Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth
![]() |
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT02553161 |
Recruitment Status : Unknown
Verified November 2016 by Melissa Delbello, University of Cincinnati.
Recruitment status was: Recruiting
First Posted : September 17, 2015
Last Update Posted : May 2, 2018
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Depression Anxiety Bipolar Disorder | Drug: Escitalopram Behavioral: Cognitive behavioral Psychotherapy | Not Applicable |
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.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 210 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Triple (Participant, Care Provider, Investigator) |
Primary Purpose: | Treatment |
Official Title: | Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth |
Actual Study Start Date : | December 2015 |
Estimated Primary Completion Date : | December 2019 |
Estimated Study Completion Date : | December 2020 |

Arm | Intervention/treatment |
---|---|
Experimental: MED - Escitalopram with psychotherapy
Youth 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.
|
Drug: Escitalopram
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.
Other Name: Lexapro |
Placebo Comparator: No MED -Psychotherapy
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.
|
Behavioral: Cognitive behavioral Psychotherapy
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.
Other Name: CBT |
No Intervention: Healthy Control
60 (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.
|
- Baseline-endpoint change in prefrontal-amygdala functional connectivity by Scan. [ Time Frame: Baseline to 16 weeks ]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.
- Week 4- endpoint change in mood by and arousal ratings [ Time Frame: Between week 4 and 16 ]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.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 12 Years to 17 Years (Child) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
Inclusion - High-Risk Youth:
- 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.
Inclusion - Healthy Controls:
- 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).
Exclusion Criteria:
Exclusion - High-Risk Youth & Healthy Controls:
- 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);
- 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.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02553161
Contact: Melissa P DelBello, MD, MS | 513-558-2989 | ||
Contact: Kaitlyn D Bruns | 513-558-5303 | BRUNSKN@ucmail.uc.edu |
United States, California | |
Stanford University | Recruiting |
Stanford, California, United States, 94305-2004 | |
Contact: Manpreet K Singh, MD MS 650-725-5922 mksingh@stanford.edu | |
United States, Ohio | |
University of Cincinnati | Recruiting |
Cincinnati, Ohio, United States, 45219 | |
Contact: Kaitlyn Bruns, B.A. 513-558-5303 BRUNSKN@ucmail.uc.edu |
Principal Investigator: | Melissa P DelBello, MD, MS | University of Cincinnati | |
Principal Investigator: | Manpreet K Singh, MD,MS | Stanford University |
Responsible Party: | Melissa Delbello, Principal Investigator, University of Cincinnati |
ClinicalTrials.gov Identifier: | NCT02553161 |
Other Study ID Numbers: |
DelBello/Singh AIM R01MH105469 ( U.S. NIH Grant/Contract ) |
First Posted: | September 17, 2015 Key Record Dates |
Last Update Posted: | May 2, 2018 |
Last Verified: | November 2016 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Depression |
Depression Bipolar Disorder Behavioral Symptoms Mental Disorders Bipolar and Related Disorders Citalopram Serotonin Uptake Inhibitors Neurotransmitter Uptake Inhibitors |
Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Serotonin Agents Physiological Effects of Drugs Antidepressive Agents, Second-Generation Antidepressive Agents Psychotropic Drugs |