Bell 1994.

Methods	Double‐blind, randomised, controlled study
Participants	26 participants (21 inpatients and 5 outpatients) included and treated Age (years): range 20 to 70 (mean ± SD age of the 17 participants who completed at least 2 weeks of active treatment 39 ± 14; 43 ± 16 in SAMe group, 33 ± 8 in desipramine group) Sex: 4 men, 13 women (4 men, 7 women in SAMe group; 0 men, 6 women in desipramine group) Diagnosis: DSM‐III‐R diagnosis of major depression and a baseline score > 20 on 17‐item HAM‐D or > 23 on an augmented 31‐item HAM‐D Exclusion criteria: history of significant medical illness, personality disorder, substance or alcohol abuse in the 6 months prior to the study, refusal to give written informed consent, history of failed response to the equivalent of 150 mg/day or more of imipramine for 4 weeks, HAM‐D scores fallen to ≤ 80% of baseline scores after an initial 3‐day evaluation and medication washout period
Interventions	SAMe: 11 participants received 1600 mg/day (tablets) in divided dose every day for the 4 weeks Desipramine: 6 participants titrated to 250 mg/day (tablets) in divided dose over the first 5 days and continued, whenever possible, at 250 mg/day until the end of the trial Duration of treatment: 4 weeks, preceded by 3‐day evaluation and medication washout period
Outcomes	Relationship between plasma levels of SAMe and clinical response Efficacy of treatment evaluated by 17‐item and 31‐item HAM‐D, assessed at baseline and weekly thereafter, as well as by BDI, completed by participants at baseline and weekly throughout the protocol. A participant classified as a treatment responder if he or she showed a reduction of > 50% on total HAM‐D‐17 scores at week 4 from baseline. Blood samples for the analysis of plasma SAMe levels collected after the washout period and at the end of study, in order to evaluate the correlation between plasma SAMe levels and the degree of clinical improvement Tolerability of treatment was evaluated by Systematic Assessment for Treatment Emergent Events, assessed at baseline and weekly thereafter. In addition, thyroid function, CBC, SMA‐18, urinalysis and ECG measured at baseline and on the last day of the study Vital signs, including blood pressure, pulse and respiration, recorded at baseline and at each weekly visit
Notes	Quote: "A subset of patients from our previously reported double‐blind study comparing oral SAMe and desipramine in the treatment of major depression participated in this study". There was no mention in the literature of this previous study (Bell, American Journal of Psychiatry). In addition, though we contacted the authors, this did not solve the issue. Therefore, we have used just this subset This study was carried out before the US Food and Drug Administration requested that all US sites conducting clinical investigations on SAMe discontinue their studies until more information was available from the company making SAMe tablets
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomly assigned". Method not stated
Allocation concealment (selection bias)	Unclear risk	Method not stated. Pharmacist not blinded
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identical tablets. States that nursing staff, raters and participants were blind to type of medication
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Stated that raters were blind to type of medication
Incomplete outcome data (attrition bias) All outcomes	High risk	26 participants randomised. 17 participants completed ≥ 2 weeks of the study (11 on SAMe and 6 on desipramine). Only used data on completers. Reason not stated
Selective reporting (reporting bias)	Low risk	HAM‐D was primary outcome measure (also BDI but not reported)
Other bias	Low risk