Pharmacy‐based management for depression in adults

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

We will examine the effects of pharmacy‐based management interventions compared to an active control, treatment as usual or no intervention/ waiting list, at improving depression outcomes in adults.

Background

Some services provided by pharmacists may have positive effects on patient health, including improved management of blood pressure and physical function (de Barra 2018). Antidepressant management for depression is usually achieved through general practitioner (GP) contact and monitoring, which typically involves regular appointments (e.g. every two to four weeks within the first three months) in order to assess response and tolerance to treatment (NICE 2018). Community pharmacists may be well placed to have a role in antidepressant management because of their unique pharmacotherapeutic knowledge and ease of access for patients. In the UK, there have been efforts to raise public awareness about the role that pharmacists can play as part of multidisciplinary team to better support people with managing their health conditions, including mental health problems (Royal Pharmaceutical Society 2018).

In England, an estimated 89.2% of the population have access to a community pharmacy within a 20‐minute walk; in the most deprived areas, this figure increases to 99.8% of the population (Todd 2014). Therefore, pharmacy teams – working in community, general practice or secondary care – are ideally placed to offer proactive interventions to people with depression or depressive symptoms. A narrative evidence synthesis by Rubio‐Valera 2014 suggests that pharmacists, specifically, have skills in medication management, provision of drug information, supporting and advising patients about their medicines and facilitating medication adherence strategies in mental health care. Although pharmacy‐based management interventions can vary in their components, there is scope for these approaches to be used in partnership with other healthcare professionals (for example, as part of a collaborative care approach). Previous research has suggested that multi‐professional approaches (involving more than one type of health professional, using a structured management plan and scheduled follow‐ups, with enhanced inter‐professional communication) have the potential to improve the management of depression in primary care settings (Archer 2012; Gilbody 2003; Gunn 2006). However, despite this potential, and the emerging evidence of the role of pharmacy‐based management interventions for depression, the effectiveness and acceptability of these interventions is not yet well understood.

Description of the condition

Depression can be characterised by low mood; markedly diminished interest or pleasure in activities; impaired cognitive function; fatigue or reduced or disturbed sleep; feelings of worthlessness; and significant decrease or increased appetite (APA 2013; Otte 2016). The aetiology and maintenance of depression is complex and multifactorial, involving environmental and social factors, as well as genetic and biological factors affecting function changes and regions of the brain (Otte 2016). The condition can be recurrent or long‐term and chronic, and often results in debilitating burden that can interfere with family, home, social and work responsibilities (Marquez 2016).

Depression is a common mental health problem, with more than 300 million people globally estimated to be living with the condition (WHO 2018). It is the leading cause of disability worldwide and a major contributor to the overall burden of disease (WHO 2018). In extensive global population research on Global Burden of Disease involving 188 countries between 1990 and 2013, depression was found to be one of the top 10 causes of years lived with disability in every country studied, with higher rates of depression typically found in women (Vos 2015). The global point prevalence of depression is reported to be 3.2% for men and 5.5% for women (Ferrari 2013a; Ferrari 2013b; Whiteford 2013). It is estimated that annually 12 billion days of lost productivity (equivalent to 50 million years of work) are attributable to depressive and anxiety disorders (which are often comorbid with each other) combined, with an estimated cost of USD 925 billion, a cost that is anticipated to grow in coming years (Chisholme 2016).

Antidepressants have long been a mainstay of pharmacological treatment for depression (Taylor 2015), and have been reported to be more effective than placebo (Cipriani 2018). However, it is common for patients not to take antidepressant medication as prescribed, with around 50% of patients likely to prematurely discontinue taking their medication after six months. Premature discontinuation of antidepressant therapy has been linked to increased healthcare costs, poor treatment outcomes, and increased risk of relapse and recurrence (Chong 2011).

Medication non‐compliance can be broken down into the concepts of 'adherence' and 'persistence'; the former defined as "the extent to which a patient acts in accordance with the prescribed interval, and dose of a dosing regimen", and the latter "the duration of time from initiation to discontinuation of therapy", which can be related to the effects of the medication itself, including any adverse effects (Cramer 2008). Non‐compliance can impact on the potential for antidepressant medication to improve symptoms of depression and may be related to specific concerns (such as experience of adverse effects, fear of addiction, lack of belief in the role of medication in helping to treat depression) as well as factors associated with medication management (such as insufficient provision of patient information/education, poor post‐prescription follow‐up, or other less explicit reasons) (Anderson 2013; Martin‐Vazquez 2016; Sansone 2012).

Description of the intervention

Pharmacy‐based management interventions can be delivered by a single pharmacist or the wider pharmacy support team. In the context of depression, pharmacy‐based management interventions are often delivered in partnership with other healthcare professionals – usually as part of a collaborative care approach – focusing on improving patient adherence and persistence with antidepressant medication. This can be done in several ways: firstly, by providing patient support, counselling, and education; secondly, by monitoring or following up adverse effects of medications; and, thirdly, under specific protocols, titrating doses of medications according to patient response (Brook 2005; Capoccia 2004; Finley 2003). These interventions can be provided face‐to‐face, using written support materials or visual information relating to medication, through telephone support, or via more formal 'counselling' strategies (Adler 2004; Al‐Saffar 2005), and they may happen alongside the involvement of care managers, mental health specialists, and primary care physicians (Aljumah 2015; Rickles 2005).

As the intervention can be delivered in multiple ways and, given the number of interacting components involved (including the number and difficulty of behaviours required by those delivering or receiving the intervention, the number and potential variability of outcomes, and the degree of flexibility or tailoring of the intervention permitted) it can be described as a complex intervention (Petticrew 2011).

