COMAD: COmprehensive Meta-Analysis for Depression[PROTOCOL]

Toshi A. Furukawa, Andrea Cipriani, Rachel Churchill, Stefan Leucht, Corrado Barbui, Vivien Hunot, Mina
Honyashiki, Kiyomi Shinohara, Hissei Imai, Sofia Dias, Georgia Salanti, Deborah Caldwell

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Background
Unipolar major depression is the third leading cause of total disease burden and the largest source of non-fatal
disease burden worldwide and is expected to show a rising trend over the next 20 years (WHO 2008). The
recent WHO World Mental Health Survey revealed the average lifetime and 12-month prevalence estimates of
DSM-IV major depressive episode of 14.6% and 5.5% in the ten high-income and 11.1% and 5.9% in theeight low- to middle-income countries that they surveyed (Bromet et al. 2011). Depression is not only
associated with marked personal morbidity and dysfunction but also is responsible for substantial direct andindirect economic costs to the society (Luppa et al. 2007).
The most common and recommended treatment options for major depression are pharmacological andpsychological interventions (NICE 2009; American Psychiatric Association 2010). Both modalities havesubstantive evidence to support their general effectiveness (Turner et al. 2008; Driessen et al. 2010; Lynch etal. 2010; Gibbons et al. 2012). The prescribing of antidepressants has increased dramatically in many Westerncountries over the last 20 years, mainly with the advent of selective serotonin reuptake inhibitors and othernewer agents, and they remain the mainstay of treatment for depression in health care settings (Gartlehner et
al. 2011). However, many (Churchill et al. 2000; van Schaik et al. 2004; Riedel-Heller et al. 2005) if not all(Dobscha et al. 2007) surveys attest to the patients' preference for psychological therapies over that byantidepressants. Psychological therapies therefore provide an important alternative intervention for depressive
disorders. For either of these treatment modalities, however, adherence remains less than optimal (Oei andKazmierczak 1997; Vergouwen et al. 2003; van Geffen et al. 2009).
Which then is more efficacious and acceptable in the acute phase treatment of major depression,
psychotherapies or drug therapies? And of the various available options within these two broad groups ofinterventions, is there any particular drug or psychotherapy that stands out and is clinically superior to theothers? Given the pragmatic importance of this and related clinical questions, it is no surprise that several
important systematic reviews and meta-analyses have already been conducted and reported in the literature.
Some are clearly outdated (Dobson 1989; Gloaguen et al. 1998; DeRubeis et al. 1999). Some compared
antidepressant medications and psychotherapies for depression without further differentiation and may haveoverlooked important differences between and among these two broad groups of interventions (Imel et al.
2008), while others focused on one psychotherapeutic approach only, most often CBT (Butler et al. 2006).
Still others have essayed to differentially evaluate different psychotherapies either as subgroup analyses(Cuijpers et al. 2008) or each separately (Hollon and Ponniah 2010) but still treated all antidepressants as asingle treatment modality.
When a range of interventions are available for the same disorder, of which some are compared against others
in randomised trials, indicating possible yet no definitive superiority or inferiority of one over the other, a newmeta-analysis approach may be of particular value in making all comparisons through the optimum use of theavailable evidence. Multiple-treatments meta-analysis (MTM, also known as network meta-analysis) is astatistical technique that allows both direct and indirect comparisons to be undertaken, even when two of thetreatments have not been directly compared (Higgins and Whitehead 1996; Lumley 2002). In other words, it isa generalisation of standard pair-wise meta-analysis for A vs B trials, to data structures that include, forexample, A vs B, B vs C, and A vs C trials.
MTM can summarise RCTs of several different treatments providing point estimates (together with 95%
credibility intervals [CIs]) for their association with a given endpoint, as well as an estimate of incoherence(that is, a measure of how well the entire network fits together, with small values suggesting better internal
agreement of the model). MTM has already been used successfully in psychiatry (Cipriani et al. 2009) and inother fields of medicine (Psaty et al. 2003; Stettler et al. 2007). Two fruitful roles for MTM have been
identified (Lu and Ades 2004):(i)to strengthen inferences concerning the relative efficacy of two treatments, by including both direct
and indirect comparisons to increase precision and combine both direct and indirect evidence;(ii)
to facilitate simultaneous inference regarding all treatments in order for example to select the besttreatment.
Considering how important comparative efficacy could be for clinical practice and policy making, it isimportant to use all the available evidence to estimate potential differences in efficacy among available
treatments. MTM thus offers the best use of currently available evidence to arrive at the most informative
inference regarding which of the many available treatments work better than the others. Consumers of healthcare research, namely patients and their families, clinicians, and policy makers, have been in dire need of such2

comparative effectiveness research in the acute phase treatment of major depression. We have thus far
conducted MTMs for drug therapies for depression (Cipriani et al, in preparation) and those forpsychotherapies depression (Churchill et al, in preparation) separately, and the present MTM essays tocombine the two in order to elucidate the relative efficacy and acceptability of various available options inpharmacotherapy and psychotherapy in major depression.

