Sequenced treatment alternatives to relieve adolescent depression (STAR-AD): a multicentre open-label randomized controlled trial protocol
BMC Psychiatry volume 23, Article number: 789 (2023)
Adolescent major depressive disorder (MDD) is a prevalent mental health problem with low treatment success rates. Whether fluoxetine or fluoxetine combined with cognitive-behavioural therapy (CBT) is the more effective initial treatment for adolescent MDD remains controversial, and few studies have investigated whether treatment switching or augmentation is preferred when the initial treatment is not working well.
We developed a multicentre open-label Sequential Multiple Assignment Randomized Trial (SMART) design, consisting of two phases lasting 8 weeks each. In phase 1 (at baseline), patients will be recruited and grouped in fluoxetine group or fluoxetine combined with CBT group by patient self-selection. In phase 2 (after 8 weeks of treatment), the nonresponders will be randomly assigned to six groups, in which participants will switch to sertraline, vortioxetine, or duloxetine or added aripiprazole, olanzapine, or lithium carbonate to fluoxetine. After the full 16 weeks of treatment, we will assess the long-term sustainability of the treatment effects by evaluating participants during their subsequent naturalistic treatment. The primary outcome will be the response rate, determined by the Children’s Depression Rating Scale-Revised (CDRS-R). Secondary outcomes include the change in scores on the Beck Depression Inventory (BDI), the Screen for Child Anxiety-Related Emotional Disorders (SCARED) and the Safe Assessment.
The results from this study will aid clinicians in making informed treatment selection decisions for adolescents with MDD.
This protocol was registered at ClinicalTrials.gov with Identifier: NCT05814640.
Major depressive disorder (MDD) is a prominent factor in disease and disability among adolescents , and the prevalence of MDD among adolescents in 2016–2019 was reported to be 4.4% . Considering the burden of this disease, especially in light of the rising rates of suicide and self-harm among adolescent MDD patients [3, 4], early intervention options for this population are urgently needed [5, 6].
Whether fluoxetine or fluoxetine combined with cognitive-behavioural therapy (CBT) is better for treating adolescent MDD remains controversial. The guidelines provided by the National Institute of Clinical Excellence (NICE) in the United Kingdom explicitly recommend prescribing fluoxetine only in conjunction with psychotherapy , but the depression practice parameters of the American Academy of Child and Adolescent Psychiatry (AACAP) suggest administration of fluoxetine alone is also a reasonable strategy, and offers no preferred for monotherapy versus combined treatment . Moreover, the Guidelines for Adolescent Depression in Primary Care (GLAD-PC) and Canadian Network for Mood and Anxiety Treatment (CANMAT) recommend combination therapy after patients demonstrate that they are unresponsive to fluoxetine monotherapy [8, 9]. Therefore, more study is urgently required to confirm whether fluoxetine or fluoxetine combined with CBT should be the first choice for treatment.
During acute phase randomized controlled trials (RCTs) with medication administered for 6–8 weeks, it was found that approximately 20–30% of adolescent patients did not respond to fluoxetine or fluoxetine combined with CBT . However, current guidance for adolescent nonresponders, mainly originating from the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) , is supported by little research about switching the initially selected treatment to a different treatment (switch) or adding a nontraditional antidepressant drug (augmentation).
The TORDIA study previously reported that in adolescents with no improvement in depression after one appropriate trial of a selective serotonin reuptake inhibitor (SSRI), there were similar response rates between switching to another SSRI or switching to the norepinephrine reuptake inhibitor (SNRI) venlafaxine. A secondary analysis of the 24-week TORDIA  outcomes suggest a potential advantage of early augmentation using an atypical antipsychotic or mood stabilizer, but the sample size used was small. Notably, there are already various evidence-based therapies for adult nonresponders [13, 14], and several guidelines recommend switching or augmentation, providing more options for clinical drug selection [15, 16].
To fill the existing gaps in the knowledge necessary for developing treatment guidelines for adolescent depression, we propose to undertake a Sequential Multiple Assignment Randomized Trial (SMART). This trial design is particularly well-suited for evaluating the effectiveness of treatment regimens in real-world settings and is commonly employed in mental health research. It combines sequential and dynamic treatment methods [17,18,19]. Our study will consist of two phases. In phase 1, we will compare fluoxetine with the combination therapy (fluoxetine combined with CBT), and in phase 2, adolescent nonresponders will be randomly allocated to switching or augmentation group. Ultimately, we will use patients’ responses and remissions to initial and subsequent treatments, along with demographic data, to derive a prioritized treatment plan for patients undergoing initial treatment and those who are nonresponsive to initial treatment.