How the intervention might work

Working alone or as part of a wider collaborative care approach, a goal of pharmacy‐based management is to improve patient adherence and persistence rates with antidepressant medication. A key aspect of effective collaborative care is 'case management' (Gilbody 2003), which has been described as a 'health worker taking responsibility for proactively following up patients, assessing patient adherence to psychological and pharmacological treatments, monitoring patient progress, taking action when treatment is unsuccessful, and delivering psychological support' (Von Korff 2001). In addition to improving patient adherence and persistence, pharmacy‐based management interventions might also involve the delivery of direct psychological interventions to patients with depression. An example of this is behavioural activation (BA) therapy, which uses principles of operant conditioning by encouraging people with depression to reconnect with environmental positive reinforcement (Ekers 2014). Behavioural activation can be effective when delivered by paraprofessionals (Gilbody 2017), and current research is exploring if it can be delivered by community pharmacies to people with long‐term physical health problems and subthreshold depression (ISRCTN11290592).

Qualitative work has shown that people tend to form different relationships with a pharmacist compared to other healthcare professionals, such as primary care practitioners or general practitioners (GPs), indicating that people might be more likely to see a pharmacist to discuss certain aspects of their health (Lindsey 2016). Previous research has demonstrated how pharmacist‐based management interventions, including providing patient support, counselling or coaching patients about their medication and what to expect, can improve antidepressant adherence rates (Al‐Saffar 2005; Brook 2005). It is proposed that pharmacy‐based management interventions, such as engaging patients through face‐to‐face or remote counselling, education and advice (e.g. via teleconferencing, or 'take‐home' audio/visual materials) alongside prescribing and monitoring of antidepressant medication, can also improve depressive symptoms.

Why it is important to do this review

Pharmacists are now engaging with patients in different ways, and it is important to bring together the randomised evidence for pharmacy‐based approaches for depression to determine effectiveness not only on adherence levels, depressive symptoms and adverse effects of prescribed medication, but also on broader patient‐centred outcomes including acceptability, quality of life and levels of social functioning. Research involving community household surveys from 21 countries showed that only a minority of people received 'minimally adequate treatment' for depression. This finding equates to 1 in 5 people in high‐income countries, and 1 in 27 in low‐/lower‐middle‐income countries, highlighting the need to implement fundamental transformations involving community education and outreach, beyond that currently being offered in primary and secondary care services (Thornicroft 2017). Treatment and support for depression clearly extends beyond the pharmacological; however, due to inadequate resources, antidepressants are more often used than treatment alternatives, for example, psychological therapies (Cipriani 2018).

Against this backdrop, there are emerging policy expectations for pharmacies to expand their professional responsibilities beyond retail and dispensing to encompass more patient‐centred services, including counselling and support, education, monitoring adverse events, and advice relating to prescribed medication and medicines optimisation and titration, resulting in a trend for community pharmacy medicine management interventions being introduced globally (including in Australia, Canada, New Zealand, Switzerland, the United States and England) (Latif 2018). Even with a stronger push for pharmacy‐based interventions, there remains ambivalence amongst pharmacists as to whether the public are willing to engage or would readily accept advice and support (Eades 2011; Rodgers 2016).

Pharmacy‐based management strategies have shown some promising effects in other areas of healthcare (de Barra 2018). Whilst existing systematic reviews in this area have examined the effects on improving patient adherence to antidepressants in general, for adherence to be clinically important, improvements in symptoms of depression and other person‐centred outcomes are essential. More evidence is needed on broader, patient‐important outcomes, including depressive symptoms, acceptability of the intervention, healthcare utilisation and quality of life (Hanlon 2004; Holland 2008; Nkansah 2010; Readdean 2018; Royal 2006; Rubio‐Valera 2013; Yaghoubi 2017). The degree to which a pharmacy‐based management approach might be beneficial, acceptable to patients, effective and cost‐effective as part of the overall management for those with depression is, to date, unclear. A systematic review of randomised controlled trials will help answer these questions and add important knowledge to the currently sparse evidence base.

Objectives

We will examine the effects of pharmacy‐based management interventions compared to an active control, treatment as usual or no intervention/ waiting list, at improving depression outcomes in adults.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomised controlled trials (RCTs) and cluster‐RCTs where a pharmacy‐based intervention is compared to treatment as usual, waiting list or an alternative intervention in the management of depression. The intervention may be delivered within the pharmacy or external to the pharmacy (e.g. in a hospital, clinic, online, etc.) and/or in the community, provided that the pharmacist/wider pharmacy team is involved.

Types of participants

We will include all adults (defined as 16 years or over with no upper age limit), with a primary diagnosis of depression according to an international diagnostic classification, including for example, the Diagnostic and Statistical Manual of Mental Disorders (APA 2013) or the International Classification of Diseases (ICD) (WHO 1992), as well as depressive symptoms diagnosed via self‐reported scales or questionnaires. We will also include trials that do not report how depression is diagnosed or classified, but we will perform a sensitivity analysis to look at their impact on the overall estimate of effect. Participants will have been prescribed an antidepressant (including but not limited to: selective serotonin reuptake inhibitors; serotonin norepinephrine reuptake inhibitors; tricyclic antidepressants; monoamine oxidase inhibitors; tetracyclic antidepressants; noradrenergic and specific serotonergic antidepressants) by their primary care physician for the treatment of their diagnosed depression or depressive symptoms. Should we identify studies that include a mixed age population (for example, including participants under the age of 16) we will attempt to obtain results from participants aged 16 years or above. If this is not possible, we will exclude the study.

