BEHAVIORAL ISSUES
Selections from Masters of Pediatrics: Contemporary and Future Pediatrics, presented by the University of Miami
Miller School of Medicine
| DEPRESSIVE DISORDERS IN CHILDREN AND ADOLESCENTS —Eugenio M. Rothe, MD, Associate Professor, Psychiatry
and Pediatrics, Department of Psychiatry; Director, Child and Adolescent Psychiatry Outpatient Clinic and School
Consultation Programs, University of Miami Miller School of Medicine, Miami, FL
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| Mood disorders: depressive disorders—major depressive disorder; dysthymic disorder; depressive disorder not otherwise
specified (NOS); secondary mood disorders—mood disorders secondary to general medical condition; substance-induced
mood disorders
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| Dysthymia: “neurotic depression”; depressed mood and irritability occurring after traumatic event (eg, divorce, sexual
abuse); characterized by lack of concentration, sleep disturbance, feelings of hopelessness, low self-esteem, and fatigue;
can evolve into major depression
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| Major depression: depressed mood and inability to experience pleasure (ie, anhedonia) key to diagnosis; signs and symptoms
vary among patients and between developmental ages; may present as primary psychiatric disorder or secondary problem;
differential diagnosis—bereavement; double depression; bipolar disorder (onset preceded by depression in 70% of
patients); bereavement—triggered by loss of loved one; usually limited to 2 mo of severe symptoms; can occur simultaneously
with major depression if other factors present, eg, children <15 yr of age who lose parents at high risk of developing
depression after bereavement later in life; patients exhibit some degree of functional impairment and can experience hallucinations
of deceased person (usually self-limiting and connected to specific loss); double depression—environmental trigger
leads to dysthymia that persists throughout childhood and adolescence, eventually resulting in major depression;
treatment must include pharmacotherapy and psychotherapy; psychotherapy enables patients to become aware of maladaptive
coping styles and pessimistic life view, and address underlying psychodynamic issues; pharmacotherapy alone results in
partial response; clinical picture by developmental age—depression manifests differently in children, adolescents, and
adults; anhedonia major symptom in adults; children exhibit separation anxiety, somatic symptoms, behavioral problems
(often mistaken for attention deficit hyperactivity disorder [ADHD]; take good history), and boredom (equivalent to anhedonia
in adults); delusions and auditory hallucinations rare in children; adolescents similar to adults, but exhibit fewer melancholic
symptoms and more irritability and behavioral problems; depressed female adolescents exhibit seasonal affective
patterns and premenstrual dysphoria
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| Comorbidity of depressive disorders: major depression has comorbidity rate of 40% to 60%; usually dysthymia, anxiety
disorders, disruptive disorders, substance abuse (adolescents particularly vulnerable to alcohol and drug abuse), and
personality disorders (associated with partial treatment response)
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| Recurrence: rates—response to treatment occurs in 20 wk in most patients; untreated depressive episode lasts average of 9
mo; treat depression in adolescents and children early and aggressively to prevent chronic course of illness; recurrence rate after
3 episodes of major depression 90%; 10% of patients with depression have intractable condition; risk factors— multiple
previous episodes; incomplete recovery between consecutive episodes (period of increased risk for suicide); severe or long
lasting episodes; episodes with bipolar or psychotic features
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| General risk factors for depression: low socioeconomic status; adverse life events (eg, early parental death); genetic
susceptibility; lack of support systems; negative family environment; negative cognitive style
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| Social cost and sequelae: unipolar major depression leading cause of years lived with disability worldwide (depression underdiagnosed
because of social stigma); sequelae in children and adolescents—poor academic functioning; interpersonal difficulties;
increased risk for suicide; increased risk for substance abuse; behavioral problems; undiagnosed subclinical
depression
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| Etiology of depression: behavioral models—depression may develop if individual interprets neutral life events as negative;
classical triad involves negative self-view, negative interpretation of experience, and negative interpretation of future;
people with depression often exhibit learned helplessness and feel they have no control over life events; genetics—
monozygotic twins show concordance for depression of 80%; major depressive disorder (MDD) has polygenic inheritance;
evidence for locus on X chromosome and on chromosome 18; cohort effect—most psychiatric conditions increased
in prevalence after World War 2; likely reasons include more attention to mental health disorders and increased
life stress that makes people more vulnerable to depression
