Corticosteroids (also known as corticoids) are hormones secreted by the outer portions of the adrenal glands. They can be divided into three groups, for each of which there are separate receptors: androgens, which are involved in the development of sexual traits; mineralocorticoids (aldosterone, corticosterone, desoxycortisone), which regulate the body's osmotic balance; and glucocorticoids (cortisone, hydrocortisone, prednisone), which, in addition to their anti-inflammatory and immunosuppressive effects, stimulate the synthesis of glucose and increase the mobilization of fatty acids and proteins to meet the higher metabolic demands generated by stress.
Glucocorticoids play an extremely important role in fear and anxiety reactions and in depressive states. These hormones often affect behaviour by increasing or decreasing the efficiency of certain neural pathways.
SEROTONIN AND OTHER MOLECULES INVOLVED IN DEPRESSION
When someone perceives a situation as disagreeable or dangerous,
a general response to this stress is triggered in their body. Depending
on the situation and the person's experience with such situations,
he or she will choose
a behaviour: either fight,
or flight, or inhibition of action (the status quo).
The body's response from the time it perceives a danger to the time it secretes
the hormones to prepare to deal with it involves the following structures, in
the following order: 1) the limbic system, 2) the hypothalamus, 3) the pituitary
gland, and 4) the adrenal glands. The adrenal glands secrete glucocorticoids
(such as cortisol, in human beings), which interact with the serotonin receptors
in the brain.
When someone experiences a stressful
event, the level of glucocorticoids in their blood rises.
Via specific receptors in the hippocampus, this activates
the hypothalamus, which then secretes corticotropin-releasing
hormone (CRH). The CRH in turn causes the pituitary gland
to release adrenocorticotropic hormone (ACTH) into the
bloodstream, from which it enters the adrenal glands
and causes them to secrete cortisol.
This process creates a negative feedback loop in which
the excess cortisol activates the brain's glucocorticoid
receptors and suppresses the production of CRH. In depressed
patients, however, this loop no longer works, resulting
in excess production of CRH and hence of cortisol. Many seriously depressed patients have high
blood levels of cortisol, caused by chronic stress.
In rats, chronic stress and/or a high level of glucocorticoids
alters certain serotonergic receptors (increases the 5-HT2Areceptors
in the cerebral cortex and reduces the 5-HT1Areceptors
in the hippocampus). These same changes have been observed in
humans who have committed suicide or
suffered from diseases that cause hypersecretion of glucocorticoids.
The continued administration of antidepressants causes changes
in the serotonergic receptors that are the opposite of the changes
produced by chronic stress. It also reverses the hypersecretion
of stress hormones.
Not incidentally, in humans, many glucocorticoid receptors (GRs) and mineralocorticoid
receptors (MRs) (see sidebar) are located in the hypothalamus and the hippocampus,
two structures involved in mood control and the ability to experience pleasure.
These receptors are sensitive both to the levels of the various corticosteroids
in the body and to the length of time that they are active, so their activation
mechanisms will have direct impacts on the behavioural response chosen to a given
stimulus.
Prolonged chronic stress also seems to alter the response of the MR and GR receptors
and to have very harmful effects on people's mental equilibrium, especially when
social or family supports are absent. Under these conditions, the glucocorticoid
response, which was originally highly adaptive, becomes clearly maladaptive.
It has long been known
that depressed persons display hyperactivity in the hypothalamic-pituitary-adrenal
(HPA) axis (see illustration and explanation above). A
prolonged state of inhibition
of action is also known to encourage the emergence
of a depressive state. This chronic excess stress on the
HPA axis is believed to result in structural changes in
certain parts of the brain. For example, region
CA3 of the hippocampus loses large numbers of neurons
when subjected to prolonged stress.
Other studies have also reported a reduced number of glucocorticoid
receptors in the hippocampus and prefrontal cortex of suicide victims.
Though it is hard to tell whether these structural changes
are of genetic origin or the result of chronic activation
of the HPA axis, they would be consistent with hyperactivity
in this axis when the natural braking effect of these receptors
was reduced.
Here's another example: people with Cushing's syndrome, a
disease in which the body produces excess cortisol, display
a high incidence of depression, and their depression lifts
when they are given treatments that bring their cortisol
levels back to normal.
Thus, all indications are that the end products of the HPA
axis—glucocorticoids— play a role in depression
by influencing several neurotransmitter systems, including
those for serotonin, norepinephrine, and dopamine, all three
of which are involved in depression.
Treatment with antidepressants
is often regarded as consisting of two phases. During the
first two weeks, the patient's depressive state does not
really improve. But after two or three weeks, the patient
gradually begins sleeping and eating again, feeling more
energetic, and having more positive thoughts. It is recommended
that treatment then be continued for several months to
minimize the risk of a relapse.