We have included adults as defined as 16 years and over. Whilst we expect most studies to use a cut of point of 18 and above, we note that people aged 16 plus can consent to take part in research. We judge those studies would be relevant to this review if identified and as such will use the lower threshold.

Comorbidities

We will also include people with any kind of physical (e.g. long‐term conditions, diabetes) or mental health comorbidity (e.g. anxiety), provided that the management of depression is the primary focus of the study.

Types of interventions

Experimental intervention

Where permissible, we will label interventions in meta‐analysis using the following criteria.

1. Delivery of the pharmacy‐based management intervention

These will be grouped according to the profession(s) responsible for delivering the intervention as follows:

1.1 Pharmacist only

1.2 Pharmacist plus the wider pharmacist team

1.3 Multidisciplinary care group (involving the pharmacist +/‐ the wider care team, and other members of the healthcare team)

2. Types of comparator intervention or control

2.1 Active control (e.g. other non‐pharmacy‐based management, or psychological intervention)

2.2 Treatment as usual (i.e. standard pharmacy interaction)

2.3 No intervention/waiting list

Two review authors will independently assess and classify the pharmacy‐based management intervention and comparator intervention/control. In the case of disagreement, consensus will be reached through discussion with a third review author.

Types of outcome measures

Where included studies use more than one tool for the same outcome measure (e.g. depression symptom severity), we will include the measure defined by the individual study as the primary outcome.

Primary outcomes

1. Depression symptom level

As measured using validated patient‐reported depression measures, such as the Beck Depression Inventory (BDI; Beck 1961), or the Patient Health Questionnaire‐9 (PHQ‐9; Kroenke 2001).

2. Acceptability of intervention

Based on the number of people discontinuing the intervention by leaving the study early.

Secondary outcomes

1. Diagnosis of depression

As measured using validated clinician‐rated depression measures, such as the Hamilton Rating Scale for Depression (HAM‐D; Hamilton 1960).

2. Non‐adherence to medication

The number of participants not taking antidepressant medication as prescribed, assessed via self‐report, through healthcare records/clinician‐reported adherence scales, such as the Morisky Medication Adherence Scale (MMAS; Krousel‐Wood 2009; Morisky 1986; Morisky 2008).

3. Frequency of primary care appointments (e.g. GP)

Based on any data relating to primary care service use as reported in the trial.

4. Quality of life

As assessed using any validated quality of life measure, such as the World Health Organization Quality of Life Assessment (WHOQOL; WHO 1998) or the Short Form (SF‐36; Ware 1993).

5. Social functioning

As assessed using any validated social functioning measure, such as the Global Assessment of Functioning scale (GAF; APA 2000), or the Social Functioning Questionnaire (SFQ; Tyrer 2005).

6. Any adverse event

As reported in the trial.

Timing of outcome assessments

We will sub‐group time outcomes as follows:

• intervention endpoint;

• 6‐12 months from intervention endpoint ('Medium‐term'); and

• 12 months or more from intervention endpoint ('Longer‐term').

Search methods for identification of studies

Cochrane Common Mental Disorders Controlled Trials Register (CCMD‐CTR)

Cochrane Common Mental Disorders maintains a specialised register of RCTs, the CCMD‐CTR. This register contains over 40,000 reference records (reports of RCTs) for anxiety disorders, depression, bipolar disorder, eating disorders, self‐harm and other mental disorders within the scope of this Group. The CCMD‐CTR is a partially studies‐based register with more than 50% of reference records tagged to around 12,500 individually PICO‐coded study records. Reports of trials for inclusion in the register are collated from (weekly) generic searches of MEDLINE (1950 onwards), Embase (1974 onwards) and PsycINFO (1967 onwards), 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 (used to identify RCTs) can be found on the Cochrane Common Mental Disorders website, with an example of the core MEDLINE search displayed in Appendix 1.

The CCMD‐CTR is current to June 2016.

Electronic searches

Searches will be developed and conducted by Information Specialist (RS) in collaboration with CCMD's Information Specialist (SD) (see Appendix 2 for details of the original search run in 2014).

1. Cochrane Specialised Register (CCMD‐CTR)

The Information Specialist with Cochrane Common Mental Disorders (SD) will search the Specialised Register (CCMD‐CTR‐Studies and CCMD‐CTR‐References) (all years to June 2016), using the following terms (for setting/healthcare professional (only): pharmacy or pharmacies or pharmacist* [all fields].

2. Additional bibliographic database searches

The Information Specialists will share searches of the following bibliographic databases, using relevant subject headings, keywords and search syntax appropriate to each resource (Appendix 3).

• Ovid MEDLINE (1946 onwards).

• The Cochrane Library Central Register of Controlled Trials (CENTAL) (current issue).

• Ovid PsycINFO (1806 onwards).

• Ovid Embase (1974 onwards).

We will not apply any restriction on date, language or publication status to the searches.

3. International Trial Registries

We will search ClinicalTrials.gov (clinicaltrials.gov), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en) to identify ongoing or unpublished studies.

Three review authors (SJS, NW and AT) will independently consider all abstracts retrieved from the search results for relevancy, and screen full text reports to identify studies for inclusion in the review using Covidence software (Covidence 2018). Any disagreement will be managed through discussion and referred to a third review author (LW). If agreement cannot be reached, the study will be excluded from the review.

Searching other resources

1. Theses

We will search the following databases to identify relevant PhD theses (all available years).

• DART‐Europe E‐theses Portal (www.dart‐europe.eu).

• EThOS ‐ the British Libraries e‐theses online service (ethos.bl.uk).

• Open Acces Theses and Dissertations (oatd.org).

• ProQuest Dissertations and theses database (c/o dissexpress.umi.com).

