Pharmacological interventions for

adjustment disorders in adults

Cochrane Systematic Review - Intervention - Protocol Version published: 04 June 2013
https://doi.org/10.1002/14651858.CD010530
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 Patricia Casey
 Divina Pillay
 Lorna Wilson
 Andreas Maercker
 Angela Rice
 Brendan Kelly

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Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and tolerability of pharmacological interventions for the treatment of AD
in adults.

Background
Description of the condition

Adjustment disorder (AD) is defined as an abnormal reaction that occurs in response to a

stressful event, such as work‐related problems, marital difficulties, familial problems and a range
of other stressors, either acute or long term (Despland 1995). AD is distinguished from normal
adaptive reactions to stressful events by the severity of symptoms or the impairment in
functioning, or both. In psychiatry it is recognised that life events often have a role in triggering
a range of illnesses such as major depressive disorder (MDD) but their presence is not essential,
unlike in AD, where the diagnosis is contingent upon the presence of an identifiable and recent
stressor. Psychiatric disorders are defined using two international systems of classification. The
International Classification of Diseases 10th edition (ICD‐10) (WHO 1992) is the World Health
Organization compendium and the Diagnostic and Statistical Manual 4th edition (DSM‐IV) is
the American Psychiatric Association equivalent (APA 1994). Both recognise AD although there
are some minor differences between the terminology and criteria used in each.
The symptoms of AD are similar to those of MDD and generalised anxiety disorder (GAD);
therefore, distinguishing AD from other syndromes is difficult (Casey 2006). As well as
symptoms, there may also be disturbance in functioning and sometimes this may be the dominant
feature. ICD‐10 requires the presence of both symptoms and impaired functioning before a
diagnosis can be made, while DSM‐IV specifies that one or the other may be present.
Several subtypes of AD are described in both DSM‐IV and ICD‐10, based on the dominant
symptom patterns or the behaviour exhibited. These consist broadly of AD with depression, AD
with anxiety, AD with disturbance of conduct and AD with mixed states (WHO 1992; APA
1994). AD may be acute (less than one month in ICD‐10 or less than six months in DSM‐IV) or
chronic (more than one month but less than two years in ICD‐10 or more than six months in
DSM‐IV). It is a self limiting condition and the prognosis is excellent with complete
symptomatic and functional resolution being common unless there are persistent stressors. Even
among those with AD who require psychiatric admission there are significantly fewer
readmissions than among those with GAD, MDD or dysthymia/sub‐threshold depression (Jones
2002), and less frequent use of outpatient and psychotherapeutic services (Bronisch 1991).
In certain groups of people AD is common. Among those who deliberately self harm (intentional
self injury or self poisoning irrespective of the underlying NICE definition motivation) (NICE
2004), AD is the most common clinical diagnosis (Taggart 2006). It is also prominent in
consultation‐liaison psychiatry, being diagnosed in about 12% of psychiatric referrals in general
hospitals (Strain 1998; Huyse 2001). Among acutely ill medical inpatients (Silverstone 1996)
and in obstetric/gynaecology consultation‐liaison (Rigatelli 2002) it is more common than other
mood disorders including MDD. In a palliative care setting a recent meta‐analysis found that the
prevalence of AD was 15.4% and only marginally less than that for major depression (16.5%),
while in oncological settings AD was more common than major depression (19.4% versus
14.9%) (Mitchell 2011). In primary care there are few studies but a prevalence range from 1% to
18% of consulters (Casey 1984; Blacker 1988) has been described, while a recent study
identified AD in 2.4% of primary care consulters with emotional problems (Fernandez 2012).
Within the psychiatric services, AD was identified in 11% to 36% of new outpatient referrals,
depending on the assessment method (Shear 2000), and in around 9% of consecutive admissions
to a public sector psychiatric unit (Koran 2002). The public health implications of AD are
unclear since the data suggest that it is an uncommon disorder in the general population, being
identified in only around 1% of the population (Ayuso‐Mateos 2001). Internationally, the focus
of service provision has been based on the very high prevalence of MDD as a major cause of
disease burden (Ustün 2004). This has led to the establishment of guidelines for the treatment of
depression (NICE 2009) in primary and secondary care including both pharmacological and
psychological treatments. However, if it is further shown (as some studies have done) that AD
might be the more appropriate diagnosis in many, due to conflation of the two conditions (Casey
2006), this could have major implications for the type and duration of treatment that is offered,
including whether any specific intervention other than general support is required for these self
limiting conditions. Major cost implications would flow from this, with significant savings on
the drugs budget.
There has been general neglect of AD in research (Casey 2001), in particular, the psychobiology
of the condition has received little attention. The focus in the few studies that have examined this
has been on the hypothalamic‐pituitary‐adrenal (HPA) axis. Cortisol levels after dexamethasone
suppression have shown different patterns in those with AD (with depressive features) in
comparison to MDD (Lindqvist 2008). There have been no studies on the psychobiology of the
other subcategories of AD. Thus, the treatment of AD is not at present underpinned by any
biological parameters.
For a condition that is as common as AD, especially in general hospital psychiatry as well as in
emergency settings involving self harming patients, it is crucial that treatment recommendations
are based on firm evidence and that the risks and benefits of recommended interventions are
carefully weighed.

