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ANTIDEPRESSANT SIDE EFFECTS ARE "SIGNIFICANT" TREATMENT CONSIDERATION, AHCPR CONCLUDES; SSRIs, SECONDARY AMINE TRICYCLICS, BUPROPION, TRAZODONE FIRST-LINE

Executive Summary

Antidepressant drug side effects are a "significant consideration" in choosing a pharmaceutical treatment for many depressed patients, an HHS Agency for Health Care Policy and Research panel has concluded. In a clinical practice guideline released April 14, the panel states: "Assuming that the patient has had no prior treatment, that the depression is of moderate or greater severity and not associated with psychotic symptoms, and that the patient has no other associated general medical disorders, side effects become a significant consideration." The guideline, "Depression in Primary Care: Detection, Diagnosis and Treatment," is intended as a blueprint for primary care physicians in dealing with patients with depression. The guide urges physicians to look at approved labeling for specific information on side effects. The presence of other general medical conditions may "favor some agents over others," the guideline says. "For example, for patients with coronary artery disease, drugs that do not lower blood pressure or are associated with no cardiac conduction changes (e.g., bupropion, fluoxetine) may be preferable." In maintenance therapy for depression, long-term side effects become "key considerations," the guide states, noting that "the newer antidepressants (e.g. bupropion, fluoxetine, paroxetine, sertraline, trazodone) are associated with fewer long-term side effects, such as weight gain, than are the older tricyclic medications." Side effects aside, "intent-to-treat meta-analyses for acute phase treatment indicate that, in general, most antidepressant medications have comparable efficacy," the guideline concludes. Drugs recommended by the guideline as both first- and second- line therapies are the secondary amine tricyclics, bupropion (Burroughs Wellcome's Wellbutrin), SSRIs and trazodone (Mead Johnson's Desyrel and generics). Secondary amines include nortriptyline (Lilly's Aventyl, Sandoz's Pamelor), protriptyline (Merck's Vivactil) and desipramine (Marion Merrell Dow's Norpramin, Rhone-Poulenc Rorer's Pertofrane and generics). The selective serotonin reuptake inhibitors recommended are fluoxetine (Lilly's Prozac), paroxetine (SmithKline Beecham's Paxil) and sertraline (Pfizer's Zoloft). Among the drugs recommended for first- and second-line therapy, efficacy rates in outpatients calculated in the meta- analyses ranged from 66.6% for bupropion to 42.5% for fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) for which Upjohn has an NDA pending under the tradename Luvox. In between were trazodone (59.8%), paroxetine (59.2%), doxepin (54.2%), desipramine (52.1%), sertraline (51.7%), fluoxetine (46.6%), and nortriptyline (44.5%). The response rates were based on the results of 39 studies of the SSRIs (including 27 of fluoxetine), 14 of the secondary amines, nine of trazodone and six of bupropion. In geriatric patients, of the drugs listed as first- and second-line therapies, paroxetine had the highest response rate in outpatients -- 64.6% -- and trazodone had the lowest at 36.7%. Fluvoxamine (57.4%), sertraline (52.2%), nortriptyline (50.2%) and fluoxetine (48.7%) showed somewhat similar response rates in geriatric patients, while no data were available in that population for bupropion or desipramine. Fewer studies were available in older populations: two for nortriptyline, two for trazodone, and one each for the four SSRIs analyzed. No data were available in either population for protriptyline. The guide urges primary care physicians not to rely too heavily on the meta-analyses' conclusions on efficacy. The methodology section of the guideline cautions: "It is important not to attach undue significance to small differences" in efficacy rates among drugs and that "it would be improper to conclude with any certainty" that a drug listed with a higher response rate is superior. The guide additionally cautions physicians that cost should not be the only deciding factor in treatment selection when efficacy rates are similar because there is "strong evidence for biologic and psychological heterogenicity among patients with major depressive disorder." This heterogenicity suggests that "more than one agent must be available to ensure adequate treatment to all patients," the guide notes. Therapies listed as "alternative agents for patients with special presentations or needs" are the tertiary amine tricyclics, monoamine oxidase inhibitors (MAOIs) and some anxiolytic medications, where the "evidence is clearest for alprazolam" (Upjohn's Xanax). Anxiolytics are not recommended for severe depression. The guide notes that alprazolam "is not recommended for routine clinical use because no continuation or maintenance phase trials have been published and because problems associated with discontinuing this compound in remitted, depressed patients have not been fully studied." However, "the presence of certain concurrent general medical conditions for which standard antidepressants are contraindicated may necessitate consideration of [alprazolam] in selected patients because of its cardiovascular safety, quick onset of action and generally low side-effect profile." The guide also lists drugs that may be preferred in certain patient groups. Secondary amines are "especially preferred" to their parent tertiary amines in the elderly "in whom the anticholinergic side effects of the tertiary amines may reduce adherence or be particularly severe," the guide states. Patients with atypical symptoms of depression, such as oversleeping or weight gain, "appear to fare better" on MAOIs or SSRIs, the document adds. In patients deemed likely to take an overdose of medication, the guide recommends "certain heterocyclic agents (bupropion or trazodone) or SSRIs, which appear safer in cases of potential overdose." If a patient is "older, has other medical conditions or is taking medications that affect the metabolism of antidepressants," or has "complex general medical conditions... an antidepressant with better established therapeutic and toxic levels, such as nortriptyline, may be preferred over another for which such levels are less well studied." There is "overwhelming" evidence that antidepressant drugs are effective in moderate to severe depression, AHCPR depression guide panel Chair John Rush, MD, University of Texas Southwestern Medical Center, stated at an April 14 press conference. "From 50%- 60% of patients respond to the first medicine prescribed," Rush estimated, adding that "medicines also appear effective in some mild depressions." The guideline states that "patients with moderate to severe major depressive disorder are appropriately treated with medication, whether or not formal psychotherapy is also used." The panel rates the strength of evidence for this conclusion "A," indicating "good research-based evidence with some panel opinion." "Patients with mild to moderate major depression who prefer psychotherapy alone as the initial acute treatment choice may be treated with this option"; however, psychotherapy should not be used alone in severe depression, the guideline recommends. Evidence for these conclusions is rated a "B" -- "fair research- based evidence, with substantial panel opinion." Patient and provider may also choose both psychotherapy and medication, although "combined treatment may provide no unique advantage for patients with uncomplicated, non-chronic major depressive disorder," the guideline adds. In reviewing treatment information, the AHCPR panel found that medication, alone or in combination with other therapy, in most cases produces a "marked improvement" within six weeks, the agency said. Psychotherapy "usually produces some improvement by six weeks, but may require up to 12 weeks for a full effect." Depressive disorders affect one in eight people at some time in their life, and about 11 mil. people every year, Rush said. In explaining the need for the guide, HHS said that more than half of depressed patients are treated by primary care practitioners. "However, the illness can be difficult to recognize and accurately diagnose. Primary care providers often fail to recognize underlying depression and instead treat the disorder's physical manifestations, such as chronic headache and stomach problems." The guide is intended as a companion to a clinical practice guideline for psychiatrists issued by the American Psychiatric Association March 29. The APA guide "focuses on the treatment of more complicated cases of major depression," APA practice guidelines steering committee Vice-Chair Sara Charles, MD, noted at the press conference. Information behind the guidelines "demonstrates that the effectiveness of treatments for depression is on par with treatments available for other medical illnesses," she added. In another effort directed at depression, the National Mental Health Association began a public education campaign April 2 designed to increase awareness "that depression is a treatable illness," NMHA said. The association is starting its campaign off with a media blitz, including TV ads on the three major networks and print ads in newspapers in 31 cities running for the first three weeks in April. The ads are being paid for by a grant from Lilly. The public service effort includes a nine-month outreach campaign funded by a $500,000 grant from Lilly. The American Psychological Association does not support NMHA's effort or the AHCPR guideline, commenting in an April 14 press release that the guide does not "encourage sufficient collaboration with mental health specialists and appears to be biased toward medication" because, the group argues, primary care physicians may "lean toward" prescribing drugs. The association also refused to endorse NMHA's ads, again because APA felt consumers might seek help with "no input from a mental health specialist." AHCPR is planning to create a guideline on anxiety and panic disorders in the primary care setting and expects to release the document in 1994. The agency has released four clinical practice guidelines in addition to the depression guide since its establishment in late 1989. The published guidelines cover: acute pain management after surgery or trauma ("The Pink Sheet" March 9, 1992, p. 3); adult urinary incontinence ("The Pink Sheet" March 30, 1992, p. 11); prevention of pressure ulcers in adults; and management of functional impairment in adults due to cataracts.
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