAD = Disability Assessment for Dementia scale; DASS = Depression & Anxiety Stress Scale; DBD = Disruptive Behavior Disorders rating scale; DHUS: Daily Hassles & Uplifts Scale; DMT: Delayed Memory Task; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, version 4; DTVP = Development Test of Visual Perception; ECQ = Emotional Control Questionnaire; EPDS = Edinburgh Postnatal Depression Scale; ESRS = Extrapyramidal Symptom Rating Scale; FADS = fatty acid deficiency symptoms; GAFS = Global Assessment of Functioning Scale (revised GAS); GAS = Global Assessment Scale; GATB = General Aptitude Test Battery; GDS = Geriatric Depression Scale; HADQ = Hospital Anxiety & Depression Questionnaire; HDRS = Hamilton Depression Rating Scale; HSCL-D-20 = 20-item Hopkins Symptom Checklist Depression Scale; IDS = Inventory for Depressive Symptomology; IMT = Immediate Memory Task; LUNSERS = Liverpool University Neuroleptic Side-Effects Rating Scale; MABC = Movement Assessment Battery for Children; MADRS = Montgomery-Asberg Depression Rating Scale; MCI = Mild Cognitive Impairment; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; OAS-M = The Overt Aggression Scale, Modified; PANSS = Positive and Negative Syndrome Scale; PGWB = Psychological General Well-Being Schedule; P-F Study: measures aggression, including extra- & intra-aggression; POMS = Profile of Mood States; PSS: Perceived Stress Scale; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; SANS = Scale for the Assessment of Negative Symptoms; SARS = Simpson-Angus Rating Scale; SAS = Survey Anger Scales; SOFAS = Social and Occupational Functioning Assessment Scale; STAEI = State-Trait Anger Expression Inventory; Stroop = Stroop color-word test; STM = Short-term memory; TEA-ch = Test of Everyday Attention for children; TOVA = Test of Variables of Attention; Vit E = Vitamin E (α-tocopheryl acetate); WISC-III = Wechsler Intelligence Scale for Children, version 3; WORD = Wechsler Objective Reading Dimensions; WJPEB-R = Woodstock-Johnston Psycho-Educational Battery – Revised; YMRS = Young Mania Rating Scale