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| Antidepressants: reserpine and antihypertensive drugs that deplete biogenic amines can cause depression; led to hypothesis
that deficiency of norepinephrine and serotonin (5HT; degraded by monoamine oxidase [MAO]) involved in development
of depression; monoamine oxidase inhibitors (MAOIs) increase norepinephrine, serotonin, and dopamine in
synaptic cleft; decreased dopamine levels found in individuals with major depression; antidepressants raise MAO levels
in all depressed patients, but only 60% of patients have immediate relief; children and adolescents—in 1970s, only tricyclic
antidepressants (TCAs) available; TCAs specific for norepinephrine, and effective in adults but not in children; serotonin
pathways in brain mature earlier than norepinephrine pathways, which do not mature until late adolescence;
therefore, need to increase serotonin levels in children and adolescents to treat depression; first serotonin reuptake inhibitor
(SSRI), fluoxetine (Prozac), introduced in late 1980s
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| Neuroendocrine changes in depression: connection between neuroendocrine system and immune system; neuroendocrine
system affected in people with depression; depression affects hypothalamic-pituitary-adrenal axis; depression releases stress
hormones, eg, cortisol, that may result in hyperfunctioning of hypothalamus and amygdala; amygdala part of brain that alerts
humans to impending danger, and hyperfunctioning can result in hallucinations; stress and depression accelerate aging process;
depression can affect cardiac functioning (depression increases risk for heart attack); depression impairs functioning of
immune system, eg, increases risk for cancer; depression associated with neuronal cell death in frontal cortex (responsible for
executive function); patients with chronic depression often become “hollow and blunted”; treat depression early to prevent
neuronal cell death; depressed patients also show decrease in volume of hippocampus, leading to depressed emotional response
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| Treatment: acute phase—first 6 to 12 wk; initiate medical therapy as early as possible; introduce psychotherapy to address
behavioral issues; identify comorbid disorders (eg, personality disorders, child abuse, substance abuse); second
(continuation) phase—6 to 12 mo after presentation; intervene at family level by performing family assessment; recommend
psycho-education for patient and family; continue psychotherapy for 1 yr; maintenance phase—>1 yr from presentation;
prevent relapse; improve social support; prevent psychologic scars
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| EDUCATIONAL AND BEHAVIORAL SEQUELAE TO CANCER TREATMENT —F. Daniel Armstrong, PhD, Professor
and Associate Chair, Department of Pediatrics; Director, Mailman Center for Child Development, University of Miami
Miller School of Medicine, Miami, FL
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| Mechanisms of central nervous system (CNS) injury: genetics—cognitive effect tied to developmental disability unrelated
to cancer; genetic modifiers influence symptomatology of behavior in child; structural damage—tumor invades
normal brain tissue; brain tumor compresses nerve, causing permanent damage; vascular injury—treatment damages
blood vessels, large vessel injury from stroke or hemorrhage secondary to surgery; microvascular injury from radiotherapy
and chemotherapy; neurotransmitter abnormalities—function of neurotransmitters altered from exposure to treatment;
metabolic abnormalities—treatment alters function of microvessels that affect blood supply, oxygenation,
nutritional supply, and metabolic activity; neuroendocrine abnormalities—affect emotional regulation and appetite,
with subsequent disruption of growth and development; myelin formation—disruption in myelin production can occur
at time of treatment; neural connections—treatment interferes with pruning and growth of additional neural connections
as child ages; environmental and learning factors—affect children with prolonged hospitalization
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| Factors related to late effects: tumor size and location—CNS or brain tumor; consequences of surgery—issues related
to excision of tumor; radiotherapy—significant effects from irradiating head to treat brain tumors;
chemotherapy—significant cognitive effects from intrathecal and systemic chemotherapy; age at time of treatment—
younger age associated with more significant risk; gender—major factor in treatment of children with acute leukemia;
females at significantly greater risk; shunts and seizures—children who require shunts or who develop seizure disorders
related to treatment more likely to develop cognitive difficulties later in life; infections of CNS—associated with
long-term and profound developmental disabilities; other considerations—genetic predisposition for ADHD or dyslexia;
birth-related injuries; injuries unrelated to cancer
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| Effect on brain development: tumor may invade tissue or press on critical areas as it grows (eg, optic nerve, ventricles)
and result in hydrocephalus or permanent nerve damage; children can have significant deficits in vision, speech, gross
motor coordination, and movement; bleeding or stroke can also occur; study data—children with low-grade pediatric
