Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

138 depressed people with alcohol dependence (56 men and 82 women; mean (± SD) age 43.6 ± 9.1 years).

Inclusion criteria:

• aged 17‐65 years

• current DSM‐IV diagnoses of alcohol dependence and depression

• MADRS score > 20

Exclusion criteria:

• past regular intravenous drug use for > 2 weeks

• recreational use of any opioid drugs in the previous 4 weeks or a current requirement for ongoing opioid use

• psychosis, including psychotic delirium complicating alcohol or other drug withdrawal

• mania or hypomania

• significant current suicidality or homicidality

• current severe psychiatric symptoms requiring hospitalization,

• unstable physical disease

• use of disulfiram, naltrexone, antidepressant, or mood stabilizing medication in past 4 weeks

• serum AST, ALT, or GGT greater than 3 × the upper limit of laboratory reference range, or a bilirubin level > upper limit of reference range

• pregnancy, breastfeeding, or unwillingness to use a reliable method of contraception in women of childbearing age

• current or pending imprisonment

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• citalopram (up to 60 mg/day) + naltrexone (up to 100 mg/day) (73 participants; 29 men and 44 women)

• placebo + naltrexone (up to 100 mg/day) (65 participants; 27 men and 38 women)

Psychotherapy: manualized clinical case management was delivered by experienced addiction clinicians.

Scheduled duration of treatment: 12 weeks

Sites: 7 addiction clinics spanning urban, provincial, and rural catchments in Australia.

Setting: outpatients

Route of administration: orally

Starting dose:

• citalopram: 20 mg/day in week 1; if tolerated, dose then increased to 40 mg/day. After 6 weeks, dose could be further increased to 60 mg/day if participants remained depressed

• naltrexone: 25 mg daily for 1 week, then increased to 50 mg in participants without significant adverse effects. Dose could be further increased to 75 mg or 100 mg after 6 weeks

Pattern of dose reduction: information not available

Outcomes

Depression:

• final MADRS score

• final SCL‐90 score

• remission

Alcohol dependence:

• rate of abstinent days

• number of heavy drinking days per week (obtained from the rate of heavy drinking days)

• number of drinks per drinking day

• final LDQ score

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression (% of participants): 76.1%

• duration (years): 19.3

• MADRS score (mean ± SD): 31.0 ± 5.8

Alcohol dependence:

• number of drinks per drinking day (mean ± SD): 14.3 ± 8.0

• duration (years): 13.8

• being actively drinking: participants were not required to be abstinent

Other psychiatric comorbidity: 47.1% of participants had current anxiety disorder.

Other substance‐use disorders: 14.5% of participants had current substance dependence.

Other characteristics of study

Other pharmacological treatment offered: all participants received naltrexone.

Funding sources: study funded by Health Research Council of New Zealand grant HRC 07/138.

Declaration of interest: authors declared no conflict of interest.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was performed using a computer‐generated random number table.

Allocation concealment (selection bias)

Low risk

Treatment allocation was conducted by an administrative staff member independent of study investigators or research clinicians, and the allocation sequence record was stored securely.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The investigators, doctors, participants, and any other staff members taking part in the experiment were unaware which of the groups any particular participant belonged to.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were imputed using appropriate methods.

Selective reporting (reporting bias)

Unclear risk

Numbers of dropouts per group were missing.

Methods

Randomized, placebo‐controlled, double‐blind trial

Participants

30 people with alcohol dependence with dysthymia (24 men and 6 women; mean (± SD) age: 44.5 ± 2.6 years).

Inclusion criteria:

• alcohol dependence and dysthymia according to DSM‐III‐R

• HRSD score ≥ 18

Exclusion criteria:

• diagnosis of cirrhosis

• substance‐use disorders by other substances

• relevant internal or neurological conditions

Participants with bipolar disorder: information not available.

Interventions

Drugs:

• viloxazine (400 mg/day, in 4 daily administrations; 15 participants; information on number of men and women not available)

• placebo (15 participants; information on number of men and women not available)

Psychotherapy: information not available

Scheduled duration of treatment: 12 weeks

Site: 1 centre, Department of Clinical Psychiatry, Policlinico, Milan, Italy

Setting: inpatient setting for first 4 weeks, then outpatients for following 8 weeks.

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score (obtained from a figure)

Alcohol dependence: information not available

Dropouts

Adverse effects: information not available

Notes

Baseline characteristics of participants

Depression:

• primary depression: "Patients were not depressed but affected by dysthymic disorder"

• duration: information not available

• HRSD score (mean ± SD): viloxazine = 26.7 ± 2.8; placebo = 25.6 ± 1.7

Alcohol dependence:

• severity: information not available

• duration of alcohol consumption (mean ± SD): 10.2 ± 1.3 years

• being actively drinking: information not available

• length of abstinence: information not available

Other psychiatric comorbidity: information not available

Other substance‐use disorders: participants with other substance‐use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: information not available

Funding sources: information not available

Declaration of interest: information not available

Other information

Standard errors were converted into SDs.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random allocation stated but no further details provided.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Information insufficient to permit judgement.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Method to account for missing data not described. Intention‐to‐treat approach not reported. No high numbers of dropouts or unbalanced between groups.

Selective reporting (reporting bias)

High risk

DBI and DOTES scores are reported in 2 figures (figures 3 and 4 of the publication) in which the titles of the y axis do not correspond to those reported in the legends and in the text, and the positions of the points do not correspond to the values indicated in the y axes. Accordingly, these results were not included in the present meta‐analysis.

Methods

Double‐blind, randomized, comparative trial

Participants

44 depressed people with alcohol dependence (number of men and women: information not available; mean age: information not available). Sociodemographic characteristics available only for 36 participants (20 mirtazapine, 16 amitriptyline).

Inclusion criteria:

• aged 18‐65 years

• current DSM‐IV diagnoses of alcohol dependence and depressive disorder

• HDRS score ≥ 14 after detoxification

Exclusion criteria:

• serious physical illness

• for women, lack of protection against pregnancy, pregnancy, or breastfeeding

• other major psychiatric disorder on the DSM‐IV axis‐I other than depressive disorder

• history of a psychiatric problem other than depressive disorder

• organic brain diseases

• history of hypersensitivity to mirtazapine or amitriptyline

• other drug dependence and abuse, excluding nicotine and caffeine

• consumption of alcohol during study

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• mirtazapine (30‐60 mg/day; 24 participants)

• amitriptyline (100‐150 mg/day; 20 participants)

Psychotherapy: information not available.

Scheduled duration of treatment: 8 weeks.

Site: Ege University School of Medicine Hospital, Specialized Addiction Unit, Izmir, Turkey

Setting: inpatient

Route of administration: orally

Starting dose:

• mirtazapine: 15 mg/day (increased to 30 mg/day at the third day; at end of first week, dose was increased to 45‐60 mg/day if severity of symptoms persisted)

• amitriptyline 50 mg/day (increased to 100 mg/day at the third day; at end of first week, dose was increased to 125‐150 mg/day if severity of symptoms persisted)

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

Alcohol dependence: data not available

Alcohol craving:

• final score in a questionnaire prepared by authors

Dropouts: data not available

Adverse effects:

• evaluated using the UKU scale

Bodyweight:

• final value

Anxiety:

• final STAI score

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 34.1%

• duration: information not available

• HRSD score (mean ± SD): mirtazapine = 24.0 ± 4.4; amitriptyline = 23.7 ± 4.8

Alcohol dependence:

• MAST score (mean ± SD): 38.9 ± 6.1

• duration (mean ± SD): 12.1 ± 3.9 years

• being actively drinking: people who consumed alcohol during study were excluded from study.

• length of abstinence: 2 weeks

Anxiety:

• STAI score (mean ± SD): mirtazapine = 51.8 ± 3.9; amitriptyline = 53.4 ± 4.5.

Global assessment: information not available.

Weight (mean ± SD):

• mirtazapine = 75.9 ± 16.2 kg; amitriptyline = 71.4 ± 10.9 kg

Other psychiatric comorbidity: participants with other psychiatric disorders were excluded.

Other substance use disorders: participants with other substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment: no other pharmacological treatment was allowed.

Funding sources: not available.

Declaration of interest: not available.

Other information

After their inclusion in study, participants were admitted at a specialized department for alcohol detoxification on an inpatient basis. Alcohol consumption was prohibited during hospitalization and people who consumed alcohol during study were excluded from study. At end of alcohol detoxification treatment (approximately 10‐14 days), people were included in study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random allocation stated. No further details provided.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind stated. Medication and placebo prepared to appear identical ("Both the clinicians and patients were blind to the treatment. Drugs were given in identical‐looking opaque capsules").

