Mischoulon (EPA) 2015.

Study characteristics
Methods	Multicentre parallel design randomised controlled trial, 8 weeks
Participants	Participants: 196 participants (split across Mischoulon (DHA) 2015 and Mischoulon (EPA) 2015): 177 participants considered evaluable (provided 1 post‐baseline assessment); Mean age 45.8 (SD 12.5) years, 59.3% women (n 105), 40.7% men (n 72). Participants recruited at Massachusetts General Hospital and Cedars‐Sinai Medical Center through advertisements and referrals from outpatient programmes, from May 2006 to June 2011 Comorbidities: anxiety disorders/dysthymia in some participants, no serious/unstable physical comorbidities Adjunctive therapy: no, for all participants Inclusion criteria: A diagnosis of MDD per the SCID‐I/P), a CGI‐S score ≥ 3, and a baseline 17‐item HDRS‐17 score ≥ 15 Exclusion criteria: pregnancy or women of childbearing potential who were not using a medically‐accepted means of contraception; suicidality or homicidality; serious or unstable medical illness; current or past history of organic mental disorders, substance use disorders, any psychotic disorders, and bipolar disorder; history of multiple adverse drug reactions or allergy to the study compounds; concurrent use of psychotropic medications, systematic corticosteroid or steroid antagonists, anticoagulants, or immunosuppressant agents; electroconvulsive therapy during the current episode; any trial of ≥ 6 weeks with citalopram 40 mg/d or equivalent antidepressant during the current episode (to select a less refractory sample that would be more likely to respond to treatment); history of use of 1 g/d of n‐3 supplements; history of a bleeding disorder; psychotherapy; smoking 10 cigarettes per day; vitamin E supplementation > 400 IU; menstruating individuals unable to have baseline and post‐treatment blood drawn during the follicular phase; and individuals unable to refrain from nonsteroidal anti‐inflammatory use for > 72 hours prior to blood work. People with a CGI‐I score of 1 or 2 (i.e. “much improved” or “very much improved”) during the baseline visit (1 week after the screen visit) were excluded from the study
Interventions	Intervention: 1000 mg EPA enriched mix (consisting of 530 mg EPA / 137 mg DHA per soft gel (EPA:DHA 4:1), plus 7% stearidonic acid (SDA, n‐3), 1% heneicosapentaenoic acid (HPA, n‐3), 1% docosapentaenoic acid (DPA, n‐3), 1% eicosatetraenoic acid (ETA, n‐3), 0.2% α‐linolenic acid (ALA, n‐3), 3% arachidonic acid (AA, n‐6), 0.2% linoleic acid (LA, n‐6), and 10% – 11% unspecified fatty acids) per soft‐gel capsule. 2 EPA enriched capsules (plus DHA arm placebo capsules) every morning Comparator: 980 mg soybean oil per capsule (formed of 53.6% LA, 7.1% ALA, 0.1% myristic acid, 11% palmitic acid, 4% stearic acid, 0.2% palmitoleic acid, and 24% oleic acid), 2 capsules every morning (plus DHA arm placebo capsules) Treatment for 8 weeks
Outcomes	Primary: HDRS (17‐item), QIDS‐SR16, every 2 weeks for 8 weeks, Adverse events (PRISE) Secondary: Depression remission and response; CGI‐S, CGI‐I, WBS (Ryff 1995), QLESQ, every 2 weeks for 8 weeks, Trial non‐completion
Notes	Supported by NIH Grant Supplements provided by Nordic Naturals Conflicts of Interest: CoIs reported for several authors Compliance: NR Depressed mood (continuous): Analysis conducted on HDRS (17‐item) scores at 8 weeks, published modified ITT (at least 1 post‐baseline assessment) data used for analyses, end outcome scores calculated from change data, SDs imputed from other studies using the HDRS (17‐item). Placebo group split across 2 intervention groups (DHA = 29 participants, EPA = 30 participants) Adverse events: Adverse events reported by individuals, 20 ‐ 30% of participants endorsed some baseline PRISE physical or depressive symptoms. The following participants experienced emerging or worsening adverse events: Intervention = 39 of 60, Comparator = 33 of 60 (correspondence from author). Values included in the analysis are for emerging or worsening AEs Depression remission defined as final HDRS (17‐item) score ≤ 7; Depression response defined as improvement ≥ 50% in HDRS (17‐item). Quality of life: CGI scale data used in analyses Trial non‐completion: Intervention group = 15 (2 insufficient time/energy, 1 increased depression, 1 dizziness, 5 lost to follow‐up, 2 violated protocol, 1 moved away, 3 NR), comparator group = 12 (1 health problems related to treatment, 1 scheduling issues, 3 lost to follow‐up, 3 violated protocol, 4 NR)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A fixed‐block size of 30 participants (MGH) or a randomly‐permuted block size between 6 and 15 participants (CSMC)." (P. 55)
Allocation concealment (selection bias)	Low risk	"Only blind treatment codes, co‐ordinated between both site pharmacies, were noted on randomisation lists provided to study staff." (P. 55)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Flavours added to mask taste but no check to assess blinding (author correspondence)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Self‐reported for mood scales (P. 55)
Blinding of outcome assessment (Adverse Events)	Unclear risk	AEs rated by participants (P. 55)
Incomplete outcome data (attrition bias) All outcomes	High risk	Mood scales ‐ not ITT and > 10% dropout ‐ P. 55, and correspondence from author
Incomplete outcome data (Adverse Events)	High risk	All reported (correspondence from author), but > 10% withdrawals.
Selective reporting (reporting bias)	High risk	Well‐being scale and n‐3PUFA blood levels still to be reported (correspondence from author)
Other bias	Low risk	Study appeared to be free from other sources of bias