Description of the intervention

The importance of AD is that it requires only limited treatment due to its tendency to be short
lived and to resolve spontaneously (Strain 2008). Pharmacological agents such as
benzodiazepines and hypnotics are recommended for symptomatic relief of anxiety and insomnia
in AD (Uhlenhuth 1995; Shaner 2000). Others recommend the use of alternative agents such as
valerian and kava‐kava since these are sometimes used in the treatment of GAD in preference to
anxiolytics because of their non‐addictive properties (Volz 1997). However, herbal remedies will
not be included in the present review as per Cochrane policy. The role of antidepressive agents is
much less clear in AD but one investigator (Stewart 1992) recommends their use in the treatment
of minor depression, a term that is often used interchangeably, albeit inaccurately, with AD. A
retrospective case note study (Hameed 2005) found that AD with depression showed a better
response to antidepressants than did MDD. No particular group of antidepressants has been
shown to be more effective than any other. Recommendations for the use of pharmacological
agents in AD are not accompanied by any guidance on dosage or duration of treatment. Neither
has there been any discussion on which antidepressive agents might be helpful in the treatment
of AD with depression, an important consideration in light of its spontaneous and, usually, rapid
resolution and the delay in onset of effect of antidepressants. On the other hand there have been
recommendations that the focus should be on psychological therapies (Strain 2008) such as
"mirror therapy", a form of holistic intervention used in those with AD post myocardial infarct
(Gonzáles‐Jaimes 2003), cognitive therapy for those who have AD associated with occupational
dysfunction (van der Klink 2003), "ego‐enhancing" therapy for older adults (Frankel 2001) and
general support (De Leo 1989). The recommendations for pharmacotherapy are based on the
opinions of individuals rather than on any examination of the evidence base for these
interventions.

