Pharmacological interventions for the treatment of depression in chronic obstructive pulmonary disease

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness of pharmacological interventions for the treatment of depression in patients with chronic obstructive pulmonary disease (COPD).

Background

Description of the condition

Chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) comprises primarily of chronic bronchitis and emphysema, conditions which are characterized by airway inflammation and destruction of pulmonary tissue. The diagnosis of COPD is based on a ratio of the post‐bronchodilator forced expiratory volume in one second, divided by the forced vital capacity (FEV1/FVC) that is less than 70% (Rabe 2007). It has been recognised as a global health concern and one of the leading causes of morbidity and mortality worldwide (Lopez 2006). With approximately 65 million people affected by COPD worldwide (Smith 2014), projections by the World Health Organization (WHO) suggest that COPD prevalence will continue to increase, and by 2030, will become the world's third leading cause of death (WHO 2008). A number of recent studies have indicated that mental health problems contribute significantly to mortality risk in COPD (Yohannes 2005; de Voogd 2009; Atlantis 2013).

Depression

Depressive illness can have a variety of presentations that can differ in severity (Pignone 2002). According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5), a diagnosis of major depressive disorder (MDD) is defined as experiencing at least five of the symptoms listed below, when at least one of the symptoms is depressed mood or loss of interest or pleasure:

• depressed mood;

• markedly diminished interest or pleasure in all, or almost all, activities most of the day;

• significant weight loss or weight gain, decrease or increase in appetite;

• insomnia or hypersomnia; fatigue or loss of energy;

• feelings of worthlessness or excessive guilt;

• diminished ability to think or concentrate;

• indecisiveness;

• recurrent suicidal ideation or a suicide attempt.

The symptoms must be present for at least two weeks, every day or nearly every day (APA 2013).

WHO's estimates indicate that by 2020, depression will be the second leading public health concern, proceeded only by cardiovascular disease (DeJean 2013).

Depression in patients with COPD

Depression is a major comorbidity in COPD, and is associated with higher rates of acute exacerbations, hospitalisations, and 30‐day mortality (Abrams 2011; Dalal 2011). The prevalence of clinical depression in patients with COPD ranges from 18% to 62% (van Manen 2002; Bentsen 2013; Fleehart 2014; Smith 2014). This variability may be due to diverse cut‐off scores, sampling, severity of COPD, or lack of standardisation of methodology. An evaluation by van Manen 2002 found that patients suffering from severe COPD had a higher risk of depression compared to control subjects, with rates of depression up to 62% in oxygen‐dependent patients.

Amongst the three chronic conditions that affect 60 million people in the US (diabetes, heart disease, and COPD) the population with COPD has the highest prevalence of MDD (Maurer 2008; Panagioti 2014). Even after adjusting for demographic variables and co‐morbidities, the risk of MDD was 2.5 times higher in patients with COPD compared to controls (Omachi 2009). There are a number of epidemiological and clinical studies that have found high rates of mood disorders among patients with COPD (Karajgi 1990; Di Marco 2006; Maurer 2008; Goodwin 2012; Dinicola 2013). A meta‐analysis that included 39,587 participants with COPD and 39,431 control subjects found that clinically significant depressive symptoms affected nearly 50% of COPD patients (Zhang 2011). This is compared to one‐year prevalence of 6.9% in the general population (Wittchen 2011).

Depression is a particularly strong predictor for mortality in COPD, with odds ratios ranging from 1.9 to 2.7 (Almagro 2002; Groenewegen 2003; Ng 2007); its predictive ability persists over and above the effects of other prognostic factors, including physiological factors, demographic factors, and disease severity (Fan 2007; de Voogd 2009). A study by Atlantis 2013 showed that the presence of depression in COPD patients increased the risk of mortality by 83%, compared to COPD patients without comorbid depression. A retrospective cohort study showed a 30% decrease in mortality in COPD patients who were using mental health services, compared with those whose depression was not treated (Hanania 2011).

Description of the intervention

Management strategies for the treatment of depression in COPD patients include both pharmacological and non‐pharmacological interventions. This review will examine the effects of pharmacological interventions for depression in people with COPD. There are many different types of pharmacotherapies, classified by their effect on different neuromodulators, such as: antidepressants, antipsychotics, benzodiazepines, and anticonvulsants.

Antidepressants

The main classes of antidepressants include non–selective antidepressants and selective reuptake inhibitors.