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Intention‐to‐treat approach not used ("Dropouts were not included in the analysis due to missing data"). People who consumed alcohol during study were excluded by study.

Selective reporting (reporting bias)

High risk

People who consumed alcohol during study were excluded by study.

Methods

Randomized, double‐blind, comparative trial

Participants

39 people with alcohol dependence (all men; mean age: information not available) with a significant degree of anxious‐depressive symptomatology.

Inclusion criteria:

• aged 20‐55 years

• significant degree of anxiety and depression as determined by psychiatric interview

• current diagnosis of alcohol dependence

Exclusion criteria:

• physical brain

• liver illnesses

• psychotic disorder

Participants with bipolar disorder: information not available

Interventions

Drugs:

• doxepin (75 mg/day; 20 participants, all men; mean age: 45 years)

• diazepam (15 mg/day; 19 participants, all men; mean age: 41 years)

Psychotherapy: information not available

Scheduled duration of treatment: 3 weeks

Site: Alcoholism Treatment Service of East Louisiana State Hospital, Mandeville, LA, USA

Setting: inpatients

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final BPRS score

• final ZUNG score

• response

Alcohol dependence: data not available

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression: information not available

• duration: information not available

• BPRS score (mean): doxepin = 76.3; diazepam = 73.8

• ZUNG score (mean): doxepin = 47.8; diazepam = 37.9

Alcohol dependence:

• severity: information not available

• being actively drinking: participants not actively drinking

Other psychiatric comorbidity: information not available

Other substance‐use disorders: information not available

Other characteristics of study

Other pharmacological treatment: other concomitant therapy not allowed

Funding source: medications were supplied by Laboratories of Pfizer Inc.

Declaration of interest: information not available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random allocation stated. No further details provided.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind stated. Medications prepared to appear identical. Evaluations conducted by 2 independent investigators and the results pooled.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

No information on dropouts provided. Methods applied to account for missing data not described. Intention‐to‐treat approach not reported.

Selective reporting (reporting bias)

High risk

No information on dropouts provided. Methods applied to account for missing data not described. Intention‐to‐treat approach not reported.

Methods

Randomized, placebo‐controlled, double‐blind trial

Participants

40 depressed people with alcohol dependence (all men; mean age: majority aged 31‐50 years)

Inclusion criteria:

• alcohol dependence requiring involuntarily admission for detoxification

• diagnoses of depression according to clinical impression

• LDRS score ≥ 12

Exclusion criteria:

• hepatic disease

• organic brain damage

• psychosis

Participants with bipolar disorder: information not available

Interventions

Drugs:

• imipramine (75‐200 mg/day; 20 participants)

• placebo (20 participants)

Psychotherapy: none

Scheduled duration of treatment: 3 weeks

Site: Alcoholic Treatment Service, East Louisiana State Hospital, Jackson, LA, USA

Setting: inpatients for first 3‐4 days for treatment of alcohol withdrawal, then 3 weeks for trial

Route of administration: orally

Starting dose:

• 75 mg/day

• increased to maximum 200 mg/day according to individual requirements

• reduced if indicated by adverse effects

Pattern of dose reduction: information not available

Outcomes

Depression:

• difference between basal and final LRDS score

• response

Alcohol dependence: data not available

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression: information not available

• duration: information not available

• after detoxification and washout, LDRS score (mean ± SD): imipramine = 16.0 ± 3.1; placebo = 15.6 ± 3.3.

Alcohol dependence:

• duration: for 24 participants = 1‐5 years; for 16 participants ≥ 10 years;

• severity: all participants required involuntarily admission for detoxification, many participants had been hospitalized repeatedly for detoxification, in some instances as many as 30 times;

• being actively drinking: participants were abstinent;

• length of abstinence: 0.5 weeks 3‐4 days for the treatment of alcohol withdrawal).

Other psychiatric comorbidity: information not available.

Other substance‐use disorders: information not available.

Other characteristics of study

Other pharmacological treatment offered: participants received pharmacological treatment to control the acute symptoms of alcohol withdrawal for 3‐4 days.

Funding sources: information not available

Declaration of interest: information not available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random allocation stated. No further details provided.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Double‐blind stated. Medication and placebo prepared to appear identical. No specific reference made to blinding of participants and personnel.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Methods applied to account for missing data not described. Intention‐to‐treat approach not reported. People who left study were replaced by other people ("One patients taking imipramine left the hospital ... and global evaluation were omitted. Two additional patients left without permission just after entering the trial, and were therefore replaced in the study. One had received six doses of imipramine and the other one placebo").

Selective reporting (reporting bias)

Unclear risk

Information insufficient to permit judgement.

Methods

Randomized comparative trial

Participants

122 depressed people with alcohol dependence (95 men and 27 women; mean age: 42 years)

Inclusion criteria:

• DSM‐IV diagnosis F10‐24

• ZUNG score > 49

Exclusion criteria: information not available

Participants with bipolar disorder: information not available

Interventions

Drugs:

• paroxetine (20 mg/day; 61 participants; 49 men and 12 women; age (mean ± SD) = 42.1 ± 11.5 years)

• amitriptyline (25 mg/day; 61 participants; 46 men and 15 women; age (mean ± SD) = 42.2 ± 10.7 years)

Psychotherapy: information not available

Scheduled duration of treatment: 3‐4 weeks

Site: Alcohol Unit, casa di Cura Villa Silvia per malattie nervose e mentali, Senigallia, Italy

Setting: inpatients

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression

• final ZUNG score

• response (according to ZUNG)

• remission (according to ZUNG)

Alcohol dependence: data not available

Dropouts: data not available

Adverse effects: data not available

Notes

Baseline characteristics of participants

Depression:

• primary depression: information not available

• duration: information not available

• ZUNG score (mean ± SD): paroxetine = 68.8 ± 9.0; amitriptyline = 63.3 ± 6.0

Alcohol dependence: data not available

Other psychiatric comorbidity: information not available

Other substance use disorders: information not available

Other characteristics of study

Other pharmacological treatment: information not available

Funding sources: information not available

Declaration of interest: information not available

Other information

Data on response and remission were excluded because evaluated using a self‐administered scale.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random allocation stated. No further details provided.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No information on the design (double‐blind or open trial), on the preparation and appearance of medications, and on blinding of participants and personnel.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on study design (double‐blind or open trial).

Blinding of outcome assessment (detection bias) subjective

High risk

No information on study design (double‐blind or open trial).

Incomplete outcome data (attrition bias)
All outcomes

High risk

Methods applied to account for missing data. Intention‐to‐treat approach not reported. No high number of dropouts or unbalanced between groups.

Selective reporting (reporting bias)

Unclear risk

Information insufficient to permit judgement.

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

51 depressed people with alcohol dependence (26 men and 25 women; age (mean ± SD) = 34.8 ± 10.2 years)

Inclusion criteria:

• current DSM‐III‐R diagnoses of depression and alcohol dependence

Exclusion criteria:

• diagnosis of bipolar disorder, schizoaffective disorder, schizophrenia, or non‐alcohol substance dependence

• hyperthyroidism or hypothyroidism

• clinically significant medical diseases

• pregnancy

• mental retardation or cognitive impairment

• use of antipsychotic or antidepressant medication in the previous month

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• fluoxetine (20 mg/day; 25 participants)

• placebo (26 participants)

Psychotherapy:

• weekly supportive psychotherapy sessions

• weekly meetings with an attending psychiatrist with expertise in treating people with dual‐disorder

• attendance at Alcoholics Anonymous was encouraged.