Objectives
To compare the efficacy and acceptability of different psychotherapies, drug therapies and their control
conditions in the acute phase treatment of major depression in adults

Methods
Criteria for considering studies for this review
Types of studies
Inclusion criteria
Randomised controlled trials (RCTs) comparing one against another of the drugs or psychotherapies inquestion (see the list below) or against pill placebo or other control conditions as monotherapy in the acutephase treatment of major depression will be included. Studies in which two treatments are compared and inwhich a co-intervention (except for protocolized antidepressant treatment intended as combination treatment)
is simultaneously provided will be accepted as a comparison of the two treatments when the co-intervention isequally administered in both arms. We will accept open studies and studies in which outcome assessors were
not blinded to the treatments (Wood et al. 2008). The influence of including open studies will be assessed in asensitivity analysis.
For trials which have a crossover design only results from the first randomisation period will be considered.
Cluster-randomised trials will be included only if intra-cluster correlation coefficients are reported.
Exclusion criteria
Quasi-randomised controlled trials, in which treatment assignment is decided through methods such asalternate days of the week, will be excluded.
Types of participantsParticipant characteristics
Inclusion criteria
Patients between ages 18 and 75, of both sexes with a primary diagnosis of unipolar major depression,
diagnosed according to any of the following operationalised criteria: Feighner criteria, Research Diagnostic
Criteria, DSM-III, DSM-III-R, DSMIV or ICD-10. Operationalised criteria essentially resembling theseofficial ones will also be eligible.
Exclusion criteria
Studies that used non-operationalised diagnostic criteria or relied on a clinician or self-report depression scale
to identify depression caseness will be excluded.
Differences in cognitive capabilities and physiologies among younger or elderly people influence theeffectiveness and acceptability of psychotherapies and pharmacotherapies (Pinquart et al. 2006). Therefore
studies of children and adolescents aged ≤18 or of older people where the mean age of participants was ≥75
years will be excluded.
Trials that focused on treatment-resistant or chronic depression including dysthymia will be excluded, because
we are interested in the treatment options for the acute phase treatment. Similarly, studies of interventions
designed to prevent a future episode of depression will be excluded. Trials in which greater than 20% of theparticipants suffered from bipolar depression will also be excluded.
Trials that focused on depression among participants who all had a concurrent primary diagnosis of anotherAxis I or II disorder will be excluded. Existence of concurrent secondary diagnosis of another psychiatricdisorder is allowed.
Trials that focused on depression among patients with a certain concomitant medical illness will be excluded.
RCTs of women with post-partum depression will also be excluded, because post-partum depression appears3

to be clinically different from major depression (Cooper and Murray 1998).
Setting
Inclusion criteria
Studies conducted in primary care and community-based settings or in outpatient specialist settings are
eligible. We will include studies with volunteer participants as well as those recruited from referrals. Studies
that focused on specific populations (eg depressed participants at a specific work place, depressed care givers,etc) will be included if the participants all met the criteria for major depression.
Exclusion criteria
Studies conducted in inpatient settings will be excluded from the review, as psychotherapies require voluntary
participation from the patients, which may not always be guaranteed in inpatient settings.
Types of interventions
Included interventions
We will include the following 10 psychotherapies, 18 antidepressant drugs as well as five control conditions in
our systematic reviews.
Psychological interventions
The psychological therapy intervention was required to be delivered through face to face meetings between
the patient and therapist. Interventions in which face to face therapy was augmented by telephone orinternet-based support were included in the review. Psychological therapy approaches conducted on either anindividual or on a group basis were also included.
In order to use the common time frame with acute phase drug treatments, the duration of the psychologicalintervention had to be between 4 and 16 weeks.
A diverse range of psychological therapies is now available for the treatment of depression. In our previous
MTM of psychotherapies for depression (Churchill et al, in preparation), we categorized psychologicaltherapies broadly into four separate philosophical and theoretical schools, each of which contains a number ofdiffering and overlapping psychotherapeutic approaches. They are psychoanalytic/dynamic (Freud 1900; Jung
1921; Klein 1932), humanistic (Maslow 1943; Rogers 1951), behavioural (Watson 1924; Skinner 1953; Marks
1981), and cognitive approaches (Beck et al. 1979; Ellis 1979). Beck and Ellis have both acknowledged thevalue of behavioural therapy, and during the 1980s and 1990s, the last two approaches merged to form
cognitive behavioural therapy (CBT) (Roth and Pilling 2008). Some other psychotherapeutic approaches, suchas interpersonal therapy (Klerman et al. 1984), also explicitly integrate components from several theoreticalschools. Based on our previous MTM, we will focus the current MTM on the following psychotherapies
which showed promises and /or provided well-delineated reproducible procedures.

Behaviour therapies
1. Behavioural therapy (Lewinsohn)
Lewinsohn 1974 proposed that depressed individuals have low rates of pleasant activities and obtained
pleasure, that their mood covaries with rates of pleasant and aversive activities, that their mood improves withincreases in pleasant activities, and that they lack social skills during the depressed phase. Therefore,
behavioural therapy based on the approach developed by Lewinsohn and colleagues involves helping
individuals increase their frequency and quality of pleasant activities, producing corresponding improvement
in mood and overall quality of life (Lewinsohn 1974).
