Review
What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies

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Abstract

Background

Treatment-resistant depression (TRD) is relatively common and accounts for a large proportion of the overall burden caused by depression. We conducted a systematic review of outcome studies of TRD in order to summarise findings on the longer term outcome of TRD and make recommendations.

Methods

Studies were identified through MEDLINE (1960 — June Week 1 2008), EMBASE (1974 — June Week 1 2008) and PsycINFO (1967 — June Week 1 2008) searches. We included studies that followed adults with highly probable TRD for a minimum of 6 months. Statistical analyses were conducted on selected outcome variables whenever possible. Methodological heterogeneity of studies prohibited formal meta-analysis.

Results

We identified nine outcome studies with a total of 1279 participants and follow-up duration of between 1 and 10 years. In the short term, TRD was highly recurrent with as many as 80% of those requiring multiple treatments relapsing within a year of achieving remission. For those with a more protracted illness, the probability of recovery within 10 years was about 40%. TRD was also associated with poorer quality of life and increased mortality.

Limitations

Included primary studies were heterogeneous.

Conclusions

TRD is associated with poorer clinical outcome, particularly among those who require multiple antidepressant medications. The main limitations of the review arise from the variability in recruitment procedures, definitions and outcome assessments of the original studies. We recommend further follow-up studies of carefully identified samples in order to gain a more detailed understanding of this domain of depression and plan effective interventions.

Introduction

Depression represents a substantial public health burden owing to its high prevalence (Jenkins et al., 1997, Kessler et al., 2005, Kessler et al., 1994, Robins et al., 1984, Weissman et al., 1988), association with premature death and disability (Lee and Murray, 1988, World Health Organisation, 2001), and considerable cost (Greenberg et al., 2003, Thomas and Morris, 2003). A large proportion of the burden caused by depression is likely to be attributable to treatment-resistant depression (TRD) (George et al., 2005, Greden, 2001, Malhi et al., 2005). There are several reasons for this. First, TRD itself is common: applying often used definitions of response it affects 20–30% of those with depression (Souery et al., 2006, Trivedi et al., 2006), with this figure rising to as high as 60% if TRD is defined – as it probably should be – as absence of remission (Greden, 2001, Trivedi et al., 2006). Second, duration and severity of illness, both of which are higher in TRD, are important determinants of disease burden (Ustun and Kessler, 2002). Third, patients with TRD are more likely to suffer from comorbid physical and mental disorders, to experience marked and protracted functional impairment, and to incur higher medical and mental healthcare costs (Fava, 2003, Keller, 2005, Kornstein and Schneider, 2001, Nelsen and Dunner, 1995, Sackeim, 2001). Thus, in order to reduce the substantial burden caused by depression, TRD should be one of the central focuses of epidemiological and interventional research.

It is only recently that researchers have focussed on TRD, and attempted to improve treatment in this area. As well as treatment challenges, there is uncertainty about the longer term outcome of patients with TRD. In order to be able to judge the efficacy of enhanced treatments specifically targeted to improve the outcome of TRD, it is necessary to understand the long term outcome of TRD in current practice. We undertook a systematic review of short and longer term outcome studies of TRD in order to assess how people with TRD fare in the longer term. We were not interested in acute treatment trials of TRD, but in studies which provided data on the longer term outcome of those who either had ongoing depressive symptoms after treatment or who had previously experienced TRD but responded successfully to treatment.

Section snippets

Search methods

Relevant outcome studies were identified using electronic searches of MEDLINE (1960 — June Week 1 2008), EMBASE (1974 — June Week 1 2008), PsycINFO (1967 — June Week 1 2008) and PubMed. Bibliographies of identified articles were also manually searched for relevant publications. We used the following key words to identify the studies: RESIST⁎; REFRACTOR⁎; DIFFICULT; INTRACTABLE; ANTIDEPRESS⁎; DEPRESS⁎ (Berlim and Turecki, 2007); THERAPY or TREATMENT, REFRACT⁎; RESISTANT; NON-RESPOND⁎;

Results

We initially identified 816 potentially relevant publications. Of these, 654 were mainly aetiological articles (neurobiological, structural and risk factor) and opinion pieces and were excluded. Further 87 studies were excluded because they were either general follow-up studies of depression or descriptive studies of TRD. Sixty eight studies were excluded because they were primarily reports of treatment trials and further three were excluded because they were follow-up studies of older

Quality of included studies

The studies included were not primarily aimed at assessing the longer term outcome of TRD. This may partly account for the heterogeneity and limitation of the studies. Our attempt to use a rather broad and inclusive definition that we felt was likely to capture most patients with probable TRD might have also introduced heterogeneity.

Given the nature of TRD itself and its current conceptualisation, the cohort in this review is predominantly formed of patients from secondary and tertiary

Role of funding source

Nothing declared.

Conflict of interest

No conflict declared.

Acknowledgement

We are grateful to Sonya Lipczynska, librarian at the Institute of Psychiatry, for assistance in literature search.

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