Scheduled duration of treatment: 12 weeks

Site: Western Psychiatric Institute and Clinic of the University of Pittsburgh, Pittsburgh, USA

Setting: inpatients for first 2 weeks of abstinence, then outpatients

Route of administration: orally

Starting dose:

• 20 mg/day

• increased to 40 mg/day after 2 weeks if substantial residual depressive symptoms persisted

Pattern of dose reduction: information not available

Outcomes

Depression:

• difference between baseline and final HRSD score

• difference between baseline and final BDI score

Alcohol dependence:

• rate of abstinent days (obtained from cumulative number of drinking days)

• number of abstinent participants

• number of drinks per drinking day

• number of heavy drinking days per week (obtained from the cumulative number of heavy drinking days)

• time to first relapse (obtained from the number of weeks until first relapse)

Global assessment:

• severity (difference between baseline and final GAS score)

Dropouts: information not available

Adverse effects: information not available

Notes

Baseline characteristics of participants

Depression:

• primary depression: 100%

• duration: information not available

• after detoxification and washout, HRSD score (mean ± SD): fluoxetine = 19.2 ± 8.2; placebo = 17.9 ± 8.1

• number of diagnostic criteria (mean ± SD): fluoxetine = 6.7 ± 1.1; placebo = 6.8 ± 1.1

• current suicide ideation: fluoxetine = 92.0%; placebo = 88.5%

Alcohol dependence:

• number of diagnostic criteria (mean ± SD): fluoxetine = 5.5 ± 1.6; placebo = 5.9 ± 1.8; range: 3.9‐7.7

• duration: information not available

• being actively drinking: participants were actively drinking

• length of abstinence: 0

• number of drinking days in past 90 days (mean ± SD): fluoxetine = 54.5 ± 29.2; placebo = 45.2 ± 28.9

• number of days drinking to drunkenness in past 90 days (mean ± SD): fluoxetine = 40.1 ± 27.7; placebo = 32.0 ± 26.4

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance‐use disorders: participants with substance‐use disorders were excluded. Abuse of other substances was not an exclusionary criterion, provided that alcohol was the main substance of abuse.

Other characteristics of study

Other pharmacological treatment: other pharmacological treatments were not allowed.

Funding sources: work was supported by the National Institute on Alcohol Abuse and Alcoholism (grants AA09127 and AA10523), and by the Mental Health Clinical Research Center, Rockville, MD (grant MH30915).

Declarations of interest: information not available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization balanced for gender and race. It was not reported whether a computer‐generated list was used.

Allocation concealment (selection bias)

Unclear risk

Information insufficient to permit judgement. Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medications were administered in identical opaque capsules. Substantial blood levels of fluoxetine were observed in more than 99% of participants assigned to fluoxetine. Not reported if blood analyses were made also to participants who received placebo.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat analysis and last point carried forward analysis applied.

Selective reporting (reporting bias)

Unclear risk

Information insufficient to permit judgement.

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

14 depressed people with alcohol dependence (10 men and 4 women; mean age = 41.3 years)

Inclusion criteria:

• aged 18‐55 years

• current DSM‐IV diagnoses of depression and alcohol dependence

• eligible for outpatient treatment

Exclusion criteria:

• aged < 18 years or over 55 years

• presence of psychotic symptoms or a diagnosis involving psychosis

• receiving psychotropic medication in the prior month

• current DSM diagnosis of dependence or abuse on substances other than alcohol, cannabis, nicotine, or caffeine

• current significant medical or neurological condition

• suicidal ideation in the last 3 months, or lifetime suicidal attempt

• positive pregnancy test or breastfeeding

• inability or unwillingness to use contraceptive methods

• inability to read or understand study forms

• pending incarceration

• current participation in another research study

Participants with bipolar disorder: information not available

Interventions

Drugs:

• mirtazapine (30 mg/day; 7 participants; 4 men and 3 women)

• placebo (7 participants; 6 men and 1 woman)

Psychotherapy:

• brief MET at each assessment

Scheduled duration of treatment: 12 weeks

Site: University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, USA

Setting: outpatients

Route of administration: orally

Starting dose:

• 15 mg/day for the first 2 weeks

• then 30 mg/day for 12 weeks

Pattern of dose reduction: information not available

Outcomes

Depression:

• final BDI score

• difference between baseline and final BDI score

Alcohol dependence:

• number of drinking days per week

• number of drinks per drinking days

• number of drinks per week

• number of heavy drinking days per week

Craving for alcohol:

• final OCDS score

• difference between baseline and final OCDS score

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression: information not available

• duration: information not available

• BDI score (mean ± SD): mirtazapine = 27.6 ± 7.7; placebo = 26.1 ± 11.7

Alcohol dependence:

• severity: information not available

• duration: information not available

• number of drinks per drinking day (mean ± SD): 6.6 ± 2.0

• being actively drinking: participants were not abstinent

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment: participants did not receive other pharmacological treatments.

Funding sources: study received grants from the National Institute on Alcohol Abuse and Alcoholism (R21 AA022123, R21 AA022863, R01 AA013370, R01 AA015173, K24 AA15320) and from the National Institute on Drug Abuse (R01 DA019142, P50 DA05605, K02 DA017822).

Declarations of interest: information not available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information about sequence generation process to permit judgement of low or high risk.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Medications were identical in appearance (identical‐looking opaque capsules).

Blinding of outcome assessment (detection bias) objective

Low risk

Medications were identical in appearance (identical‐looking opaque capsules).

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat approach reported.

Selective reporting (reporting bias)

Low risk

No dropouts

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

76 people with alcohol dependence (all men; mean age = 42 years) in association with a predominant chronic anxiety or depressive reaction.

Inclusion criteria: information not available

Exclusion criteria:

• psychotic disorders

Participants with bipolar disorder: information not available

Interventions

Drugs:

• doxepin (150 mg/day, in 3 daily administrations; 24 participants; all men)

• doxepin (75 mg/day, in 3 daily administrations; 23 participants; all men)

• placebo (29 participants; all men)

Psychotherapy: information not available

Scheduled duration of treatment: 3 weeks

Site: Alcoholism Treatment Service of Southeast Louisiana Hospital, Mandeville, LA, USA

Setting: inpatients

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• response

Alcohol dependence: data not available

Dropouts

Adverse effects

Notes

Baseline characteristics of participants included inGallant 1969 arm a; Gallant 1969 arm b

Depression:

• primary depression: information not available

• duration: information not available

• severity: information not available

Alcohol dependence:

• severity: information not available

• being actively drinking: information not available

• duration: information not available

Other psychiatric comorbidity: participants with other mental disorders were included.

Other substance use disorders: information not available

Other characteristics of study

Other pharmacological treatment offered: information not available

Funding source: the project was partially supported by PHS Grant MH‐03701‐08, Psychopharmacology Research Branch, NIMH.

Declarations of interest: information not available

Other information

In the original study, 100 participants were divided into 4 groups:

• doxepin 150 mg/day (24 participants)

• doxepin 75 mg/day (23 participants)

• diazepam 15 mg/day (24 participants)

• placebo (29 participants)

In the present meta‐analysis, participants were divided into 2 substudies:

• Gallant 1969 arm a (76 participants), in which the 2 groups with different doses of doxepin were combined into a single group and compared to placebo group

• Gallant 1969 arm b (71 participants), in which the 2 groups with different doses of doxepin were combined into a single group and compared to diazepam group

The first arm (Gallant 1969 arm a) was included in the 'Effects of interventions: Antidepressants versus placebo' comparison and the second arm (Gallant 1969 arm b) in the 'Effects of interventions: Antidepressants versus other medications' comparison.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information about sequence generation process to permit judgement of low or high risk.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Medications were identical in appearance and were coded in accordance with double‐blind procedure to ensure that all personal involved in project remained blind as to which group any given participant belonged.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Methods applied to account for missing data not described. Intention‐to‐treat approach not reported. However, there were no dropouts.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement. However, there were no dropouts.

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

71 people with alcohol dependence (all men; mean age: 42 years) in association with a predominant chronic anxiety or depressive reaction (diagnosis of depression was uncertain).

Inclusion criteria: information not available

Exclusion criteria:

• psychotic disorders

Participants with bipolar disorder: information not available

Interventions

Drugs:

• doxepin (150 mg/day, in 3 daily administrations; 24 participants; all men)

• doxepin (75 mg/day, in 3 daily administrations; 23 participants; all men)

• diazepam (24 participants; all men)

Psychotherapy: information not available

Scheduled duration of treatment: 3 weeks

Site: Alcoholism Treatment Service of Southeast Louisiana Hospital, Mandeville, LA, USA

Setting: inpatients

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• response

Alcohol dependence: data not available (probably because of inpatient setting).

Dropouts

Adverse effects

Notes

Baseline characteristics of participants included inGallant 1969 arm a; Gallant 1969 arm b

Depression:

• primary depression: information not available

• duration: information not available

• severity: information not available

Alcohol dependence:

• severity: information not available

• being actively drinking: information not available

• duration: information not available

Other psychiatric comorbidity: participants with other mental disorders were included.

Other substance use disorders: information not available

Other characteristics of study

Other pharmacological treatment offered: information not available

Funding source: the project was partially supported by PHS Grant MH‐03701‐08, Psychopharmacology Research Branch, NIMH.

