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Antidepressants modulate the activity of serotonin and norepinephine to achieve their effect. The class of selective serotonin reuptake inhibitors (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline (Fig. 72–1). Atypical antidepressants expand the pharmacologic principles of SSRIs to achieve additional beneficial effects for patients with depression.

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Figure 72–1.
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Structures of common selective serotonin reuptake inhibitors. Citalopram is shown as the S-enantiomer (escitalopram).

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In a brief period of time these new xenobiotics have become the standard, with excellent profiles as compared to the monoamine oxidase inhibitors and the cyclic antidepressants. Like many new xenobiotics the appropriateness of their use and the associated morbidity and mortality have come into question as the patient population has aged and comorbidity profiles of those using the SSRIs have changed.

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SSRIs initially were marketed in the United States in the early 1980s and still are considered a first-line therapy for treatment of depressive disorders in the United States and in Europe.18,164,209 SSRIs are as effective as the cyclic antidepressants and monoamine oxidase inhibitors for treatment of major depression and have fewer significant side effects associated with therapeutic use and overdose (Chaps. 71 and 73).67,135 SSRIs also are used to treat obsessive-compulsive disorders, panic disorders, alcoholism, obesity, and various medical and psychologic disorders such as migraine headache and chronic pain syndromes.10,147,154

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An increased risk of suicidal behavior is reported with the use of many antidepressants compared with nondrug therapy or no therapy.6,126 This is particularly true in children. The reason for this finding may be related to delayed onset of drug efficacy coupled with the increased energy associated with the initiation of drug therapy.

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Table 72–1 lists the pharmacology, therapeutic doses, and metabolism of the currently available SSRIs and the atypical antidepressants. Modulation of serotonin and norepinephrine neurotransmission has a significant role in the treatment of depression.173 The selectivity of SSRIs for serotonin reuptake is structurally related to p-trifluoromethyl or p-fluoro substitution, which is present in many of these drugs.218 Serotonin neurons are located almost exclusively in the median raphe nucleus of the brainstem, where they extend into and are in close proximity to norepinephrine neurons that are located primarily in the locus coeruleus (Fig. 72–2).9 The interplay between norepinephrine and serotonin likely explains the effectiveness of other atypical antidepressants that do not directly modulate serotonin neurotransmission.

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Table 72–1. Pharmacology of Currently Available SSRIs and Atypical Antidepressants

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