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Chapter 18

Depression
Introduction
We will wrap up this review of neuroscience by looking closer at the pathophysiology of four
common psychiatric disorders. The first will be the depressive disorders. Although we will often
use the term depression, the reader should keep in mind that there are probably a multitude of
discrete diseases that all end up with the syndrome we now call depression. For example,
psychotic depression, atypical depression, bipolar depression, and pathologic grief may be
variants of the same phenomena or they could be different conditions with different mechanisms
of action. We have no objective measures to distinguish between the depressive disorders at this
time. In the 1920s, we would have talked about pneumonia as one disease, as they all produced
coughs and fever, although we now know that there are many different causes of pneumonia
(e.g., tuberculosis, pneumococcus, H. flu, etc.).
Depression is a common condition recognized by Hippocrates (melancholia). Yet, in spite of all
our technologic advances since the time of the ancient Greeks, we know surprisingly little about
the pathophysiology of the disorder. We know even less about bipolar disorder.
Monoamine Hypothesis
The accidental discovery in the 1950s that the tricyclic and monoamine oxidase inhibitor
medications could relieve depression transformed the treatment of the disorder. Numerous spinoff medications have been developed since the 1950s. Most are safer and better tolerated than the
earlier medications, but none are more effective. In addition, they all work through the same
mechanism: the monoamines. This has driven the common conceptualization of depression as a
disorder of serotonin and/or norepinephrine (NE).
Again, we see that treatment response generates pathophysiology theories. Clinicians call this the
monoamine hypothesis, and the lay public calls it a chemical imbalance. Unfortunately, neither is
an accurate description of the biologic mechanisms of depression. At least two factors argue
against the monoamine hypothesis as being the only cause of depression:

Medications take 6 to 10 weeks to reach full effectiveness, although the neurotransmitter


activity at the synapse is altered within a few doses.

Studies of neurotransmitter levels in the plasma, cerebrospinal fluid (CSF), and brain
tissue have failed to find deficiencies in patients who are depressed compared with
healthy controls.

Clearly, the depressions are more complex than the simple replacement of an insufficient
neurotransmitter.
The Depressed Brain
If a biopsy were to be done in patients with depression, it is not clear from where the tissue
should be removed. However, structural imaging, functional imaging, and postmortem studies
have established five regions that are consistently dysfunctional in most patients with depression.
The five regions are shown in Figure 18.1. Note the extensive prefrontal involvement.

It is tempting to match depressive symptoms from the Diagnostic and Statistical Manual of
Mental Disorders (DSM) criteria with specific regions in the brain. For example, anhedonia can
be attributed to dysfunction of the nucleus accumbens or cognitive deficits to the anterior
cingulate cortex. However, while a few symptoms seem to match up with a brain region, most do
not. Most symptoms are likely the product of simultaneous dysfunction in several regions.
Alternatively, it is possible to envision depression as the result of overactivity in some regions
and underactivity in other. For example, the hippocampus and nucleus accumbens are considered
underactive in depressed patients whereas the hypothalamic-pituitary-adrenal (HPA) axis and
amygdala are overactive. This is appealing because some of the symptoms of depression appear
to be caused by loss of function (low motivation, lack of hope, low appetite) whereas others
appear to be caused by hyperactivity (insomnia, anxiety, suicidal thoughts). However, the
situation in the frontal cortex is more complex.
Frontal Cortex
The activity level in the frontal cortex in depressed patients is generally hypoactive when
measured in resting positron emission tomography (PET) scans. However, the specific region
affected varies from one study to the next. Likewise, functional magnetic resonance imaging
(fMRIs) gives a varying picture of activity in the depressed frontal cortex. There is no consensus.
Furthermore, one would expect that successful treatment would have an activating effect on the
frontal cortex, but that is not the case. Figure 18.2 shows the paradoxical effect that
electroconvulsive therapy (ECT) has on the frontal cortex. Remarkably, a successful course of
ECT unequivocally turns DOWN the frontal cortex. Perhaps even more confusing,
antidepressants and transcranial magnetic stimulation (TMS) have been shown to activate the
frontal cortex whereas cognitive-behavioral therapy decreases the activity.