How the intervention might work

The psychobiology of AD has received scant attention. Therefore, the biological rationale for
using pharmacological agents is unclear, apart from the pragmatic approach to prescribing for
symptomatic relief irrespective of the underlying psychobiology of the illness. This assumes that
the pathophysiology of subsyndromal conditions such as AD and full syndromes such as MDD
and GAD are the same and that the response to treatment will therefore be the same. This view
was reinforced by a recent systematic review that found antidepressants to be effective in
depression (MDD, AD and dysthymia) with physical illness (Rayner 2010).
In the treatment of MDD, antidepressants are believed to act by enhancing the activity of
monoamines (serotonin, adrenaline and dopamine) in the central nervous system and this might
be one possible mechanism by which this occurs in AD. A possible impact on the HPA axis,
thought to be involved in stress reactions and in MDD (Pariante 2008), might also be a
possibility although there is little firm evidence in the literature to support this in the case of AD.
Another view on the psychobiology of AD is that it is a stress reaction similar to acute stress
reaction and post‐traumatic stress disorder (PTSD) (Maercker 2008). Following from this, it is
arguable that broadly similar conditions such as AD might benefit from similar treatments that
include the selective serotonin reuptake inhibitors (SSRIs), as these have been shown to be
efficacious in this condition in a heterogeneous group of traumas of varying duration and
severity (Stein 2006). Their efficacy is thought to result from their impact in controlling the
dysregulation of the neurotransmitter systems and neuroendocrine systems (HPA axis), some of
which may also be abnormal in AD.
With regard to benzodiazepines in AD with anxiety disorders, it is likely that they will work in a
manner similar to that in GAD, by enhancing the action of gamma‐amino‐butyric acid (GABA)
although the role of GABA has not been studied in the AD with anxiety subtype.

Why it is important to do this review

Recommendations for pharmacological treatments for AD have been developed by expert

opinion rather than as a result of randomised controlled trials. Since it is a self limiting disorder,
the treatment recommendations are for brief interventions with an emphasis on psychological
therapies (Strain 2008) although there may be a role for the symptomatic treatment of insomnia
and anxiety symptoms with hypnotics or tranquillizers (Uhlenhuth 1995; Shaner 2000).
Despite the limited evidence of the benefits of pharmacological treatments, in particular
antidepressants, there are indications that antidepressants are increasingly being used in the
treatment of AD (Diefenbacher 2002), due to what some authors describe as the "culture of
prescribing" (Strain 2008). Recent data indicate that the condition which has shown the greatest
increase in antidepressant usage is AD, with the rate of prescription changing from 22.26 per 100
cases in 1996 to 39.37 per 100 cases in 2005 (Olfson 2009). Therefore, it is important to consider
the evidence, if any, for the use of pharmacological agents in general, and antidepressants in
particular, in the treatment of AD. Since suicidal ideation and behaviour is common in those with
AD (Kryzhanovskaya 2001), it is also of clinical relevance to identify whether pharmacological
agents assist in reducing these.

Objectives
To assess the efficacy and tolerability of pharmacological interventions for the treatment of AD
in adults.

Methods
Criteria for considering studies for this review

Types of studies
Published and unpublished studies will be included if they are double blind (participants and
personnel), randomised controlled trials. Those that have a cross‐over design and cluster
randomised trials will also be included.
There will be no language restrictions.

Types of participants
Participant characteristics
Participants will be adults, both male and female, over the age of 18. There will be no ethnic
restriction.

Diagnosis
Participants must have a diagnosis of AD according to the following criteria:
a) a clinical diagnosis based on ICD‐10 (WHO 1992) or DSM‐IV (APA 1994) or earlier versions
of ICD and DSM criteria; or
b) made by a valid diagnostic instrument such as the SCAN (Wing 1990), SCID (First 1995) or
earlier versions of SCAN or SCID; or
c) using some other validated diagnostic instrument.
Participants must meet the criteria for acute AD (< 1 month in ICD‐10 or < 6 months in DSM‐
IV) or chronic AD (> 1 month but < 2 years in ICD‐10 or > 6 months in DSM‐IV).
Since AD was introduced in 1984 in DSM‐III (APA 1980) and introduced in ICD‐10 in 1992
(WHO 1992), trials that predate these criteria will be included if the participants are diagnosed
with the older term 'situational disturbance' or the interchangeable terms 'reactive depression',
provided the trials were undertaken prior to the introduction of the current diagnostic terms.

Setting
There will be no restriction on the setting of these studies, e.g. whether in general practice,
inpatient psychiatric units, outpatient psychiatric clinics or consultation‐liaison psychiatry
settings.