Non‐selective or first generation antidepressants:

• Tricyclic antidepressants (TCAs) act by serotonin and noradrenaline reuptake inhibition, with effects on multiple receptor system and sodium conductance, e.g. amitriptyline, nortriptyline, and doxepin.

• Monamine oxidase inhibitors (MAOIs) act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monamine neurotransmitters and thereby increasing their availability, e.g. phenelzine and selegiline.

Selective reuptake inhibitors or second generation antidepressants:

• Selective serotonin reuptake inhibitors (SSRI) act only on the neurotransmitter serotonin, e.g. citalopram, fluoxetine, paroxetine, and sertraline.

• Serotonin and norepinephrine reuptake inhibitors (SNRI) act by slowing down the reuptake of both serotonin and noradrenaline, but more selectively than other drugs, e.g. venlafaxine and duloxetine.

• Norepinephrine and dopamine reuptake inhibitors (NDRIs) increase the levels of norepinephrine and dopamine, e.g. bupropion.

• Serotonin modulators antagonise postsynaptic serotonin receptors and inhibit reuptake of postsynaptic serotonin, e.g. nefazadone, trazodone, and vilazodone (NIH 2010).

Other medications

• Atypical antipsychotics, e.g. olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole can be used in the treatment of depression, especially with psychotic or delusional depression (Schatzberg 1992).

• Antipsychotics have a complex mechanism of action, and exert an effect to block alpha–adrenergic (alpha 1 and alpha 2), dopamine (primarily D2, but also D1 and D4), histamine (H1), muscarinic (primarily M1), and serotoninergic (primarily 5‐HT1A, 5‐HT2a and 5‐HT1c) receptors (Kaplan 2009).

• Benzodiazepines, e.g. diazepam, alprazolam, and lorazepam, show therapeutic effects by acting on the norepinephrine, serotonergic, and dopaminergic system.

• Anticonvulsants, e.g. gabapentin, topiramate, and lamotrigine, have varied mechanism of action, for example, increasing alpha‐aminobutyric acid (9GABA) function, thereby, enhancing neuronal inhibition or reducing neuronal excitation by decreasing glutamatergic function (Kaplan 2009).

How the intervention might work

The understanding of mechanisms of mood control by antidepressants has evolved over time. Since the late 1950s, a wide range of antidepressants targeting the monoaminergic neurotransmitter system have been available to alleviate the symptoms of MDD. However, the efficacy of these antidepressants cannot be solely explained by their modulatory effects on brain monoamines (Hisaoka‐Nakashima 2015). In the past decade, has been postulated that glial degeneration or dysfunction, especially of astrocytes, plays a critical role in the pathogenesis of MDD (Rajkowska 2013). One of the major roles of astrocytes is the production of neurotrophic or growth factors, which support neurogenesis, gliogenesis, brain development, neural plasticity, and survival (Allen 2009). Recently, both clinical and preclinical animal studies have demonstrated that multiple neurotrophic or growth factors, such as glial cell‐derived neurotrophic factor (GDNF), play an important role in the therapeutic effect of antidepressants (Bespalov 2007). In studies with COPD patients, older tricyclic antidepressants and newer SSRI have been tested. Tricyclic antidepressants have been in use for many years. Their antidepressant effect is a result of the inhibition of the reuptake of neurotransmitters such as serotonin, noradrenalin, and dopamine from synaptic cleft. Previous studies have also demonstrated that an amitriptyline‐evoked matrix metalloproteinase (MMP)/fibroblast growth factor receptor (FGFR)/FGFR substrate2α (FRS2α)/extracellular signal‐regulated kinase (ERK) cascade is crucial for GDNF production. However, how amitriptyline triggers this cascade remains unknown (Hisaoka‐Nakashima 2015).

Currently, SSRIs are commonly prescribed antidepressant drugs. They support the role of serotonin and SNRIs, such as maprotiline and reboxetine, and underline the relevance of norepinephrine (Skaer 2009). Studies on SSRIs have shown benefits with both fluoxetine and paroxetine over placebo, leading to an improvement of symptoms of depression that was also correlated with an increase in walking distance in COPD patients (Lacasse 2004; Eiser 2005).

It has been hypothesized that various antidepressant medications benefit patients with COPD by reducing the excessive distress associated with COPD. This facilitates increased physical activity, which leads to better endurance of the physiological changes (Borson 1992).

