Methods	Design: placebo-controlled parallel trial
Participants	Participants: men with alcohol dependence and comorbid psychiatric disorders (subgroup with AsPD) Sex: male only Age: not reported for AsPD subgroup; for the whole sample, mean 41.3 (SD = 9.2) years Unit of allocation: individual participant Number randomised: 65 with AsPD (out of 216; see note 1) Number completing: 29 with AsPD (out of 99; see note 1) Setting: initially inpatient, then outpatient; two sites; USA (Kansas and Topeka) Inclusion criteria: alcohol dependence (DSM-III-R; measured using the PDI-R) Exclusion criteria: medical condition contraindicating use of tricyclic antidepressants or bromocriptine; receiving psychotropic medication (see note 2), living more than 150 miles from treatment site Ethnicity: for the whole sample: white (63%); black (32%); native American (2%); other (3%) Baseline characteristics: for the whole sample: all veterans; college degree (4%); some college or vocational training (39%); high school education or equivalent (47%); less than high school education (10%); married (21%); separated (15%); divorced/widowed (43%); never married (20%); employed full or part time in the month before admission (50%); retired (4%); student (1%); unemployed (45%)
Interventions	Three conditions: nortriptyline / bromocriptine / placebo nortriptyline arm nortriptyline (oral, 25 to 75 mg/day, at night) (number randomised not reported; completed, n = 9) placebo (oral, identical capsules, at night) (in analysis, the two placebo groups were combined such that total completed = 9; see note 3) bromocriptine arm bromocriptine (oral, 5 mg, three times/day) (number randomised not reported; completed, n = 11) placebo (oral, identical capsules, three times/day) (in analysis, the two placebo groups were combined such that total completed = 9; see note 3) Duration of intervention: 6 months Duration of trial: 6 months Length of follow up: participants were not followed up beyond the end of the intervention period Dose adjustment: nortriptyline dose adjusted to therapeutic levels (50 to 150 ng/ml) with corresponding increase in capsules made for placebo patients; bromocriptine initially 2.5 mg three times daily, but increased to 5 mg three times daily from month 4 to month 6; placebo as matching capsules with number adjusted to match a participant in the active treatment group Other notes: participants reimbursed USD 15 for each clinic visit; payment was not made until the participant either dropped out or completed the study
Outcomes	Primary outcomes Global state/functioning: Global Assessment Scale (GAS); global severity index sub scale of the Symptom Check List-90 (SCL-90) Adverse effects: via participant self-report Secondary outcomes Substance misuse: Severity of alcoholism (Alcohol Severity Scale, self report); alcohol craving (visual analogue scale); alcohol dependence (Severity of Alcohol Dependence Questionnaire) Other outcomes depression (Beck Depression Inventory; SCL-90 depression sub scale); anxiety (Beck Anxiety Inventory; SCL-90 anxiety sub scale); problem behaviours (Problem Behavior Checklist)
Notes	This review focuses on a subgroup of participants (n = 65 randomised, n = 29 completers) with AsPD out of the whole sample (n = 216 randomised, n = 99 completers); data available from completers only All participants had been fully detoxified on the inpatient Substance Abuse Treatment Unit; those requiring pharmacological therapy for alcohol withdrawal were drug free for 14 days before commencing the study The two placebo groups were combined in the investigators’ analysis; this was justified because MANOVA analysis on outcome measures of alcohol and symptom severity did not reveal significant differences when comparing placebo patients on the bromocriptine and nortriptyline arms
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	A two-stage randomisation process was used; patients within each of the subgroups (alcoholism alone, alcoholism + mood/anxietydis-orders, alcoholism + AsPD) “were first randomly assigned to the bromocriptine or nor-triptyline arm of the study. Patients within each drug arm were then randomised to receive either active drug or placebo” (p.463, col 1). No further information given. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Allocation concealment?	Unclear	A two-stage randomisation process was used (see above). “Patients within each drug arm were then randomised to receive either active drug or placebo” (p.463, col 1). No further information given. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Blinding? of participants	Yes	Investigators reported that “both active medications and placebo were prepared as identical-appearing capsules … . when the number of pills was increased for a given patient, a corresponding increase in pills was made for a placebo patient” (p.463, col 1). Review authors judged that appropriate care was taken to ensure blinding of participants, and that it was unlikely that this blinding could have been broken
Blinding? of personnel	Yes	Investigators reported that “at each visit, a physician blinded to the patients’ treatment assignment obtained blood samples and systematically recorded pill counts, medication side effects and other medical information” (p.463, col 2). Review authors judged that appropriate care was taken to ensure blinding of trial personnel, and that it was unlikely that this blinding could have been broken
Blinding? of outcome assessors	Unclear	Investigators reported that “a research assistant then recorded number of drinking days and patient rating of alcohol craving since the last follow-up visit” (p.463, col 2), but there was no indication that this research assistant was blinded, other than the statement that the study was “double-blind”. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Incomplete outcome data addressed? All outcomes	No	Incomplete outcome data arise from participants not completing the study and applies to all measured outcomes. The investigators reported significant dropout rates for the comorbidity and medication subgroups which ranged from 52.1% to 55.4%, and note that there were 99 participants (overall) who completed the study and 117 (overall) who did not (p.464, col 1). No details on missing data were provided for the AsPD subgroup. Clarification has been requested from the trial investigators but no further information was available at the time this review was prepared In this review, data from the 29 participants with AsPD who completed the study were included in the analysis (bromocriptine condition, n = 9; nortriptyline condition, n = 11; control condition, n = 9)
Free of selective reporting?	Yes	Study protocol is not available but it seems clear that the published report includes all expected outcomes, including those that were pre-specified
Free of other bias?	Yes	The study appeared to be free of other sources of bias.