Methods

Design: single‐centre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 12 weeks and 6 days of dose‐tapering

Post‐treatment: no follow‐up

Placebo run‐in: 1‐week assessment period without medication

Participants

Sample size: 92 randomised to paroxetine and placebo

Mean age: 41 years

Sex: 48 men and 44 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Aged 18‐65 years with previously untreated and incapacitating social anxiety; DSM‐IV social anxiety disorder causing substantial impairment and with a duration of at least 1 year; DSM‐IV diagnoses of generalised anxiety, dysthymia or a cluster C personality disorder were the only concurrent psychiatric disorders allowed".

Exclusion criteria: quote: "No psychoactive medications were permitted, including beta‐receptor‐blocking agents; the blood and urine of all subjects was screened for substance abuse"

Dropouts: 27/92 (8/44 in the paroxetine group and 19/48 in the placebo group)

Interventions

Pharmacological intervention: quote: "The subjects were randomly allocated at baseline to double‐blind treatment for three months with paroxetine 20‐50 mg daily administered in 10‐mg weekly increments, or placebo. One dose reduction was allowed in case of adverse events."

Outcomes

Primary outcomes: LSAS (for reduction of anxiety) and CGI (for treatment efficacy)

Secondary outcomes: BSPS (for reduction of anxiety), SDI (for reduction of functional disability), FNES (for reduction of anxiety) and VAS scores (reflecting self‐confidence in social interactions, anticipatory anxiety, acute anxiety reactions in social situations, and dysphoria following anxiety reactions)

Time points: Quote: "Assessments were made after 1, 2, 4, 6, 8 and 12 weeks, and after 6 days of dose‐tapering"

Notes

Industry funded: yes. Quote: "This study was funded by Novo Nordisk Pharma, Sweden."

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed at the hospital pharmacy using tabulated random numbers"

Allocation concealment (selection bias)

Low risk

Author correspondence: quote: "The randomization and blinding and packaging of study materials were undertaken by our hospital pharmacy and by Wyeth"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No description of blinding is provided in the study report. Quote: "Patients were randomized to double‐blind treatment with paroxetine 20‐50 mg daily or placebo for 3 months"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No mention is made of whether the outcome assessors were indeed blinded and independent. Quote: "To reduce variability in assessments, all subjects were treated and assessed in one centre by the author and a research nurse"

Incomplete outcome data (attrition bias)
All outcomes

High risk

A larger proportion of participants discontinued the study in the paroxetine (8/44; 18%) group compared to the placebo group (19/48; 39%). Reasons for treatment withdrawal were provided for the treatment group with only reasons given for 5 participants in the placebo group. No information was provided on sample characteristics at endpoint. Overall 29% of the participants dropped out of the study. All analyses were intention‐to‐treat (ITT)

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. Quote: "Comparatively high response rate of subjects on paroxetine and the low response rate of those on placebo in this study may be due to the low variability in assessments in a single centre, the use of self‐rating instruments, or the fact that only previously untreated cases were included"

Methods

Design: multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group trial

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1‐week, single‐blind, placebo lead‐in period

Participants

Sample size: 434 were randomised to venlafaxine, paroxetine, or placebo (2 individuals excluded; 389 ITT population)

Mean age (SD): 38.8 (10.97) years

Sex: 183 men and 206 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Study participants were adult (18 years of age) outpatients who met DSM‐IV criteria for generalized SAD for at least 6 months prior to study day 1. Participants were eligible if they had a score 54 on item 1 (severity of illness) of the clinical global impression severity (CGI‐S) scale; a minimum total score of at least 50 on the Liebowitz social anxiety scale (LSAS), with 430% decrease between the prestudy and baseline visits (i.e. during the placebo lead‐in period); a prestudy Raskin depression total score 49, and a 17‐item Hamilton rating scale for depression (HAM‐D17) score <15; and provided informed consent".

Exclusion criteria: quote: "Patients were excluded if they had been treated with venlafaxine immediate release or venlafaxine ER within 6 months of study day 1 or had concurrent disorders that confounded the evaluation of treatment, including substance use disorders, personality disorders (except avoidant personality disorder), depression or other primary anxiety disorders, diagnosed by clinical interview. While patients who had not responded to previous treatment with paroxetine were not prohibited from participating in the study, ongoing psychotherapy and recent treatment with psychoactive medications precluded entry into the study".

Dropouts: 26/434 (6/144 in the paroxetine group, 7/144 in the venlafaxine group, and 13/146 in the placebo group)

Interventions

Pharmacological intervention: quote: "After a 1‐week, single‐blind, placebo lead‐in period to eliminate subjects with situational anxiety and ascertain generalized social anxiety disorder, patients symptomatic at baseline were randomly assigned to receive flexible doses of venlafaxine ER (75–225 mg/day), paroxetine (20–50 mg/day), or placebo for up to 84 days".

Outcomes

Primary outcome: LSAS (for reduction of anxiety)

Secondary outcomes: CGI‐S (for reduction of anxiety), CGI‐I (for treatment efficacy), SPIN (for reduction of anxiety), the fear/anxiety and avoidance subscales of the LSAS (for reduction of anxiety), SDI (for reduction of functional disability) and the WPAI questionnaire (for reduction of functional disability)

Time points: Quote: "Patient evaluations occurred at baseline and on days 7, 14, 21, 28, 42, 56, 70 and 84. Final efficacy evaluations were performed on the last day that the patient received a full dose of study medication or within 3 days thereafter"

Notes

Industry funded: yes. Quote: "Contract/grant sponsor: Wyeth Research"

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Authors report that participants were randomised; however, no mention is made of the method of randomisation. Quote: "Adult outpatients with generalized SAD (n=434) were randomized to receive capsules of venlafaxine ER 75 mg to 225 mg/day, paroxetine 20 mg to 50 mg/day, or placebo for 12 weeks ... At the baseline visit, after the investigator had ascertained that the patient was qualified to enter the study, the patient was also given a randomization number and the accompanying treatment supplies".

Allocation concealment (selection bias)

Low risk

Author correspondence: quote: "The randomization and blinding and packaging of study materials were undertaken by our hospital pharmacy and by Wyeth".

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether both participants and personnel were blinded. Quote: "study medication was provided in identically appearing capsules containing venlafaxine ER 75 mg, paroxetine 10 mg, paroxetine 20 mg, or placebo, and the number of capsules was identical for all treatments".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "In order to ensure that the assessor (i.e. the investigator) was unaware of the treatment group to which a patient was assigned, study medication was provided in identically appearing capsules containing venlafaxine ER 75 mg, paroxetine 10 mg, paroxetine 20 mg, or placebo, and the number of capsules was identical for all treatments".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

More participants withdrew from the placebo group (13/132; 10%) compared to the paroxetine (6/128; 5%) and venlafaxine (7/129; 5%) group. The most common reasons for withdrawal were adverse events and unsatisfactory response. No information was provided on whether participants differed in terms of characteristics by group at week 12, however. Nevertheless, the total proportion of dropouts (7%) is relatively low, suggesting that dropout rates may not have biased the outcomes. Quote: "A total of 363 (84%) patients completed the 12‐week double‐blind treatment period (119 in the placebo group, 122 in the venlafaxine ER group and 122 in the paroxetine group) ... the most common reasons for withdrawal were adverse events and unsatisfactory response. Significantly more participants in the placebo group withdrew due to unsatisfactory response than in the venlafaxine ER group or the paroxetine group". Overall 7% of the participants dropped out of the study. Baseline analysis were intention‐to‐treat (ITT) whereas the analysis of the primary and secondary outcomes were last observation carried forward (LOCF).

Selective reporting (reporting bias)

Low risk

All outcomes were reported as specified in the protocol.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias was identified.

Methods

Design: multicentre, randomised, double‐blind, placebo‐controlled study

Duration of intervention: 10 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 273 randomised to fluvoxamine or placebo (273 randomised: 2 excluded; 271 ITT population)

Mean age (SD): 38.6 (11.25) years

Sex: 179 men and 86 women (265 randomised in the efficacy analysis population)

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Eligible patients were aged 18–65 yr and were required to meet the DSM‐IV criteria for GSAD, have a minimum score of > 60 on the Liebowitz Social Anxiety Scale – Japanese Version, have no serious medical history, and to have taken no psychotropic medications for at least 14 d prior to randomization. The diagnosis of GSAD was made according to DSM‐IV criteria by well‐trained research psychiatrists. Patients were required, in addition to meeting DSM‐IV criteria for SAD, to exhibit fear and/or avoidance of at least four social situations (at least two involving interpersonal interactions)".

Exclusion criteria: quote: "Patients were excluded if they had any Axis I psychiatric disorder (e.g. schizophrenia, bipolar disorder, major depressive disorder, dysthymic disorder, panic disorder, alcohol abuse/dependence), or medical or neurological disorder. Other exclusion criteria were any clinically significant abnormal laboratory or electrocardiogram (ECG) findings at the screening visit. Women who were pregnant, lactating, or not using an acceptable method of contraception were also ineligible".

Dropouts: 6/271 (4/93 and 2/89 in the fluvoxamine groups and 0/89 in the placebo group; the additional two were excluded prior to the allocation of treatment).

Interventions

Pharmacological intervention: quote: "Eligible patients were randomly assigned to either fluvoxamine (at an initial dose of 50 mg/d fluvoxamine in two divided doses) or placebo in a 2:1 ratio. Fluvoxamine‐treated patients were randomly divided into two subgroups; a daily dose was increased by 50mg increments per week to a maintenance dose of 150 mg/d in one subgroup and to that of 300 mg/d in the other subgroup".

Outcomes

Primary outcome: LSAS‐J (for reduction of anxiety)

Secondary outcomes: CGI (for treatment efficacy) and SDS (for reduction of functional disability)

Time points: Quote: "Patients were evaluated at nine study visits (baseline and weeks 1, 2, 3, 4, 5, 6, 8, and 10)"

Notes

Industry funded: yes. Quote: "This study was sponsored by Solvay Seiyaku K.K. and Meiji Seika Kaisha, Ltd".

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Author correspondence: quote: "This was a double‐blind study, meaning both the subjects and the investigators were blinded to the randomization scheme by double‐dummy method".

Allocation concealment (selection bias)

Low risk

Author correspondence: quote: "An independent third party (CRO) randomly allocated the packages of investigational drug using SAS procedure, as a set consisted of investigational drug for 4 cases for fluvoxamine group and 2 cases for placebo group, and sealed the packages. They held the key code during the course of the study and were to break the blind after all CRFs were collected and all CRF data had been entered into the database and the database locked".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Author correspondence: quote: "This was a double‐blind study, meaning both the subjects and the investigators were blinded to the randomization scheme by double‐dummy method".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Author correspondence: quote: "This was a double‐blind study, meaning both the subjects and the investigators were blinded to the randomization scheme by double‐dummy method".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

A small proportion of participants withdrew from the fluvoxamine groups (4/93, 2/89) with no reported dropouts for the placebo group (0/89). Patients withdrew due to adverse events and protocol deviations. No information was provided on whether participants differed by group characteristics at at week 10, however. Nevertheless, the total proportion of dropouts (2%) is relatively low, suggesting that dropout rates may not have biased the outcomes. Quote: "The efficacy analysis population was composed of 265 patients (176 receiving fluvoxamine and 89 receiving placebo), excluding six patients for whom no valid post‐baseline efficacy evaluation was obtained due to premature discontinuation [four withdrew due to adverse events and two withdrew due to protocol deviations (inappropriate concomitant medications)]". Overall 2% of the participants dropped out of the study. Quote: "Efficacy data are presented for the last observation carried forward (LOCF) dataset. The LOCF dataset used the last available on‐treatment observation for each patient to estimate missing data‐points".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. There was a difference in gender proportions, but there is no reason to believe that this may have biased the study. Quote: "Our findings on the gender ratio confirmed that men were predominant in this study. However, it is unknown whether the finding represents the status of gender ratio in Japanese SAD patients. There seems to be no clear sex predominance for this disorder".

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: one‐week, single blind, placebo run‐in phase

Participants

Sample size: 290 randomised to paroxetine or placebo

Mean age (SD): 36 (11.5) years

Sex: 133 men and 157 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Male or female out‐patients, aged 18 years or over, patients with a primary diagnosis of social phobia according to the DSM‐IV criteria were included in the study following the provision of written informed consent".

Exclusion criteria: quote: "Patients were excluded at the screening visit if they had a primary diagnosis of any other Axis I disorder within the past six months, if they had been diagnosed as having body dysmorphic disorder or if they had a history of schizophrenia or bipolar affective disorder. Patients were excluded if they had a past history of seizure disorders or any serious medical disorder that could preclude the administration of paroxetine. In addition, patients requiring concomitant therapy with beta‐adrenergic blockers, monoamine oxidase inhibitors, benzodiazepines or other psychoactive medications were not included. Patients were also not included if: they had taken psychotropic drugs or antidepressants within the past two weeks or depot neuroleptics within 12 weeks; they had been previously unresponsive or intolerant to paroxetine, or they had used an investigational drug during the past month; they had undergone previous treatment for social phobia with an SSRI at a dose and duration that would have been adequate to show a response, or undergone electroconvulsive therapy (within three months) or psychotherapy (except ongoing stabilised therapies of six months or more). Other exclusion criteria included pregnancy (or a likelihood of becoming pregnant), lactation and alcohol substance misuse (within the past three months) or dependence (within the past six months). Patients were also excluded if they posed a current serious risk of suicide or homicide".

Dropouts: 77/290 (35/139 in the paroxetine and 42/151 in the placebo group)

Interventions

Pharmacological intervention: quote: "Patients initially received 20 mg/day paroxetine or placebo for two weeks, followed by 10 mg/day at weekly intervals to a maximum dose of 50 mg/day according to clinical response and tolerability".

Outcomes

Primary outcomes: LSAS (for reduction of anxiety) and CGI‐I (for treatment efficacy)

Secondary outcomes: SADS (for reduction of anxiety), SDS (for reduction of functional disability) and CGI‐S (for reduction of anxiety)

Time points: Quote: "Efficacy and safety assessments were made at weeks 1,2,3,4,6,8 and 12 and additional, further safety assessments were made at week 15. At week 12, or on early withdrawal from the study, a physical examination, laboratory tests, body weight determination and HAM‐D (17‐item) assessments were performed. After the week 12 visit, the dose of study medication was reduced during a thno week tapering period; safety assessments (but not efficacy assessments) were made during this period. Patients also attended a follow‐up visit when safety pammetcrs were assessed if they had withdrawn from the study prematurely owing to an adverse event, or if they had completed the study with an ongoing adverse event"

Notes

Industry funded: yes. Quote: "Smith Kline Beecharn Pharmaceuticals provided financial support for this study".