How can these successful treatments have such disparate effects on the frontal cortex? The
answer is not known. We think one explanation is that depression results from dysfunction of the
frontal cortex and that successful treatment restores harmony to the region. A sports analogy may
be helpful. A team that is disorganized will not be successful. Interventions that help the players
to work together can improve the team's performance. However, some interventions enhance
defensive skills whereas others enhance offense. In either case a team that works in harmony
(whether on defense or offense) is more likely to win. Likewise with the brain, a frontal cortex
that is organized and working together (whether more active or less active) may be less
depressed.

The Hypothalamic-Pituitary- Adrenal Axis


Since the 1950s it has been recognized that depressed patients have excessive activity of the HPA
axis. Figure 18.3 shows the increased plasma cortisol levels over 24 hours in patients with
depression compared with controls. The hypercortisolemia is stimulated by increased expression
of corticotropin-releasing hormone (CRH) and reduced feedback inhibition of the HPA axis (see
Figure 6.9). As discussed in Chapter 6, Hormones and the Brain, one theory of depression
postulates that chronic, unremitting stress leads to the inability of the brain to turn down the HPA
axis.

Postmortem studies of depressed patients have shown increased neurons in the paraventricular
nucleus of the hypothalamus. The increased neurons are believed to be driving the increased
activity in the HPA axis. It is unclear why these patients have more neurons in the hypothalamus.
It could be genetic or a reaction to chronic stress.
Depression Laboratory Test
The activation of the HPA axis is so consistent in depression that there were early efforts to use it
as a laboratory test to diagnose depression. Unfortunately, the sensitivity and specificity of
increased adrenocorticotropic hormone (ACTH) for depression are not to the level where it is
clinically useful. Other medical conditions also result in elevations of ACTH and there is even a
subset of depressed patients who have low ACTH!
The dexamethasone-suppression test (DST) was piloted in the early 1980s in an alternative
attempt to develop a laboratory test for depression. Patients are given dexamethasone at 11 P.M.
and cortisol levels are drawn the next morning. Dexamethasone binds to the glucocorticoid
receptors, which in turn inhibits the secretion of ACTH and subsequently cortisol. Healthy
subjects will suppress the release of cortisol. Depressed patients will fail to suppress the cortisol
and show a bump in their cortisol level the next morning. Unfortunately, the test has not been
sensitive or specific enoughonly 25% to 40%. It fails to detect most patients who are truly
depressed, and some general medical conditions also fail to suppress cortisol.
Subsequently, with the availability of CRH, a new test has been developed using both
dexamethasone and CRH (dex/CRH). Although the dex/CRH test is more accurate (the
sensitivity increases to 80%), the clinical utility of this cumbersome test as a diagnostic tool
remains doubtful.

Some patients with excess cortisoleither taken orally or generated internallyhave reduced
hippocampal volume. A recent meta-analysis of magnetic resonance imaging (MRI) studies has
confirmed that hippocampal volume is reduced in patients with depression. It is believed that the
excess cortisol produced by depressed patients is toxic to the hippocampus and causes the
volume loss.
Effective treatments for depression (antidepressants, ECT, and lithium) are known to restore
normal HPA function in most patients. It is postulated that this effect is due to increased
glucocorticoid receptor production stimulated by the treatments, which has the effect of making
the hypothalamus more receptive to negative feedback from cortisol. Finally, effective treatment
of depression is believed to preserve and possibly restore hippocampal function (more on this
later). A healthy hippocampus provides more inhibitory feedback on the HPA axis, as shown in
Figure 6.9.
Consequently, depression appears to result in the breakdown of the normal relationship between
the hippocampus and HPA axis. Increased cortisol from the adrenal gland causes hippocampal
damage, which results in decreased inhibitory feedback on the HPA axiswhich in turn causes
increased cortisol release, and so forth.
Restoring normal functioning of the HPA axis as a treatment option has generated considerable
interest. Several groups have tested CRH receptor blockers as novel treatments for depression.
Although the early small studies were favorable, the results were not consistent and were
associated with a risk of hepatotoxicity. Research in this area has stalled.
Neurogenesis and Brain-Derived Neurotrophic Factor

