Interventions for preventing relapse and recurrence after the first episode of a depressive disorder in young people
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objectives of the review are to examine the impact of intervention on the likelihood of relapse and recurrence in two early intervention groups; (1) those experiencing a case level episode during childhood or adolescence (defined as ages up to 18 years old), and (2) those experiencing a first case level episode of depression, irrespective of their age.
Background
Description of the condition
It is well established that depressive disorders are highly recurrent (Belsher 1988). Indeed, for approximately 50% of those who suffer from depression their illness will follow a chronic, relapsing course associated with considerable disability and impairment (Crown 2002). Furthermore, research suggests that in many individuals, depressive episodes show a worsening pattern over the course of repeated episodes, characterized by increased severity, frequency, and autonomy (i.e., episodes are less clearly precipitated by psychosocial stress), and lack of responsiveness to initially effective treatments (Kendler 2000; Post 1992). Despite advances in the treatment of depression, research shows that the long‐term outcome for those who experience multiple episodes has altered little over the last 20 years (Kennedy 2003). In sum, it appears that for many people the first case level episode of depression becomes a gateway to a relapsing form of depression that is associated with considerable disability over the lifespan.
In a review of epidemiological studies, estimates of prevalence ranged between 0.4% and 2.5% for major depressive disorder (MDD) in children and 0.4% and 8.3% for MDD in adolescents and between 0.6% and 1.7% for dysthymic disorder (DD) in children and 1.6% and 8.0% for DD in adolescents (Birmaher 1996). A more recent meta‐analysis put the prevalence of depressive disorders in children (aged under 13 years) at 2.8% and adolescents (aged 13‐18years) at 5.7% (Costello 2006). Depressive disorders tend to have their onset in adolescence or early adulthood (Kessler 2005; Rutter 1995), suggesting that interventions that have the potential to reduce relapse are particularly critical in this age group, and may be able to influence a critical change to the lifetime course of the disorder. This is especially important given the high level of continuity between depressive disorders in childhood/adolescence and adulthood (Harrington 1990; Lewinsohn 1999), and the fact that early onset of depression is associated with significant reductions in "human capital" (i.e., educational and vocational attainment) in affected individuals (Berndt 2000).
Description of the intervention
The provision of effective interventions at the first episode is important in order to reduce the likelihood of recurrent episodes, which have been demonstrated to occur more frequently as the illness progresses (Kessing 2004). There is compelling evidence that intervention in this early stage may prevent the development of cognitive factors associated with recurrent episodes (Kendler 2000; Ma 2004; Lewinsohn 1999).
While the terminology 'first episode' is now frequently used in the area of psychosis (McGorry 2006), and is the basis of much research in early intervention, it is not yet widely used in the area of depression, nevertheless it has the potential to serve a similar purpose as it has in psychosis and drive the area of early intervention (Allen 2007; Hetrick 2008).
Any early intervention approach to depressive disorders must have a strong emphasis on relapse prevention as a primary outcome of interest. In order for early intervention approaches to have a truly significant impact, they must not only reduce the acute symptoms associated with depressive disorder, but should also aim to alter, or prevent the development of, underlying vulnerability factors that determine the likelihood of relapse and chronicity following the first episode.
Despite this compelling argument for early intervention to prevent relapse, there have been no specific studies of relapse prevention for the first episode of depression. Given that for many the first episode occurs during childhood or adolescence, studies in this population are potentially relevant. Some studies undertaken in children and adolescents, for example, Emslie and colleagues (Emslie 2004), have found that treatment with fluoxetine significantly delayed the return of symptoms. Booster CBT sessions have not been shown to reduce the rate of recurrence compared to assessment sessions, but have accelerated recovery for adolescents who remain depressed at the end of the acute phase of treatment (Clarke 1999). However, in another small study, booster CBT sessions resulted in relapse rates of 6% compared to 50% in a comparison group who had no continued therapy (Kroll 1996). Studies in adult populations suggest medication is effective, but only while it is being taken (Geddes 2003; Keller 2005; Rapaport 2004; Simon 2004). Cognitive behavioural therapy (Hensley 2004) and more recently, mindfulness based cognitive therapy, have shown longer lasting effects (Ma 2004; Teasdale 2000).
It has been demonstrated, however, that what is considered effective for adults may not be effective in younger populations, as in the case of tricyclic antidepressants (Hazell 2002). Recent reviews highlight uncertainty about the risk‐benefit ratio of SSRIs (Bridge 2007; Hetrick 2007) and suggest the effects of CBT and other psychotherapies are modest at best in this younger population (Weisz 2006). Further, there have been inconsistent findings regarding the combined use of SSRIs and CBT with adolescents (Clarke 2005; Goodyer 2007; March 2004; Melvin 2006).
Why it is important to do this review
Given the uncertainties and inconsistencies regarding effective treatment of depressive disorders to prevent relapse of the first episode (and in children and adolescents), a systematic review of the literature is warranted.
Objectives
The objectives of the review are to examine the impact of intervention on the likelihood of relapse and recurrence in two early intervention groups; (1) those experiencing a case level episode during childhood or adolescence (defined as ages up to 18 years old), and (2) those experiencing a first case level episode of depression, irrespective of their age.
