Participant characteristics

We will include participants 18 years of age and older of any gender and ethnicity.

Diagnosis

We will include participants who have a diagnosis of persistent depressive disorder or have had this diagnosis before their last previous acute treatment. The diagnosis of depression needs to rely on a formal classification system, such as the International Classification of Diseases (ICD) (WHO 1992), or DSM (APA 2013). Participants need to be either currently remitted from persistent depressive disorder or need to have at least partially responded to an acute intervention (at least 25% symptom reduction from baseline) at the beginning of the continuation or maintenance treatment. We will include participants described as "treatment resistant" if they fulfil the formerly mentioned criteria. As the distinction between subtypes of persistent depressive disorder (chronic major depression, dysthymia, double depression, or recurrent depression without a complete remission between episodes) is controversial, inclusion will be primarily driven by the duration of the existing depressive disorder. Consequently, we will include studies that investigate participants with chronic major depression, dysthymia, double depression, or recurrent depression without a complete remission between episodes if the target disorders are or have been of at least two years' duration. We will exclude studies that report to investigate "chronically depressed" participants without fulfilling these criteria (e.g. less than two years duration).

Co‐morbidities

We will exclude studies that focus exclusively on persistently depressed participants with a specific concurrent mental or somatic disorder; we assume that the interventions in these types of studies (primarily) address the comorbid condition and are not focused exclusively on persistent depression. We will include studies that do not define specific concurrent mental or somatic conditions as inclusion criteria but report on comorbidities in addition to the persistent depressive disorder.

Setting

We will not place any restrictions based on setting.

Subset data

We will only consider studies in which both participants with persistent and acute forms of depression for inclusion if data are reported separately for the persistent subgroup (or if 80% or more of the total sample has a diagnosis of persistent depression). If randomization is based on the total sample, we will include studies and we will categorize them as non‐RCTs.

Experimental Intervention

We will consider pharmacological, psychological, and combined continuation and maintenance interventions for inclusion. Continuation treatments are defined as treatments given to currently remitted individuals or to individuals that previously responded to an antidepressant treatment, whereas maintenance treatments are defined as treatments given to people who are currently recovered. Continuation/maintenance treatments need to be started within one year after termination of an acute treatment. We will consider all interventions that satisfy these definitions. Additionally, we will consider for inclusion studies that do not report all the above mentioned criteria but report data on interventions that are clearly labelled as “continuation” or “maintenance” treatments. Pharmacological interventions include the oral administration of classified antidepressants:

• tricyclic antidepressants;

• selective serotonin reuptake inhibitors;

• monoamine oxidase inhibitors;

• alpha2‐receptor‐antagonists;

• selective noradrenalin dopamine reuptake inhibitors;

• melatonin receptor agonists; and

• serotonin 5 HT2C receptor antagonists;

as well as the following:

• non‐classified antidepressants (Trazodone);

• lithium;

• Hypericum perforatum; and

• antipsychotic drugs;

as these drugs can be used (alone or in combination) in treating different forms of depression (DGPPN 2015).

Psychological therapies must fulfil the following criteria:

• the intervention must be based on a scientific theory (described in detail, manualized or referenced);

• at least one contact between therapist and participant either face‐to‐face or via telecommunication technologies (e.g. online therapy) must take place. Thus, for example, we will not consider the general dissemination of information material in form of leaflets in waiting rooms as a psychological therapy;

• the intervention must consider the personal needs of the participant or a group of participants and must be individually tailored in an interpersonal process. Thus, we will include group therapies.

Concerning psychological therapies, we will include behaviour therapy/behaviour modification, CBT, third wave CBTs, psychodynamic therapies, humanistic therapies, integrative therapies, systemic therapies, and other psychologically‐oriented interventions (based on the definition of the Cochrane Common Mental Disorders Group).

Combined interventions include the administration of one or more pharmacological agents combined with one or more psychological therapy.

We will not consider for inclusion somatic (e.g. electroconvulsive therapy, vagus nerve stimulation, acupuncture), non‐pharmacological (e.g. physical exercise, bright light therapy), and organizational (e.g. case management) interventions as including too many different interventions is likely to result in large clinical and methodological heterogeneity.

Comparator intervention

We will include both controlled and comparative effectiveness studies. The comparators may be:

• pharmacological placebo (participants receive placebo pills);

• attention‐placebo/nonspecific control (participants receive a treatment that involves nonspecific psychosocial factors);

• TAU;

• (other) psychological therapy;

• (other) pharmacological treatment;

• (other) combined psychological/pharmacological therapy.

