Description of the condition
By 2030, depression is predicted to be the leading cause of disability in high-income countries (Mathers 2005). Severity of depression can be classified using the Diagnostic and Statistical Manual of Mental disorders, fourth edition (DSM-IV) criteria as mild (five or more symptoms with minor functional impairment), moderate (symptoms or functional impairment are between 'mild' and 'severe') and severe (most symptoms present and interfere with functioning) (NICE 2009).
Antidepressants are often prescribed as the first-line treatment for adults with moderate to severe depression (NICE 2009). In England in 2010, 42.8 million prescriptions for antidepressants were issued at a cost of GBP220 million (The NHS Information Centre 2011). However, two-thirds of people do not respond fully to such pharmacotherapy (Trivedi 2006). Such non-response may be because of intolerance to the prescribed medication or non-adherence to the treatment regimen but may also be the result of treatment 'resistance', where an adequate dose and duration of treatment has been given. The earliest definition of treatment-'resistant' depression was given by the World Psychiatric Association; it defined 'resistance' as "an absence of clinical response to treatment with a tricyclic antidepressant at a minimum dose of 150 mg per day of Imipramine (or equivalent drug) for 4 to 6 weeks" (WPA 1974). Subsequently, others have suggested more complex classification systems based on non-response to multiple courses of treatment (Thase 1997; Fava 2005; Fekadu 2009), and used other terms such as 'treatment-refractory' depression and 'antidepressant-resistant' depression to describe this condition. For the purpose of this review, we will use the term 'treatment-resistant depression' as this is the descriptor that has, generally, represented the broadest definition of the condition.
The burden of depression is substantial and in the UK the average service cost to the National Health Service (NHS) has been estimated as GBP2085 per patient (McCrone 2008). The total costs of services for depression in 2007 was estimated as GBP1.7 billion, although these costs were dwarfed by the cost of lost productivity, which accounted for a further GBP5.8 billion (McCrone 2008). Similar substantial costs have been estimated for the US, with direct treatment costs estimated as USD26.1 billion and a further USD51.5 billion in workplace costs in 2000 (Greenberg 2003). If up to one-third of patients have 'treatment-resistant' depression, it is thus clear that this condition represents a considerable burden to patients, the NHS and society.
Description of the intervention
First-line treatment for adults with moderate to severe depression is commonly an antidepressant (NICE 2009). There are five main types of antidepressants: tricyclic (TCAs) and related antidepressants; monoamine-oxidase inhibitors (MAOIs); selective serotonin re-uptake inhibitors (SSRIs); serotonin and noradrenaline reuptake inhibitors (SNRIs); and noradrenergic and specific serotonin antidepressants (NaSSAs). SSRIs are safer in terms of overdose than TCAs and tend to be better tolerated than other classes of antidepressants. Hence, it is not surprising that SSRIs are the most commonly prescribed antidepressants for treating depression (Olfson 2009; The NHS Information Centre 2011).
There is no standard approach to the treatment of those whose depression does not respond to antidepressant medication. Guidance published by the American Psychiatric Association (APA 2010) and the National Institute for Health and Clinical Excellence (NICE 2009) suggests that the 'next step' may include increasing the dose of the antidepressant medication or switching to another antidepressant (within the same or a different pharmacological class) or augmentation with another pharmacological or psychological treatment. Psychological therapies that may be given as an adjunct can be broadly categorised into four separate philosophical and theoretical schools: (1) psychodynamic/psychoanalytic (Freud 1949; Klein 1960; Jung 1963); (2) behavioural (Watson 1924; Skinner 1953; Marks 1981); (3) humanistic (Maslow 1943; Rogers 1951; May 1961) and (4) cognitive (Lazarus 1971; Beck 1979). In addition, the 'third wave' (Hayes 2004; Hayes 2006; Hofmann 2008) and 'integrative' (Klerman 1984; McCullough 1984; Ryle 1990; Shapiro 1990; Hollanders 2007; Weissman 2007) psychological approaches may also be used. There are elements that both overlap and differ between these approaches. For example, cognitive analytic therapy (CAT) (Ryle 1990) incorporates elements from several theoretic schools, whereas interpersonal therapy for depression (IPT) (Klerman 1984) is disorder specific. The most influential cognitive approaches have merged with the behavioural approach to form cognitive behavioural therapy (CBT) (Ellis 1962; Beck 1979), which is now viewed as a family of therapies that draw upon a common base of cognitive and behavioural models of psychological disorders (Mansell 2008).
