Review
Staging methods for treatment resistant depression. A systematic review

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Abstract

Background

Treatment resistant depressant (TRD) is classified in different staging models, but these are not used routinely. We aimed to identify staging models for TRD and compare them regarding predictive utility and reliability.

Methods

Systematic review of Pubmed, Embase and PsycINFO (1985–January 2010) without language limits, plus articles identified from reference lists of previous reviews. We excluded articles focusing on TRD treatment. We qualitatively summarized characteristics of the identified staging models, describing strengths and limitations for each model. If available, we reported results of validation studies.

Results

From 950 retrieved articles five staging models were found; the Antidepressant Treatment History Form, Thase and Rush Model, European Staging Model, Massachusetts General Hospital Staging model and the Maudsley Staging Model (MSM). Six studies investigated the predictive utility (of four models). We observed an evolution from single antidepressant adequacy ratings, towards a multidimensional and more continuous scored staging model which also introduced TRD characteristics (severity and duration). The operationalization criteria improved; the scoring of different treatment strategies (between/within class switching and augmentation/combination) changed according to the existing evidence. Over time, efforts to validate models improved. The predictive utility was assessed best for the MSM.

Limitations

Few staging models existed; their reliability was hardly assessed.

Conclusions

Despite validation of the MSM, further investigation of the reliability and predictive utility of TRD staging models and additional disease characteristics is required. Correct staging of TRD might improve generalizability of results from clinical studies and improve delivery of care to TRD patients. We propose methods to validate staging models in TRD.

Introduction

In major depressive disorder (MDD), complete remission followed by sustained recovery is the optimal therapeutic goal (Trivedi and Kleiber, 2001). Despite effective pharmacotherapeutic strategies, only 30–40% of the patients will reach remission after the first trial of antidepressants. In order to classify patients as nonremitters, treatment needs to be adequate in terms of duration and dosage (Berlim and Turecki, 2007b; Fava and Davidson, 1996; Trivedi et al., 2006b), and patients should be compliant (Vergouwen et al., 2003). Even after sequential treatments, 10% to 20% of the MDD patients remain significantly symptomatic for 2 years or longer (Keitner et al., 2006; Keller et al., 1982). In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the cumulative remission rate after 4 trials of antidepressant treatment (within 14 months) was only 67% (Rush et al., 2006). Chronically depressed patients have a lower chance of recovery (Mueller and Leon, 1996), and often suffer from treatment resistant (refractory) depression (TRD) (Crown et al., 2002; Malhi et al., 2005). TRD is associated with prolonged, costly inpatient periods of treatment (Ustun and Kessler, 2002).

Since the introduction of the concept of TRD in 1974 (Fawcett and Kravitz, 1985; Heimann, 1974; Lehmann, 1974; Nierenberg et al., 1991), many studies were published to investigate the best treatment strategy for TRD, but authors used different definitions of TRD (Berman et al., 1997; Fava and Davidson, 1996). A recent review of these definitions (Berlim and Turecki, 2007b), identified a range from nonresponse to one antidepressant (for ≤ 4 weeks) to a failure to respond to multiple adequate (in terms of duration and dosage) trials of different classes of antidepressants and electroconvulsive therapy (ECT). Furthermore, TRD assessment was often unspecified, or assessed retrospectively (based on patient-recall only), with occasional assessment of previous nonresponse by clinical global impression or validated rating scales. All definitions of TRD only focused on previous pharmacological treatment, leaving out psychological treatments like cognitive behavioral therapy (CBT) or interpersonal therapy (IPT). Besides differences in criteria, none of the identified definitions of TRD have been systematically examined for reliability and predictive utility (Souery et al., 1999).

Inconsistencies in definitions of TRD impair estimations of the prevalence of TRD (Nemeroff, 2007) and the identification of most efficacious next-step treatments. Different definitions of TRD result in heterogeneous study samples, which impair reliable comparisons or meta-analyses of results from next-step studies (Ruhe et al., 2006b).