2. Social skills training/assertiveness training
The social skills training model (SST) proposes that depressed people may have difficulty initiating,
maintaining and ending conversations (Jackson 1985). Because of these deficits, the individual is unable toelicit mutually reinforcing behaviour from other people in their environment. SST subsumes assertion andconversational skills, together with more specialised subskills such as dating and job interview skills. Foursocial contexts of interacting with strangers, friends, family members and people at work or school are
targeted (Bellack 1980) and interventions such as instruction, modelling, rehearsal, feedback andreinforcement are used to enable the development of new responses (Jackson 1985). As assertiveness training
comprises a key component of SST, it will be included in the SST category.
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Cognitive-behaviour therapies
3. Cognitive therapy
The cognitive model of depression (Beck 1979) proposes that biased thinking and unrealistic cognitive
appraisals of events negatively affect feelings and behaviour in a reciprocal interaction. Negative automatic
thoughts are thought to be influenced by schema, or thought patterns, which are formed early in life. These arecharacterised in depressed individuals as a negative cognitive triad, in which views of the self, world andfuture are affected. CT aims to restructure the individual’s unhelpful appraisal of life events, throughunderstanding the relationship between thoughts, feelings and behaviours, recognising and monitoring
negative automatic thoughts, and enabling the development of more realistic and balanced appraisals.
Studies of interventions described as ‘CBT’ by trial authors, but which are based predominantly on cognitive
restructuring methods, and/or cite the Beck 1979 manual, will be included in this group.
4. Problem-solving therapy
PST was developed as an intervention to train individuals to function as their own therapist (D’Zurilla 1971).
Five overlapping stages are proposed to represent the problem-solving process, including general orientation,
problem definition and formulation, generation of alternatives, decision-making and verification. Training in
problem-solving involves teaching individuals these skills and providing guidance in their application for
identified problems (Dobson 2001). As a pragmatic and flexible approach, PST has been adapted andmanualised for evaluation in a number of different populations, including depression (Nezu 1986).
5. Coping with Depression course
Developed and evaluated as a group intervention for depression (Lewinsohn 1984), the CWD course for
adults is a structured, psychoeducational programme that emphasises learning simple behavioural principles
such as activity monitoring, scheduling and progressive goal achievement. Participants learn to improve social
skills, use relaxation techniques, increase or rediscover involvement in pleasant activities and to use simple
cognitive strategies.
3rd wave therapies
6. Acceptance and commitment therapy
In acceptance and commitment therapy (ACT) (Hayes 1999; Hayes 2004) therapists aim to transform therelationship between the experience of symptoms and difficult thoughts/feelings, so that symptoms no longer
need to be avoided and become just uncomfortable transient psychological events (Harris 2006). In this way,
symptom reduction becomes a by-product of treatment (Harris 2006). Clients are encouraged to develop
psychological flexibility through six core principles: cognitive defusion (perceiving thoughts, images,
emotions, and memories as what they are, rather than what they appear to be); acceptance (allowing these tocome and go without struggling with them); contact with the present moment (awareness of and receptivenessto the here and now); use of the observing self (accessing a transcendent sense of self ); personal values(discovering what is most important to one’s true self ); and committed action (setting goals according tovalues and carrying them out responsibly) (Hayes 1999). In terms of committed action, ACT uses methods inline with traditional behaviour therapy, such as exposure, skills acquisition and goal setting.
7. Extended behavioural activation
The original behavioural activation (BA) approach manualised by Jacobson 1996 includes teaching relaxation
skills, increasing pleasant events and social and problem-solving skills training, and is regarded as a
traditional behavioural therapy model. More recently, the BA approach has been extended byMartell 2001,
building on the original behavioural models of depression (Lewinsohn 1974) by introducing a contextual
approach to depression. The extended BAmodel suggests that just as avoidance maintains anxiety, avoidant
coping patterns (withdrawal fromsituations and people) maintain depressed mood, and, therefore, avoidant
coping is targeted as a primary problem. Following functional analysis, in which a detailed assessment of how
an individual maintains depressive behaviour is carried out, the individual is taught to formulate andaccomplish behavioural goals, irrespective of prevailing negative thoughts and mood states (Hopko 2003).
Traditional behavioural therapy strategies such as activity charts, relaxation training and increasing pleasantevents are also used (Dobson 2001). A second BA approach, behavioral activation treatment for depression(BATD) (Lejuez 2001), proposes that depression ismaintained through the use of reinforcers such as increasedsocial attention and escape from aversive tasks. Following functional analysis as described in the extended BA
model above, access is weakened to reinforcements such as sympathy and escape from responsibility, and5healthy behaviour is systematically activated through the use of goal setting and increased activities (Hopko
2003).