Aims and hypotheses.
We aimed to establish adaptive treatment strategies for adolescent MDD patients. We hypothesized that the combination of fluoxetine with CBT yields superior effectiveness compared to fluoxetine alone.
We aimed to establish suitable treatment approaches for adolescents with MDD who did not respond to their initial antidepressant trial. Our hypothesis suggests that various treatment modalities demonstrate comparable efficacy in alleviating symptoms of depression. However, they may differ in terms of their tolerability, side effects, functional outcomes, and compliance.
Figure 1 depicts the schematic of the trial, which is a multicentre open-label SMART in patients with adolescent MDD. It consists of two treatment phases (phase 1 and phase 2), with each phase spanning 8 weeks, followed by a 12-month naturalistic follow-up phase.
Subjects who complete phase 1 and proceed to phase 2 will include both nonresponsive participants and those who show a response without remission. Nonresponse is determined by a symptom severity reduction of less than 50% as measured by the Children’s Depression Rating Scale-Revised (CDRS-R). Remission, indicating the absence of depressive symptoms, refers to a CDRS-R score of 28 or lower. On the other hand, response without remission is characterized by a reduction of at least 50% from the baseline CDRS-R score, but with a CDRS-R score higher than 28. The clinician determines the transition to phase 2 according to symptom severity, taking into account clinical judgement and considering the total score of the CDRS-R assessment. Participants who do not show a response at the completion of phase 1 may proceed to phase 2, whereas those who achieve remission can proceed to the follow-up phase. Individuals who demonstrate a response but do not achieve remission are also eligible to enter the follow-up phase, although they are strongly advised to move to phase 2 after an adequate dose.
Patients in the follow-up phase will be evaluated over the course of their naturalistic treatment and evaluated for relapse. We established relapse as a situation where there is a single occurrence of a CDRS-R score of 40 or higher, accompanied by a decline in depressive symptoms persisting for a minimum of 2 weeks.
The rationale of protocol treatments
In phase 1, adolescents with MDD will be selected into fluoxetine or fluoxetine combination CBT therapy groups and the choice of treatment will be at the discretion of patient. Some studies have evaluated the effectiveness and safety of these therapies in adolescent MDD [20,21,22]. Our previous meta-analyses also have shown that for children and adolescents with moderate-to-severe MDD, fluoxetine (either alone or combined with CBT) appears to be the most favourable option for acute treatment .
In phase 2, sertraline, duloxetine, and vortioxetine are the possible alternative treatments for switching. The reason for selecting sertraline in phase 2 is that a pooled analysis showed that sertraline exhibited greater efficacy compared to a placebo in treating MDD among children and adolescents. Furthermore, the observed side effects were predominantly of mild to moderate intensity, and there were no notable differences in side effects when compared to the placebo . Additionally, according to the NICE and CANMAT 2016 guidelines, sertraline is the recommended second-line treatment. And it is also the most commonly used medicine in public hospitals in China [7, 8, 25]. Duloxetine was chosen based on our previous meta-analysis, which indicated that it has one of the highest likelihoods of being ranked as the most effective . Another meta-analysis supported the consideration of duloxetine as a first-line treatment option . Vortioxetine was selected for its multimodal mechanism of action . Despite a randomized, placebo-controlled study in adolescent MDD treated with vortioxetine showing negative results compared with a placebo , there is an open-label study showing that vortioxetine surpass a placebo in terms of effectiveness and is regarded as safe and well-received in adolescents with MDD . In addition, the efficacy of vortioxetine has been well established in adults with MDD in two meta-analyses [31, 32].
For augmentation therapy, aripiprazole, olanzapine, and lithium carbonate were selected. There is a paucity of literature on the augmentation of treatments of adolescent MDD. Thus, we draw considerably on the literature describing adults with MDD who are nonresponders. Aripiprazole was chosen based on its demonstrated efficacy and tolerability as an augmentation agent in adult MDD patients who were nonresponsive [33,34,35] and has been recommended by several treatment guidelines [16, 36]. Olanzapine was selected based on the findings from two meta-analyses in adults with MDD who were nonresponders, which indicated that augmentation of SSRIs (primarily fluoxetine) with olanzapine results in a greater remission rate in comparison to SSRI alone or a placebo [33, 37]. Lithium carbonate, a mood stabilizer, was chosen for its demonstrated antidepressant efficacy, which has been supported by two meta-analyses of adult MDD patients who were nonresponders [33, 38].
