Page 557 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 30 Antidepressant Agents 543

of α adrenoceptors can result in substantial orthostatic hypoten- and norepinephrine neurons and is found primarily in the brain,
sion, particularly in older patients. gut, placenta, and liver; its primary substrates are norepineph-
rine, epinephrine, and serotonin. MAO-B is found primarily in
C. 5-HT Receptor Modulators serotonergic and histaminergic neurons and is distributed in the
The principle action of both nefazodone and trazodone appears brain, liver, and platelets. MAO-B acts primarily on dopamine,
to be blockade of the 5-HT receptor. Inhibition of this receptor tyramine, phenylethylamine, and benzylamine. Both MAO-A
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in both animal and human studies is associated with substantial and -B metabolize tryptamine.
antianxiety, antipsychotic, and antidepressant effects. Conversely, MAOIs are classified by their specificity for MAO-A or
agonists of the 5-HT receptor, eg, lysergic acid (LSD) and -B and whether their effects are reversible or irreversible.
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mescaline, are often hallucinogenic and anxiogenic. The 5-HT Phenelzine and tranylcypromine are examples of irreversible,
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receptor is a G protein-coupled receptor and is distributed nonselective MAOIs. Moclobemide is a reversible and selec-
throughout the neocortex. tive inhibitor of MAO-A but is not available in the USA.
Nefazodone is a weak inhibitor of both SERT and NET but Moclobemide can be displaced from MAO-A by tyramine,
is a potent antagonist of the postsynaptic 5-HT receptor, as are and this mitigates the risk of food interactions. In contrast,
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its metabolites. Trazodone is also a weak but selective inhibitor of selegiline is an irreversible MAO-B–specific agent at low doses.
SERT with little effect on NET. Its primary metabolite, m-cpp, is Selegiline is useful in the treatment of Parkinson’s disease at
a potent 5-HT antagonist, and much of trazodone’s benefits as an these low doses, but at higher doses it becomes a nonselective
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antidepressant might be attributed to this effect. Trazodone also MAOI similar to other agents.
has weak-to-moderate presynaptic α-adrenergic–blocking proper-
ties and is a modest antagonist of the H receptor. ■ CLINICAL PHARMACOLOGY OF
1
As described above, vortioxetine has multimodal effects on a
variety of 5-HT receptors and is an allosteric inhibitor of SERT. ANTIDEPRESSANTS
It has no known direct activity on norepinephrine or dopamine
receptors. Clinical Indications
A. Depression
D. Tetracyclic and Unicyclic Antidepressants The FDA indication for the use of the antidepressants in the treat-
The actions of bupropion remain poorly understood. Bupropion ment of major depression is fairly broad. Most antidepressants are
and its major metabolite hydroxybupropion are modest to mod- approved for both acute and long-term treatment of major depres-
erate inhibitors of norepinephrine and dopamine reuptake in sion. Acute episodes of MDD tend to last about 6–14 months
animal studies. However, these effects seem less than are typically untreated, but at least 20% of episodes last 2 years or longer.
associated with antidepressant benefit. A more significant effect The goal of acute treatment of MDD is remission of all
of bupropion is presynaptic release of catecholamines. In animal symptoms. Since antidepressants may not achieve their maximum
studies, bupropion appears to substantially increase the presynap- benefit for 1–2 months or longer, it is not unusual for a trial of
tic availability of norepinephrine, and dopamine to a lesser extent. therapy to last 8–12 weeks at therapeutic doses. The antidepres-
Bupropion has virtually no direct effects on the serotonin system. sants are successful in achieving remission in about 30–40% of
Mirtazapine has a complex pharmacology. It is an antagonist of patients within a single trial of 8–12 weeks. If an inadequate
the presynaptic α autoreceptor and enhances the release of both response is obtained, therapy is often switched to another agent or
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norepinephrine and 5-HT. In addition, mirtazapine is an antagonist augmented by addition of another drug. For example, bupropion,
of 5-HT and 5-HT receptors. Finally, mirtazapine is a potent H an atypical antipsychotic, or mirtazapine might be added to an
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antagonist, which is associated with the drug’s sedative effects. SSRI or SNRI to augment antidepressant benefit if monotherapy
The actions of amoxapine and maprotiline resemble those of is unsuccessful. Seventy to eighty percent of patients are able to
TCAs such as desipramine. Both are potent NET inhibitors and achieve remission with sequenced augmentation or switching
less potent SERT inhibitors. In addition, both possess anticho- strategies. Once an adequate response is achieved, continuation
linergic properties. Unlike the TCAs or other antidepressants, therapy is recommended for a minimum of 6–12 months to
receptor.
amoxapine is a moderate inhibitor of the postsynaptic D 2 reduce the substantial risk of relapse.
As such, amoxapine possesses some antipsychotic properties. Approximately 85% of patients who have a single episode of
Vilazodone is a potent serotonin reuptake inhibitor and a par- MDD will have at least one recurrence in a lifetime. Many patients
tial agonist of the 5-HT receptor. Partial agonists of the 5-HT have multiple recurrences, and these recurrences may progress to
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receptor such as buspirone are thought to have mild to moderate more serious, chronic, and treatment-resistant episodes. Thus,
antidepressant and anxiolytic properties. it is not unusual for patients to require maintenance treatment
to prevent recurrences. Although maintenance treatment stud-
E. Monoamine Oxidase Inhibitors ies of more than 5 years are uncommon, long-term studies with
MAOIs act by mitigating the actions of monoamine oxidase in the TCAs, SNRIs, and SSRIs suggest a significant protective benefit
neuron and increasing monoamine content. There are two forms when given chronically. Thus, it is commonly recommended that
of monoamine oxidase. MAO-A is present in both dopamine patients be considered for long-term maintenance treatment if