8. Psychodynamic therapies
9. Interpersonal therapy (IPT)
IPT was developed in order to operationalise what was considered to be a set of helpful procedures commonlyused in psychotherapy for depressed outpatients (Weissman 2007) for a series of treatment studies in
depression conducted in the US (Elkin 1989; Frank 1990). Whilst described by the International Society forInterpersonal Psychotherapy (ISIPT) as having ’no specific theoretical origin’ (isIPT [ND]), IPT draws in partfrom attachment theory (Bowlby 1980), and is based on the premise that depressive symptoms may be
influenced strongly by the disruption of close personal attachments in four key domains of grief, role disputes,
role transitions and interpersonal deficits (Weissman 2007). Within the therapeutic process, IPT uses
techniques borrowed fromother therapies such as cognitive-behaviour therapy and brief crisis intervention(isIPT [ND]), including clarification (seeking to obviate the patient’s biases in describing interpersonal issues),role playing and communication analysis, together with supportive listening, encouragement of affect and useof the therapeutic relationship. Since the development of IPT in 1984, there has been ongoing debate over its
potential categorisation as a time-limited psychodynamic psychotherapy (Markowitz 1998). Systematic
reviews of psychodynamic therapy approaches for depression have obtained different findings according to its
inclusion (Crits 1992; Anderson 1995) or exclusion (Svartberg 1991; Leichsenring 2004). Following detailed
comparison of IPT and brief psychodynamic psychotherapy, Markowitz 1998 has concluded that despite
overlaps and similarities, IPT is distinct from STPP. Given its use of CBT techniques, coupled with its
psychodynamic features and atheoretical origins, IPT will be considered an integrative therapy for the
purposes of this review, in accordance with technical integration principles.
10. Non-directive/supportive therapies
In person-centred therapy (PCT), core conditions of empathy, genuineness and unconditional positive regard,
considered to be the ’antithesis’ of a therapeutic technique (Cooper 2008) are considered sufficient to facilitate
personality change (Rogers 1951). Use of a non-directive stance by the therapist is a key feature of PCT(Mearns 2007). Moving through three phases of trust, intimacy and mutuality within the therapeutic
relationship (Mearns 2007), change occurs as the client shifts from a negative evaluation of self towards abelief that they are worth caring for (Thorne 2002). Therapies described as ‘non-directive’ or ‘supportive’, andnot explicitly underpinned by person-centered theory, principles and supporting references, will be included
here also.
Antidepressant drugs
We will include the following selected first- and second-generation antidepressants.
1. TCA
Amitriptyline, Clomipramine
2. SSRI
Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline
3. SNRI
Desvenlafaxine, Duloxetine, Milnacipran, Venlafaxine
4. Other second-generation antidepressantsAgomelatine, Bupropion, Mirtazapine, Reboxetine, Trazodone, Vilazdone
We will include only studies randomising patients to drugs within the therapeutic dose (Cipriani et al. 2011).
Both fixed-dose and flexible-dose designs will be accepted.
Control comparators
Control comparators will be categorised as follows. In each study, descriptions of the various control
conditions will be scrutinised to ensure that they did not comprise an active psychological therapy treatment.
1. Treatment as usual (TAU)
In this condition, participants could receive any appropriate medical care during the course of the study on anaturalistic basis, including pharmacotherapy and/or psychological therapy, as deemed necessary by the6clinician. Standard care, usual care or no treatment conditions were also included in this category.
2. Waiting list (WL)
A commonly used ‘treatment as usual’ is to randomise participants to active intervention groups and control
group, to provide the active intervention to both groups but to delay delivery of the intervention to the control
group until after those in the intervention group have completed treatment. As in TAU, patients in the WL
condition could receive any appropriate medical care during the course of the study on a naturalistic basis.
3. Attention placebo (AP)This was defined as a control condition that is regarded as inactive both by researchers and by participants in atrial
4. Psychological placebo (PP)This was defined as a control condition that is regarded as inactive by researchers in a trial but is regarded as
active by the participants
We planned to document additional naturalistic treatment(s) received by participants in both the control andactive comparisons for each included study.
5. Pill placebo
Excluded interventions
Psychological therapy models based on social constructionist principles (that focus on the ways in which
individuals and groups participate in the construction of their perceived social reality) including couples
therapy (Barbato 2006), family therapy (Henken 2007), solution-focused therapy, narrative therapy, personal
construct therapy, neuro-linguistic programming and brief problem-solving (Watzlavick 1974) will be
excluded. These psychological therapies work with patterns and dynamics of relating within and between
family, social and cultural systems in order to create a socially constructed framework of ideas (O'Connell
2007), rather than focusing on one individual's reality.
Guided self-help, in which the practitioner provides brief face-to-face non-therapeutic support to patients who
are using a self-help psychological therapy intervention, were excluded, as were bibliotherapy and writing
therapies.
Psychological therapies provided wholly by telephone or over the internet were also excluded.
Studies of dual modality treatments, in which patients are randomised to receive a psychological therapy
intervention combined with pharmacological treatment, were excluded from the current review.
Component or dismantling studies (in which the effectiveness of individual components of a
cognitive-behavioural therapeutic approach are investigated) will not be included unless there were viable
comparisons to be made with another psychological therapy approach.