Declarations of interest: information not available

Other information

In the original study, 100 patients were divided into 4 groups:

• doxepin 150 mg/day (24 participants)

• doxepin 75 mg/day (23 participants)

• diazepam 15 mg/day (24 participants)

• placebo (29 participants)

In the present meta‐analysis, participants were divided into 2 substudies:

• Gallant 1969 arm a (76 participants), in which the 2 groups with different doses of doxepin were combined into a single group and compared to placebo group

• Gallant 1969 arm b (71 participants), in which the 2 groups with different doses of doxepin were combined into a single group and compared to diazepam group

The first arm (Gallant 1969 arm a) was included in the 'Effects of interventions: Antidepressants versus placebo' comparison and the second arm (Gallant 1969 arm b) in the 'Effects of interventions: Antidepressants versus other medications' comparison.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation process to permit judgement

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Medications were identical in appearance and were coded in accordance with double‐blind procedure to ensure that all personal involved in project remained blind as to which group any given participant belonged.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Methods applied to account for missing data not described. Intention‐to‐treat approach not reported. However, there were no dropouts.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement.

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

83 depressed people with alcohol dependence (44 men and 39 women; mean age = 47 years)

Inclusion criteria:

• age ≥ 18 years

• current DSM‐IV and ICD‐10 diagnoses of alcohol dependence and depression or dysthymia

Exclusion criteria:

• women who were pregnant, breastfeeding, or who were of childbearing potential and were not using reliable contraception or who wished to become pregnant during study or within 1 month after study

• psychiatric disorders apart from alcohol dependence and depressive symptoms

• moderate or severe liver disease including active cirrhosis or acute hepatitis

• high suicide risk

• requiring therapy with additional psychotropic drugs, ECT, or intensive psychotherapy during study

• history of convulsive disorders, cerebral organic disease, or laxative misuse within the 6 months prior to receiving test drug

• had received therapy with depot neuroleptics during the 6 months prior to their inclusion in study

• requiring medical treatment

• history of failure on sertraline or any other serotonin reuptake selective inhibitor, either alone or combined with another therapy

• people in whom sertraline therapy was contraindicated

• other severe organic diseases

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• sertraline (50–150 mg/day; 44 participants)

• placebo (39 participants)

Psychotherapy: information not available

Scheduled duration of treatment: 24 weeks

Site: Alcohol Unit of the Hospital ‘Clínico y Provincial' in Barcelona, Spain

Setting: outpatients

Route of administration: orally

Starting dose: 50 mg/day

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score (data obtained from a figure)

• final MADRS score (data obtained from a figure)

• response

• remission

Alcohol dependence:

• rate of abstinent days

• number of heavy drinkers

• time to first relapse

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression: information not available

• duration: about 3 years for men; about 1 year for women

• MADRS score (mean ± SD): sertraline = 22 ± 7; placebo = 23 ± 8

• HRSD score (mean ± SD): sertraline = 14 ± 6, placebo = 13 ± 4

Alcohol dependence:

• severity: information not available

• duration: about 16 years

• being actively drinking: participants had to be "abstinent for at least 2 weeks following detoxification" and "to have a negative drug and alcohol urine screen at inclusion"

• length of abstinence: ≥ 2 weeks

Other psychiatric comorbidity: people with other mental disorders were excluded.

Other substance‐use disorders: people with substance‐use disorders were excluded.

Other characteristics of study

Other pharmacological treatment: other pharmacological treatments were not allowed.

Funding source: information not available

Declarations of interest: information not available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random allocation stated. The investigator did not have access to the randomization code.

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Matching packets containing placebo were provided for all possible sertraline dose progressions, so that titration could be performed double blind. Medication was dispensed in bottles with MEMS caps, which contain an electronic monitoring device that records the date and time of bottle cap openings (Aprex Corp, San Diego, CA).

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat method utilized in all statistical analyses.

Selective reporting (reporting bias)

Low risk

For alcohol consumption data, participants with missing assessments at last observation were treated as non‐abstinent. For depression scale scores, missing data were handled on the principle of last observation carried forward.

Methods

Randomized, double‐blind, comparative trial

Participants

286 depressed people with alcohol dependence (222 men and 64 women; mean age: information not available).

Inclusion criteria:

• aged 21‐65 years

• ICD‐10 diagnoses of alcohol dependence or alcohol abuse and depression or bipolar disorder

• HRSD score ≥ 16

Exclusion criteria:

• any condition potentially dangerous, e.g. suicidal thoughts, psychotic depression, or pregnancy

• needs of treatment for other diseases

• treatments in near past with drugs that interfere with drugs in research or influence investigated therapy

• lack of conscious agreement

• depression resistant to pharmacotherapy

Participants with bipolar disorder were included.

Interventions

Drugs:

• tianeptine (37.5 mg/day; 146 participants; 109 men and 37 women; age: information not available)

• fluvoxamine (100 mg/day; 140 participants; 113 men and 27 women; age: information not available)

Psychotherapy: information not available

Scheduled duration of treatment: 6 weeks (responders were proposed to continue the same treatment up to 12 weeks).

Site: Department of Substance Use Prevention and Treatment, Institute of Psychiatry and Neurology, Warsaw, Poland

Setting: outpatients

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

• response

Alcohol dependence: data not available

Craving for alcohol:

• final OCDS score

Anxiety:

• final HRSA score

Dropout

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 12.2%

• duration: information not available

• HRSD score (mean ± SD): tianeptine = 22.2 ± 4.9; fluvoxamine = 21.8 ± 4.2

Alcohol dependence:

• alcohol dependence = 89.3%; alcohol abuse = 10.7%

• severity: information not available

• duration: information not available

• being actively drinking: participants had to be abstinent

• length of abstinence: ≥ 2 weeks

Craving for alcohol:

• OCDS score (mean ± SD): tianeptine = 18.2 ± 7.3; fluvoxamine = 18.1 ± 7.7

Anxiety:

• HRSA score (mean ± SD): tianeptine = 19.2 ± 6.2; fluvoxamine = 19.5 ± 6.9

Other psychiatric comorbidity: information not available

Other substance use disorders: information not available

Other characteristics of study

Other pharmacological treatment: other pharmacological treatments were not allowed.

Funding source: information not available

Declarations of interest: information not available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information to permit judgement.

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of participants and key study personnel ensured. Both drugs were blinded to participants.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only full analysis set were evaluated by the present meta‐analysis.

Selective reporting (reporting bias)

Low risk

Only full analysis set were evaluated by the present meta‐analysis.

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

41 depressed people with alcohol dependence (20 men and 21 women; age (mean ± SD): 42.9 ± 8.6 years)

Inclusion criteria:

• current DSM‐IV diagnoses of alcohol dependence and depression

• HRSD score ≥ 17 with a score ≥ 1 on item 1

• aged 21‐65 years

Exclusion criteria:

• history of major medical or psychiatric problems other than major depression or an anxiety disorder

• clinically significant baseline laboratory abnormalities or a positive pregnancy test

• current DSM‐IV diagnosis of drug dependence other than for alcohol or nicotine

• positive urine drug screen

• being treated with disulfiram or naltrexone or with any psychotropic drug

• being at serious suicide risk

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• nefazodone (200‐600 mg/day; 21 participants; 10 men and 11 women; age (mean ± SD): 43.1 ± 9.0 years)

• placebo (20 participants; 10 men and 10 women; age (mean ± SD): 42.7 ± 8.4 years)

Psychotherapy:

• participants received manual‐guided supportive psychotherapy at each study visit

Scheduled duration of treatment: 10 weeks

Site: Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA

Setting: outpatients

Route of administration: orally

Starting dose:

• 100 mg twice daily

• then titrated up to a maximum dose of 300 mg twice daily

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

Alcohol dependence:

• rate of abstinent days (obtained from weekly drinking days)

• number of abstinent participants

• number of drinking days per week

• number of drinks per week

• number of heavy drinking days per week

• final DrinC score

• final GGT levels

Anxiety:

• final STAI score

Sleep quality:

• final PSQI score

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression: information not available

• duration: information not available

• HRSD score (mean ± SD): nefazodone = 16.3 ± 2.3; placebo = 17.3 ± 2.0

Alcohol dependence:

• drinks per drinking days (mean ± SD): nefazodone = 6.4 ± 6.5; placebo = 8.4 ± 5.2

• duration: information not available

• being actively drinking: participants were not abstinent alcohol (their consumption had to be a mean ≥ 18 drinks per week for men or 14 drinks per week for women; heavy drinking (≥ 5 drinks for men and ≥ 4 drinks for women) on at least 1 day/week during the month preceding screening)

• length of abstinence at entry: 0 weeks

Anxiety:

• STAI score (mean ± SD): nefazodone = 51.1 ± 9.9; placebo = 47.9 ± 9.4

Quality of sleep

• PSQI score (mean ± SD): nefazodone = 22.2 ± 4.5; placebo = 22.1 ± 3.9

Other psychiatric comorbidity: participants with other mental disorders were included.

