Page 548 - Basic _ Clinical Pharmacology ( PDFDrive )

534 SECTION V Drugs That Act in the Central Nervous System

attention functions, whereas the medial orbital frontal cortex is patients who respond to serotonergic antidepressants such as
also thought to play a role in memory, learning, and emotion. fluoxetine often rapidly suffer relapse when given diets free of
Over 30 structural imaging studies suggest that major depression tryptophan, a precursor of serotonin synthesis. Patients who
is associated with a 5–10% loss of volume in the hippocampus, respond to noradrenergic antidepressants such as desipramine are
although some studies have not replicated this finding. Depression less likely to relapse on a tryptophan-free diet. Moreover, deplet-
and chronic stress states have also been associated with a substantial ing catecholamines in depressed patients who have previously
loss of volume in the anterior cingulate and medial orbital frontal responded to noradrenergic agents likewise tends to be associated
cortex. Loss of volume in structures such as the hippocampus also with relapse. Administration of an inhibitor of norepinephrine
appears to increase as a function of the duration of illness and the synthesis is also associated with a rapid return of depressive symp-
amount of time that the depression remains untreated. toms in patients who respond to noradrenergic but not necessarily
Another source of evidence supporting the neurotrophic in patients who had responded to serotonergic antidepressants.
hypothesis of depression comes from studies of the direct effects Another line of evidence supporting the monoamine hypoth-
of BDNF on emotional regulation. Direct infusion of BDNF esis comes from genetic studies. A functional polymorphism
into the midbrain, hippocampus, and lateral ventricles of rodents exists for the promoter region of the serotonin transporter gene,
has an antidepressant-like effect in animal models. Moreover, all which regulates how much of the transporter protein is available.
known classes of antidepressants are associated with an increase Subjects who are homozygous for the s (short) allele may be more
in BDNF levels in animal models with chronic (but not acute) vulnerable to developing major depression and suicidal behavior
administration. This increase in BDNF levels is consistently in response to stress. In addition, homozygotes for the s allele
associated with increased neurogenesis in the hippocampus in may also be less likely to respond to and tolerate serotonergic
these animal models. Other interventions thought to be effective antidepressants. Conversely, subjects with the l (long) allele tend
in the treatment of major depression, including electroconvulsive to be more resistant to stress and may be more likely to respond
therapy, also appear to robustly stimulate BDNF levels and hip- to serotonergic antidepressants.
pocampus neurogenesis in animal models. Studies of depressed patients have sometimes shown an altera-
Human studies seem to support the animal data on the role tion in monoamine function. For example, some studies have found
of neurotrophic factors in stress states. Depression appears to be evidence of alteration in serotonin receptor numbers (5-HT and
1A
associated with a drop in BDNF levels in the cerebrospinal fluid 5-HT ) or norepinephrine (α ) receptors in depressed and suicidal
2
2C
and serum as well as with a decrease in tyrosine kinase receptor patients, but these findings have not been consistent. A reduction
B activity. Conversely, administration of antidepressants increases in the primary serotonin metabolite 5-hydroxyindoleacetic acid
BDNF levels in clinical trials and may be associated with an in the cerebrospinal fluid is associated with violent and impulsive
increase in hippocampus volume in some patients. behavior, including violent suicide attempts. However, this finding
Much evidence supports the neurotrophic hypothesis of is not specific to major depression and is associated more generally
depression, but not all evidence is consistent with this concept. with violent and impulsive behavior.
Animal studies in BDNF knockout mice have not always sug- Finally, perhaps the most convincing line of evidence support-
gested an increase in depressive or anxious behaviors that would ing the monoamine hypothesis is the fact that (at the time of this
be expected with a deficiency of BDNF. In addition, some animal writing) all available antidepressants appear to have significant
studies have found an increase in BDNF levels after some types effects on the monoamine system. All classes of antidepressants
of social stress and an increase rather than a decrease in depressive appear to enhance the synaptic availability of 5-HT, norepineph-
behaviors with lateral ventricle injections of BDNF. rine, or dopamine. Attempts to develop antidepressants that work
A proposed explanation for the discrepant findings on the role of on other neurotransmitter systems have not been effective to date.
neurotrophic factors in depression is that there are polymorphisms The monoamine hypothesis, like the neurotrophic hypothesis,
for BDNF that may yield very different effects. Mutations in the is at best incomplete. Many studies have not found an alteration
BDNF gene have been found to be associated with altered anxiety in function or levels of monoamines in depressed patients. In
and depressive behavior in both animal and human studies. addition, some candidate antidepressant agents under study do
Thus, the neurotrophic hypothesis continues to be intensely not act directly on the monoamine system.
investigated and has yielded new insights and potential targets in In addition to the monoamines, the excitatory neurotransmit-
the treatment of MDD. ter glutamate appears to be important in the pathophysiology of
depression. A number of studies of depressed patients have found
Monoamines & Other Neurotransmitters elevated glutamate content in the cerebrospinal fluid of depressed
patients and decreased glutamine/glutamate ratios in their plasma.
The monoamine hypothesis of depression (Figure 30–2) suggests In addition, postmortem studies have revealed significant increases
that depression is related to a deficiency in the amount or function in the frontal and dorsolateral prefrontal cortex of depressed
of cortical and limbic serotonin (5-HT), norepinephrine (NE), patients. Likewise, structural neuroimaging studies have consis-
and dopamine (DA). tently found volumetric changes in the brain areas of depressed
Evidence to support the monoamine hypothesis comes from patients in which glutamate neurons and their connections are
several sources. It has been known for many years that reserpine most abundant, including the amygdala and hippocampus.
treatment, which is known to deplete monoamines, is associ- Antidepressants are known to impact glutamate neurotrans-
ated with depression in a subset of patients. Similarly, depressed mission in a variety of ways. For example, chronic antidepressant