Depression is Not a Synapse Problem, it’s a Network Problem. And Real Estate Counts!

A recent episode of the Charlie Rose Brain Series provides an exciting discussion of the evolution of our knowledge of depression, specifically of how our understanding has evolved from the synapse or “Big Pharma” model to a Network Model that reveals how many areas of the brain are implicated in depression.

First, a brief historical sketch. Years ago it was discovered that Monoamine Oxidase Inhibitors (MAOIs), originally used to treat tuberculosis, also caused patients to jump around so physicians started using it to treat depression. It was also found that the Tricyclics proved effective in treating depression.

These drugs affect the modulatory neurons, i.e., the dopaminergic, serotonergic and noradrenergic neurons. And this lead to the hypothesis that depression results from a depletion of these modulatory transmitters and that the MAOI’s and Tricyclics replenished these transmitters to varying degrees. Furthermore, it was believed that serotonin was the most important of the three neurotransmitters.

More effective drugs were subsequently developed that lead to the pharmacological bridge, i.e., serotonin pathways, norepinephrine pathways and combined pathways were understood to be superhighways that start in the ancient brain stem, then arborize like a tree over the whole frontal lobe, the cortex, the most human part of us. We began to understand that the pathways worked together and most of the early drugs influenced all of of them. Depression was understood to be a synapse disorder involving serotonin, serotonin binding and serotonin re-uptake.

The early drugs had undesirable side effects and refinements came from the pharmaceutical companies which lead to Selective Serotonin Reuptake Inhibitors (SSRIs) that block serotonin reuptake and cause addiitional serotonin binding.



Serotonin reuptake blocked

                                SSRIs        Synapse         SSRIs



Additional Serotonin binding

The therapeutic value of imaging is that it permits us to see the anguish going on inside somebody’s head in terms of blood flow. This lead from thinking about depression, not as a synapse problem, but as a system problem. And real estate counts! As Helen Mayberg, on the forefront of depression research at Emory University, once said, “It’s not just a bowl of soup, add Serotonin and stir.”

The problem is how to dissect the symptoms into their component parts. Today, prominent researches like Helen Mayberg are using fMRIs to answer the question: When you’re depressed, what areas of the brain are not working properly?

Before fMRIs, the old medical joke was: If you could cut it and see it, it was neurology. If you couldn’t see it, it was psychiatry. It was only the imaginative, gifted psychiatrists like Freud who believed there was always a problem, but they couldn’t measure it.

We now know that some areas of the brain are under-active, some overactive, but there’s starting to be a pattern, nodes that are turning out to be important.A place deep in the frontal lobe, the Area 25 of the subcallosal singulate, always lights up with a negative experience:

Here is a video in which Helen Mayberg discusses how Deep Brain Stimulation (DBS) is applied to the subcallosal cingulate. It should be pointed out that Deep Brain Stimulation is in no way related to Electro-Convulsive Therapy (ECT).

We’ve further learned that Area 25 is a negative mood regulator that’s also associated with the amygdala, the prime hub for mediating all novel emotional experiences, and there are direct links from Area 25 to the hypothalamus and from the hypothalamus to the amygdala.

Today, there is a clear consensus among neuroscience researchers and practitioners that of all the psycho-pathologies, our knowledge of depression and the human suffering that it causes is greatest.

Furthermore, because of imaging techniques like fMRIs, we’re steadily accumulating a body of evidence based research that supports the effectiveness of cognitive behavioral therapy, emotionally focused therapy, narrative therapy and others, because they all have a biological impact on the human brain that can be measured.



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