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Gartlehner G, Hansen RA, Reichenpfader U, et al. Drug Class Review: Second-Generation Antidepressants: Final Update 5 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Mar.

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Drug Class Review: Second-Generation Antidepressants: Final Update 5 Report [Internet].

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A. Overview

Axis I psychiatric disorders such as depressive disorder, anxiety disorder, adjustment disorder, and premenstrual disorders are serious disabling illnesses. Combined, they affect approximately one in five Americans.2 Major depressive disorder (MDD) is the most prevalent, affecting more than 16 percent (lifetime) of US adults.3 In 2000, the economic burden of depressive disorders was estimated to be $83.1 billion.4 More than 30 percent of these costs were attributable to direct medical expenses.

Pharmacotherapy dominates the medical management of Axis I psychiatric disease. Before the late 1980s, pharmacologic treatment was limited to tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) (with the exception of premenstrual disorder, which historically was untreated). TCAs and MAOIs sometimes are referred to as traditional or first -generation antidepressants. These drugs are often accompanied by multiple side effects that many patients find intolerable; e.g., TCAs tend to cause anticholinergic effects including dry mouth and eyes, urinary hesitancy, and sometimes retention and constipation and MAOIs have the potential to produce hypertensive crisis if taken along with certain foods or dietary supplements containing excessive amounts of tyramine. Thus, first-generation antidepressants are no longer agents of choice in many circumstances.

Newer treatments include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other second-generation drugs. The first of the second-generation drugs was introduced to the US market in 1985, when bupropion was approved for the treatment of major depressive disorders. In 1987, the US Food and Drug Administration (FDA) approved the first SSRI, fluoxetine. Since then, five other SSRIs have been introduced: sertraline (1991), paroxetine (1992), citalopram (1999), fluvoxamine (2000), and escitalopram (2002). The SNRIs were first introduced to the market in 1993 with the approval of venlafaxine. In 1994, nefazodone, which is essentially an SSRI with additional 5-hydroxytryptamine-2 (5-HT2) and 5-hydroxytryptamine-3 (5-HT3) antagonist properties, was FDA-approved. Mirtazapine, a drug that acts centrally on adrenergic autoreceptors, was added to the therapeutic arsenal in 1996.5 Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), was approved for the treatment of MDD and diabetic peripheral neuropathic pain in 2004. The latest second-generation antidepressant approved for the treatment of MDD in adults was desvenlafaxine, an SNRI, which was FDA-approved in 2008. Desvenlafaxine is the major active metabolite of venlafaxine XR, which will lose patent protection in 2010.

The mechanism of action of most second-generation antidepressants is only poorly understood. In general, these drugs work through their effect on prominent neurotransmitters in the central nervous system. The SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) act by selectively inhibiting the reuptake of serotonin (5-hydroxy-tryptamine, 5-HT) at the presynaptic neuronal membrane. The SNRIs (desvenlafaine, venlafaxine) are potent inhibitors of serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Mirtazapine, sometimes characterized as an SNRI, is believed to enhance central noradrenergic and serotonergic activity as a 5-HT2 and 5-HT3 receptor antagonist. Nefazodone is believed to inhibit neuronal uptake of serotonin and norepineprhine. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine. Preclinical studies of duloxetine suggest that it is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.

With the exception of fluvoxamine, which is approved only for the treatment of obsessive-compulsive disorder (OCD), all of the other second-generation antidepressants are approved for the treatment of MDD. Table 1 summarizes the newer products that are available in the US by mechanism of action.

Table 1. Second-generation antidepressants approved for use in the United States.

Table 1

Second-generation antidepressants approved for use in the United States.

Since their introduction, the second-generation antidepressants have established a prominent role in the US pharmaceutical market. To illustrate their importance, the top 10 drug therapy classes accounted for 35.1 percent of US prescription sales in 2003. The antidepressant class, including SSRIs and SNRIs, ranked third among this group, accounting for $10.9 billion in US prescription sales.6 The serotonergic class dominates this market, accounting for 57.6 percent of market share in 2002.6 Prescription drug spending for these products is not anticipated to decline until 2009, when the leading brands will suffer patent expirations.

