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

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.

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.