DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

398 disease, especially myocardial infarction) (Andrews and
Nemeroff, 1994).
Depression is underdiagnosed and undertreated
(Suominen et al., 1998). This is of particular concern
due to the inherent risk of suicide associated with
depression. Approximately 10-15% of those with
severe depression attempt suicide at some time (Chen
and Dilsaver, 1996). Thus, it is important that symptoms
of depression be recognized and treated in a
timely manner. Furthermore, the response to treatment
must be assessed and decisions made regarding continued
treatment with the initial drug, dose adjustment,
adjunctive therapy, or alternative medication.
SECTION II
NEUROPHARMACOLOGY
Symptoms of Anxiety
Anxiety disorders encompass a constellation of symptoms,
and include generalized anxiety disorder,
obsessive- compulsive disorder, panic disorder, posttraumatic
stress disorder, separation anxiety disorder,
social phobia, specific phobias, and acute stress (Atack,
2003). In general, symptoms of anxiety that lead to
pharmacological treatment are those that interfere significantly
with normal function. Symptoms of anxiety
also are often associated with depression and other
medical conditions.
Anxiety is a normal human emotion that serves
an adaptive function from a psychobiological perspective.
However, in the psychiatric setting, feelings of fear
or dread that are unfocused (e.g., generalized anxiety
disorder) or out of scale with the perceived threat (e.g.,
specific phobias) often require treatment. Drug treatment
includes acute drug administration to manage
episodes of anxiety, and chronic or repeated treatment
to manage unrelieved and continuing anxiety disorders.
ANTIDEPRESSANT DRUGS
Mechanisms of Action. Many different antidepressants
have established track records of efficacy for treating
major depression (Millan, 2006). However, they all
suffer some limitations in efficacy, since at least 20%
of all depressed patients are refractory to multiple different
antidepressants at adequate doses (Rush et al.,
2006). The most commonly used medications, often
referred to as second- generation antidepressants, are the
selective serotonin reuptake inhibitors (SSRIs) and the
serotonin- norepinephrine reuptake inhibitors (SNRIs),
which have greater efficacy and safety compared to
most older drugs (i.e., first- generation antidepressants).
Relatively selective norepinephrine reuptake inhibitors
also have been developed as antidepressants (e.g.,
maprotiline, reboxetine).
In monoamine systems, reuptake of the transmitter is
the main mechanism by which neurotransmission is terminated;
thus, inhibition of reuptake can enhance neurotransmission,
presumably by slowing clearance of the
transmitter from the synapse and prolonging the dwell- time
of the transmitter in the synapse. Enhancing neurotransmission
may subsequently lead to adaptive changes
(described later). Reuptake inhibitors inhibit either SERT,
the neuronal serotonin (5-hydroxytryptamine; 5-HT) transporter;
NET, the neuronal norepinephrine (NE) transporter;
or both (Figure 15–1). Similarly, the first- generation drugs,
which include monoamine oxidase inhibitors (MAOIs) and
tricyclic antidepressants (TCAs), also enhance monoaminergic
neurotransmission: the MAOIs by inhibiting
monoamine metabolism and thereby enhancing neurotransmitter
storage in secretory granules, the TCAs by
inhibiting 5-HT and norepinephrine reuptake. While efficacious,
these first- generation agents exhibit side effects and
drug and food interactions that limit their use relative to the
newer drugs. Table 15–1 summarizes the actions of the
most widely used antidepressants.
All drugs commonly used to treat depression share, at some
level, primary effects on serotonergic or noradrenergic neurotransmitter
systems (Shelton and Lester, 2006). In general, antidepressants
enhance serotonergic or noradrenergic transmission, although
the nature of this effect may change with chronic treatment (Shelton,
2000). The dependence of many current treatments on serotonergic
or noradrenergic mechanisms is highlighted by clinical studies
employing monoamine depletion strategies. For example, tryptophan
depletion that acutely reduces 5-HT neurotransmission results in a
relatively brisk relapse (within 5-10 hours) of the symptoms of
depression in patients who had shown remission on an SSRI but not
a NE reuptake inhibitor (Delgado et al., 1991). Conversely, catecholamine
depletion by blocking the rate- limiting enzyme for the
synthesis of NE and dopamine (DA) results in a relapse of symptoms
in patients who had recently remitted on an NE reuptake
inhibitor, but not an SSRI (Miller et al., 1996). Sites of interaction of
antidepressant drugs with noradrenergic and serotonergic neurons
are depicted in Figure 15–1.
Long- term effects of antidepressant drugs evoke adaptive or
regulatory mechanisms that enhance the effectiveness of therapy.
These responses include increased adrenergic or serotonergic receptor
density or sensitivity, increased receptor- G protein coupling and
cyclic nucleotide signaling, induction of neurotrophic factors, and
increased neurogenesis in the hippocampus (Schmidt and Duman,
2007). Persistent antidepressant effects depend on the continued
inhibition of 5-HT or NE transporters, or enhanced serotonergic or
noradrenergic neurotransmission achieved by an alternative pharmacological
mechanism. For example, chronic treatment with some
antidepressants that interact directly with monoamine transporters
(e.g., SSRIs, SNRIs, or NE reuptake inhibitors) reduces the expression
and activity of 5-HT or NE transporters in the brain, which
results in enhanced serotonergic or noradrenergic neurotransmission
(Benmansour et al., 1999; Zhao et al., 2008). Compelling evidence
suggests that sustained signaling via NE or 5-HT increases the