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

of the studies included in the meta- analyses used a daily venlafaxine
dose of 150 mg, which would have modest effects on noradrenergic
neurotransmission. Duloxetine, in addition to being approved
for use in the treatment of depression and anxiety, also is used for
treatment of fibromyalgia and neuropathic pain associated with
peripheral neuropathy.
Mechanism of Action. SNRIs inhibit both SERT and NET (Table 15–2).
Depending on the drug, the dose, and the potency at each site, SNRIs
cause enhanced serotonergic and/or noradrenergic neurotransmission.
Similar to the action of SSRIs, the initial inhibition of SERT
induces activation of 5-HT 1A
and 5-HT 1D
autoreceptors. This action
decreases serotonergic neurotransmission by a negative feedback
mechanism until these serotonergic autoreceptors are desensitized.
Then, the enhanced serotonin concentration in the synapse can interact
with postsynaptic 5-HT receptors.
Serotonin Receptor Antagonists
Several antagonists of the 5-HT 2
family of receptors are effective
antidepressants, although most agents of this class affect other receptor
classes as well. The class includes two pairs of close structural
analogues, trazodone and nefazodone, as well as mirtazapine
(REMERON, others) and mianserin (not marketed in the U.S.).
The efficacy of trazodone may be somewhat more limited
than the SSRIs; however, low doses of trazodone (50-100 mg) have
been used widely both alone and concurrently with SSRIs or SNRIs
to treat insomnia. When used to treat depression, trazodone typically
is started at 150 mg/day in divided doses with 50 mg increments
every 3-4 days. The maximally recommended dose is 400 mg/day
for outpatients and 600 mg/day for inpatients.
Both mianserin and mirtazapine are quite sedating and are
treatments of choice for some depressed patients with insomnia.
The recommended initial dosing of mirtazapine is 15 mg/day
with a maximal recommended dose of 45 mg/day. Since the t 1/2
is 16-30 hours, the recommended interval for dose changes is no
less than 2 weeks.
Mechanism of Action. The most potent pharmacological effects of
trazodone are blockade of the 5-HT 2
and α 1
adrenergic receptors.
Trazodone also inhibits the serotonin transporter, but is markedly
less potent for this action relative to its blockade of 5-HT 2A
receptors.
Similarly, the most potent pharmacological action of nefazodone
also is the blockade of the 5-HT 2
family of receptors.
Both mirtazapine and mianserin potently block histamine H 1
receptors. They also have some affinity for α 2
adrenergic receptors,
which is claimed to be related to their therapeutic efficacy, but this
point is questionable. Their affinities for 5-HT 2A
, 5-HT 2C
, and 5-HT 3
receptors are high, though less so than for histamine H 1
receptors.
Both of these drugs have been shown in double- blind, placebocontrolled
studies to increase the antidepressant response when
combined with SSRIs compared to the action of the SSRIs alone.
The exact monoamine receptor accounting for the effects of mirtazapine
and mianserin is not clear, although the data from clinical trials
suggest that olanzapine, aripiprazole, and quetiapine enhance the
therapeutic effects of SSRIs or SNRIs, an important hint that their
unique capacity to block the 5-HT 2A
receptor is the most potent
shared pharmacological action amongst these antidepressant and
antipsychotic drugs.
Bupropion
Bupropion (WELLBUTRIN, others) is discussed separately because it
appears to act via multiple mechanisms. It enhances both noradrenergic
and dopaminergic neurotransmission via reuptake inhibition
(Table 15–2); in addition, its mechanism of action may involve the
presynaptic release of NE and DA (Foley et al., 2006). Bupropion is
indicated for the treatment of depression, prevention of seasonal
depressive disorder, and as a smoking cessation treatment (under the
ZYBAN brand). Bupropion has effects on sleep EEG that are opposite
those of most antidepressant drugs. Bupropion may improve symptoms
of attention deficit hyperactivity disorder (ADHD) and has
been used off- label for neuropathic pain and weight loss. Clinically,
bupropion is widely used in combination with SSRIs to obtain a
greater antidepressant response; however, there are very limited clinical
data providing strong support for this practice.
Mechanism of Action. Bupropion appears to inhibit NET. It also
blocks the DAT but its effects on this transporter are not particularly
potent in animal studies. In addition, it has effects on VMAT2, the
vesicular monoamine transporter (see Figure 8–6). The hydroxybupropion
metabolite may contribute to the therapeutic effects of
bupropion: this metabolite appears to have a similar pharmacology
and is present in substantial levels.
Atypical Antipsychotics
In addition to their use in schizophrenia, bipolar depression, and
major depression with psychotic disorders, atypical antipsychotics
have gained further, off- label use for major depression without psychotic
features (Jarema, 2007). In fact, both aripiprazole (ABILIFY)
added to SSRIs and SNRIs and a combination of olanzapine and the
SSRI fluoxetine (SYMBYAX) have been approved by the FDA for
treatment-resistant major depression (i.e., following an inadequate
response to at least two different antidepressants).
The initial recommended dose of aripiprazole is 2-5 mg/day
with a recommended maximal dose of 15 mg/day following increments
of no more than 5 mg/day every week. The olanzapine- fluoxetine
combination is available in fixed- dose combinations of either 6 or
12 mg of olanzapine and 25 or 50 mg of fluoxetine. Quetiapine
(SEROQUEL) may have either primary antidepressant actions on its
own or adjunctive benefit for treatment-resistant depression; it is
used off- label for insomnia. Quetiapine also is currently under
review by the FDA for additional indications in major depression
and generalized anxiety disorder.
Mechanism of Action. The mechanism of action and adverse effects
of the atypical antipsychotics are described in detail in Chapter 16.
The side effects seen with atypical antipsychotics in patients with
schizophrenia may not exactly translate to patients with major
depression, due to a predisposition toward metabolic syndrome in
patients with schizophrenia. The major risks of these agents are
weight gain and metabolic syndrome, a greater problem for quetiapine
and olanzapine than for aripiprazole.
Tricyclic Antidepressants
Due to their potential to cause serious side effects, the TCAs generally
are not used as first- line drugs for the treatment of depression.
Nevertheless, these drugs have established value for the treatment
of major depression (Hollister, 1981). TCAs and first- generation
407
CHAPTER 15
DRUG THERAPY OF DEPRESSION AND ANXIETY DISORDERS