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Proposal 1173

Title of the Proposed Research

Initial severity and antidepressant efficacy for anxiety disorders: an individual patient data meta-analysis

Lead Researcher

Ymkje Anna de Vries

Affiliation

Interdisciplinary Center Psychopathology and Emotion regulation, Department of Psychiatry, University Medical Center Groningen, the Netherlands

Funding Source

No specific funding will be used for the proposed project. All members of the research team are employed by and receive a salary from the University Medical Center Groningen.

Potential Conflicts of Interest

Potential conflicts of interest will be disclosed when the research is presented and published.

Data Sharing Agreement Date

23 June 2015

Lay Summary

Anxiety disorders form a heterogeneous group of disorders characterized by excessive fear or worry. The group includes generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and panic disorder (PD). In any given year, 18.1% of the US population will suffer from an anxiety disorder, while the lifetime risk stands at 28.8%. As these disorders are also characterized by an early age of onset and a chronic course, they pose a major public health burden.

Anxiety disorders are often treated with medications. In particular, second-generation antidepressants, which include selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have been found to be effective treatments and are now considered the pharmacological treatment of first choice for anxiety.

However, much of what is known about antidepressants is derived from research in depression rather than anxiety. In recent years, researchers have found that the efficacy of antidepressants for depression depends upon the initial severity of symptoms. While severely depressed patients experience considerable benefit from taking antidepressants, as compared to placebo, mildly depressed patients experience a much smaller benefit. Consequently, it has been recommended that antidepressants should not be a first-line treatment for mild depression.

It is possible that a similar relationship between symptom severity and antidepressant efficacy exists for anxiety disorders. As antidepressants are frequently prescribed for patients with mild or moderate anxiety, a clear understanding of their effectiveness across the severity range is vital to inform treatment decisions. The evidence, however, is limited. We have previously conducted a meta-analysis of all premarketing studies of second-generation antidepressants that are approved in the US for the short-term treatment of anxiety. In this meta-analysis, we found no evidence that initial severity affects antidepressant efficacy for anxiety disorders, in contrast to findings in depression. However, as we relied upon trial-level rather than patient-level data, definitive conclusions cannot be drawn yet.

In the proposed project, we therefore plan to use individual patient data to examine whether initial symptom severity affects antidepressant efficacy for anxiety disorders. We will make use of data from 30 randomized controlled trials of antidepressants (specifically: duloxetine, fluoxetine, and paroxetine) for GAD, SAD, OCD, PTSD or PD. We will model improvement in drug and placebo groups over time and investigate whether greater initial severity predicts a greater difference in improvement between drug-treated and placebo-treated patients. Our findings will be presented at international conferences and published in a major medical journal.

