DOI: 10.25934/pr00009384
title: Episode duration and severity as predictors of response to desvenlafaxine and placebo in patients with major depressive disorder

description: Major Depressive Disorder (MDD) is a severe and debilitating mental illness that will affect up to 15% of the population at some point in their lives. It is characterized by episodes of profound low mood that pervade all aspects of a person life. These are accompanied by other symptoms such as slowed speech and thinking; thoughts and feelings of worthlessness, inappropriate guilt, hopelessness, and suicidal thinking; disturbed sleep and appetite; lack of motivation and energy; and, in its most severe form, hallucinations and delusions. MDD is a leading cause of disability worldwide, the burden of which is expected to grow over the next decade. Most people who develop a depressive episode will suffer from another at some point in their life. Dozens of antidepressant medications have been approved to treat MDD. Although there have been advances in terms of reducing unwanted medication side effects, newer antidepressants are not appreciably more effective than older medications, many of which share similar underlying properties. Up to 20-30% depressed patients will not respond well to any of these conventional antidepressant medications, and there remains a serious need to develop novel medications to help these patients. 

When a new medication is being developed or tested in a clinical trial it is often compared to a placebo—an inert pill that has no active medical properties. Antidepressant clinical trials are known to suffer from high placebo response rates, and this makes it difficult to develop new antidepressant medications. It is not uncommon to observe placebo response rates as high as 40-45%, meaning almost half of the patients in the trial improved significantly from taking an inert placebo. It is not surprising that depression would have such a high placebo response rate since depression tends to be an episodic condition (the symptoms come and go over time). In fact, research has suggested that a significant part of the "placebo effect" observed in depression trials is just symptoms naturally improving over time.

Researchers have attempted to identify which depressed patients are more or less likely to respond to a placebo. Two variables that have been identified as potentially important are baseline depression severity (i.e., how severely depressed a patient is when they enter a trial, measured by their score on a depression symptom rating scale) and episode duration (i.e., how long the patient's current depressive episode has lasted at the time they enter the study). Interestingly, these variables, to some extent, are expected to be mutually exclusive and it may even be counter-productive to consider only one of them in isolation. For example, patients with very severe depressive episodes (historically referred to as 'melancholia') have lower placebo response rates, but left untreated, these episodes tend to resolve over time, usually within 6-12 months. In contrast, patients with very mild but chronic depressive episodes (also called dysthymia or persistent depressive disorder) can have much longer episodes, lasting well over two years, yet they also tend to have lower placebo response rates. It is also problematic that many clinical trials actually deliberately exclude patients with chronic depression lasting more than two years under the assumption that these patients will be less responsive to medication. While this is the case for patients with dysthymia, their placebo response rate is decreased to an even larger degree, resulting in larger drug-placebo differences compared to patients with non-chronic depression. Thus, this assumption has likely hindered drug development.

We plan to analyse data from 7 randomized placebo-controlled trials of the antidepressant desvenlafaxine to examine how baseline severity and episode duration influence placebo response rates. By using data from 7 different trials, we are able to test hypotheses that would otherwise be difficult with a smaller sample size. We hope our results will help drug developers design future clinical trials with lower placebo response rates, thus aiding the establishment of effective treatments for depression.