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Author correspondence: quote: "Block randomisation"

Allocation concealment (selection bias)

Low risk

Author correspondence: quote: "Randomisation was performed in the pharmacy at a distant site to the clinical site where the research team were based".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Author correspondence: quote: "All patients and research staff were blinded to treatment allocation at all centres throughout the study".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

A similar proportion of participants withdrew from the paroxetine group (35/139, 25%) compared to the placebo group (42/151; 28%). Common withdrawals in the paroxetine group were adverse experience and lack of efficacy in the placebo group. The 2 groups did not differ by sample characteristics at baseline. Quote: "There was no overall difference between the treatment groups in the number of patients who withdrew during the study: 35 (25%) patients in the paroxetine group v. 42 (28%) in the placebo group ... The number of patients lost to follow‐up, although comparable between the groups was high and is probably characteristic of the patient population under study; owing to the nature of the disorder". Overall 27% of the participants dropped out of the study. Quote: "Outcome measures were performed on the intent‐to‐treat (lTT) efficacy population. Last on‐therapy observations were carried forward for patients with missing data points".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: single‐centre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 8 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1‐week single‐blind placebo lead‐in

Participants

Sample size: 12 randomised to olanzapine or placebo

Participant age range: 18‐65 years

Sex: not specified

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Subjects included men and women aged 18–65 years with a diagnosis of SAD and a minimum Brief Social Phobia Scale (BSPS) score of 20".

Exclusion criteria: quote: "At the initial visit, blood samples were obtained from eligible subjects for serum chemistry, haematology, and serum beta‐human chorionic gonadotropin for women of childbearing potential ... No concomitant psychotropic medications were permitted during the study".

Dropouts: 5/12 (3/7 in the olanzapine group and 2/5 in the placebo group)

Interventions

Pharmacological intervention: quote: "Olanzapine was begun at a dose of 5 mg/day (or placebo equivalent) and was titrated upwards as tolerated and clinically indicated at the rate of 5 mg per week to a maximum of 20 mg/day".

Outcomes

Primary and secondary outcomes: LSAS (for reduction of anxiety), BSPS (for reduction of anxiety), SPIN (for reduction of anxiety), SDS (for reduction of functional disability), CGI‐I (for treatment efficacy) and BAS, AIMS and SSS (side effects)

Time points: Quote: "The BSPS, SPIN and SDS were performed at weeks 2, 3, 4, 6 and 8, and the LSAS at weeks 4 and 8. Global improvement was measured by the Clinical Global Impression‐Improvement scale (CGI‐I) at all post‐baseline visits (including week 1). Safety was assessed by recording adverse events using the Severity of Symptoms Scale, weight and vital signs, the Barnes Akathisia Scale (BAS) and the Abnormal Involuntary Movements Scale
(AIMS)"

Notes

Industry funded: yes. Quote: "This study was supported by a grant from Eli Lilly and Company to Dr R. T. Davidson"

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method of randomisation was not reported. Quote: "Subjects were then randomised in a 2:1 ratio to receive flexible‐dose olanzapine or placebo, respectively, for 8 weeks".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

A similar proportion of participants withdrew from the olanzapine group (3/7; 43%) compared to the placebo group (2/5; 40%). Participants withdrew due to adverse experience or were lost to follow‐up. The 2 groups did not differ by sample characteristics at baseline. Quote: "Data analysis was performed on the intent‐to‐treat (ITT) population using the last‐observation‐carried‐forward (LOCF) method for missing data ... Missing data has been imputed using appropriate methods ... Of the 12 randomized subjects, seven received olanzapine and five received placebo. Demographic characteristics did not differ significantly between groups. Seven subjects (four olanzapine and three placebo) completed the study through week 8 ... Reasons for early discontinuation were similar in both groups and included loss to follow‐up and adverse experience. Adverse experiences associated with subject discontinuation included gastrointestinal distress (placebo) and sedation (olanzapine). Overall 42% of the subjects dropped out of the study."

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias was identified.

Methods

Design: multicentre, randomised, double‐blind, placebo‐controlled trial, maintenance study

Duration of intervention: 12 weeks

Post‐treatment: 6 months follow‐up

Placebo run‐in: no

Participants

Sample size: 84 randomised to phenelzine sulfate or placebo (166 randomised: 45 phenelzine sulfate, 40 cognitive behavioural group therapy, 42 combination therapy, 39 placebo)

Mean age (SD): 31.35 (8.36) years

Sex: 63 men and 21 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "The inclusion criteria were (1) a primary DSM‐IV diagnosis of SAD and (2) age 18 to 65 years".

Exclusion criteria: quote: "The exclusion criteria were (1) a comorbid anxiety disorder more clinically salient for the patient; (2) a lifetime history of schizophrenia, bipolar disorder, or mental disorder due to a general medical condition; (3) major depressive disorder or substance use disorder in the past 6 months; (4) previous failure of treatment with phenelzine or CBT, defined as nonresponse to 60 mg or more of phenelzine (or the equivalent dose of another monoamine oxidase inhibitor) for at least 4 weeks or to 6 sessions of CBT for SAD; (5) concurrent psychiatric or psychological treatment; and (6) pregnancy, lactation, or inability or unwillingness to use contraceptive measures for the duration of the study".

Dropouts: 18/84 (13/45 in the phenelzine sulfate group and 5/39 in the placebo group; 40 dropouts across all 4 groups: 22 participants withdrew before receiving treatment, 18 withdrew after receiving treatment)

Interventions

Pharmacological intervention: quote: "Pharmacotherapy patients began with phenelzine sulfate, 15 mg/d, or matching placebo for 3 days, then 30 mg/d for 4 days, 45 mg/d for week 2, and 60 mg/d for weeks 3 and 4. Depending on clinical progress and adverse effects, the dosage could be raised to 75 mg for week 5 and to 90 mg for weeks 6 to 12".

Outcomes

Primary and secondary outcomes: LSAS (for reduction of anxiety), ADIS (diagnostic measure), CGI‐S (for reduction of anxiety), HRSD (for reduction of depression), CGI‐I (for treatment efficacy), FQ (for reduction of anxiety), SIAS (for reduction of anxiety), SPS (for reduction of anxiety) and SDS (for reduction of functional disability)

Time points: Quote: "The study had 4 phases. The first phase (acute treatment) lasted 12 weeks. Medication visits occurred weekly for 4 weeks, then every 2 weeks during this phase" The second, third and fourth phase was also 12 weeks each

Notes

Industry funded: no. Quote: "This study was supported in part by grants DA023200 (Dr Blanco), MH44119 (Dr Heimberg), and MH57148 (Dr Liebowitz) from the National Institutes of Health; by the New York State Psychiatric
Institute (Drs Blanco, Schneier, Campeas, and Liebowitz and Ms Vermes); and in part by General Clinical Research Center grant RR00349 from the National Center for Research Resources, National Institutes of Health, to Temple University".

Medication provided by industry: no

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomized according to a table of pseudorandom numbers by the New York site data manager (A.B.S.), who had no patient contact".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether the participants were blinded. Quote: "Pharmacotherapy patients began with phenelzine sulfate, 15 mg/d, or matching placebo for 3 days ... Patient allocation was concealed from all other research personnel at both sites before randomization and from independent evaluators providing the clinician administered ..."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Measures administered by independent evaluators blinded to treatment condition".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportion of participants withdrew from the phenelzine sulfate group (13/45; 29%) compared to the placebo group (5/27; 19%). No information was provided regarding the reasons for treatment withdrawal. Nevertheless, participants did not differ by group characteristics at baseline. Quote: "Of the 166 individuals randomized, 12 from the placebo group and 10 from the phenelzine group withdrew from the study before receiving any treatment and were excluded from the analyses ... Groups did not differ significantly in demographic characteristics ... Rates of discontinuation were 37.1% (13 of 35) in the phenelzine group and 18.5% (5 of 27) in the placebo group. Those rates were not significantly different when examining all groups jointly or in pairwise treatment comparisons". Overall 25% of the participants dropped out of the study. Quote: "Using linear mixed‐effects models ... Response and remission rates were compared between groups using 2 tests of independence, using the last observation carried forward for individuals who dropped out before the endpoint".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Low risk

No other sources of bias was identified. Quote: "There were some baseline differences across treatment groups and sites. However, the results remained significant after appropriate statistical adjustments, suggesting the robustness of the findings".

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind, maintenance study

Duration of intervention: 24 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1 week single blind placebo period

Participants

Sample size: 196 randomised to sertraline or placebo (387 randomised: 98 sertraline, 98 sertraline and exposure therapy, 93 exposure therapy, 98 placebo)

Mean age (SD): 40.4 (10.4) years for all 4 groups, not specified for the sertraline and placebo separately

Sex: 153 men and 234 women (for all 4 groups, not specified for the sertraline and placebo separately)

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Subjects aged 18‐65 years with GSP according to DSM‐IV criteria study of at least 1 years duration and rated as moderately ill were included in the study ... Patients with comorbid dysthymia or specific phobias were allowed to enter the study".

Exclusion criteria: quote: "Patients with panic disorder with onset before social phobia or any other current anxiety, major depression, substance use or eating disorder were not eligible. In addition, patients with a lifetime history of bipolar disorder or psychosis were excluded".

Dropouts: 16/196 (9/98 in the sertraline and 7/98 in the placebo groups)

Interventions

Pharmacological intervention: all participants received either 1 tablet of sertraline 50 mg or placebo once daily, the dose was increased to 100 mg at 4 weeks and 150 mg at 8 and 12 weeks

Outcomes

Primary outcomes: CGI (for treatment efficacy) and SPS (for reduction of anxiety)

Secondary outcomes: BSPS (for reduction of anxiety), MFQ (for reduction of anxiety), FNES (for reduction of anxiety), SDS (for reduction of functional disability) and SF‐36 (quality‐of‐life measure)

Time points: Quote: "Investigators made intermediate efficacy ratings after 4, 8, 12, and 16 weeks, and final efficacy assessment after 24 weeks of treatment".

Notes

Industry funded: yes. Quote: "Funding was obtained from Pfizer Inc".

Medication provided by industry: yes

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Three hundred and eighty‐seven patients were randomly assigned by a computer to receive double‐blind sertraline or placebo in blocks of eight subjects so that four patients in each block were randomised to each of the treatments".

Allocation concealment (selection bias)

Low risk

Quote: "Sealed envelopes of allocations from this list were kept by the investigators and opened after the inclusion of the patient into the study ... Tablets were packaged and numbered by the sponsor and personally delivered to each investigator".

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in sealed envelopes. However, it is not clear whether both participants and personnel were blinded. Quote: "Sealed envelopes of allocations from this list were kept by the investigators and opened after the inclusion of the patient into the study".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Outcome assessors were not blinded to treatment. Quote: "Since many of the general practitioners included as investigators worked in single practices, it was not possible to obtain blinded efficacy assessment".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

A small proportion of participants withdrew from the sertraline (9/98; 9%) and placebo groups (7/98; 7%). Reasons for withdrawal were not clearly stated by treatment group. Participants did not differ by group characteristics at week 24. Quote: "Two hundred and fifty‐three patients completed 24 weeks of treatment (65%). Three hundred and fifty‐four patients were included in the intent‐to‐treat efficacy population (93%) ... In individual analyses, no interaction was observed between response and each of the variables gender, age, country, recruitment method, medication or exposure therapy". Overall 8% of the participants dropped out of the study.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Medication and study funded by industry. No other sources of bias was identified.

Methods

Design: single‐centre, double‐blind, placebo‐controlled study (NCT00246441)

Duration of intervention: 16 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 42 randomised to paroxetine or placebo

Mean age (SD): 29 (7.4) years

Sex: 22 men and 20 women

Diagnostic measure: Structured Clinical Interview for DSM‐IV (SCID).

Inclusion criteria: quote: "To be included in the study, individuals had to (1) be 18–65 years old; (2) have sufficiently severe social anxiety disorder, as defined by a total score of at least 60 on the Liebowitz Social Anxiety Scale; (3) report using alcohol to cope with social anxiety; and (4) consume at least 15 standard drinks in the previous 30‐day period".

Exclusion criteria: quote: "Medical exclusion factors included: (1) history of prior medical detoxification from alcohol; (2) current use of psychotropic medications; (3) seeking treatment for alcohol problems; (4) urine drug screen positive for illicit drugs other than marijuana; and (5) liver enzymes greater than three times normal levels. History of prior medical detoxification or treatment seeking for alcohol problems was exclusionary for ethical reasons since no explicit alcohol intervention was provided ... They were excluded if they had current bipolar disorder, schizophrenia, substance abuse or dependence other than alcohol, nicotine, marijuana, or presence of significant suicidality".

Dropouts: 4 (insufficient information to determine dropout rates for the 2 groups separately)

Interventions

Pharmacological intervention: quote: "All subjects were initiated at a dose of 10 mg per day of paroxetine or matching placebo. Active medication and placebo were over‐encapsulated by the investigational pharmacy with 100 mg of riboflavin, a biomarker used to measure medication compliance. The titration plan in the protocol was to increase the dose weekly over 4 weeks from 10 to 20 to 40 to 60 mg daily, pending tolerability".

Outcomes

Primary outcome: LSAS (for reduction of anxiety)

Secondary outcomes: LSAS (for reduction of anxiety), CGI‐I (for treatment efficacy), and SPIN (for reduction of anxiety)

Time points: Quote: "At weekly visits throughout the trial the clinician also rates improvement in social anxiety severity as compared to baseline on the same 1–7 point scale (CGI‐I)"

Notes

Industry funded: no. Quote: "This work was supported by grants R01 AA013379 (CLR), K24 AA013314 (CLR), P50 AA010761, and K23 AA014430 (SWB) from the National Institute on Alcohol Abuse and Alcoholism".

Medication provided by GlaxoSmithKline

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomised using a computerised urn randomisation programme. Quote: "Following determination of eligibility, subjects were randomized to either paroxetine or matching capsule placebo, using a computerized urn randomization program".

Allocation concealment (selection bias)

Low risk

Quote: "Group assignment was maintained by an investigational pharmacist, who also prepared each week’s supply of study medication".