Co‐morbidities
We will include medically ill participants.
We will exclude studies where participants have another axis 1 psychiatric disorder although this
is unlikely to be a problem since a diagnosis of AD cannot be made in the presence of another
axis 1 diagnosis.
Types of interventions
Experimental interventions
1. Antidepressants (tricyclics, SSRIs, others) given in any dosage and for any period of
time. The effect of different dosages will be examined.
2. Benzodiazepines (anxiolytics and hypnotics).
3. Non‐benzodiazepine hypnotics.
4. Other pharmacological interventions (e.g. mood stabilisers, antipsychotic agents).
These may be used as monotherapy or in combination.

Comparator interventions
1. Waiting list control.
2. Placebo.
3. Watchful waiting.
4. Treatment as usual.
5. Psychological therapies (behavioural, cognitive behavioural, third wave cognitive
behavioural therapy, psychodynamic, humanistic/supportive and integrative).
6. Any other pharmacological intervention.
7. Combinations of the above.

Types of outcome measures

Primary outcomes
1. An evaluation of a change in total symptom scores. Symptoms that will be considered
include:
1. depression, measured using the Hamilton Rating Scale for Depression (Hamilton
1960), the Montgomery‐Asberg Depression Rating Scale (Montgomery 1979) or the
Beck Depression Inventory (Beck 1960) measured either as a continuous variable (total
score) or dichotomous (above or below the threshold for possible 'caseness');
2. anxiety, measured using the Hospital Anxiety Depression Rating Scale (Zigmond
1983) measured either as a continuous variable (total score) or dichotomous (above or
below the threshold for possible 'caseness').
2. Adverse effects of treatment as measured by:
 1. the total number of dropouts from each arm due to side effects as a proportion of
the total randomised;
2. any increase in deliberate self harm in the treatment group in comparison to the
control group.
The list of scales is not exhaustive and others will also be examined provided they have been
validated as symptom measures of anxiety or depression. There are currently no validated scales
to specifically measure AD.

Secondary outcomes
1. Changes to social function score using a validated measure such as the Global
Assessment of Function (Luborsky 1962) (continuous measure).
2. Changes to quality of life score using measures such as the SF‐36 (Ware 1993), or the
HoNOS (Wing 1994) (continuous measure).
3. Changes to suicidal ideation scores using item 9 of the BDI (Beck 1960) or some specific
suicidal ideation scale such as the Beck Scale for Suicidal Ideation (Beck 1979) (continuous
measure).
4. Changes to 'caseness' status if diagnostic instruments such as SCAN (Wing 1990) or
SCID (First 1995) are used (dichotomous measure).
5. The number of participants from each arm experiencing at least one adverse event as a
proportion of the total randomised (dichotomous measure).
6. The number of dropouts from each arm due to inefficacy as a proportion of the total
randomised (dichotomous measure).
The list of scales mentioned above is not exhaustive and others will also be examined provided
they have been validated.

Search methods for identification of studies

The Cochrane Depression, Anxiety and

Neurosis Review Group's Specialised 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 Coordinator 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 c/o the World Health Organization's trials portal (ICTRP), drug
companies, the handsearching of key journals, conference proceedings and other (non‐Cochrane)
systematic reviews and meta‐analyses.
Details of CCDAN's generic search strategies (used to identify RCTs) can be found on the
Group's website.