Methods
Criteria for considering studies for this review
Types of studies
Any published (including Internet publication) or unpublished randomised controlled trials, including unpublished abstracts and reports of any intervention to prevent relapse or recurrence from major depressive disorder (MDD) or dysthymic disorder (DD) after a first episode including children and adolescents.
There will be no time or language restrictions.
Types of participants
Patients of any age or gender after response/remission from a first episode of major depressive disorder (MDD) or dysthymic disorder (DD), diagnosed by a clinician using any diagnostic system (DSM or ICD), as well as children and adolescents after response/remission from a diagnosed episode of MDD or DD, will be included.
Given the difficulties in defining recovery and relapse in DD, MDD and DD will be treated separately. MDD or DD must have been the primary diagnosis, but comorbidity will be permitted, except for psychosis or bipolar disorder.
Trials of participants with an intellectual quotient (IQ) of less than 70, organic brain injury or serious medical condition will be excluded.
Types of interventions
Intervention
Any type of pharmacotherapy or psychological therapy will be included. Categories of pharmacotherapy will include tricyclic antidepressants, SSRIs, SNRIs, anxiolytic medication, mood stabilizers and other. Categories of psychological therapy will include CBT based, psychodynamic, family, interpersonal and supportive/non‐directive and other.
It is anticipated that two potential study designs will be encountered: 1) where acute treatment of a depressive episode occurs with long term follow‐up to collect measures of relapse/recurrence and; 2) where those who have recovered from an episode of depression are recruited into a study of intervention to prevent relapse/recurrence. Both designs will be included but analysed separately.
Within the first type of study (1), there is likely to be considerable heterogeneity in the design of the study, for example, some psychological studies may use 'booster sessions'; pharmacological studies include both those where participants are continued on acute medication and followed up, and those where participants are re‐randomised to new types of intervention (including placebo). These studies will be analysed separately.
Control comparison
Intervention groups will be compared to: no intervention (including waitlist control), placebo control as well as other active intervention control groups (pharmacological or psychological).
Types of outcome measures
Primary outcomes
1. Prevention of second or next episode measured by:
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The number who meet criteria for relapse (as defined by trialists on a scale of depression symptoms or by diagnosis using DSM or ICD criteria) or
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The number who are readmitted or re‐present to a service for treatment
Relapse and recurrence are defined variously by trialists, and the definition used by trialists will be used as it is unlikely that individual patient data will be collected so that a consistent definition can be used as the review outcome. Rather, the definitions used will be extracted and documented.
2. Time to relapse
3. Functioning including overall functioning, social, academic/occupational functioning and quality of life
Secondary outcomes
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Symptoms measured on any standardised, validated and reliable rating scale
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Suicidal ideation/attempt
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Emergence of secondary morbidity including emergence of secondary co‐morbid conditions and switch to bipolar disorder
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Drop‐outs
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Adverse outcomes
Search methods for identification of studies
For more information see: Depression, Anxiety and Neurosis Collaborative Review Group search strategy
Electronic searches
The register of trials kept by the CCDAN Cochrane Group will be searched by the Trials Search Co‐ordinator using the following terms:
CCDANCTR‐Studies
Diagnosis = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood
Disorder*" or "Affective Disorder" or "Affective Symptoms")
and
Note = "Relapse prevention"
CCDANCTR‐References
Keyword = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood
Disorder*" or "Affective Disorder" or "Affective Symptoms")
and
Free‐text = maintenance* or maintain* or continu* or discontinu* or
prevent* or relapse* or prophyla*
Searching other resources
Reference lists
The reference lists of articles and other reviews retrieved in the search will be searched.
Handsearching
Conference abstracts for the Child Depression Consortium in 2000‐2005 will be handsearched where a hard copy is available.
Personal Communication
In order to ensure that as many as possible RCTs are identified, the authors of the included trials and other experts in the field will be consulted to find out if they know of any published or unpublished RCTs in the area, and which were not yet identified.
Data collection and analysis
Selection of studies
Two review authors will independently select trials for possible inclusion in the study. Firstly, the titles and abstracts of trials identified from the search will be independently reviewed. Secondly, each review author will independently examine the full text of all studies that they consider to be of possible relevance. Each review author will compile a list of studies, which they believe meet the inclusion criteria. The contents of each review author's list will be compared, and any discrepancies discussed. Any disagreement will be resolved by discussion and consensus between all of the review authors.
Data extraction and management
Two review authors will independently extract data using specially developed data extraction forms. Information will be collected on:
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participants (including summary information where applicable): age, gender, how the diagnosis was made, length of untreated illness, length of index episode, number of previous episodes, age of onset, baseline severity of depression, setting including inpatient versus outpatient, suicide‐related behaviours/level of suicidal ideation/risk of suicide, index of socio‐economic status (SES) including any of household income, family employment, neighbourhood SES etc, family factors including any of number of parents residing at home, family employment/education/family history of physical and mental illness, child medical illness, child co‐morbid conditions (physical and mental, Axis I and II), child temperament/personality, recruitment strategy, country
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interventions and comparisons: description of medication including method of delivery, dose, length of treatment, intended and actual dose received, and/or description of psychological intervention including type, whether it is delivered to groups or individuals, is manualised, who delivers it and for how long, and the actual number of sessions attended. Information on other adjunctive interventions will also be collected.