Compared to the first-generation antidepressants, the SSRIs and other second-generation antidepressant have comparable efficacy and comparable or better side effect profiles.7, 8 However, comparative differences in efficacy, tolerability, and safety are not well defined for the second-generation drugs. The tremendous volume and large variability in the quality of evidence to support use of these products makes it difficult for clinicians and decision makers to make evidence-based decisions.

The purpose of this review is to help policymakers and clinicians make informed choices about the use of SSRIs and newer antidepressants. Given the prominent role of drug therapy in psychiatric disease and the prevalent use of these drugs, our goal is to summarize comparative data on the efficacy, tolerability, and safety of newer antidepressants. This review will focus on newer antidepressant agents: citalopram, escitalopram, desvenlafaxine, fluoxetine, fluvoxamine, paroxetine, sertraline, mirtazapine, duloxetine, venlafaxine, bupropion, and nefazodone. We will examine the role of these agents in treating patients with conditions in diagnostic categories classified by the Diagnostic and Statistical Manual of Mental Disorders (DSM); these include depressive disorders (MDD, dysthymic disorder, subsyndromal depression, and seasonal affective disorder), generalized anxiety disorder (GAD), OCD, panic disorder, post-traumatic stress disorder (PTSD), and social anxiety disorder. We focus this review on these disorders in adult outpatient populations.

Also, we examine the role of these agents in treating premenstrual dysphoric disorder (PMDD, known as late luteal phase dysphoric disorder [LLPDD] in the DSM, version III revised [III-R]) among adult outpatient populations. Technically, PMDD is not considered a discrete diagnostic entity by DSM version IV; instead, it is listed as an example of a Depressive Disorder Not Otherwise Specified. It does, however, have specific research criteria defined in DSM -IV; these are identical to LLPDD in DSM III-R except for the addition of one item. Of note, as of 1999, the FDA Neuropharmacology Advisory Committee supported the concept of PMDD as a distinct clinical entity.

Finally, we examine the role of these agents in treating MDD in pediatric outpatient populations. Tables 1 and 2 show included drugs, dosage forms and recommended doses, and FDA-approved (labeled) uses.

Table 2. Usual dosing range and frequency of administration (adults).

Table 2

Usual dosing range and frequency of administration (adults).

B. Scope and Key Questions

The purpose of this review is to compare the efficacy, effectiveness, and tolerability (adverse events) of second-generation antidepressant medications. The participating organizations of the Drug Effectiveness Review Project (DERP) are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to their constituencies. Initially, the Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed, revised, and approved by representatives of organizations participating in the DERP in conjunction with experts in the fields of health policy, psychiatry, pharmacotherapy, and research methods. The participating organizations approved the following key questions:

  1. For outpatients with depressive, anxiety, and/or premenstrual dysphoric disorders, do second-generation antidepressants differ in efficacy or effectiveness?
  2. For outpatients with depressive, anxiety, and/or premenstrual dysphoric disorders, do second-generation antidepressants differ in safety or adverse events?
  3. Are there subgroups of patients based on demographics (age, racial groups, and sex), other medications, or comorbidities for which one second-generation antidepressant is more effective or associated with fewer adverse events than another?

This report addresses the initial use of antidepressants. The use of these agents for patients who are not responding to initial treatment are not addressed in this report. Throughout this report, we highlight effectiveness studies conducted in primary care or office-based settings that use less stringent eligibility criteria, assess health outcomes, and have longer follow-up periods than most efficacy studies.9 The results of effectiveness studies are more applicable to the average patient than results from highly selected populations in efficacy studies.

For each of the three key questions, we evaluated specific outcome measures (where appropriate), as reported in Table 3. For efficacy and effectiveness, we focused on head-to-head trials comparing one second-generation antidepressant to another. When sufficient head-to-head evidence was not available, we evaluated placebo-controlled evidence of efficacy for medications not already approved by the FDA for the stated disorder. Observational studies were included to assess safety and tolerability. Studies were organized by disease state; we generalize efficacy, safety, and tolerability only to the disease state for which it was studied.

Table 3. Outcome measures and study eligibility criteria.

Table 3

Outcome measures and study eligibility criteria.

Copyright © 2011 Oregon Health & Science University.
Bookshelf ID: NBK54346
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