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

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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
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Melissa Delbello, University of Cincinnati

Tracking Information
First Submitted Date  ICMJE September 10, 2015
First Posted Date  ICMJE September 17, 2015
Last Update Posted Date May 2, 2018
Actual Study Start Date  ICMJE December 2015
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 15, 2015)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2015)
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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth
Official Title  ICMJE Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth
Brief 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. 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Depression
  • Anxiety
  • Bipolar Disorder
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Escitalopram
  • 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.
    Intervention: Behavioral: Cognitive behavioral Psychotherapy
  • 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.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: September 15, 2015)
210
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Inclusion - High-Risk Youth:

  1. age 12 years, 0 mos. - 17 years, 11 mos.;
  2. at least one parent or step-parent/guardian with whom the subject lives is willing to participate in research sessions;
  3. the child and relative(s) are able and willing to give written informed assent/consent to participate, respectively;
  4. 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:

  1. age 12 years, 0 mos. - 17 years, 11 mos.;
  2. at least one parent or step-parent/guardian with whom the subject lives is willing to participate in research sessions;
  3. the child and relative(s) are able and willing to give written informed assent/consent to participate, respectively;
  4. 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:

  1. any history of syndromal bipolar I or II disorder (i.e., history of mania, mixed episode, or major depression with hypomania);
  2. a history of previous antidepressant exposure
  3. a DSM-5 diagnosis of autism, pervasive developmental disorder, OCD(Obsessive-Compulsive Disorder), PTSD, Tourette's disorder, or any psychotic disorder including schizophrenia;
  4. evidence of mental retardation (IQ < 70) as determined by the Weschler Abbreviated Scale of Intelligence (WASI; Psychological Corporation, 1999);
  5. comorbid neurologic diseases such as seizure disorder;
  6. 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);
  7. evidence of an unstable medical or psychiatric disorder that requires immediate hospitalization or other emergency medical treatment;
  8. 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.
  9. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02553161
Other Study ID Numbers  ICMJE DelBello/Singh AIM
R01MH105469 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Melissa Delbello, University of Cincinnati
Study Sponsor  ICMJE University of Cincinnati
Collaborators  ICMJE National Institute of Mental Health (NIMH)
Investigators  ICMJE
Principal Investigator: Melissa P DelBello, MD, MS University of Cincinnati
Principal Investigator: Manpreet K Singh, MD,MS Stanford University
PRS Account University of Cincinnati
Verification Date November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP