Hi everyone, welcome to 10 minute neuroscience.
In this installment, I’ll be discussing depression.
I’ll talk first about the serotonin hypothesis, or the idea that low levels of serotonin might
lead to depression, and I’ll explain why this doesn’t seem to be the full story of
what's going on in the brain in depression.
Then I’ll cover several other hypotheses about the neuroscience of depression that
have gained traction over the years.
Along the way, I’ll also very briefly cover the mechanisms behind some of the most commonly
used drugs to treat depression, like SSRIs.
It’s important to mention from the start that the neuroscience of depression is an
area of active research, meaning we still have a lot of questions that need to be answered.
I won’t be able to cover all of the hypotheses about the neuroscience of depression in 10
minutes, so by necessity I’ll be excluding some important ideas, and I won’t be delving
into specific genetic or environmental factors at all—even though genetics, environment,
and the interaction between the two is thought to be a critical component of depression.
Instead, I’ll be focusing primarily on hypotheses about the specific neurological mechanisms
that lead to changes in brain function that are associated with depression.
If we’re talking about the neuroscience of depression, I think we need to start with
the hypothesis that dominated the field for decades, and is still influential today: the
serotonin hypothesis.
This hypothesis appeared after we discovered the first true antidepressant drugs.
Before these drugs, there were not many options for drugs to specifically treat depression,
and doctors sometimes used barbiturates, amphetamines, and even opioids as treatment.
This all changed with the discovery of the first antidepressant, iproniazid.
Iproniazid was intended to be an anti-tuberculosis drug, but when it was tested on tuberculosis
patients, it was noted that the drug had positive effects on mood.
This led to iproniazid becoming a popular treatment for depression and an understanding
of how iproniazid worked in the brain was part of the basis for the serotonin hypothesis.
Iproniazid acts to inhibit an enzyme called monoamine oxidase, and it belongs to a class
of drugs called monoamine oxidase inhibitors, or MAOis.
Monoamine oxidase is involved with the breakdown of a group of neurotransmitters called the
monoamines, which include serotonin.
Thus, by inhibiting the breakdown of these monoamine neurotransmitters, iproniazid leads
to higher levels of them, and research suggested the effects on serotonin might play an especially
important role in the drug’s antidepressant effects.
Around the same time that iproniazid became a popular treatment for depression, a type
of drug known as a tricyclic antidepressant was discovered to be effective in treating
depression, and it was eventually learned that these drugs worked by blocking the reabsorption,
or reuptake, of neurotransmitters like serotonin and norepinephrine.
Reuptake is a process used by neurons to remove excess neurotransmitters from the synaptic
cleft—the space between neurons that neurotransmitters have to travel across to allow for communication
between neurons to occur.
By inhibiting this process of removing neurotransmitters, it causes neurotransmitters to accumulate
in the synaptic cleft, thereby raising neurotransmitter levels and leaving more neurotransmitters
available to interact with receptors.
So tricyclic antidepressants seemed to be working by increasing serotonin and norepinephrine
levels, and again research eventually suggested that the effects on serotonin might be especially
important for the therapeutic action of the drugs.
So there was a consensus emerging based on the mechanisms of these antidepressants (and
other research that I’m not going into here) that suggested depression might be caused
by a deficiency of serotonin in the brain, which is the main idea of the serotonin hypothesis.
And this hypothesis was further bolstered by the development of drugs called selective
serotonin reuptake inhibitors, or SSRIs.
These drugs were designed with the serotonin hypothesis in mind.
They specifically inhibit the reuptake of serotonin—which is why they’re called
selective serotonin reuptake inhibitors—and they raise serotonin levels as a result.
The success of these drugs helped the serotonin hypothesis to become the most widely accepted
hypothesis for what causes depression.
Over time, however, researchers began to identify some flaws in the serotonin hypothesis.
For example, studies have failed to consistently find reduced serotonin activity in patients
with depression.
Other studies have attempted to reduce serotonin levels by giving participants a diet deficient
in tryptophan, an essential amino acid that’s necessary for serotonin production; these
studies have also not consistently found a link between tryptophan depletion and depressed
mood.
Additionally, when someone takes a drug like an SSRI, we think that serotonin levels go
up quickly—probably within hours, but many patients don’t begin to experience the full
benefit of these drugs until they’ve been taking them for weeks.
This is important because if low serotonin levels were the sole factor responsible for
making people depressed, we might expect mood to changes to occur along with changes in serotonin
levels.
And finally, we now have discovered other drugs that don’t seem to have major effects
on the serotonin system, but still are as effective at treating depression as drugs
that have a serotonin-based mechanism.
These lines of evidence point to the idea that serotonin is at best only part of the
story when it comes to explaining the neuroscience of depression.
