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

same time, selective inhibitors of norepinephrine reuptake entered
clinical development; while not approved for use in the U.S. for the
treatment of depression, one norepinephrine reuptake inhibitor, atomoxetine,
is used for the treatment of attention deficit hyperactivity
disorder. Subsequent drug development efforts focused on serotonin
and norepinephrine reuptake inhibitors (SNRIs), resulting in venlafaxine
and duloxetine, which lack the complex receptor pharmacology
exhibited by the TCAs.
Selective Serotonin Reuptake Inhibitors
A number of SSRIs were introduced from 1984-1997,
including fluoxetine, paroxetine, sertraline, citalopram,
escitalopram, and fluvoxamine; the FDA has approved
fluvoxamine for treatment of obsessive- compulsive disorder
and social anxiety disorder, but not depression.
Citalopram is labeled for use in premenstrual dysphoric
disorder. All of the SSRIs show a clear improvement in
safety margin compared to the TCAs and are much
safer in overdose, and in clinical practice have affected
a broad range of psychiatric, behavioral, and medical
conditions, for which they are used, on and off label.
The SSRIs are effective in treating major depression.
In typical studies, only about two- thirds of SSRItreated
patients, compared to about one- third of
placebo- treated patients, exhibit a 50% reduction of
depressive symptoms during a 6-8 week trial. SSRI
treatment results in ~ 35% of patients enjoying a remission,
as defined by a Hamilton Depression Rating Score
< 7, indicative of a complete resolution of symptoms,
compared to 25% of patients who experience a remission
with placebo treatment (Rush et al., 2006).
In addition to use as an antidepressant, SSRIs
also are anxiolytics with demonstrated efficacy in the
treatment of generalized anxiety, panic, social anxiety,
and obsessive- compulsive disorders. Sertraline and
paroxetine also have been approved for the treatment
of posttraumatic stress disorder (PTSD), although
treatment of this condition remains highly challenging.
SSRIs also are used for treatment of premenstrual dysphoric
syndrome and for preventing vasovagal symptoms
in post- menopausal women (although the SNRI
venlafaxine is the most extensively studied drug for
this problem).
Mechanism of Action. SERT mediates the reuptake of
serotonin into the presynaptic terminal; neuronal uptake
is the primary process by which neurotransmission via
5-HT is terminated (Figure 15–1). Thus, treatment with
an SSRI initially blocks reuptake and results in
enhanced and prolonged serotonergic neurotransmission.
SSRIs used clinically are relatively selective, that
is, 10-fold or more, for inhibition of SERT relative to
NET (Table 15–2). Increased synaptic availability of
serotonin stimulates a large number of postsynaptic 5-HT
receptor subtypes, as well as somatodendritic and
presynaptic terminal receptors that regulate serotoninergic
neuron activity and serotonin release.
SSRI treatment causes stimulation of 5-HT 1A
and 5-HT 7
autoreceptors on cell bodies in the raphe nucleus and of 5-HT 1D
autoreceptors on serotonergic terminals, and this reduces serotonin
synthesis and release toward pre- drug levels. With repeated treatment
with SSRIs, there is a gradual down- regulation and desensitization of
these autoreceptor mechanisms. In addition, down- regulation of postsynaptic
5-HT 2A
receptors may contribute to antidepressant efficacy
directly or by influencing the function of noradrenergic and other neurons
via serotonergic heteroreceptors. Other postsynaptic 5-HT receptors
likely remain responsive to increased synaptic concentrations of
5-HT and contribute to the therapeutic effects of the SSRIs.
Later- developing effects of SSRI treatment also may be important
in mediating ultimate therapeutic responses. These include sustained
increases in cyclic AMP signaling and phosphorylation of the
nuclear transcription factor CREB, as well as increases in the expression
of trophic factors such as BDNF. In addition, SSRI treatment
increases neurogenesis from progenitor cells in the dentate nucleus of
the hippocampus and subventricular zone (Santarelli et al., 2003). In
animals models, some behavioral effects of SSRIs depend on
increased neurogenesis (probably via increased expression of BDNF
and its receptor TrkB), suggesting a role for this mechanism in the
antidepressant effects. Recent evidence indicates the presence of neural
progenitor cells in the human hippocampus, providing some support
for the relevance of this mechanism to the clinical situation
(Manganas et al., 2007). Further, repeated treatment with SSRIs
reduces the expression of SERT, resulting in reduced clearance of
released 5-HT and increased serotonergic neurotransmission. These
changes in transporter expression parallel behavioral changes observed
in animal models, suggesting some role for this regulatory mechanism
in the late- developing effects of SsRIs (Zhao et al., 2009). These persistent
behavioral changes depend on increased serotonergic neurotransmission,
similar to what has been demonstrated clinically using
depletion strategies (Delgado et al., 1991).
Serotonin- Norepinephrine Reuptake Inhibitors
Many older TCAs block both SERT and NET, but at a high side
effect burden. Four medications with a non- tricyclic structure that
inhibit the reuptake of both 5-HT and norepinephrine have been
approved for use in the U.S. for treatment of depression, anxiety disorders,
and pain: venlafaxine and its demethylated metabolite,
desvenlafaxine; duloxetine; and milnacipran (approved only for
fibromyalgia pain in the U.S.). Off- label uses include stress urinary
incontinence (duloxetine), autism, binge eating disorders, hot
flashes, pain syndromes, premenstrual dysphoric disorders, and posttraumatic
stress disorders (venlafaxine)
The rationale behind the development of these newer agents
was that targeting both SERT and NET, analogous to the effects of
some TCAs, might improve overall treatment response. Metaanalyses
provide some support for this hypothesis (Entsuah et al.,
2001). Specifically, the remission rate for venlafaxine appears
slightly better than for SSRIs in head- to- head trials. However, many
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CHAPTER 15
DRUG THERAPY OF DEPRESSION AND ANXIETY DISORDERS