2. Reference lists

The Information Specialist with Cochrane Common Mental Disorders (CCMD) will perform a search for systematic reviews and meta‐analyses on the Cochrane Database of Systematic Reviews (CDSR) (current issue); Database of Reviews of Effects (DARE), Health Technology Assessments database (HTA), Ovid MEDLINE (1946 onwards); Embase (1974 onwards) and PsycINFO (1806 onwards). We will check the reference list of all relevant reviews retrieved from this search together with reports of included studies to help identify additional research relevant to the review.

3. Personal communication

We will contact principal investigators of relevant studies to ensure we have included all relevant published or unpublished research and to request additional data where necessary.

Prior to publication we will search for retractions or errata of all included studies. We will also ensure the search date is within 12 months of publication.

Data collection and analysis

We will use the systematic review management software, Covidence (Covidence 2018), for managing citations, screening titles and abstracts, uploading references, screening full texts, data extraction, and assessing risk of bias. We will then use Review Manager 5 software for data synthesis and analysis (Review Manager 2014).

Selection of studies

In the first stage, review authors (RS, SJS, NW and AT) will independently screen titles and abstracts from the results of the literature searches, including potential trials relevant to the review and excluding others based on the prespecified criteria. If any disagreements arise, this will be discussed with a fourth review author (LW). In the second stage, the same review authors (RS, SJS, NW and AT) will collate all potentially relevant full records and perform a second screening, inspecting the full‐texts, selecting studies that will be included in the review, excluding studies that are not relevant and providing reasons for our decision. Any disagreements that arise will be resolved by discussion with the fourth review author (LW). Where it is not possible to reach an agreement on the inclusion or exclusion of a study, we will add that study to the list of those 'awaiting assessment' and contact the trial authors to request further information relating to the trial in order to make a decision.

We will document and present the study search process and subsequent exclusion and inclusion decisions using a PRISMA study flow diagram, and we will also produce narrative text summarising identified studies.

Data extraction and management

We will qualitatively extract methodological, participant, intervention and outcome characteristics of included studies (including author details; country of study; study design; description of study setting; recruitment process; description of participants; description of intervention; primary and secondary outcomes at all assessments; as well as funding and potential conflicts of interest of study authors). Data will then be extracted from each trial for prespecified outcomes at endpoint; this will be done independently by four review authors (SJS, LW, NW and AT) using the Cochrane Consumer and Communicaton Group's standardised data extraction tool (cccrg.cochrane.org/author‐resources). Findings will be compared and any differences referred back to the original text. If agreement cannot be reached, the outstanding issue will be discussed with a fourth review author (DE).

Assessment of risk of bias in included studies

We will rate risk of bias according to Cochrane's 'Risk of bias' tool (Higgins 2011a). The six domains of which include:

1. random sequence generation;

2. allocation concealment;

3. blinding of outcome assessment;

4. incomplete outcome data;

5. selective reporting;

6. other sources of bias (e.g. funding, affiliations and declarations of interest of study authors).

Three authors (SJS NW and AT) will independently perform 'Risk of bias' assessments across individual studies, rating domains as either a 'low', 'unclear', or 'high' risk of bias. We will accompany our assessment with a supporting quotation from the study report, including quotes and page numbers in the risk of bias tables. We will also summarise the 'Risk of bias' judgements across different studies for each of the domains listed above. Any disagreement will be resolved by discussion with either authors DE or LW.

Measures of treatment effect

We will input all data into Review Manager 5 software (Review Manager 2014). For dichotomous outcomes, we will calculate the risk ratio (RR) and where overall risks are statistically significant (P = 0.05) we plan to calculate the number needed to treat for an additional beneficial outcome (NNTB) using the risk difference (RD). For continuous data we will use standardised mean differences (SMDs), where different standardised scales are used to measure the same outcome, and the mean difference (MD) when the same scale is used, or only one study is included in the meta‐analysis. We will consider SMD effect sizes of 2 as small, 5 as medium, and 8 and above as large (Cohen 1988; Pace 2011).

Unit of analysis issues

Cluster‐randomised trials

Should we identify any cluster‐RCTs, we plan to incorporate results into the review, ensuring that data were analysed within the individual study with consideration of their clustering. As per the guidance of the Cochrane Handbook for Systematic Reviews of Interventions, we will report data where proper adjustment for the intracluster correlation coefficient (ICC) had been undertaken (Higgins 2011c). If the ICC is not provided, we will contact individual study authors to request them.

Many of these studies, however, are incorrectly analysed as though the unit of allocation had been the individual participants, as opposed to a group (or 'cluster') of participants. This is often referred to as a ‘unit of analysis error’ because the unit of analysis is different from the unit of allocation. If this is the situation, we will approximately correct analyses if the following information can be extracted:

• the number of clusters (or groups) randomised to each intervention group; or the average (mean) size of each cluster;

• the outcome data ignoring the cluster design for the total number of individuals (for example, number or proportion of individuals with events, or means and standard deviations); and

• an estimate of the ICC (Higgins 2011c).

Trials with multiple treatment arms

Where trials have additional arms that do not include a pharmacy‐based intervention, we will only include data relating to pharmacy‐based interventions and control arms. We will include data from other treatment arms provided the interventions are relevant to our inclusion criteria. If we include data from multiple treatment arms, we will combine groups to create a single pair‐wise comparison (Higgins 2011c). If there were two potential control groups, we would present them in separate comparisons (either: an active control, treatment as usual, or no intervention/waiting list – see Types of interventions). If however, the control arms displayed marked similarities (e.g. two types of active controls that did not involve a pharmacy‐based management intervention) then we will combine the results of these and present them in one comparison, e.g. ‘Pharmacy‐based management versus active control’.