How the intervention might work
Psychological therapies such as CBT have been shown to be effective treatments for people with depression (Churchill 2001). When a psychological therapy is given as an adjunct to pharmacological treatment it is hoped that this may optimise the benefits gained from these different treatment approaches. In terms of the mechanism of action for the different psychological therapies, in CBT, the person's unrealistic and unhelpful negative thoughts ("dysfunctional attitudes") are targeted in order to improve outcome, whereas in behavioural therapy, the focus is on changing maladaptive patterns of behaviour. In contrast, humanistic therapy is focused on increasing an individuals self awareness, and psychodynamic therapy focuses on past experiences and understanding how these events might have influenced the individual and their current thoughts and behaviours.
Why it is important to do this review
Antidepressants continue to be the first-line treatment for many people with depression. However, only one-third of people prescribed antidepressants for depression will respond fully to such medication (Trivedi 2006). It is, therefore, important to summarise the evidence for the effectiveness of psychological therapies for people with treatment-resistant depression (TRD) in order to establish the best 'next step' treatment for this patient group.
There have several narrative reviews of the evidence on the treatment of people whose depression has not responded to antidepressant medication alone (e.g. Nierenberg 2007; Carvalho 2008; Papakostas 2009). Systematic reviews of the effectiveness of combination treatment for people with depression have not examined the evidence for the treatment-resistant population (Friedman 2004; Pampallona 2004). Others have summarised the evidence for the effectiveness of particular treatment strategies for those who have not responded to antidepressants: (1) augmentation (Carvalho 2007) with lithium (Bauer 1999) or atypical antipsychotics (Shelton 2008); (2) within- or between-class switches (Papakostas 2008) and (3) psychological treatments (McPherson 2005). One review focused on interventions for older people (≥ 55 years of age) (Cooper 2011). However, a number of these reviews included uncontrolled studies, non-randomised studies, or a combination of these, as well as randomised controlled trials (RCTs) (McPherson 2005; Carvalho 2007; Shelton 2008; Cooper 2011).
A previous systematic review of RCTs investigating pharmacological and psychological therapies for people with TRD found no strong evidence to guide the management of such people (Stimpson 2002). However this review, along with others (e.g. Bauer 1999, which summarised the evidence for lithium up to June 1997) is out-of-date and a number of relevant RCTs have been published subsequently.
While many studies have defined TRD as 'failure to respond to at least two previous antidepressants', we know that many people do not respond to an initial course of antidepressants and there is little evidence to inform the most appropriate 'next step' treatment for this group (NICE 2009). Therefore, given the continued reliance upon antidepressants as a first-line treatment for adults with depression, we propose using an inclusive definition of treatment resistance (based on non-response to at least four weeks of antidepressant medication) in order to help establish the best 'next step' of treatment for the significant number of people whose depression does not respond to antidepressant medication. The rise in antidepressant prescribing in recent years means that a review of the evidence for the effectiveness of psychological therapies for people with TRD is timely (Pincus 1998, McManus 2000, Middleton 2001).
Studies examining pharmacological interventions for TRD will be excluded as these are the focus of another review (Williams 2013). Together, the evidence from these two linked reviews will provide a comprehensive review of the main interventions for the management of TRD, which will inform clinical decision-making with regards to the best 'next step' for adults whose depression has not responded to first-line treatment with medication.
To assess the effectiveness of psychological therapies for TRD in adults.
Criteria for considering studies for this review
Types of studies
RCTs and cluster RCTs will be included.
Trials using a cross-over design will be included but only data from the first treatment phase will be used.
Any other study design, including quasi-randomised studies and non-randomised studies will be excluded from this review.
Types of participants
Participants must be aged 18 to 74 years.