As discussed in Chapter 7, Adult Development and Plasticity, the brain is more dynamic than
previously thought. The brain contains undeveloped stem cells that can migrate and mature into
neurons or glial cells (see Neurogenesis in Chapter 7, Adult Development and Plasticity). There
is compelling evidence that this process is disrupted in depression and corrected with successful
treatment.
Volume Loss
Structural imaging studies and postmortem analysis of depressed patients have documented
subtle volumetric loss. The findings of a smaller hippocampus (mentioned above) are the best
known, but other findings include decreased prefrontal cortex (PFC), cingulate gyrus, and
cerebellum. Additionally, microscopic examinations have shown decreased cortical thickness as
well as diminished neural size. One possible explanation is that HPA axis activation is neurotoxic
to the brain. Another possibility involves a disruption of normal nerve growth.
The prospect that depression is related to problems with nerve growth factors opens a new way
to conceptualize the pathophysiology of the disorder. A failure of neurogenesis and growth factor
proteins, such as brain-derived neurotrophic factor (BDNF), may cause subtle shrinkage of the
brain in depression.
BDNF is one of a family of neurotrophins that regulate the differentiation and survival of
neurons (see Figure 7.8). Most likely there are a multitude of growth factor proteins maintaining
and stimulating nerve growth, but BDNF is the most widely studied at this point. Figure 18.4
shows a dramatic example of the effects of BDNF on serotonergic neurons in the rat cortex.
Saline or BDNF was infused directly into the rat frontal cortex for 21 days. Then the animals
were sacrificed and the cortex at the site of the infusion was stained for 5-hydroxytryptamine (5HT) neurons. Note the remarkable arborization of the 5-HT axons in the cortex of the rat exposed
to BDNF.

Growth factor proteins such as BDNF provide ongoing maintenance of neurons in the brain.
Disruption of these nerve growth factors results in the reduction in the size of neurons, as well as
some cell loss. Such reductions and loss may produce psychiatric symptoms.
It is difficult to assess the quantity and quality of BDNF in living humans, so the evidence
connecting BDNF and depression is indirect. A postmortem analysis of suicide subjects found a
marked decrease in BDNF in their PFC and hippocampus compared with controls (see Figure
18.5).
Psychiatric Treatment and Brain-Derived Neurotrophic Factor
Of great interest to psychiatrists are the increases in BDNF and neurogenesis seen with
treatments that relieve depression. In rats, the following interventions have been shown to
increase BDNF:

Antidepressants

Lithium

Stimulation treatments: ECT, TMS, and VNS

Estrogen

Exercise

This is a remarkable discovery. It is the first time that one mechanism of action has been found
that could explain how all these disparate modes of treatments relieve depression. Presumably,
psychotherapy would also increase BDNF, but no one has yet developed a credible animal model
that could be tested.

With humans, there is less data on studies following depression treatment and BDNF levels.
Recently, a group in Turkey examined serum BDNF levels in depressed patients before and after
the initiation of antidepressant treatment. The results were compared with healthy control
subjects. Although serum BDNF levels are not as accurate as direct central measurements, the
results are still impressive (see Figure 18.6). The BDNF levels in the depressed patients before
treatment were significantly less than the levels in the healthy subjects. After 8 weeks of
antidepressant treatment, the serum BDNF levels increased significantly and no longer differed
from those of the controls.
Neurogenesis

Numerous studies have shown that increased BDNF leads to increased neurogenesis. Therefore,
interventions that increase BDNF should also increase the development of new nerve cells. A
unique study with rats has demonstrated that fluoxetine stimulates neurogenesis in about the
same amount of time as it takes for humans to respond to the treatment. The rats given fluoxetine
did not generate new neurons at a rate any different from placebo after 5 days, but did separate
from placebo by 28 days (see Figure 18.7). Of particular interest, it also took 28 days for the rats
to change their behaviordemonstrate a greater willingness to move into open, lighted areas to
eat.