Dealing with missing data

When reported, we will extract data where appropriate imputation methods (e.g. multiple imputation, simple imputation methods with adjustment to the standard error etc.) or statistical models allowing for missing data have been used. However, where such data is not available we will extract observed case data. Where a combination of imputed and observed case data are available we will meta‐analyse these using the generic inverse variance method and investigate the impact of excluding imputed data in a Sensitivity analysis.

If data are missing, we will contact the trial authors to request further information and document their responses. For dichotomous outcomes, we will use intention‐to‐treat (ITT) analysis where this is reported, and mention in the 'Risk of bias' table whether or not ITT analysis was done. We will assume that dropouts from treatment are treatment failures unless trialists expressly state otherwise.

For continuous data, we will contact trial authors for any missing statistics or calculate them using available reported data. For example, we will calculate the SDs from the standard error (SE) or P values (Altman 1996), or from confidence interval (CI), T values, or P values, as described the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

Assessment of heterogeneity

Statistical heterogeneity will be examined using the I² statistic for statistical variation across studies (Deeks 2011). The I² statistic provides a measure of the proportion of dispersion of effects across studies that reflect real differences rather than random error. Benchmark values of 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity, and 75% to 100% would represent considerable heterogeneity, and we will report with 95% CIs. When we detect substantial levels of statistical heterogeneity (via visual inspection of graphs, and the presence of an I² greater than or equal to 75%, accompanied by a statistically significant Chi²), we will closely inspect data to ensure they have been inputted correctly. When making this inspection, to avoid imposing arbitrary thresholds, we will take into account (i) the magnitude and direction of the observed effect, and (ii) the strength of the evidence for heterogeneity (for example, the P value from Chi² test, or CI from the I² test). We will also judge clinical and methodological heterogeneity between included trials by inspecting for any outlying people, situations or methods which we did not expect would arise. We will document and discuss these factors (see Subgroup analysis and investigation of heterogeneity and Sensitivity analysis).

Assessment of reporting biases

Should meta‐analysis include more than 10 trials, we will use a funnel plot to help detect instances of reporting biases, where a symmetrical funnel plot is likely to indicate low publication bias while an asymmetric funnel plot may indicate likely publication bias in included trials (Sterne 2011).

Data synthesis

Previous systematic reviews have highlighted wide variation in pharmacist‐based interventions and reported outcomes, and have noted high levels of heterogeneity in their data (de Barra 2018; Bell 2005; Bower 2006). We will therefore use a random‐effects model for our analyses, taking account of both within‐ and between‐study variance and following the assumption that different studies are estimating different, yet related, intervention effects (Deeks 2011). We will test heterogeneity using both the Chi² test and the I² statistic (as outlined above). In cases of doubt, we will seek expert advice regarding combining treatment groups to ensure that findings are clinically meaningful. If a meta‐analysis is not possible (e.g. due to insufficient data or high heterogeneity), we plan to provide a narrative synthesis of the evidence (Noyes 2011).

Subgroup analysis and investigation of heterogeneity

We plan to conduct the following subgroup analysis in order to reduce the likelihood of spurious findings on factors that may influence heterogeneity. Such factors include whether participants have additional mental and/or physical health comorbidities, as well as their baseline severity of depression. In addition, delivery method of the pharmacy‐based intervention can be varied, for this reason we plan to utilise subgroups for when the intervention is delivered in‐person or remotely (i.e. without in‐person contact with the pharmacy/ multidisciplinary team). In order to limit the number of subgroups, and to prevent knowledge of trial results from dictating which subgroups should be analysed, we anticipate the following subgroups:

1. Participant characteristics

1.1 Patients with physical and mental health comorbidities

Subgrouping trials according to whether or not they provided data for participants either with no comorbidities, or with physical and/or mental health comorbidities.

1.2 Baseline severity of depression

As defined as mild, moderate or severe in individual studies, or using cut‐points for validated rating scales, such as the Patient Health Questionnaire 9 (PHQ‐9; Kroenke 2001), or the Beck Depression Inventory, second edition (BDI‐II; Beck 1996).

2. Intervention characteristics: delivery method

2.1 In‐person

Likely subgroups to include, for example, one‐to‐one/individual; group support; home/clinic visits.

2.2 Remote

Likely subgroups to include, for example, telephone; digital tech‐based including email or app‐based; other written communication.

Sensitivity analysis

We plan to conduct a sensitivity analysis for primary outcomes for the following reasons.

1. Risk of bias

If an included trial is rated as a high risk of bias on two or more of the risk of bias domains, we will remove this trial to see whether removal would make a substantive difference to the results.

2. Assumptions for missing data

Where meta‐analyses include data from a combination of imputed and completer data we will conduct sensitivity analyses excluding imputed data. We will compare these estimates with the main analyses to assess any important differences.

3. Classification of depression

Where a trial does not report how depression is classified, we will remove this trial to see whether removal would make a substantive difference to the results.

'Summary of findings' table

We plan to construct a 'Summary of findings' table using the GRADE approach to assess the extent to which there may be confidence that the observed effect estimate reflects the true underlying effect (Guyatt 1998). The approach will also allow us to make a judgement on the quality of the available evidence. We choose the following outcomes at intervention endpoint as the most important.

1. Depression symptom level (patient‐reported)

2. Acceptability of intervention

3. Diagnosis of depression (clinician‐rated)

4. Non‐adherence to medication

5. Frequency of primary care appointments (e.g. GP)

6. Quality of life

7. Social functioning

Appendices

Appendix 1. Specialised Register: CCMD's core MEDLINE search strategy

The search strategy listed below is the weekly OVID MEDLINE search used to inform Cochrane Common Mental Disorders specialised register. It is based on a list of terms for all conditions within the scope of Cochrane Common Mental Disorders plus a sensitive RCT filter

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 randomised 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 randomised 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.

