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

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: Unknown
• Conditions: Anxiety Disorders; Generalized Anxiety Disorder; Social Anxiety Disorder; Panic Disorder; Post-traumatic Stress Disorder; Obsessive-compulsive Disorder
• Intervention / Treatment: Drug: paroxetine, duloxetine, fluoxetine or venlafaxine

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: Observational
• Enrollment (Anticipated): 8800

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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

Outcome Measure	Time Frame
Change from baseline on the Hamilton Anxiety Rating Scale (HAM-A)	Baseline to trial endpoint (8 to 10 weeks)
Change from baseline on the Liebowitz Social Anxiety Scale (LSAS)	Baseline to trial endpoint (12 weeks)
Change from baseline on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)	Baseline to trial endpoint (12 to 13 weeks)
Change from baseline on the Clinician-Administered PTSD Scale (CAPS)	Baseline to trial endpoint (12 weeks)
The total number of panic attacks	Baseline to trial endpoint (10 to 12 weeks)

Collaborators and Investigators

• Sponsor: prof. Peter de Jonge

Publications and helpful links

General Publications

• de Vries YA, Roest AM, Burgerhof JGM, de Jonge P. Initial severity and antidepressant efficacy for anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder: An individual patient data meta-analysis. Depress Anxiety. 2018 Jun;35(6):515-522. doi: 10.1002/da.22737. Epub 2018 Apr 16.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: June 3, 2015
• First Submitted That Met QC Criteria: June 16, 2015
• First Posted (Estimate): June 19, 2015

Study Record Updates

• Last Update Posted (Estimate): September 27, 2016
• Last Update Submitted That Met QC Criteria: September 26, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: anxiety disorder; antidepressants; individual patient data meta-analysis; selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Trauma and Stressor Related Disorders; Phobic Disorders; Disease; Obsessive-Compulsive Disorder; Anxiety Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Phobia, Social; Panic Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Cytochrome P-450 CYP2D6 Inhibitors; Duloxetine Hydrochloride; Paroxetine; Venlafaxine Hydrochloride; Fluoxetine
• Other Study ID Numbers: CSDR-1173

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No