Happy images trigger sad reactions in the brains of people with severe depression, researchers have found.
Some people do not respond to treatment for depression
They were studying people with treatment-resistant depression, which does not respond to conventional therapies.
The research, published in Biological Psychiatry, found "happy" images triggered a part of the brain linked to sadness in healthy people.
The scientists said the discovery would help them understand depression.
They say it may also lead to the development of new drugs for the hard-to-treat group of patients.
Around 5 million people in the UK experience depression at any one time.
The majority respond to either medication or talking therapies, but around 30 to 40% do not.
Researchers from the Clinical Neuroscience Research Centre in Dartford examined six women with treatment resistant depression and six healthy female volunteers.
They were shown a series of images that contained a picture and a caption while the researchers observed their emotional reaction using functional magnetic resonance imaging (fMRI), which shows activity in the brain.
It was found that people with depression processed their emotional response to the images differently from the healthy individuals.
Some parts of the brain were less active in people with depression than the control group.
But an area called the subgenual cingulate, associated with sadness in healthy people, was activated when the women with depression were shown the positive images.
Professor Tonmoy Sharma, director of the Clinical Neuroscience Research Centre, who led the research, said: "This is a significant step in unravelling the reasons why these people may not be responding to the antidepressant drugs currently available."
But Marjorie Wallace, chief executive of the mental health charity Sane, told BBC News Online: "This is a study on only six women with treatment depression, where results are based on subjective interpretations of emotions.
"Without national and international replication, we would be surprised if this heralds a new era in drug development."