Participants and recruitment
Participants were recruited at 6 clinical centres in China: The First Affiliated Hospital of Chongqing Medical University, The Second Affiliated Hospital of Chongqing Medical University, Children’s Hospital of Chongqing Medical University, The Southwest Hospital of Army Medical University, The Second Xiangya Hospital of Central South University and Peking University Sixth Hospital. The procedure will be approved and supervised by the committee responsible for overseeing research ethics at each clinical centre. Patients will be recruited from psychiatric outpatient clinics at each centre regardless of their gender, race, or ethnicity mainly. Table 1 outlines the criteria for including and excluding patients with MDD.
In phase 1, adolescents with MDD will be administered flexibly dosed fluoxetine (10–60 mg/day) for a duration of 8 weeks. The treatment will commence with a daily dose of 10 mg, with doses increasing to 40 mg/d at week 4 for those who have not achieved a ≥ 50% reduction in CDRS-R score. The decision to further increase the fluoxetine dose (maximum dose should not exceed 60 mg/d) will be at the discretion of the physician and depend on the patient’s condition.
In phase 2, some adolescent MDD patients will switch to a flexible dosage of either sertraline (25–200 mg/d), duloxetine (10–60 mg/d), or votioxetine (5–20 mg/d) for a period of 8 weeks. For patients who do not experience a reduction of at least 50% in CDRS-R score by week 4, the drug dosage will be adjusted to 150 mg/d for patients taking sertraline, or 40 mg/d for patients taking duloxetine, or 15 mg/d for patients taking vortioxetine. For other patients, augmentation will involve the flexible addition of either aripiprazole (2.5–15 mg/d), olanzapine (1.25–10 mg/d), or lithium carbonate (125–500 mg/d) to fluoxetine (40–60 mg/d). The decision to further increase the dose (not exceeding the maximum dose) will be at the discretion of the physician and depend on the patient’s condition.
This standardized protocol mirrors routine clinical practice and will promote uniformity across all clinical sites. The adherence to medication will be tracked through pill counts conducted at every visit, and the treatment will be open-label. In cases where patients are affected by severe anxiety or insomnia, appropriate sedative and hypnotic drugs (Table 2) may be administered; clinicians will be required to document the reasoning behind such a prescription. Notably, discontinuing or altering the antipsychotic medication will be considered quitting the research.
Adolescent MDD patients who enter the combined treatment group in the first phase will receive CBT and fluoxetine. The CBT manual, developed and revised by experienced psychologists, consists of 7 core modules, including psychoeducation, behavioural activation, mood monitoring and management, improving social skills, cognitive restructuring, negotiation and problem solving, and maintaining gains. The treatment process will take place in two formats; the main format will be adolescent and parent-adolescent groups meeting for a total of 11 sessions lasting 90–120 min each over 8 weeks. (Table 3). Our psychotherapists will receive regular supervision to ensure rigorous psychotherapy processes, and all treatment sessions will be videotaped.
During the screening phase, each patient will undergo a comprehensive psychiatric consultation to verify the diagnosis of MDD based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Additionally, their medical history (including present and previous therapies) will be collected, and for females, their menstrual/reproductive history will also be documented. A medical assessment will be conducted, including height and weight measurement, laboratory tests, physical examination, and 12-lead ECG, as well as collection of basic information about demographics, race, education, social relationships, children trauma, domestic violence, school bullying, depressive symptoms, rumination, and suicidal self-injury will be required for participants. Participants’ magnetic resonance imaging (MRI) contraindications will also be noted.
Adolescent MDD patients will attend 8 follow-up visits to perform clinical examinations and assessments according to the schedule (Table 4). The examinations and assessments were selected considering their theoretical and clinical usefulness while minimizing the burden on respondents. Raters underwent training, and the reliability between different raters has been established through the use of recorded interviews.
Children’s Depression Rating Scale (CDRS-R)
The primary outcomes are the treatment remission rate and response rate. The CDRS-R is a scale consisting of 17 items that are evaluated by clinicians to assess the intensity of depressive symptoms in adolescents, with items scored on scales of 1 to 5 or 1 to 7, resulting in a possible total score range of 17 to 113 .
The Beck Depression Inventory (BDI)
The BDI is a self-report rating scale containing 21 items. Based on the BDI scores, depression can be classified into six levels: normal (1–10), mild mood disorder (11–16), borderline clinical depression (17–20), moderate depression (21–30), severe depression (31–40), and extreme depression (over 40) .