Why it is important to do this review

Given the prevalence and the impact of depressive disorders in patients with COPD, it is essential that effective therapies are identified and implemented. Findings by Kim 2000 and Kunik 2005 suggest that fewer than one third of COPD patients receive appropriate treatment for depression. A number of other studies also found that depression is often untreated (Cafarella 2012; Kim 2014), or inappropriately treated in patients with COPD (van Manen 2002; Cully 2006; Maurer 2008). This is associated with worse compliance with medical treatment (Yohannes 2008), poor quality of life, increased hospital readmissions, prolonged length of hospital stay (Coventry 2013), and subsequently increased costs to the health care system (Gudmundsson 2005; Kunik 2005; Ng 2007; Maurer 2008; Felker 2010; Pumar 2014). Evidence from systematic reviews shows that the presence of mental health problems inflates the costs of care for chronic conditions by at least 45%, after controlling for severity of the physical illness (Hutter 2010; Naylor 2012). Regrettably, evidence‐based guidelines for COPD do not provide any recommendation for screening, diagnosing, or treating depression. As the decision to use pharmacological therapies should be based on reliable, methodologically rigorous research, it is important to evaluate the effectiveness of pharmacological therapies for COPD patients with depressive disorders, and to provide a review of available, up‐to‐date evidence. The findings may help clinicians, health professionals, or policy makers decide what therapies can be implemented as part of guidelines for routine treatment for depression in COPD. This review is one of four linked Cochrane reviews that address both pharmacological and psychological interventions for the treatment of depression and anxiety in patients with COPD (Usmani 2011; Usmani 2013).

Objectives

To assess the effectiveness of pharmacological interventions for the treatment of depression in patients with chronic obstructive pulmonary disease (COPD).

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), including cross‐over trials and cluster randomised trials.

Types of participants

Participant characteristics

We will include studies of adults who are over 40 years of age (as it is unlikely that people under 40 years of age would be diagnosed with clinically significant COPD (GOLD 2011)), of either sex, and of any ethnicity.

Diagnosis

We will include studies with participants diagnosed with COPD (FEV1/FVC less than 70) and a recognised depressive disorder, or depressive symptoms at the time of recruitment to the trial (assessed using a standardised diagnostic criteria, a formal, validated psychological instrument (i.e. questionnaire), or both).

The COPD diagnosis would have been made by a medical professional clinically, by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, or both.

We will accept the following diagnostic criteria for depression: DSM‐3, DSM‐4 (APA 2000), DSM‐5 (APA 2013). We will accept the following depression measures: Beck Depression Inventory (BDI; Beck 1961), Hamilton Depression Rating Scale (HDRS; Hamilton 1960), Patient Health Questionnaire (PHQ; Spitzer 1999), Depression Anxiety Stress Scales (Lovibond 1995), or any other depression scale.

Co‐morbidities

As long as the co‐morbidity is not the main focus, we will include studies with participants with co‐morbid chronic physical conditions (e.g. hypertension, cardiovascular disease, metabolic disease, asthma), co‐morbid mental disorders (e.g. anxiety), or both.

Setting

All types of settings will be eligible for inclusion: inpatient (psychiatric setting, inpatient treatment for COPD), outpatient, and primary care.

Subset data

We will include studies that include a subset of eligible participants as long as 60% of participants have clinically diagnosed COPD and a depressive disorder.

Types of interventions

We will include studies that used pharmacological therapies (of any dosage, as specified by original study authors) for the treatment of depression in COPD patients, and where comparisons to either placebo or to no treatment were used. Studies in which the pharmacological intervention is delivered in combination with another intervention (co‐intervention) will be included only if there is a comparison group that received the co‐intervention alone.

Experimental intervention

1. pharmacological

Non‐selective or first generation antidepressants:

• tricyclic antidepressants (TCAs), e.g. amitriptyline, nortriptyline and doxepin;

• monamine oxidase inhibitors (MAOIs), e.g. phenelzine and selegiline.

Selective reuptake inhibitors or second generation antidepressants:

• selective serotonin reuptake inhibitors (SSRI), e.g. citalopram, fluoxetine, paroxetine and sertraline;

• serotonin and norepinephrine reuptake inhibitors (SNRI), e.g. venlafaxine and duloxetine;

• norepinephrine and dopamine reuptake inhibitors (NDRIs), e.g. bupropion;

• serotonin modulators, e.g. nefazadone, trazodone, vilazodone.