For the rest of this video, I’ll cover a few other hypotheses that have emerged as
potential explanations for brain mechanisms underlying depression.
One hypothesis about what might cause depression involves dysregulation in the hypothalamic-pituitary-adrenal,
or HPA axis.
The HPA axis is a system that involves the hypothalamus, the pituitary gland, and adrenal
glands—which are not shown here but are endocrine glands that sit on top of the kidneys.
Together these structures play an important role in the stress response; their interaction
is responsible for the secretion of the hormone cortisol, which helps the body to make energy
available during stressful situations.
Some studies have found abnormalities in the HPA axis that were linked to a hyperactive
response to stress in depressed patients.
For example, depressed patients are more likely to have increased cortisol levels compared
to non-depressed individuals.
And there is also evidence that chronically high cortisol levels might disrupt the activity
of several brain regions, including the prefrontal cortex, the hippocampus, and the amygdala, as well
as functional circuits these brain regions might be a part of.The prefrontal cortex plays
an important role in a variety of cognitive functions as well as emotional regulation,
the hippocampus is critical for memory consolidation and learning, and the amygdala is also involved
in processing emotions.
Thus, disruptions to the function of these brain regions could impair one’s ability
to think and reason clearly, regulate emotions, and learn new ways to cope with challenges
in life—all problems that might be linked to depressive symptoms.
Another hypothesis suggests a role for the immune system in depression.
This hypothesis is not mutually exclusive from hypotheses that focus on the role of
the HPA axis, because the immune system interacts with the HPA axis and other nervous system
structures, and thus immune dysfunction could impact the function of the nervous system
as well.
A number of studies have linked depression with immune dysfunction and chronic inflammation,
which is a prolonged increase in immune activity that can have negative effects on the body
and/or the brain.
Some have hypothesized that chronic inflammation can cause changes in brain function, as well
as changes in behavior that in some ways might mimic what one might experience if they’re sick—fatigue,
a negative mood, a desire to be isolated from others, irritability, and so on.
These, of course, are behaviors that also resemble what people experience when they’re
depressed.
This hypothesis is supported by research that has found that administering cytokines, which
are signaling proteins involved in immune responses including inflammation, can lead
to symptoms of depression.
Additionally, some studies have found that cytokines are elevated in depressed patients.
We don’t know, however, what might be the cause of the immune dysfunction or inflammation
in the first place—it could be stress, diet, infection, or other factors or combinations
of factors.
It’s possible things like increased cortisol levels or inflammation might lead to depression
by disrupting brain function at a cellular level, and specifically a couple functions
that these changes might disrupt are neuroplasticity and neurogenesis.
Neuroplasticity refers to the brain’s ability to create and eliminate synapses and flexibly
alter neural connections, which makes the brain capable of healthy learning, adaptation,
and change.
Neurogenesis is the production of new neurons.
For much of the history of neuroscience, it was believed that the neurons we’re born
with and those that develop perinatally are all we ever get, but in the late 1990s evidence
started to emerge that suggested the hippocampus was one of a couple regions in the brain that
might continue to produce new neurons into adulthood.
As a side note, I should add that this is a controversial area, with some evidence supporting
the idea of adult neurogenesis in humans and other evidence refuting it.
Both neuroplasticity and neurogenesis are thought to depend on a substance called brain-derived
neurotrophic factor, or BDNF, which helps regulate neuroplasticity and is especially
important to the growth of new neurons as well as the health and survival of neurons
in general.
Some studies have linked depression to low levels of BDNF, and other studies have found
antidepressants to increase BDNF levels.
Still other studies have linked antidepressant administration in lab animals with increased
neurogenesis.
So, one hypothesis is that antidepressants might treat depression not simply by raising
serotonin levels, but by causing downstream effects that promote neurogenesis and neuroplasticity
in areas like the hippocampus (which some studies have found is actually reduced in
size in depressed patients, a structural change that could be the result of impaired neurogenesis,
high cortisol levels, increased inflammation, or something else altogether).
So maybe it’s this neurogenesis and enhanced neuroplasticity that helps depressed patients
taking antidepressants to develop more cognitive flexibility, leading to improvements in symptoms.
It’s important to note that the evidence to support this hypothesis comes mostly from
animal studies, and it’s mixed—some studies support it and some don’t.
So it’s far from conclusive that this is a mechanism in human depression.
The difficulty in identifying a unified theory of depression suggests that there may be multiple
mechanisms at play in the disorder, and different mechanisms may be responsible for depression
in different people.
Unfortunately, this doesn’t make depression easy to understand or treat, and I think it’s
safe to say at this time that we still have a lot to learn about what’s going on in
the brain to cause it.
So it’s a complex, uncertain area, and while there are many other hypotheses we could consider,
I hope this video gave you a good introduction to some of the most popular hypotheses about
the neurological origins of depression.