Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression.

OBJECTIVE: To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. METHODS: Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. RESULTS: 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). CONCLUSION: Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients.

OBJECTIVE: New evidence indicates that treatment response can be predicted with high sensitivity after 2 weeks of treatment. Here, we assess whether early improvement with antidepressant treatment predicts treatment outcome in patients with major depressive disorder (MDD). DATA SOURCES: Forty-one clinical trials comparing mirtazapine with active comparators or placebo in inpatients and outpatients (all-treated population, N = 6907; intent-to-treat population, N = 6562) with MDD (DSM-III-R or DSM-IV Criteria) were examined for early improvement (>or= 20% score reduction from baseline on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] within 2 weeks of treatment) and its relationship to treatment outcome. STUDY SELECTION: Data were obtained from a systematic search of single- or double-blind clinical trials (clinical trials database, Organon, a part of Schering-Plough Corporation, Oss, The Netherlands). All included trials (a total of 41) employed antidepressant treatment for more than 4 weeks and a maximum of 8 weeks. The studies ranged from March 1982 to December 2003. Trials were excluded if there were no HAM-D-17 ratings available, no diagnosis of MDD, or if the study was not blinded. Trials were also excluded if HAM-D-17 assessments were not available at week 2, week 4, and at least once beyond week 4. DATA SYNTHESIS: Early improvement predicted stable response and stable remission with high sensitivity (>or= 81% and >or= 87%, respectively). Studies utilizing rapid titration vs. slow titration of mirtazapine demonstrated improved sensitivity for stable responders (98%, [95% CI = 93% to 100%] vs. 91% [95% CI = 89% to 93%]) and stable remitters (100%, [95% CI = 92% to 100%] vs. 93% [95% CI = 91% to 95%]). Negative predictive values for stable responders and stable remitters were much higher (range = 82%-100%) than positive predictive values (range = 19%-60%). CONCLUSIONS: These results indicate that early improvement with antidepressant medication can predict subsequent treatment outcome with high sensitivity in patients with major depressive disorder. The high negative predictive values indicate little chance of stable response or stable remission in the absence of improvement within 2 weeks. A lack of improvement during the first 2 weeks of therapy may indicate that changes in depression management should be considered earlier than conventionally thought.