News Author: Pauline Anderson
CME Author: Charles Vega, MD, FAAFP

November 24, 2008 — Clinicians should consider adverse effects, cost, and a patient's personal preferences when prescribing second-generation antidepressants, since research shows all of these agents have equivalent efficacy, according to a new guideline issued by the American College of Physicians (ACP).

This was 1 of 4 recommendations included in the new guideline published in the November 18 issue of the Annals of Internal Medicine.

The other recommendations highlight the importance of regularly assessing patients for response and adverse effects, changing drugs when necessary, and continuing therapy for an adequate period.

"With 16% of the American population diagnosed with depression at some point in their lives, and with the economic burden of depression approaching $85 billion, it's important to provide primary-care physicians with evidence-based information on what steps to take to treat patients with this disorder," the guideline's lead author, Amir Qaseem, MD, PhD, senior medical associate in ACP's clinical programs and quality-of-care department, told Medscape Psychiatry.

In developing the guideline, investigators conducted a systematic review of published research. Using various medical databases, they searched for studies that included at least 1 of 12 antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine) that were restricted for use in adults 19 years of age or older. Their review included 203 head-to-head or placebo-controlled trials.

Same Efficacy, Effectiveness and Qualify of Life

Among various categories of antidepressant drugs, including selective serotonin-reuptake inhibitors (SSRIs), serotonin-norepinephrine-reuptake inhibitors (SNRIs), or selective serotonin-norepinephrine-reuptake inhibitors (SSNRIs), the researchers found no difference in efficacy, effectiveness, or quality of life in patients with major depressive disorder (MDD).

The review also did not reveal any difference in efficacy among these drugs in patients with accompanying symptoms or subgroups based on age, sex, race or ethnicity, or other comorbid conditions.

However, the researchers did find several differences among these drugs with respect to response rate and the incidence of certain adverse events. For example, some studies found that mirtazapine had a faster onset of action than citalopram, fluoxetine, paroxetine, or sertraline and that bupropion has fewer sexual adverse events than fluoxetine, paroxetine, or sertraline.

SSRIs in general were associated with an increased risk for suicide attempts compared with placebo. "The side effects of these medications vary from mild ones like constipation and diarrhea to some major ones like suicidality and sexual dysfunction," said Dr. Qaseem. Since each of these drugs has benefits and drawbacks, clinicians should be sure to discuss these issues with patients, he added.

Patient Preferences Also Important

Patients themselves may have drug preferences, and clinicians need to explore these. For example, they may have had a previous negative experience with a particular antidepressant and want to avoid further use of the drug. Discussions with patients should also include cost, as insurance companies may have varying coverage, said Dr. Qaseem.

The review also showed that 38% of patients did not achieve a treatment response during 6 to 12 weeks of therapy and more than 50% did not achieve remission.

The guideline also recommends that clinicians assess patient status, therapeutic response, and adverse effects on a regular basis starting 1 to 2 weeks after initiating therapy. "The major reason for this is that the risk of suicide attempts is greater during the first 1 to 2 months of treatment," said Dr. Qaseem.

In addition, the guideline recommends treatment modification if the patient does not adequately respond within 6 to 8 weeks after starting therapy. "The response might not be sufficient, and you might need to add an additional drug, or multiple drugs may be required," he said.

Keep Relapse in Mind

Finally, the guideline suggests patients with a first episode of MDD continue treatment for 4 to 9 months after a satisfactory response and possibly longer in patients with a history of relapse.

"In depression, relapse and recurrence are important to keep in mind. Patients with 2 or more episodes may need to take [antidepressant] mediation for years or even for life," said Dr. Qaseem.

Prescribing maximum but tolerable doses for at least 8 weeks seems at least as important as the choice of specific drug, according to the authors of an accompanying background article created for the ACP.  

"Given the difficulty in predicting what medication will be both efficacious for and tolerated by an individual patient, familiarity with a broad spectrum of antidepressants is prudent," they write.

With first author Gerald Gartlehner, MD, from Danube University, in Krems, Austria, the investigators assert more research is needed on the most appropriate duration of drug treatment and the effects of different doses on maintaining response and remission.

Future studies should evaluate whether different formulations affect adherence and relapse or recurrence.