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether the participants were blinded. Quote: "Subjects were randomized to either paroxetine or matching capsule placebo ... All individuals involved in direct care or evaluation of study subjects, or who were involved in study supervision, were blind to group assignment".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "All individuals involved in direct care or evaluation of study subjects, or who were involved in study supervision, were blind to group assignment ... Clinical and research ratings were collected independently".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

38 (90%) of the 42 participants completed the study. No information was provided on the reasons for study withdrawal. Participants did not differ by group characteristics at baseline. Nevertheless, the total proportion of dropouts (10%) is relatively low, suggesting that dropout rates may not have biased the outcomes. Quote: "All but four participants provided week 16 (end of trial) data, for a 90% research data completion rate ... There were no significant differences at baseline between groups, including age, gender, ethnicity, social anxiety severity, and alcohol use severity ... There were no significant differences between groups, all p values >.05 ... The number of subjects who dropped out of the trial because of side effects were 1 and 0 for the paroxetine and placebo group, respectively" Quote: "Using a mixed model analysis ... Data from all subjects who were randomised to treatment were included in the analysis, according to intent to treat (ITT) standards".

Selective reporting (reporting bias)

High risk

Pre‐specified secondary outcomes (i.e. for quality of life and depression) were not mentioned or measured in the study.

Other bias

Unclear risk

Medication was provided by industry. No other sources of bias was identified.

Methods

Design: single‐centre, randomised, placebo‐controlled, flexible dose, double‐blind

Duration of intervention: 20 weeks or to undergo discontinuation treatment every 2 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 36 randomised to clonazepam or placebo

Mean age (SD): 40.05 (7.6) years

Sex: 23 men and 13 women

Diagnostic measure: DSM‐III‐R.

Inclusion criteria: quote: "Subjects entered the study if they fulfilled DSM‐III‐R criteria for a principal diagnosis of social phobia, granted informed consent, and were between the ages of 18 and 55".

Exclusion criteria: quote: "Exclusion criteria were as follows: a history of schizophrenia, bipolar disorder, organic brain syndrome, antisocial personality disorder, mental retardation, major depression within the past 12 months, panic disorder, alcohol or substance abuse; the concomitant need for other psychotropic drugs; or any ongoing psychotherapy".

Dropouts: 8/36 (2/17 in the clonazepam and 6/19 in the placebo group)

Interventions

Pharmacological intervention: quote: "At week 24, all subjects exhibiting good clinical response on the CGI‐Improvement scale were randomly assigned to receive either continuation treatment (CT) at the same clonazepam dose for 5 additional months, or discontinuation treatment (DT), which required a fixed‐dose taper of 0.25 mg every 2 weeks. Therefore, 6 weeks of tapered doses were required for the group receiving 1.0 mg/day to reach 0.0 mg, 10 weeks for the 1.5‐mg group, 14 weeks for the 2‐mg group, and 18 weeks for the 2.5‐mg group".

Outcomes

Primary and secondary outcomes: CGI‐S (for reduction of anxiety), BSPS (for reduction of anxiety), MSPSS (for reduction of anxiety), BWC (side effects measure), and fear was measured on a 0‐10 scale, and avoidance was measured along a 5‐point scale.

Time points: Quote: "After patients were randomly assigned at week 24, all scales were administered at 2‐week intervals until study completion"

Notes

Industry funded: yes. Quote: "This work was supported by a grant from Hoffmann‐LaRoche to Dr. Jonathan Davidson".

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "All subjects exhibiting good clinical response on the CGI‐Improvement scale were randomly assigned to receive either continuation treatment (CT) at the same clonazepam dose for 5 additional months, or discontinuation treatment (DT)".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Participants were blinded to treatment however there was insufficient evidence to determine if personnel were blinded. Quote: "Subjects received the same number of pills at each visit, with the diminishing dose supplemented by means of matching placebo. From weeks 24 to 26, all subjects received their usual dosage in double‐blind packaging to allow for adjustment to the double‐blind form of medication, having received the regular, marketed brand of the drug up to that time".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

A larger proportion of participants discontinued the study in the placebo group (6/19; 32%) compared to the clonazepam (2/17; 12%) group. Similiar withdrawals were reported across groups. The 2 groups did not differ by treatment characteristics at baseline. Quote: "Within the group of 36 subjects providing discontinuation data, no significant differences were observed between subjects assigned to CT vs. DT groups in age, gender, or ethnic status ... Two subjects in the CT and six in the DT group dropped out of the study for reasons either related to relapse or to other circumstances. The two CT dropouts were a result of side effects and loss to follow‐up. The six DT dropouts were a result of relapse, marital problems that became aggravated during the time of taper, and work obligations". Overall 22% of the participants dropped out of the study. Quote: "In the event of occasional missing measurement points, the immediately prior observation was carried forward (LOCF)".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other source of bias was identified for this study.

Methods

Design: single‐centre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 10 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 2 week medication washout period

Participants

Sample size: 75 randomised to clonazepam or placebo

Mean age (SD): 37.2 (8.45) years

Sex: 43 men and 32 women

Diagnostic measure: DSM‐III‐R

Inclusion criteria: quote: "To be eligible for the study, subjects were required to fulfil DSM‐III‐R criteria for social phobia, with absence of major depression or panic disorder in the last 6 months. Additionally, at least 12 months absence of alcohol or substance abuse was required".
Exclusion criteria: quote: "Histories of bipolar disorder, psychotic illness, or organic brain disease represented exclusion.

Dropouts: 19/75 (10/39 in the clonazepam and 9/36 in the placebo group)

Interventions

Pharmacological intervention: quote: "Subjects were assigned to receive either clonazepam or placebo ... The initial dose was 0.25 mg per day for days 1 to 3, increasing to 0.25 mg twice daily on days 4 to 7.05 mg twice daily from days 8 to 14, 0.5 mg in the morning and 1mg at bedtime on days 15 to 17.1 mg twice daily on days 18 to 21, 1 mg in the morning and 1.5mg at bedtime on days 22 to 25, and 1.5 mg twice daily after day 25".

Outcomes

Primary and secondary outcomes: CGI‐S (for reduction of anxiety), LSAS (for reduction of anxiety), FQ (for reduction of anxiety), FNES (for reduction of anxiety), HAMD (for reduction of depression) and Marks‐Kelly Disability Scale (SDS) (for reduction of functional disability)

Time points: Quote: "All scales were administered at baseline and at weeks 2, 4, 6, 8, and 10, except for the FQ, which was administered at baseline and at weeks 6 and 10, and the Hamilton Rating Scale for Depression, which was administered at baseline and at week 10"

Notes

Industry funded: no

Medication provided by industry: no

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Author correspondence: quote: "The randomization was determined by a list of computer‐generated numbers".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Author correspondence: quote: "For the clonazepam trial, I can say that the only person who was not blinded was the statistician, and we never had any talk or contact with him about the matter of blinding during the trial. Neither patients, staff nor raters were unblinded".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Author correspondence: quote: "For the clonazepam trial, I can say that the only person who was not blinded was the statistician, and we never had any talk or contact with him about the matter of blinding during the trial. Neither patients, staff nor raters were unblinded".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the clonazepam (10/39; 26%) and placebo group (9/36; 25%). Common withdrawals were a result of poor response. No information was provided on sample characteristics and how groups differed at end point. Quote: "The numbers of subjects remaining in treatment with clonazepam and placebo were at week 19, n=29 and n=27. 75% of clonazepam subjects and 75% of placebo subjects competed the full course of treatment ... Dropout rates at week 8 were generally the result of poor response". Overall 25% of the participants dropped out of the study. Both intention‐to‐treat and last observation carried forward (LOCF) was carried out.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Low risk

No other source of bias was identified for this study.

Methods

Design: multicentre, randomised, placebo‐controlled, double‐blind, parallel group study

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no, however, quote: "patients taking psychotropic medications were required to discontinue medication 14 days (fluoxetine 30 days) prior to baseline".

Participants

Sample size: 279 randomised to fluvoxamine or placebo

Mean age (SD): 37.25 (0.95) years

Sex: 179 men and 100 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Patients had to meet the following inclusion criteria: male or female aged 18 to 70 years, Diagnostic and Statistical Manual, 4th Edition (DSM‐IV) diagnosis of GSAD according to the modified Structured Clinical Interview for the DSM‐IV, minimum score of 60 on the Liebowitz Social Anxiety Scale (LSAS) at the screening visit, a score of less than 18 on the Montgomery‐Asberg Depression Rating Scale at the screening visit, and fluency in English. Women with less than 1 year postmenopausal were required to use an acceptable form of birth control. Pregnant or lactating women were not eligible".
Exclusion criteria: quote: "Patients were excluded from study participation if they had any of the following comorbid psychiatric disorders deemed to be primary in clinical significance: major depressive disorder, dysthymic disorder, or panic disorder. Patients with a history or current diagnosis of schizophrenia, psychotic disorder, obsessive compulsive disorder, bipolar affective disorder, or borderline personality disorder were also excluded. Patients with evidence of substance or alcohol abuse within the previous 6 months, patients with positive results on a urine drug screen, and patients requiring cognitive behavioral therapy to treat social anxiety disorder within the previous month were also excluded from participation. Patients taking psychotropic medications were required to discontinue medication 14 days (fluoxetine 30 days) prior to baseline. Patients were also excluded if they had a clinically significant medical condition or required medications that could put them at risk for taking fluvoxamine CR".

Dropouts: 119/279 (66/139 in the fluvoxamine and 53/140 in the placebo group)

Interventions

Pharmacological intervention: quote: "Patients randomized to receive fluvoxamine CR began treatment at 100 mg/d at day 1 (baseline). The dose could be increased, based on efficacy and tolerability, in increments of 50 mg/d at 1‐week intervals up to a maximum dose of 300 mg/d. The dose remained constant during weeks 6 through 12. The minimum dose allowed at any time during the study was 100 mg/d".

Outcomes

Primary outcome: LSAS (for reduction of anxiety)

Secondary outcomes: CGI (for treatment efficacy), SDS (for reduction of functional disability), PGI (for treatment efficacy), ASEX (assesses sexual experiences), and MADRS (for reduction of depression)

Time points: Quote: "Efficacy measures were assessed at baseline, weeks 2, 4, 6, 8, 10, and 12, or upon early termination"

Notes

Industry funded: yes. Quote: "This study was supported by a grant from Solvay Pharmaceuticals, Inc".

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Author correspondence: quote: "For fluvoxamine, randomization was determined for each site by the sponsor (Solvay) from a central source".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Author correspondence: quote: "All site study personnel and the patients remained blind throughout the study".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Similar proportions of participants withdrew from the fluvoxamine CR (66/139; 47%) and placebo group (53/140; 39%). Reasons for withdrawal were similar between groups except for lack of efficacy and adverse events. No information was provided on sample characteristics at endpoint, although groups did not differ significantly on demographics and clinical history at baseline. Quote: "Of these 279 patients, 73/139 (53%) in the fluvoxamine CR treatment group and 87/140 (62%) in the placebo treatment group completed the study, a non statistically significant difference. The reasons for withdrawal were similar between treatment groups with the exception of lack of efficacy (8% of the placebo group compared with <1% of the fluvoxamine CR group) and adverse events (26% of the fluvoxamine CR group vs. 1% of the placebo group)". Overall 43% of the participants dropped out of the study. Quote: "All analyses of response refer to the conventional last observation carried forward algorithm for all patients who had at least 1 dose of study medication, evaluable efficacy data at baseline and at least 1 post baseline efficacy assessment (intent‐to‐treat efficacy population, fluvoxamine CR = 121 patients; placebo = 126 patients)".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias was identified.

Methods

Design: multicentre, randomised, double‐blind, placebo‐controlled parallel group trial

Duration of intervention: 14 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 117 randomised to fluoxetine or placebo (295 randomised: 57 fluoxetine, 60 comprehensive cognitive behaviour therapy group, 59 combinations of comprehensive cognitive behaviour therapy and fluoxetine, 59 combinations of comprehensive cognitive behaviour therapy and placebo, 60 placebo group)

Mean age (SD): 36.6 (10.65) years

Sex: 66 men and 51 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Inclusion criteria were: (1) DSM‐IV diagnosis of GSP; (2) age between 18 and 65 years; (3) fluency in English; and (4) provision of written informed consent".
Exclusion criteria: quote: "Exclusion criteria were: (1) a primary comorbid anxiety disorder (defined by which disorder was the more debilitating and clinically salient); (2) lifetime history of schizophrenia, bipolar disorder, or organic brain syndrome; (3) major depression within the last 6 months; (4) substance abuse or dependence within the past year; (5) mental retardation or pervasive developmental disability; (6) unstable medical condition; (7) prior failure of response to fluoxetine at 60 mg/d for at least 4 weeks or to 12 weekly sessions of CCBT for GSP; (8) concurrent psychiatric treatment or other psychoactive medications; (9) positive urine drug screen results; (10) inability to maintain 2 weeks’ psychotropic drug‐free washout; and (11) pregnancy or lactation".

Dropouts: 33/117 (13/57 in the fluoxetine and 20/60 in the placebo group)

Interventions

Pharmacological intervention: quote: "Fluoxetine was started at 10 mg/d, increasing on day 8 to 20 mg/d, on day 15 to 30 mg/d, and on day 29 to 40 mg/d".

Outcomes

Primary outcomes: CGI (for treatment efficacy) and BSPS (for reduction of anxiety)

Secondary outcome: SPAI (for reduction of anxiety)

Time points: Quote: "Independent evaluator ratings were conducted at baseline and at weeks 4, 8, and 14"

Notes

Industry funded: no. Quote: "This study was supported by grant R10‐ MH49339‐05A1 from the National Institute of Mental Health, Bethesda, Md (Drs Davidson and Foa)".

Medication provided by industry: quote: "Medication and matching placebo were provided by Eli Lilly, Indianapolis, Ind".

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Subjects were assigned to treatment by block randomisation, which was generated by computer program".

Allocation concealment (selection bias)

Low risk

Author correspondence: quote: "The fluoxetine study ‐ I believe we provided medication in bottles which carried a pre‐numbered label based on the randomization".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Author correspondence: quote: "Patients, raters and medical staff were blind as to whether drug or placebo was given".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "An independent rater, blinded to treatment assignments, conducted the primary outcome assessments".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the clonazepam (13/57; 23%) and placebo group (20/60; 33%). Reasons for withdrawals were similar across groups (i.e. adverse effects, unclear, depression, not improving, treatment too difficult etc). No information was provided on sample characteristics at end point. Quote: "The overall significance for rate of dropout by treatment type was not statistically significant". Overall 28% of the participants dropped out of the study. Quote: "Linear mixed‐effect model analyses included all randomised subjects and were conducted using pretreatment and posttreatment behavioral measures, with the behavioral measure as the dependent variable".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Medication and study funded by industry. No other sources of bias were identified.

