Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder. A replication of findings with the use of a double-blind, placebo-controlled trial of Hypericum perforatum versus fluoxetine.

BACKGROUND: Our objective was to assess for the relationship between timing of clinical improvement and resolution of depressive symptoms during the treatment of major depressive disorder (MDD). Thirty-nine MDD outpatients who responded following a 12-week, double-blind study comparing Hypericum perforatum, fluoxetine or placebo were included in the analysis. METHODS: Onset of clinical improvement was defined as a 25% decrease in 17-item Hamilton Depression Scale (HDRS-17) scores that was not followed by a subsequent worsening of symptoms. Controlling for baseline symptom severity, we then assessed for the relationship between timing of clinical improvement and depressive symptom severity at endpoint. RESULTS: Among responders, earlier clinical improvement predicted lower HDRS-17 scores at week 12 (p = 0013). This was also true of responders who received active treatment (n = 29, p = 0.0113) but not placebo responders (n = 10; p > 0.05). Finally, patients with an early onset of clinical improvement (occurring during the first 2 weeks) had lower week 12 HDRS-17 scores than patients with a late onset of clinical improvement (p = 0.0404). CONCLUSION: In the present work, earlier as well as early clinical improvement during treatment is predictive of greater symptom resolution at endpoint among responders. This was replicated among patients who received active treatment (either hypericum or fluoxetine) but not placebo.

A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder.

CONTEXT: Pattern analysis suggests that "true" drug response is characterized by clinical improvement that is not subsequently followed by a worsening of symptoms (sustained clinical response). To date, several reports demonstrate that early response rates are equivalent between antidepressant-treated and placebo-treated groups of patients with major depressive disorder, suggesting that patients who demonstrate significant and sustained symptom improvement during the first 2 weeks of treatment are not responding to the antidepressant itself, but to nonspecific, placebo-like factors. OBJECTIVE: To compare early sustained response rates between antidepressant- and placebo-treated adults with major depressive disorder. DATA SOURCES: Medline/Pubmed were searched. No year of publication limits were used. STUDY SELECTION: Randomized, double-blind, placebo-controlled antidepressant trials or pooled reports/meta-analyses of such trials reporting early sustained response rates for major depressive disorder. The decision to include studies in the meta-analysis was performed by 2 reviewers. DATA EXTRACTION: Data were extracted with the use of a precoded form. DATA SYNTHESIS: Analyses were performed on the proportion of patients who achieved a sustained response the first 2 weeks of treatment, as well as the first week of treatment. A random-effects model with fixed drug effects was used to combine the studies and make comparisons of sustained early response rates between antidepressant- and placebo-treated groups. Data from 8 reports involving a total of 7121 major depressive disorder patients (4076 randomized to treatment with an antidepressant and 3045 randomized to placebo) were analyzed. Antidepressant-treated patients were more likely to demonstrate sustained clinical response by 2 weeks (odds ratio 2.06, 95% CI: 1.52-2.8) or 1 week of treatment (odds ratio 1.50, 95% CI: 1.08-2.08) than placebo-treated patients. CONCLUSIONS: The results of the present analysis suggest that "true" drug response can occur the first 2 week as well as the first week of treatment of major depressive disorder with conventional antidepressants.

A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment.

BACKGROUND: Antidepressant therapies have been associated with a variety of side effects of both physical and psychological nature. Until recently, however, the majority of the studies focusing on side effects of antidepressants have not routinely included assessment of cognitive side effects. The purpose of the present work is to examine cross-sectionally the prevalence of cognitive and physical side effects of antidepressants during long-term treatment of depression. METHOD: Patients at least 18 years of age who were deemed responders to antidepressant therapy following at least 3 months of treatment for major depressive disorder (MDD) (diagnosed according to DSM-IV criteria) and whose MDD was considered to be in partial or full remission were eligible for inclusion in this study. Eligible patients were enrolled between January 2003 and December 2004. Study participants were administered the Harvard Department of Psychiatry/National Depression Screening Day (HANDS) scale, the Epworth Sleepiness Scale, the Brief Fatigue Inventory, the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), and a study-specific questionnaire inquiring about the emergence of specific side effects such as apathy, fatigue, and inattentiveness. RESULTS: 117 MDD patients (mean +/- SD age: 43.4 +/- 12.6 years; women: N = 78 [66.7%]) met criteria for response according to the HANDS (score < 9). Cognitive symptoms (apathy, inattentiveness, forgetfulness, word-finding difficulty, and mental slowing) were each reported on both the CPFQ and the study-specific questionnaire by more than 30% of the responders on antidepressants. The physical symptoms of fatigue and sleepiness/sedation were reported by over 40% of the responders on both the CPFQ and the study-specific questionnaire. A significant, positive relationship was found between the CPFQ and the severity of residual depressive symptoms as measured by the HANDS total score (F = 15.3, p = .0002). CONCLUSION: Physical and cognitive symptoms are frequently reported by MDD patients who have responded to antidepressants and are treated in the long term with these agents. It is likely that these symptoms are both side effects of the antidepressants as well as residual symptoms of MDD.