Metabolism to Blame for Resistance to Antidepressants: Study

Metabolism to Blame for Resistance to Antidepressants: Study

For many patients of depression who do not respond to conventional methods of treatment, the reason could lie in their metabolism, says a recent study. The researchers from the Rockefeller University in New York and the Karolinska Institutet, Sweden observed that depression is often marked by abnormalities in the body, such as elevated blood sugar level. Thus, depression and metabolism are intrinsically entwined, the researchers said.

“Many patients who suffer from depression do not respond to conventional antidepressant treatment, so we set out to examine the molecular changes that might explain this resistance,” said first author of the study Benedetta Bigio, a bioinformatics specialist in Bruce McEwen’s Rockefeller lab. She said that their findings established a link between the activity of energy metabolism genes within one part of the brain to a predisposition to depression and resistance to treatment.

Rats and mice with LAC developed depression-like symptoms

There are no known causes why depression is accompanied by metabolic deformities, like abnormal levels of sugar and triglycerides, a type of fat in the blood. However, the researchers managed to have established a link between the two by studying collated data on acetyl carnitine (LAC), which is produced naturally by the brain, liver and kidneys. They observed that when given to rats and mice, they rapidly developed depression-like symptoms by enhancing harmful imbalances in the glutamate signaling system in the brain.

They used those rats whose certain behaviors were akin to symptoms of depression in humans, such as abhorrence of sweet solutions which are otherwise preferred by normal rats. The rats produced extremely low levels of LAC, but they showed improvement in their behavior when given the compound.

Meanwhile, the researchers have also started to look for abnormalities in natural LAC levels of depressed people. These LAC studies have opened a glut of avenues on to the neurobiology of depression treatment.

Resistance to treatment

In order to investigate the reason behind resistance to treatment, the researchers exposed the rats to stressful situations in which the rodents were made to swim for a good 15 minutes. Next day, the rats were tested with a shorter swim test. Those with successful LAC treatment swam more, while others exhibited depression-like symptoms, such as immobility predicting an ineffective treatment.

Probing further into why such a discrepancy existed among the rats led the researchers to a region in the brain within each rat’s hippocampus, called the ventral dentate gyrus (vDG), which is crucial for stress responses.

When the genes were sequenced within this region, the researchers found differences in many genes responsible for regulating metabolism among rats that responded well to the treatment, the ones that didn’t, and the untreated ones.

Clues from blood

The researchers found 27 genes that seemed to be involved in resistance to the low-dose LAC treatment and hence, to antidepressants. The genes included those responsible for the body’s ability to use fatty acids, as well as to respond to insulin.

“If these findings hold true in humans, it is possible that altered levels of blood sugar or insulin may serve as markers that could help doctors determine which patients are likely to do well on an antidepressant before prescribing it,” said Carla Nasca, a senior author and postdoc in the lab.

The research suggested that the role of vDG in energy metabolism should be taken into consideration in developing new treatments for depression.

Recovery roadmap

Depression is a treatable mental health condition, which when left untreated can complicate matters. Many are leading a healthy life post treatment intervention for depression.