Outcome measures
Primary outcomes(1) Treatment efficacy: the number of patients who respond to treatment, based on changes on Hamilton
Rating Scale for Depression (HAM-D) (Hamilton 1960) or Montgomery-Asberg Depression Rating Scale(MADRS) (Montgomery and Asberg 1979) or Beck Depression Inventory (Beck et al. 1961), or any othervalidated depression scale at the end of acute phase treatment (8 weeks, range 4-16 weeks). Many studies
define response by 50% or greater reduction on the rating scale but some studies define response using
Jacobson's Reliable Change Index (Jacobson and Truax 1991). We will focus on 50% or greater reduction in
depression severity. If the original authors report several outcomes corresponding with our definition of
response, we will give preference to HAM-D. Any version of HAM-D will be accepted.
(2) Treatment acceptability: the number of participants who drop out of treatment for any reasons during thefirst 8 weeks of treatment (range: 4-16 weeks).
Secondary outcomes(3) Remission: The number of patients who remit on treatment, based on the endpoint absolute status of thepatients, as measured by HAM-D, MADRS, or any other validated depression scale. Examples of definitionsof remission include 7 or less on 17-item HAM-D (Furukawa et al. 2007) or 11 or less on MADRS (Bandelow
et al. 2006); we will accept the study authors' original definition. If the original authors report several
outcomes corresponding with our definition of response, we will give preference to HAM-D.
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(4) Severity of depression symptoms, based on a continuous outcome of group mean scores at the end oftreatment using HAM-D, MADRS, BDI, or any other validated depression scale.
Search methods for identification of studies
Electronic searches
1. CCDANCTR Specialised Registers
We will search two clinical trials registers created and maintained by the Cochrane Depression, Anxiety and
Neurosis Group (CCDAN), the CCDANCTR-Studies Register and the CCDANCTR-References Register.
References to trials for inclusion in the Group's registers are collated from routine (weekly) searches of
MEDLINE, EMBASE and PsycINFO, quarterly searches of the Cochrane Central Register of Controlled
Trials (CENTRAL) and additional ad hoc searches of other databases (PSYNDEX, LILACS, AMED,
CINAHL). These searches employ generic terms for depression, anxiety and neuroses; together with sensitive(database specific) RCT filters. Details of the generic search strategies can be found in the ‘Specialized
Register’ section of the Cochrane Depression, Anxiety and Neurosis Group’s module text.
References to trials are also sourced from international trials registers via the World Health Organisation’s
trials portal (http://apps.who.int/trialsearch/); drug companies; the hand-searching of key journals, conference
proceedings and other (non-Cochrane) systematic reviews and meta-analyses. Trial databases of the following
drug-approving agencies (the Food and Drug Administration in the USA, the Medicines and Healthcare
products Regulatory Agency in the UK, the European Medicines Agency in the EU, the Medicines Evaluation
Board in the Netherlands, the Medical Products Agency in Sweden, the Pharmaceuticals and Medical Devices
Agency (PMDA) in Japan, the Therapeutic Goods Administration (TGA) in Australia) will be hand-searchedfor published, unpublished and ongoing controlled trials. The National Institute for Clinical Excellence (UK)and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (Germany) will also be contacted for
additional information. No language restriction will be applied.
The CCDANCTR-Studies Register
The CCDANCTR-Studies Register contains over 11,000 trials for the treatment or prevention of depression,anxiety and neurosis. Each trial has been coded using the EU-Psi coding manual (as a guide) and includes
information on intervention, condition, comorbidities, age, treatment setting etc.
In order to identify all the studies that compared among the psychotherapies in question, the studies register
will be searched using the following search terms:
Condition = (depress* or dysthymi*) and Intervention = (*therap* or training)
In order to identify all the studies that compared the psychotherapies in question against the included
antidepressants, the studies register will be searched using the following search terms:
Condition=depress* AND Intervention = (cognitive* or behavi* or *therap* or training or treatment or
counsel* or psycho* or humanistic or mindfulness) AND Intervention=(Amitriptylin* or Chlorimipramin* or
Clomipramin* or Chlomipramin* or Clorimipramine or or Citalopram or Escitalopram or Fluoxetine or
Fluvoxamine or Paroxetine or Sertraline or Desvenlafaxine or Duloxetine or Milnacipran or Venlafaxine orAgomelatine or Bupropion or Mirtazapine or Reboxetine or Trazodone or Vilazdone or tricyclic drugs" or(serotonin or selective) and "reuptake inhibitors"))
The CCDANCTR-References Register
The CCDANCTR-References Register contains bibliographic records of reports of trials coded in the
CCDANCTR-Studies Register together with several other uncoded references (total number ofrecords=24,500). This register will be searched using a comprehensive list of terms for ‘psychotherapies’ as
indicated in below. Records already retrieved from the search of the CCDANCTR-Studies Register will bede-duplicated.