Other medications:

• atypical antipsychotics e.g. olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole;

• benzodiazepines, e.g. diazepam, alprazolam, and lorazepam;

• anticonvulsants, e.g. gabapentin, topiramate, and lamotrigine.

2. pharmacological and co‐interventions

We will only include co‐interventions that include pulmonary rehabilitation, self‐management, written action plans, or psychotherapy, such as, cognitive behavorial therapy.

Comparator intervention

1. no treatment (e.g. waiting list and usual care)

2. placebo

3. co‐intervention (only if it is the same co‐intervention used in the intervention arm of the study)

The co‐intervention can include natural products, provided that the usage between intervention and control arms is similar, or the intervention is natural treatments alone, or as part of a package of pharmacological, psychological, and natural treatments. We will document additional natural‐product therapies received by participants for each included study.

We will include multi‐arm trials, provided there is an intervention arm with any of the interventions mentioned above, and a control arm with any of the controls mentioned above.

Types of outcome measures

Primary outcomes

1. Change in depressive symptoms, measured by a standardised or validated depression measure, e.g. Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), Patient Health Questionnaire (PHQ), Depression Anxiety Stress Scales (DASS), or any other validated depression scale

2. Adverse events ‐ separated into three subgroups:

• treatment‐related adverse events as a result of:

  • tricyclic antidepressants (e.g. constipation, dry mouth, urinary retention, sedation, weight gain, confusion);

  • selective serotonin reuptake inhibitors (e.g. sexual dysfunction, drowsiness, insomnia, dizziness, nausea, tremors, constipation);

  • atypical antipsychotics (e.g. hypotension, sedation, cardiac effects, extrapyramidal side effects, cataracts);

  • benzodiazepines (e.g. drowsiness, apnoea, bradypnoea, amnesia, confusion).

• disease‐related adverse events (e.g. exacerbation of illness, breathlessness, respiratory infections, pulmonary hypertension)

• mortality (30‐day and long‐term), measured by the total number of deaths

Secondary outcomes

1. Change in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ; Jones 1991), Short Form (SF)‐36 (Ware 1993), and other validated tools ‐ in this order if authors report multiple scales)

2. Change in dyspnoea (measured by the BORG scale (Borg 1982), or other validated tools

3. Change in forced expiratory volume in one second (FEV1)

4. Change in exercise tolerance (measured by the six‐minute walk test (6MWT), twelve‐minute walk test (Butland 1982; ATS 2002), or other validated tools)

5. Change in hospital length‐of‐stay or readmission rate

6. Cost‐effectiveness (e.g. measured as reduction of costs of treatment, number of appointments with a health professional, use of additional treatments or ability to work)

Timing of outcome assessment

Time frames will be defined as short‐term (less than six months), medium‐term (six to 12 months), and long‐term (12 months or longer) follow‐up periods. In some studies with multiple reported long‐term follow up periods, e.g. 12 and 24 months, we will use the final follow‐up period reported. The primary time‐point to be reported in the 'Summary of findings' tables will be the final follow‐up period.

Hierarchy of outcome measures

We will treat the four scales: BDI, HDRS, PHQ, and DASS as equivalent scales. We will rate all other depression scales lower. If a study uses two or more of the depression scales mentioned, we will use the generic inverse variance method to combine the outcomes. If a study employs more than one quality of life measure, we will apply the following hierarchy of scales: 1. SGCRQ, 2. Short Form (SF)‐36, 3. any other quality of life measures used. For the reduction in length of hospital stay or readmission rate, we will apply the following hierarchy: 1. length of stay, 2. readmission rate. If other measures are used, we will use them as defined and reported by the study authors.

For secondary outcomes, we will aim to show treatments that provide short‐term or medium‐term benefits in remission.

Search methods for identification of studies

We will conduct searches to identify all published and unpublished RCTs without applying any date or language restrictions.

Electronic searches

Cochrane Specialised Registers

1. CCMD Register (CCMDCTR)

The Cochrane Common Mental Disorders Group maintains a register of randomised controlled trials: the CCMDCTR. The register contains over 40,000 reference records (reports of RCTs) for depression, anxiety, and other common mental disorders. It is a partially studies‐based register with more than 50% of reference records tagged to approximately 12,500 individually PICO‐coded study records, which can help facilitate precision searching. Reports of trials for inclusion in the register are collated from weekly generic searches of MEDLINE, EMBASE and PsycINFO, 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 trial registries, drug companies, the handsearching of key journals, conference proceedings, and other (non‐Cochrane) systematic reviews and meta‐analyses. Details of CCMD's core search strategies can be found on the Group's website, with an example of the core MEDLINE search displayed in Appendix 1.