Other substance use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding sources: study supported by NIH Grants P50‐AA03510, K24‐AA13736, and M01‐RR06192 and the Bristol‐Myers Squibb Co.

Declarations of interest: information not available

Other information

After a baseline assessment, participants entered a 1‐week single‐blind placebo treatment, followed by random assignment to nefazodone or placebo groups.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Assignment to treatment groups used an urn randomization procedure, which balanced group assignment on sex, age, educational level, percentage of heavy drinking days, and severity of depressive symptoms at the time of the initial assessment.

Allocation concealment (selection bias)

Low risk

Method of concealment not reported but unlikely that selection bias was introduced.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of participants and key study personnel ensured.

Blinding of outcome assessment (detection bias) objective

Low risk

No information provided on blinding of assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information provided on blinding of assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Mixed model analysis used to examine variables measured at each visit during study. This procedure allows the inclusion of all cases (41 participants) by estimating individual trajectories even when other data points are missing because of participant attrition.

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported.

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

189 depressed people with alcohol dependence (123 men; 66 women; age (mean ± SD): placebo = 44.0 ± 8.0 years; sertraline = 41.7 ± 9.4 years)

Inclusion criteria:

• aged 21‐65 years

• current DSM‐IV diagnoses of alcohol dependence and depression (modified: to meet DSM‐IV criteria for depression, except that symptoms could have occurred during a period of heavy alcohol use)

• HRSD score ≥ 17

Exclusion criteria:

• pregnant, nursing, or of childbearing potential not using an effective method of contraception

• clinically significant co‐occurring psychiatric or medical diagnoses, including dependence on any psychoactive substance other than alcohol or nicotine during the preceding year

• current treatment with disulfiram, naltrexone, or psychotropic medication

• serum aminotransferase levels or other measures of hepatic function that were > 250% of normal

• significant suicidal risk

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• sertraline (up to 200 mg/day; 89 participants)

• placebo (100 participants)

Psychotherapy: at each study visit, participants received supportive therapy delivered according to a manual developed specifically for study consisting in:

• general support for abstinence

• promotion of compliance

• monitoring of medication adverse effects

Scheduled duration of treatment: for up to 10 weeks

Sites: 13 investigative sites in USA

Setting: outpatients

Route of administration: orally

Starting dose: 50 mg/day

Pattern of dose reduction:

• participants who achieved a satisfactory therapeutic response and who wished to continue treatment beyond the end of week 10 were continued double‐blind on the same medication they were taking at the end of week 10 for an additional 14‐week period;

• participants who did not continue in the extension study were tapered off medication by reducing the daily dose by one capsule every 2 to 3 days until the medication was completely discontinued.

Outcomes

Depression:

• final HRSD score (obtained from a figure)

• difference between baseline and final HRSD score

• response

Alcohol dependence:

• rate of abstinent days (obtained from a figure)

Dropout

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 100%

• duration: information not available

• number of DSM‐IV criteria (mean ± SD): sertraline = 6.7 ± 1.0; placebo = 6.8 ± 1.2

• HRSD score (mean ± SD): sertraline = 20.3 ± 2.8; placebo = 20.9 ± 4.0

Alcohol dependence:

• number of DSM‐IV criteria (mean ± SD): sertraline = 5.6 ± 0.9; placebo = 5.5 ± 0.9

• number of drinks per week (mean ± SD): sertraline = 45.9 ± 32.2; placebo = 63.1 ± 44.4

• duration (mean ± SD): sertraline = 11.9 ± 9.0 years; placebo = 11.9 ± 9.9 years

• being actively drinking: participants had to have drunk a mean of 18 drinks weekly for men or 14 drinks weekly for women and at least 1 heavy drinking day per week during the month before screening

• length of abstinence: at least 4 days with no heavy drinking and no more than 16 days of abstinence

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding source: supported by Pfizer Pharmaceuticals. Manuscript preparation supported by NIH grant K24 AA13736.

Declarations of interest: information not available.

Other information

In the original study, 328 participants were divided into the 2 groups on whether initially elevated HRSD score declined with cessation of heavy drinking:

• HRSD score ≥ 17 (189 participants);

• HRSD score ≤ 16 (139 participants).

In the present meta‐analysis, participants were divided into 2 substudies:

• Kranzler 2006 arm A (189 participants with HRSD scores ≥ 17);

• Kranzler 2006 arm B (139 participants which HRSD scores ≤ 16).

Both the substudies (Kranzler 2006 arm A; Kranzler 2006 arm B) were included in the 'Effects of interventions: Antidepressants versus placebo' comparison. Unfortunately, the original study did not report the adverse events for the single substudies.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomization schedule.

Allocation concealment (selection bias)

Unclear risk

Assignment to medication group was done according to a computer‐generated randomization schedule for groups A and B, with the medication groups within each stratum balanced for recent outpatient/inpatient status.

Despite random assignment, participants who received placebo were older, reported more drinks per week during the pretreatment period, and had higher CGI depression scores at baseline.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All analyses used an intention‐to‐treat approach.

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported. However, some of them were reported only as a % reduction (e.g. BDI score).

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

139 depressed people with alcohol dependence (86 men and 53 women; age (mean ± SD): placebo = 42.9 ± 9.2 years; sertraline = 41.8 ± 9.4 years)

Inclusion criteria:

• aged 21‐65 years

• current DSM‐IV diagnoses of alcohol dependence and depression (modified: to meet DSM‐IV criteria for depression, except that symptoms could have occurred during a period of heavy alcohol use)

• HRSD score ≤ 16 with cessation of heavy drinking

Exclusion criteria:

• pregnant, nursing, or women of childbearing potential not using an effective method of contraception

• clinically significant co‐occurring psychiatric or medical diagnoses

• including dependence on any psychoactive substance other than alcohol or nicotine during the preceding year

• current treatment with disulfiram, naltrexone, or psychotropic medication

• serum aminotransferase levels or other measures of hepatic function > 250% of normal

• significant suicidal risk

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• sertraline (up to 200 mg/day; 70 participants)

• placebo (69 participants)

Psychotherapy:

At each study visit, participants received supportive therapy delivered according to a manual developed specifically for study consisting of:

• general support for abstinence;

• promotion of compliance;

• monitoring of medication adverse effects.

Scheduled duration of treatment: up to 10 weeks

Sites: 13 investigative sites in the USA

Setting: outpatients

Route of administration: orally

Starting dose: 50 mg/day

Pattern of dose reduction:

• participants who achieved a satisfactory therapeutic response and who wished to continue treatment beyond the end of week 10 were continued double‐blind on the same medication they were taking at the end of week 10 for an additional 14‐week period;

• participants who did not continue in the extension study were tapered off medication by reducing the daily dose by 1 capsule every 2 or 3 days until the medication was completely discontinued.

Outcomes

Depression:

• final HRSD score (obtained from a figure)

• difference between baseline and final HRSD score

• response

Alcohol dependence:

• rate of abstinent days (obtained from a figure)

Dropout

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 0%

• duration: information not available

• number of DSM‐IV criteria (mean ± SD): sertraline = 5.3 ± 1.3; placebo = 5.4 ± 1.1

• HRSD score (mean ± SD): sertraline = 12.6 ± 2.8; placebo = 12.5 ± 2.9

Alcohol dependence:

• number of DSM‐IV criteria (mean ± SD): sertraline = 4.6 ± 1.2; placebo = 4.5 ± 1.0

• number of drinks per week (mean ± SD): sertraline = 54.4 ± 40.5; placebo = 46.8 ± 27.9

• duration (mean ± SD): sertraline = 10.7 ± 8.1 years; placebo = 11.1 ± 8.5 years

• being actively drinking: participants had to have drunk a mean of 18 drinks weekly for men or 14 drinks weekly for women and at least 1 heavy drinking day per week during the month before screening

• length of abstinence: at least 4 days with no heavy drinking and no more than 16 days of abstinence

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding source: study supported by Pfizer Pharmaceuticals. Manuscript preparation supported by NIH grant K24 AA13736.

Declarations of interest: information not available

Other information

In the original study, 328 participants were divided into the 2 groups on whether initially elevated HRSD score declined with cessation of heavy drinking:

• HRSD score ≥ 17 (189 participants);

• HRSD score ≤ 16 (139 participants).