Berlim and Turecki (2007a) defined TRD as an episode of MDD which has not improved after at least two adequate trials of different classes of antidepressants, which is supported by the deteriorating chances of response after the second antidepressant observed in STAR*D (Ruhe et al., 2006b; Rush et al., 2006). They suggested that consequent and international use of this definition would improve understanding of research findings and communication between investigators and clinicians. Recently, the European Medicines Agency (EMEA) started a revision of their definition of TRD, stating that a “clinically relevant TRD is a current episode of depressive disorder which has not benefited from at least two adequate trials of antidepressant compounds of different mechanism of action” (CHMP, 2009). Although still under construction, this will define TRD for clinical registration studies of (new) antidepressant agents, especially to license next-step treatments. This definition will exclude the inclusion of partial responders, and increase homogeneity of study populations. However, these definitions of TRD imply a dichotomy, which does not acknowledge the dimensional nature of TRD.

Ideally, a staging model for TRD should be able to classify patients according to their level of resistance to treatment for MDD, predict chances of future remission and guide clinical treatment selection. A dimensional staging model for TRD might be more appropriate instead of a dichotomous definition. Like in oncology (Fagiolini and Kupfer, 2003), psychopathological and biological markers for staging of TRD could be used to better predict the course and prognosis of the disease. Several clinical variables might influence the development or level of TRD: duration of the episode, depression subtype, depression severity, and psychiatric and/or somatic co-morbidity (Berlim and Turecki, 2007b).

Previous approaches for staging MDD and TRD have been reviewed (Berlim and Turecki, 2007a; Hetrick et al., 2008). More recently, a more comprehensive clinical staging/profiling model for TRD in general was proposed and validated thereafter (Fekadu et al., 2009a). To date, no staging model has been widely accepted. Furthermore, the methodology for the validation of staging methods needs further development. We therefore systematically reviewed the literature to identify staging models for TRD and compare these models regarding predictive utility (possibility to discriminate different levels of treatment response in relation to unresponsiveness to subsequent treatments) and reliability (adequacy of staging between and within raters). We also describe the requirements for adequate validation studies of staging models for TRD.

Section snippets

Search strategy

To indentify papers concerning staging models for TRD, we searched Pubmed (MEDLINE), Embase and PsycINFO (from 1985 until January 1st 2010) with a comprehensive search strategy for potential relevant articles. Search terms were [(antidepressant*.mp. OR depression.mp.) AND (resistan*.mp. OR refractory.mp.) AND treatment.mp. OR (treatment failure/ or treatment failure$.ab,ti.) AND (depression or depressive).mp OR trd.ab,ti] AND [((level* or degree*) adj2 resistance).mp OR (stage or staging).mp OR

Results

Fig. 1 shows the results of the systematic search and selection of articles. Our search identified many papers describing treatment strategies for, but not staging of TRD. We finally selected 11 articles, including 5 staging models for TRD, which will be discussed chronologically. A qualitative summary is given in Table 1.

Discussion

This study aimed to identify and compare the definitions and content of various staging models for TRD and ascertain their reliability and predictive utility. We found five staging models, which gradually evolved from a first proposal of rating adequacy of an antidepressant trial to a more comprehensive three-dimensional staging model addressing duration of illness, initial severity and treatment response. Despite six empirical studies, which investigated the ATHF, TRSM, MGH-s and the MSM,

Conclusion

We reviewed the current staging models for TRD described in the literature. We found the descriptions of five staging models. The validity of these models was investigated by six studies, and reliability was hardly studied. Although the psychometric investigation of the MSM was most thorough, reliability must be assessed and results should be replicated in a new sample of TRD patients. Therefore, we recommend further study of the reliability and sensitivity/specificity of staging models for

Role of funding source

Nothing declared.

Conflicts of interest

Dr. J Spijker received speaking fees and/or participated in advisory boards from/for AstraZeneca, Glaxo Smith Kline, Eli Lilly, Servier and Wyeth. Dr. F. Peeters received speakers' fees from GlaxoSmithKline, Wyeth, Astra Zeneca, Lundbeck, Eli Lilly, Servier, and Janssen-Cilag. All other authors reported no potential competing interests.

Acknowledgements

The authors wish to thank Joost G. Daams, librarian at the Academic Medical Center, for his excellent help with the systematic searches.

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