Primary outcomes

• Relapse or recurrence rate of depression, preferentially defined as:

(a) fulfilment of formal diagnostic criteria for depression (DSM, ICD); or

(b) exceeding a cut‐off on a depression symptom rating scale used by the authors, specifically:
i. the Hamilton Depression Rating Scale (HDRS) (Hamilton 1960);
ii.the Montgomery ‐Åsberg Depression Rating Scale (MADRS) (Montgomery 1979);
iii.the Beck‐Depression‐Inventory (BDI) (Beck 1996);
iv.the Inventory of Depressive Symptomatology (IDS) (Rush 2000);
v. the Patient Health Questionnaire (PHQ) (Spitzer 1999); or
vi.any other depression symptom scale.

Due to the long tradition of depression research, most instruments used in clinical trials are usually psychometrically sound. Such measures will be preferred throughout the review (either referenced and/or sufficient psychometric quality reported).

• Dropout due to any reason.

Secondary outcomes

• Symptom severity of depression at the end of treatment (metric outcome of depression scale as defined above);

• health‐related quality of life e.g. WHO Quality of Life (WHOQOL) (Skevington 2004);

• dropout due to adverse events;

• experiencing any adverse event;

• serious adverse events.

Grey literature

We will search the following sources of grey literature:

• ProQuest Dissertations & Theses Database (www.proquest.com/);

• Depression. The treatment and management of depression in adults (NICE 2010);

• S3 Guideline/National Disease Management Guideline. Unipolar Depression (DGPPN 2015);

• Canadian Network for Mood and Anxiety Treatments (CANMAT). Clinical guidelines for the management of major depressive disorder in adults (Kennedy 2009)

• Open Grey (www.opengrey.eu/).

Handsearching

As all relevant journals are included in the bibliographic databases being searched, we will not conduct any no further handsearches of journals.

Reference lists

We will check the reference lists of all included studies and relevant systematic reviews to identify additional studies missed from the original electronic searches (e.g. unpublished or in‐press citations). Also we will conduct a cited reference search on the Web of Science.

Correspondence

We will contact the first author of each included study for information on unpublished or ongoing studies, or to request additional trial data.

Main comparisons

We have chosen seven main comparisons from the list of possible comparisons based on clinical importance and expected frequency of the comparisons in clinical trials:

• pharmacological continuation and maintenance therapies versus placebo;

• pharmacological continuation and maintenance therapies versus TAU;

• psychological continuation and maintenance therapies versus attention placebo/nonspecific control;

• psychological continuation and maintenance therapies versus TAU;

• psychological continuation and maintenance therapies versus pharmacological continuation and maintenance therapies;

• combined psychological and pharmacological continuation and maintenance therapies versus pharmacological continuation and maintenance therapies alone;

• combined psychological and pharmacological continuation and maintenance therapies versus psychotherapeutic continuation and maintenance therapies alone.

Dichotomous data

In order to increase clinical applicability of the findings, we will calculate the relative risk of relapse/recurrence for the primary outcomes, as they are more likely to help clinicians to make informed decisions in specific clinical situations. If primary studies used time‐to‐event data, we will calculate pooled hazard ratios. For rare outcomes (adverse events, and possibly dropout rates) or endpoints with highly varying baseline rates, we will estimate the odds ratios.

Continuous data

We will analyse continuous data as mean differences (MD). If the included studies used different rating scales to assess the same outcome, we will calculate the standardized mean differences (SMD). We will enter data presented as a scale with a consistent direction of effect. We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants, and the underlying clinical question are similar enough for useful pooling. We will narratively describe skewed data reported as medians and interquartile ranges if effect size calculation is not possible.

Cluster‐randomized trials

As we expect a small number of overall available studies, we will include data from controlled clinical trials, cross‐over trials, and cluster‐randomized trials in the analysis, regardless of the level of randomization. Concerning cluster‐randomized trials, we will include direct effect estimates of the primary studies, only if they were obtained from analyses that account for the clustering in the data (e.g. using a multilevel model). Otherwise, we will approximate the effect estimates using an inflated standard error that incorporates the design effect (Higgins 2011).

Cross‐over trials

We will only use the first comparison (pre‐crossover) meeting our inclusion criteria from cross‐over trials.

Studies with multiple treatment groups

Concerning studies with multiple treatment groups, we will only consider data from the comparison of interest for each of the main objectives addressed in our review. If the study provides more than one comparison of interest for one of the main objectives, we will split the ‘shared’ group into two or more groups with smaller sample sizes to avoid including participants more than once in the analysis.

'Summary of findings' table

We will construct 'Summary of findings' tables for the seven main comparisons: effectiveness of pharmacotherapy and effectiveness of psychological therapy for persistent depressive disorder, the effectiveness of psychological therapy in comparison to pharmacotherapy for persistent depressive disorder, and the effectiveness of combined treatments in comparison to pure pharmacological/pure psychological therapies for persistent depressive disorder. The 'Summary of findings' tables will include a summary of the quality of evidence, the magnitude of effects of the according intervention, and a summary of available data on main outcomes. We will express findings as measures of risk ratio and absolute risk for the main outcomes of relapse/recurrence and dropout. We will use the GRADE approach to assess the quality of the evidence (Guyatt 2011).