The screen for child anxiety-related emotional Disorders (SCARED)
The SCARED is employed to evaluate child anxiety symptoms. Each question is rated from 0 to 2, with 0 denoting “not true or hardly ever true,” 1 denoting “somewhat true or sometimes true,” and 2 denoting “extremely true or often true” [41, 42]. The maximum total score is 63. The recommended total score cut-off of 25 points in Chinese children was used to group patients with and without anxiety symptoms, with higher scores indicating a greater number of anxiety symptoms.
Columbia suicide severity rating scale (C-SSRS)
The measurement of suicidal ideation involves the use of the C-SSRS, a semi-structured clinician-rated interview specifically designed to evaluate the severity of suicidal behaviour and ideation among individuals aged 11 years and older in various settings, including research, clinical, and community environments [43, 44].
Hypomania Symptom Checklist-32 (HCL-32)
The HCL-32 is an excellent tool to screen for past episodes of hypomania developed by Jules Angst [45, 46]. It consists of 32 items describing symptoms of hypomania which require a yes/no answer based on whether the participant experienced that symptom. The final score is derived by summing the affirmative answers, and patients with a total score of 13 or higher are identified as having probable bipolar disorder (BD).
Pittsburgh Sleep Quality Index (PSQI)
The PSQI is self-administered questionnaire with 19 items that evaluate sleep quality and disturbances more than one month. It includes seven “component” scores: daytime dysfunction, sleep latency, use of sleeping medication, subjective sleep quality, sleep disturbances, sleep duration, and habitual sleep efficiency [47,48,49]. Participants rated each item on a scale from 0 to 3, with 0 indicating that the experience did not occur in the past month and 3 indicating that it occurred three or more times a week. The PSQI total score spans from 0 to 21, and if the global score exceeds 5, it suggests subpar sleep quality.
The Pediatric Quality of Life Inventory 4.0 generic core scales (PedsQL4.0)
The PedsQL4.0 is a standard questionnaire used to evaluate the quality of life over the previous week in population aged 8 to 18 . There are 23 items in total, and items are divided into four categories: physical functioning, emotional functioning, school functioning, and social functioning. The total score of the PedsQL is determined by averaging all the items across the entire questionnaire, with a range from 0 to 100. Higher scores signify a higher quality of life.
Ruminative responses Scale (RSS)
The RRS comprises 22 items that assess three aspects of rumination (brooding, symptom rumination, and reflective pondering); each item is rated on a scale from 1 to 4 [51, 52]. The total score on the RRS spans from 22 to 88, with higher scores indicating greater intensity of rumination.
Clinical global impressions-severity (CGI-S)
The CGI-S evaluates the degree of global functional impairment, including but not restricted to issues with social interaction and internalizing and externalizing issues . A treating practitioner determines the CGI-S rating on a 7-point scale, with 1 being normal and 7 being among the most severe.
Clinical global impressions-improvement (CGI-I)
The improvement in overall functioning over the past week since the start of treatment will be measured using the CGI-I . A treating practitioner will determine the score based on a 7-point scale, with 1 denoting a very significant improvement, 7 denoting a very significant deterioration, and 4 denoting no change. Clinical judgement will be guided by all available information.
Childhood trauma questionnaire-short form (CTQ)
The CTQ questionnaire comprises 28 items that assess different forms of childhood trauma, including sexual, physical, and emotional abuse, as well as emotional and physical neglect. The questionnaire is used to evaluate childhood trauma, where respondents rate each item on a five-point Likert scale that ranges from “Never” (assigned a value of 1) to “Always” (assigned a value of 5) . The overall score was calculated by adding up the scores of all the items, and higher scores indicated a greater frequency and severity of child maltreatment experiences prior to the age of 16.
Olweus Bully/Victim questionnaire (OB/VQ)
The OBVQ is a self-report questionnaire with 42 items, we selected 7 of the questions from the school bullying section for the experiment in order to perform a simple survey of the school bullying situation of adolescent patients with depression . All answers were scored as a Likert 5-point scale: several times a week, once a week, two or three times per month, once or twice, and never happened.
The Morisky Medication Adherence Questionnaire-8 (MMA-8) is a widely utilized and dependable measure for assessing medication adherence. It comprises eight questions, each targeting a distinct aspect of adherence behaviour, with a total score range of 0 to 8 . The first seven items are answered with a “yes” or “no,“ while the final item offers five response options. Adherence levels are classified as low, moderate, or high based on MMAS-8 scores of < 6, 6 to 8, and 8, respectively [56,57,58]. And pill count also will be used to enhance validity of data (Adherence was considered to be poor with a tablet count of less than 80% or more than 120%).
