VIENNA – A novel method of individualizing antidepressant drug therapy while drastically shortening the time required to figure out whether a given agent will be effective in a depressed patient is undergoing its definitive evaluation in five European countries.

“I think this study will provide a critical test of whether we can use these kinds of correlations with emotional processing of information to actually improve the treatment of depression,” Catherine J. Harmer, DPhil, said at the annual congress of the European College of Neuropsychopharmacology.

The clinical trial, known as PReDicT (Predicting Response to Depression Treatment), has been funded with a 4 million Euro grant from the European Commission through its Horizon 2020 public health improvement program. PReDicT represents the culmination of years of original work by Dr. Harmer, who is credited with developing and validating an influential cognitive neuropsychological theory of antidepressant drug action.

As early as 2009, she and her coinvestigators demonstrated that depression is associated with a measurable negative bias in the processing of emotional information. Depressed patients selectively pay more attention to and better remember negative information. For example, when depressed patients taking the Facial Expression Recognition Test are quickly shown a photo of a smiling face, they are more likely to describe it as “sad.” Similarly, in a word recall test that includes “positive” adjectives such as cheerful, poised, original, and optimistic and “negative” words such as mean, hostile, domineering, and untidy, they recall fewer positive words than nondepressed people.

This negative emotional bias is a key factor in maintenance of depression. Many weeks before patients report feeling improvement in their mood and clinical symptoms of depression in response to effective antidepressant medication, the drug produces a favorable effect on their cognitive biases in emotional processing, explained Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).

Dr. Harmer hypothesized that antidepressants don’t necessarily act as direct mood enhancers, but instead change the balance away from negative to more positive emotional processing, resulting in neural modulation in limbic and prefrontal circuitry. These neural changes take time to reach the subjective conscious mind, which is why improvement in clinical symptoms of depression doesn’t manifest until 2-3 weeks into therapy, with the drug’s full effects not seen until 6-7 weeks (Br J Psychiatry. 2009 Aug;195[2]:102-8).

“Antidepressants can target cognitive biases surprisingly early on in treatment, before patients report any change in their clinical symptoms. This could explain the delay in antidepressant effect. You need life events, stressors, and environmental stimuli before a change in bias would be expected to result in a change in clinical state,” she said.

Together with her colleagues, she employed functional MRI to study changes in the brain associated with the improvement in negative biases in emotional processing that occur when depressed patients go on antidepressant medication. Forty-two unmedicated depressed patients were randomized to 10 mg of escitalopram (Lexapro) daily for 7 days or placebo. At baseline, all subjects demonstrated amygdala hyperactivity in response to fearful facial expressions, a response that didn’t occur in healthy controls. After 7 days of escitalopram – weeks before any improvement in depressed mood – amygdala activity was normalized in the active treatment group but not in placebo-treated controls (Psychol Med. 2012 Dec;42[12]:2609-17).

Dr. Harmer and a colleague expanded on her theory of depression in a review article aptly titled, “It’s the way that you look at it” (Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368[1615]:20120407).

A measurable improvement in emotional processing can be seen within a few hours after a depressed patient takes the first dose of an effective antidepressant. Thus, early change in negative emotional processing is predictive of subsequent clinical outcome. Lack of an early shift to positive emotional processing has been associated in multiple studies by Dr. Harmer and others with a high likelihood that an antidepressant won’t provide significant improvement in depressive symptoms at week 6.

The predictive accuracy of tests of emotional processing is higher when testing is done after a patient has been on an antidepressant medication for a few days rather than after the very first dose. Based upon Dr. Harmer’s work, pharmaceutical companies are now using tests of change in emotional processing at 1 week to help screen and select novel treatments for depression and anxiety.

In PReDicT, depressed patients being treated in primary care clinics across Europe will undergo emotional processing testing at baseline. In the active intervention arm, participants will be retested after 1 week on antidepressant therapy in order to identify those who are unlikely to have a favorable clinical response to that drug, enabling physicians to accelerate decision making about the appropriate next treatment. Treatment decisions in the control group will be made without the emotional processing results, mirroring current everyday practice.

Instead of waiting 4-6 weeks before concluding that a switch to another antidepressant with a different mechanism of action is warranted, as is now routine, participating PReDicT physicians whose patients are in the active intervention arm can make an informed change after just 1 week. The study hypothesis is that participants randomized to this study arm will take less time to respond to antidepressant therapy, because their physicians will be able to find the right drug faster than in the control group. The primary study endpoint will be the percentage of patients in the two study arms showing at least a 50% reduction in their Quick Inventory of Depressive Symptomatology (QIDS SR-16) score at 8 weeks. Secondary endpoints will focus on cumulative health care costs at weeks 24 and 48.

The PReDicT study is being run by P1vital Products Ltd., an Oxfordshire health care company that will use its proprietary Internet-based eHealth Emotional Test Battery to assess early changes in emotional processing. The test battery, which is classified as a medical device, is based upon Dr. Harmer’s earlier work. She is an investigator in PReDicT.

Her research funding comes from the U.K. Medical Research Council, Eli Lilly, and the EU’s Horizon 2020 program.

bjancin@frontlinemedcom.com

Early change in emotional processing predicts antidepressant response