1:Title/Abstract=therap* or psychotherap*
2:Keywords=psychotherapy
3:Free-Text=acceptance* or commitment* or “activity scheduling” or adlerian or art or aversion or brief or“client cent*” or cognitive or color or colour or compassion-focused or “compassion* focus*” orcompassionate or conjoint or conversion or conversational or couples or dance or dialectic* or diffusion or
distraction or eclectic or (emotion and focus*) or emotion-focus* or existential or experiential or exposure or
expressive or family or focus-oriented or “focus oriented” or freudian or gestalt or “group” or humanistic or8

implosive or insight or integrative or interpersonal or jungian or kleinian or logo or marital or metacognitiveor meta-cognitive or milieu or morita or multimodal or multi-modal or music or narrative or nondirective or
non-directive or “non directive” or nonspecific or non-specific or “non specific” or “object relations” or“personal construct” or “person cent*” or person-cent* or persuasion or play or ((pleasant or pleasing) andevent*) or primal or problem-focused or “problem focused” or problem-solving or “problem solving” orprocess-experiential or “process experiential” or psychodynamic or “rational emotive” or reality or “reciprocal
inhibition” or relationship* or reminiscence or restructuring or rogerian or schema* or self-control* or “selfcontrol*” or “short term” or short-term or sex or “social effectiveness” or “social skill*” orsocio-environment* or “socio environment*” or “solution focused” or solution-focused or “stress management”
or supportive or time-limited or “time limited” or “third wave” or transference or transtheoretical or validation
4:Free-Text=(abreaction or “acting out” or “age regression” or ((assertive* or autogenic or mind or sensitivity)
and train*) or autosuggestion or “balint group” or ((behavior* or behaviour*) and (activation or therap* or
treatment or contracting or modification)) or biofeedback or catharsis or cognitive or “mind training” orcounsel* or “contingency management” or countertransference or “covert sensitization” or “eye movement
desensiti*” or “crisis intervention” or “dream analysis” or “emotional freedom” or “free association” or“functional analys*” or griefwork or “guided imagery” or hypno* or imagery or meditation* or “mental
healing” or mindfulness* or psychoanaly* or psychodrama or psychoeducat* or “psycho* support*” orpsychotherap* or relaxation or “role play*” or “self analysis” or “self esteem” or “sensitivity training” or“support* group*” or therapist or “therapeutic technique*” or “transactional analysis”)
5:((1 or 2) and 3) or 4
2. In order to identify all published and unpublished RCTs that compared one antidepressant with another orplacebo in the treatment of major depression, all the original databases will be searched using the following
phrase: [depress* or dysthymi* or adjustment disorder* or mood disorder* or affective disorder or affective
symptoms] and combined with a list of all included antidepressants.
We are aware that there are many trials carried out in China (Chakrabarti et al. 2007). However, for many ofthese studies only incomplete or conflicting information is available and it has been reported many of them do
not use appropriate randomisation procedures (Wu et al. 2006). In an effort to avoid the potential biases that
may be introduced by including these trials without further information, we will exclude these studies.
Searching other resources
1. Reference lists
The references of all selected studies will be searched for more published reports and citations of unpublishedstudies. Relevant review papers will be checked.
2. Personal communication
Subject experts will be contacted to check that all relevant studies, either published or unpublished, have been
considered for inclusion.
Data collection
Selection of studies
Two review authors will examine the titles and abstracts of all publications obtained through the searchstrategy. Full articles of all the studies identified by either of the review authors will then be obtained andinspected by the same two review authors to identify trials meeting the following criteria:
1. Randomised controlled trial;
2. Participants have depression diagnosed by operationalised criteria
3. And compared any of the above-listed psychotherapies or drug therapies
Conflicts of opinion regarding eligibility of a study will be discussed with a third review author, having
retrieved the full paper and consulted the authors if necessary, until consensus is reached.
Data extraction and management
Data from each study will be extracted independently by two review authors. Any disagreement will be
resolved through discussion and in consultation with the principal investigators. Where necessary, the authorsof the studies will be contacted for further information.
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Information relating to study population, sample size, interventions, comparators, potential biases in the
conduct of the trial, and outcomes will be abstracted from the original reports into specially designed paper
forms then entered into a spreadsheet.
Management of time points
It is a problem of systematic reviews that usually trials have different durations. Clinically, the assessment ofefficacy after 8 weeks of treatment or after 24 weeks or more may lead to differences in terms of treatment
outcome. Clinicians need to know whether (and to what extent) treatments work within a clinically reasonable
period of time. Unfortunately, there is no consensus on what the appropriate duration of an acute phase trial is.
In the present review, acute treatment will be defined as an 8-week treatment in both the efficacy andacceptability analyses. If 8-week data are not available, we will use data ranging between 4 to 16 weeks andthe time point given in the original study as the study endpoint will be given the preference. Longer-term
studies will be excluded if they do not provide data for the 4-16 weeks period.
Assessment of risk of bias in included studies
Risk of bias will be assessed for each included study using the Cochrane Collaboration 'risk of bias' tool
(Higgins and Green 2011). The following 10 domains will be considered:
1. Sequence generation: was the allocation sequence adequately generated?
2. Allocation concealment: was allocation adequately concealed?
3. Blinding of participants, personnel and outcome assessors for the primary outcome: was knowledge ofthe allocated treatment adequately prevented during the study?
