Depression medications are prescribed to one in every 10 Americans, but do not work for many patients. A new study may help explain why antidepressants are often ineffective, with an alternative brain model for depression that could debunk existing ideas about its causes and lead to more effective treatments.

A group of University of Maryland researchers explored the brain chemical serotonin's role in depression, with results that could dramatically shift the way doctors understand the condition and prescribe antidepressants.

For over 50 years, serotonin has been the main focus in treating depression. Although the causes of major depression are still unknown, many researchers assume that it is caused by low levels of the brain chemical serotonin.

Because elevating serotonin levels improves the mood of some depressed patients, selective serotonin reuptake inhibitors (SSRIs), which increase serotonin availability to neurons in the brain, have become the dominant antidepressants today. SSRI depression medications like Prozac, Celexa, and Zoloft are effective for many patients, but they fail to help many others.

A new study from the University of Maryland challenges the prevailing serotonin theory of depression, suggesting that depression results mainly from a disturbance in the way that brain cells communicate with each other, not simply from a drop in serotonin levels.

The researchers, led by Dr. Scott M. Thompson of the University of the Maryland School of Medicine, believe that the exchange of excitatory signals between neurons becomes abnormal in the depressed brain. The study was published in the journal Nature Neuroscience on March 17.

"Dr. Thompson's groundbreaking research could alter the field of psychiatric medicine, changing how we understand the crippling public health problem of depression and other mental illness," said Dr. E. Albert Reece of the University of Maryland School in a statement.

The study's first finding highlighted an important new role for serotonin: strengthening the communication between brain cells.

"Like speaking louder to your companion at a noisy cocktail party, serotonin amplifies excitatory interactions in brain regions important for emotional and cognitive function and apparently helps to make sure that crucial conversations between neurons get heard," said Dr. Thompson.

"Then we asked, does this action of serotonin play any role in the therapeutic action of drugs like Prozac?"

Thompson's team compared the brains healthy rats and mice to those of depressed animals, which were models for stress and depression in people. The depressed animals were diagnosed after losing any signs of enjoying sugar water, a treat for healthy rodents.

They found that serotonin levels were not markedly different in the depressed animals' brains. The major difference was a decrease in the excitatory connections that respond to serotonin.

"In the depressed brain, serotonin appears to be trying hard to amplify that cocktail party conversation, but the message still doesn't get through," said Dr. Thompson.

SSRI depression medications can sometimes help serotonin repair abnormal brain connections so they can communicate normally, but not in all cases.

The group used specially bioengineered mice from the Johns Hopkins University School of Medicine to find that antidepressant medications are only effective when excitatory connections in the brain are strengthened by serotonin. If serotonin is unable to influence those brain connections, SSRIs are unlikely to work.

The results help explain why depressed people often have trouble concentrating, learning new information, and making decisions- depression results from the inability of brain cells to work together effectively.

The study concludes that serotonin is an important part of the brain's normal mood regulation, but not in the way previously thought. Serotonin helps strengthen the brain connections that are necessary for healthy mood and cognition, but people become can become depressed when something keeps serotonin from acting on those connections.

Thompson and his team expect that more research can figure out what gets in the way of serotonin for patients who are unaffected by typical antidepressants.

Eventually, they hope to lead to a shift away from SSRIs that simply increase serotonin levels, and towards better depression medications that strengthen excitatory brain connections.

Depression typically affects one in four American adults at some point in their lives, according to the National Institutes of Mental Health. The World Health Organization predicts that by 2020, more people will be affected by depression than by any other health problem.

SSRIs are likely to remain an important tool in treating depression, but new drugs may be able to help many patients who do not respond to typical antidepressants.