Depression manifests in countless ways, yet one sentiment echoes across nearly every account that I’ve heard: “I feel stuck.” Each day — no matter how eventful — feels as exhausting and monotonous as the one before. Hours melt into weeks, and sometimes weeks into years, forming a murky haze against which effort seems futile and fruitless.

Is this really the result of a ‘chemical imbalance’ or could something deeper and more intricate be at work? What if the biology behind depression mirrors this sense of stagnation?

The monoamine hypothesis 

The idea that depression is a chemical imbalance comes from a model of depression called the monoamine hypothesis. Monoamines refer to a type of neurotransmitter — the chemical messengers that cells in the brain communicate with — and can be thought of as a language through which the brain and body communicate. 

For example, dopamine and serotonin fall under this category. They’re responsible for processes ranging from movement to creating memory and even regulating emotion. Without proper production of these important chemicals, we lose major functions in our cognition.  

In the mid-twentieth century, it was discovered that both a drug that treated tuberculosis and an antihistamine — an anti-allergy drug — alleviated symptoms of depression separately. Though structurally quite different these two drugs shared something in common: both increased the availability of monoamine neurotransmitters — such as noradrenaline and serotonin — in the brain. 

It was then hypothesized that people with depression must naturally lack the proper monoamines to regulate their mood and energy and that restoring these was the cure. Thus, the monoamine hypothesis of depression was born, and its legacy has never left the public conversation about depression. 

Yet over half a century later, very little evidence has come to support the theory. Selective serotonin reuptake inhibitors — the most common type of antidepressant — increase levels of monoamines nearly immediately. However, the change in depressive symptoms only appears weeks later, suggesting that monoamine deficiency might simply be one aspect of depression rather than the main cause.

The neuroplasticity model 

We currently view depression as the sole cause of its associated symptoms: anhedonia — the inability to feel pleasure — hopelessness, and low self-esteem, to name a few. What if we looked at depression instead as a maladaptive response to environmental factors? 

The neuroplasticity model proposes this. This theory emphasizes the brain’s ability to adapt and rewire in response to the surrounding environment in both healthy and maladaptive ways. In this framework, depression is seen as a state where the brain’s capacity to form and strengthen neural connections — communication between different parts of the brain — is diminished due to biological and environmental factors. 

Take Seasonal Affective Disorder (SAD) as an example. SAD typically manifests during winter months when daylight is scarce. This persistent darkness and isolation can prevent people from socializing and exercising, which are important for maintaining a healthy mental state. Despite SAD’s severity, once the days get longer, symptoms alleviate as if they were never there. 

How does this happen? In depressed individuals, key regions such as the hippocampus — which plays a critical role in memory and emotion regulation — often exhibit reduced volume. This is attributed to a phenomenon called neural ‘pruning,’ the decay of neural connections which aren’t often used. 

A growing body of evidence is accumulating as a foundation for this model. Meditation, physical exercise, and social interaction are known to alleviate symptoms of depression. Meditation has been shown to increase neural connectivity in the hippocampus and the prefrontal cortex, a large part of the brain which aids in social behaviour, decision-making, and cognition. Physical exercise releases a protein that aids neuron growth, which ultimately helps neurons in the prefrontal cortex to keep communicating and avoid being pruned. 

New methods of fighting depression, such as ketamine therapy — an anesthetic administered under medical supervision as a nasal spray — work to promote neural plasticity and growth. Ketamine therapy has near-immediate positive effects within as little as one treatment, effects which persist long after the drug has left the patient’s system. 

I’m not depressed, why should I care?

Importantly, the neuroplasticity model isn’t just a helpful lens for depression — it offers a fresh way to view mental illness that can transcend diagnosis. Certain traumas, chronic stress, and a slew of other factors can lead to depression, post-traumatic stress disorder (PTSD), and anxiety, disorders which are often comorbid and which exhibit similar diminished connectivity in important areas such as the prefrontal cortex and hippocampus. 

Though the monoamine hypothesis was critical in suggesting a scientific basis for depression it may be time to give up the mantle of ‘main theory’ to the neuroplasticity model. Not only does the neuroplasticity model have a larger body of evidence to support it, but the model also suggests tangible methods aside from medication to help relieve and prevent depressive symptoms. 

As we struggle through the remaining winter months, it can be helpful to keep the neuroplasticity model in mind, even for those of us who don’t experience clinical depression or SAD. Even a simple break from schoolwork or a short walk can help increase our mental resilience.