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, fixed dose, double‐ blind

Duration of intervention: 12 weeks

Post‐treatment: 6, 9 and 12 months follow‐up

Placebo run‐in: no

Participants

Sample size: 77 randomised to brofaromine or placebo

Mean age (SD): 37.8 (10.3) years

Sex: 45 men and 32 women

Diagnostic measure: DSM‐III‐R

Inclusion criteria: quote: "Patients with comorbid DSM‐III‐R generalized anxiety disorder, simple phobia or dysthymia were accepted in the study".

Exclusion criteria: quote: "Patients with a history of DSM‐III‐R major depressive episode, a total score of 15 or more on the HDRS, those with other Axis I disorders, suicidal ideation, severe sleep disturbances, organic brain diseases, alcohol or drug abuse within the last 5 years, pregnancy or lactation or some other clinically relevant medical condition that might interfere with the study were excluded".

Dropouts: 8/77 (5/37 in the brofaromine and 3/40 in the placebo group).

Interventions

Pharmacological intervention: quote: "Brofaromine or placebo was given twice daily; the first week 2 x 25 mg, the second week 2 x 75 mg to the dose of 150 mg/day".

Outcomes

Primary outcomes: LSAS (for reduction of anxiety) and CGI (for treatment efficacy)

Secondary outcomes: HRSD (for reduction of depression), MADRS (for reduction of depression), HARS (for reduction of anxiety), STAI (for reduction of anxiety) and SCL‐90 (for reduction of anxiety)

Time points: Quote: "Assessments were made before treatment and at weeks 1, 2, 4, 6, 8 and 12. The HRSD was administered before treatment and at week 12 or when the patient prematurely discontinued the trial (end‐point). The Montgomery‐Asberg Depression Rating Scale (MADRS) was used at every visit"

Notes

Industry funded: yes. Quote: "Grants for the study were given by Ciba, Pharmaceuticals Division, Sweden".

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "The study was double blind and patients were randomised (1:1) to brofaromine or placebo and treated for 12 weeks".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

A small proportion of participants withdrew from the brofaromine (5/37; 14%) and placebo group (3/40; 8%). More participants in the brofaromine group withdrew due to side effects compared to the placebo group. However, the 2 groups did not differ significantly. Quote: "Five patients in the brofaromine group and 3 in the placebo group withdrew prematurely from the study. One brofaromine patient withdrew because of untolerable side effects, 1 after 3 days (increased anxiety) and 3 between week 2 and 10 (sleep disturbance, nausea and diarrhoea, and irritability and hyperactivity). The 3 placebo patients withdrew for administrative reasons, poor compliance and unsatisfactory therapeutic effect, respectively ... In all 35 different adverse symptoms were reported. The total number of such reports was 192 in the brofaromine group (n=36) and 94 in the placebo group (n=40). Most of the reported symptoms did not differ significantly between groups". Overall 10% of the participants dropped out of the study. ITT population was assessed and LOCF was used for missing data.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias was identified.

Methods

Design: multicentre, randomised, double‐blind, fixed dose study

Duration of intervention: 11 weeks, with a 6‐day titration period and 1‐week taper period

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 329 randomised to pregabalin or placebo

Mean age (SD): 35.4 (5.68) years

Sex: 195 men and 134 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Patients were enrolled if they were at least 18 years of age and met the DSM‐IV criteria for SAD, generalized subtype, confirmed using the Mini‐International Neuropsychiatric Interview, with a LSAS score of at least 50 at both screening and baseline. Women were enrolled if they were using a hormonal or barrier method of contraception, or were menopausal or surgically sterilized, and had a negative pregnancy test at the screening visit, and were not lactating".

Exclusion criteria: quote: "Patients were excluded from the study for any of the following reasons: a current DSM‐IV diagnosis of panic disorder, with or without agoraphobia, GAD, anorexia, bulimia, delirium, dementia, or any other clinically significant cognitive disorders, major depressive disorder, obsessive‐compulsive disorder, posttraumatic stress disorder, or borderline or antisocial personality disorder; a current or past history of schizophrenic or psychotic disorder, bipolar disorder, or factitious disorder; a diagnosis of substance abuse/dependence unless in full remission for at least 6 months or a positive urine drug screen; a score of at least 3 on item 1 (depressed mood) at screening of the Hamilton Depression Rating Scale (HAM‐D); a creatinine clearance of less than 60 ml/min; any clinically significant or unstable hematological, autoimmune, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disorder; electrocardiogram (ECG) changes indicating acute ischemia; a recent history of seizure disorder, and any need for treatment with anti‐convulsants; any previous treatment with pregabalin, or use of gabapentin or benzodiazepines within 2 weeks of baseline; or current use of any psychotropic medications".

Dropouts: 96/329 (25/78, 25/86, 26/82 in the pregabalin and 20/82 in the placebo groups)

Interventions

Pharmacological intervention: quote: "Patients who continued to meet eligibility criteria at the end of the screening phase were randomized to double‐blind, parallel‐group treatment with one of three fixed daily doses of pregabalin, 300 mg [administered 100 mg three times daily (TID)], 450 mg (administered 150 mg TID), 600 mg (administered 200 mg TID), or matching placebo".

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: HARS (for reduction of anxiety), HAM‐D (for reduction of depression), CGI‐I (for treatment efficacy), MFQ (for reduction of anxiety) and the SF‐36 Health Survey (measure of health status)

Time points: Quote: "The LSAS and the MFQ were administered at screening, baseline, and weeks 1, 2, 4, 6, 8, and 10 (the LSAS was also administered at a follow‐up visit). The CGI‐I was administered on the same schedule starting at week 1. Other secondary measures were obtained at screening, baseline, and at week 10 (or the time of early termination)"

Notes

Industry funded: yes. Quote: "This study was funded by Pfizer Inc".

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "Patients who continued to meet eligibility criteria at the end of the screening phase were randomized to double‐blind, parallel‐group treatment with one of three fixed daily doses of pregabalin...".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether both participants and personnel were blinded. Quote: "Patients who continued to meet eligibility criteria at the end of the screening phase were randomized to double‐blind, parallel‐group treatment with one of three fixed daily doses of pregabalin, 300 mg [administered 100 mg three times daily (TID)], 450 mg (administered 150 mg TID), 600 mg (administered 200 mg TID), or matching placebo".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

A similar proportion of participants withdrew from the pregabalin groups (25/78 300mg; 25/86 450mg; 26/82 600mg, 32%, 29%, and 31% respectively) and placebo group (20/82; 24%). More participants in the pregabalin groups withdrew due to side effects. Other reasons for withdrawal were similar across groups (i.e. discontinued, adverse events, lack of efficacy, withdrew consent, lost to follow‐up and miscellaneous). No information was provided on sample characteristics at endpoint; however, the groups were comparable on baseline characteristics. Quote: "The proportion of patients completing study treatment was slightly lower for patients in the pregabalin 300 (67.9%), 450 (70.9%), and 600 mg (68.3%) dosage groups compared with the placebo group (75.65) ... Baseline demographic and clinical characteristics were comparable among the four treatment groups ... The majority of patients in all treatment groups experienced adverse events during the double‐blind treatment phase. The proportion of patients experiencing at least one adverse event was higher in the pregabalin treatment groups than in the placebo group, though the rates among the three pregabalin dose groups were similar". Overall 29% of the participants dropped out of the study. Quote: "Efficacy measures were analysed using the intent‐to‐treat (ITT) population ... Endpoint was defined as last observation carried forward (LOCF)".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. Quote: "The relatively high attrition rate in the pregabalin treatment groups (29–32%) may have biased this analysis".

Methods

Design: multicentre, randomised, double‐blind, placebo controlled, experimental trial

Duration of intervention: 6 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 36 randomised to NK1 antagonist GR205171, citalopram or placebo

Mean age (SD): 31.6 (7.7) years

Sex: 17 men and 19 women

Diagnostic measure: DSM‐IV

Inclusion criteria: DSM‐IV criteria for social phobia with no other serious psychiatric disorders

Exclusion criteria: quote: "Main criteria for exclusion were treatment of social anxiety in the past 6 months, current serious or dominant psychiatric disorder other than social phobia (e.g., psychosis, major depressive or bipolar disorder), neurological disorders, somatic disease, chronic use of prescribed medication, abuse of alcohol/narcotics, pregnancy, menopause, left handedness, previous PET examination, and positive family history of cancer".

Dropouts: 0

Interventions

Pharmacological intervention: quote: "The NK1 group received a daily oral dose of 5 mg GR205171, which started after 14 days of placebo because of limited available safety data on repeated dosing. GR205171 was taken as 4 mL solution made up to 100 mL in orange juice. The SSRI group was treated with 40 mg citalopram (one tablet), starting with 20 mg (half tablet) during the first week".

Outcomes

Primary outcome measures: CGI‐I (for treatment efficacy), STAI‐S (for reduction of anxiety) and LSAS‐SR (for reduction of anxiety)

Secondary outcome measures: CGI‐S (for reduction of anxiety), CGI‐I (for treatment efficacy), SPSQ (for reduction of anxiety), SPS (for reduction of anxiety), SIAS (for reduction of anxiety), GAF (for reduction of functional disability), PRCS (for performance anxiety), and SDI (for reduction of functional disability)

Time points: Quote: "Response rate was determined by the Clinical Global Impression improvement item (CGI‐I) administered by a psychiatrist (K.W.) at weeks 2, 4, and 6 and at follow‐ups"

Notes

Industry funded: yes. Quote: "This research was funded by GlaxoSmithKline, with additional support from the Swedish Research Council (MF and TF), the Bank of Sweden Tercentenary Foundation (MF), and the Swedish Brain Foundation (TF)".

Medication provided by industry: quote: "GlaxoSmithKline (Verona, Italy) supplied the study drugs for a 6‐week treatment period".

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Author correspondence: quote: "Randomization was performed by the statisticians at their Verona (Italy) research unit. Only the randomization list was provided to us, in my recollection a blocked randomization as the sample sizes were equal across the three arms".

Allocation concealment (selection bias)

Low risk

Author correspondence: quote: "The study codes (opaque envelopes) were locked in and kept safe by a Quintiles confederate during the whole study period until the study was unblinded".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Author correspondence: quote: "Personnel involved in the study only had access to a randomization list containing randomization numbers. The randomization list was created in Verona and the allocation was kept secret there in accordance with GSK research standards, also see above regarding the study codes. All participants and personnel involved in the study (planning, treatment, data collection, imaging, analyses, CRO activities etc) were blinded".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Author correspondence: quote: "All participants and personnel involved in the study (planning, treatment, data collection, imaging, analyses, CRO activities etc) were blinded".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no dropouts reported during this study.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Medication and study funded by industry. No other sources of bias was identified.

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 12 weeks

Post‐treatment: 6 months follow‐up

Placebo run‐in: no

Participants

Sample size: 64 randomised to phenelzine sulfate or pill‐placebo (133 randomised: 36 CBGT, 31 phenelzine sulfate, 33 pill‐placebo, 33 educational‐supportive group therapy)

Mean age (SD): 34.1 (9.3) years

Sex: 36 men and 28 women

Diagnostic measure: DSM‐III‐R

Inclusion criteria: quote: "For study inclusion, prospective patients had to meet criteria for social phobia and had to be between 18 and 65 years old, fluent in English, willing to provide written informed consent, and able to participate responsibly in treatment".
Exclusion criteria: quote: "Exclusions included schizophrenia, major depression, prominent risk of self‐harm, organic mental disorder, history of bipolar I disorder, alcohol or substance abuse (within the past six months), a previous adequate trial of cognitive behavioural therapy (> 6 sessions) or MAOI treatment for social phobia, or any serious medical condition that would increase the patients chances of being harmed by study participation".

Dropouts: 11/26 of 64 (5/31 in the phenelzine sulfate and 6/33 in the placebo groups, the additional dropouts were found in the CBGT (n=8) and ES group (n=7))

Interventions

Pharmacological intervention: quote: "Patients received 15 mg phenelzine sulfate tablets (n=31) or matching placebo (n=33) in 1 morning dose; dosages of 60 mg/d and greater were split between morning and noontime. Dosage started at 15 mg/d and increased to 30 mg/d on day 4, to 45 mg/d on day 8, and to 60 mg/d on day 15. After 4 weeks dosages could be raised to 75 mg/d depending on symptoms and adverse effects. After 5 weeks dosages could be raised to 90 mg/d".

Outcomes

Primary and secondary outcome measures: CGI‐I (SPDS) (for treatment efficacy), LSAS (for reduction of anxiety), ADIS‐R (for reduction of anxiety), FNES (for reduction of anxiety), FQ (for reduction of anxiety), SIAS (for reduction of anxiety), SPS (for reduction of anxiety) and SCL‐90 (for reduction of anxiety)

Time points: Quote: "Assessments were repeated after 6 (interviews and questionnaires only) and 12 weeks of treatment"

Notes

Industry funded: no. Quote: "Supported by grant MH44 119 and MH40 121 from the National Institute of Mental Health, Bethesda, Md, and grant PO5 MH30906 from the New York State Psychiatric Institute Mental Health Clincal Research Center, New York".

Medication provided by industry: quote: "Parke‐Davis Pharmaceuticals, Morris Plains, NJ, supplied Nardil and matching placebo".

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Author correspondence: quote: "The randomization sequence was generated by using a printed random numbers table from a statistics text book and was prepared before the study began, separately for each of the two study sites. The last digit of each number sequence was used to determine treatment allocation for cohorts of approximately 6 patients at a time (this was a study of group psychotherapy versus phenelzine)".

Allocation concealment (selection bias)

Low risk

Author correspondence: quote: "Cohorts of approximately 6 patients included both phenelzine and placebo patients randomly intermixed".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Author correspondence: quote: "Blinding was carried out by separating of functions between personnel, by separation of location of offices used for different purposes, and by the mixing of drug and placebo patients in the same cohort. Regarding medication/placebo status, patients, physicians, and assessors were blinded".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Author correspondence: quote: "Regarding medication/placebo status, patients, physicians, and assessors were blinded. We conducted regular assessments of the integrity of blinding, and on the few occasions when it appeared necessary, we switched patients to different assessors. Regarding psychotherapy status, this was clearly known to patients and therapists".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the phenelzine sulfate (5/31; 16%) and pill‐placebo group (6/33; 18%). Reasons for withdrawal were similar across groups (i.e. noncompliance, lack of efficacy, adverse effects, non treatment effects, unknown reasons, and positive effects) and groups did not differ by sample characteristics at week 12. Quote: "Attrition (n=26) did not differ across conditions. Eight patients discontinued CBGT, 5 discontinued phenelzine sulfate therapy, 6 discontinued placebo use, and 7 discontinued ES. Five patients were noncompliant, 5 patients discontinued therapy because of positive treatment effects, 3 because of lack of efficacy, 5 because of adverse effects, 2 because of non treatment‐related events, and 6 because of unknown reasons. There were no severe adverse effects ... Completers and dropouts did not differ on demographic or pretreatment clinical measures or group cohesion". Overall 17% of the participants dropped out of the study. All analyses were ITT with LOCF for dropouts.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Medication was provided by industry. No other sources of bias was identified.

