Papakostas 2010a.

Methods	Double‐blind, randomised, placebo‐controlled study
Participants	73 participants included and treated Age (years): range 18 to 80 Sex: 29 men, 44 women (18 men, 21 women in SAMe group, 11 men, 23 women in placebo group) Diagnosis: SSRI non‐responders with DSM‐IV current major depressive disorder and a score of ≥ 16 on HAM‐D; treatment with an SSRI at adequate doses (a minimally adequate dose was defined as fluoxetine, citalopram or paroxetine at ≥ 20 mg/day; escitalopram ≥ 10 mg/day; sertraline ≥ 50 mg/day; duloxetine ≥ 60 mg/day and venlafaxine ≥ 150 mg/day; this was defined historically); treatment with SSRIs for an adequate duration (defined as treatment at an adequate dose for at least 6 weeks). At baseline visit, participants must have been taking a stable dose of an SSRI for the past 4 weeks Exclusion criteria: breastfeeding or pregnant women, or women of childbearing potential who were not using a medically accepted means of contraception; a decrease in depressive symptoms as reflected by the HAM‐D total score between the screen and baseline visits > 15%; serious suicide or homicide risk, unstable medical illness; active alcohol‐ or drug‐use disorder within the last 6 months; history of mania, hypomania (including antidepressant‐induced), psychotic symptoms, or seizure disorder; clinical evidence of untreated hypothyroidism; failure to experience sufficient symptom improvement following more than 4 antidepressant trials during the current major depressive episode; prior course of SAMe or intolerance to SAMe at any dose
Interventions	Adjunctive SAMe: 39 participants received 2 SAMe tosylate 400 mg tablets daily Adjunctive placebo: 34 participants received placebo tablets All participants had their number of tablets doubled upon completion of 2 weeks of treatment (target dose of SAMe was 800 mg twice daily) Participants continued to receive their SSRI treatment at a stable dose throughout the 6‐week trial. Participants who were unable to tolerate the study medications, per protocol, were withdrawn Duration of treatment: 6‐weeks
Outcomes	Primary outcome measure was defined as difference in response rates, according to 17‐item HAM‐D, between the 2 treatment groups. Response according to HAM‐D ratings was defined as a ≥ 50% reduction in scores during treatment (or a final score of ≤ 7) Secondary outcome measures included continuous change in HAM‐D scores and CGI‐Severity ratings during treatment; proportion of participants meeting remission status according to HAM‐D scores (final score of ≤ 7) or CGI‐Severity ratings (score of 1 at endpoint) and response status according to CGI‐Improvement ratings (score of < 3 at endpoint) Adverse effects were reported Postbaseline study visits occurred weekly
Notes	The authors inadvertently made a calculation error in the results. The quoted percentage is 36.1% for SAMe + antidepressant treatment among responders, whereas the actual number of responders indicated on page 945 was 18/39, or 46.1%. Likewise, the quoted percentage for SAMe + antidepressant treatment among participants who remitted was 25.8%, whereas the actual number of these participants cited on page 945 was 14/39, or 35.1%. So, 36.1% was given instead of 46.1% and 25.8% instead of 35.8% (Fleisch 2010; Papakostas 2010b)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation process not described ‐ "randomly assigned"
Allocation concealment (selection bias)	Low risk	Dummy pills used for placebo
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as double‐blind trial, but methods not detailed, except above
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Described as double‐blind trial, but methods not detailed, except above
Incomplete outcome data (attrition bias) All outcomes	Low risk	73 participants assigned to treatment. 55 completed (31 in SAMe group; 24 in placebo group). All non‐completers were mentioned, with reasons for drop‐out. 4 participants in the control group and 2 in SAMe group dropped out because of inefficacy; 3 in placebo and 2 in SAMe discontinued because of intolerance; 2 in placebo and 3 in SAMe discontinued for other reasons; and 1 in each group was lost to follow‐up LOCF used
Selective reporting (reporting bias)	Low risk	Primary and secondary outcome measures not stated, but HAM‐D, CGI‐Severity and CGI‐Improvement used and reported
Other bias	Low risk

BDI: Beck Depression Inventory; CBC: complete blood count; CGI: Clinical Global Impression; DSM: Diagnostic and Statistical Manual of Mental Disorders; DST: dexamethasone suppression test; ECG: electrocardiogram; HAM‐D: Hamilton Depression Rating Scale; HAM‐D: Hamilton Depression Rating Scale; IDS‐C: Inventory of Depressive‐Symptomatology ‐ Clinician‐Rated; ITT: intention‐to‐treat; iv: intravenous; LOCF: last observation carried forward; MADRS: Montgomery‐Åsberg Depression Rating Scale; SAMe: S‐adenosyl methionine; SD: standard deviation; SMA‐18: 18 panel blood test; SSRI: selective serotonin reuptake inhibitor.