Initial Severity and Antidepressant Efficacy for Anxiety Disorders: an Individual Patient Data Meta-analysis

September 26, 2016 updated by: prof. Peter de Jonge
Anxiety disorders are common disorders, which pose a major burden to society and the individual. An anxiety disorder may be treated with medication, in particular with antidepressants such as the selective serotonin reuptake inhibitors (SSRIs). However, much of what is known about antidepressants is derived from research in depression rather than anxiety. In recent years, researchers have found that antidepressants are more effective for severely depressed patients than they are for patients with milder symptoms. It is possible that a similar relationship between symptom severity and antidepressant efficacy exists for anxiety disorders, but there is currently little evidence available to answer this question. As antidepressants are frequently prescribed to patients with mild or moderate anxiety, a clear understanding of their effectiveness across the severity range is vital to inform treatment decisions. Therefore, the purpose of this meta-analysis is to examine whether initial symptom severity affects antidepressant efficacy for anxiety disorders.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Study design:

The proposed project is an individual patient data meta-analysis. The investigators will collate data from 29 randomized controlled trials of second-generation antidepressants (specifically: paroxetine, paroxetine controlled release (CR), duloxetine, and fluoxetine) for the short-term treatment of an anxiety disorder, including a total of approximately 8,800 participants. The anxiety disorders that are included in the proposed project are generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder (PD). Generalized linear mixed models will be used to investigate whether initial symptom severity is related to antidepressant efficacy.

Statistical analysis plan:

A separate longitudinal analysis will be conducted for each disorder. For GAD, SAD, OCD, and PTSD, linear mixed models will be used; for PD, a generalized linear mixed model (multilevel negative binomial regression) will be used, as the dependent variable for this disorder (number of panic attacks) is a discrete count variable. Maximum likelihood estimation will be used as the estimation method for the linear mixed models, while Laplace approximation will be used as the estimation method for the multilevel negative binomial regression for PD. In all models, measurement occasion represents level 1, participants represent level 2, and trial represents level 3. The effect measure of interest is the change in symptoms from baseline, except for PD, for which the effect measure of interest is the total number of panic attacks per two weeks.

The initial model will be built by including all the fixed effects of interest, regardless of significance. These include initial severity, treatment group and covariates (see below). Linear and quadratic terms for time (in days since baseline) will be included. For each participant, the actual visit dates will be used (if available) rather than the intended weekly visit date. The following two- and three-way interactions will also be included: severity x group, severity x linear time, group x linear time, severity x group x linear time, severity x quadratic time, group x quadratic time, severity x group x quadratic time.

Using this first model, the variance-covariance structure of the nested data will be modeled by including random effects. Random effects for study, subject and (linear and quadratic) time, as well as various covariance structures (unstructured, autocorrelated errors, Toeplitz, etc.) will be considered. Restricted maximum likelihood (REML) will be used for estimation, and the best-fitting model will be selected based upon the Akaike Information Criterion (AICc).

In this best-fitting model, backward selection with maximum likelihood (ML) will be used to select the significant fixed effects. Non-significant interaction terms will be removed from the model (unless the three-way interaction of group x severity x (linear or quadratic) time is significant, in which case all two-way interactions and main effects that use these variables will be retained). The best-fitting model will again be selected based upon the Akaike Information Criterion (AICc).

Covariates: Models with and without the following covariates will be tested: age, gender, and duration of illness (if available). Only the main effect of these covariates will be included; no interactions with other variables will be included.

Missing data: Baseline variables (such as initial severity) are likely to be essentially complete, but some change scores are likely to be missing due to dropout or missed measurement occasions. The assumption is made that these data are missing at random (MAR), that is: missingness of the dependent variable may depend upon observed variables (such as previous symptom scores or covariates), but it does not depend upon the value of the unobserved (missing) variable. When MAR holds, the mixed model yields unbiased estimates of coefficients and standard errors even when some data is missing, and no other methods for handling missing data are required.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
8800

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The study population consists of adults aged 18 and older (with the exception of OCD trials, which may include adolescents aged 14 and older) who have been diagnosed with generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), or panic disorder (PD) and who were randomized to placebo or to treatment with a second-generation antidepressant.

Description

Inclusion Criteria:

  • Inclusion in the intent-to-treat population of a randomized controlled trial of a second-generation antidepressant for the short-term treatment of an anxiety disorder
  • Diagnosed with an anxiety disorder (GAD, SAD, OCD, PTSD or PD)

Exclusion Criteria:

  • Assignment to an active comparator that is not a second-generation antidepressant (e.g. a benzodiazepine)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Placebo group
Patients participating in one of the included randomized controlled trials, assigned to the placebo group
Intervention group
Patients participating in one of the included randomized controlled trials, assigned to the investigational antidepressant (paroxetine, duloxetine or fluoxetine) or active comparator (venlafaxine) group.
Drug: paroxetine, duloxetine, fluoxetine or venlafaxine
Other Names:
  • Cymbalta
  • Effexor
  • Prozac
  • Paxil

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Change from baseline on the Hamilton Anxiety Rating Scale (HAM-A)
Time Frame: Baseline to trial endpoint (8 to 10 weeks)
Baseline to trial endpoint (8 to 10 weeks)
Change from baseline on the Liebowitz Social Anxiety Scale (LSAS)
Time Frame: Baseline to trial endpoint (12 weeks)
Baseline to trial endpoint (12 weeks)
Change from baseline on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)
Time Frame: Baseline to trial endpoint (12 to 13 weeks)
Baseline to trial endpoint (12 to 13 weeks)
Change from baseline on the Clinician-Administered PTSD Scale (CAPS)
Time Frame: Baseline to trial endpoint (12 weeks)
Baseline to trial endpoint (12 weeks)
The total number of panic attacks
Time Frame: Baseline to trial endpoint (10 to 12 weeks)
Baseline to trial endpoint (10 to 12 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
prof. Peter de Jonge

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 1, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2016

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2016

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 3, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 16, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 19, 2015

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 27, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 26, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CSDR-1173

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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