Theravive Home

Why is it that antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), don’t work on nearly 30 per cent of people with major depressive disorder (MDD)?

SSRIs are the most commonly prescribed antidepressants for MDD. Though the cause of MDD is still unknown, researchers have found that it has something to do with the serotonergic circuit in the brain, thus why increasing the neurotransmitter serotonin via SSRIs seems to work, at least for 70 per cent of patients. 

A new study has found that patients with the same mental illness but different drug response profiles may have different underlying neurobiological mechanisms. The results could change the way mental illnesses are defined and categorized in the future.

The study, published in the Journal of Molecular Psychiatry, examined SSRI resistance in major depression using patient-derived neurons. 

“We specifically studied serotonergic neurons from robust SSRI responders and non-responders,” study author Krishna Vadodaria told us. “We wanted to find out whether alterations in serotonin neurons were associated with SSRI resistance.”

Ten per cent of Americans take antidepressants and the rate of Americans taking antidepressants increased by 400 per cent between 2005 and 2008. Based on the fact that SSRIs increase serotonin levels, researchers hypothesized that there may be some alterations in serotonin biochemistry in depressed-patient-derived neurons. In 2019, in England, it was a record year for antidepressant prescriptions given out by the National Health Service. In the past decade in England, prescriptions for antidepressants doubled. 

“Neuropsychiatric disorders and especially treatment resistance has been difficult to study, particularly at the cellular and molecular level,” Vadodaria told us. “Using iPSC technology (induced pluripotent stem cells) has allowed us to tap into the potential of studying neurons from patients whose symptom history, genetics, and pharmacological response profiles we know.”

Researchers examined the biochemistry, transcriptome and growth patterns of serotonergic neurons from SSRI-responsive and SSRI-resistant depressed patients.

“We found that SSRI-resistant patient-derived neurons displayed longer neurites and this correlated with lowered levels of protochaderin genes – PCDHA6 and PCDHA8,” Vadodaria told us. “Additionally, we observed that lowering PCDHA6/8 levels impacted serotonergic neurite growth.”

MDD affects 7.1 per cent of the US population (17.3 million adults) per year. In Canada, the prevalence rate for mood disorders is one in eight adults - 11.3 per cent for depression and 2.6 per cent for bipolar disorder. Symptoms of MDD include a depressed mood, decreased energy, poor concentration, feelings of guilt and worthlessness, thoughts of death and change in weight or appetite.

More than half of people with MDD relapse. It’s more prevalent in women and people with MDD are more susceptible to coronary artery disease than the general population as well as obesity, epilepsy, arthritis, cancer, and chronic obstructive pulmonary disease. As well as MDD, the results of the study will potentially also be able to help people with bipolar disorder and schizophrenia.

“We found it interesting that genes typically associated with alterations in serotonin biochemistry were not differentially regulated between groups,” Vadodaria told us. “Our results suggest that altered serotonergic neurite growth may lead to malformed serotonergic circuits that contribute to treatment resistance. Further studies with a larger patient cohort would be helpful.”