3.1. Methods – benefit assessment

The target population of the benefit assessment was children and adolescents (≤ 18 years) with diagnosed depression. This report does not focus on children and adolescents suffering from dysthymia or other affective disorders (e.g. bipolar affective disorder) or mental disorders. Likewise excluded were children and adolescents who, according to the authors of the systematic review, suffered from treatment-resistant depression or in whom depression was a comorbidity of an underlying somatic disorder (e.g. thyroid dysfunction, cancer) or those with a special form of depression (perinatal/postnatal depression in adolescent girls). The experimental intervention was psychotherapy either as monotherapy or as an add-on to antidepressant treatment. The focus was on cognitive behavioural therapy, interpersonal psychotherapy, and psychodynamic psychotherapy, which includes depth psychology-based therapy and analytical psychotherapy. Computerized cognitive behavioural therapy (cCBT) was included as well, provided it involved qualified professionals. Inactive control interventions included sham treatment (psychological placebo), no treatment, waiting list, or usual care.

Patients on the waiting list or on usual care typically receive no interventions during the study, but for ethical reasons, they are not prevented from utilizing routine healthcare services. For psychological placebo, sham therapy is performed, e.g. in the form of conversations. This does not correspond to any recognized type of psychotherapy, however, and can therefore not be deemed active therapy. Other possible comparator interventions were treatment with antidepressants (AD), with other non-drug interventions (e.g. relaxation exercises or exercise) as well as active monitoring (mental health education).

The following patient-relevant outcomes were included in the assessment:

• Mortality (all-cause mortality, suicide mortality)
• Morbidity
  • suicidal ideation and behaviour
  • Response
  • Remission of depression
  • Change in depressive symptoms
  • Functioning (social, cognitive, mental, physical)
• Health-related quality of life
• Adverse events

Due to their major importance, suicidal ideation and behaviour were defined as a separate outcome despite these aspects also being surveyed as an item on many scales for depressive symptoms.

In addition to the above-mentioned patient-relevant outcomes, treatment acceptance was analysed using the outcome of patient satisfaction.

The benefit assessment was informed by systematic reviews of randomized controlled trials in German or English language, provided that the systematic reviews were published in 2010 or later and used adequate methodologies (Oxman-Guyatt index ≥ 5). No restrictions were in place regarding study duration of the included randomized controlled trials (RCTs).

A systematic literature search for systematic reviews was carried out in the databases MEDLINE (which includes the Cochrane Database of Systematic Reviews), Embase, and HTA Database. The following sources of information and search techniques were additionally used: search in PROSPERO (registry for systematic reviews), contacting of authors of relevant systematic reviews registered in PROSPERO but not published; viewing of reference lists of identified systematic reviews and overviews of reviews; search on the websites of the National Institute for Health and Care Excellence (NICE) and the Agency for Healthcare Research and Quality (AHRQ). Any additional relevant documents identified during the commenting procedure for the preliminary HTA were to be taken into account before the finalization of the report.

Relevant systematic reviews were selected by 2 persons independently from one another. Any discrepancies were resolved by discussion between them. One person extracted the data into standardized tables, and another person reviewed them. The qualitative certainty of results was assessed based on the risk of bias of the primary studies as reported in the systematic reviews. Additionally, the methodological quality of the systematic reviews was assessed by 2 persons independently from each other by means of the Oxman-Guyatt index. Rather than metaanalyses, a narrative summary was generated because the systematic reviews were insufficiently comparable with regard to their research question and relevant characteristics. The results description of the systematic reviews was organized by outcomes and type of psychotherapy. In cases where systematic reviews used several depression scales to report results on the same outcome, the data from the scale most commonly used across all systematic reviews were chosen. If data were available on both third-party and self-assessment, both were extracted. Based on the systematic reviews’ presentation of results, subgroup results were reported for children and adolescents, for psychotherapy with and without parental involvement, and for follow-up durations. A 12-to-16-week follow-up (short term) was distinguished from follow-ups of about 6 months (medium term) and 12 months or more (long term). It was not possible to analyse subgroups by severity of depression, patient sex, or psychosocial aspects.

The assessment of the primary studies’ risk of bias was adopted from the systematic reviews. Where the same study was rated differently by different systematic reviews, a cautious approach was taken, using the assessment with the highest risk of bias in this HTA.

Pooled effect estimators from metaanalyses were adopted if 80% of included patients met the above inclusion criteria. Otherwise, the results from the appropriate individual studies were narratively extracted. However, exceptions applied to NMAs and large metaanalyses, from which pooled effect estimators were extracted even if fewer than 80% of patients taken into account met the inclusion criteria since similarity was assumed and deviations were minimal.