The Group's Information Specialist will cross‐search the CCDMDCTR (studies and references) using the following terms (all years to date):

#1 (depress* or dysthymi* or "mood disorder*" or "affective disorder*" or "affective symptom*"):ti,ab,kw,ky,emt,mh #2 ((obstruct* and (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)) or COPD or emphysema or (chronic* and bronchiti*)):ti,ab,kw,ky,emt,mh #3 (#1 and #2)

We will screen records for pharmacological interventions for the treatment of depression in COPD.

2. CAG Register (CAGR)

The Cochrane Airways Group's Specialised Register is also derived from systematic searches of bibliographic databases including: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts (details of the CAGR can be found on the Group's website).

The Group's Information Specialist will search their register for records coded as 'COPD' and 'depression'.

Searching other resources

We will search online clinical trial registers for ongoing and recently completed studies, including the ISRCTN Registry, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry (who.int/trialsearch/).

Grey literature

We will search sources of grey literature, including theses and dissertations, clinical guidelines, and reports from regulatory agencies where appropriate, in order to reduce the risk of publication bias and to identify as much relevant evidence as possible.

• Open Grey (opengrey.eu)

• Trove (trove.nla.gov.au)

• The Agency for Healthcare Research and Quality (ahrq.gov)

• Grey Literature Network Service (greynet.org)

Handsearching

We will not perform any handsearching for this study.

Reference lists

We will check the reference lists of all included studies and relevant systematic reviews to identify studies that may have been missed from the original electronic searches (for example, unpublished or in‐press citations). A cited reference search will also be conducted on the Web of Science.

Correspondence

We will contact trialists and subject experts for information on unpublished or ongoing studies, or to request additional trial data.

Data collection and analysis

Selection of studies

Two review authors (from SN, ZU, JP, JV) will independently assess the studies identified by the search strategies to determine whether they satisfy the inclusion criteria, by screening the title, abstract, and descriptors. We will retrieve the full‐text articles of studies identified as potentially relevant, and two of the three review authors will independently assess them and make the final decision on inclusion. We will resolve disagreements through discussion and if necessary, by consulting with a third party (KC or BS).

We will record the decision process in enough detail to complete a PRISMA flow diagram that will be included in the review.

Data extraction and management

Two review authors (from SN, ZU, JP, JV) will independently extract the following data from each study onto a standardised and piloted data extraction form. We will resolve disagreements through discussion and if necessary, by consulting with a third party (KC or BS).

Study Eligibility

Study design, population group, and description of pharmacological intervention.

Participants

Number of participants, age, gender distribution, ethnicity, and other relevant information, e.g. co‐morbidities, severity of condition, and exclusion criteria.

Interventions

Medication name, trade name, dose, duration of treatment, placebo. or description of co‐intervention.

We will resolve any discrepancies by discussion between the review authors and consult with a third party as indicated.

Main comparisons

We will summarise the evidence for each class of drugs and present the evidence for each of these classes separately (i.e. first generation, second generation antidepressants and 'other medications'). We will group the comparisons within each class according to a broad pharmacological category, and compare each to placebo or no treatment. We will also compare medications with co‐interventions versus the same co‐intervention alone, as outlined above. Including an individual medication (within a class) as a main comparison may increase clinical relevance of the findings, however, we do not expect to find sufficient studies to evaluate specific medications.

Non‐selective or first generation antidepressants

1. TCAs versus placebo or no treatment

2. MAOIs versus placebo or no treatment

3. TCAs and co‐intervention versus the co‐intervention alone

4. MAOIs and co‐intervention versus the co‐intervention alone

Selective reuptake inhibitors or second generation antidepressants

1. SSRIs versus placebo or no treatment

2. SNRIs versus placebo or no treatment

3. NDRIs versus placebo or no treatment

4. Serotonin modulators versus placebo or no treatment

5. SSRIs and co‐intervention versus the co‐intervention alone

6. SNRI and co‐intervention versus the co‐intervention alone

7. NDRIs and co‐intervention versus the co‐intervention alone

8. Serotonin modulators and co‐intervention versus the co‐intervention alone

Other medications

1. atypical antipsychotics versus placebo or no treatment

2. benzodiazepines versus placebo or no treatment

3. anticonvulsants versus placebo or no treatment

4. atypical antipsychotics and co‐intervention versus the co‐intervention alone

5. benzodiazepines and co‐intervention versus the co‐intervention alone

6. anticonvulsants and co‐intervention versus the co‐intervention alone

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias for all the included studies, as per the Handbook of Systematic Reviews of Interventions guidelines, using a domain‐based evaluation. We will assess the risk of bias for each domain as 'low risk of bias', 'high risk of bias', and 'unclear risk of bias' (Higgins 2011). We will resolve conflicts in the assessment either by consensus or by referring to a third party. We will evaluate the following domains (Higgins 2011):