Scarring the DNA


Nestler et al. at the University of Texas Southwestern Medical Center have taken these ideas one
step further. They have looked at the effect of animal models of depression on the DNA that
codes for BDNF. First, they stressed mice by placing them in the presence of a different
aggressor mouse for 10 consecutive days. The exposed micecalled defeated micewere
later socially avoidant with unfamiliar mice. Such a reaction is similar to that of humans with
depression and post-traumatic stress disorder (PTSD). The messenger RNA (mRNA) that
encodes for BDNF was analyzed in the defeated mice and comparable controls. As expected, it
was greatly reduced in the defeated mice.
The defeated mice were given imipramine, fluoxetine, or placebo for 30 days. The
antidepressants not only reversed the avoidant behavior, but also returned the BDNF mRNA to
almost normal levels. On the basis of these results the researchers speculated that depression (or
in this case, social defeat) must affect the DNA. What they have found may change the way we
view depression.

We discussed in Chapter 14, Social Attachment, how DNA must unravel in order for the mRNA
to be transcribed (see Figure 14.7). Likewise, we discussed the profound effect that a mother rat's
behavior has on gene expression (see Figure 14.8). The results from Nestler's laboratory suggest
that depression too may be a disorder of gene expressionor what they call gene silencing.
The DNA in the region that codes for BDNF was examined in the defeated mice as well as
healthy controls. Figure 18.8 shows the results. In the healthy controls there were a few methyl
groups attached to the histones that package the DNA. In the defeated mice the methyl groups
were greatly increased, which had the effect of limiting access to the DNA. The antidepressanttreated group had the addition of many acetyl groups to the histones although there was no
change in the number of methyl groups. The acetyl groups have the effect of opening up the
DNA and allowing BDNF mRNA to be transcribed.
Human studies examining methylation of the DNA in depressed patients have not been
conducted. Although we would never biopsy the brain of a living depressed person, it would be
interesting to compare methylation of the DNA in postmortem studies of depressed patients and
nondepressed controls.
In summary, these studies suggest a mechanism for depression. Stress in conjunction with a
genetic vulnerability decreases growth factor proteins (such as BDNF) due to clogging of
the DNA (see Figure 18.9). This leads to thinning of the neuronal structures, which results in
depressive symptoms. These structural changes make the prefrontal limbic governing system
vulnerable to disruption and dysregulation. Stress, loss, or other processes cause the system to
lose self-regulation. Furthermore, it appears that effective treatments such as antidepressants,
lithium, ECT, and exercise (and presumably psychotherapy and good social support) will reverse
the process. Presumably the treatment increases the production of growth factor proteins, such as
BDNF, that result in renewed neuronal growth, more resilient self-regulating circuits, and a
return to healthy mood.
Clearly, this is a simplistic description of what is a very complex and heterogenous process.
Much more remains to be discovered.
Are Antidepressants Neuroprotective?
An intriguing study looking at stress, neurogenesis, and antidepressants with tree shrews
suggests that antidepressants are neuroprotective. The tree shrew is actually closely related to
primates and has a relatively large brain. They are nothing like a shrew.
Stressed out tree shrews showed reduced neurogenesis whereas the administration of an
antidepressant (one that is available in Europe but not in the United States) preserved normal cell
development (see Figure 18.10). Further analysis showed that the antidepressant did not suppress
the elevated cortisol in the stressed tree shrews, suggesting that the benefit was not mediated
through the HPA axis.