If the study includes some participants that are aged under 75 years and some over the age of 74 years, we will exclude the study if the mean age of participants is over 74 years. Similarly, if the study includes some participants that are aged under 18 years and some aged 18 years or older, we will exclude the study if the mean age of participants is less than 18 years.
Definition of treatment-resistant depression
A primary diagnosis of unipolar depression that has not responded (or has only partially responded) to a minimum of four weeks of antidepressant treatment at a recommended dose (at least 150 mg/day imipramine or equivalent antidepressant (e.g. 20 mg/day citalopram)).
Studies that include people who have not responded because of intolerance of antidepressant medication will be excluded.
While there have been initiatives to improve access to psychological therapies in England and elsewhere, access to psychological treatment is still limited and antidepressants are often the first-line treatment for adults with depression. Therefore, this review will not include studies of interventions for those who have not responded to psychological treatment.
Acceptable diagnoses of unipolar depression include those based on criteria from DSM-IV-TR or earlier versions (APA 2000), International Classification of Diseases (ICD)-10 (WHO 1992) or Feighner criteria (Feighner 1972) or Research Diagnostic Criteria (Spitzer 1978). Studies that have not used standardised diagnostic criteria will be excluded.
Studies of participants with comorbid schizophrenia or bipolar disorder will be excluded.
Studies including both unipolar and bipolar participants will be excluded unless data are available for the subgroup of unipolar participants.
Studies involving participants with comorbid physical conditions or other psychological disorders (e.g. anxiety) will be eligible for inclusion as long as the comorbidity is not the focus of the study.
Types of interventions
- Any psychological therapy as monotherapy: that is, where the intervention comprises only a psychological therapy; or
- Any psychological therapy as an adjunct to antidepressant therapy: that is, where the intervention has been given in addition to an antidepressant.
Psychological therapies will be grouped into (1) psychodynamic/psychoanalytic; (2) cognitive/behavioural; (3) humanistic and (4) integrated therapies. The 'integrated therapies' category will include integrative therapies such as IPT and CAT that include components of different psychological therapy models. 'Third wave' cognitive/behavioural therapy-based approaches will be included in group 2.
- An antidepressant, of which there are five main types: TCA, MAOIs, SSRIs, SNRIs and NaSSAs; or
- Another psychological therapy, which will be grouped as above; or
- An attentional control that provides the same amount of support and attention from a practitioner (as is received by those in the experimental intervention arm) but does not contain any of the key 'active' ingredients of the experimental intervention.
Studies examining pharmacological interventions for individuals with TRD will be included in another review (Williams 2013).
Types of outcome measures
1. Change in depressive symptoms as measured on rating scales for depression, either clinician rated (e.g. Hamilton Rating Scale for Depression (HAM-D; Hamilton 1960) or Montgomery-Asberg Depression Rating Scale (MADRS; Montgomery 1979)), or self report (e.g. Beck Depression Inventory (BDI; Beck 1961; Beck 1996) or other validated measures). Data on observer-rated and self report outcomes will be analysed separately.
2. Number of drop-outs within the trials, which indicates compliance rates with different treatments. Data on reasons for drop-out will be collected, where available, and will be summarised in narrative form.
3. Response or remission rates, or both, based on changes in depression measures - either clinician rated (e.g. HAM-D; Hamilton 1960)) or self report (e.g. BDI; Beck 1961; Beck 1996) or other validated measures). Response is frequently quantified as at least a 50% reduction in symptoms on the HAM-D or BDI but we will accept the study's original definition. Remission is based on the absolute score on the depression measure. Examples of definitions of remission include 7 or less on the HAM-D and 10 or less on the BDI. Again, we will accept the study authors' original definition.
4. Improvement in social adjustment and social functioning including the Global Assessment of Function (Luborsky 1962) scores, where reported will be summarised in narrative form.
5. Improvement in quality of life as measured on the Short Form (SF)-36 (Ware 1993), Health of the Nation Outcome Scales (HoNOS) (Wing 1994), or World Health Organization Quality of Life (WHOQOL) (WHOQOL 1998) or similar scale, where reported will be summarised in narrative form.