Sequence generation

Methods considered to be adequate may include: random number table, computer random number generator, coin toss, shuffling cards or envelopes, throwing dice, and drawing lots.

Allocation concealment

Methods considered to be adequate may include: central allocation (phone, web, pharmacy), sequentially numbered identical drug containers, and serially numbered sealed and opaque envelopes.

Blinding (of participants)

Blinding will be considered adequate if: authors mention that participants were blinded to the allocation concealment, blinding was not broken, and an identical placebo was used for pharmacological interventions.

Blinding (of outcome assessors)

Blinding will be considered adequate if: authors mention that outcome assessors were blinded to sequence allocation.

Incomplete outcome data

The risk of bias due to incomplete outcome data will be assessed on the grounds of whether the incomplete outcome data was adequately addressed, as per the Handbook of Systematic Reviews of Interventions, Section 8.13.

Selective outcome reporting

Studies will be considered to have minimal bias if a protocol is available and all pre‐specified outcomes are reported in the pre‐specified way, or in the absence of a protocol, if all expected outcomes are reported (as per recommendations in the Handbook of Systematic Reviews of Interventions, Table 8.5.d.

Other bias

We will consider studies to be at low risk of bias if they were conducted in such a way as to ensure that no other influencing factors that could potentially affect the outcome, were evident. Examples of other biases include: carry over in a cross‐over trial or extreme baseline imbalance.

We will consider studies with inadequate or unclear randomisation, allocation concealment, or both at high risk of bias.

We will present the results of our assessment in a 'Risk of bias' table and describe it in the text using a narrative synthesis.

Measures of treatment effect

Continuous data

For continuous outcomes, we will enter data from validated depression rating scales, quality of life questionnaires, or other clinical measures. We will summarise available data by either mean differences (MD) or standardised mean differences (SMD) if different measurement tools are measuring the same outcome, with 95% confidence intervals (CI), using mean values and standard deviations (SD).

Dichotomous data

For binary data, we will calculate odds ratios with 95% CI.

We will present data from final values (post‐intervention).

We will consult a statistician for additional support if required for any of our analyses.

Unit of analysis issues

Cross‐over trials

We will not use the data from cross‐over trials from the second period (after the cross‐over) if there is any doubt about the validity of the data due to a significant carry‐over effect.

Cluster randomised trials

For cluster randomised studies, we will perform analyses at the level of individuals, whilst accounting for the clustering in the data by using a random‐effects model for meta‐analysis as recommended in Chapter 16.3 (Higgins 2011). For those studies which do not adjust for clustering, the actual sample size will be replaced with the effective sample size (ESS), calculated using a rho = 0.02 as per Campbell 2000.

Studies with multiple treatment groups

We will include multi‐arm trials, provided there is an intervention arm with any of the interventions of interest and a control arm with any of comparators mentioned above. We will include each pair‐wise comparison separately, but shared intervention groups will be equally divided among the comparisons. However, if the intervention groups are deemed similar enough to be pooled, we will combine the groups using appropriate formulae from Chapters 16.5 and 16.6 (Higgins 2011).

Dealing with missing data

We will contact study authors for any missing information. We will evaluate missing participant information on an available case analysis basis, as described in Chapter 16.2.2 (Higgins 2011). We will address missing standard deviations by imputing data from studies within the same meta‐analysis, or from a different meta‐analysis with studies that used the same measurement scales, have the same degree of measurement error, and the same time periods (between baseline and final value measurement), as described in Chapter 16.1.3.2 (Higgins 2011). Where statistics essential for analysis are missing and cannot be calculated from other data (e.g. group means and standard deviations for both groups are not reported), we will attempt to contact the study authors to obtain data. We will assume that the loss of participants before baseline measurements were acquired will not affect the outcome data. We will assess and discuss the implications of any losses that occur after baseline measurements were taken. We will discuss attrition in the 'Risk of bias' tables and in the text. Studies that have more than 20% dropout rate will be reported in the text.