In the present meta‐analysis, participants were divided into 2 substudies:

• Kranzler 2006 arm A (189 participants with HRSD scores ≥ 17);

• Kranzler 2006 arm B (139 participants which HRSD scores ≤ 16).

Both the substudies (Kranzler 2006 arm A; Kranzler 2006 arm B) were included in the 'Effects of interventions: Antidepressants versus placebo' comparison. Unfortunately, the original study did not report the adverse events for the single substudies.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomization schedule reported.

Allocation concealment (selection bias)

Unclear risk

The method of concealment was not described. Despite random assignment, participants who received placebo were older, reported more drinks per week during the pretreatment period, and had higher CGI depression scores at baseline.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information provided.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All analyses used an intention‐to‐treat approach. Weekly comparisons including only participants for whom data were available from that visit, whereas end of study analyses used last observation carried forward analysis.

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported. However, some of them were reported only as a % reduction (e.g. BDI score).

Methods

Randomized, placebo‐controlled trial

Participants

41 people with alcohol dependence (number of men and women not available; mean age = 36‐37 years) with non‐severe affective disorders

Inclusion criteria: information not available

Exclusion criteria: information not available

Participants with bipolar disorder: information not available

Interventions

Drugs:

• amitriptyline (dose: 75 mg/day; 18 participants; number of men and women not available; age (mean ± SD): 36.3 ± 1.9 years)

• placebo (23 participants; number of men and women not available; age (mean ± SD): 37.3 ± 1.7 years)

Psychotherapy: information not available

Scheduled duration of treatment: 3 weeks

Site: Russia

Setting: inpatients

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final ZUNG score

• final MMPI score

Alcohol dependence: no information provided

Anxiety:

• final STAI score

• final MMPI score

Dropouts: data not available

Adverse effects: information not provided

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 100%

• duration: information not available

• ZUNG score (mean ± SD): amitriptyline = 55.6 ± 1.2; placebo = 55.3 ± 1.0

• MMPI score (mean ± SD): amitriptyline = 82.1 ± 1.5; placebo = 81.3 ± 3.9

Alcohol dependence:

• severity: information not available

• duration: information not available

• participants were abstinent for at least 3‐4 weeks

Anxiety:

• STAI score (mean ± SD): amitriptyline = 51.9 ± 2.6; placebo = 52.5 ± 2.9

• MMPI score (mean ± SD): amitriptyline = 25.5 ± 1.9; placebo = 28.0 ± 2.0

Other psychiatric comorbidity: information not available

Other substance use disorders: information not available

Other characteristics of study

Other pharmacological treatment offered: other treatments were not administrated during study

Funding sources: information not available.

Other information

In the original study, 90 people with alcohol dependence were randomly divided into 4 groups:

• baclofen (37.5 mg/day, 29 participants)

• diazepam (15 mg/day; 20 participants)

• amitriptyline (75 mg/day, 18 participants)

• placebo (23 participants)

In the present meta‐analysis, study was divided into 2 substudies:

• Krupitsky 1993 arm A, which included the group 'amitriptyline' and the group 'placebo'

• Krupitsky 1993 arm B, which included the group 'amitriptyline' and the group 'diazepam'

The first substudy (Krupitsky 1993 arm A) was included in the 'Effects of interventions: Antidepressants versus placebo' comparison and the second substudy (Krupitsky 1993 arm B) in the 'Antidepressants versus other medications' comparison

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information about the sequence generation process to permit judgement.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not reported if it was a double‐ or single‐blind study.

Blinding of outcome assessment (detection bias) objective

Low risk

Not reported if it was a double‐ or single‐blind study.

Blinding of outcome assessment (detection bias) subjective

High risk

Not reported if it was a double‐ or single‐blind study.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Number of dropouts not reported.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement.

Methods

Randomized, controlled trial

Participants

38 people with alcohol dependence (number of men and women not available; mean age = 36‐37 years) with affective disorders not severe

Inclusion criteria: information not available

Exclusion criteria: information not available

Participants with bipolar disorder: information not available

Interventions

Drugs:

• amitriptyline (75 mg/day; 18 participants; number of men and women not available; age (mean ± SD): 36.3 ± 1.9 years)

• diazepam (15 mg/day; 20 participants; number of men and women not available; age (mean ± SD): 38.3 ± 1.8 years)

Psychotherapy: information not available

Scheduled duration of treatment: 3 weeks

Site: Russia

Setting: inpatients

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final ZUNG score

• final MMPI score

Alcohol dependence: no information provided

Anxiety:

• final STAI score

• final MMPI score

Dropouts: data not available

Adverse effects: data not available

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 100%

• duration: information not available

• ZUNG score (mean ± SD): amitriptyline = 55.6 ± 1.2; diazepam = 54.2 ± 0.6

• MMPI score (mean ± SD): amitriptyline = 82.1 ± 1.5; diazepam =81.1 ± 3.3

Alcohol dependence:

• severity: information not available

• duration: information not available

• being actively drinking: participants were abstinent for at least 3‐4 weeks

Anxiety:

• STAI score (mean ± SD): amitriptyline = 51.9 ± 2.6; diazepam = 51.8 ± 1.5

• MMPI score (mean ± SD): amitriptyline = 25.5 ± 1.9; diazepam = 27.0 ± 1.7

Other psychiatric comorbidity: information not available

Other substance use disorders: information not available

Other characteristics of study

Other pharmacological treatment offered: other treatments were not administrated during study

Funding sources: information not available

Other information

In the original study, 90 people with alcohol dependence were randomly divided into 4 groups:

• baclofen (37.5 mg/day, 29 participants)

• diazepam (15 mg/day; 20 participants)

• amitriptyline (75 mg/day, 18 participants)

• placebo (23 participants)

In the present meta‐analysis, study was divided into 2 substudies:

• Krupitsky 1993 arm A, which included the group 'amitriptyline' and the group 'placebo'

• Krupitsky 1993 arm B, which included the group 'amitriptyline' and the group 'diazepam'

The first substudy (Krupitsky 1993 arm A) was included in the 'Effects of interventions: Antidepressants versus placebo' comparison and the second substudy (Krupitsky 1993 arm B) in the 'Antidepressants versus other medications' comparison.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information about sequence generation process to permit judgement.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not reported if it was a double‐ or single‐blind study.

Blinding of outcome assessment (detection bias) objective

Low risk

Not reported if it was a double‐ or single‐blind study.

Blinding of outcome assessment (detection bias) subjective

High risk

Not reported if it was a double‐ or single‐blind study.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Number of dropouts not reported.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement.

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

60 depressed people with alcohol dependence (47 men and 13 women; age (mean ± SD): escitalopram = 43.9 ± 1.1 years; placebo = 40.9 ± 1.3 years).

Inclusion criteria:

• current ICD‐10 diagnoses of alcohol dependence and affective disorders (a depression episode, a moderate depression episode, or a recurrent depression disorder)

• HRSD score: 7‐23

Exclusion criteria:

• substance dependence besides alcohol or nicotine dependence

• bipolar‐affective disorder, schizophrenia, or other psychotic or organic mental disorders

• other psychotropic drug

• severe medical illnesses

• pregnancy

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• escitalopram (10 mg/day; 29 participants; 22 men and 7 women)

• placebo (31 participants, 25 men and 6 women)

Psychotherapy:

• medical management which included elements of cognitive behavioural psychotherapy, once a week

Scheduled duration of treatment: 13 weeks

Site: a single‐site at the Department of Narcology (Addiction Psychiatry) of the Bekhterev PsychoNeurological Research Institute, St Petersburg, Russia

Setting: outpatients

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

• final MADRS score

• final ZUNG score

Alcohol dependence:

• heavy drinkers

• time to first relapse

• final GGT levels

Craving for alcohol:

• final PACS score

• final OCDS score

• final VAS score

Global response:

• response

• final GAF score

Anxiety:

• final HRSA score

• final STAI score

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): information not available

• duration: information not available

• severity: mild or moderate depression

Alcohol dependence:

• duration (mean ± SD): escitalopram = 11.5 ± 1.5 years; placebo = 9.5 ± 1.4 years

• being actively drinking: participants had to be abstinent at least 7 days and had a negative alcohol test on expired air

• length of abstinence: 1 week

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding source: information not available.

Declarations of interest: information not available.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was performed by means of generation random numbers in Excel.

Allocation concealment (selection bias)

Low risk

Sequentially numbered drug containers of identical appearance.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The investigators, doctors, participants, and any other staff members taking part in the experiment were unaware which of the groups any particular person belonged to.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Methods: participants who relapsed to heavy drinking were excluded from study.