The MMAS-8 Scale, content, name, and trademarks are protected by US copyright and trademark laws. Permission for use of the scale and its coding is required. A license agreement is available from MMAR, LLC.,www.moriskyscale.com.
Safety will be assessed with all-cause discontinuation, which encompasses both side effects and efficacy. All-cause discontinuation refers to discontinuation for any reason, such as insufficient effectiveness, intolerable adverse effects, or poor adherence. Adverse events (AE) and Significant adverse events (SAE) are defined as in previous studies, such as the Treatment for Adolescents With Depression Study (TAD) . Adverse events will be collected after the subject has provided consent and enrolled in the study. If a subject experiences an adverse event after the informed consent document is signed (entry) but the subject has not started to receive study intervention, the event will be reported as not related to study drug. All adverse events occurring after entry into the study and until finish the study will be recorded. An AE that meets the criteria for SAE between study enrollment and hospital discharge will be arbitration by the STAR-AD Clinical Events Safety Committee which constitute with three independent clinical event reviewers. Side-effect discontinuations will also be recorded.
Blood, urine, saliva, and faecal samples will be obtained from all participants during the initial assessment, as well as at weeks 8 and 16. Samples will be processed and stored at the Chongqing Medical University. The laboratory adheres to Good Clinical Laboratory Practice and Good Manufacturing Practices, and follows standardized Standard Operating Procedures (SOPs) and protocols for receiving and processing samples. The samples will be frozen at -80 °C for later testing.
Adolescent MDD patients will undergo 3 or 4 imaging sessions using a 3T MRI scanner: (1) before treatment initiation (baseline), (2) following 4 weeks of treatment, (3) following 8 weeks of treatment, and (4) following 4 months of treatment for responders. At each session, data from resting-state functional MRI, structural MRI, and diffusion tensor imaging will be collected. Neuroimaging will be performed to discover potential predictors of response and nonresponse in adolescent MDD and investigate alterations in brain characteristics throughout phase 1 and 2 of the treatment.
According to the preliminary pilot study, we hypothesized that the response rates of fluoxetine and combination therapy in stage 1 were 40% and 60%, respectively. The significance level (α) was set at 0.025 (one-tailed), the test power (1-β) was set to 0.8, and the distribution ratio of fluoxetine and combination therapy in phase 1 was established as 1:1 according the preliminary pilot study. Considering a 20% dropout rate, the sample size must be greater than 238.
However, in order to achieve statistical significance, phase 2 of clinical trials necessitates a minimum sample size of at least 30 patients in each group . Considering a 20% dropout rate, the sample size going into phase 2 cannot be less than 216. Therefore, combining the sample size from both stages and accounting for the response rate in the first phase, our sample size target for this trial is 520 patients.
After week 8 of the Phase 1 intervention, nonresponding patients and those with a response without remission will be randomly assigned by central allocation. The randomization sequence will be created using StataPM.14 software and stratified by the centre, ensuring these patients will be ramdomly equally assigned to one of six treatment groups. To simulate a clinical environment reflecting real-world conditions, the medications are administered in an open-label manner with flexible dosing. The patient, psychiatrist, and outcome assessor are aware of the group allocation, whereas the data analyst will remain blinded to this information. The clinicians providing the intervention will not conduct the evaluation. All investigators, staff, and participants will maintain strict confidentiality regarding the outcome measures and trial results.
Data collection and management
We will use Yiducloud (https://www.yiducloud.com.cn/), a secure and extensively utilized web-based research application, for data collection and entry. The application offers a user-friendly interface for accurate data entry, allows tracking of data manipulation through audit trails, and provides automated export functions for convenient data downloads to Excel. Our database will require complete responses to all interview questions and survey, and will include tools to bring in data from external sources.
We will implement a robust data management strategy to ensure the reliability and availability of the study data. All participant information will be securely stored in a Yiducloud database and managed for efficient updating, tracking, and exporting of data in various formats. We will implement procedures to ensure compliance with local institutional review boards and manage data requests through a data use agreement.
Data entry will be conducted by a trained officer and each data entry is then carefully double-checked by another research team member. Data completeness will be reviewed monthly. Reasons for missing data will be documented in real time during data collection and entry, and a second reviewer will review and verify 10% of the data for quality control. This plan will ensure the reliability of data used for analysis and dissemination while ensuring ethical and regulatory compliance.