cerebellar astrocytomas (tumors easy to reach, have clearly defined margins, and easily removed); 4 yr after treatment,
scores on intelligence quotient (IQ), reading, arithmetic, spelling, motor performance, adaptive functioning, and internalizing
behavior problems fell within range of concern for general population; culprits—exposure to radiotherapy or chemotherapy
agents can damage small blood vessels in brain resulting in calcification and altered brain metabolism and
chemistry; interference with normal brain growth and development through disruption of growth of myelin sheath
(smaller amount of myelin available in brain of child treated for childhood cancer) and interruption of pruning of connecting
structures and development of more efficient structures; combination treatment with platin-based chemotherapy
and radiotherapy can produce high-frequency hearing loss; peripheral neuropathy associated with vincristine (slows fine
motor coordination and speed, which affects writing and school performance); study data—children with medulloblastoma
<6 yr of age treated with standard radiotherapy had IQ scores and full-scale verbal and performance scores in mid-
70s; with reduced dose radiotherapy, scores increased to low-80s; reduced dose radiotherapy in older children produced
performance closer to average range; similar affects seen in academic performance, with performance in mathematics
more significantly affected by radiotherapy than reading
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| Diseases with greatest risk for CNS injury: malignant brain tumors; acute lymphoblastic leukemia (ALL) treated with
intrathecal chemotherapy with or without radiotherapy and high-dose methotrexate during consolidation; ALL treated with
bone marrow transplant and total body irradiation; face or head tumors in which treatment involved brain irradiation; some
neuroblastomas; young children with prolonged hospitalization
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| Developmental acquisition of abilities: birth to 2.5 yr of age—development of language and motor skills; 2.5 to 6 yr
of age—development of higher-order skills, eg, fine motor coordination; 6 to 25 yr of age—complex reasoning; more
advanced visuospatial abilities; planning and organization skills develop at 10 to 12 yr of age; processing speed improves;
information and social information processing; developmental patterns—rapid acquisition of language skills
and gross motor skills during first 2 to 3 yr, then rate of acquisition of new skills slows down; development of fine motor
skills begins at 2.5 yr, with rapid development and leveling off over time; emerging cognitive deficits—treatment disrupts
development of brain and abilities; treatment has greatest effect on part of brain that develops after treatment; parts
of brain that developed before treatment relatively safe
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| Strategies for intervention: context of intervention—school re-entry programs; educating teachers, parents, peers, and
child; approaches—rehabilitative, medical, and compensatory; methylphenidate—60% to 70% of children respond
positively to methylphenidate; study—cognitive rehabilitation using mass practice with various computer tasks to promote
exercising of brain pathways in children who have difficulties; 50 1.5-hr sessions of mass practice intervention associated
with similar outcome to methylphenidate 10 mg
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| Compensatory interventions: development of individual education plans (IEP) or 504 plans; accommodations applied to
college settings; anticipate emergence of new problems over time; accommodations include extended time to complete
assignments, reducing homework demands, and shift from read/write to listen/speak learning plans; listen/speak plans
use books on tape, text to speech and speech to text computer programs, voice recognition software, text capture/scanning,
calculators, oral testing, and support devices; teaching simple organizational strategies; study data—10 children
with medulloblastoma and <6 yr of age at time of diagnosis treated with surgery, radiotherapy, and chemotherapy; majority
had IQ <70; school-based interventions provided; 2 children treated with methylphenidate; all children graduated
from high school; 5 of 10 were Florida American Cancer Society (ACS) American College Scholarship recipients with
B- average GPA; currently, 4 in college and 1 in graduate school; ACS clinical trial—compensatory intervention in
school system for all children; one group of children randomized to have IEP monitored once yearly, other group monitored
quarterly; children undergoing quarterly monitoring show improvements in processing speed and mathematics
skills
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| Plans for prevention: age-appropriate interventions to promote development of myelination, connecting structures, and
vasculature beginning at time of diagnosis
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Educational Objectives
| The goal of this program is to educate the listener about depressive disorders in children and adolescents and the educational
and behavioral sequelae to cancer treatment. After hearing and assimilating this program, the clinician will be better
able to:
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 | 1. Discuss the differential diagnosis of depressive disorders in children and adolescents.