Electronic searches
The CCDANCTR‐Studies Register will be searched using the following terms (condition only):
Diagnosis = (“adjustment disorder*” or ((reactive or mild or minor or situational or subclinical or
sub‐clinical or subthreshold or sub‐threshold) and depress*) or “reactive disorder*” or
“situational disturbance*” or “anniversary reaction*” or “maladaptive behav*” or “complicated
grief”).
The CCDANCTR‐References Register will be searched using free‐text terms to find additional
reports of RCTs not yet tagged to individual studies:
("adjustment disorder*" or "reactive depressi*"  or "situational depress*" or "mild depress*" or
"minor depress* or "subclinical depress*" or "sub‐clinical depress*" or "subthreshold depress*"
or sub‐threshold depress*" or "subsyndromal depress*" or "sub‐syndromal depress*" or "reactive
disorder*" or "situational disturbance*" or "anniversary reaction*" or "maladaptive behav*" or
"maladaptive coping" or "maladaptive reaction*" or "maladaptive trait*" or grief or bereavement
or stressor* or "emotional symptom*").
An additional search of PsycINFO will be conducted, using a more sensitive set of terms for
'adjustment disorders', exceeding those routinely used by CCDAN, to check that no studies have
been missed (Appendix 1). Complementary searches will also be carried out on LILACS and
Dissertation Abstracts.
Details of unpublished or ongoing trials, or both, will be sourced from international trials
registers c/o the WHO trials portal (ICTRP) and ClinicalTrials.gov.
The following grey literature databases will also be searched:
OpenGrey (http://www.opengrey.eu).
No date or language restrictions will be applied to the search.

Searching other resources

Handsearches of relevant conference proceedings (last three years) will be carried out, for
example:
 World Psychiatric Association (WPA) (http://www.wpanet.org/);
 American Psychiatric Association (http://www.psych.org/);
 European College of Neuropsychopharmacology (ECNP) Congress (http://www.ecnp.eu)
(ECNP abstracts published in European Neuropsychopharmacology).
The reference lists of all included and excluded studies will be screened to help identify any
additional studies and a cited reference search will be conducted on the Web of Science.
Chapters in relevant books will be scrutinised and experts in the field contacted to identify any
unpublished studies.

Data collection and analysis

Selection of studies
The initial screening, to decide on potential eligibility, will be carried out by PC and LW by
reading the abstract. Those studies that do not deal with adjustment disorder or the terms listed
above (situational disturbance/depression or reactive depression) will be rejected. Doubtful
studies will be included at this stage.
Thereafter, the selection of studies will be carried out by two of the authors independently (PC
and LW or DP) by reading the abstract and if it seems to meet the inclusion criteria then the
paper will be read in full to evaluate its suitability for inclusion in this review. Where the abstract
is unclear the paper will be included and read in full. Where there is disagreement an attempt will
be made to resolve it by discussion. If this is not successful the paper will be sent to a third
reviewer (AM) who will make the final decision on inclusion.

Data extraction and management

Two authors (BK and PC) will carry out data extraction, collecting the data independently of
each other onto an extraction sheet developed and piloted for this purpose, as recommended
by Higgins 2008. One author will carry out the initial extraction (PC) and this will be cross‐
checked by the other author (BK) to ensure reliability. We will contact trial authors when data
are missing or when discrepancies arise during the extraction process that cannot be resolved by
discussion.
The following information will be collated from each trial.
 Description of the trials, including the primary researcher, the year of publication, the
country in which the study was carried out and the source of funding.
 Characteristics of trial methodology including the diagnostic criteria (e.g. DSM‐IV or
ICD‐10), the exclusion criteria employed, whether the diagnosis was based on clinical or
structured interview, the use of a placebo run‐in.
 The diagnostic subtype (if specified).
 Characteristics of the subjects and controls, including gender distribution and age
distribution and their baseline measures of anxiety, depressive, suicidal symptoms, quality of
life and social functioning.
 Characteristics of the interventions, including the number of participants randomised to
the treatment and control groups, the number of total dropouts per group as well as the
number that dropped out due to poor tolerability or due to inefficacy.
 Outcome measures for subjects and controls including measures of anxiety, depressive,
suicidal symptoms, quality of life and social functioning.
 Changes to 'caseness' status and information on attrition due to inefficacy, adverse events,
or loss to follow‐up will also be extracted, as will the percentage with at least one adverse
event.
 Quality assessment ‐ data from the risk of bias assessment will also be extracted
(see Assessment of risk of bias in included studies).
 Additional information will be included, such as whether results were based on the
intention‐to‐treat (ITT) analysis with last observation carried forward (LOCF) for completers
only, and the minimal period required for inclusion of participants in the LOCF analyses.

