Understanding Antidepressants: The Role of Neuroplasticity and the Long Wait for Effects

Despite being amongst the most treatable mood disorders, clinical depression and the drugs used against it are not fully understood. First-line treatments often involve Selective Serotonin Reuptake Inhibitors (SSRIs), believed to increase serotonin neurotransmitters to improve neuron communication. Yet, scientists estimate that over 30 percent of patients do not benefit from SSRIs. Furthermore, these drugs take several weeks to manifest noticeable mood effects despite achieving their chemical goal within a day or two.

"To expect that the same kind of medication would be helpful for all patients with depression is perhaps a bit naive. It makes a lot of sense to rethink what depression is and how it should be treated.” - Gitte Knudsen.

The Mystery of SSRIs' Delayed Response

Gitte Knudsen, a neurobiologist and neurologist at the University of Copenhagen, Denmark, is among the experts intrigued by this delay. She finds the most compelling theories involve our brains' physical ability to readjust over time, a characteristic known as neuroplasticity. The brain adapts by rewiring, forming new interconnections between existing neurons, improving cognitive function and emotional processing. Knudsen believes that this rewiring could break someone free from the cycles of negative rumination—a hallmark of depressive episodes.

SSRIs and Neuroplasticity

Knudsen and her team recently tested this theory on human subjects using a special PET scan. They recruited 32 people to take the SSRI escitalopram or a placebo for one month. At the end of the trial, they used radioactive tracers during the PET scan to track where in the brain new synapses were forming. They discovered that the longer someone was on the antidepressant, the more synaptic signals the team detected—a proxy for increased connections.

This finding suggests that SSRIs improve neuroplasticity during the first weeks or months of treatments, contributing to the drugs' benefit and explaining the delay before users feel better.

The Potential of PET Scans

Since their development in 2016, PET scans have become an unparalleled resource for measuring wiring in human brains. These scans detect light emitted by radioactive "labels" designed to stick to specific proteins. The patient receives an injection of these radioactive markers, which diffuse to the target proteins in the brain. The scan reveals a map of where exactly those proteins are.

Knudsen's team organized a clinical trial in which healthy participants received a standard SSRI or a placebo daily. After three to five weeks, the team collected PET scans of the synapses in each person’s neocortex and hippocampus. The results showed that participants who spent longer on the drug had more synapses than those who spent less time.

Looking Forward

Despite these breakthroughs, there is still much to learn about depression and its treatment. The SSRI's effects on healthy individuals may differ from those diagnosed with clinical depression. Therefore, the project's next phase, including participants with depression, is ongoing.

Ultimately, understanding depression and its treatment is akin to treating a fever. It is essential to know the exact cause to be confident about the medication given. As neuroscientists deepen their understanding of the biological causes of depression, it may lead to more targeted and effective treatments.