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

PRESYNAPTIC
5-HT
POSTSYNAPTIC
399
5-HTR 1D/2A
5-HTR 1A/1D/7
5-HTR 1-7
IP 3
IP
Noradrenergic
neuron
α 2 AR
TCAs
α 1 AR
NE
synthesis
5-HT
synthesis
Serotonergic
neuron
MAOIs
NE
5-HT
α 2 AR
MAO
MAO
NE
NET
SERT
5-HT
Reuptake
TCAs
SNRIs
SSRIs
TCAs
SNRIs
Reuptake
NE
Figure 15–1. Sites of action of antidepressants. Schematics representing noradrenergic (top) and serotonergic (bottom) nerve terminals.
SSRIs, SNRIs, and TCAs increase noradrenergic or serotonergic neurotransmission by blocking the norepinephrine or serotonergic
transporter at presynaptic terminals (NET, SERT). MAOIs inhibit the catabolism of norepinephrine and serotonin. Some
antidepressants such as trazodone and related drugs have direct effects on serotonergic receptors that contribute to their clinical effects.
Chronic treatment with a number of antidepressants desensitizes presynaptic autoreceptors and heteroreceptors, producing longlasting
changes in monoaminergic neurotransmission. Post- receptor effects of antidepressant treatment, including modulation of
GPCR signaling and activation of protein kinases and ion channels, are involved in the mediation of the long- term effects of antidepressant
drugs. Note that NE and 5-HT also affect each other’s neurons.
PIP 2
βAR
I Li +
Modulation
of cell signaling
pathways and
cell function
CHAPTER 15
DRUG THERAPY OF DEPRESSION AND ANXIETY DISORDERS
expression of specific downstream gene products, particularly
brain- derived neurotrophic factor (BDNF), which appears to be
related to the ultimate mechanism of action of these drugs (Sen et al.,
2008). Unfortunately, neither earlier theories of monoaminergic
receptor down- regulation and altered signaling nor current theories
of neurogenesis and modulation of neurotrophic factors has yet led
to new antidepressant treatments. Glutamate, neurokinin, corticotropin
releasing hormone receptors and cyclic nucleotide phosphodiesterases
may be potential targets for the development of novel
antidepressant drugs (O’Donnell and Zhang, 2004; Rakofsky et al.,
2009; Witkin et al., 2007; Zarate et al., 2006).
Clinical Considerations with
Antidepressant Drugs
Following initiation of antidepressant drug treatment
there is generally a “therapeutic lag” lasting 3-4 weeks
before a measurable therapeutic response becomes evident.
This is the reason that electroconvulsive therapy
may be the treatment of choice for agitated, depressed
patients with a high risk of suicide. Some patients
may respond to antidepressant treatment sooner than
3-4 weeks; others may require > 8 weeks for an adequate
response. Some symptoms respond more rapidly
and are predictive of a more global response (Katz et al.,
2004). Approximately two- thirds of depressed patients
will show a 50% decrease in depressive symptoms over
the course of an 8-week antidepressant trial; one- third
will experience a complete remission with a single antidepressant
(Rush et al., 2006). In general, if a patient
does not respond to a given antidepressant after an
8-week trial on an adequate dose, then switching to