Assessment of heterogeneity

We expect this review to have some heterogeneity contributed by factors such as baseline severity of depression, severity of underlying COPD, time of measurement of results and varying measuring tools used to assess outcomes. We will use Chi² and I² statistics to quantify inconsistency across studies in combination with visual inspection of the data for differences between studies (e.g. types of interventions, participants, etc). Thresholds for the interpretation of I² can be misleading, since the inconsistency depends on several factors, including magnitude and direction of the effect and strength of the evidence for heterogeneity, for example the P value from the Chi² test, or a confidence interval for I². For the purpose of this review, we will investigate possible causes of an I² statistic that represents considerable heterogeneity through subgroup analyses, as per Chapter 9.5.2 (Higgins 2011). Details of the subgroup analyses are explained in the later sections of this protocol. We will examine the I² value using the following overlapping bands provided in the Cochrane Handbook for Systematic Reviews of Intervenions (Higgins 2011).

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

If there are more than ten included studies, we will assess potential reporting bias using a funnel plot. Asymmetry in the plot could be attributed to publication bias, but may well be due to true heterogeneity, or poor methodological design. In case of asymmetry, contour lines may be included that correspond to perceived milestones of statistical significance (P = 0.01, 0.05, 0.1, etc.) to funnel plots, which may help to differentiate between asymmetry due to publication bias and other factors (Higgins 2011). In instances of fewer than ten studies, the reporting biases will be reported as ’other bias’ in the 'Risk of bias' table.

Data synthesis

We will pool the extracted data in meta‐analyses using the random‐effects model to allow for expected heterogeneity in the interventions and populations. We will include all the included studies in the primary analysis. Data will be analysed using Review Manager 5.3 (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

We expect that the included studies will be heterogeneous due to multiple factors, including baseline severity of depression, severity of underlying COPD, duration of intervention, and the use of multiple measuring tools to assess the same outcome. As such, we have pre‐specified subgroups to investigate heterogeneity to reduce the likelihood of spurious findings, first, by limiting the number of subgroups investigated, and second, by preventing knowledge of the studies' results to influence which subgroups are analysed (Higgins 2011).

We will explore heterogeneity through a number of possible sub‐group analyses within each drug classification, which will include:

• intervention characteristics (i.e. duration of the intervention (less than one month; one month or longer), dosage (low, medium, or high, as defined by each study author)

• intervention setting (inpatient, outpatient, primary care)

• participant characteristics (i.e. gender, age, co‐morbidities)

• severity of depression symptoms (i.e. mild, moderate, severe)

• individual medication type (if the results permit it)

We will use meta‐regression and visual presentation using bubble plots to investigate the sources of heterogeneity. The variability may influence our primary and secondary outcomes, however, we will only conduct them for primary outcomes. Participant characteristics may vary between studies and we expect differences in outcomes based on gender, age and co‐morbidities. We also expect severity of depression symptoms to be a significant indicator of possible efficacy for the different outcomes.

Sensitivity analysis

We will perform sensitivity analyses to assess the impact of study design and the effects of methodological decisions taken throughout the review process on the overall results, particularly in regard to the inclusion criteria. We will test the validity and robustness of the findings by removing studies based on the following criteria:

1. inadequate sequence generation (unclear or high risk of bias)

2. inadequate allocation concealment (unclear or high risk of bias)

3. significant attrition of the study population (20% or higher attrition)

4. cluster randomised trials

5. cross‐over studies

6. studies containing data imputed by the review authors

7. quality of the studies (i.e. high risk of bias for: two or fewer domains, three or four domains or five to seven domains)

Sensitivity analysis will only be conducted for primary outcomes.

Summary of findings

We will use the GRADE approach to evaluate the quality of evidence as described in Chapter 12.8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use GRADEprofiler (GRADEpro GDT 2015) to prepare a 'Summary of findings' table. We will assess the following domains: limitation in design, directness, inconsistency, imprecision, and reporting bias.

We will assess the following outcomes: 1) reduction of depressive symptoms, 2) adverse events, 3) improvement in quality of life, 4) reduction of dyspnoea, 5) improvement of forced expiratory volume in one second (FEV1), 6) increased exercise tolerance.

We will report the final follow‐up period in the 'Summary of findings' table.