4. Incomplete outcome data for the primary outcome: were incomplete outcome data adequately addressed?
5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?
We also assessed
6. Researcher allegiance
7. Therapist allegiance
8. Therapist qualification
9. Treatment fidelity
in the case of psychotherapy interventions, and
10. Sponsorshipin the case of drug trials. We did not classify a study as industry-sponsored when only the medication wasprovided by the pharmaceutical company.
Other sources of bias included but are not limited to:
Suboptimal randomization, such as recruiting additional patients to one arm which had a large numberof dropouts, or reporting only a subset of the patients randomised without stratification (e.g. only thosewith major depression are reported when the authors originally randomised all patients who wanted totake the course)
Stopped early due to some data-dependent process (including a formal-stopping rule)
Had extreme baseline imbalance
Differential treatment duration among the arms
Insufficient delivery of treatment or insensitive scales to measure outcomes, leading to null results
A judgment on the risk of bias will be made for each domain, based on the following three categories:
High risk of bias
Low risk of bias
Unclear risk of bias.
Two independent review authors will assess the risk of bias in selected studies. Any disagreement will be
resolved through discussion and in consultation with the principal investigators. Where necessary, the authorsof the studies will be contacted for further information.
Statistical analyses
Measures of treatment effectConsidering that depression trials are usually small and that data distribution is difficult to assess for studies
with small samples, in this review priority will be given to the use and analysis of dichotomous variables bothfor efficacy and acceptability.
Dichotomous outcomes: these outcomes will be analysed by calculating a pooled odds ratio (OR) and 95%
10

confidence intervals for each comparison.
Continuous outcomes: Where different measures are used to assess the same outcome, data will be pooledwith standardised mean difference (SMD) and 95% confidence intervals calculated.
Dealing with missing data
Missing dichotomous data will be managed according to the intention to treat (ITT) principle, and it will beassumed that patients who dropped out after randomisation had a negative outcome. When dichotomous
efficacy outcomes are not reported but baseline mean and endpoint mean and standard deviation of thedepression rating scales are provided, we will calculate the number of responding patients at 8 weeks (range 4
to 16 weeks) employing a validated imputation method (Furukawa et al. 2005). We are aware that othermethods to impute response rate are available and have been investigated (Anzures-Cabrera et al. 2011). Even
though these imputation methods are valid and may give odds ratios (ORs) with narrower CIs, they only
produce logORs and their variances rather than raw data. As we opt for a model based on 2x2 tables using thebinomial likelihood, the Fukurawa method will be used in our review.
Missing continuous data will either be analysed on an endpoint basis, including only participants with a final
assessment, or analysed using the last observation carried forward to the final assessment (LOCF) if LOCF
data were reported by the trial authors. Where possible, exact SDs will be calculated from P values, t-values,
confidence intervals or standard errors, when these are reported in articles (Altman and Bland 1996). Whereno such information is available, attempts will be made to obtain these data through contacting trial authors.
Where the vast majority of actual SDs are available and only a minority of SDs are unavailable orunobtainable, a method used for imputing SDs and calculating percentage responders devised by Furukawa
and colleagues (Furukawa et al. 2006) will be used. We will check that the original standard deviations areproperly distributed, so that the imputed standard deviation represents the average. Where this method is
employed, data will be interpreted with caution, taking account of the degree of heterogeneity observed. A
sensitivity analysis will also be undertaken to examine the effect of the decision to use imputed data.
Where additional figures are not available or obtainable, and it is not deemed appropriate to use the Furukawa
method described above, the study data will not be included in the comparison of interest.
Data synthesis
We will generate descriptive statistics for trial and study population characteristics across all eligible trials,
describing the types of comparisons and some important variables, either clinical or methodological (such as
year of publication, age, severity of illness, clinical setting).
Pairwise meta-analysis
For each pair-wise comparison between treatments, the odds ratio will be calculated with a 95% CI. A
standard, pairwise meta-analysis will be conducted for each pairwise comparison of treatments using RevMan.
We anticipate some clinical heterogeneity between studies and so where there are ≥3 studies we plan to use arandom-effects model to incorporate the assumption that the different studies are estimating different, yet
related, treatment effects (DerSimonian and Laird 1986). Where there are <3 studies we will combine in a
fixed effect analysis (Mantel and Haenszel 1959).
As the correct interpretation of the pooled summary from a random effects analysis is an “average” effectacross the studies, it can be difficult to apply to individual study settings (Riley et al. 2011). A prediction
interval, which captures the uncertainty in the summary estimate, the estimate of the between study standard
deviation (Tau) and the uncertainty in Tau (Higgins et al. 2009), will therefore also be estimated.
MTM
To ensure that the network is connected, a network diagram will be constructed for the primary outcome only.
Note that MTM is only possible for a connected set of treatments.