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 12 weeks

Post‐treatment: 1 month follow‐up

Placebo run‐in: 1‐week, single‐blind, placebo lead‐in period

Participants

Sample size: 358 randomised to escitalopram or placebo

Mean age (SD): 38 (11) years

Sex: 195 men and 163 women

Diagnostic measure: DSM‐IV and MINI

Inclusion criteria: quote: "The patient population comprised female and male out‐patients with a primary diagnosis of generalised social anxiety disorder established by means of a diagnostic interview following DSM–IV criteria, using the MINI to assist in the exclusion of disallowed comorbidity. At the screening visit, patients 18–65 years old were selected if they had a total score of at least 70 on the LSAS; with exhibited fear or avoidance traits in at least four social situations, and were otherwise healthy based on a physical examination".

Exclusion criteria: quote: "Patients were excluded if they had another Axis I disorder that was considered the primary diagnosis within the previous 6 months, if the investigator diagnosed a serious risk of suicide or if the MADRS total score was higher than 19. Patients were also excluded if they had a DSM–IV diagnosis of alcohol or drug misuse during the past 6 months, or if they had taken a psychoactive drug (including any type of antidepressant, beta‐blocker, benzodiazepine, narcotic, analgesic, antipsychotic, or herbal remedy) within 2 weeks (5 weeks for fluoxetine and 6 months for depot neuroleptics) before screening, or if the patient had a positive urine drug screen for opiates, methadone, cocaine, amphetamines or benzodiazepines. The only allowed concomitant use of a psychotropic drug during the study was chloral hydrate taken as a hypnotic but not for more than three consecutive nights. Furthermore, patients with a diagnosis of mania or hypomania, body dysmorphic disorder, schizophrenia/other psychotic disorder, eating disorders, mental retardation or any Axis II cluster diagnosis were also excluded. Patients with a known drug (including citalopram) allergy or hypersensitivity or a known lack of therapeutic response to an adequate trial with citalopram were also excluded. Patients participating in a formal psychotherapy programme that went beyond medical counselling were not included".

Dropouts: 68/358 (36/181 in the escitalopram and 32/177 in the placebo groups)

Interventions

Pharmacological intervention: quote: "The initial dosage of escitalopram was 10 mg per day. The dosage could be increased to 20 mg per day after 4, 6 or 8 weeks of treatment in case of an unsatisfactory response, judged as a score above 5 on the CGI–S rating for severity or no decrease in CGI–S score since baseline. The mean daily dose of escitalopram was 17.6mg at week 12".

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: LSAS subscales (for reduction of anxiety), CGI‐I (for treatment efficacy), CGI‐S (for reduction of anxiety), SDS (for reduction of functional disability), and MADRS (for reduction of depression)

Time points: Quote: "Efficacy and tolerability were assessed at baseline and after 1, 2, 3, 4, 6, 8 and 12 weeks of treatment"

Notes

Industry funded: yes. Quote: "The study was sponsored by H. Lundbeck A/S."

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "Patients with generalised social anxiety disorder were randomised to receive placebo (n=177) or 10‐20 mg escitalopram (n=181) in a 12‐week, double‐blind trial".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether both participants and personnel were blinded. Quote: "Patients who met selection criteria entered a 1‐week, single‐blind, placebo lead‐in period before being randomised to 12 weeks of double‐blind treatment with escitalopram or matched placebo capsules".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the escitalopram (36/181; 20%) and placebo group (32/177; 18%). Withdrawals differed slightly, although not significantly, across groups (i.e. withdrew treatment, adverse effects, lack of efficacy, consent withdrawn, protocol violation, other administrative forms). More participants in the escitalopram group withdrew due to adverse effects, and more participants withdrew due to lack of efficacy in the placebo. The 2 groups did not differ by sample characteristics at baseline. Quote: "A total of 68 patients (19%) withdrew from the study, with no overall between group difference (18% in the placebo group and 20% in the escitalopram group). However, numerically more patients in the escitalopram group (8.8%) than in the placebo group (4.5%) withdrew because of adverse events and numerically more patients in the placebo group (6.2%) than in the escitalopram group (2.2%) withdrew because of lack of efficacy, with the latter difference approaching statistical significance ... There were slightly more men than women in both treatment groups. Baseline characteristics were similar for the two treatment groups with the exception of age and duration of the disorder, both of which were slightly higher in the escitalopram group". Overall 19% of the participants dropped out of the study. All analyses were ITT with LOCF for missing data. Observed cases analysed.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias was identified.

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, fixed dose, double‐blind

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1‐week placebo run‐in period

Participants

Sample size: 578 randomised to moclobemide or placebo

Mean age (SD): 36.4 (9.9) years

Sex: 329 men and 249 women

Diagnostic measure: SCID‐Ro (adapted from the DSM‐IV)

Inclusion criteria: quote: "Patients to be included in the study were adult men and non‐pregnant, non‐lactating women who satisfied the DSM IV criteria for social phobia".
Exclusion criteria: quote: "Patients with any of the following disorders concurrently or within the prior 6 months were excluded from the study: panic disorder, agoraphobia, obsessive‐compulsive disorder, or major depression. Patients who met SCID‐Ro criteria for probable or definite substance abuse within the prior 6 months, as well as those who met lifetime criteria for bipolar disorder, schizophrenia or any other psychotic disorder, were also excluded. The patients were free of any significant unstabIe or uncontrolled medical disease, physical or psychological condition, medication, or treatment that might put them at risk or obscure or confound the effects of treatment".

Dropouts: 133/578 (insufficient information to determine dropout rates for the 2 groups separately)

Interventions

Pharmacological intervention: quote: "After a 1‐week placebo run‐in period, patients fulfilling the entry criteria were randomly assigned to one of the three treatment groups to receive either 300 mg moclobemide, 600 mg moclobemide, or placebo in two divided daily doses for a 12‐week period. Patients were to take their tablets in the morning and in the evening after a meal. The patients of the 600 mg treatment group started with a reduced daily dose of 300 mg for the first 3 days, increasing to 600 mg on the 4th day".

Outcomes

Primary and secondary outcome measures: LSPS (for reduction of anxiety), CIC‐SP (for treatment efficacy), SDS (for reduction of functional disability), CIS‐SP (for reduction of anxiety), PIC‐SP (for reduction of anxiety), HAM‐A (for reduction of anxiety), and the MADRS (for reduction of depression)

Time points: Quote: "Assessments were performed at screen, on baseline and on weeks 1, 2, 3, 4, 6, 8, 10, and 12"

Notes

Industry funded: no

Medication provided by industry: medication was supplied by F Hoffmann‐La Roche Ltd

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "After a 1‐week placebo run‐in period, patients fulfilling the entry criteria were randomly assigned to one of the three treatment groups to receive either 300 mg moclobemide, 600 mg moclobemide, or placebo in two divided daily doses for a 12‐week period".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed. Quote: "Moclobemide was supplied by F. Hoffmann‐La Roche Ltd as an oval, cylindrical, biconvex, film‐ coated tablet light yellow in colour and scored on one side, containing 150 mg moclobemide. Placebo tablets were identical both in appearance and composition".

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether both participants and personnel were blinded. Quote: "Moclobemide was supplied by F. Hoffmann‐La Roche Ltd as an oval, cylindrical, biconvex, film‐ coated tablet light yellow in colour and scored on one side, containing 150 mg moclobemide. Placebo tablets were identical both in appearance and composition".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

There was insufficient information to determine dropout rates for the 2 groups separately, although the study reported that dropouts were similar across groups. Common reasons for withdrawal across group were insufficient therapeutic response, withdrawal of consent, and adverse events. Quote: "The ITT population comprised 578 patients, who had received treatment and had at least one assessment after baseline; 445 patients completed the study through week 12. The most frequently cited reasons for discontinuation were insufficient therapeutic response (63 patients), withdrawal of consent (22 patients), and adverse events (19 patients). Attrition rates were similar among the three treatment groups (< 30%). The groups did not differ with respect to reasons for early termination, except that insufficient therapeutic response was somewhat more frequent in the placebo group (26 patients) than in the moclobemide 300 mg (18 patients) or 600 mg groups (19 patients). The three treatment groups were similar with respect to their demographic data and baseline characteristics of social phobia and concurrent psychiatric illnesses". Quote: "Demographic results presented in this paper are based on the ITT population. Efficacy results of weeks 8 and 12 were analysed with the last observation carried forward in the case of missing observations (LOCF analysis)".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Medication was provided by industry. No other sources of bias were identified.

Methods

Design: single‐centre, randomised, placebo‐controlled, crossover, flexible dose, double‐blind

Duration of intervention: 10 weeks

Post‐treatment: 3 and 4 months follow‐up

Placebo run‐in: no

Participants

Sample size: 12 randomised to sertraline or placebo

Mean age (SD): 42.62 (7.54) years

Sex: 8 men and 4 women

Diagnostic measure: DSM‐III‐R

Inclusion criteria: men and women with a DSM‐III‐R social phobia diagnosis.

Exclusion criteria: not specified

Dropouts: 2/12 (2/6 in the sertraline and 0/6 in the placebo groups)

Interventions

Pharmacological intervention: quote: "The subjects were randomly assigned to receive either sertraline (N=6) (50‐200 mg/day, flexible dosing) or placebo (N=6) for 10 weeks, followed by taper and no treatment for 2 weeks. The subjects were then crossed over to the other treatment for a further 10 weeks. The sertraline dose was begun at 50 mg/day and was increased 50 mg/day every 2 weeks if there was no treatment response, except if the drug was not tolerated".

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: BSPS (for reduction of anxiety), FQ (for reduction of anxiety), SDS (for reduction of functional disability), SF‐36 (MOS) (to measure general health), MADRS (for reduction of depression), and the Liebowitz Social Phobic Disorders Rating Form (for reduction of anxiety) change and severity scales

Time points: Quote: "The patients were seen for administration of the outcome measures at baseline and at the end of weeks 2, 6, 10, 12, 14, 18, and 22"

Notes

Industry funded: yes. Quote: "Supported in part by a grant from Pfizer Pharmaceuticals".

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "The subjects were randomly assigned to receive either sertraline (N=6) (50‐200 mg/day, flexible dosing) or placebo (N=6) for 10 weeks ...".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

A larger proportion of participants discontinued the study in the sertraline (2/6; 33%) group compared to the placebo group (0/6; 0%). One participant withdrew because of an adverse effect and the other withdrew because of lack of efficacy. No information was provided on whether groups differed by sample characteristics at week 10. Quote: "Overall, sertraline was well tolerated. Only one patient left the study early because of adverse events (e.g., queasiness, anxiety, and insomnia); that patient did so after treatment with sertraline, before crossover to placebo. The only other patient to discontinue early dropped out 1 week after crossover to placebo, because of a lack of efficacy after a substantial clinical response to sertraline during the first half of the study". Overall 17% of the participants dropped out of the study. All analyses were intention‐to‐treat.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: single‐centre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 14 weeks

Post‐treatment: 1 month follow‐up

Placebo run‐in: 1‐week, single‐blind, placebo lead‐in

Participants

Sample size: 60 randomised to fluoxetine or placebo

Mean age (SD): 39.47 (12.84) years

Sex: 25 men and 35 women.

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "The sample consisted of 60 subjects with a primary DSM‐IV diagnosis of generalized social phobia with a duration of at least 6 months".

Exclusion criteria: quote: "Patients were excluded from the study for the following reasons: other concurrent Axis I disorders within the past 12 months; intolerance or nonresponse to previous fluoxetine treatment; previous participation in a fluoxetine study; concurrent use of psychotropic or centrally acting drugs, anticonvulsants, corticosteroids, or tryptophan; pregnancy or lactation; serious suicide risk; serious medical illness or abnormal lab or electrocardiogram results; history of severe allergies, multiple adverse drug reactions, or seizure disorder (with seizure during the last 12 months); or treatment with any form of psychotherapy during the trial".

Dropouts: 12/60 (5/30 in the fluoxetine and 7/30 in the placebo groups)

Interventions

Pharmacological intervention: quote: "During the first 8 weeks of the 14‐week initial treatment phase, patients were started on either placebo or a fixed dose of fluoxetine 20 mg/day. During this time, a patient’s dose could be decreased to 10 mg/day at any time if an adverse event occurred that would have caused the patient to withdraw from the study. The patient could be increased back to 20 mg/day at the investigator’s discretion if the patient did not experience adverse events while receiving 10 mg/day and was not improving. During the last 6 weeks of the 14‐week initial phase, the patient’s dose could be increased every 2 weeks in 20 mg/day increments to a maximum of 60 mg/day, except for patients who were on 10 mg/day, who must first have been increased to 20 mg/day. A patient’s dose could also be reduced in decrements of 20 mg/day (or from 20 to 10 mg/day) at any time at the investigator’s discretion if an adverse event occurred that would have caused the patient to discontinue the study. Subsequently, a patient’s dose could be increased in increments of 20 mg/day (at scheduled visits only) back to a maximum of 60 mg/day (or from 10 to 20 mg/day followed by increments of 20/mg day to a maximum of 60 mg/day) if the patient did not experience adverse events at a subsequent visit and was not improving. This dosing schedule was used in order to evaluate whether patients would respond to 20 mg (an effective dose for depression) after 8 weeks, and if not, whether increasing the dose to as much as 60 mg would result in a positive response"

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: the Social Phobia Subscale of the FQ (for reduction of anxiety), CGI‐S (for reduction of anxiety), CGI‐I (for treatment efficacy), PGI (for treatment efficacy), HAM‐A (for reduction of anxiety), BSPS (for reduction of anxiety), HAM‐D (for reduction of depression), GAF (for reduction of functional disability) and SF‐36 (for quality of life)

Time points: Quote: "The LSAS, CGI‐S, FQ, and BSPS were administered at all visits. The CGI‐I and PGI scales were administered at visits 2 through 17. The HAM‐A, HAM‐D, GAF, and SF‐36 were administered at visits 2, 5, 7, 10, and 17 (or final visit if discontinued early). The HAM‐A and HAM‐D were also administered at visit 1"

Notes

Industry funded: yes. Quote: "This work was supported by a grant from Eli Lilly & Co".