The principle of intention to treat, safety set, per-protocol set, full analysis set will be incorporated into the analysis. All statistical tests will be performed as two-sided tests, and P value below 0.05 will be deemed as indicating statistical significance. Quantitative indicators will be described by their mean and standard deviation. Classification indicators will be described by the number of cases and percentages in each category. To evaluate the impact of treatments on primary and secondary effectiveness endpoints, measured at baseline, 8 weeks, and 16 weeks, analysis of covariance will be utilized for quantitative data, considering the baseline measurement as a covariate. For qualitative data, a chi-squared test adjusted for central effects will be employed to compare groups.
This protocol describes the reasoning, purpose, and design of the trial. The objective of this trial is to examine the effectiveness and safety of different treatment regimens for depression in adolescents who are initially treated successfully or are nonresponsive. The findings from this trial will offer valuable evidence for clinicians in their choice of monotherapy or combination therapy for adolescent MDD patients. It will also offer evidence for identifying patients who do not respond to initial treatment and contribute to the understanding of the effectiveness and safety of antidepressants with various mechanisms and booster agents. The study employs a combination of dynamic therapy and sequential therapy, making it well-suited for evaluating the effectiveness of treatment options in real-world clinical settings. At the same time, we will also include a rubric for specific symptoms associated with depression, such as anxiety symptoms, suicide risk, sleep status, and quality of survival, and will also analyse the short-term effects of treatment over 6 months and the long-term effects over 12 months, including by evaluating relapse rates. Therefore, we hope that this study can provide guidance in developing optimal treatment protocol for adolescents with MDD.
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Sequenced Treatment Alternatives to Relieve Adolescent Depression (STAR-AD)
major depressive disorder
Sequential Multiple Assignment Randomized Trial
the Children’s Depression Rating Scale-Revised
the Beck Depression Inventory
the Screen for Child Anxiety-Related Emotional Disorders
the National Institute of Clinical Excellence
the American Academy of Child and Adolescent Psychiatry
the Guidelines for Adolescent Depression in Primary Care
Canadian Network for Mood and Anxiety Treatment
randomized controlled trial
the Treatment of SSRI-Resistant Depression in Adolescents
selective serotonin reuptake inhibitor
norepinephrine reuptake inhibitor
the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
magnetic resonance imaging
Columbia Suicide Severity Rating Scale
Hypomania Symptom Checklist-32
Pittsburgh Sleep Quality Index
The Pediatric Quality of Life Inventory 4.0 generic core scales
Ruminative Responses Scale
Clinical Global Impressions-Severity
Clinical Global Impressions-Improvement
Childhood Trauma Questionnaire-Short Form
Olweus Bully/Victim Questionnaire
The Morisky Medication Adherence Questionnaire-8
significant adverse events
Standard Operating Procedures
Depression. and Other Common Mental Disorders Global Health Estimates Available from:https://apps.who.int/iris/handle/10665/254610.pdf. Accessed May 20, 2023.
Bitsko RH, Claussen AH, Lichstein J, Black LI, Jones SE, Danielson ML, et al. Mental Health Surveillance among Children - United States, 2013–2019. MMWR Suppl. 2022;71(2):1–42.
Gunlicks-Stoessel M, Mufson L, Bernstein G, Westervelt A, Reigstad K, Klimes-Dougan B, et al. Critical decision points for augmenting interpersonal psychotherapy for depressed adolescents: a pilot sequential multiple assignment Randomized Trial. J Am Acad Child Adolesc Psychiatry. 2019;58(1):80–91.
Twenge JM, Cooper AB, Joiner TE, Duffy ME, Binau SG. Age, period, and cohort trends in mood disorder indicators and suicide-related outcomes in a nationally representative dataset, 2005–2017. J Abnorm Psychol. 2019;128(3):185–99.
McCarty CA, Weisz JR. Effects of psychotherapy for depression in children and adolescents: what we can (and can’t) learn from meta-analysis and component profiling. J Am Acad Child Adolesc Psychiatry. 2007;46(7):879–86.
Birmaher B, Brent D, Issues AWGQ, Bernet W, Bukstein O, Walter H, et al. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503–26.
Luxton R, Kyriakopoulos M. Depression in children and young people: identification and management NICE guidelines. Arch Dis Child Educ Pract Ed. 2022;107(1):36–8.