6. Economic outcomes, for example days of work absence/ability to return to work, number of appointments with primary care physician, number of referrals to secondary services, use of additional treatments, where reported will be summarised in narrative form.
7. Adverse effects, for example completed/attempted suicides, where reported, will be summarised in narrative form
Timing of outcome assessment
Outcomes at each reported follow-up point will be summarised. Where appropriate and if the data allow, outcomes will be categorised as short term (up to six months), medium term (seven to 12 months post-treatment) and long term (longer than 12 months).
Search methods for identification of studies
Cochrane Depression, Anxiety and Neurosis group's Specialized Register (CCDANCTR)
The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) maintain two clinical trials registers at their editorial base in Bristol, UK, a references register and a studies-based register. The CCDANCTR-References Register contains over 31,500 reports of trials in depression, anxiety and neurosis. Approximately 65% of these references have been tagged to individual, coded trials. The coded trials are held in the CCDANCTR-Studies Register and records are linked between the two registers through the use of unique Study ID tags. Coding of trials is based on the EU-Psi coding manual. Please contact the CCDAN Trials Search Co-ordinator for further details. Reports of trials for inclusion in the Group's registers are collated from routine (weekly), generic searches of MEDLINE (1950-), EMBASE (1974-) and PsycINFO (1967-); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review-specific searches of additional databases. Reports of trials are also sourced from international trials registers via the World Health Organization's trials portal (ICTRP); drug companies; and handsearching of key journals, conference proceedings and other (non-Cochrane) systematic reviews and meta-analyses.
Details of CCDAN's generic search strategies can be found on the Group's website.
The CCDANCTR-Studies Register will be searched using the following terms:
Condition = ((depressi* or "affective disorder" or "mood disorder*") and ("treatment resistant" or recurrent))
The CCDANCTR-References will be searched using a more sensitive set of terms (keywords and subject headings) to identify additional untagged/uncoded references:
1. depressi* [Ti, Ab, KW]
2. (*refractory* or *resistan* or *recurren*) [Ti, Ab]
3. (augment* or potentiat*) [Ti, Ab]
4. (chronicity or "chronic depress*" or "chronically depress*" or "depressed chronic*" or "chronic major depressi*" or "chronic affective disorder*" or "chronic mood disorder*" or (chronic* and (relaps* or recurr*))) [Ti, Ab, KW]
5. ("persistent depress*" or "persistently depress*" or "depression persist*" or "persistent major depress*" or "persistence of depress*" or "persistence of major depress*") [Ti, Ab]
6. (nonrespon* or non-respon* or "non respon*" or "not respon*" or "no respon*" or "partial respon*" or "partially respon*" or "incomplete respon*" or "incompletely respon*" or unrespon*) [Ti, Ab]
7. ("failed to respond" or "failed to improve" or "failure to respon*" or "failure to improve" or "failed medication*" or "antidepressant fail*" or "treatment fail*") [Ti, Ab]
8. (inadequate* and respon*) [Ti, Ab]
9. "treatment resistant depression" [KW]
10. (recurrence or "recurrent depression" or "recurrent disease") [KW]
11. "drug resistance" [KW]
12. "treatment failure" [KW]
13. "drug potentiation" [KW]
14. augmentation [KW]
16. (1 and 15)
The WHO trials portal (ICTRP) and ClinicalTrials.gov will also be searched for 'treatment resistant' or 'treatment refractory' depression to identifying any additional ongoing or unpublished studies. Principal Investigators will be contacted, where necessary, to obtain further details of ongoing/unpublished studies, or trials reported as conference abstracts only.
There will be no date or language restrictions applied to our search.
Searching other resources
Reference lists of all included studies and other relevant systematic reviews will be searched for papers that may meet inclusion criteria. Subject experts will also be contacted to ensure that all relevant published and unpublished studies have been considered for inclusion.
Data collection and analysis
Selection of studies
One review author (NW) will examine titles and abstracts to remove obviously irrelevant reports and then screen study abstracts against inclusion criteria using a standardised abstract screening form. In any case of uncertainty an over-inclusive approach will be taken and the full paper will be obtained along with those for the studies assessed as meeting the inclusion criteria. Two review authors will screen each paper for inclusion or exclusion from the review. If any disagreements arise these will be discussed with a third review author. If it is not possible to determine eligibility for a study, it will be added to the list of those awaiting assessment and the authors will be contacted for further information or clarification.
