iACT & iTBS for Sleep Quality in Depressed Adolescents

This was a four-arm, parallel-group, randomized controlled superiority trial conducted in the outpatient department of a psychiatric hospital in Anhui Mental Health Center. The study was retrospectively registered on the Open Science Framework in May 2024. The study protocol was approved by the institutional review board (Approval No.: CCNU-IRB-202306017b). Written informed consent was obtained from a parent or legal guardian, and written assent was obtained from each adolescent participant.

Participants were recruited by convenience sampling between August 2023 and January 2024. Eligible participants were 11 to 19 years old; had a primary DSM-5 depressive disorder confirmed by independent evaluations from two board-certified psychiatrists using semistructured clinical interviews; had a Hamilton Depression Rating Scale, 17-item version (HAMD-17) score of at least 8; and reported a concurrent subjective sleep disturbance, such as difficulty initiating sleep, frequent nighttime awakenings, or nonrestorative sleep. Participants were required either to be receiving stable antidepressant pharmacotherapy for at least 2 weeks or to be taking no antidepressant medication. Participants could not be receiving another systematic psychological or physical treatment and were required to be right-handed.

Participants were excluded for a history of epilepsy, a major neurological disorder, a contraindication to transcranial magnetic stimulation, acute suicide risk, a substance use disorder within the preceding year, severe somatic illness, or current use of targeted hypnotic or sedative medication.

Participants were randomly assigned in a 1:1:1:1 ratio using a computer-generated permuted-block randomization sequence. Allocation was managed by personnel independent of outcome assessment. Independent HAMD-17 raters were masked to treatment assignment. Participants and intervention-delivery personnel were not masked because the treatment formats and waitlist condition were distinguishable. Self-report outcome measures were completed by participants.

The internet-delivered Acceptance and Commitment Therapy program was provided through a custom-developed WeChat mini-program. The program included an introduction, six sequential treatment modules, and a concluding session. The content was delivered over 12 days and covered psychoeducation, acceptance, cognitive defusion, mindfulness, values clarification, and values-consistent action. The modules were unlocked on days 1, 3, 5, 7, 9, and 11, with approximately 15 minutes required for each component. The total planned exposure was approximately 120 minutes. All modules were completed on site during daily hospital visits. Online records and staff monitoring were used to document module completion and practice activities. A crisis hotline was embedded in the program.

Intermittent theta burst stimulation was administered once daily for 12 consecutive days using a Magstim Rapid2 stimulator with a 70-mm figure-of-eight coil. The individualized stimulation target was located over the left dorsolateral prefrontal cortex using integrated neuronavigation. Resting motor threshold was measured before treatment. Each session delivered 1,800 pulses in three 600-pulse blocks. Stimulation consisted of three-pulse 50-Hz bursts repeated at 5 Hz, delivered in 2-second trains separated by 8-second intervals. Stimulation intensity was 100% of the participant's resting motor threshold.

Participants in the combined group received both interventions. On days when a new Acceptance and Commitment Therapy module was available, theta burst stimulation was delivered first and was immediately followed by the module. On intervening days, participants received theta burst stimulation only. Participants in the internet-delivered therapy-only group followed the module schedule without theta burst stimulation. Participants in the stimulation-only group received theta burst stimulation without the therapy program during the intervention period. Participants assigned to the waitlist received no targeted intervention during the 42-day study period and completed assessments on the same schedule as the active-treatment groups. Access to the internet-delivered Acceptance and Commitment Therapy program was offered to participants in the waitlist and stimulation-only groups after the final follow-up assessment.

Assessments were conducted at baseline, immediately after the 12-day intervention, and at a 30-day follow-up. The primary outcome was subjective sleep quality, measured with the 19-item Pittsburgh Sleep Quality Index, with total scores ranging from 0 to 21 and higher scores indicating worse sleep quality. Secondary outcomes were depressive symptom severity, measured with the 17-item Hamilton Depression Rating Scale, and psychological flexibility, measured with the 12-item flexibility subscale of the Multidimensional Psychological Flexibility Inventory-24. Demographic information, including age, gender, school grade, only-child status, and urban or rural residence, was collected at baseline.

Adverse events and unintended effects were assessed through spontaneous participant reports during and after the intervention procedures. Examples included headache and scalp discomfort associated with intermittent theta burst stimulation.

The primary analyses examined changes from baseline to post-treatment and follow-up across the four groups. Repeated-measures models were used to account for the correlation among observations from the same participant. The main comparisons evaluated the combined intervention against the waitlist and against each monotherapy, as well as each monotherapy against the waitlist. Analyses adjusted for age, gender, and only-child status. Additional analyses examined clinical response in sleep quality, the robustness of findings under alternative model specifications, and whether the combined intervention showed evidence of greater-than-additive change relative to the two monotherapies. All 152 participants completed the three scheduled assessments.

This study was registered retrospectively after participant recruitment and data collection had begun.

Inclusion criteria

• Age 11 to 19 years.
• A primary depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), confirmed by independent evaluations conducted by two board-certified psychiatrists using semistructured clinical interviews. Any discrepancy was adjudicated by a senior psychiatrist.
• Hamilton Depression Rating Scale, 17-item version (HAMD-17) score of at least 8.
• Current subjective sleep disturbance, including difficulty initiating sleep, frequent nighttime awakenings, or nonrestorative sleep, confirmed during the diagnostic interview.
• Either no antidepressant medication or stable antidepressant pharmacotherapy for at least 2 weeks before enrollment.
• No concurrent systematic psychological or physical treatment during the study.
• Right-handedness.
• Written informed consent from a parent or legal guardian and written assent from the adolescent participant.

Exclusion criteria

• History of epilepsy, major neurological disorder, or any contraindication to transcranial magnetic stimulation, including relevant metal implants.
• Acute suicide risk requiring immediate clinical intervention.
• Substance use disorder within the previous year.
• Severe somatic illness that could interfere with study participation or outcome assessment.
• Current use of targeted hypnotic or sedative medication.