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DepressionNCT02553161

Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth

A study testing Escitalopram and Cognitive behavioral Psychotherapy in people with Depression and Anxiety, run by University of Cincinnati at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

A 16-week double blind, placebo-controlled investigation of escitalopram in adolescents with depression and/or anxiety with a family history of Bipolar Disorder. Subjects will be evaluated using semi-structured diagnostic interviews and symptom ratings, participate in a MRI scan and then randomized to treatment. Read more about this study

Who is it for?
Ages 12 to 17 yearsHealthy volunteers can take part
Conditions the study is for
Depression, Anxiety, Bipolar Disorder
What is being tested?
Escitalopram and Cognitive behavioral Psychotherapy
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
214 participants
Where
2 sitesUnited States
Study dates
Dec 2015to Dec 2022
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 to 17 years
  • All sexes
  • Healthy volunteers accepted
  • Child

Who may be able to join

  • age 12 years, 0 mos. - 17 years, 11 mos.;
  • at least one parent or step-parent/guardian with whom the subject lives is willing to participate in research sessions;
  • the child and relative(s) are able and willing to give written informed assent/consent to participate, respectively;
  • the youth meets criteria for high-risk:
  • has at least one first degree relative with Bipolar I Disorder, as assessed by the Structured Clinical Interview for DSM (SCID; First et al. 1995), the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-PL, Kaufman et al., 1997), and the Family History-Research Diagnostic Criteria (FH-RDC; Andreasen et al., 1977);
  • the youth shows evidence of current significant depressive or anxiety symptoms as determined by a current Childhood Depression Rating Scale-Revised (CDRS-R, Poznanski et al.,1984) score > 35 and/or a current Pediatric Anxiety Rating Scale (PARS, 2002) score > 15.
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  • age 12 years, 0 mos. - 17 years, 11 mos.;
  • at least one parent or step-parent/guardian with whom the subject lives is willing to participate in research sessions;
  • the child and relative(s) are able and willing to give written informed assent/consent to participate, respectively;
  • no personal or family history of any psychopathology as assessed by the KSADS-PL structured clinical interview (Kaufman et al., 1997) and the Family History-Research Diagnostic Criteria (FH-RDC; Andreasen et al., 1977).

Who cannot join

  • any history of syndromal bipolar I or II disorder (i.e., history of mania, mixed episode, or major depression with hypomania);
  • a history of previous antidepressant exposure
  • a DSM-5 diagnosis of autism, pervasive developmental disorder, OCD(Obsessive-Compulsive Disorder), PTSD, Tourette's disorder, or any psychotic disorder including schizophrenia;
  • evidence of mental retardation (IQ < 70) as determined by the Weschler Abbreviated Scale of Intelligence (WASI; Psychological Corporation, 1999);
  • comorbid neurologic diseases such as seizure disorder;
  • Drug or alcohol abuse or dependence disorders in the 4 months prior to study recruitment, although a lifetime history of substance or alcohol disorders can be present if the child has been abstinent for at least 6 months (see further discussion below);
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  • evidence of an unstable medical or psychiatric disorder that requires immediate hospitalization or other emergency medical treatment;
  • a positive pregnancy test; participants will be encouraged but not mandated to discuss a positive pregnancy test with their guardians and we will follow local laws.
  • any contraindication for MRI, including metal in the body related to an injury or surgery (e.g., surgical clips, metal fragments in the eyes), piercings that cannot be removed, braces, or permanent retainers.

Trial locations and contacts

2 sites in 1 country.

United States2 sites
  • University of Cincinnati

    Cincinnati, Ohio, 45219

  • Stanford University

    Stanford, California, 94305-2004

Other trials in United States

About this study

A 16-week double blind, placebo-controlled investigation of escitalopram in adolescents with depression and/or anxiety with a family history of Bipolar Disorder. Subjects will be evaluated using semi-structured diagnostic interviews and symptom ratings, participate in a MRI scan and then randomized to treatment. Following randomization, high-risk youth will have visits every week for the first 4 weeks of treatment then biweekly up to 16 weeks during which time tolerability and ratings will be performed. MRI scan will be repeated at week 4.

