Managing Partial Response or Nonresponse: Switching, Augmentation, and Combination Strategies for Major Depressive Disorder

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston, MA 01224, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 01/2009; 70 Suppl 6:16-25. DOI: 10.4088/JCP.8133su1c.03
Source: PubMed


Despite the multitude of agents approved for the treatment of major depressive disorder, approximately 50% of patients experience no response to treatment with a first-line antidepressant. Clinicians have 4 broad pharmacologic strategies to choose from for treating antidepressant nonresponders: increasing the dose of the antidepressant, switching to a different antidepressant, augmenting the treatment regimen with a nonantidepressant agent, and combining the original antidepressant with a second antidepressant. To date, the most comprehensively studied treatment strategy for nonresponse or partial response to antidepressants is augmentation with atypical antipsychotic agents, including aripiprazole, olanzapine, quetiapine, and risperidone. However, augmentation or combination with other agents such as mirtazapine, mianserin, and omega-3 fatty acids is also supported by considerable efficacy data. Lithium, desipramine, triiodothyronine, and modafinil have mixed data. While more studies are needed, agents such as bupropion, desipramine, mecamylamine, and testosterone look promising. Switching antidepressants, especially to the newer agents, including selective serotonin reuptake inhibitors, bupropion, mirtazapine, and venlafaxine, is also supported by considerable efficacy data. Clinicians should carefully reevaluate patients with major depressive disorder who are nonresponders to treatment, particularly those who have had several adequate trials. When choosing the best treatment strategy for antidepressant nonresponders, clinicians should take into account the efficacy and tolerability of treatment as well as patient preference and treatment history. Finally, the risk of potential loss of partial therapeutic benefit from the first-line antidepressant, as well as the risk of withdrawal symptoms, should be taken into account when considering switching antidepressants, while the risk of drug interactions and poor adherence should be taken into account when considering combination and augmentation treatments.

44 Reads
  • Source
    • "An effective choice can improve outcomes, while persistent depression may lead to a more chronic and deteriorating course (Tranter et al. 2002). Several options exist, including antidepressant switching, augmentation with antidepressants with different mechanisms, augmentation with non-antidepressant psychotropic, such as second-generation antipsychotics or lithium, nonpsychotropic medications (thyroid hormone), or nonpharmacologic treatments (psychotherapy, transcranial magnetic stimulation, electroconvulsive therapy) (Fleurence et al. 2009; Papakostas 2009; Spielmans et al. 2013). However, guidance as to which options are most efficacious or have the best risk-benefit profile remains limited. "
    [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionAlthough a growing selection of antidepressants is available, a significant number of patients do not reach clinical remission, despite multiple trials. Data concerning the efficacy and safety of combination therapies with newer antidepressants are limited.Methods Fifteen inpatients with treatment-resistant depression (TRD), defined as Beck Depression Inventory-2 (BDI-2) scores >14 despite treatment with adequate doses of ≥1 antidepressant classes for ≥6 weeks, were treated with agomelatine plus bupropion for ≥6 weeks, and compared to 15 patients on antidepressant monotherapy with TRD matched on age, sex, and TRD stage based on retrospective chart review. The primary outcome was change in BDI-2 scores. Secondary outcomes included treatment response (BDI-2 score decrease by ≥50%), remission (BDI-2 score <13), routinely measured cardiometabolic parameters and adverse effects.ResultsAfter a mean of 6 ± 1 weeks, BDI-2 scores decreased by 20.3 ± 5.6 points in the combination group compared to 12.5 ± 15.1 points in the monotherapy group (P = 0.073; Cohen's d = 0.7). Altogether, 73.3% in the combination group responded compared to 53.3% on monotherapy (P = 0.27). About 60.0% on combination therapy reached remission compared to 40% on monotherapy (P = 0.28), a difference equivalent to a number-needed-to-treat = 4. Treatment response was independent of the degree of TRD (P = 0.27). Bupropion-agomelatine cotreatment was well tolerated and laboratory adverse effect parameters were not altered.Conclusion Despite the small sample and uncontrolled study design, the good remission rate in TRD patients receiving agomelatine plus bupropion, particularly in comparison to the monotherapy group, indicates that this combination treatment should be explored further as a potentially promising strategy for patients with TRD.
    Brain and Behavior 02/2015; 5(4). DOI:10.1002/brb3.318 · 2.24 Impact Factor
  • Source
    • "Major depressive disorder (MDD) is a severe mental health problem affecting millions worldwide. In spite of a variety of treatment modalities, not all patients respond to current pharmacotherapy or psychotherapy interventions (Papakostas, 2009). Furthermore, when challenged by antidepressant (AD) nonresponse , treatment options are limited (Shelton et al., 2010; Ward and Irazoqui, 2010; Kupfer et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although well-defined predictors of response are still unclear, clinicians refer a variety of depressed patients for a repetitive Transcranial Magnetic Stimulation (rTMS) treatment. It has been suggested that personality features such as Harm Avoidance (HA) and self-directedness (SD) might provide some guidance for a classical antidepressant treatment outcome. However, to date no such research has been performed in rTMS treatment paradigms. In this open study, we wanted to examine whether these temperament and character scores in particular would predict clinical outcome in refractory unipolar depressed patients when a typical high-frequency (HF)-rTMS treatment protocol is applied. Thirty six unipolar right-handed antidepressant-free treatment resistant depressed (TRD) patients, all of the melancholic subtype, received 10 HF-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). All patients were classified as at least stage III TRD and were assessed with the Temperament and Character Inventory (TCI) before a HF-rTMS treatment. Only the individual scores on SD predicted clinical outcome. No other personality scales were found to be a predictor of this kind of application. Our results suggest that refractory MDD patients who score higher on the character scale SD may be more responsive to the HF-rTMS treatment.
    Psychiatry Research 08/2014; 220(1-2). DOI:10.1016/j.psychres.2014.07.084 · 2.47 Impact Factor
  • Source
    • "Treatment-resistant depression (TRD) represents a common condition, with 50 to 60% of major depressive disorder (MDD) patients receiving antidepressant drugs failing to achieve a clinically meaningful response (Souery et al., 1999). 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). "
    [Show abstract] [Hide abstract]
    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.
    European Neuropsychopharmacology 08/2014; DOI:10.1016/j.euroneuro.2014.04.004 · 4.37 Impact Factor
Show more