If Serotonin Doesn't Cause Depression, Then What Does?

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For the last half-century, the dominant explanation for depression has centered on serotonin. The basic idea: low levels of brain serotonin or serotonin activity lead to symptoms of depression. This theory, which is known as the “serotonin hypothesis,” is based on several data points, including animal research and the effects of antidepressants that are supposed to work by increasing brain serotonin levels. But in the last several decades, a number of researchers have challenged the idea that serotonin plays a principal or even major role in depression.

In recent days, the serotonin hypothesis of depression has been explicitly challenged by a number of scientific publications. Most notably (at the time of this writing), a paper published in Nature Molecular Psychiatry reviewed several lines of evidence on the subject of the serotonin-depression connection and concluded that “the main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

Datapoints like this recent study point to a major question: If serotonin isn’t driving depression, what does explain the brain state of the hundreds of millions of people living with it? While there are many potential explanations, here are four major systems that may prove more important to the brains of people with depression, and some ways we may be able to target them.

1. Brain Rewiring (Neuroplasticity)

One of the most empowering results of neuroscience research is the idea that our brains are constantly being rewired. Specifically, our neurons are actively changing the number and strength of their connections to other neurons and to non-neuron brain cells called “glia.” This is a process called “neuroplasticity,” and it’s increasingly thought to play a role in mood disorders like depression.

Supporting factors for the neuroplasticity-depression connection include imaging findings, cell study research, and measurements connected to the rewiring process. The basic idea is that in depression, there may be issues with the quality, number, and type of connections our neurons make, and this may help explain depression symptoms. Importantly, research is showing that we may be able to positively affect neuroplasticity through lifestyle factors like exercise, learning new things, and, potentially, certain dietary modifications. There is also data showing that conventional antidepressants, as well as psychedelics, may positively influence neuroplasticity.

2. Inflammation

The planet had a wake-up call to the significance of immune health in the context of the pandemic. But immune health is linked to far more than just risk for infectious disease. In the world of neuroscience and affective disorders, immune activation, and especially inflammation, is thought to be a risk factor for the development of conditions like depression. Higher levels of inflammation in our bloodstream have been linked to worse brain function.

When excess or chronic inflammation is present in the brain, it appears to influence a number of pathways involved in depression. First, it may impair the healthy function of neurons by physically damaging them. Inflammation also may block healthy neuroplasticity, while leading to the generation of toxic breakdown molecules like quinolinic acid that could further damage neuron health and contribute to depressive pathology. Within the brain, research shows that unique immune cells called microglia may be key to sustaining inflammation.

So how is our inflammatory status regulated? It appears to be sensitive to the quality of our diet, sleep, exercise, stress-lowering interventions, and potentially even nature exposure.

3. The Gut-Brain Connection

The gut is home to trillions of bacteria and the majority of our immune cells, making it a major hub for information transfer. A wide range of research now suggests that the gut and the brain are in constant communication, and it’s been proposed that this data exchange may have an effect on everything from our cognitive state to our mood. Researchers have proposed that the state of our gut health (e.g., the leakiness of our gut lining, the immune cells in the gut, and the diversity of the microbes that live in our gut) plays a major role in our mental health and may significantly influence depression symptomatology.

One of the most impressive aspects of our gut is the quantity and diversity of microbes that call it home. These bacteria make up the gut microbiome. Alterations in the bacteria that live in the gut microbiome have been linked to depression. It’s thought that these bacteria may influence brain function through their effects on the vagus nerve (which runs from the gut to the brain), their impact on the immune system (e.g., by affecting levels of inflammation), and through tiny molecules they create (e.g., short-chain fatty acids) which may reach the brain by way of the bloodstream.

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4. Endocrine (Hormonal) Changes

When it comes to the regulation of brain function, a wide range of hormone pathways are thought to play important roles. This research extends to depression. And while certain hormonal changes can be hard to reverse, there’s also much we can do to help improve aspects of our endocrine signaling pathways.

Likely the strongest endocrine-depression connection, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (a.k.a. the stress system) is thought to significantly increase the risk for depression. For example, people with an episode of major depression are 2.5 times more likely to have experienced a stressful event prior, and a single high-stress event has been found to increase the risk for a depressive episode by 1.4 times.

Issues with HPA system balance may contribute to depression by negatively impacting the hippocampus, increasing inflammation, damaging neuroplasticity, and even killing off neurons. A number of strategies have been shown to be successful in regulating HPA function ranging from daily meditation to regular exercise to time in nature.

Another important link between hormones and depression relates to estrogen. This hormone is thought to have a number of brain-protective roles, including enhancing neuroplasticity. It has been proposed that declining levels of estrogen and related hormones during and after menopause may help explain the higher rates of depression seen by women in this period. While some research suggests that estrogen replacement therapies may present an interesting treatment strategy, there’s still considerable debate about the safety of this practice.

Insulin is a key metabolic hormone that facilitates the uptake of glucose by cells throughout the body. In the brain, insulin is thought to regulate blood sugar as well as influence memory and behavior. Insulin resistance is an increasingly common condition of metabolic dysfunction, where our bodies have trouble sensing insulin and using glucose, and it’s now been linked to a substantially higher risk of developing depression. A wide range of techniques can help improve insulin resistance in most people, especially those related to dietary modification and exercise.

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