Chapter 69: Serotonin Reuptake Inhibitors and Atypical Antidepressants

INTRODUCTION

In the United States, major depressive disorder is a leading cause of disability and affects 15.7 million American adults; representing 6.7% of all US adults in 2015.⁹⁷ Although major depressive disorder can develop at any age, a higher percentage of 15- to 25-year-old adults are found to have depression, and women are affected nearly twice as often as men. The exact etiology of depression and the mechanism by which increased serotonergic and norepinephrine neurotransmission modulates mood remain unclear. A complex interaction of genetics and altered serotonin neurotransmission along with alterations in brain-derived neurotrophic factor, neurotrophin-3, dopamine, norepinephrine, and excitatory neuronal pathways likely have a role in depressive disorders.¹¹⁹ Although termed selective serotonin reuptake inhibitors (SSRIs), these antidepressants have complex pharmacologic effects and interact with a number of other receptors and neurotransmitters. The class of SSRIs includes citalopram, escitalopram (citalopram’s active enantiomer), fluoxetine, fluvoxamine, paroxetine, and sertraline (Fig. 69–1). 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.⁷⁰ The SSRIs also are used to treat anxiety disorders, insomnia, chronic pain, panic disorders, social phobia, fibromyalgia, migraine, obsessive–compulsive disorders, bipolar disorders, premenstrual syndrome, menopausal symptoms, nicotine dependence, attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder, sexual dysfunction, digestive system disorders, urinary system disorders, and bulimia nervosa.^{10,110,116,125} They have excellent safety profiles compared with previous antidepressants such as monoamine oxidase inhibitors (MAOIs) and the cyclic antidepressants (Cas) (Chaps. 68 and 71). Similar to many xenobiotics, the appropriateness of their use, their effectiveness, and the associated morbidity and mortality have made their use increasingly controversial as the patient population, especially those at the extremes of age, and the comorbidity profiles of those using the SSRIs are expanding.

HISTORY AND EPIDEMIOLOGY

Serotonin (5-hydroxytryptamine) got its name after its initial discovery as a vasoconstrictor. The SSRIs were initially marketed in the United States in the early 1980s and are today considered one of the first-line therapies for treatment of major depressive disorders.⁵⁴ The SSRIs are as effective as the CAs and MAOIs for the treatment of major depression, have fewer significant adverse events associated with their therapeutic use, and are less problematic in overdose (Chaps. 68 and 71) An increased risk of suicidal behavior is reported with the use of many antidepressants compared with herbals or counseling alone in children and adults.^65,92 This may be related to delayed onset of therapeutic efficacy coupled with increased energy associated with the initiation of therapy.

PATHOPHYSIOLOGY

Table 69–1 lists the pharmacology, therapeutic doses, ...