Treating Depression After Initial Treatment Failure Directly Comparing Switch and Augmenting Strategies in STAR*D

Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Journal of clinical psychopharmacology (Impact Factor: 3.24). 12/2011; 32(1):114-9. DOI: 10.1097/JCP.0b013e31823f705d
Source: PubMed


Augmenting and switching antidepressant medications are the 2 most common next-step strategies for depressed patients failing initial medication treatment. These approaches have not been directly compared; thus, our objectives are to compare outcomes for medication augmentation versus switching for patients with major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial.
We conducted a retrospective analysis of participants aged 18 to 75 years with DSM-IV nonpsychotic depression who failed to remit with initial treatment in the STAR*D clinical trial (N = 1292). We compared depressive symptom remission, response, and quality of life among participants in each study arm using propensity score matching to minimize selection bias.
The propensity-score-matched augment (N = 269) and switch (N = 269) groups were well balanced on measured characteristics. Neither the likelihood of remission (risk ratio, 1.14; 95% confidence level, 0.82-1.58) or response (risk ratio, 1.14; 95% confidence level, 0.82-1.58), nor the time to remission (log-rank test, P = 0.946) or response (log-rank test, P = 0.243) differed by treatment strategy. Similarly, quality of life did not differ. Post hoc analyses suggested that augmentation improved outcomes for patients tolerating 12 or more weeks of initial treatment and those with partial initial treatment response.
For patients receiving and tolerating aggressive initial antidepressant trials, there is no clear preference for next-step augmentation versus switching. Findings tentatively suggest that those who complete an initial treatment of 12 weeks or more and have a partial response with residual mild depressive severity may benefit more from augmentation relative to switching.

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    • "at an adequate dose, fail to induce an acceptable effect " (Committee for Medicinal Products for Human Use 2002), though this defi nition has been revised in the more recent CHMP document (Committee for Medicinal Products for Human Use 2013) due to current negative evidence about defi ning TRD by antidepressant classes. An increasing number of reports showed no advantage in favour of switching to a different class of antidepressant in patients with MDD (Ruhe et al. 2006; Rush et al. 2006; Bschor and Baethge 2010; Souery et al. 2011a,b; Gaynes et al. 2012). The issue remains con- troversial. "
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    ABSTRACT: Objectives. Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants. Methods. A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3). Results. Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non-responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%. Conclusions. Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters.
    No preview · Article · Dec 2014 · The World Journal of Biological Psychiatry
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    • "Therefore, " augmentation strategies " (addition of one or more nonantidepressant drugs to an existing antidepressant regimen to enhance mood and overall antidepressant response), " adjunctive therapies " (addition of one or more agents to target specific symptoms of depression) (DeBattista, 2006) or " combination treatments " (augmentations made using two or more drugs from the same class, e.g., two antidepressants) (Papakostas, 2009) represent popular treatment strategies for TRD. While some augmentation strategies for standard antidepressants , including atypical antipsychotics (Nelson and Papakostas, 2009) and lithium or thyroid hormones (DeBattista, 2006), have consistent and/or increasing levels of evidence of support, the actual usefulness of most antidepressant within-or across-class combinations vs. monotherapy remains substantially not supported by existing studies, at least for melancholic cases of TRD or moderately to severe nonpsychotic chronic and/or recurrent MDD according to the acute and long-term outcomes reported by the single-blind randomized " Combining Medications to Enhance Depression Outcomes (CO-MED) " study (Rush et al., 2011), despite the popularity of this practice among clinicians (Bares et al., 2013; Gaynes et al., 2012; Souery et al., 2011). This issue could also affect TRD cases with atypical features, which apart from nosological revisions (Fornaro and Giosue, 2010; Perugi et al., 2011; Stewart et al., 2009; Thase, 2009), require further controlled studies on the matter compared with " typical " (melancholic) TRD. "
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    ABSTRACT: The efficacy, safety, and tolerability of combined bupropion versus placebo using duloxetine as active reference drug, in patients with a DSM-IV diagnosis of major depression with atypical features and a history of treatment resistance, were evaluated in this preliminary six-week study. Patients (n=46) had a baseline Hamilton Depression Scale (HAM-D) ≥14 and were randomly assigned to 150/300 mg/day bupropion vs. placebo, which was added to 60 to 120 mg/day duloxetine depending on baseline depression severity. Atypical features of depression were assessed using the additional eight-item module of the Structured Interview Guide for the HAM-D with the Atypical Depression Supplement. By week 6, only five (21.7%) patients receiving duloxetine+placebo vs. six (26.1%) patients on the bupropion combination achieved response. No significant difference in final HAM-D scores between the two groups was observed between those patients achieving response. The presence of a higher number of atypical features significantly predicted non-response, with the relevant binary logistic regression model correctly classifying 17 out 22 (77.3%) of non-responders [Exp(B)=0.294; p=.016] vs. 17 out 23 (73.9%) [Exp(B)=0.353; p=.028] non-responder cases in the “+placebo” and “+bupropion” groups, respectively. In those patients receiving bupropion, treatment-emergent adverse events leading to withdrawal were more common among those receiving lower doses of the combination drug, and no life-threating dangers were noted. Additional studies, including an adequate course of duloxetine trial, are nonetheless aimed to allow a firm conclusion about the usefulness of the combination of duloxetine and bupropion for treatment-resistant cases of major depression with atypical features.
    Full-text · Article · Aug 2014 · European Neuropsychopharmacology
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    • "The most valuable evidence comes from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, a four-level study that evaluated different strategies in non-responders [21]. The results of a retrospective analysis comparing switching and augmentation strategies in patients participating in the STAR*D trial has recently been published [22]. Such analysis showed that patients who complete initial treatment of 12 weeks or more and have a partial response with residual mild depressive symptoms may benefit more from augmentation than switching. "
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    ABSTRACT: Background The aim of the study was to determine the most common pharmacological strategies used in the management of major depressive disorder (MDD) after an inadequate response to first-line antidepressant treatment in clinical practice. Methods Multicenter, non-interventional study in adult outpatients with a DSM-IV-TR diagnosis of MDD and inadequate response to first-line antidepressant medication. Multiple logistic regression analyses were performed to identify independent factors associated with the adoption of a specific second-line strategy. Results A total of 273 patients were analyzed (mean age: 46.8 years, 67.8% female). Baseline mean Montgomery-Asberg Depression Rating Scale total score was 32.1 (95%CI 31.2-32.9). The most common strategies were: switching antidepressant medication (39.6%), augmentation (18.8%), and combination therapy (17.9%). Atypical antipsychotic drugs were the most commonly used agent for augmenting antidepressant effect. The presence of psychotic symptoms and the number of previous major depressive episodes were associated with the adoption of augmenting strategy (OR = 3.2 and 1.2, respectively). Conclusion The switch to another antidepressant agent was the most common second-line therapeutic approach. Psychiatrists chose augmentation based on a worse patients’ clinical profile (number of previous episodes and presence of psychotic symptoms).
    Full-text · Article · Sep 2012 · BMC Psychiatry
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