The American College of Physicians (ACP) released a clinical guideline in November 2008 that gave recommendations for using second-generation antidepressants in the treatment of depressive disorders and accompanying symptoms in adults. The guideline presented available evidence derived from 203 studies and described a literature search that included keywords for depression treatment with 12 second-generation antidepressants: bupropion (Wellbutrin), citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine, mirtazapine (Remeron), nefazodone, paroxetine (Paxil), sertraline (Zoloft), trazodone (formerly Desyrel), and venlafaxine (Effexor).

The ACP classified the guideline's quality of evidence as high, moderate, low, or insufficient to determine benefits or risks. Strength of recommendation was classified as strong or weak, with a strong recommendation indicating that benefits clearly outweigh risks and burden (or risks and burden clearly outweigh benefits), and a weak recommendation indicating that benefits are finely balanced with risks and burden.

Types of Depression

Depressive disorders addressed in the guideline include major depressive disorder (MDD), dysthymia, minor depression, and melancholia. MDD was defined as having a duration of at least two weeks of depressed mood or anhedonia, plus at least five of the following symptoms: persistent depressed mood throughout most days; persistent, substantial loss of interest or pleasure in most activities; significant changes in weight or appetite; sleep disturbances (insomnia or hypersomnia); psychomotor agitation or retardation; inappropriate guilt; indecisiveness, or difficulty thinking or concentrating; recurring thoughts of death, including suicidal thoughts.

Dysthymia is a chronic form of depression characterized by depressed mood on most days for at least two years. Minor depression is a mood disturbance that continues for at least two weeks, but with fewer symptoms of depression than MDD. Melancholia, a depressive subtype, is a severe form of MDD with the essential feature of loss of interest or pleasure in all, or almost all, activities, or a lack of response to usually pleasurable stimuli. Physical symptoms include early morning awakening, marked psychomotor retardation or agitation, and significant anorexia or weight loss.

Treatment

The course of depression treatment occurs in three phases: acute, continuation, and maintenance. A relapse is considered part of the same depressive episode and occurs when there is a loss of response to treatment during the acute or continuation phases, whereas recurrence is a loss of response to treatment during the maintenance phase and is considered a new, distinct episode of depression.

Treatment of depression can incorporate various approaches, including pharmacotherapy, psychotherapy, and cognitive behavior therapy, but the ACP guideline focuses on pharmacologic treatment. Specifically, the guideline addresses treatment with second-generation antidepressants (i.e., selective serotonin reuptake inhibitors [SSRIs], serotoninnorepinephrine reuptake inhibitors, and selective serotoninnorepinephrine reuptake inhibitors), which have similar effectiveness and lower toxicity in overdose than first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors). Table 1 outlines the key questions about antidepressant treatment addressed in the guideline.

Overall, the second-generation antidepressants did not significantly differ in effectiveness or quality of life in the treatment of acute-phase MDD. More than one third of these patients did not achieve a treatment response during six to 12 weeks of treatment, and more than one half did not achieve remission. The medications did not differ from each other in the rate of achieving remission, but mirtazapine had a significantly faster onset of action.

For the treatment of dysthymia, there was mixed evidence on the effectiveness of fluoxetine, paroxetine, and sertraline. The second-generation antidepressants were equally effective for the treatment of accompanying anxiety, insomnia, and pain in patients with depression that had accompanying symptom clusters. However, venlafaxine may be superior to fluoxetine for treating anxiety, and limited evidence suggests that sertraline was more effective in the management of melancholia and psychomotor agitation. The antidepressants also were equally effective in the treatment of accompanying anxiety, pain, and somatization in patients who had symptom clusters with accompanying depression. However, limited evidence suggests that some of the antidepressants (escitalopram, nefazodone, trazodone) may be more effective for the treatment of insomnia. There was no difference in effectiveness for overall treatment among subgroups and special populations categorized according to age, sex, race or ethnicity, or comorbid conditions.

Most of the second-generation antidepressants had similar adverse effects, in which the most common were constipation, diarrhea, dizziness, headache, insomnia, nausea, sexual adverse events (with an increased risk of sexual dysfunction associated with paroxetine), and somnolence. The most common reasons for treatment discontinuation were nausea and vomiting. Patients taking SSRIs showed an increased risk of nonfatal suicide attempts.

ACP Recommendations

Recommendation 1: The ACP recommends that when physicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences (Grade: strong recommendation; moderate-quality evidence).

There is insufficient evidence to recommend one second-generation antidepressant over another with regard to effectiveness, which does not differ among subgroups based on age, sex, or race or ethnicity. However, with regard to adverse effects, bupropion had a lower rate of sexual adverse events compared with fluoxetine or sertraline, whereas paroxetine had increased rates of sexual dysfunction compared with f luoxetine, f luvoxamine, nefazodone, or sertraline. As a class, SSRIs were associated with an increased risk of suicide attempts compared with placebo. Before selecting a medication, physicians and patients should discuss treatment options, taking into consideration the possible adverse effects associated with certain antidepressants.

Recommendation 2: The ACP recommends that physicians assess patient status, therapeutic response, and adverse effects of antidepressant treatment on a regular basis, beginning within one to two weeks of treatment initiation (Grade: strong recommendation; moderate-quality evidence).

The risk of suicide attempts is greater during the first one to two months of treatment with antidepressants. For all patients taking antidepressants, the U.S. Food and Drug Administration advises careful, consistent monitoring for increases in suicidal thoughts and behaviors, and to begin monitoring one to two weeks after treatment initiation. Patients should be monitored for new or increased agitation, irritability, or unusual changes in behavior, which may indicate that the depression is getting worse.

Recommendation 3: The ACP recommends that physicians modify treatment if the patient does not have an adequate response to pharmacotherapy within six to eight weeks of the initiation of treatment for MDD (Grade: strong recommendation; moderate-quality evidence).

The response rate to pharmacologic treatment for MDD may be as low as 50 percent, and evidence is insufficient to indicate which patient factors will reliably predict response to an individual medication. For patients who do not respond to first- or second-line treatments, multiple pharmacologic treatments may be required and the addition of other therapeutic modalities may be indicated. There is insufficient evidence to recommend one medication over another as second-line treatment.

Recommendation 4: The ACP recommends that physicians continue treatment for four to nine months after a satisfactory response in patients with a first episode of MDD. For patients who have had two or more episodes of depression, an even longer duration of treatment may be beneficial (Grade: strong recommendation; moderate-quality evidence).

Treatment duration of MDD depends on the patient's risk of relapse or recurrence. There is no evidence of differences among second-generation antidepressants in preventing relapse or recurrence. To prevent relapse, patients who achieve remission with acute-phase treatment should continue antidepressant treatment for four to nine months. Patients who have had two or more depressive episodes may benefit from a longer duration of treatment (years to lifelong).