In May 2016, the Library of Congress and the John Kluge Center hosted a symposium on Can Depression be Cured? at which four of the top medical researchers into depression and its treatments presented their latest research findings. A full unedited transcript of the presentations can be found here and the video is here.
The first presentation was given by Dr. Philip Gold who has been a member of the Library of Congress’s Scholars Council since 2004. He received his undergraduate medical degrees at Duke University and his post-graduate medical training at the Harvard Medical School. He has been at the NIH Clinical Center since 1974 where he served as chief neuroendocrine research in the NIMH intramural research program. I’ve summarized his address below and over the coming days, I’ll try to do the same for the other addresses, before summing up with a reflection on the research.
The main findings in Dr. Gold’s research are really quite stunning and should result in a major re-evaluation of the understanding of depression. Here’s a simplified summary of the findings followed by a brief explanation of each one:
1. Depression is a disorder of the human stress response.
2. Depression is a disease which involves brain tissue loss and damage.
3. Anti-depressants work by increasing the growth of brain cells and the connections between them.
4. Depression causes serious damage to the rest of the body
5. The best treatment for depression at present is a mix of talking therapies and medication
Main Finding 1: Depression is a disorder (dysregulation) of the human stress response
The stress response is our reaction to stressors in our life (physical, psychological, spiritual, etc.). For example, if you are being chased by a bear the stress response should kick in to maximize chances of survival. The stress response includes:
- Fear-related behaviors and anxiety.
- A decreased capacity for pleasure (in order to focus attention on the threat).
- Inflexible mood and cognition.
- Stress hormone production (especially of cortisol and norepinephrine).
- Redirection of fuel to the bloodstream and the brain through development of insulin resistance.
- Increase of inflammation and coagulation (blood clotting), both priming the system to respond to possible injury.
- Inhibition of neurovegetative program, meaning suspension of appetite, rest, sleep, sexual desire.
- Increased neuroplasticity (the brain’s ability to form new neural connections) and neurogenesis (growth of brain cells).
In melancholic depression (which affects 35% of those with major depression), the stress response is disordered in that when triggered it does not terminate quickly enough or sufficiently enough. It gets stuck in the “on” position, resulting in:
- Increased and prolonged fear-related behaviors and anxiety.
- Inhibition of the capacity to anticipate or experience pleasure.
- Inflexible mood and cognition (mood and thinking patterns are in a rut).
- Increased and prolonged stress hormone production.
- Increased insulin resistance in order to redirect fuel to bloodstream and brain.
- Increased and prolonged inflammation and coagulation.
- Increased and prolonged inhibition of neurovegetative programs (appetite, rest, sleep, sex).
- Decreased neuroplasticity and neurogenesis.
Main Finding Two: Depression is a neurodegenerative systemic disorder rather than a chemical imbalance.
There is chemical imbalance in depression but the primary cause is a loss of brain tissue in key areas (and abnormal increase of brain tissue in one key area).
A number of areas in the brain are physically changed in this disorder of the stress response.
1. The subgenual prefrontal cortex is reduced in size by as much as 40% in patients with familial depression. The subgenual prefrontal cortex:
- Regulates and restrains the brains fear system.
- Plays a large role in self-assessment.
- Estimates the likelihood of punishment or reward.
- Modulates the pleasure and reward center.
- Restrains cortisol secretion.
When the subgenual prefrontal cortex is decreased in size all of these functions are similarly decreased resulting in excessive anxiety, feelings of worthlessness, decreased pleasure, and increased production of stress hormone.
2. The amygdala increases in size and goes into overdrive in depression and this further restrains the working of the subgenual prefrontal cortex.
3. The ventral striatum is significantly reduced in size during depression. This area is the pleasure and motivational center.
4. The hippocampus serves multiple memory functions and is the main place where neurogenesis (growth of new brain cells) occurs. Its size is significantly reduced in depression.
Summing up the loss of or damage to brain tissue, Dr. Gold said: “There’s more loss of tissue in depression than there is in Parkinson’s disease!” “Depression as a full-blown disease,” he warned, “a systemic full body disorder with neurodegenerative aspects and is a progressive disease, much more serious, I think, than we had previously appreciated.”
Main Finding Three: Anti-depressants work by improving neuroplasticity and neurogenesis
Almost all antidepressants significantly improve neuroplasticity and neurogenesis. There are few other (if any) compounds which actually increase neurogenesis, and people are experimenting using antidepressants to try to treat disease of the retina, for instance, to get neurogenesis active there and other sites of the body. The challenge for the next generation of anti-depressants, then, is to develop compounds that promote neurogenesis and neuroplasticity.
Main Finding Four: Depression damages the rest of the body
The pathological losses or gains in tissue in specific sites set into motion pathologic changes outside of the brain:
- They’re responsible for the premature onset of coronary artery disease, stroke, diabetes, and osteoporosis.
- Increased cortisol (growth hormone) secretion affects every cell in the body.
- Increased insulin resistance and cholesterol levels increases inflammation, produces bad lipids, and increases clotting.
- Premenopausal women with major depression have much higher incidence of osteoporosis
- Depression is really the tip of the iceberg. The syndrome is serious and systemically widespread.
- Patients with untreated depressive illness lose approximately seven years of life, much as untreated hypertension predictably shortens a life.
Main Finding Five: The best treatment for depression at present is a mix of talking therapies and medication
Depression is a serious disorder that impacts the whole body, it is progressive, and it needs to be treated.
60% of people with depression in the United States remain untreated.
The most effective way to treat depression at present is a combination of talking therapies and medication.
Data shows that people who successfully respond to talking therapies have positive physical changes in the three key areas of the brain that are affected in depression: the subgenual prefrontal cortex, the amygdala, and the ventral striatum.
As for the future, there are trials ongoing of new medications (like ketamine) which are producing rapid remission of depression (within 1-2 hours).
There are also psychosurgery trials involving the implanting and stimulating of electrodes in the subgenual prefrontal cortex which are producing immediate and sometimes lasting response.
Magnetic resonance treatments (MRI) are also being used to treat areas of depressed patients brains in a non-invasive way.
Training in resilience is also proving helpful:
- The American Psychological Association defines resilience as the process of adapting well in the face of adversity, tragedy, trauma, threats, and even significant sources of threat.
- Mild to moderate controllable stress early in life can have an inoculating effect. Such experience leads to increased neuroplasticity and neurogenesis, and increases the size of the subgenual prefrontal cortex.
- An enriched, nurturing environment in early life with exposure to manageable novelty increases resilience later in life.
- Positive emotion, optimism, loving caretakers, flexibility, the capacity to reframe adversity, and strong social support also increase resiliency.
- Altruism, commitment to a valid cause, a capacity to extract meaning from adverse situations, and a tolerance for emotional pain and sadness promote resiliency as well.