Appendix 2. Previous scoping searches (2014)

In 2014, extensive searches were undertaken by RS and LW to identify any existing or on going studies of pharmacy‐based management for depression in adults (See PROSPERO ref CRD42014013517). We identified studies by searching electronic databases and clinical trials registries. Databases searched included:

• AMED

• Embase

• CINAHL

• ClinicalTrials.gov

• Cochrane Central Register for Controlled Trials

• Cochrane Database of Systematic Reviews

• Database of Abstracts of Reviews of Effects (DARE)

• HTA Database

• ISI Web of Science

• ISRCTN registry

• Medline

• PsychArticles

• PsycINFO

We also examined the reference lists of all included studies to identify any additional research relevant to the review question. LW and RS independently considered whether abstracts of studies retrieved met the inclusion criteria and screened the full text of selected studies for relevance. Disagreements were resolved by consensus or by referral to a third reviewer (DE).

We identified a total of 851 studies with a focus on depression interventions in community pharmacy settings. Of these, we excluded 734 on the basis of title and/or abstract review, and a further 35 following full text review if they did not meet the inclusion criteria. There were a total of 60 duplicates, leaving 22 studies for inclusion.

Appendix 3. Review Searches

Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily <1946 onwards> Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ [Intervention/Setting] 1 COMMUNITY PHARMACY SERVICES/ 2 PHARMACISTS/ 3 PHARMACISTS' AIDES/ 4 (pharmacy or pharmacies or pharmacist*).ti,kf,hw. 5 ((pharmacy or pharmacies or pharmacist*) adj3 (advis* or advice or care or healthcare or coach* or commun* or counsel* or intervention* or model* or program* or service* or support* or treat* or therap* or psychotherap* or prevent*)).ab. 6 (pharmacy or pharmacies or pharmacist*).af. 7 ((collaborat* or coordinat* or co‐ordinat* or shared or integrat* or interdisciplinary or inter‐disciplinary or stepped) adj3 (care or healthcare or coach* or counsel* or working or service or model or effort* or intervention* or manage* or program* or treat* or therap* or psychotherap* or prevent*)).ti,ab,kf. 8 ((treatment or drug* or medicat* or pharmacotherap* or pharmaceutical* or therap* or psychotherap*) adj2 (adher* or comply or complian* or nonadher* or noncomplian* or collabor$ or commun* or educat* or advis* or advice or direct* or coach* or counsel* or support* or proactive* or pro‐active* or follow‐up or collaborat* or coordinat* or co‐ordinat* or shared or integrat* or stepped)).ti,ab,kf. 9 (6 and (7 or 8)) 10 or/1‐5,9 [Population‐1] 11 (depress$ or dysthymi$ or mood or affective disorder* or affective symptom*).ti,ab,kf. 12 ((mental* or psychiatr*) adj1 (ill* or disorder* or health or disease or diagnos* or condition)).ti,kf,hw. 13 exp DEPRESSIVE DISORDER/ 14 DEPRESSION/ 15 or/11‐14 [Population‐2] 16 exp ANTIDEPRESSIVE AGENTS/ 17 exp NEUROTRANSMITTER UPTAKE INHIBITORS/ 18 exp MONOAMINE OXIDASE INHIBITORS/ 19 PATIENT COMPLIANCE/ or MEDICATION ADHERENCE/ 20 (or/16‐18) and 19 21 ((adheren* or compliance or nonadheren* or noncompliance or collabor$ or communic* or educat* or advis* or advice or direct* or counsel* or support* or proactive* or pro‐active* or follow‐up) adj3 (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit* or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) adj3 (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or psychotropic* or psychoactive*)).ti,ab,kf. 22 (20 or 21) [RCT Filter] 23 controlled clinical trial.pt. 24 randomized controlled trial.pt. 25 (randomi#ed or randomi#ation or randomi#ing).ti,ab,kf. 26 (RCT or "at random" or (random* adj3 (administ* or allocat* or assign* or class* or cluster or control* or determine* or divide* or division or distribut* or expose* or fashion or number* or place* or pragmatic or quasi or recruit* or split or subsitut* or treat*))).ti,ab,kf. 27 placebo*.ab,ti,kf. 28 trial.ab,ti,kf. 29 (control* and (trial or study or group*) and (placebo or waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,kf,hw. 30 ((single or double or triple or treble) adj2 (blind* or mask* or dummy)).ti,ab,kf. 31 double‐blind method/ or random allocation/ or single‐blind method/ 32 exp animals/ not humans.sh. 33 (or/23‐31) not 32 34 (10 and 15 and 33) 35 (10 and 22 and 33) 36 (34 or 35) ***************************