Read the detailed description

The primary goals of this proposal are to investigate the etiological mechanisms associated with antidepressant-related dysfunctional emotional arousal and to characterize baseline neurobiological risk factors that predict the development of dysfunctional emotional arousal in treatment seeking youth with a family history of BD.

Antidepressants have moderate benefit for treating mood and anxiety disorders in childhood but their effects on the developing brain are largely unknown. Antidepressants are among the most commonly prescribed medications used by youth in the United States and are used to treat many psychiatric disorders including depression, dysthymia and anxiety. However, recent reviews suggest that antidepressants provide only mild to moderate benefit. Moreover, a growing number of case reports and clinical studies have described antidepressant-related psychiatric adverse events such as aggression, psychosis, agitation, suicidal ideation, hypomania or mania, all behaviors associated with increased emotional arousal. Importantly, these adverse events are more likely to occur in children than adults. With younger ages of treatment combined with increased and repeated exposure during critical sensitive periods of neurodevelopment, these adverse events are becoming a rising concern for youth, and may lead to the development of serious psychopathologies in youth that carry an enormous burden of illness, such as bipolar disorder (BD). Given that BD typically begins before 18 years of age and with a depressive episode, there are millions of youth in the U.S. each year who experience their first bipolar episode as a depressive episode that is routinely treated with antidepressants. However, the mechanisms and risk factors through which antidepressants increase risk for developing adverse outcomes are largely unknown.

Youth with a family history of BD have a high likelihood of developing adverse responses to antidepressants, possibly because such youth are already vulnerable to developing dysfunctional emotional arousal and may use antidepressants to treat mood and anxiety symptoms. Indeed, a family history of BD is among the strongest risk factors for developing disorders of emotional arousal in youth. Twin and family studies have provided compelling evidence that having a parent with BD is associated with dramatic increases in risk for the offspring's development of disorders of emotional arousal compared with the general population. Moreover, when these offspring develop dysfunctional emotional arousal, their risk of developing BD increases even further. Antidepressants are commonly used to treat initial mood presentations; however, they may also accelerate the onset of dysfunctional emotional arousal in these high-risk youth. In this context, it becomes difficult to disentangle a natural illness progression from an antidepressant-related dysfunction leading to BD. Thus, there is a significant clinical dilemma regarding whether antidepressants should be prescribed to treat youth with a family history of BD, who also have DSM-5 (Diagnostic and Statistical Manual of Mental Disorders) depressive and anxiety disorders.

Being tested
Escitalopram, Cognitive behavioral Psychotherapy
Keywords
Depression
Medical subject headings
Depression, Anxiety Disorders, Bipolar Disorder

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EscitalopramDrug

    Also called Lexapro

    Youth in the MED condition will be given the USFDA approved antidepressant, escitalopram for the treatment of depression or anxiety in youth and follow a standard dose titration schedule of 5 mg/day for 1 week, 10mg/day for 1 week, then with a target dose of 20-30 mg/day by 4 weeks. Titration will be no faster than 5mg/week. This titration guideline was drawn from the escitalopram package insert for pediatric dosing, which states that target doses may be achieved by 4 weeks.

  • Cognitive behavioral PsychotherapyBehavioural

    Also called CBT

    All participants (No MED and MED) will be assigned a study-trained therapist who will provide hour-long weekly individual cognitive behavioral psychotherapy (CBT) based on current evidence-based practices for the treatment of anxiety and depressive symptoms for youth.

Study groups in NCT02553161
Study groupRoleWhat they receive
MED - Escitalopram with psychotherapyExperimentalYouth will also be assigned a board certified child psychiatrist (Drs. Singh or Chang at Stanford; Drs. DelBello or Patino at UC), who will be blind to treatment condition and see youth weekly for the first 4 weeks, then biweekly until 16 weeks. Youth in the MED condition will be given the USFDA (US Food \& Drug Administration) approved antidepressant, escitalopram for the treatment of depression or anxiety in youth and follow a standard dose titration schedule of 5 mg/day for 1 week, 10mg/day for 1 week, then with a target dose of 20-30 mg/day by 4 weeks.
Receives: Drug: Escitalopram
No MED -PsychotherapyPlacebo comparatorAll participants (No MED and MED) will be assigned a study-trained therapist who will provide hour-long weekly individual cognitive behavioral psychotherapy (CBT) based on current evidence-based practices for the treatment of anxiety and depressive symptoms for youth.
Receives: Behavioral: Cognitive behavioral Psychotherapy
Healthy ControlNo intervention60 (30 at Stanford, 30 at University of Cincinnati) 12- to 17-year old male and female typically developing healthy controls. Healthy controls will receive behavioral, neural, and physiological assessments at baseline only. healthy controls will be scanned at baseline only and serve as a reference group to determine whether MRI changes observed in the high-risk group from baseline to week 4 are toward or away from normal.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Baseline-endpoint change in prefrontal-amygdala functional connectivity by Scan.

