ReviewStaging methods for treatment resistant depression. A systematic review
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.
References (74)
- et al.
What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials
Eur. Neuropsychopharmacol.
(2007) - et al.
Severity and duration of depression, not personality factors, predict short term outcome in the treatment of major depression
J. Affect. Disord.
(2007) - et al.
Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment
Biol. Psychiatry
(2007) - et al.
Is treatment-resistant depression a unique subtype of depression?
Biol. Psychiatry
(2003) Diagnosis and definition of treatment-resistant depression
Biol. Psychiatry
(2003)- et al.
Definition and epidemiology of treatment-resistant depression
Psychiatr. Clin. North Am.
(1996) - et al.
Major depressive subtypes and treatment response
Biol. Psychiatry
(1997) - et al.
The predictors of persistence of depression in primary care
J. Affect. Disord.
(1994) - et al.
Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy
J. Affect. Disord.
(2009) - et al.
Recovery, chronicity, and levels of psychopathology in major depression
Psychiatr. Clin. North Am.
(1996)
Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches
Biol. Psychiatry
Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design
Control. Clin. Trials
Efficacy of interpersonal psychotherapy plus pharmacotherapy in chronically depressed inpatients
J. Affect. Disord.
Treatment resistant depression: methodological overview and operational criteria
Eur. Neuropsychopharmacol.
Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology Guidelines
J. Psychopharmacol.
Management of Mental Disorders
Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods
Can. J. Psychiatry
Treatment-refractory depression: definitions and characteristics
Depress. Anxiety
Concept Paper on the Need for Revision of Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Depression with regard to Treatment Resistant Depression
The impact of treatment-resistant depression on health care utilization and costs
J. Clin. Psychiatry
Is electroconvulsive therapy effective for the depressed patient with comorbid borderline personality disorder?
J. ECT
Treatment refractory depression
A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method
J. Clin. Psychiatry
The Maudsley staging method for treatment-resistant depression: prediction of longer-term outcome and persistence of symptoms
J. Clin. Psychiatry
A rating scale for depression
J. Neurol. Neurosurg. Psychiatry
Therapy-resistant depressions: symptoms and syndromes. Contributions to symptomatology and syndromes
Pharmakopsychiatr. Neuropsychopharmakol.
Early identification and intervention in depressive disorders: towards a clinical staging model
Psychother. Psychosom.
Personality disorders and depression: comorbidity
Depress. Anxiety
Realistic expectations and a disease management model for depressed patients with persistent symptoms
J. Clin. Psychiatry
Recovery in major depressive disorder: analysis with the life table and regression models
Arch. Gen. Psychiatry
A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression
N. Engl. J. Med.
Cognitive behavioral analysis system of psychotherapy and brief supportive psychotherapy for augmentation of antidepressant nonresponse in chronic depression: the REVAMP trial
Arch. Gen. Psychiatry
Therapy-resistant depressions — a clinical classification
Pharmakopsychiatr. Neuropsychopharmakol.
Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression
Expert Opin. Pharmacother.
Treatment-resistant depression: resistant to definition?
Acta Psychiatr. Scandinavian
Cingulate function in depression: a potential predictor of treatment response [see comments]
NeuroReport
Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions
Aust. N.Z. J. Psychiatry
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Both authors contributed equally.