Science of Depression

Get your brain unstuck

There have been many important developments in the science of depression in the past few years, but understanding of these has not become widespread in the general public, or even among patients with major depressive disorder (MDD).  The “serotonin deficit” or “chemical imbalance” theories of the cause of depression remain more widely understood and commonly used explanations, while theories underlying more recent research that has moved the scientific community into a more complex understanding remain less well known.

Serotonin remains important in brain chemistry, and we don’t want to imply that it is no longer an issue, or that medication such as selective serotonin reuptake inhibitors (SSRIs) is not useful.  However, the role of serotonin no longer takes center stage. A variety of supporting actors now have equal billing, making the “show” more complex, but also more exciting and hopeful.

The new picture of our understanding of depression is less about “imbalance” and more about “inflexibility”. Researchers have identified areas of the brain that lose their flexibility, leaving the patient “stuck in a rut” in terms of cognitive and emotional information processing.  People with MDD may have difficulty changing their strategies for working on a task when the rules change. Emotional inflexibility may mean they have a harder time switching between positive and negative emotional states, or experiencing the full range of emotions.

Another area being “stuck” may be negativity bias, in which a person may place heightened importance on negative outcomes or punishments, and remain indifferent or unaware of positive developments or rewards.  These areas of inflexibility may result from factors such as genetic load, in utero exposures, stress and trauma, neuroinflammation, and medical conditions, thus, MDD is not to be understood as only one “thing” but is rather a complex of responses within the brain that require different approaches to treat.

The effects of being “stuck” occur in key cognitive and emotional brain regions, including executive functioning in the prefrontal cortex (PFC), reward and motivation in the nucleus accumbens, learning and memory in the hippocampus, and emotional processing in the amygdala. These brain regions primarily show decreased activity and connectivity with each other in MDD.  And the lack of communication within and between these core functional hubs impairs their ability to regulate one another, leaving them stuck in the dysfunctional states of negativity bias and cognitive and emotional inflexibility.

New treatment approaches to MDD, therefore, focus not on chemical deficit, but rather on neuroplasticity, the ability of the brain to grow, learn, develop new pathways, and adapt to new conditions. Treatment will most likely consist of a combination of approaches which may include:

•  Antidepressant medications (like SSRIs):
  Help activate brain-growth pathways over time
  (This is why they take weeks to work)
  
• Psychotherapy:
  Provides new experiences and patterns of thinking that shape healthier brain circuits
  
• Exercise, meditation, sleep, and social connection:
  All increase brain flexibility and resilience
  
• Advanced treatments (TMS, ECT, ketamine):
  Directly stimulate brain circuits to restart healthy communication

As you can see, all the treatments focus on the brain’s growth, flexibility, and resilience.  Such an approach directly addresses the inflexibility associated with depression and leads towards healing and positive achievement.  Depression is not a life sentence, it’s an illness that you can recover from and leave behind in the past.

Reference:

Chloe E. Page, Ph.D.  Communicating the Neurobiology of MDD. Psychiatric News, Volume 60, Number 12 26 November 2025.  https://doi.org/10.1176/appi.pn.2025.12.12.2