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "randomly assigned to one of three treatment conditions".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the fluoxetine (5/30; 17%) and placebo groups (7/30; 23%). The proportions of women to men was 35:25. Common withdrawals included: participant moved, protocol violation, clinical relapse and adverse events. No information was provided on sample characteristics at end point, however. Quote: "Five (16%) of the 30 fluoxetine patients and 7 (23%) of the 30 placebo patients discontinued before completion of the 14‐week, double‐blind initial therapy phase. Fluoxetine was discontinued because the patient moved (1) or there was a protocol violation (2), clinical relapse (1), or adverse event (1) (palpitations). Placebo was discontinued because the patient moved (1) or there was a lack of efficacy (2), clinical relapse (1), or adverse event (3) (diarrhea, depression, and rash, respectively)". Overall 23% of the participants dropped out of the study.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. There was a high placebo response in this trial. Quote: "By comparison, the change on placebo in the current trial (23.37) was greater than any other individual trial and much greater than the mean placebo change found in the previous studies (11.13). The reason for the high placebo response in this trial is unknown".

Methods

Design: multicentre randomised, placebo‐controlled, fixed‐dose, active‐reference study

Duration of intervention: 12 and 24 weeks

Post‐treatment: 1 month follow‐up

Placebo run‐in: 1‐week, single‐blind, placebo lead‐in period

Participants

Sample size: 839 randomised to escitalopram, paroxetine, or placebo

Mean age (SD): 36.98 (11.2) years

Sex: 394 men and 445 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "The selection criteria were chosen to select physically healthy female and male outpatients with a primary diagnosis of generalised SAD according to DSM‐IV criteria. At the screening visit, patients between 18–65 years of age were included if they had a total score > 70 on the Liebowitz Social Anxiety Scale (LSAS), demonstrable fear and avoidance traits in at least four social situations, and a score > 5 on one or more of the Sheehan Disability Scale (SDS) subscales".

Exclusion criteria: quote: "Patients were excluded if: a) they had another Axis I disorder designated the primary diagnosis within the previous 6 months; b) they had a MADRS total score > 18; c) they had a DSM‐IV diagnosis of schizophrenia/other psychotic disorder, mania or hypomania or history thereof, or were currently suffering from alcohol or drug abuse, eating disorders, MDD, panic disorders (patients with panic attacks not due to panic disorders could be included), obsessive compulsive disorders (OCD), body dysmorphic disorder; d) they had an Axis II Cluster B diagnosis; e) they had learning difficulties or had other cognitive disorder; f) the investigator detected a serious risk of suicide or the patient had a score > 5 in the MADRS item 10 (suicidal tendencies); g) they had a known lack of therapeutic response to any SSRI; h) they had a known hypersensitivity to citalopram or escitalopram or a history of severe drug allergy or hypersensitivity; i) they had taken a psychoactive drug (including antidepressants, beta‐blockers, benzodiazepines, antipsychotics, and psychoactive herbal remedies), monoamine oxidase inhibitors (MAOI), or prophylactic treatment (lithium, valproate, or carbamazepine) within 2 weeks (5 weeks for fluoxetine) before screening, an investigational drug (within 3 months before), or triptans; or j) they were receiving (or planning to initiate) formal psychotherapy".

Dropouts: 242/839 (42/167, 56/167, and 49/170 in the escitalopram groups, 45/169 in the paroxetine group, and 50/166 in the placebo group, 24 weeks).

Interventions

Pharmacological intervention: quote: "After screening, patients entered a 1‐week, single‐blind, placebo lead‐in period before being randomised equally to 24 weeks of double‐blind treatment with fixed doses of escitalopram (5, 10, or 20 mg/day), paroxetine (20 mg/day), or placebo. Patients who completed double‐blind treatment
entered a 2‐week, single‐blind, placebo run‐out period".

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: LSAS (fear/anxiety, avoidance) scores (for reduction of anxiety), CGI‐S (for reduction of anxiety), CGI‐I (for treatment efficacy), SDS (for reduction of functional disability) and DESS (assess side effects)

Time points: Quote: "Efficacy and tolerability were assessed at baseline and after 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 25, and 26 weeks of treatment; tolerability was also assessed 30 days after the last double‐blind dose of study product. Adverse events were assessed at all visits and the clinical assessments were made at the screening visit, and at Weeks 12 and 24"

Notes

Industry funded: yes. Quote: "Contract grant sponsor: H. Lundbeck A/S"

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participantubjects were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "After screening, patients entered a 1‐week, single‐blind, placebo lead‐in period before being randomised equally to 24 weeks of double‐blind treatment with fixed doses of escitalopram".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the escitalopram (42/167, 25.1%; 56/167, 33.5%; 49/170, 28.8%) paroxetine (45/169, 26.6%) and placebo groups (50/166, 30.1%). Primary reasons for withdrawals were adverse events, lack of efficacy, withdrawal of consent and lost to follow‐up. The groups did not differ by sample characteristics at baseline. Quote: "There were no clinically relevant differences in patient demographics or baseline values between the five treatment groups. The treatment groups did not differ significantly in age of SAD onset or duration of SAD, baseline height, weight, or BMI ... Two hundred forty‐two patients (29%) withdrew from the study during the 24‐week, double‐blind period, with similar withdrawal rates in all treatment groups; 22% of all patients had withdrawn by Week 12. Withdrawals due to adverse events were lowest in the 5 mg escitalopram group, whereas withdrawals due to lack of effect were highest in the placebo group. Withdrawal of consent and loss to follow‐up each accounted for < 7% of withdrawals in any treatment group. Because most of the withdrawals occurred in the first 12 weeks of the study, the remaining 12 weeks was too long a period to carry observations forward, so most of the efficacy analyses are based on observed case (OC) analysis". Overall 29% of the participants dropped out of the study.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: multicentre, randomised, double‐blind, placebo‐controlled, flexible‐dose (GSK protocol ID: 29060/790)

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1‐week, single‐blind, placebo run‐in period

Participants

Sample size: 370 randomised to paroxetine or placebo (375 randomised: 5 participants withdrew prior to treatment and were excluded from the study, the ITT sample comprised of 370 participants)

Mean age (SD): 38.85 (11) years

Sex: 270 men and 100 women

Diagnostic measure: MINI (according to DSM‐IV criteria)

Inclusion criteria: quote: "The Mini‐International Neuropsychiatric Interview (Version 5.0; MINI) was used to screen for social anxiety disorder according to DSM‐IV criteria. Outpatients (≥ 18 years of age) who met the criteria as their primary diagnosis were enrolled. Patients older than 65 years were included if they did not have renal or hepatic impairment".

Exclusion criteria: quote: "Patients with a Clinical Global Impressions (CGI)‐Global Improvement score of 1 or 2 at baseline (following the placebo run‐in period) or a score on the 17‐item Hamilton Rating Scale for Depression (HAM‐D) of ≥ 15 at baseline were excluded. Patients evaluated with the MINI who met DSM‐IV criteria for Axis I disorders such as major depressive disorder, obsessive‐compulsive disorder, or panic disorder as a primary diagnosis currently or within 6 months prior to the screening visit were excluded. Also excluded were patients with substance abuse within 3 months of screening or substance dependence within 6 months of screening and patients considered a current homicidal or suicidal risk. Patients with a history of seizures (except febrile seizures), schizophrenia, or bipolar disorder or a current diagnosis of body dysmorphic disorder or a serious medical illness were excluded. In addition, patients who had been treated with psychotropic medications or antidepressants within 14 days of screening, monoamine oxidase inhibitors or fluoxetine within 4 weeks of screening, depot neuroleptics within 12 weeks of screening, or electroconvulsive therapy within the past 3 months were excluded. Patients requiring concomitant therapy with β‐adrenergic blockers, monoamine oxidase inhibitors, benzodiazepines, or other psychoactive medications were excluded. Women who were pregnant, lactating, or of childbearing potential and not practicing a clinically accepted method of contraception were ineligible".

Dropouts: 77/370 (30/186 in the paroxetine group and 47/184 in the placebo groups)

Interventions

Pharmacological intervention: quote: "All patients randomly assigned to paroxetine CR began therapy at 12.5 mg and remained at this daily dose for the first 2 weeks of treatment. Dose elevation was permitted in 12.5‐mg/day increments no more frequently than every 7 days to a maximum of 37.5 mg/day. One dose reduction was permitted only when made necessary by the development of an adverse event. Patients completing the study (or withdrawing prematurely) at doses of 37.5 mg/day received 1 week of taper phase medication at a daily dose of 25 mg before stopping treatment".

Outcomes

Primary outcome measures: LSAS (for reduction of anxiety) and CGI‐I (for treatment efficacy)

Secondary outcome measures: CGI‐S (for reduction of anxiety), SADS (for reduction of anxiety), SDS (for reduction of functional disability) and HAM‐D (for reduction of depression)

Time points: Quote: "After the initial screening visit, these efficacy assessments were administered at baseline and weeks 1, 2, 3, 4, 6, 8, and 12 (or at the time of early withdrawal from the study). In addition, the 17‐item HAM‐D was administered by a clinician at baseline and at week 12 (or at the time of early withdrawal)"

Notes

Industry funded: yes. Quote: "This study was funded by GlaxoSmithKline, Research Triangle Park, N.C".

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "Eligible patients were then randomly assigned at baseline to receive paroxetine CR (paroxetine hydrochloride) (flexible dose range of 12.5–37.5 mg/day) or placebo once daily in a 1:1 ratio for a treatment duration of 12 weeks".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether both participants and personnel were blinded. Quote: "Patients randomly assigned to placebo medication received placebo throughout the study and were dosed in an identical manner to patients randomly assigned to paroxetine CR".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the paroxetine (30/186, 16%) and placebo groups (47/184, 26%). Five participants withdrew prior to treatment and were excluded from the ITT analysis. Common withdrawals include adverse events, protocol deviation, loss to follow‐up and other. More participants in the placebo group discontinued due to lack of efficacy. The 2 groups did not differ by sample characteristics a baseline. Quote: "The treatment groups were generally comparable with respect to age, gender, and race ... A total of 156 patients (83.9%) in the paroxetine CR group and 137 patients (74.5%) in the placebo group completed the 12‐week study. Dropout rates due to adverse events were low and comparable in the 2 treatment groups (2.7% in the paroxetine CR group and 1.6% in the placebo group). A greater proportion of patients in the placebo group withdrew from the study prematurely due to lack of efficacy (2.2% in the paroxetine CR group and 15.8% in the placebo group)". Overall 21% of the participants dropped out of the study. The ITT population was assessed and LOCF and observed cases were used for primary and or secondary missing data.

Selective reporting (reporting bias)

Low risk

All outcomes were reported.

Other bias

Unclear risk

Funding for study provided by industry. The study had various limitations with regards to comparisons of paroxetine CR and IR, as well as dosage ranges different to prior studies conducted. The high percentage of dropouts in the placebo group due to lack of efficacy, however, raises the question of whether blinding of participants was broken. Quote: "It must be emphasized that this study did not include a comparison of paroxetine CR and paroxetine IR. Moreover, the dose ranges studied in the current study were not identical to the dose ranges employed in prior studies, hence conclusions regarding their relative tolerability and efficacy profiles cannot be drawn from these trials ... A greater proportion of patients in the placebo group withdrew from the study prematurely due to lack of efficacy (2.2% in the paroxetine CR group and 15.8% in the placebo group)".

Methods

Design: single‐centre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 8 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1‐week, single‐blind, placebo run‐in

Participants

Sample size: 85 randomised to phenelzine, atenolol or placebo (data however is reported for 74 completers)

Mean age (SD): 34.3 (8.5) years

Sex: 51 men and 23 women

Diagnostic measure: DSM‐III

Inclusion criteria: quote: "Medically healthy patients aged 18 to 50 with a DSM‐III criteria for social phobia".

Exclusion criteria: quote: "Current major depression or substance abuse, a history of schizophrenia, organicity, or bipolar disorder, avoidant personality disorder, and other medical conditions (e.g. benign essential tumours), as well as prior treatment of phenelzine or atenolol".

Dropouts: 11/85 (4/29 in the phenelzine, 5/28 in the atenolol and 2/28 in the placebo groups)

Interventions

Pharmacological intervention: "Treatment with atenolol began at 50 mg/d given in the morning and raised to 100 mg/d, if tolerated, after 2 weeks. Treatment with phenelzine sulfate was begun at 15mg/d and increased to 39 mg/d on day 4, to 45 mg/d on day 8, and to 60 mg/d on day 15. After 4 weeks, depending on clinical state and side effects, the dose of phenelzine sulfate could be optimally raised to 75 mg/d, and to 90 mg/d after 5 weeks. In addition to the 8 week short term treatment phase, the study had maintenance (8 weeks) and discontinuation phases (8 weeks)".

Outcomes

Primary and secondary outcome measures: self‐report versions of the CGI‐S (for reduction of anxiety), LSPS (for reduction of anxiety), CGI‐I (for treatment efficacy), HSC (for reduction of anxiety), SADS (for reduction of anxiety), FNES (for reduction of anxiety), FQ (for reduction of anxiety), WPI (personality measure), HAM‐D (for reduction of depression), HAM‐A (for reduction of anxiety) and SDS (for reduction of functional disability)

Time points: Quote: "These occurred before placebo washout, before randomisation, and at 4‐week intervals thereafter. Patients also underwent weekly physician and self‐ratings"

Notes

Industry funded: no. Quote: "This study was supported in part by grant MH 40121 from the National Institute of Mental Health, Bethesda, Md".

Medication provided by industry: yes. Quote: "Parke‐Davis Pharmaceuticals Co, Morris Plains, NJ, kindly supplied phenelzine, and Stuart Pharmaceuticals, Wilmington, Del, kindly supported atenolol for the study".

