Challenging Treatment-Resistant Major Depressive Disorder: A Roadmap for Improved Therapeutics

Abstract

Major depressive disorder (MDD) is associated with a significant burden and costs to the society. As remission of depressive symptoms is achieved in only one-third of the MDD patients after the first antidepressant trial, unsuccessful treatments contribute largely to the observed suffering and social costs of MDD. The present article provides a summary of the therapeutic strategies that have been tested for treatment-resistant depression (TRD). A computerized search on MedLine/PubMed database from 1975 to September 2014 was performed, using the keywords "treatment-resistant depression", "major depressive disorder", "adjunctive", "refractory" and "augmentation". From the 581 articles retrieved, two authors selected 79 papers. A manual searching further considered relevant articles of the reference lists. The evidence found supports adding or switching to another antidepressant from a different class is an effective strategy in more severe MDD after failure to an initial antidepressant trial. Also, in subjects resistant to two or more classes of antidepressants, some augmentation strategies and antidepressant combinations should be considered, although the overall response and remission rates are relatively low, except for fast acting glutamatergic modulators. The wide range of available treatments for TRD reflects the complexity of MDD, which does not underlie diverse key features of the disorder. Larger and well-designed studies applying dimensional approaches to measure efficacy and effectiveness are warranted.

The Role of Lipid Biomarkers in Major Depression

“…This suggests that cholesterol, particularly in the prefrontal cortex, influences the sensitivity of the 5-HT1A receptor in the pathology and treatment of depression. However, the serotonergic explanation of depression is not sufficient to fully explain the development of depression, as evidenced by large proportion of patients that do not respond to antidepressants which target the serotoninergic system [11,75,76]. …”

“…Whilst these aim to reduce subjectivity and inter-clinician variability, they are arguably inadequate to provide a complete assessment and appropriate treatment plan [10]. In addition to inadequacies in diagnosis, up to 30% of patients do not respond to antidepressant medication and are diagnosed as having treatment-resistant depression [11]. Those that do exhibit a response often only receive a partial reduction in symptoms and a large proportion of the apparent efficacy of antidepressants has been proposed to be due to the placebo effect [12].…”

Investigation of early and lifetime clinical features and comorbidities for the risk of developing treatment-resistance depression in a 13-year nationwide cohort study

“…Thirdly, tolerance to antidepressants has been reported [36]. Patients with TRD also had more complex treatment regimens, since it is a common strategy to use higher doses and adjunctive psychotropics to counter poor response to medication [37]. A recent meta-analysis of placebo-controlled trials demonstrated that adjunctive antipsychotics were effective for the treatment of TRD [38].…”

Biobanking in der Psychiatrie

“…B. 30 % bei Depressionen [7]) kann allerdings als Indiz dafür gelten, dass die überwiegend psychopathologisch abgeleiteten Diagnosezuordnungen (s. o. ) mit den biologischen Wirkkategorien der Psychopharmaka unzureichend übereinstimmen.…”