Who Relapses On Fluoxetine?
Who Relapses On Fluoxetine?
Abstract & Commentary
Source: McGrath PJ, et al. Predictors of relapse during fluoxetine continuation or maintenance treatment of major depression. J Clin Psychiatry 2000;61(7):518-524.
The current study by mcgrath and associates reports analyses using data from a multicenter, double-blind, randomized clinical trial comparing fluoxetine continuation/maintenance treatment for periods of up to 50 weeks with placebo substitution. Male and female outpatients 18-65 years of age were eligible for the study if they met DSM-III-R criteria for major depression of at least one month’s duration and scored a minimum of 16 on a modified Hamilton Rating Scale for Depression (HAM-D-17). Patients with unstable medical illness, pregnancy or lactation, serious suicidal impulses, history of psychosis or organic mental disorder, history of mania or antisocial personality disorder, substance abuse disorders active within the last year, or biochemical hypothyroidism were excluded. Patients were also excluded if they had received prior treatment with fluoxetine. Fluox- etine was initially administered at a fixed dose of 20 mg per day for 12-14 days. Remission was defined as three consecutive weeks with a HAM-D-17 score no greater than 7, and failure to meet criteria for major depression. Of remitted patients, 395 were then randomized to four treatment groups: 1) fluoxetine for 14 weeks followed by placebo for 36 weeks; 2) fluoxetine for 38 weeks fol- lowed by placebo for 12 weeks; 3) fluoxetine for 50 weeks; and 4) placebo for 50 weeks. Medication was discontinued without tapering due to the long half-life of fluoxetine’s active metabolite. A patient who scored 14 or greater on HAM-D-17 for three consecutive weeks or met criteria for major depression for two weeks at anytime was considered relapsed and was removed from the study. Patients randomized to discontinue fluoxetine after weeks 14, 38, and 50 were included in the statistical analysis and censored after the point of switch to placebo. Cox proportional hazard models were used to identify predictors of time to relapse.
Fluoxetine continuation/maintenance was superior to placebo. Median times of survival were 284 days for the fluoxetine group (n = 299) and 84 days for the placebo group (n = 96). McGrath et al identified three significant predictors of relapse: longitudinal pattern of response to treatment, neurovegetative symptom pattern, and age at onset/chronicity of depression. Patients whose pattern of response was persistent and with an onset after the second week of treatment were shown to benefit significantly from continuation/maintenance treatment with fluoxetine compared to placebo, thus supporting McGrath et al’s hypothesis that this specific longitudinal pattern is indicative of true pharmacologic response to medication. In other words, placebo responses tend to occur quickly after the initiation of treatment and are short lived, and a pattern consistent with placebo response was shown to be predictive of increased risk of relapse of depression dur- ing fluoxetine continuation/maintenance treatment. Patients with the typical neurovegetative symptoms of depression (e.g., insomnia, decreased appetite, depres- sion worse in the morning), and the above-mentioned pattern of true pharmacologic response showed the most significant drug-placebo differences of any subgroup and the greatest benefit from fluoxetine continuation/mainte- nance. Survival was generally poorer for patients with the reversed neurovegetative symptoms of atypical depres- sion than for patients with typical depressive symptoms. In addition, patients who were 20 years old or younger at the onset of depression, and patients with chronic depres- sion showed a higher risk of relapse than patients with later onset and less chronicity. Age and gender were variables found to have no association with risk of relapse.
Limitations of the study include a patient population of predominantly white females, which may not adequately represent patient populations seen in other settings. Additionally, the fixed 20 mg dosage of fluoxetine may not represent treatment in usual clinical practice.
Comment by Lauren B. Marangell, MD & Christopher D. Martin
McGrath et al have presented a well-designed large-scale longitudinal study demonstrating that continuation/maintenance treatment with 20 mg of fluoxetine daily is advantageous compared to placebo over a period of 50 weeks. The study identified three factors, a specific longitudinal response to treatment, typical neurovegetative status, and early onset/chronicity of depression, which, if present, indicate a potential to benefit from fluoxetine continuation/maintenance therapy and an increased risk of relapse if therapy with fluoxetine is not maintained.
This information is potentially useful to physicians treating patients undergoing pharmacotherapy for depression. Patients taking antidepressant medications may be reluctant to maintain compliance, particularly once they begin to enter remission or develop side effects. However, given the high rate of relapse and chronicity of depression, it is important that these patients continue medication. The results of this study may be applied to aid clinicians in addressing this issue. For patients with a history of early onset and persisting response to therapy, typical neurovegetative symptoms, and chronic or early onset depression, the data indicate that continuation/maintenance is particularly important as the advantage of fluoxetine over placebo in preventing relapse is large. The greatest risk of relapse occurred within the first six months after acute response. Thus, continuation should be strongly advised during this period in this group of patients, and efforts should be made to control side effects without discontinuing medication. McGrath et al present no evidence showing benefit of fluoxetine continuation/maintenance therapy for patients without these features. However, McGrath et al allude to data suggesting that an increase in dose above 20 mg in this group may provide benefit in about two-thirds of patients.
Though the study does not examine predictors of relapse associated with treatment with other medications, one may expect similar results to be seen with other selective serotonin reuptake inhibitors (SSRIs). However, discontinuation of other SSRIs should not be performed abruptly, as was done with fluoxetine in this study, as the other drugs in this class do not share fluoxetine’s long half-life, and require tapering of the dose to prevent a discontinuation syndrome. Also, McGrath et al comment that despite their hypothesis that fluoxetine would provide improved survival for patients with atypical depression, the drug showed no significant effect in preventing relapse in this population. McGrath et al suggest that atypical features may not affect acute response to medication, but rather predict loss of effect during maintenance. It is of interest to note that in previous studies imipramine has also been shown to bear no effect upon relapse rates when compared to placebo in patients with atypical depression who remitted on imipramine treatment. Phenelzine however, has been shown to provide a significant benefit in preventing relapse of atypical depression during maintenance. Thus, in patients with atypical depression, monoamine oxidase inhibitors may provide better maintenance treatment than TCAs or SSRIs.
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