Various hypotheses have been offered to explain this lag
before antidepressants become effective. One hypothesis is
that at the start of the treatment, once the antidepressant
medication has inhibited the reuptake of serotonin, the serotonin
autoreceptors quickly become saturated, so that their inhibitory
effect predominates, reducing the amount of serotonin released
into the synaptic gap. But over time, these autoreceptors
become desensitized, and the presynaptic neuron can produce
action potentials more readily. Because the antidepressants
are still preventing the serotonin from being reabsorbed,
its extracellular concentration increases, and serotonergic
transmission is facilitated.
The effect of antidepressants
can be compared with that of ecstasy,
which causes the release of large amounts of serotonin
from the nerve endings of neurons. This excess of serotonin
is suspected to be the source of the particular mental
effects of ecstasy, including those associated with feelings
of well-being—effects analogous to those of antidepressants.
An initial hypothesis formulated in the 1960s identified norepinephrine as
the main neurotransmitter involved in depression. According
to this “catecholamine
hypothesis”, depression was due to a
deficiency of norepinephrine in certain circuits of the
brain, while mania was due to an overabundance of this
same neurotransmitter. Though this hypothesis is still
recognized, it does not explain everything, in particular
why there are some people whose mood is not affected by
fluctuations in their norepinephrine levels.
In the 1970s, the “permissive hypothesis” emerged,
which postulated that another neurotransmitter, serotonin,
was involved in depression. According to this hypothesis,
a reduction in the amount of serotonin in certain synapses
may cause depression by triggering or “permitting” a
drop in norepinephrine. Consequently, though norepinephrine
was still acknowledged to play an important role in depression,
attempts could now be made to treat depression by acting
on the body's serotonin levels. This has been the therapeutic
approach applied using Prozac and all the other selective
serotonin reuptake inhibitors (SSRIs) that have come on
the market since the 1980s.
Fluoxetine (Prozac)
A third neurotransmitter of importance in depression is dopamine,
the same molecule that is involved in schizophrenia and Parkinson's disease.
Dopamine plays an important role in rewards and positive reinforcement— in
other words, in the pursuit of gratification. The use of dopaminergic substances
and stimulants as antidepressants produces quick, positive results in many patients,
which makes these substances useful complements to other antidepressants that
may take several weeks to act.
Medications that act directly on dopamine must be used cautiously, however, because
they can create dependencies. Many drugs, such as cocaine, opiates, and alcohol,
increase the production of dopamine, which may explain why many people with depression
use them.
The effects of antidepressants
are not limited to the presynaptic neurons. In postsynaptic
neurons, the antidepressive effect of tricyclics and
MAOIs may be attributable to “down-regulation” (reduction
in the number but not the sensitivity) of the beta-adrenergic
receptors and the 5-HT2 serotonergic receptors.
Desensitization is also observed in the norepinephrinergic
receptors coupled to adenylate cyclase . The phenomena
of transduction via the G-proteins paired with the receptors
represent another possible site of postsynaptic effects,
as is probably the case for lithium.
Many researchers
now believe that it is not really appropriate to describe
the physiological causes of depression as a "chemical
imbalance".
The hypothesis that depression
was caused by a "chemical imbalance" originated
in the 1960s. The first antidepressant medications,
developed around that time, were tricyclics and monoamine
oxidase inhibitors (MAOIs). In addition to alleviating
the symptoms of depression in many patients, these
molecules were known to increase brain levels of dopamine,
norepinephrine, and serotonin in various ways. For
this reason, researchers hypothesized that depression
might be due to an imbalance in these neurotransmitters.
This hypothesis did indeed yield some fairly useful
research findings during the last decades of the 20th
century. In addition, by emphasizing that mood disorders
might be related to a physiological malfunction and
not simply to a character defect or a lack of will
power, this hypothesis reduced the needless feelings
of guilt that often haunted people with depression.
However, the results of efforts
to identify this "chemical imbalance" more
precisely have been rather disappointing and contradictory.
Research is now focusing less on the neurotransmitters
themselves and more on the receptors for these molecules
and on the molecular events involved in regulating genes.
But here too, there is room for controversy. Relatively
little direct evidence has been found of alterations
in receptors or anomalies in gene expression related
to these receptors or other enzymes in cases of depression.
Moreover, the reason for the two to three week lag between
the time when antidepresssants first affect neurotransmitters
and the time when they begin to affect mood (see sidebar
to the left) is still not well understood. In short,
the situation is far more complex than scientists believed
in the 1960s when they first formulated the "chemical
imbalance" hypothesis.
Given these problems in securing
any unequivocal data to support this hypothesis, some
scientists have begun to ask whether the extensive use
that continues to be made of the term "chemical
imbalance" might raise some ethical problems, or
even political ones. In the United States, for example,
where advertisements for antidepressants are allowed
in the
mass media, the pharmaceutical companies
have not always worried about this fine point. Simplistic
advertisements tell Americans that when they are depressed,
a substance in their brain is out of balance, and that
if they take the right antidepressants, the ideal balance
will be magically restored. These advertisements may
well have something to do with the stunning success of
SSRI antidepressants, such as Prozac, Zoloft, and Paxil,
in the marketplace, and the billions of dollars that
they have earned for the companies that make them.