Results: the relatively small number of alcohol consumption days in the groups was due to participants who relapsed being excluded from trial.

Selective reporting (reporting bias)

High risk

Methods: participants who relapsed to heavy drinking were excluded from study.

Results: the relatively small number of alcohol consumption days in the groups was due to participants who relapsed being excluded from trial.

Methods

Randomized, single‐blind, comparative trial

Participants

30 people with alcohol dependence of an original group constituted by 60 participants (41 men and 19 women; mean age: 47 years)

Inclusion criteria:

• current DSM‐IV diagnosis of alcohol abuse or alcohol dependence

• aged 18‐70 years

Exclusion criteria:

• DSM‐IV diagnosis of primary depression; secondary depression was not an exclusion criterion

• serious physical illness

• other pre‐ or coexisting major psychiatric disorder, i.e. any psychotic disorder and bipolar disorder

• other drug abuse, excluding nicotine

Participants with bipolar disorder were excluded.

Interventions

Treatment:

• mirtazapine (30‐60 mg/day, in 1‐2 divided doses per day; 20 participants; 13 men and 7 women) and psychotherapy

• only psychotherapy (10 participants)

Psychotherapy: cognitive behavioural psychotherapy administered in individual sessions and family interventions, twice a week

Scheduled duration of treatment: 3 weeks

Site: Drug and Alcohol Addiction Clinic, Athens University Psychiatric Clinic, Eginition Hospital, Athens, Greece

Setting: inpatients for 1 week, then residential treatment

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

Alcohol dependence: no information available

Anxiety:

• final HRSA score

Global assessment:

• final GAS score

Dropouts

Adverse effects: data not available

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 0%

• duration: information not available

• HRSD score (mean ± SD): mirtazepine = 37.9 ± 7.8; controls = 39

Alcohol dependence:

• drinks per drinking days (mean ± SD): mirtazepine = 27.6 ± 18.5; controls = 22.1,

• duration (mean ± SD): mirtazepine = 15 years; controls = 14 years,

• being actively drinking: participants were detoxicated before treatment,

• length of abstinence: 1 week

Anxiety:

• HRSA score (mean ± SD): mirtazapine = 33.2 ± 12.6; controls = 33.

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance‐use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding source: information not available

Declarations of interest: information not available

Other information

In the original study, 60 participants were included into 4 groups:

• only psychotherapy (20 participants)

• mirtazapine plus psychotherapy (20 participants)

• venlafaxine plus psychotherapy (20 participants)

Participants but not clinicians were blind to group status

In the present meta‐analysis, we divided the control group (only psychotherapy) into 2 smaller groups, and compared these 2 smaller groups to the 2 antidepressants, using 3 subgroups:

• Liappas 2005 arm A ('Effects of interventions: Antidepressants versus psychotherapy') included 10 participants of the group 'only psychotherapy' and the group 'mirtazapine plus psychotherapy'

• Liappas 2005 arm B ('Effects of interventions: Antidepressants versus psychotherapy') included 10 participants of the group 'only psychotherapy' and the group 'venlafaxine plus psychotherapy'

• Liappas 2005 arm C ('Effects of interventions: Antidepressants versus another antidepressant') included the group 'mirtazapine plus psychotherapy' and the group 'venlafaxine plus psychotherapy'

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer random sequence generation was used ("At the end of the first week, individuals were randomly/electronically allocated to one of the three groups").

Allocation concealment (selection bias)

Low risk

Computer sequence of allocation used.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Single‐blind study ("Patients but not clinicians were blind to group status").

Blinding of outcome assessment (detection bias) objective

Low risk

Single‐blind study ("Patients but not clinicians were blind to group status").

Blinding of outcome assessment (detection bias) subjective

High risk

Single‐blind study ("Patients but not clinicians were blind to group status").

Incomplete outcome data (attrition bias)
All outcomes

High risk

Dropouts were not included in the analysis due to missing data.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement.

Methods

Randomized, single‐blind, comparative trial

Participants

30 people with alcohol dependence of an original group constituted by 60 participants (41 men and 19 women; mean age: 47 years)

Inclusion criteria:

• current DSM‐IV diagnosis of alcohol abuse or alcohol dependence

• aged 18‐70 years

Exclusion criteria:

• DSM‐IV diagnosis of primary depression; secondary depression was not an exclusion criterion

• serious physical illness

• other pre‐ or coexisting major psychiatric disorder, i.e. any psychotic disorder and bipolar disorder

• other drug abuse, excluding nicotine

Participants with bipolar disorder were excluded.

Interventions

Treatment:

• venlafaxine (150‐300 mg/day, in 1‐2 divided doses per day; 20 participants; 13 men and 7 women) and psychotherapy

• only psychotherapy (10 participants)

Psychotherapy: cognitive behavioural psychotherapy was administered in individual sessions and family interventions, twice a week

Scheduled duration of treatment: 3 weeks

Site: Drug and Alcohol Addiction Clinic, Athens University Psychiatric Clinic, Eginition Hospital, Athens, Greece

Setting: inpatients for 1 week, then residential treatment

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

Alcohol dependence: no information available

Anxiety:

• final HRSA score

Global assessment:

• final GAS score

Dropouts

Adverse effects: data not available

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 0%

• duration: information not available

• HRSD score (mean ± SD): venlafaxine = 41.9 ± 4.5; controls = 39

Alcohol dependence:

• drinks per drinking days (mean ± SD): venlafaxine = 18.4 ± 6.2; controls = 22.1

• duration (mean ± SD): venlafaxine = 17 years; controls = 14 years

• being actively drinking: participants were detoxicated before treatment

• length of abstinence: 1 week

Anxiety:

• HRSA score (mean ± SD): venlafaxine = 36.6 ± 5.4; controls = 33

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance‐use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding source: information not available

Declarations of interest: information not available

Other information

In the original study, 60 participants were included into 4 groups:

• only psychotherapy (20 participants)

• mirtazapine plus psychotherapy (20 participants)

• venlafaxine plus psychotherapy (20 participants)

Participants but not clinicians were blind to group status

In the present meta‐analysis, we divided the control group (only psychotherapy) into 2 smaller groups, and compared these 2 smaller groups to the 2 antidepressants, using 3 subgroups:

• Liappas 2005 arm A ('Effects of interventions: Antidepressants versus psychotherapy') included 10 participants of the group 'only psychotherapy' and the group 'mirtazapine plus psychotherapy'

• Liappas 2005 arm B ('Effects of interventions: Antidepressants versus psychotherapy') included 10 participants of the group 'only psychotherapy' and the group 'venlafaxine plus psychotherapy'

• Liappas 2005 arm C ('Effects of interventions: Antidepressants versus vs another antidepressant') included the group 'mirtazapine plus psychotherapy' and the group 'venlafaxine plus psychotherapy'

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer random sequence generation reported ("At the end of the first week, individuals were randomly/electronically allocated to one of the three groups")

Allocation concealment (selection bias)

Low risk

Computer sequence of allocation reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Single‐blind study ("Patients but not clinicians were blind to group status").

Blinding of outcome assessment (detection bias) objective

Low risk

Single‐blind study ("Patients but not clinicians were blind to group status").

Blinding of outcome assessment (detection bias) subjective

High risk

Single‐blind study ("Patients but not clinicians were blind to group status").

Incomplete outcome data (attrition bias)
All outcomes

High risk

Dropouts were not included in the analysis due to missing data.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement.

Methods

Randomized, single‐blind, comparative trial

Participants

40 people with alcohol dependence of an original group constituted by 60 participants (41 men and 19 women; mean age: 47 years)

Inclusion criteria:

• current DSM‐IV diagnosis of alcohol abuse or alcohol dependence

• aged 18‐70 years

Exclusion criteria:

• DSM‐IV diagnosis of primary depression; secondary depression was not an exclusion criterion

• serious physical illness

• other pre‐ or coexisting major psychiatric disorder, i.e. any psychotic disorder and bipolar disorder

• other drug abuse, excluding nicotine

Participants with bipolar disorder were excluded.

Interventions

Drugs:

• mirtazapine (30‐60 mg/day, in 1‐2 divided doses per day, 20 participants; 13 men and 7 women) and psychotherapy

• venlafaxine (150‐300 mg/day, in 1‐2 divided doses per day; 20 participants; 13 men and 7 women) and psychotherapy

Psychotherapy: cognitive behavioural psychotherapy was administered in individual sessions and family interventions, twice a week.