Cochrane Library (current issue) #1MeSH descriptor: [Community Pharmacy Services] this term only #2MeSH descriptor: [Pharmacists] this term only #3MeSH descriptor: [Pharmacy Technicians] this term only #4(pharmacy or pharmacies or pharmacist*):ti,kw #5((pharmacy or pharmacies or pharmacist*) near (advis* or advice or care or healthcare or coach* or commun* or counsel* or intervention* or model* or program* or service* or support* or treat* or therap* or psychotherap* or prevent*)):ab #6(pharmacy or pharmacies or pharmacist*):ti,ab,kw #7((collaborat* or coordinat* or co‐ordinat* or shared or integrat* or interdisciplinary or inter‐disciplinary or stepped) near (care or healthcare or coach* or counsel* or working or service or model or effort* or intervention* or manage* or program* or treat* or therap* or psychotherap* or prevent*)):ab #8((treatment or drug* or medicat* or pharmacotherap* or pharmaceutical* or therap* or psychotherap*) near/2 (adher* or comply or complian* or nonadher* or noncomplian* or collabor* or commun* or educat* or advis* or advice or direct* or coach* or counsel* or support* or proactive* or pro‐active* or follow‐up or coordinat* or co‐ordinat* or shared or integrat* or stepped)):ti,ab,kw #9#6 AND (#7 OR #8) #10#1 OR #2 OR #3 OR #4 OR #5 OR #9 #11(depress* or dysthymi* or mood or moods or (affective next disorder*) or (affective next symptom*)):ti,ab,kw #12((mental* or psychiatr*) NEAR/2 (ill* or disorder* or health or disease or diagnos*)):ti,ab,kw #13MeSH descriptor: [Depression] this term only #14MeSH descriptor: [Depressive Disorder] explode all trees #15#11 OR #12 OR #13 OR #14 #16#10 AND #15 #17MeSH descriptor: [Antidepressive Agents] explode all trees #18MeSH descriptor: [Neurotransmitter Uptake Inhibitors] explode all trees #19MeSH descriptor: [Monoamine Oxidase Inhibitors] explode all trees #20MeSH descriptor: [Patient Compliance] this term only #21MeSH descriptor: [Medication Adherence] this term only #22(#17 OR #18 OR #19) AND (#20 OR #21) #23((adheren* or compliance or nonadheren* or noncompliance or collabor* or communic* or educat* or advis* or advice or direct* or counsel* or support* or proactive* or pro‐active* or follow‐up) NEAR (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit* or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) NEAR (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or psychotropic*)):ti,ab,kw #24#22 OR #23 #25#10 AND #24 #26#16 OR #25