MacQueen GM, Frey BN, Ismail Z, Jaworska N, Steiner M, Lieshout RJ, et al. Canadian Network for Mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Sect. 6. Special populations: Youth, Women, and the Elderly. Can J Psychiatry. 2016;61(9):588–603.
Cheung AH, Zuckerbrot RA, Jensen PS, Laraque D, Stein REK, Glad-Pc Steering G. Guidelines for adolescent depression in primary care (GLAD-PC): part II. Treatment and Ongoing Management. Pediatrics 2018;141(3).
March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for adolescents with Depression Study (TADS) randomized controlled trial. JAMA. 2004;292(7):807–20.
Brent D, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller M, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA. 2008;299(8):901–13.
Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD, et al. Treatment of resistant depression in adolescents (TORDIA): week 24 outcomes. Am J Psychiatry. 2010;167(7):782–91.
El-Hage W. [Roadmap for therapeutic strategies of treatment resistant depression]. Presse Med. 2016;45(3):320–2.
Sinyor M, Schaffer A, Levitt A. The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review. Can J Psychiatry. 2010;55(3):126–35.
Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12):1087–206.
Depression in adults: recognition and management https://www.nice.org.uk/guidance/ng222. Accessed May 20, 2023.
Murphy SA. An experimental design for the development of adaptive treatment strategies. Stat Med. 2005;24(10):1455–81.
Ogbagaber SB, Karp J, Wahed AS. Design of sequentially randomized trials for testing adaptive treatment strategies. Stat Med. 2016;35(6):840–58.
Liu Y, Zeng D, Wang Y. Use of personalized dynamic treatment regimes (DTRs) and sequential multiple assignment randomized trials (SMARTs) in mental health studies. Shanghai Arch Psychiatry. 2014;26(6):376–83.
Emslie GJ, Mayes TL. Mood disorders in children and adolescents: psychopharmacological treatment. Biol Psychiatry. 2001;49(12):1082–90.
Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2002;41(10):1205–15.
Thome-Souza MS, Kuczynski E, Valente KD. Sertraline and fluoxetine: safe treatments for children and adolescents with epilepsy and depression. Epilepsy Behav. 2007;10(3):417–25.
Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7(7):581–601.
Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA. 2003;290(8):1033–41.
Review. and opportunity analysis of antidepressant drug market in China https://www.menet.com.cn/. Accessed May 20, 2023.
Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet. 2016;388(10047):881–90.
Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, et al. New generation antidepressants for depression in children and adolescents: a network meta-analysis. Cochrane Database Syst Rev. 2021;5(5):CD013674.
Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011;54(9):3206–21.
Findling RL, DelBello MP, Zuddas A, Emslie GJ, Ettrup A, Petersen ML, et al. Vortioxetine for major depressive disorder in adolescents: 12-Week randomized, Placebo-Controlled, Fluoxetine-Referenced, fixed-dose study. J Am Acad Child Adolesc Psychiatry. 2022;61(9):1106–18. e1102.
Makrogiannis S, Zheng K, Harris C. Discriminative localized sparse approximations for Mass characterization in Mammograms. Front Oncol. 2021;11:725320.
Thase ME, Mahableshwarkar AR, Dragheim M, Loft H, Vieta E. A meta-analysis of randomized, placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults. Eur Neuropsychopharmacol. 2016;26(6):979–93.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the Acute treatment of adults with major depressive disorder: a systematic review and network Meta-analysis. Focus (Am Psychiatr Publ). 2018;16(4):420–9.
Nunez NA, Joseph B, Pahwa M, Kumar R, Resendez MG, Prokop LJ, et al. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord. 2022;302:385–400.
Seshadri A, Wermers ME, Habermann TJ, Singh B. Long-term efficacy and tolerability of adjunctive aripiprazole for major depressive disorder: systematic review and Meta-analysis. Prim Care Companion CNS Disord 2021;23(4).
Strawbridge R, Carter B, Marwood L, Bandelow B, Tsapekos D, Nikolova VL, et al. Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis. Br J Psychiatry. 2019;214(1):42–51.
Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Sect. 3. Pharmacological treatments. Can J Psychiatry. 2016;61(9):540–60.
Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC. Adjunctive atypical antipsychotic treatment for major depressive disorder: a Meta-analysis of Depression, Quality of Life, and Safety Outcomes. Focus (Am Psychiatr Publ). 2016;14(2):244–65.
Vazquez GH, Bahji A, Undurraga J, Tondo L, Baldessarini RJ. Efficacy and tolerability of combination treatments for Major Depression: Antidepressants plus Second-Generation Antipsychotics vs. esketamine vs. Lithium J Psychopharmacol. 2021;35(8):890–900.