Encouraging News

Psychiatrists have long known that second-generation antidepressants are about the same when it comes to efficacy, so it is encouraging to see that this information is being extended to the field of primary care, said Alan Gelenberg, MD, from the University of Wisconsin, in Madison, who is developing a new guideline on major depression for the American Psychiatric Association.

"What's newsworthy to me as a psychiatrist is that this organization of internal-medicine doctors has seen depression as important," he said. "Depression should be recognized. It's treatable, but no treatment works if the patient doesn't take it. Therefore, you should discuss the treatment with the patient, see them at regular intervals and monitor the patient for side effects."

The guideline was supported by the ACP's operating budget and by a contract with the Agency for Healthcare Research and Quality to the RTI International–University of North Carolina Evidence-based Practice Center. A complete list of disclosures for the authors appears in the original articles.

Ann Intern Med. 2008;149:725-733, 734-750.

Clinical Context

The lifetime prevalence of depression among adults in the United States is approximately 16%. Many of these patients receive antidepressant medications, and second-generation antidepressants, including SSRIs, SNRIs, and SSNRIs, have largely supplanted older medications such as tricyclic antidepressants because of improved safety and tolerability. However, clinicians may struggle with the choice of antidepressant for a particular patient.

The current clinical practice guideline from the ACP provides recommendations regarding how to use antidepressant medications most effectively. They focus on questions regarding efficacy in treating depression and associated symptoms as well as tolerability.

Study Highlights

• Reviewers gathered evidence from research published between 1980 and April 2007. Specifically, they examined the following 12 second-generation antidepressants: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine.
• 80 trials focused on antidepressant efficacy in the acute phase of MDD. There were no major differences between different SSRIs or in comparing SSRIs vs SNRIs. Any statistical differences noted between treatments were thought to be clinically insignificant.
• 18 trials examined quality-of-life data, and several medications were demonstrated to improve health-related quality of life. However, there was no significant difference between antidepressants in this outcome.
• Mirtazapine has been demonstrated to have a faster onset of action vs citalopram, fluoxetine, paroxetine, and sertraline. However, after 4 weeks, the overall response to medications is similar.
• 38% of patients did not achieve a treatment response during 6 to 12 weeks of treatment with an antidepressant, and 54% did not achieve remission. However, switching medications for nonresponders has been found to be effective in 25% of patients.
• There was limited evidence that the presence of anxiety, insomnia, melancholia, or pain significantly altered the generally similar effectiveness of medications for depressive symptoms.
• There was no significant difference between medications regarding the effectiveness of treating anxiety or pain associated with depression. Nefazodone and trazodone might be more effective to treat insomnia in depression.
• No studies focused directly on subgroups of the general population, but several contained subgroup analyses. They demonstrated limited difference in efficacy based on age or sex.
• Some antidepressants were associated with a higher rate of particular adverse events:
  • Venlafaxine: nausea and vomiting
  • Sertraline: diarrhea
  • Mirtazapine, paroxetine: weight gain
  • Trazodone: somnolence
• Bupropion and paroxetine promote a lower risk for sexual dysfunction vs other antidepressants.
• SSRIs as a class have been associated with a higher risk for suicide attempts.
• The authors' final recommendations are as follows:
  • Clinicians should select second-generation antidepressant medications based on adverse event profiles, cost, and patient preference. Efficacy is not a primary consideration in this choice, given that these medications have similar efficacy data.
  • Clinicians should assess patient status within 1 to 2 weeks after initiation of therapy, particularly for signs of worsening depression or suicidal ideation.
  • If patients do not have an adequate response to treatment in 6 to 8 weeks, the clinician should modify depression therapy.
  • For a first episode of MDD, patients should continue treatment for 4 to 9 months after a satisfactory response. After 2 or more episodes of depression, patients should continue therapy for years or even lifelong.

Pearls for Practice

• Among second-generation antidepressants, venlafaxine is associated with nausea and vomiting; sertraline, with diarrhea; mirtazapine and paroxetine, with weight gain; and trazodone, with somnolence. Bupropion and paroxetine promote less sexual dysfunction vs other antidepressants.
• Clinicians should select second-generation antidepressant medications based on adverse event profiles, cost, and patient preference. Efficacy is not a primary consideration in this choice, given that these medications have similar efficacy data.

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