A random-effects MTM, taking into account the correlations induced by multi-arm trials, will be conducted ina Bayesian framework and implemented using WinBUGS 1.4.1 (http://www.mrc- bsu.cam.ac.uk/bugs/). The
probability that each treatment is the most effective at improving response will also be calculated. The
goodness of fit of the model to the data will be measured by the posterior mean of the residual deviance. Thisis defined as the difference between the deviance for the fitted model and the deviance for the saturated model,
where deviance measures the fit of the model to the data points using the likelihood function. We will examine
11leverage plots to help identify any specific data points (trial arms) that were fitting poorly in each model. A
leverage plot displays the leverage (a measure of influence equal to the contribution of each trial arm to PD,
the effective number of parameters) versus the signed, square root of the residual deviance (a measure of fit)
for each data point. Points with a high leverage are influential, which means that they have a strong influenceon the model parameters that generate their fitted values. Convergence will be assessed using two chains andbased on the Brooks-Gelman-Rubin diagnostic tool in WinBUGS.
Unit of analysis issues
Studies with more than two intervention arms can pose analytical problems in pair-wise meta-analysis. Where
studies have two or more active treatment arms to be compared against treatment as usual, data will be
managed in this review as follows:
Continuous data: Means, SDs and 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 thecontrol group (Higgins 2008; Higgins 2008b; Law 2003).
Dichotomous data: Active treatment groups will be collapsed into a single arm for comparison against thecontrol group, or the control group will be split equally between the treatment groups.
Assessment of heterogeneity
Pairwise meta-analyses
Visual inspection of the forest plots will be used to investigate the possibility of statistical heterogeneity. This
will be supplemented using the I-squared statistic. This provides an estimate of the percentage of variability
due to heterogeneity rather than a sampling error (Higgins et al. 2003). 95% confidence intervals will becalculated for I-squared, and a P value from a χ2 test for heterogeneity will be used to assess evidence of its
presence. We will also report Tau2 (the between study variance). We consider a degree of heterogeneity
inevitable and therefore only I2 values ≥50% will be explored further using subgroup analyses for the primary
outcome only.
MTM
Inconsistency can be considered an additional layer of heterogeneity which can occur in networks of evidence.
It can occur when there is a discrepancy between a direct and indirect estimate of treatment effect. As suchinconsistency is considered a property of ‘closed loops’ of evidence. As a first step, we will calculate thedifference between indirect and direct estimates in each closed loop formed by the network of trials as ameasure of inconsistency and we will subsequently examine whether there are any material discrepancies. We
will also use model fit statistics as an informal check of inconsistency. In case of considerable inconsistency
we will investigate possible sources of it.
In the network meta-analysis we will assume homogeneous between study variability across studies (Lu andAdes 2004). We will report Tau (the standard deviation of underlying effects across studies) as our estimate ofheterogeneity. We will also report the effective number of parameters, pD, which increases with the degree ofheterogeneity in the random effect models, and so can also be viewed as a measure of heterogeneity.
Assessment of reporting biases
As far as possible, the impact of reporting biases will be minimised by undertaking comprehensive searches ofmultiple sources (including trial registries), increasing efforts to identify unpublished material including
contacts with the original study authors, and including non-English language publications.
We will also try and identify outcome reporting bias in trials by focusing on our predefined primary andsecondary outcomes and using the imputation to increase the number of studies included in the review(Furukawa et al. 2007).
Pairwise meta-analyses
Only if there are greater than 10 studies per pairwise meta-analysis will we consider using funnel plots toassess the impact of reporting bias on the estimates of treatment effect. We will investigate the presence ofsmall study effects for the primary outcomes only. For dichotomous outcomes several tests are available. Notethat our choice of test for funnel plot asymmetry will depend on the degree of heterogeneity observed.
MTM
The assessment of reporting biases is a new area in network meta-analysis and no agreed methodology
12currently exists. As such, we propose a simple approach to the evaluation of small study effects, and willconduct a sensitivity analysis excluding studies with sample ≤50 participants per arm. We will also use
Tanaka’s method [ref] and Chaimani’s method (Chaimani and Salanti 2012) to assess small study effects in
MTM.
Effect modifiers and investigation of heterogeneity
The following sources of possible clinical heterogeneity are listed a priori and will be examined as effectmodifiers in the MTM.
1. Year of publication
2. Baseline depression severity: 17-item HAMD scores at baseline will be entered as a covariate.
3. Researcher allegiance in psychotherapy arms and sponsorship in pharmacotherapy arms
Sensitivity analysis
In order to examine if the obtained results are preserved when we limit the included studies to high quality
ones only, we will examine the following variables.
1. Allocation concealment: Allocation concealment will be used as a marker of trial quality (Wood et al.
2008). Studies that were rated at high or unclear risk of bias for allocation concealment will be excluded.
2. Blinding: The influence of including open studies and single-blind studies will be examined.
3. Length of treatment: Four weeks may be too short to differentiate psychotherapies andpharmacotherapies. Studies will be limited to those whose outcomes are reported at 6 weeks or later.
4. Psychotherapy fidelity: Studies that were rated at high or unclear risk of bias for psychotherapy fidelity
will be excluded.
5. If pharmacotherapy/GP visits allowed as a cointervention in psychotherapy arms
6. Imputation: Trials where missing data have been imputed will be excluded.

Results

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