    Study the neural mechanisms of antidepressant-related dysfunctional arousal by ensuring that the treatment assignment precedes the 4-week scan, and the 4-week scan precedes the assessment of highest arousal measured between 4 and 16 weeks.The change in amygdala hyperactivity from the baseline to 4-week scan will be treated as the outcome and the treatment status (MED vs. No MED) will be treated as the predictor variable. The primary outcome is the level of post-treatment arousal (highest after the 4-week scan). The early change (baseline to 4 weeks) in amygdala hyperactivity, treatment assignment (MED vs. No MED), and the interaction between the two will be the predictors of arousal.

    Measured: Baseline to 16 weeks

Secondary outcomes (1)
  1. Week 4- endpoint change in mood by and arousal ratings

    We will also explore subgroups of arousal due to worsening symptom severities of mania, anxiety, depression, psychosis, suicidality, and anxiety, using clinical, self, and parent (e.g. TEASAP) report measures of emotional reactivity and lability, and reaction times during the Continuous Performance Task with Emotional and Neutral Distracters (CPT-END) as secondary predictors of dysfunctional emotional arousal.

    Measured: Between week 4 and 16

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Sep 2015 (estimated)
  2. Study startDec 2015
  3. Primary completionJul 2022
  4. Study completionDec 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
214 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02553161
Sponsor's protocol ID
DelBello/Singh AIM
Other IDs
R01MH105469
Status last verified
Feb 2024
First submitted
10 Sep 2015
Last updated
26 Feb 2024
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Tang B, Patino LR, Blom TJ, Welge JA, Strawn JR, Bruns KM, Zhang W, Lui S, Singh MK, DelBello MP. Hippocampal subregion volume alterations at baseline and following antidepressant treatment in youth at high risk for bipolar disorder. Transl Psychiatry. 2026 Aug 1;16(1):597. doi: 10.1038/s41398-026-04314-w.

    PubMed 42957641
  • Zhang L, Qin K, Jones CR, Patino LR, Pan N, Zhu Z, Xu H, Blom TJ, Strawn JR, Gong Q, Singh MK, DelBello MP. Elevated Galvanic Skin Response and Associated Brain Network Patterns in Youth at High Familial Risk for Bipolar Disorder. JAACAP Open. 2026 Jul 1;4(5):842-851. doi: 10.1016/j.jaacop.2026.06.009. eCollection 2026 Oct.

    PubMed 42846741
  • Honeycutt DC, Blom TJ, Ramsey LB, Strawn JR, Bruns KM, Welge JA, Patino LR, Singh MK, DelBello MP. Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study. J Child Adolesc Psychopharmacol. 2024 Feb;34(1):42-51. doi: 10.1089/cap.2023.0073.

    PubMed 38377518
  • Pan N, Qin K, Patino LR, Tallman MJ, Lei D, Lu L, Li W, Blom TJ, Bruns KM, Welge JA, Strawn JR, Gong Q, Sweeney JA, Singh MK, DelBello MP. Aberrant brain network topology in youth with a familial risk for bipolar disorder: a task-based fMRI connectome study. J Child Psychol Psychiatry. 2024 Aug;65(8):1072-1086. doi: 10.1111/jcpp.13946. Epub 2024 Jan 14.

    PubMed 38220469

Questions about this trial

What is this clinical trial studying?

A study testing Escitalopram and Cognitive behavioral Psychotherapy in people with Depression and Anxiety, run by University of Cincinnati at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Baseline-endpoint change in prefrontal-amygdala functional connectivity by Scan. (time frame: Baseline to 16 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02553161, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2024.

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