Dr. Bob Murray

Depression literally changes the brain over time

Importantly the new research found that persistent depression may need a different therapeutic approach from all those that have been tried so far. They findings also raised the question: Is clinical depression always the same illness, or does it change over time?

What the researchers say

New brain imaging research shows that the brain alters after years of persistent depression, suggesting the need to change how we think about depression as it progresses. The study was published in The Lancet Psychiatry.

The research shows that people with longer periods of untreated depression, lasting more than a decade, had significantly more brain inflammation compared to those who had less than 10 years of untreated depression. In an earlier study the team discovered the first definitive evidence of inflammation in the brain in clinical depression.

This study provides the first biological evidence for large brain changes in long-lasting depression, suggesting that it is a different stage of illness that needs different therapeutics—the same perspective taken for early and later stages of Alzheimer’s disease, the lead author says.

“Greater inflammation in the brain is a common response with degenerative brain diseases as they progress, such as with Alzheimer’s disease and Parkinson´s disease,” he adds. While depression is not considered a degenerative brain disease, the change in inflammation shows that, for those in whom depression persists, it may be progressive and not a static condition.

Yet currently, regardless of how long a person has been ill, major depressive disorder is mainly treated with the same approach. Some people may have a couple of episodes of depression over a few years. Others may have persistent episodes over a decade with worsening symptoms, including increasing difficulty going to work or carrying out routine activities.

Treatment options for this later stage of illness, such as medications targeting inflammation, are now being investigated. This includes re-purposing current medications designed for inflammation in other illnesses to be used in major depressive disorder

In the study, brain inflammation was measured using a type of brain imaging called positron emission tomography (PET). The brain’s immune cells, known as microglia, are involved in the brain’s normal inflammatory response to trauma or injury, but too much inflammation is associated with degenerative illnesses as well as depression.

The study involved 25 people with more than 10 years of depression, 25 with less than 10 years of illness, and 30 people with no depression as a comparison group. Inflammation levels were about 30 per cent higher in different brain regions among those with long-lasting untreated depression, compared to those with shorter periods of untreated depression. The group with long-term depression also had higher inflammation levels than those with no depression.

The researchers also note that in treatment studies, patients with serious, longstanding depression tend to be excluded, so there is a lack of evidence of how to treat this stage of illness, which needs to be addressed.

So, what?

Treating depression with anti-inflammatory drugs is not a new idea. Nor is the idea that depression can increase in severity with age. What is new in this study is the idea that the two are linked and that depression becomes something very different involving changes in the way the brain functions over time. This will hopefully lead to the discovery of new and better treatments for people with long-standing depression—which is actually most depression sufferers of major depressive disorder over the age of 40.

A pathway to a better way to treat depression?

As I said at the start about 30-40% of depression is genetic in origin. A really interesting study just published, outlines a new and rather dramatic look at this aspect of depression. Essentially it indicates that all current treatments are looking at the wrong areas of the brain and therefore that is the reason all existing treatments fail so many sufferers.

What the researchers say

The new research shows that individuals with high levels of a little-studied neural receptor called GPR158 may be more susceptible to depression following chronic stress.

“The next step in this process is to come up with a drug that can target this receptor,” said the lead researcher. His team zeroed in on GPR158 as a player in depression after discovering that the protein linked to its specialized receptors, and thus to the gene, is elevated in people with major depressive disorder. To better understand GPR158’s role, the scientists studied male and female mice with and without GPR158 receptors.

Behavioral tests revealed that both male and female mice with active GPR158 receptors show signs of depression following chronic stress. On the flip side, suppression of GPR158 protects mice from developing depressive-like behaviors and make them resilient to stress.

Next, the researchers examined why GPR158 has these effects on depression. The team demonstrated that GPR158 affects key signaling pathways involved in mood regulation in the prefrontal cortex (the thinking and reasoning part of the brain), though the researchers emphasized that the exact mechanisms remain to be established.

The lead author explains that GPR158 is a so-called “orphan receptor” (which gets its name because its binding partner/partners are unknown) with a poorly understood biology and mechanism of action. GPR158 appears to work downstream from other important brain systems, such as the GABA system (GABA is the most prevalent neurochemical in the brain), a major player in the brain’s inhibitory control and adrenergic system involved in our reaction to stress.

“This is really new biology and we still need to learn a lot,” say the researchers.

The study also offers a potential clue to why some people are more susceptible to mental illness. Because mice without GPR158 don’t alter their behavior after chronic stress, the researchers concluded these mice were naturally more resilient against depression. Their genetics, or more precisely their gene expression, offer a layer of protection.

The researchers say this finding matches what doctors have noticed in people who have experienced chronic stress. “There’s always a small population that is resilient—they don’t show the depressive phenotype.”

As the search goes on for additional targets for depression, scientists are increasingly using new tools in genome analysis to identify orphan receptors like GPR158. “Those are the untapped biology of our genomes, with significant potential for development of innovative therapeutics,” the team says.

So, what?

It’s well possible—indeed almost certain—that there are many genetic pathways to depressive illness. The genes that control the neurochemicals dopamine, oxytocin, serotonin and glutamate are all suspects which are “helping the (depression) police with their enquiries.” GPR158 is another. All of these genes are affected by stress and it could be that GPR158 in some way amplifies the effects of stressful events.

The other really fascinating point of this study is that it shows that resilience is largely inherited—an argument that I have been making in academic and business circles for over two decades.

(editor: if you want to read the first part of “The truth about depression (1nd part)“, please click here)