Scheduled duration of treatment: 3 weeks

Site: Drug and Alcohol Addiction Clinic, Athens University Psychiatric Clinic, Eginition Hospital, Athens, Greece

Setting: inpatients for 1 week, then residential treatment

Route of administration: orally

Starting dose: information not available

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

Alcohol dependence: no information available

Anxiety:

• final HRSA score

Global assessment:

• final GAS score

Dropouts

Adverse effects: data not available

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 0%

• duration: information not available

• HRSD score (mean ± SD): mirtazepine = 37.9 ± 7.8; venlafaxine = 41.9 ± 4.5

Alcohol dependence:

• drinks per drinking days: mirtazepine = 27.6 ± 18.5; venlafaxine = 18.4 ± 6.2

• duration: venlafaxine = 17 years; controls = 14 years

• being actively drinking: participants were detoxicated before treatment

• length of abstinence: 1 week

Anxiety:

• HRSA score (mean ± SD): mirtazapine: 33.2 ± 12.6; venlafaxine = 36.6 ± 5.4

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding source: information not available

Declarations of interest: information not available

Other information

In the original study, 60 participants were included into 4 groups:

• only psychotherapy (20 participants)

• mirtazapine plus psychotherapy (20 participants)

• venlafaxine plus psychotherapy (20 participants)

Participants but not clinicians were blind to group status.

In the present meta‐analysis, we divided the control group (only psychotherapy) into 2 smaller groups, and compared these 2 smaller groups to the 2 antidepressants, using 3 subgroups:

• Liappas 2005 arm A ('Effects of interventions: Antidepressants versus psychotherapy') included 10 participants of the group 'only psychotherapy' and the group 'mirtazapine plus psychotherapy'

• Liappas 2005 arm B ('Effects of interventions: Antidepressants versus psychotherapy') included 10 participants of the group 'only psychotherapy' and the group 'venlafaxine plus psychotherapy'

• Liappas 2005 arm C ('Effects of interventions: Antidepressants versus another antidepressant') included the group 'mirtazapine plus psychotherapy' and the group 'venlafaxine plus psychotherapy'

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer random sequence generation reported ("At the end of the first week, individuals were randomly/electronically allocated to one of the three groups")

Allocation concealment (selection bias)

Low risk

Computer sequence of allocation reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Single‐blind study, and the outcomes are likely to be influenced by lack of blinding ("Patients but not clinicians were blind to group status").

Blinding of outcome assessment (detection bias) objective

Low risk

Single‐blind study, and the outcomes are likely to be influenced by lack of blinding ("Patients but not clinicians were blind to group status").

Blinding of outcome assessment (detection bias) subjective

High risk

Single‐blind study, and the outcomes are likely to be influenced by lack of blinding ("Patients but not clinicians were blind to group status").

Incomplete outcome data (attrition bias)
All outcomes

High risk

Dropouts were not included in the analysis due to missing data.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement.

Methods

Randomized, double‐blind, comparative trial

Participants

129 people with alcohol dependence with depression or dysthymic disorder (111 men and 18 women; mean age: approximately 38 years)

Inclusion criteria:

• DSM‐III diagnoses of alcohol dependence or alcohol abuse and depression or dysthymia

• MADRS score ≥ 20

Exclusion criteria:

• persistent alcohol intoxication at time of trial

• presence of psychotic traits

• recent antidepressant or neuroleptic treatment

• serious somatic illness

• pregnancy or absence of contraception in a woman of childbearing potential

Participants with bipolar disorder: information not available

Interventions

Drugs:

• tianeptine (37.5 mg/day; 64 participants; 57 men and 7 women; age (mean ± SD): 37.9 ± 1.0 years)

• amitriptyline (75.0 mg/day; 65 participants; 54 men and 11 women)

Psychotherapy: information not available

Scheduled duration of treatment: 4‐8 weeks (depending on the centre concerned)

Sites: 7 centres, in France

Setting: unclear

Route of administration: orally

Starting dose: tianeptine = 37.5 mg/day; amitriptyline = 75.0 mg/day

Pattern of dose reduction: information not available

Outcomes

Depression:

• final MADRS score (obtained from a figure)

• final SCL‐90 (obtained from a figure)

• response

Alcohol dependence: data not available

Anxiety:

• final HRSA score (obtained from a figure)

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 100%

• duration: information not available

• MADRS score (mean ± SD): tianeptine = 30.0 ± 0.8; amitriptyline = 29.3 ± 0.8

Alcohol dependence:

• duration: information not available

• severity: information not available

• being actively drinking: participants were withdrawn from alcohol 2‐5 weeks before inclusion

Other psychiatric comorbidity: information not available

Other substance use disorders: information not available

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were allowed.

Funding source: information not available

Declarations of interest: information not available

Other information

In the original study, the duration of the trial was 4‐8 weeks depending on the centre concerned. In the present meta‐analysis, only data of 4 weeks were analyzed.

Before the onset of the trial, participants received a pretreatment with a placebo for 3‐10 days to screen out placebo‐responder participants. After this period, participants received tianeptine or amitriptyline.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information to permit judgement.

Allocation concealment (selection bias)

Unclear risk

Method of concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Double‐blind stated. Medication and placebo prepared to appear identical. No specific reference made to blinding of participants and personnel.

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.

Blinding of outcome assessment (detection bias) subjective

Unclear risk

No information on the blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Intention‐to‐treat analysis not used. However, the numbers of dropouts were low (10/64, 12/65) and were not unbalanced between groups.

Selective reporting (reporting bias)

High risk

Several data were missing (final MADRS score for amitriptyline, adverse effects, and alcohol consumption).

Methods

Randomized, double‐blind, placebo‐controlled trial

Participants

28 depressed people with alcohol dependence (24 men and 4 women; mean age = desimipramine: 36.0 ± 22 years; placebo = 41.0 ± 15.5 years)

Inclusion criteria:

• current DSM‐III‐R diagnoses of alcohol dependence and depression

• secondary depression

• aged 18‐65 years

Exclusion criteria:

• primary depression

• instable medical illnesses

• pregnancy

• psychosis

• suicidal ideation

• cognitively impairment

• dependence on any substance except alcohol or nicotine

Participants with bipolar disorder: information not available

Interventions

Drugs:

• desimipramine (200 mg/day; 15 participants; 13 men and 2 women)

• placebo (13 participants; 11 men and 2 women)

Psychotherapy: participants were encouraged to participate in Alcoholics Anonymous and any other psychosocial treatments.

Scheduled duration of treatment: 6 months

Sites: Department of the New York (NY) Hospital‐Cornell Medical Center, and the University of Miami (FL), School of Medicine, USA

Setting: outpatients

Route of administration: orally

Starting dose: medication was prescribed in divided doses for the first week, then changed to bedtime dosing

Pattern of dose reduction: information not available

Outcomes

Depression:

• final HRSD score

• difference between baseline and final HRSD score

• response

Alcohol dependence:

• number of heavy drinkers (obtained from a figure)

Dropouts

Adverse effects

Notes

Baseline characteristics of participants

Depression:

• primary depression (rate of participants): 0%

• HRSD score (mean ± SD): desimipramine = 20.5 ± 9.7; placebo = 19.0 ± 11.0

• family history of depression: desimipramine = 41%; placebo = 83%

Alcohol dependence:

• ADS score (mean ± SD): desimipramine = 23.5 ± 10.5; placebo = 23.0 ± 13.0

• duration: information not available

• being actively drinking: participants had to be abstinent (maximum = 3 months; minimum = 1 week)

• number of drinks per drinking days (mean ± SD): desimipramine = 15.0 ± 15.0; placebo = 13.0 ± 6.7

• family history of alcohol dependence: desimipramine = 66%; placebo = 66%

Other psychiatric comorbidity: participants with other mental disorders were excluded.

Other substance use disorders: participants with substance use disorders were excluded.

Other characteristics of study

Other pharmacological treatment offered: other pharmacological treatments were not allowed.

Funding source: grants from the National Institute on Alcohol Abuse and Alcoholism (AA06866 and AA08111)

Declarations of interest: information not available

Other information

Final HRSD score and difference between baseline and final HRSD score were excluded because they were expressed as medians and interquartile ranges.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information about sequence generation process to permit judgement.

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind stated and blinding of key study personnel ensured by sentences of the evaluation of plasma desipramine concentration. "Plasma desipramine concentration was assessed and results were reviewed by a physician not involved in patient ratings to verify compliance and make dose recommendations. Equivalent dosing instructions were given by the nonblinded physician to blinded therapists for placebo‐treated patients to preserve the double‐blind study design."

Blinding of outcome assessment (detection bias) objective

Low risk

No information on the blinding of outcome assessors.