Comparisons will be made between the outcomes of

interest in the following groups:
1. Antidepressants vs controls (placebo, waiting list control, watchful waiting combined).
2. Antidepressants vs anxiolytics.
3. Antidepressants vs other pharmacological treatments (excluding anxiolytics).
4. Antidepressants vs psychological therapies.
5. Anxiolytics vs controls (placebo, waiting list control, watchful waiting).
6. Anxiolytics vs psychological therapies.
7. Anxiolytics vs other pharmacological treatments (excluding antidepressants).
8. Pharmacological interventions versus psychological therapies.
9. Where combinations of interventions are used comparisons will made using the structure
detailed above.
Where studies have allowed medications for physical illnesses to continue, the principal
investigator will be contacted in order to establish what these medications were and if they have
any effect on psychological symptoms. The information obtained will be analysed by means of a
sensitivity analysis or a subgroup analysis, depending on the responses received (or not
received).
If different interventions are used in an individual subtype the analysis will be stratified by class
of intervention, so that the results of multiple analyses can be presented in a single graph with a
subtotal summary score for each instead of an overall summary effect.
Timepoint management ‐ outcomes will be based on measures at three months and six months.
Assessment of risk of bias in included studies
Risk of bias will be assessed independently by two authors (PC and AM) in the following
domains:
 random sequence generation;
 concealment of allocation;
 blinding of participants and personnel and blinding of outcome;
 incomplete outcome data (including attrition);
 selective outcome reporting;
 other sources of bias (e.g. study design, baseline imbalance, sponsorship or some other
aspect of the study not included above).
The risk of bias in each domain and overall will be rated as high, low or unclear, according to the
criteria in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Each
assessment will be accompanied by a support for judgement comment.
If the information provided in the paper is inadequate, we will contact the authors for further
details.
Where there is disagreement this will be resolved by discussion. If consensus is still not reached,
a third author (BK) will adjudicate.

Measures of treatment effect

For continuous data, we will measure treatment effect using mean differences (MDs) or
standardised mean differences (SMDs) and their 95% confidence intervals (CI). The MD will be
used when the outcome of interest is measured using the same scale in all studies while the SMD
will be implemented when the scales used differ across studies.
For dichotomous data, we will use risk ratios (RRs) in response to treatment, including 95%
confidence intervals, instead of odds ratios (ORs) since the latter are more difficult to interpret. If
only ORs are provided, these will be converted to RR using the formula in Higgins 2008.
Numbers needed to treat (NNT) will be calculated from risk differences (RD) according to the
formula provided in Higgins 2008.

Unit of analysis issues

Multiple treatment groups
Where there are multiple treatment groups (e.g. different doses, different medications) only one
intervention will be evaluated for each meta‐analysis, thus satisfying the assumption of
independent observations and avoiding bias through multiple comparisons with the same control
group. Where the same treatment is given to different groups (e.g. men and women) data from
the groups will be averaged to produce a single mean and standard deviation. For other
combinations we will take care to avoid loss of information as recommended by Higgins 2008.

Cross‐over trials
These studies will be included in the analysis when it is possible to extract data from the active
treatment and control arms for the first treatment period only.

Cluster randomised trials

These will be included in the analysis and the data extracted will take account of the cluster
design as recommended by Higgins 2008. To avoid unit of analysis errors a summary score will
be calculated for each cluster so that the sample size will be the number of clusters and the
analysis will proceed as if the clusters represent individuals. If the information required for this
analysis is not presented in the study, we will contact the authors to seek the required data,
including:
 the number of clusters randomised to each arm or the mean of each cluster;
 the outcome data for the individuals in each cluster;
 an estimation of the intracluster correlation.

