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

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SECTION II
NEUROPHARMACOLOGY
another antidepressant with a different mechanism of
action is a reasonable next step (e.g., SSRI to SNRI). If
a partial response has been observed, other drugs may
be added to the primary SSRI or SNRI medications;
these additive medications include the antidepressant
drug bupropion, thyroid hormone (triiodothyronine), or
an atypical antipsychotics (aripiprazole or olanzapine)
(Shelton, 2007). After the successful initial treatment
phase, a 6-12 month maintenance treatment phase is
typical, after which the drug is gradually withdrawn. If
a patient has experienced two separate episodes of major
depression or is chronically depressed (i.e., > 2 years),
lifelong treatment with an antidepressant is advisable.
Certain psychotherapies such as cognitive behavioral
therapy or behavioral activation therapy are suitable
options for many patients and may reduce the risk for
relapse (DeRubeis et al., 2008). Finally, in addition to
electroconvulsive therapy, other non- pharmacological
interventions have been developed; these include transmagnetic
stimulation of the brain and deep brain stimulation
(Rakofsky et al., 2009).
The challenge of management of the depressive
episode through the “therapeutic lag” is compounded
by the early emergence of side effects. Most of the
adverse reactions are well tolerated. A significant aspect
of effective management of depression is informing the
patient about the time course of both the therapeutic
and side effects of medications and encouraging persistence
with treatment.
Another important issue in the use of antidepressants is a phenomenon
known as the “switch” from a depressed episode to a
manic or hypomanic episode (Goldberg and Truman, 2003), a significant
challenge in managing bipolar illness. For this reason, antidepressants
are not recommended as monotherapy for bipolar illness.
However, patients with bipolar illness may present with major
depressive episodes early in the course of their illness. SSRIs and
bupropion may be somewhat less likely to induce the switch from
depression to mania than antidepressants from other pharmacological
classes.
A controversial issue regarding the use of all antidepressants
is their relationship to suicide (Mann et al., 2006). Data establishing
a clear link between antidepressant treatment and suicide are lacking.
In general, for reasons of safety, suicidal patients are not
enrolled in clinical trials designed to seek approval for marketing a
new medication. Thus, the FDA uses “suicidality” (i.e., suicidal
ideation or suicide attempts and self- injurious behavior) as a proxy
for risk of suicide. The FDA has issued a “black box” warning
regarding the use of SSRIs and a number of other antidepressants in
children and adolescents, particularly during the early phase of treatment,
due to the possibility of an association between antidepressant
treatment and suicide. However, there is strong epidemiological
evidence that the rate of suicide has been decreasing since the time
that SSRIs were first prescribed and then gained widespread usage;
these data, however, cannot demonstrate a causal relationship. An
analysis of health records of over 65,000 patients undergoing different
types of pharmacological treatment for depression found no suggestion
of increases in suicide or suicide attempts (Simon et al.,
2006). Relevant to this point is the observation that an increase in
suicide occurred for children and adolescents after regulatory authorities
in the U.S. and Europe issued public health warnings about a
possible association between antidepressants and suicidal ideation
and acts, perhaps due to a reduction in the use of antidepressants in
these patient populations after the announcement (Gibbons et al.,
2007). Most clinicians agree that for seriously depressed patients,
the risk of not being on an effective antidepressant drug outweighs
the risk of being treated with one. Of course, clinical common sense
also demands that special attention be paid to potentially suicidal
patients regardless of their medication status. In addition, patients
and family members should be warned to look for the exacerbation
of symptoms such as insomnia, agitation, anxiety, or either the onset
or worsening of suicidal thoughts and behaviors, particularly early
in the course of therapy.
Monoamine Oxidase Inhibitors
The first class of drugs with relatively specific antidepressant effects
were the MAOIs (Hollister, 1981). Iproniazid, which was developed
initially for the treatment of tuberculosis, was found to have moodelevating
effects in patients with tuberculosis. Subsequently, iproniazid
was shown to inhibit MAO, leading to the development of
additional MAOIs including phenelzine, isocarboxazid, and tranylcypromine.
As irreversible inhibitors of both MAO- A and MAO- B,
these drugs have pronounced effects on the body’s ability to metabolize
endogenous monoamines (e.g., 5-HT, NE, and DA) and exogenous
monoamines (e.g., tyramine). The protection of exogenous
monoamines leads to significant drug and food interactions. More
recently, reversible and selective inhibitors of MAO- A and MAO- B
have been developed (Livingston and Livingston, 1996), and these
have fewer side effects and fewer interactions with food and other
drugs. The MAO- B selective inhibitor selegiline is used in the treatment
of Parkinson disease; selective inhibitors of MAO- A, such as
moclobemide, are effective antidepressants but are not approved for
use in the U.S.
Tricyclic Antidepressant and Selective
Reuptake Inhibitors
The initial development of the TCAs resulted from psychopharmacological
characterization of a series of structural analogs that had been
developed as potential antihistamines, sedatives, analgesics, and
antiparkinson drugs (Hollister, 1981). One of the compounds,
imipramine, which has a phenothiazine- like structure, modified behavior
in animal models. Unlike the phenothiazines, imipramine had limited
efficacy in schizophrenic patients, but improved symptoms of
depression. Imipramine and related TCAs became the mainstay of
drug treatment of depression until the later development of the SSRIs.
TCAs with a tertiary- amine side chain, including amitriptyline,
doxepin, and imipramine, inhibit both norepinephrine and serotonin
uptake, while clomipramine is somewhat selective for
inhibition of serotonin uptake. Chemical modification of the TCA
structure led to the earliest SSRI zimelidine which, while effective,
was withdrawn from the market due to serious adverse effects.
Fluoxetine and fluvoxamine were the first widely used SSRIs. At the