Scientists find out why SSRIs fail to work in 30 percent cases of MDD

Scientists find out why SSRIs fail to work in 30 percent cases of MDD

Even though selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression, scientists fail to comprehend why this treatment fails in almost 30 percent of individuals suffering from this mental disease. To figure out this mystery, researchers at the Salk Institute for Biological Studies (SIBS) carried out a study wherein they discovered certain differences in the growth of neurons especially in patients resistant to SSRIs. The study was published in the Molecular Psychiatry journal and its findings had implications for other mental disorders, like schizophrenia and bipolar disorder, which also entail abnormalities pertaining to the serotonin circuit in the brain.

Senior study author Rusty Gage stated that as more and more research is carried out scientists are getting a better insight of the neural circuitry related to neuropsychiatric ailments. This study offers a fresh insight into treatment with SSRIs and also suggests alternative medications like serotonergic antagonists, which may serve as additional treatment options for patients.

Depression is partially connected to serotonergic circuit in brain

Although the actual reason behind depression has still not been discovered, scientists are of the opinion that major depressive disorder (MDD) is partially connected to the serotonergic pathway in the brain. Since SSRIs increase serotonin levels, it helps in alleviating depression symptoms. That is why SSRIs are commonly prescribed in the case of MDD. However, till some time back, researchers failed to understand why this particular treatment failed to respond in some patients.

It was somewhat challenging to unravel the mystery behind this SSRI resistance, since it entailed studying around 300,000 neurons that utilized serotonin to communicate with a total of 100 billion neurons within the brain. The scientists recently managed to overcome this challenge by generating serotonergic neurons synthetically.

In a previous research carried out by the same team, the researchers revealed that patients resistant to SSRIs had increased serotonin receptors. This led the neurons to react in a hyperactive manner when exposed to serotonin.

The present study wanted to find out if gene expression, circuitry, and serotonin biochemistry were transformed in the case of patients in whom SSRIs proved ineffective. It compared these in serotonergic neurons obtained from depression patients. According to lead author Krishna Vadodaria, the process of utilizing neurons obtained from depression patients was a new way of comparing patients who responded to SSRIs and those who did not.

Neurons respond on basis of shape

For the purpose of this study, the researchers considered 800 patients suffering from MDD. They selected patients, who showed significant improvement while they were on SSRIs, and those on whom SSRIs had no impact. In order to create serotonergic neurons for their study, the researchers gathered samples of skin from these patients. They then recalibrated the cells into stem cells with induced pluripotency.

The researchers analyzed the serotonin targets in the serotonergic neurons of these patients. They also examined the serotonin producing enzyme, the protein responsible for its transportation, and the enzyme that broke it down. However, they did not find any differences in the biochemical reactions between these groups. But the researchers did notice that the neurons responded differently basis their shape.

The scientists observed that compared to responders, the neurons from patients irresponsive to SSRIs had longer projections of neuron. After conducting a gene analysis, the researchers concluded that patients who did not respond to SSRIs had low range of two protocadherins, namely PCDHA6 and PCDHA8, the key genes involved in the formation of neuronal circuits. When the researchers suppressed these key genes in serotonergic neurons, the latter developed similar long projections as observed in patients irresponsive to SSRIs.

The scientists further revealed that these unusual features may have led to an increased neuronal communication in only certain sections of the brain. This transforms communication pathways within the serotonergic circuit of the brain and that is primarily the reason why some depression patients do not respond well to SSRIs.

As a next step, the researchers plan to analyze the protocadherin genes in order to understand the genetic behavior of patients in whom SSRIs have no impact in a better manner.

Seeking help for depression

According to the Anxiety and Depression Association of America (ADAA), major depression affects more than 16.1 million Americans. Depression is a debilitating mental disorder that can impact an individual’s personal, professional, and social life. Hence, why it is of utmost significance to seek treatment for depression when the symptoms manifest.

If you or a loved one is looking for a reliable depression treatment facility, get in touch with the Depression Treatment Helpline. Call our 24/7 depression treatment helpline center at 866-619-7729. You can also chat online with one of our representatives to understand our depression treatment programs.