Poznanski EO, Freeman LN, Mokros HB. Children’s Depression Rating Scale Revised. Psychopharmacol Bull 1985:979–89.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561–71.
Birmaher B, Khetarpal S, Brent D, Cully M, Balach L, Kaufman J, et al. The screen for child anxiety related Emotional Disorders (SCARED): scale construction and psychometric characteristics. J Am Acad Child Adolesc Psychiatry. 1997;36(4):545–53.
Su L, Wang K, Fan F, Su Y, Gao X. Reliability and validity of the screen for child anxiety related emotional disorders (SCARED) in chinese children. J Anxiety Disord. 2008;22(4):612–21.
Phillips MR, Li X, Zhang Y. Suicide rates in China, 1995-99. Lancet. 2002;359(9309):835–40.
Viguera AC, Milano N, Laurel R, Thompson NR, Griffith SD, Baldessarini RJ, et al. Comparison of electronic screening for suicidal risk with the Patient Health Questionnaire Item 9 and the Columbia suicide severity rating scale in an Outpatient Psychiatric Clinic. Psychosomatics. 2015;56(5):460–9.
Angst J, Adolfsson R, Benazzi F, Gamma A, Hantouche E, Meyer TD, et al. The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients. J Affect Disord. 2005;88(2):217–33.
Yang HC, Yuan CM, Liu TB, Li LJ, Peng HJ, Liao CP, et al. Validity of the 32-item Hypomania Checklist (HCL-32) in a clinical sample with mood disorders in China. BMC Psychiatry. 2011;11:84.
Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213.
X L. Reliability and validity of the Pittsburgh sleep quality index. Chin J Psychiatry 1996;29:103.
Wang YYCD, Yang XT, et al. Reliability and validity of Pittsburgh sleep quality index in adolescents with myopia modern. Prev Med. 2019;46(6):1062–5.
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 2001;39(8):800–12.
Nolen-Hoeksema S, Morrow J. A prospective study of depression and posttraumatic stress symptoms after a natural disaster: the 1989 Loma Prieta Earthquake. J Pers Soc Psychol. 1991;61(1):115–21.
Han XYH. Chinese version of Nolen-Hoeksema ruminative responses scale (RRS) used in 912 college students: reliability and validity. Chin J Clin Psychol 2009.
Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28–37.
Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2003;27(2):169–90.
Olweus D. The revised Olweus bully/victim questionnaire[M]. University of Bergen, Research Center for Health Promotion; 1996.
Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens (Greenwich). 2008;10(5):348–54.
Bress AP, Bellows BK, King JB, Hess R, Beddhu S, Zhang Z, et al. Cost-effectiveness of intensive versus standard blood-pressure control. N Engl J Med. 2017;377(8):745–55.
Berlowitz DR, Foy CG, Kazis LE, Bolin LP, Conroy MB, Fitzpatrick P, et al. Effect of intensive blood-pressure treatment on patient-reported outcomes. N Engl J Med. 2017;377(8):733–44.
Li TJ, Sun YC, Ma QY, Wu Y, Yang C, Zhang N, et al. Clinical observation of Dan-Hong Hua-Yu oral solution in treating retinal vein occlusion. Med (Baltim). 2020;99(21):e20173.
This work was supported by the scientific and technological innovation 2030 - the major project of the Brain Science (2022ZD0212900 to Xinyu Zhou).
Ethics approval and consent to participate
Full ethical approval for the outlined study was granted in February 2023 (2023-011-02) by the Ethics Committee of Chongqing Medical University. The collection of biological sample was approved in June 2023 (CJ1310) by the Ministry of Science and Technology of the People’s Republic of China. Written informed consent will be obtained from all the study participants prior to investigation. All research is carried out in accordance with the Declaration of Helsinki, data protection laws and good clinical practice (GCP) as well as other relevant guidelines and regulations. Written informed consent will be obtained from all the study participants and their parents or legal guardians for minors prior to investigation.
Consent for publication
The manuscript does not contain sensitive information on any individual that participated in STAR-AD. The participants will provide consent for publication if any identifying information/images are included in the manuscript.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
He, Y., Gan, X., Li, X. et al. Sequenced treatment alternatives to relieve adolescent depression (STAR-AD): a multicentre open-label randomized controlled trial protocol. BMC Psychiatry 23, 789 (2023). https://doi.org/10.1186/s12888-023-05221-w