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "randomised to an 8 week short term comparison"

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

A larger proportion of participants discontinued the study in the phenelzine (4/25; 16%) and atenolol groups (5/23; 22%) compared to the placebo group (2/26; 8%). Common withdrawals included rash and other sides effects and change of mind. Groups did not differ by sample characteristics at end point, however. Quote: "Of the 85 patients randomised, 74 completers met prospectively determined criteria for inclusion in end‐phase analyses of at least four weeks of randomised treatment with 2 weeks of phenelzine or atenolol. Eleven other, including two placebo‐, four phenelzine‐, and five atenolol‐blind treatment failed to complete at least four weeks of double‐blind treatment. Reasons for doing so included rash, and cheese rash, change of mind, rediagnosis of schizophrenia,and painful erection, rash and other side effects and non compliance with study procedures ... There were no significant difference in demographic or baseline scores amongst the 74 completers". Overall 15% of the participants dropped out of the study.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Medication was provided by industry. No other sources of bias were identified.

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, fixed dose, double‐blind

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1 week, single blind, placebo run‐in

Participants

Sample size: 384 randomised to paroxetine or placebo

Mean age (SD): 36.95 (40.2) years

Sex: 225 men and 159 women

Diagnostic measure: SCID (modified version of the DSM‐IV)

Inclusion criteria: quote: "Adult outpatients (>18 years of age) who met the criteria for the generalised sub‐type of social anxiety disorder were enrolled; patients older than 65 years were permitted if they did not have renal or hepatic impairment and could tolerate paroxetine starting dose of at least 20 mg/day".

Exclusion criteria: quote: "Patients who scored 1 or 2 on the CGI‐I scale at baseline or who had a score greater than or equal to 15 at baseline on the HAM‐D scale were excluded. Patients with comorbid psychiatric disorders such as major depression, OCD, generalised anxiety disorder, and panic disorder were excluded using the SCID if comorbid disorder occurred within the past 6 months and was predominant. Also excluded were patients with substance abuse or dependence within 6 months of baseline, body dysmorphic disorder, schizophrenia, bipolar disorder, homicidal/suicidal tendencies, serious medical illness, or a history of seizures, as well as patients who had started psychotherapy within 6 months of baseline or who had been treated with other psychotropic medications or antidepressants within 14 days of baseline, fluoxetine within 5 weeks of baseline, electroconvulsive therapy within the past 3 months. Patients requiring concomitant therapy with beat‐adrenergic medications, warfarin, anticoagulants, digitalis glycosides, phenytoin, cimetidine, or sumatriptan were not included. Women who were pregnant, lactating, or of child‐bearing potential and not practicing a clinically accepted method of contraception were ineligible".

Dropouts: 142/384 (31/97, 40/95, 43/97 in the paroxetine and 28/95 in the placebo groups)

Interventions

Pharmacological intervention: quote: "All patients randomly assigned to paroxetine began therapy at 20 mg/day. Patients were instructed to take 2 capsules each morning irrespective of treatment assignment. Those randomly assigned to paroxetine 20 mg, remained at that dose for the duration of the study. At week 1, patients randomly assigned to the 40 mg paroxetine group were titrated to that daily dose. Doses for the 60 mg paroxetine group were titrated to 40 mg at week 1 and 60 mg at week 2".

Outcomes

Primary outcome measures: LSAS (for reduction of anxiety) and CGI (for treatment efficacy)

Secondary outcome measures: LSAS (fear and anxiety subscales) (for reduction of anxiety), CGI‐S (for reduction of anxiety), SADS (for reduction of anxiety), SDS (for reduction of functional disability) and HAM‐D (for reduction of depression)

Time points: Quote: "After the initial screening visit, all other tests were administered to patients at baseline and weeks 1, 2, 3, 4, 6, 8, and 12 (at the time of discontinuation). Safety was assessed by monitoring adverse experiences and vital signs at weeks 1, 2, 3, 4, 6, 8, and 12 (or at discontinuation)"

Notes

Industry funded: yes. Quote: "[s]upported by SmithKline Beecham Pharmaceuticals"

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "After a one week placebo run‐in: "Eligible patients then began a 12 week double blind treatment phase and were randomly assigned at baseline to receive paroxetine, 20, 40, or 60mg or placebo once daily in a 1:1:1:1 ratio".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

The medication and placebo groups did not differ significantly in attrition rate nor by sample characteristics at baseline. The proportion of dropouts increased with increasing dose of paroxetine (20 mg/d: 31/97, 31.9%; 40 mg/d: 40/95, 42.1%; 60 mg/d: 43/97, 44.3%), with the dropout rate in the arm receiving the lowest dose of medication similar to that observed amongst participants receiving placebo (28/95, 29.5%). The proportion of dropouts were higher in the paroxetine group due to adverse experience compared to the placebo group due to lack of efficacy. Withdrawals similar across groups included withdrawn, protocol violation, loss to follow‐up, and other reasons. Quote: "The demographic characteristics of the 4 treatment groups were well matched ... Approximately 63% of the randomly assigned subjects (242/384) completed the 12‐week study. There were no significant differences between the 20‐,40‐, or 60‐mg paroxetine groups and the placebo group in the overall attrition rates ... patients remaining in the study beyond week 2, discontinuation rates were comparable between the paroxetine (8%‐23%) and placebo (20%) groups. The primary reason for early discontinuation in any of the paroxetine groups was adverse experiences (17.5%, 21.1% and 23.7%) , whereas the primary reason for early discontinuation in the placebo group was lack of efficacy (10%) ... However there was no difference in the overall incidence of reported adverse experiences between 20‐mg (92%), 40 ‐mg (91%) and 60‐mg (88%) paroxetine groups ane the placebo group (83%)". Overall 37% of the participants dropped out of the study. Efficacy data are presented at both LOCF and OC for missing points.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1 week, single blind, placebo lead‐in period

Participants

Sample size: 415 randomised to sertraline or placebo

Mean age (SD): 35.05 (10.6) years

Sex: 247 men and 168 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Study entry criteria required patients to be aged 18 years or over with a primary diagnosis of generalised social phobia of at least 2 years duration and a LSAS score > 68 at baseline. Social phobia was diagnosed using the DSM‐IV. In addition to meeting DSM‐IV criteria for social phobia, patients were required to exhibit fear and/or avoidance of at least 4 social situations. Women of childbearing potential were required to have negative results on a serum beta‐human chorionic gonadotropin pregnancy test and to be using a medically accepted form of contraception".

Exclusion criteria: quote: "Patients were excluded if they met DSM‐IV criteria in the previous 6 months for substance dependence, body dysmorphic disorder, major depressive disorder, dysthymia, panic disorder, post‐traumatic stress disorder, or an eating disorder; if they reported any current or past diagnosis of schizophrenia, psychotic disorder, bipolar disorder, or obsessive‐compulsive disorder (OCD); or if they met criteria for a primary diagnosis of generalised anxiety disorder. Patients were also excluded for the following reasons: (1) HAM‐D score of 14 or items 1 rating moderate or greater in severity; (2) currently reporting serious suicidal or homicidal risk; (3) currently receiving specific behavioural or supportive therapy for social phobia or another anxiety disorder; (4) any history of seizure disorder; (5) any serious or uncontrolled medical illness or condition that preludes sertraline use; (6) women who were pregnant, nursing, or lactating; (7) receiving any concomitant therapy with any psychotropic drug or with any drug with a psychotropic component, except zolpidem for insomnia".

Dropouts: 122/415 (59/211 in the sertraline and 63/204 in the placebo groups)

Interventions

Pharmacological intervention: quote: "Sertraline treatment was initiated at a daily dose of 25 mg, which was increased at week 1 to 50 mg. After 2 weeks at a dally dose of 50 mg, patients with sufficient clinical response but good tolerability were permitted to increase to 100 mg, and then by 50 mg increments per week to a maximum dose of 200 mg/day.

Outcomes

Primary outcome measures: LSAS (for reduction of anxiety)

Secondary outcome measures: CGI‐I (for treatment efficacy), CGI‐S (for reduction of anxiety) and SPI (for reduction of anxiety)

Time points: Quote: "Patients were evaluated for medication safety and efficacy at weeks 1, 2, 3, 4, 6, 8, and 12"

Notes

Industry funded: yes. Quote: "Funded by Pfizer Inc, New York, N.Y".

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "Patients who continued to meet all inclusion and exclusion criteria were then randomly assigned in a double blind fashion to 12 weeks of double blind treatment with flexible doses of sertraline or matching placebo".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Medication and placebo was provided in identical capsules. However, it is not clear whether both participants and personnel were blinded. Quote: "Patients who continued to meet all inclusion and exclusion criteria were then randomly assigned in a double blind fashion to 12 weeks of double blind treatment with flexible doses of sertraline or matching placebo".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of patients withdrew from the sertraline (59/211; 28%) and placebo groups (63/204; 31%). More participants in the sertraline group withdrew due to adverse events compared to others reasons in the placebo groups. Quote: "Patient characteristics were similar in both groups at baseline ... One hundred fifty‐two (72%) of the 211 patients treated with sertraline and 141 (69%) of the patients treated with placebo completed 12 weeks of double‐blind treatment. Reasons for premature discontinuation during treatment with sertraline and placebo, respectively, included the following: withdrawal of consent, 11 (5.2%) versus 17 (8.3%); lost to follow‐up, 17 (8.1%) versus 10 (4.9%); adverse events, 16 (7.6%) versus 6 (2.9%); insufficient clinical response, 5 (2.4%) versus 9 (4.4%); protocol violation, 3 (1.4%) versus 3 (1.5%); and miscellaneous other reasons, 7 (3.3%) versus 18 (8.8%)". Overall 29% of the participants dropped out of the study. All analyses were ITT and LOCF.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: multicentre, randomised, double blind, placebo controlled, parallel group, flexible dose study

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1 week, single blind, placebo lead‐in period

Participants

Sample size: 279 randomised to venlafaxine ER or placebo

Mean age (SD): 35.4 (11.55) years (271 randomised, LOCF scores)

Sex: 148 men and 123 women (271 randomised, LOCF scores)

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Outpatients at least 18 years of age who met DSM‐IV criteria for social anxiety disorder for a least 6 months before study initiation were eligible for screening. Inclusion was dependent on a CGI‐S baseline score > 50 with a decrease of < 30% between prestudy and baseline, and a Covi Anxiety Scale score greater than Raskin Depression Scale score".

Exclusion criteria: quote: "Individuals with a history of hepatic or medical disease, mental disorder due to a general medical condition, psychotic disorder or organic brain disorder, seizure disorder, or head trauma were excluded from enrolment. Patients with clinically important Axis I or Axis II comorbidities were excluded from study participation if the disorder was current or was predominant with 6 months of the start of the study. Also excluded were patients with a history of alcohol abuse within 1 year of the study, those who regularly used alcohol, and those with a urine drug screen positive for drugs of abuse. Those with multiple drug allergies or a clinically meaningful abnormality in vital signs and findings from physical examination, ECG, laboratory tests, or urine drug screen were not included. Individuals who used the investigational drugs, antipsychotics, sedative hypnotic drugs, antidepressants, anxiolytics, or migraine medication or received electroconvulsive therapy within 6 months before the study or formal psychotherapy within 30 days of the study day 1 were excluded, as were women of childbearing potential who were pregnant or breastfeeding or who did not utilise a medically acceptable form of contraception".

Dropouts: 106/279 (51/139 in the venlafaxine ER and 55/140 in the placebo groups)

Interventions

Pharmacological intervention: quote: "The venlafaxine ER regimen was potentially 3‐step dose‐escalation process with an initial 75 mg/day dose during the first week ± 3 days. During the second week, the dose was increased to 150 mg/day if clinically indicated to enhance response. The dose was increased to 225 mg/day if clinically indicated on study day 15 ± 3 days. At study completion (or early termination), patients who had been taking more than 1 capsule daily for more than 1 week had their dose tapered".

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: CGI‐S (for reduction of anxiety), CGI‐I (for treatment efficacy), SPIN (for reduction of anxiety), LSAS subscales (for reduction of anxiety), SDS (for reduction of functional disability) and HAM‐D (for reduction of depression)

Time points: Quote: "The primary efficacy variable was the LSAS Total score, which was assessed at weeks 1, 2, 3, 4, 6, 8, 10, and 12. The LSAS, CGI‐S, CGI‐I and SPIN assessments were performed at baseline and on study days 7, 14, 21, 28, 42, 56, 70, and 84; the SDS was administered at baseline and on study days 28 and 84; and the HAM‐D and Covi‐Raskin scales were administered at the prestudy visit and on study days 42 and 84 as ancillary evaluations. Final ratings for efficacy were obtained on the last day of full dose administration before tapering or within 3 days of the last full dose"

Notes

Industry funded: yes. Quote: "This study was supported by Wyeth research, Collegeville, Pa".

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "eligible patients were randomly assigned to receive either venlafaxine ER or placebo for up to 12 weeks".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the venlafaxine ER (51/139; 37%) and placebo groups (55/140; 39%). More participants in the venlafaxine group discontinued due to adverse events compared to unsatisfactory response in the placebo group. No information was provided on the other reasons for withdrawal, however the 2 groups did not differ by sample characteristics at baseline or at week 12. Quote: "A comparable number of patients in each treatment group completed the study, i.e., 88 in the venlafaxine group and 85 in the placebo group. Significantly more patients in the placebo group (15%) than in the venlafaxine group (2%) discontinued treatment because of unsatisfactory response, while significantly more patients in the venlafaxine group discontinued treatment because of adverse events (17%) ... There were no significant differences between treatment groups for any of the demographic or baseline characteristics, nor did the demographic and baseline characteristics of the ITT patient population differ appreciably from those of the safety population". Overall 38% of the participants dropped out of the study. All analyses were ITT and LOCF.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group comparison

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1 week, single blind, placebo lead‐in period

Participants

Sample size: 440 randomised to venlafaxine ER, paroxetine or placebo

Mean age (SD): 36.27 (11.3) years (for 413 participants)

Sex: 221 men and 192 women (for 429 participants)

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Outpatients 18 years and older who fulfilled the DSM‐IV criteria for SAD for 6 months or longer at screening were eligible to participate in the study. In addition, patients were required to have a LSAS score of 50 or more at prestudy and baseline evaluations; a score of 4 or more on the CGI‐S scale; a prestudy Covi Anxiety Scale total score greater than the Raskin Depression Scale total score; and a prestudy HAM‐D score of less than 15, with a score of 2 or less on the depressed mood items".

Exclusion criteria: quote: "Patients with a clinically important Axis I or Axis II disorder other than SAD or avoidant personality disorder were excluded, as were those with a history or current diagnosis of any psychotic illness, patients who were suicidal, and those with a history of drug or alcohol dependence within 1 year of study start. In addition, patients were ineligible if they had used any psychopharmacologic medications within 7 days before study day 1; used antidepressants, anxiolytics, or herbal products intended to treat anxiety or depression within 14 days of the study; received electroconvulsive therapy within 6 months of the study; or used antipsychotic medication or fluoxetine or received treatment with formal psychotherapy within 30 days of the study. Patients with clinically significant abnormal findings on laboratory tests, electrocardiograms, or physical examinations; those with abnormal vital signs; those with a history or presence of clinically important medical conditions; and women of childbearing potential who were pregnant, breastfeeding, or not using a medically acceptable form of contraception were prohibited from participating".