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outcome measures: description of measures used, timing of assessment, continuous/dichotomous nature, psychometric properties, references;
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results: point estimates and measures of variability, frequency counts for dichotomous variables
One review author will compile all comparisons and enter outcome data into Review Manager software for meta‐analysis. A second review author will perform double‐data entry to ensure accuracy of results. Missing data will be obtained from trial authors wherever possible.
Assessment of risk of bias in included studies
Two review authors will independently assess the risk of bias of the included trials using a descriptive approach as advocated by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). For the following items, a description of methods be noted, and the review author's judgement about the resulting risk of bias will be made:
1. Adequate sequence generation?
2. Allocation concealment?
3. Blinding? (participant ratings and clinician ratings)?
4. Incomplete outcome data addressed?
5. Free of selective reporting?To assess reporting bias, we will record which of the review outcomes were available with usable data from each included trial, as well as noting which of the review outcomes were only reported in terms of whether there were significant differences between groups. Additionally, the other outcomes (not collected for the review) reported by the trialists in the paper publication(s) will be compiled.
6. Free of other bias?
Measures of treatment effect
For dichotomous outcomes, such as 'relapse', results from each trial will be expressed as a Risk Ratio (RR) with 95% confidence intervals, and combined in meta‐analysis.
Continuous outcomes, such as symptom measures, may be presented in several ways. When absolute values of post‐treatment means and standard deviations (SD) are given, using the same rating scale across studies, these will be used to calculate the mean difference (MD) and 95% confidence intervals. If different scales are used to measure the same outcomes the standardised mean difference (SMD) will be calculated with 95% confidence intervals and then combined for meta‐analysis. Many trials in psychiatry report estimates of treatment effects from multiple linear regression models. These models adjust for varying factors such as age, sex, and baseline of the outcome. Treatment estimates from these trials will be pooled (inverse variance) meta‐analysis. P‐values and confidence intervals for treatment effect will be converted to standard errors and entered into RevMan using the generic inverse variance.
Unit of analysis issues
Where a study has more than one active treatment arm, the appropriate arms for each of our main comparisons would be extracted. If more than one comparison was relevant, both could be included in the comparison, however, only subtotals, rather than totals would be allowed in the meta‐analysis, so that double counting of data would not occur.
Dealing with missing data
Missing data will be obtained from trial authors wherever possible. Missing data will be imputed where necessary (e.g. calculating SDs from standard errors and p‐values) and this will be clearly documented in the review. If available, intention to treat data will be used, with a note of the methods used (such as last observation carried forward or other types of modelling) for imputing missing data. If possible, observed case data will be also analysed and the results checked for robustness.
Assessment of heterogeneity
Clinical homogeneity will be satisfied when participants, interventions and outcome measures are considered to be similar. For trials that are clinically heterogeneous or present insufficient information for pooling, a descriptive analysis will be performed. For trials that are clinically heterogeneous or present insufficient information for pooling, a descriptive analysis will be performed. Statistical homogeneity will be assessed using the I2. If statistical heterogeneity is found (>50%). it will be examined using specified subgroup and sensitivity analyses. It should be noted that sensitivity analyses will also be carried out regardless of heterogeneity to assess the robustness of results to methods used.
Assessment of reporting biases
We will investigate the potential for publication bias using a funnel plot for the primary outcomes relating to AN recovery and/or symptoms. Publication bias has long been associated with funnel plot asymmetry, however, asymmetry may be due to reasons other than publication bias and is difficult to assess in the case of a small number of trials. For this reason, an assessment of the risk of reporting bias will also be included as stated above.
Data synthesis
For all meta‐analyses a fixed effects (Mantel 1959) meta‐analysis will be used in the first instance. If statistical heterogeneity is found it will be examined by subgroup and sensitivity analyses. If this does not account for heterogeneity, we will use random effects models (DerSimonian 1986). When the pooled summary statistic differs clinically between models, this will be reported.
Subgroup analysis and investigation of heterogeneity
1. Trials of children/adolescents versus trials of first episode
2. Subgroup children versus adolescents in trials of children/adolescents
3. Subgroup children versus adolescents versus adults in trials of first episode
4. Type of intervention (psychological and pharmacological) and comparison (no intervention or placebo and other type of active intervention ‐ psychological and pharmacological).
Sensitivity analysis
Sensitivity analyses will be performed to assess the effect of risk of bias that may be introduced due to the decisions made in the process of undertaking the review. For example, how robust are results to the influence of the type of analysis undertaken, whether fixed or random effects. In psychiatry trials it is important to investigate the impact of assumptions made in various imputation methods used to account for missing data so that comparisons will be made between analysis using last observation carried forward (LOCF) and observed case (OC) data where possible. Sensitivity analysis will also be undertaken excluding trials where there is a greater than 20% drop out.
Timeline
The review will be completed within 12 months of publication of the protocol.
