Antidepressants are commonly prescribed medications used by American youth today to treat a variety of childhood onset psychiatric disorders. However, serious psychiatric adverse events may also emerge from antidepressant use including irritability, agitation, elevated mood, and other adverse events associated with increased dysfunctional emotional arousal. For some youth, these adverse events lead to the development of lifelong psychopathologies such as bipolar disorder. Importantly, the mechanisms through which antidepressants increase risk for developing these adverse events are largely unknown. Moreover, there is a pressing clinical need to better identify which youth taking antidepressants will develop adverse outcomes. Youth who are highly likely to develop adverse responses to antidepressants are those who are already vulnerable to developing dysfunctional emotional arousal. Compelling data from family studies have shown that youth with a family history of bipolar disorder have high rates of major mood and other disorders of emotional arousal, and demonstrate early disruptions of neurobiological systems critical for the regulation of emotional arousal, most notably in the amygdala and ventrolateral prefrontal cortex (VLPFC) neural circuit. Antidepressants are commonly used to treat dysfunctional emotional arousal in high-risk youth; however, they may also increase and accelerate the onset of mood disorders in some of these youth. Research has implicated involvement of the Arousal construct of the NIMH Research Domain Criteria (RDoC) Arousal and Regulatory Systems, which describes fundamental aspects of emotional dysfunction when youth experience an adverse antidepressant-related psychiatric event. This application aims to use an RDoC framework in a randomized trial to investigate the etiological mechanisms and risk factors associated with antidepressant-related dysfunctional emotional arousal in high-risk youth. To accomplish these aims, 150 (75/site) high-risk youth, i.e. having at least one first- or second-degree relative with bipolar I disorder, who have moderate to severe depression or anxiety symptoms, will be randomized to receive double-blind treatment either with psychotherapy plus escitalopram or psychotherapy plus placebo. Prior to randomization, we will collect baseline magnetic resonance imaging (MRI), behavioral, and physiological measures of arousal. After randomization, youth will undergo a second MRI scan at 4 weeks, and then will be clinically assessed for up to 16 weeks to evaluate for changes in arousal.
We aim to determine whether antidepressant-related changes in arousal are mediated by changes in amygdala-VLPFC circuitry, and to identify neurobiological risk factors for developing dysfunctional arousal. This knowledge will be vitally important to mental health professionals who have limited empirical evidence on which to base their treatment of youth most vulnerable for emotion dysregulation. It also has potential to inform the pathophysiology of disorders associated with dysfunctional emotional arousal and the development of novel targets for treating this complex problem.

Public Health Relevance

Antidepressants are among the most commonly prescribed drugs used by American youth today. However, certain adverse events from antidepressants have been associated with the development of serious lifelong psychiatric disorders. The proposed research will help to identify mechanisms and modifiable neurobiological risk factors for antidepressant-related adverse events in youth that could prevent the development of lifelong and adverse long-term outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH105469-05
Application #
9769869
Study Section
Interventions Committee for Adult Disorders (ITVA)
Program Officer
Grabb, Margaret C
Project Start
2015-09-23
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Gershon, Anda; Johnson, Sheri L; Thomas, Leigh et al. (2018) Double trouble: weekend sleep changes are associated with increased impulsivity among adolescents with bipolar I disorder. Bipolar Disord :
Colich, Natalie L; Ho, Tiffany C; Foland-Ross, Lara C et al. (2017) Hyperactivation in Cognitive Control and Visual Attention Brain Regions During Emotional Interference in Adolescent Depression. Biol Psychiatry Cogn Neurosci Neuroimaging 2:388-395
Zalpuri, Isheeta; Singh, Manpreet K (2017) Treatment of psychiatric symptoms among offspring of parents with bipolar disorder. Curr Treat Options Psychiatry 4:341-356
Gershon, Anda; Singh, Manpreet K (2017) Sleep in Adolescents With Bipolar I Disorder: Stability and Relation to Symptom Change. J Clin Child Adolesc Psychol 46:247-257