Dropouts: 111/440 (insufficient information to determine dropout rates for the three groups separately)

Interventions

Pharmacological intervention: quote: "After a 7 day, single‐blind, placebo lead‐in period, eligible patients were randomly assigned to receive flexible doses of venlafaxine ER (75‐225 mg/d), paroxetine (20‐50 mg/d), or placebo for up to 12 weeks, followed by a taper period of up to 2 weeks. Starting doses were 75 mg/d for venlafaxine ER and 20 mg/d for paroxetine if clinically indicated to improve response, daily doses could be titrated upward each week by 75 mg for venlafaxine ER or 20 mg for paroxetine to a maximum 225 mg/d of venlafaxine ER and 50 mg/d of paroxetine. The dosage could be reduced at any time to improve tolerance; however, the minimum allowed dosages after day 7 were 75 mg/d for venlafaxine ER and 20 mg/d for paroxetine".

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: CGI‐I (for treatment efficacy), CGI‐S (for reduction of anxiety), and SPI (for reduction of anxiety)

Time points: Quote: "The primary efficacy time point was the final on‐therapy (defined as observations that occurred within 3 days of the patient’s last full dose of study medication) LSAS total score. The week 12 last‐observation‐carried‐forward values were the final on‐therapy observations"

Notes

Industry funded: yes. Quote: "This study was supported by Wyeth research, Collegeville, Pa".

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "...patients were randomly assigned to receive flexible doses of venlafaxine hydrochloride ER (75‐225 mg/d), paroxetine (20‐50 mg/d), or placebo for up to 12 weeks".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

There was insufficient information to determine the proportion of dropouts for the three treatment groups. Nevertheless, the three groups did not differ by sample characteristics at baseline nor did they significantly differ by withdrawals. More participants in the venlafaxine and paroxetine group discontinued due to adverse events compared to unsatisfactory response in the placebo group. Quote: "There were no statistically significant differences between the treatment groups for any of the demographic or baseline characteristics ... Three hundred eighteen patients (74.1%) completed the 12‐week double‐blind treatment period and 111 (25.9%) withdrew from the study. Significantly more patients in the active treatment groups (venlafaxine ER and paroxetine) withdrew because of adverse events than in the placebo group, while significantly more patients in the placebo group withdrew because of lack of efficacy; however, there were no significant differences between the active treatment groups. Statistical analyses were performed using last‐observation carried‐forward values for the intent‐to‐treat population".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: multicentre, randomised, placebo‐controlled, parallel, flexible dose, double‐blind

Duration of intervention: 10 weeks

Post‐treatment: no follow‐up

Placebo run‐in: 1‐week single‐blind placebo washout

Participants

Sample size: 106 randomised to brofaromine or placebo

Mean age (SD): 36.5 (9.8) years

Sex: 62 men and 40 women (for 102 ITT participants)

Diagnostic measure: DSM‐III‐R

Inclusion criteria: quote: "Participants were 102 outpatients (62 men and 40 women) with a primary DSM‐III‐R diagnosis of social phobia of at least 6 months' duration. Primary social phobia was defined as dominating the clinical picture and temporally preceding any secondary diagnosis ... A minimum score of 8 was required on the Avoidance Subscale of the LSAS ... A minimum score of 4 (moderately ill) was required on the Liebowitz Social Phobia Global Severity Rating Scale. A maximum score of 15 was allowed on the MADRS".

Exclusion criteria: quote: "Patients were excluded for the following reasons: alcohol or drug abuse in the past 6 months; a DSM‐III‐R diagnosis of organic mental syndrome, organic anxiety syndrome, or caffeinism; clear and immediate suicide risk; personality pathology that might interfere with trial compliance; previous participation in another brofaromine trial; a previous failure to respond to an adequate trial of an SRI or MAO inhibitor; clinically significant comorbid medical disease; concurrent use of other psychotropic drugs, opiates, or certain dietary or prescription amines (patients were allowed to take chloral hydrate, diphenhydramine, and doxylamine); and patients who in the judgment of the investigator were likely to be noncompliant".

Dropouts: 31/106 (14/52 in the brofaromine and 17/54 in the placebo groups).

Interventions

Pharmacological intervention: quote: "Brofaromine dosage began at 50 mg/day and was titrated up to a maximum of 150 mg/day, depending on response to treatment. Patient visits were scheduled at weekly intervals for the first 2 weeks of double‐blind treatment and biweekly thereafter. After 10 weeks of double‐blind treatment (or at early termination), patients entered a 1‐to 2‐week double‐blind weaning period during which the trial drug dose was tapered and discontinued".

Outcomes

Primary outcome measure: LSAS (for reduction of anxiety)

Secondary outcome measures: CGI (for treatment efficacy), GAF (for reduction of functional disability), HAM‐A (for reduction of anxiety), MADRS (for reduction of depression), FONE (for reduction of anxiety), LSAS (for reduction of anxiety), CSPS (for reduction of anxiety), and SDS (for reduction of functional disability)

Time points: Quote: "Efficacy measures were obtained at bassline and at end of 2, 6, and 10 week of double‐blind treatment"

Notes

Industry funded: yes. Quote: "This study was supported by the Ciba‐Geigy Corporation, Summit, NJ".

Medication provided by industry: unclear

Any of the authors work for industry: yes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "patients who still met inclusion criteria and and did not respond to placebo ... were randomly assigned to 10 weeks of treatment with either brofaromine or place".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on which parties were blinded and how blinding was achieved.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The study was described as "double‐blind", though no information was provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar proportions of participants withdrew from the brofaromine (14/52; 27%) and placebo groups (17/50; 34%). More participants in the brofaromine group discontinued due to adverse events compared to withdrawal of consent in the placebo group. The 2 groups did not differ by sample characteristics at baseline. Quote: "Fourteen brofaromine patients and 17 placebo patients discontinued the trial prematurely. Eleven of the 14 brofaromine early terminators discontinued because of adverse experiences, as did four of the 17 placebo early terminators. Other reasons for early termination included unsatisfactory therapeutic effect (N = 3, placebo); did not meet protocol criteria (N = 1, placebo); patient noncompliance (N = 2, placebo); patient withdrew consent (N = 1, brofaromine; N = 6 placebo); and lost to follow‐up (N = 2, brofaromine; N = 1, placebo) ... No significant baseline differences were found between treatment groups on race, gender, age, or LSAS total score". Overall 30% of the participants dropped out of the study. Quote: "An intent‐to‐treat analysis was employed, with the last evaluable visit past baseline carried forward as endpoint".

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Unclear risk

Funding for study provided by industry. No other sources of bias were identified.

Methods

Design: single‐centre, quasi‐experimental, randomised‐controlled, wait‐list study

Duration of intervention: 12 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 30 randomised to sertraline or placebo (the additional 15 participants were randomised to psychotherapy)

Mean age (SD): 24.5 (2.2) years

Sex: 30 men

Diagnostic measure: DSM‐IV‐TR (based on SCID)

Inclusion criteria: quote: "SPIN score ≥ 24, age between 18 to 50 years, and meeting the DSM‐IV‐TR criteria for social phobia based on SCID"

Exclusion criteria: quote: "being psychotic, or obsessive‐compulsive; having bipolar, or organic brain disorders; drug and alcohol dependency; having impulse control disorders, cluster A and B personality disorders, active disorder on axis III, a history of suicidal thoughts and actions, a history of violent behavior; being on psychotropic medications or receiving psychotherapy for the treatment of social phobia during the last 6 months, or experiencing the symptoms of social phobia as part of other psychiatric disorders".

Dropouts: not specified

Interventions

Pharmacological intervention: quote: "Members of the MED group received pharmacotherapy (sertraline) for 12 weeks. Patients in the WL group received no intervention. However, after the waiting period, they received preferred treatment services. Each group was evaluated 4 times during the study".

Outcomes

Primary outcome measure: SPIN (for reduction of anxiety)

Secondary outcome measures: GAF (for reduction of functional disability), CGI‐I (for treatment efficacy), CGI‐S (for reduction of anxiety)

Time points: Quote: "In this randomized‐controlled trial study, 13 male students were treated with short‐term dynamic psychotherapy (McCullough method) lasting 25 sessions, 11 students received sertraline for 12 weeks, and 14 students, as the waiting list, received no intervention for 8 weeks. Participants completed the Social Phobia Inventory (SPIN) as primary efficacy variable 4 times, and were rated with Clinical Global Impression scale (CGI) and Global Assessment of Functioning (GAF) as secondary efficacy variables". Time points were not specified

Notes

Industry funded: no. Quote: "This research was funded by Tehran University of Medical Sciences and Mental Health Research Network (MHRN)".

Medication provided by industry: unclear

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomly assigned to treatment and comparison. However, the procedure was not specified. Quote: "The participants were randomly assigned into 3 groups: 1‐psychotherapy (STDP), 2‐ medical therapy (MED) and 3‐ waiting list (WL)".

Allocation concealment (selection bias)

Unclear risk

There was insufficient information provided to determine if study medication allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No information was provided to determine if participants and personnel were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No information was provided to determine if outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

No dropout rates were reported.

Selective reporting (reporting bias)

Low risk

All outcomes were reported on as specified in the protocol.

Other bias

Low risk

No other sources of bias were identified.

Methods

Design: single‐centre, randomised, double‐blind, fixed dose, placebo‐controlled study

Duration of intervention: 10 weeks

Post‐treatment: no follow‐up

Placebo run‐in: no

Participants

Sample size: 66 randomised to mirtazepine or placebo

Mean age (SD): 24 (3.45) years

Sex: 66 women

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Women aged 18 or older who have social phobia were included in the study".

Exclusion criteria: quote: "Exclusion criteria were psychotic symptoms, a severe major depressive episode (according to the DSM‐IV criteria), the current use of mirtazepine or other psychotropic medication, and psychotherapy. Potential subjects were also excluded if they currently were pregnant (or planning to be or not using contraception), severely somatically ill, currently suicidal, or abusing alcohol or drugs".

Dropouts: 7/66 (insufficient information to determine dropout rates for the 2 groups separately)

Interventions

Pharmacological intervention: quote: "Subjects received blinded capsule per day, either 30 mg of mirtazepine or matching placebo. The dosage of mirtazepine stayed constant".

Outcomes

Primary outcome measures: SPI (for reduction of anxiety), LSAS (for reduction of anxiety) and SF‐36 (for quality of life)

Secondary outcome measures: none

Time points: Weekly examinations.

Notes

Industry funded: no. Quote: "This study was not funded and was not influenced by outside economic interests".

Medication provided by industry: no

Any of the authors work for industry: no

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Author correspondence: quote: "We used an excel sheet with random number generator".

Allocation concealment (selection bias)

Low risk

Quote: "Subjects received blinded capsule per day, either 30 mg of mirtazepine or matching placebo. The dosage of mirtazepine stayed constant. Tablets were supplied in numbered boxes".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Both subjects and clinicians were blinded to mirtazepine/placebo assignment".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Both subjects and clinicians were blinded to mirtazepine/placebo assignment".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There was insufficient information to determine the proportion of dropouts for the three treatment groups, though a relatively small number dropped out overall (N = 7, 11%). No information was provided on the reasons for study withdrawal. There was also no information on group characteristics. Quote: "Seven patients who failed to appear more than twice for the weekly evaluations dropped out of the study". All analyses were ITT.

Selective reporting (reporting bias)

Unclear risk

The study protocol was not available for this study.

Other bias

Low risk

Self reported measures were used but No other sources of bias were identified. Quote: "The questionnaires were filled out by the patients both independently and anonymously".

Methods

Design: multicentre, randomised, double‐blind, placebo‐controlled, parallel, forced‐dose titration study (NKF100110)

Duration of intervention: 12 weeks

Post‐treatment: follow‐up not specified

Placebo run‐in: not specified

Participants

Sample size: 107 randomised to paroxetine or placebo (the additional participants were randomised to NCE, the results will be available once NCE is approved by the FDA).

Mean age (SD): 34.4 (10.83) years

Sex: 60 men and 44 women (for 104 participants)

Diagnostic measure: DSM‐IV

Inclusion criteria: quote: "Male or female subjects between 18‐65 years of age; A primary diagnosis of Generalized Social Anxiety Disorder/Social Phobia (DSM‐IV, 300.23)".

Exclusion criteria: quote: "CGI‐I item score of 1 or 2 at baseline; Montgomery‐Asberg Depression Rating Scale (MADRS) score of 18 or more at screening; DSM‐IV criteria for any other Axis I disorder as a current primary disorder or within 6 months prior to the screening visit; Subjects with Body Dysmorphic Disorder; History of Schizophrenia, Schizoaffective Disorder, or a Bipolar Disorder; Current, serious suicidal or homicidal risk or suicide attempt within the past 6 months or have ever been homicidal; Unstable medical disorder; or a disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of the NCE or paroxetine; may pose a safety concern; or interfere with the accurate assessment of safety or efficacy".

Dropouts: 44/107 (14/36 in the paroxetine and 30/71 in the placebo group)

Interventions

Pharmacological intervention: quote: "After completion of a screening period, subjects fulfilling the inclusion/exclusion criteria were randomised (2:2:2:1) to two dose ranges of an NCE, placebo, or paroxetine (20‐30 mg/day). A forced‐flexible dose titration scheme was employed".

Outcomes

Primary outcome measures: LSAS (for reduction of anxiety)

Secondary outcome measures: CGI‐I (for treatment efficacy), CGI‐S (for reduction of anxiety), LSAS Fear and Avoidance subscales (for reduction of anxiety), SDS (for reduction of functional disability), MOS‐12 (assess changes in sleep quality), and LSEQ (assess changes in sleep quality)

Time points: Week 1 and 12. Quote: "Adverse events (AEs) and Serious Adverse Events (SAEs) were reported during treatment weeks 1 through 12, the taper visit, and at the 14‐day follow‐up visit or early withdrawal visit. This summary includes data for the paroxetine and placebo groups. Results for the unmarketed NCE will be added, if and when the NCE is approved and marketed"

Notes

Industry funded: not specified

Medication provided by industry: not specified

Any of the authors work for industry: not specified

Risk of bias

Bias