Appendices

Appendix 1. CCMDCTR ‐ core MEDLINE search

Core search strategy used to inform the Cochrane Common Mental Disorders Group's specialised register: OVID Medline A weekly search alert based on condition + RCT filter only 1. [MeSH Headings]: eating disorders/ or anorexia nervosa/ or binge‐eating disorder/ or bulimia nervosa/ or female athlete triad syndrome/ or pica/ or hyperphagia/ or bulimia/ or self‐injurious behavior/ or self mutilation/ or suicide/ or suicidal ideation/ or suicide, attempted/ or mood disorders/ or affective disorders, psychotic/ or bipolar disorder/ or cyclothymic disorder/ or depressive disorder/ or depression, postpartum/ or depressive disorder, major/ or depressive disorder, treatment‐resistant/ or dysthymic disorder/ or seasonal affective disorder/ or neurotic disorders/ or depression/ or adjustment disorders/ or exp antidepressive agents/ or anxiety disorders/ or agoraphobia/ or neurocirculatory asthenia/ or obsessive‐compulsive disorder/ or obsessive hoarding/ or panic disorder/ or phobic disorders/ or stress disorders, traumatic/ or combat disorders/ or stress disorders, post‐traumatic/ or stress disorders, traumatic, acute/ or anxiety/ or anxiety, castration/ or koro/ or anxiety, separation/ or panic/ or exp anti‐anxiety agents/ or somatoform disorders/ or body dysmorphic disorders/ or conversion disorder/ or hypochondriasis/ or neurasthenia/ or hysteria/ or munchausen syndrome by proxy/ or munchausen syndrome/ or fatigue syndrome, chronic/ or obsessive behavior/ or compulsive behavior/ or behavior, addictive/ or impulse control disorders/ or firesetting behavior/ or gambling/ or trichotillomania/ or stress, psychological/ or burnout, professional/ or sexual dysfunctions, psychological/ or vaginismus/ or Anhedonia/ or Affective Symptoms/ or *Mental Disorders/

2. [Title/ Author Keywords]: (eating disorder* or anorexia nervosa or bulimi* or binge eat* or (self adj (injur* or mutilat*)) or suicide* or suicidal or parasuicid* or mood disorder* or affective disorder* or bipolar i or bipolar ii or (bipolar and (affective or disorder*)) or mania or manic or cyclothymic* or depression or depressive or dysthymi* or neurotic or neurosis or adjustment disorder* or antidepress* or anxiety disorder* or agoraphobia or obsess* or compulsi* or panic or phobi* or ptsd or posttrauma* or post trauma* or combat or somatoform or somati#ation or medical* unexplained or body dysmorphi* or conversion disorder or hypochondria* or neurastheni* or hysteria or munchausen or chronic fatigue* or gambling or trichotillomania or vaginismus or anhedoni* or affective symptoms or mental disorder* or mental health).ti,kf.

3. [RCT filter]: (controlled clinical trial.pt. or randomized controlled trial.pt. or (randomi#ed or randomi#ation).ab,ti. or randomly.ab. or (random* adj3 (administ* or allocat* or assign* or class* or control* or determine* or divide* or distribut* or expose* or fashion or number* or place* or recruit* or subsitut* or treat*)).ab. or placebo*.ab,ti. or drug therapy.fs. or trial.ab,ti. or groups.ab. or (control* adj3 (trial* or study or studies)).ab,ti. or ((singl* or doubl* or tripl* or trebl*) adj3 (blind* or mask* or dummy*)).mp. or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or randomized controlled trial/ or pragmatic clinical trial/ or (quasi adj (experimental or random*)).ti,ab. or ((waitlist* or wait* list* or treatment as usual or TAU) adj3 (control or group)).ab.)

4. (1 and 2 and 3)

Records are screened for reports of RCTs within the scope of the Cochrane Common Mental Disorders Group. Secondary reports of RCTs are tagged to the appropriate study record. Similar weekly search alerts are also conducted on OVID EMBASE and PsycINFO, using relevant subject headings (controlled vocabularies) and search syntax, appropriate to each resource.

Contributions of authors

Protocol prepared by Syeda Naqvi, Justyna Pollok, Kristin Carson, Zafar Usmani with feedback provided by Adrian Esterman and Brian Smith.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Respiratory Medicine Department at the Queen Elizabeth Hospital, Adelaide, Australia.

Declarations of interest

Not known

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