Study Data Provided

Study LILLY-F1J-MC-HMBR: Duloxetine Hydrochloride 60 mg or 120 mg Once Daily Compared With Placebo in Patients With Generalized Anxiety Disorder
Study LILLY-F1J-MC-HMDT: Duloxetine Hydrochloride Once Daily Compared With Placebo in the Treatment of Generalized Anxiety Disorder
Study LILLY-F1J-MC-HMDU: A Comparison of Duloxetine Hydrochloride, Venlafaxine Extended Release, and Placebo in the Treatment of Generalized Anxiety Disorder
Study LILLY-F1J-MC-HMDW: A Comparison of Duloxetine Hydrochloride, Venlafaxine Extended Release, and Placebo in the Treatment of Generalized Anxiety Disorder
Study LILLY-B1Y-EW-HCHQ: A Double-Blind Placebo-Controlled Study of Fluoxetine and Clomipramine in the Treatment of Panic Disorder
Study LILLY-B1Y-MC-HCEP: Fluoxetine vs Placebo in Obsessive Compulsive Disorder
Study LILLY-B1Y-MC-HCHG: Fluoxetine versus Placebo in Panic Disorder
Study LILLY-B1Y-MC-HCJB: Fluoxetine versus Placebo in Panic Disorder
Study LILLY-B1Y-MC-HCJC: AFluoxetine versus Placebo in Panic Disorder
Study GSK-BRL-029060/CPMS- 116: Paroxetine versus Placebo in the Treatment of Obsessive-Compulsive Disorder
Study GSK-MY- 1028/BRL-029060/1/CPMS-118: Paroxetine versus Clomipramine and Placebo in the Treatment of Obsessive-Compulsive Disorder
Study GSK-MY1047/BRL-029060/1/CPMS-120: A double-blind, placebo-controlled, multicenter study of fixed doses of paroxetine (10, 20, and 40mg) given as a single oral dose daily, in the treatment of panic disorder
Study GSK-MY-1037/BRL-029060/1/CPMS-136: A Double-Blind Study to Assess the Efficacy and Tolerance of a Flexible Dose of Paroxetine Compared with a Flexible Dose of Clomipramine and Placebo in the Treatment of Obsessive Compulsive Disorder
Study GSK-MY-1036/BRL-029060/1/CPMS-187 (PAR187): A Double-Blind Placebo Controlled Comparative Study of Paroxetine and Clomipramine
Study GSK-MY-1048/BRL-029060/1/CPMS-223 (PAR 223): A Double-Blind, Multicentered, Flexible-Dose Study of Paroxetine, Alprazolam and Placebo in the Treatment of Panic Disorder
Study GSK-PAR 029060-382: A Randomized, Double-Blind, Comparison of Paroxetine and Placebo in the Treatment of Generalized Social Phobia
Study GSK-PAR 454: A Randomized, Double-Blind, Fixed Dose Comparison of 20, 40, and 60mg Daily of Paroxetine and Placebo in the Treatment of Generalized Social Phobia
Study GSK-29060-494: A Double-Blind, Placebo-Controlled, Flexible-Dosing Trial to Evaluate the Efficacy of Modified-Release Paroxetine in the Treatment of Panic Disorder
Study GSK-29060/495: A Double-Blind, Placebo-Controlled, Flexible-Dosing Trial to Evaluate the Efficacy of Controlled-Release Paroxetine in the Treatment of Panic Disorder
Study GSK-29060/497: A Double-Blind, Placebo-Controlled, Flexible-Dosing Trial to Evaluate the Efficacy of Controlled-Release Paroxetine in the Treatment of Panic Disorder
Study GSK-PAR 029060-502: A Randomised, Double-blind Study of Paroxetine and Placebo in the Treatment of Social Phobia
Study GSK-PAR 29060/627: A 12-Week, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess the Efficacy and Tolerability of Paroxetine in Patients Suffering from Post-traumatic Stress Disorder (PTSD)
Study GSK-PAR 29060 637: A double-blind, placebo controlled study to evaluate the efficacy and tolerability of paroxetine in patients with Generalised Anxiety Disorder (GAD)
Study GSK-BRL-029060/RSD-101336/1/CPMS-641: A Randomized, Double-Blind, Placebo Controlled, Fixed Dosage Trial to Evaluate the Efficacy and Tolerability of 20 and 40mg/day Paroxetine in Patients with Generalized Anxiety Disorder
Study GSK-PAR 29060/642: A Randomized, Double-Blind, Placebo Controlled, Flexible Dosage Trial to Evaluate the Efficacy and Tolerability of 20 and 40mg/day Paroxetine in Patients with Generalized Anxiety Disorder
Study GSK-PAR 648: A 12 Week, Double-blind, Placebo-controlled, parallel group study to assess the efficacy and tolerability of Paroxetine in Patients suffering from Posttraumatic Stress Disorder (PTSD)
Study GSK-PAR 29060 651 (BRL – 02960): A 12 week, double-blind, fixed dose comparison of 20 and 40 mg daily of paroxetine and placebo in Patients suffering from Posttraumatic Stress Disorder (PTSD).
Study GSK-BRL-029060/CPMS-790: A Double-blind, Placebo-controlled, Flexible-dose Study of Paroxetine CR in the Treatment of Patients with Social Anxiety Disorder
Study GSK-29060/791: A Randomized, Double-Blind, Placebo-Controlled, Flexible Dosage Trial to Evaluate the Efficacy and Tolerability of Paroxetine CR in Patients with Generalized Anxiety Disorder (GAD)

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation