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Am Fam Physician. 2003;67(4):842-845

Despite recent trends, more tricyclic antidepressants are prescribed than selective serotonin reuptake inhibitors (SSRIs) in the United States, and tricyclics continue to be used extensively worldwide for treatment of depression. In Great Britain, prescriptions for tricyclics outnumber those for SSRIs by 56 percent for patients with new-onset depression. Side effects are the major limitation of tricyclic use, and these are dose-related. Current guidelines recommend daily dosages higher than 125 mg daily, but there is little evidence supporting the efficacy of lower doses. Furukawa and colleagues reviewed the evidence supporting the use of low-dose tricyclics in adult depression.

They identified randomized trials of at least four weeks of treatment with a tricyclic medication equivalent to 100 mg per day or less of imipramine. Studies differed in outcome measures, but the most consistent outcome reported was a reduction of 50 percent or more in severity of depressive symptoms. From reviews of electronic databases and references, they identified 141 relevant studies. After screening for eligibility and quality, 35 studies of low-dose tricyclics compared with placebo and six studies comparing low and standard dosages of tricyclics were included in the analysis. The studies collectively included more than 2,500 patients, and 10 were conducted in primary care. Amitriptyline was the most frequently studied drug (16 studies), followed by imipramine (13 studies).

Compared with placebo, patients taking tricyclics in dosages of 75 to 100 mg per day were 65 percent more likely to achieve response at four weeks. This rate rose to 114 percent for studies of treatment lasting three to 12 months. Although 63 percent of patients taking low-dose tricyclics reported at least one side effect, the number of dropouts did not differ between placebo and active treatment.

The response after up to eight weeks of treatment with low-dose tricyclics was equivalent to that of standard dosages (relative risks, 0.89 at four weeks and 1.11 at six to eight weeks). Patients taking low-dose therapy were 55 percent less likely to drop out of studies because of side effects, but the overall dropout rate for any reason did not differ between patients treated with low-dose therapy and those receiving standard therapy.

The authors calculate that tricyclic dosages of 75 to 100 mg per day reduce depression compared with placebo, with a number needed to treat of four to six for up to six months of therapy. An estimated one in 24 of such patients would drop out of treatment because of side effects. Low-dose treatment appears to compare favorably with standard therapy in effectiveness, and it is associated with a much lower rate of dropout attributable to side effects.

editor's note: Articles in this issue of BMJ challenged two of the most common criticisms of primary care physicians in the management of depression—that we fail to make the diagnosis and that we under-treat this serious condition. On the subject of recognition of depression, Kessler and colleagues conclude that the prevalence of these conditions is high in primary care, but that physicians recognize six out of seven such patients, compared with the 50 percent figure that usually is quoted in the literature. They also conclude that approximately 14 percent of patients could have benefited from treatment. The study by Furukawa shows that the much-criticized low dosages of tricyclics can be effective and acceptable to patients. As with everything else, the key is matching the therapy to the individual patient. Some patients do well with SSRIs, but others are disappointed in their response or experience unsettling side effects. The situation is the same with tricyclics. We need to take the time to establish which symptoms and potential side effects are most distressing to each patient and negotiate the therapy accordingly. This is especially important because longer treatment periods are becoming more common, and some patients will require long-term maintenance therapy. Having the option of low-dose tricyclic agents brought back into the mainstream will be useful.—A.D.W.

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