Dealing with missing data

Should more than 40% of participants be lost by completion of the study, the data will be
included in the initial analysis but the effect of this inclusion evaluated in a sensitivity analysis.
We will contact the authors to obtain missing information where possible and we will discuss the
likely impact on the results.
The reasons for missing data, their number, characteristics and whether they differed
significantly from completers will be considered.
If data from intention‐to‐treat analyses are unavailable, the study will be excluded from the
intention‐to‐treat meta‐analysis. If available, best/worst case scenario calculations will be carried
out so that the boundaries of the treatment effect can be described. If data are available on
completers only these will still be used.
For continuous data either end point analysis or last observation carried forward (LOCF) analysis
will be carried out if such data are provided in the papers or by the authors when contacted.
If some statistics are missing (e.g. standard deviations) and are not available from trial authors
we will attempt to calculate them from P values.
The likely impact of missing data will be considered in the discussion.

Assessment of heterogeneity
An assessment of clinical heterogeneity will be made by examining differences in study
populations and interventions.
We will examine statistical heterogeneity by studying the degree of overlap of the confidence
intervals for individual studies in a forest plot.
We will also carry out more formal assessments using a Chi2 test with the P value set at 0.1. As
this statistic has low power to detect diversity when the number of studies is low or sample size
is small, we may also need to calculate I2. As I2 only provides a rough estimate of the variability
due to heterogeneity, the following overlapping bands will guide the interpretation of the
I2 statistic, as suggested in the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2008).
 0% to 40% might not be important;
 30% to 60% may represent moderate heterogeneity;
 50% to 90% may represent substantial heterogeneity;
 75% to 100% represents considerable heterogeneity.
However, as there is an a priori expectation that clinical and statistical heterogeneity will be
present, it is anticipated that a random‐effects model will be used.

Assessment of reporting biases

A detailed exploration for possible unpublished trials will be carried out in several ways.
1. Trials registers (detailed in Search methods for identification of studies) will be examined for
trials registered but not identified in the search. Information on these will be sought from the
investigators.
2. Authors who have previously carried out trials will be contacted for information on other
possible unpublished material.
3. We will assess reporting bias by creating a funnel plot (sample size plotted against effect size)
based on the published studies, using Review Manager software. This will be visually inspected
for asymmetry. Formal tests for asymmetry will only be carried out if there are sufficient studies
(i.e. greater than 10) to distinguish true from chance asymmetry and provided the studies are not
of similar size (Higgins 2008). However, there are causes of funnel plot asymmetry other than
reporting bias (e.g. small sample size) that will also be considered (Higgins 2008).

Data synthesis
A meta‐analysis will be carried out if there are sufficient studies. It is likely that a random‐effects
model will be used but this will depend on the level of heterogeneity. The outcomes will be
expressed in terms of an average effect size for each outcome measure and their 95% confidence
intervals.
If there are insufficient studies the review will be written in narrative form.
Subgroup analysis and investigation of
heterogeneity
We plan to carry out a subgroup analysis for the various subtypes of adjustment disorder
categorised in DSM‐IV and ICD‐10 (1 to 4 listed below) since treatments for these are likely to
differ (Higgins 2008):
1. adjustment disorder with depression;
2. adjustment disorder with anxiety;
3. adjustment disorder with disturbance of conduct;
4. adjustment disorder mixed type;
We also plan to perform subgroup analysis by control condition where appropriate (i.e. placebo,
waiting list control, watchful waiting).
Each of these subgroups will be examined for the comparisons described in Data Extraction and
Management above and for the same time points.

Sensitivity analysis
We plan to carry out a sensitivity analysis to determine the impact of decisions made during the
review process on the robustness of the conclusions. We will examine the impact of:
1. excluding studies where randomisation or the level of blinding is low or unclear;
2. excluding studies that potentially use older terms for adjustment disorders (such as
reactive depression, acute situational disturbance or situational depression) in order to be
confident that the conclusions will apply to those with definite AD;
3. including studies in which more than 40% of participants had dropped out.