*************************** Ovid PsycINFO <1806 onwards> Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 pharmacy/ or pharmacists/ 2 (pharmacy or pharmacies or pharmacist*).ti,id. 3 ((pharmacy or pharmacies or pharmacist*) adj3 (advis* or advice or care or healthcare or coach* or commun* or counsel* or intervention* or model* or program* or service* or support* or treat* or therap* or psychotherap* or prevent*)).ab. 4 (pharmacy or pharmacies or pharmacist*).af. 5 ((collaborat* or coordinat* or co‐ordinat* or shared or integrat* or interdisciplinary or inter‐disciplinary or stepped) adj3 (care or healthcare or coach* or counsel* or working or service or model or effort* or intervention* or manage* or program* or treat* or therap* or psychotherap* or prevent*)).ti,ab,id. 6 ((treatment or drug* or medicat* or pharmacotherap* or pharmaceutical* or therap* or psychotherap*) adj2 (adher* or comply or complian* or nonadher* or noncomplian* or collabor* or commun* or educat* or advis* or advice or direct* or coach* or counsel* or support* or proactive* or pro‐active* or follow‐up or coordinat* or co‐ordinat* or shared or integrat* or stepped)).ti,ab,id. 7 (4 and (5 or 6)) 8 or/1‐3,7 9 (depress$ or dysthymi$ or mood or affective disorder* or affective symptom*).ti,ab,id. 10 ((mental* or psychiatr*) adj1 (ill* or disorder* or health or disease or diagnos*)).ti,id,hw. 11 depression.hw. 12 or/9‐11 13 Psychopharmacology/ or Neuropsychopharmacology/ 14 "3340".cc. 15 exp Antidepressant Drugs/ 16 Neurotransmitter Uptake Inhibitors/ or exp Serotonin Norepinepherine Reuptake Inhibitors/ or exp Serotonin Reuptake Inhibitors/ 17 exp Monoamine Oxidase Inhibitors/ 18 exp Tricyclic Antidepressant Drugs/ 19 treatment compliance/ or client education/ or client participation/ or disease management/ or coaching/ or counseling/ 20 (or/13‐18) and 19 21 ((adheren* or compliance or nonadheren* or noncompliance or collabor* or communic* or educat* or advis* or advice or direct* or counsel* or support* or proactive* or pro‐active* or follow‐up) adj3 (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit* or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) adj3 (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or psychotropic*)).ti,ab,id. 22 20 or 21 23 clinical trials.sh. 24 (randomi#ed or randomi#ation or randomi#ing).ti,ab,id. 25 (RCT or at random or (random* adj3 (administ* or allocat* or assign* or class* or control* or determine* or divide* or division or distribut* or expose* or fashion or number* or place* or recruit* or split or subsitut* or treat*))).ti,ab,id. 26 (control* and (trial or study or group) and (placebo or waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,id,hw. 27 ((single or double or triple or treble) adj2 (blind* or mask* or dummy)).ti,ab,id. 28 trial.ti. 29 placebo.ti,ab,id,hw. 30 treatment outcome.md. 31 treatment effectiveness evaluation.sh. 32 mental health program evaluation.sh. 33 or/23‐32 34 (8 and 12 and 33) 35 (8 and 22 and 33) 36 (34 or 35) *************************** Ovid Embase <1974 onwards> Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Intervention/Setting [Pharmacist/pharmacy services‐1] 1 PHARMACY/ or PHARMACY TECHNICIAN/ 2 PHARMACIST/ 3 PHARMACIST ATTITUDE/ 4 (pharmacy or pharmacies or pharmacist*).ti,kw,hw. 5 ((pharmacy or pharmacies or pharmacist*) adj3 (advis* or advice or care or healthcare or coach* or commun* or counsel* or intervention* or model* or program* or service* or support* or treat* or therap* or psychotherap* or prevent*)).ab. [Pharmacist/pharmacy services‐2] 6 (pharmacy or pharmacies or pharmacist*).af. 7 ((collaborat* or coordinat* or co‐ordinat* or shared or integrat* or interdisciplinary or inter‐disciplinary or stepped) adj3 (care or healthcare or coach* or counsel* or working or service or model or effort* or intervention* or manage* or program* or treat* or therap* or psychotherap* or prevent*)).ti,ab,kw. 8 ((treatment or drug* or medicat* or pharmacotherap* or pharmaceutical* or therap* or psychotherap*) adj2 (adher* or comply or complian* or nonadher* or noncomplian* or collabor$ or commun* or educat* or advis* or advice or direct* or coach* or counsel* or support* or proactive* or pro‐active* or follow‐up or collaborat* or coordinat* or co‐ordinat* or shared or integrat* or stepped)).ti,ab,kw. 9 (6 and (7 or 8)) 10 or/1‐5,9 Population‐1 11 (depress* or dysthymi* or mood or affective disorder* or affective symptom*).ti,ab,kw. 12 ((mental* or psychiatr*) adj1 (ill* or disorder* or health or disease or diagnos* or condition*)).ti,kw,hw. 13 exp DEPRESSION/ 14 or/11‐13 Population‐2 15 exp ANTIDEPRESSIVE AGENT/ 16 exp NEUROTRANSMITTER UPTAKE INHIBITORS/ 17 exp MONOAMINE OXIDASE INHIBITORS/ 18 exp TETRACYCLIC ANTIDEPRESSANT AGENT/ or exp TRICYCLIC ANTIDEPRESSANT AGENT/ or exp SEROTONIN UPTAKE INHIBITOR/ 19 PATIENT COMPLIANCE/ or MEDICATION COMPLIANCE/ or MEDICATION THERAPY MANAGEMENT/ or PATIENT EDUCATION/ or COUNSELING/ or *PHARMACEUTICAL CARE/ 20 (or/15‐18) and 19 21 ((adheren* or compliance or nonadheren* or noncompliance or collabor$ or communic* or educat* or advis* or advice or direct* or counsel* or support* or proactive* or pro‐active* or follow‐up) adj3 (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit*)).ti,ab. 22 ((adheren* or compliance or nonadheren* or noncompliance or collabor$ or communic* or educat* or advis* or advice or direct* or counsel* or support* or proactive* or pro‐active* or follow‐up) adj3 ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) adj3 (uptake or reuptake or re‐uptake))).ti,ab. 23 ((adheren* or compliance or nonadheren* or noncompliance or collabor$ or communic* or educat* or advis* or advice or direct* or counsel* or support* or proactive* or pro‐active* or follow‐up) adj3 (noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or psychotropic* or psychoactive*)).ti,ab. 24 (20 or 21 or 22 or 23) [RCT Filter] 25 randomized controlled trial/ 26 randomization.de. 27 controlled clinical trial/ and (Disease Management or Drug Therapy or Prevention or Rehabilitation or Therapy).fs. 28 *clinical trial/ 29 placebo.de. 30 placebo.ti,ab. 31 trial.ti. 32 (randomi#ed or randomi#ation or randomi#ing).ti,ab,kw. 33 (RCT or "at random" or (random* adj3 (administ* or allocat* or assign* or class* or control* or determine* or divide* or division or distribut* or expose* or fashion or number* or place* or recruit* or split or subsitut* or treat*))).ti,ab,kw. 34 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp. 35 (control* and (trial or study or group) and (placebo or waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,kw,hw. 36 or/25‐35 37 ((animal or nonhuman) not (human and (animal or nonhuman))).de. 38 (36 not 37) 39 (10 and 14 and 38) or (10 and 24 and 38) ***************************

Contributions of authors

DE, SG, DM, RS, AT, NW and LW helped to draft the original 2014 PROSPERO.

DE, RC, RS, SJS, AT and LW helped to draft and write the 2018 Cochrane protocol.

Sources of support

Internal sources

• Tees, Esk and Wear Valleys NHS Foundation Trust (TEWV), UK.

  RS and RC time on this project is funded by TEWV as a matched contribution to a University of York ESRC Impact Accelaration Account award.

• University of York, UK.

External sources

• Economic and Social Research Council (ESRC), UK.

  SJS time on this project is part funded by the University of York ESRC Impact Accelaration Account (ES/M500574/1).

• Northumberland, Tyne and Wear NHS Foundation Trust (NTW), UK.

  SJS time on this project is part funded by NTW as a matched contribution to a University of York ESRC Impact Accelaration Account award.

Declarations of interest

Stephanie Jayne Sampson: no conflicts of interest Adam Todd: no conflicts of interest Nick Walton: no conflicts of interest Rachel Steele: no conflicts of interest Lisa Webster: no conflicts of interest Rachel Churchill: no conflicts of interest Dean McMillan: no conflicts of interest Simon Gilbody: no conflicts of interest David Ekers: Chief Investigator of the Community Pharmacy Mood Intervention Feasibility and Pilot Study funded by the National Institute for Health Research. This study is relevant to the subject matter of the review however, the author has no associated financial or commercial conflicts of interest.

This protocol was initially registered in 2014 with PROSPERO (NIHR‐funded international prospective register of systematic reviews, University of York, Centre for Reviews and Dissemination). This is an updated and amended version of the original 2014 protocol, however with no differences between the original aim, and no substantial differences in predefined outcomes and measures of assessment. The original protocol is available to view from: www.crd.york.ac.uk/prospero.

New