For each outcome, a conclusion was drawn regarding evidence for (greater) benefit and (greater) harm, with 4 levels of certainty of conclusions: either proof (highest certainty of conclusions), indication (moderate certainty of conclusions), hint (lowest certainty of conclusions), or none of the above. The latter was the case if no data were available, or the available data did not permit classification into one of the other categories. In that case, no hint of (greater) benefit or (greater) harm was derived. Where results of a systematic review or results from individual studies were available for a comparison and outcome, evidence was derived based on the standardized IQWiG guidelines. Where multiple systematic reviews reported on the same outcome and comparison, it was first checked whether the results are in the same direction. If so, the data were synthesized into a narrative summary. Otherwise, priority was given to results from systematic reviews with higher quality ratings. Whenever the ratings were equal, priority was given to the results which were based on the most RCTs, reported direct comparisons or results from pairwise metaanalyses from the NMAs, and had a current search date. Since the individual studies in all systematic reviews tended to have a high risk of bias, no prioritization was possible on this basis.

3.2. Methods – health economic assessment

3.3. Methods – ethical aspects

Based on the overarching questions from the simplified questionnaire according to Hofmann et al. 2014 [31], the information on ethical aspects was analysed in terms of social and moral norms and values related to psychotherapy and depression in children and adolescents. In addition, the authors of the report applied the reflective thoughts method, i.e. they reflected on potential ethical aspects based on their own knowledge [32].

The scoping search was performed using the information sources of Belit, CINAHL, EthxWeb, ETHICSWEB, MEDLINE, PsycINFO, and Scopus. In addition, the studies included for the benefit and economic assessment as well as websites of interest groups and the documented expert interviews were consulted.

One person viewed information from all sources identified in the searches for conclusions on ethical arguments and aspects of the intervention to be investigated, extracted them into standardized tables, and also provided a narrative. A 2^nd person assured the quality of the result.

3.4. Methods – social, legal, and organizational aspects

For the analysis of social and organizational aspects, scoping searches were carried out in MEDLINE, the Association of the Scientific Medical Societies in Germany (AMWF) guideline database, and websites of relevant institutes (Robert Koch Institute [RKI], G-BA, Gesundheitsinformation.de). The systematic reviews and the studies included for the health economic assessment were likewise searched for social aspects. In addition, the documented expert interviews were reviewed. As supplementary information, the reflective-thoughts method was applied in accordance with INTEGRATE-HTA instructions [32].

The information processing on social aspects followed the conceptional framework proposed by Mozygemba et al. 2016 [33], while the information processing on organizational aspects was based on the grid template proposed by Perleth 2014 [34] for the assessment of organizational consequences of treatment methods.

One reviewer screened information from all sources found in the scoping searches for conclusions on social and/or organizational arguments and aspects of the treatment options to be investigated. The result was scrutinized for quality by a 2^nd person. All arguments and aspects necessary for information processing were extracted into tables and summarized as a narrative.

For the literature search regarding the analysis of legal aspects, the databases of the German Federal Court of Justice (BGH), the Federal Information System for Law, and the legislative databases by Manz and Lexis Nexis were used. Additional searches were conducted at the library of the University for Continuing Education Krems and on the Internet (Google), and relevant comments and handbooks were consulted.

Information processing on legal aspects was based on the guideline developed by Brönneke 2016 [35].

One person screened information for conclusions regarding legal aspects of the treatment options to be investigated. Comments were selected by recency, relevance, and availability. A 2^nd person critically read the arguments and comments to assure quality.

3.5. Incorporation of the patient perspective

The original plan provided for 8 interviews with affected children, adolescents, and parents. However, the ethics committee of the University of Continuing Education Krems did not approve these interviews because it deemed the target group to be too vulnerable. To obtain indirect information on the situation of affected people, guide-based expert interviews with a child and adolescent psychiatrist and a child and adolescent psychotherapist who led a self-help group for adolescents were therefore conducted alternatively. The interviews aimed to verify the patient relevance of this HTA report’s outcomes as well as to examine additional ethical, social, and organizational aspects of the implementation of psychotherapy in children and adolescents with depression. The experts were informed about the goals of the interview and the HTA as well as the approach used in conducting the interview. They were informed in advance about the interviews being analysed in an anonymized fashion and that their name would be mentioned in the HTA report, if desired. The interviews were conducted online due to the COVID pandemic, took 45 to 70 minutes, and were recorded using the Zoom software. While the audio track was stored for later analysis, the video track was erased immediately after the interview. After the interviews were transcribed, the recordings were erased. A 2^nd person checked the interview transcripts for comprehensibility. Insights gained from these interviews informed the assessment of ethical, social, and organizational aspects.