The study selection processed will be documented using a PRISMA study selection flow diagram, which will be presented in the review.
Data extraction and management
Data regarding participants, interventions and their comparators, methodological details, treatment effects including dropouts, and possible biases will be independently extracted by two review authors using a standardised data extraction form. If any disagreements arise these will be discussed with a third review author. The data extraction form will be piloted during the first phase of data extraction.
Information relating to the study population, definition of TRD, sample size, interventions, comparators, potential biases in the conduct of the trial, outcomes, follow-up and methods of statistical analysis will be abstracted.
Main planned comparisons
- Any psychological therapy that was compared to antidepressant treatment alone;
- Any psychological therapy that was compared to another psychological therapy; and
- Any psychological therapy given in addition to antidepressant medication compared to antidepressant treatment alone.
- Any psychological therapy given in addition to antidepressant medication compared to a psychological therapy alone.
For comparison 2, the different types of psychological therapies will be grouped according to the list given earlier.
If possible, the effectiveness of different types of psychological therapies (as listed earlier) within such strategies will be examined for comparisons 1, 3 and 4.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each included study using The Cochrane Collaboration's 'Risk of bias' tool (Higgins 2011a). If any disagreements arise these will be discussed with a third review author. The following criteria will be assessed:
- sequence generation: was the allocation sequence adequately generated?
- allocation concealment: was allocation adequately concealed?
- blinding of participants, study personnel and outcome assessors for each outcome: was knowledge of the allocated treatment adequately prevented during the study?
- incomplete outcome data for each main outcome or class of outcomes: were incomplete outcome data adequately addressed?
- selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?
- other sources of bias: was the study apparently free of other problems that could put it at a high risk of bias?
A description of what was reported to have happened in each study will be provided and a judgement on the risk of bias will be made for each domain within and across studies, based on the following three categories: low risk of bias; unclear risk of bias; high risk of bias.
Where studies provide few or no details about randomisation review authors will be contacted to seek clarification.
All 'Risk of bias' data will be presented graphically and described in the text.
Measures of treatment effect
Continuous outcomes will be analysed by calculating the mean difference (MD) between groups, if studies use the same outcome measure for comparison. If different outcome measures are used to assess the same outcome, the standardised mean difference (SMD) and 95% confidence intervals (CI) will be calculated. The SMD will be interpreted as follows: 0.2 represents a small effect, 0.5 a moderate effect, and 0.8 a large effect (Cohen 1988).
Dichotomous outcomes will be analysed by calculating the odds ratio (OR) and 95% CIs for each comparison, and then converted to risk ratios (RR) using the formula provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When overall risks are significant, the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) to produce one outcome will be calculated by combining the overall RR with an estimate of prevalence of the event in the control group of the trials.
Unit of analysis issues
Results from cluster RCTs will be incorporated into the review using generic inverse variance methods (Higgins 2011). With cluster RCTs, it is important to ensure that the data have been analysed taking into account the clustered nature of the data. The intracluster correlation coefficient (ICC) will be extracted for each trial. Where no such data are reported, this information will be requested from study authors. If this is not available, in line with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will use estimates from similar studies in order to 'correct' data for clustering, where this has not been done.
For cross-over trials only results from the first randomised treatment period will be included in the analysis.
Studies with multiple treatment groups
Studies that have more than two arms (e.g. psychological intervention (A); psychological intervention (B) and control) can cause problems in pair-wise meta-analysis. If any studies are identified with two or more active treatment arms, then the following approach will be undertaken dependent on whether the outcome is continuous or dichotomous.
For a continuous outcome: means, standard deviations (SDs) and the number of participants for each active treatment group will be pooled across treatment arms as a function of the number of participants in each arm to be compared against the control group (Higgins 2011).
For a dichotomous outcome: active treatment groups will be combined into a single arm for comparison against the control group (in terms of the number of people with events and sample sizes), or the control group will be split equally (Higgins 2011).
