75: Serotonin Reuptake Inhibitors and Atypical Antidepressants

INTRODUCTION

In the United States, major depressive disorder is a leading cause of disability and affects 14.8 million American adults; it is also the largest cause of disability for adolescents and those 15 to 44 years of age.^1,93 Although major depressive disorder can develop at any age, the median age at onset is 32 years and it is more prevalent in women.^94,95 The exact etiology of depression and the mechanism by which increased serotonergic and norepinephrine neurotransmission modulates mood remains unclear. Antidepressants modulate the activity of serotonin and norepinephrine and dopamine to achieve their effect. The class of selective serotonin reuptake inhibitors (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone (Fig. 75–1). Atypical antidepressants extend the pharmacologic principles of SSRIs to achieve beneficial effects for patients with depression. The SSRIs and atypical antidepressants comprise the current standard for the treatment of depression.⁸⁰ SSRIs also are used to treat obsessive–compulsive disorders, panic disorders, alcoholism, obesity, and various nonpsychiatric disorders such as migraine headaches and chronic pain syndromes.^11,125,131 They have excellent safety profiles when compared with monoamine oxidase inhibitors (MAOIs) and the cyclic antidepressants. Like many xenobiotics, the appropriateness of their use and the associated morbidity and mortality is questioned as the patient population has aged and the comorbidity profiles of those using the SSRIs have changed.

HISTORY AND EPIDEMIOLOGY

Serotonin (5-hydroxytryptamine) got its name after its initial discovery as a vasoconstrictor. Synonyms for 5-hydroxytryptamine include thrombotin, enteramin, substance DS, and 3-(β-aminoethyl)-5-hydroxyindole. 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 Europe.⁶³ SSRIs are as effective as the cyclic antidepressants and MAOIs for the treatment of major depression and have fewer significant adverse events associated with their therapeutic use and are less problematic in overdose (Chaps. 71 and 73). An increased risk of suicidal behavior is reported with the use of many antidepressants compared with herbals or counseling alone.¹⁰⁸ This is particularly true in children and adolescents, and may be related to delayed onset of therapeutic efficacy coupled with increased energy associated with the initiation of therapy.

PHARMACOLOGY

Table 75–1 lists the pharmacology, therapeutic doses, and metabolism of available SSRIs and atypical antidepressants. Modulation of serotonin and norepinephrine neurotransmission has a significant role in the treatment of depression.¹⁴⁶ There are seven widely known classes of serotonin receptors, with many exhibiting subtype classifications (Chap. 14). SSRIs selectively inhibit serotonin reuptake via the serotonin transporter due to the p-trifluoromethyl or p-fluoro substitution, present ...