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| 2. List predictors of relapse in patients diagnosed with a depressive disorder.
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| 3. Manage a depressive disorder in a child or adolescent.
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| 4. Identify a child at risk for cognitive deficit after treatment for cancer.
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| 5. Describe compensatory intervention strategies designed to promote cognitive functioning in children treated for cancer.
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Discussed on This Program
Cisplatin (CDDP) [Platinol-AQ]
Fluoxetine HCl [Prozac, Prozac Pulvules, Prozac Weekly, Sarafem, Sarafem Pulvules]
Methotrexate (amethopterin; MTX) [Methotrexate LPF, Rheumatrex Dose Pack, Trexall]
Methylphenidate HCl [Concerta, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin LA, Ritalin–
SR]
Reserpine [Rau-Sed, Sandril, Serpasil, Serpiloid]
Vincristine sulfate (VCR; LCR) [Oncovin, Vincasar PFS]
Suggested Reading
Andrews G et al: Lifetime risk of depression: restricted to a minority or waiting for most? Br J Psychiatry 187:495, 2005;
Armstrong FD: Acute and long-term neurodevelopmental outcomes in children following bone marrow transplantation.
Front Biosci 6:G6, 2001; Armstrong FD et al: Children's Oncology Group. Psychological research in childhood cancer:
the Children's Oncology Group perspective. J Pediatr Psychol 30:89, 2005; Beebe DW et al: Cognitive and adaptive outcome
in low-grade pediatric cerebellar astrocytomas: evidence of diminished cognitive and adaptive functioning in National
Collaborative Research Studies (CCG 9891/POG 9130). J Clin Oncol 23:5198, 2005; Gilman SE et al: Socio-
economic status, family disruption and residential stability in childhood: relation to onset, recurrence and remission of major
depression. Psychol Med 33:1341, 2003; Kratochvil CJ et al: Selecting an antidepressant for the treatment of pediatric
depression. J Am Acad Child Adolesc Psychiatry 45:371, 2006; Landier W et al: Development of risk-based
guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's
Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 22:4979, 2004; Maunsell E et al:
Quality of life among long-term adolescent and adult survivors of childhood cancer. J Clin Oncol 24:2527, 2006; Mulhern
RK et al: Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional
or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol 16:1723, 1998;
O'Sullivan C: The psychosocial determinants of depression: a lifespan perspective. J Nerv Ment Dis 192:585, 2004;
Paradis AD et al: Major depression in the transition to adulthood: the impact of active and past depression on young adult
functioning. J Nerv Ment Dis 194:318, 2006; Skinner R et al: UK Children's Cancer Study Group Late Effects Group.
Long-term follow-up of people who have survived cancer during childhood. Lancet Oncol 7:489, 2006; Weissman MM:
Recent advances in depression across the generations. Epidemiol Psichiatr Soc 15:16, 2006.
Faculty Disclosure
In adherence with ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the following
has been disclosed: Dr. Armstrong receives research funding from Novartis Pharmaceuticals.
Drs. Armstrong and Rothe were recorded at Masters of Pediatrics: Contemporary and Future Pediatrics presented
January 25-30, 2006, in Bal Harbour, FL, and sponsored by the University of Miami Miller School of Medicine. The
Audio-Digest Foundation thanks the speakers and the sponsor for their cooperaion in the production of this program.
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