Dealing with missing data
Where there are missing data, study authors will be contacted to obtain data. If an outcome is missing for more than 50% of participants this study will be excluded from the analysis. If SD data are unobtainable but are available for the majority of other included studies, these will be calculated by using an imputation that which is based on the SDs of the other included studies (Furukawa 2006).
Missing dichotomous data will be managed using an intention-to-treat (ITT) analysis in which it will be assumed that participants who dropped out after randomisation had a negative outcome. In addition, best/worse-case scenarios will also be calculated, in which it will be assumed that dropouts in the intervention group have positive outcomes and those in the comparator group have negative outcomes (best-case scenario) and that dropouts in the intervention group had negative outcomes and those in the comparator group had positive outcomes (worst-case scenario), thus giving boundaries for the observed treatment effect
Missing continuous data will be managed using a last observation carried forward (LOCF) analysis if LOCF data was reported, or on end point data alone.
Assessment of heterogeneity
Heterogeneity will be assessed using the Chi
Assessment of reporting biases
Reporting bias will be managed by undertaking comprehensive searches for papers that will not be restricted to the English language. Outcome reporting bias will be determined for all included studies and trial protocols will be sought wherever possible. If outcome data are missing this will be requested from authors. Funnel plots will be used to help detect reporting biases if at least 10 studies are included (Higgins 2011). Formal testing of asymmetry in the funnel plot will be examined using the Egger test (Egger 1997).
Given the potential for heterogeneity in the included interventions, we will use a random-effects model for all analyses.
This approach will incorporate the assumption that the different studies are estimating different, yet related, intervention effects and it takes into account differences between studies even if there is no statistically significant heterogeneity. Heterogeneity will be tested formally using both the Chi
If a meta-analysis is not possible (for example, due to insufficient data or substantial heterogeneity), a narrative assessment of the evidence will be given. This will summarise the evidence according to intervention type.
Subgroup analysis and investigation of heterogeneity
The degree of treatment resistance recorded at the point of entry to the trial is expected to have an impact on outcome. Therefore, the following subgroup analysis will be undertaken:
- severity of depression (non-responders compared with partial responders): the severity of depression is expected to have an impact on outcome. Heterogeneity analyses are, therefore, planned to categorise severity according to whether participants were classified as being 'non-responders' or 'partial responders' at baseline;
- length of acute treatment phase: there are likely to be differences in the length of the duration of antidepressant treatment prior to trial entry that would be expected to affect outcome. Length of acute treatment phase will be categorised as: four weeks or longer; 12 weeks or longer; six months or longer.
Such subgroup analyses will only be conducted when there are data from at least 10 studies to be included (Higgins 2011).
Sensitivity analyses were planned to explore how much of the variation between studies comparing psychological therapies for TRD was accounted for by between-study differences in:
- study quality: allocation concealment is to be used as a marker of trial quality. Studies that have not used allocation concealment will be excluded;
- attrition: studies with more than 20% dropout will be excluded;
- missing data: studies that have imputed missing data will be excluded;
- treatment fidelity: studies that have not measured treatment fidelity of the psychological model will be excluded;
- publication type: studies that have not been published in full (conference abstract/proceedings, doctoral dissertation) will be excluded.
Summary of findings table
'Summary of findings' tables will be prepared for all relevant comparisons. Each table will include all outcomes.
CRG funding acknowledgement
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Depression, Anxiety and Neurosis Group.
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.
Contributions of authors
NW drafted the protocol, which was finalised following comments from all review authors. NW will undertake the abstract screening. All review authors will contribute to the extraction of data from those papers included in the second stage of the review. NW will write the first draft of the review, which will be commented upon by all review authors. NW will act as guarantor of the review.
Declarations of interest
NW is Chief Investigator of the National Institute for Health Research HTA funded COBALT trial (CBT as an adjunct to pharmacotherapy for TRD in primary care: ISRCTN38231611) and DK and GL are Principle Investigators. NW, DK, and GL are authors on two papers (Wiles 2008; Wiles 2013) included in this review. CW has no conflicts to declare.