Sheline et al. looked at hippocampal volume in medically healthy depressed women. They found
that hippocampal size correlated with days of untreated depression (see Figure 18.11). This study
and the tree shrew study suggest that antidepressants might protect the brain from the effects of
depression and stress. If this is true, one wonders if soldiers in combat would have less PTSDrelated sequela if they were taking antidepressants during the hostilities. Clearly, more research
on this important topic is needed.
Glial Cells
An unexpected finding in postmortem studies of depressed patients has been the reduced number
and density of glial cells in the PFC. Subsequent studies have shown that electroconvulsive
seizures in rats will increase proliferation of new glial cells but not new neurons in the PFC.
Glial cells may play a larger role in depression and its treatment than traditionally believed.

Bipolar Disorder
Bipolar disorder is a prevalent illness with strong genetic links and unique clinical features.
Unfortunately, there is disappointingly little to report about the neuroscience of bipolar disorder.
This may be due to the difficultly in distinguishing the subtle differences in bipolar patients'
brains from those with unipolar depression as well as healthy controls. The essential feature of
bipolar disorderepisodes of maniais clinically very distinctive, but have no obvious
structural, functional, or molecular markers yet identified in the brain.
Global Activation
One would think that manic episodes would be easy to differentiate in functional imaging
studiesif the subjects could remain still enough in the scanner. In a manic episode the patient's
brain appears to be revved upgoing way too fast. One would imagine that the manic brain
would light up in a functional imaging study, but that has not been the case.
The Medical University of South Carolina Functional Neuroimaging Team conducted a
prospective fMRI study of six rapid cycling bipolar patients in an effort to identify changes in the
brain with different moods. The patients were matched with appropriate controls and asked to
call the imaging center whenever in an altered mood. Numerous scans were performed at many
unusual hours of the day on each patient and control. The absolute blood flow measures did
change over time and were softly, but not significantly, associated with depression and mood.

The results from one subject are shown in Figure 18.12. Note how the total brain activity (shown
in black) roughly follows the mood changes (shown in brown). Unfortunately, larger studies
attempting to show this same phenomenon have been disappointing.

Lithium and Gray Matter


Some imaging studies have found decreased size and activity in the PFC of patients with bipolar
disordersimilar to that found in patients with unipolar depression. We mentioned earlier that
lithium has been shown to stimulate BDNF synthesis. A group at Wayne State University
conducted a clever study matching these two concepts. They examined the gray matter volume
changes in bipolar patients after initiating lithium treatment. MRI scans were conducted at
baseline and after 4 weeks of lithium. A computer outlined and measured the gray matter volume
in each scan (see Figure 18.13). Eight of the ten patients showed significant increases in total
gray matter volumeaveraging 3%.

Subsequent studies by other groups have replicated this data. Of interest, valproic acid has not
been shown to have the same effect.

Bipolar Summary
Although these studies are interesting, they fail to provide the neuroscientific basis for bipolar
disorder that we would like to see. Haldane and Frangou reviewed the literature on imaging
studies on patients with bipolar disorder. They suggest that bipolar patients share some features
with unipolar depression (reduced activity in the PFC). Yet, other areas such as the amygdala are
larger and more active in the bipolar patients. The authors suggest that bipolar disorder may be
the result of abnormal interactions between the PFC and subcortical regions such as the
amygdalaan abnormality not seen with unipolar depression. Clearly, more research is needed
on this interesting topic.
BDNF Utopia?

One can get the impression that nerve growth factors such as BDNF are the solution to all
problems. Although future psychiatric treatments may provide better ways to restore nerve
growth factor deficiencies in mentally ill patients, it will not be as simple as just finding ways to
get more BDNF into the brain. Too much BDNF in some regions of the brain may be
detrimental. For example, Nestler et al. using the same defeated mouse protocol found
that the defeated mice had increased BDNF in the nucleus accumbens. The researchers speculate
that the development of the social phobia seen with the defeated mice may be related to too
much BDNF in the brain's reward system. Additionally, too much growth, in an uncontrolled
manner is another way to describe cancer.

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