The document summarizes safety considerations for commonly used psychotropic medications in children and teens. It reviews the adverse effect profiles and risks of second-generation antipsychotics, antidepressants, stimulants, and mood stabilizers. It also discusses monitoring standards for potential adverse events during pharmacologic treatment of youth. Specific topics covered include the metabolic effects and monitoring of antipsychotics, risks of tardive dyskinesia, suicidal ideation risks of antidepressants varying by condition, side effects of stimulants including cardiovascular risks and effects on growth, and side effects of mood stabilizers.

1. Safety Considerations in the
use of Psychotropic
Medication in Children and
Teens
Stephen Grcevich, MD
President, Family Center by the Falls, Chagrin Falls OH
Clinical Associate Professor of Psychiatry, NEOMED
Transitional Medical Director
Child and Adolescent Behavioral Health
September 5, 2018

2. Learning objectives:
• Review the comparative safety and adverse effect
profiles of the following classes of medication
indicated for use in commonly seen mental health
conditions in children and teens…
• Antipsychotics
• Antidepressants
• Stimulants
• Mood stabilizers
• Discuss current standards for monitoring for
potential adverse events during pharmacologic
treatment of children and teens.

3. True or false…
• Aripiprazole is not associated with significantweight gainwhen used
asmonotherapy in youth with bipolar disorder (and other
conditions) who are naïve to pharmacotherapy.

4. The answer is…FALSE

5. Metabolic effects of second-generation
antipsychotics in pediatric patients:
Agent: Metabolic Effects:
Olanzapine fasting glucose
triglycerides
insulin
insulin resistance
Quetiapine total cholesterol
triglycerides
HDL cholesterol
triglyceride:HDL ratio
Risperidone triglycerides
Aripiprazole No significant metabolic effects
Correll,CU etal., JAMA.2009;302:1765–1773.

6. Metabolic Monitoring with
SGAs

7. Tardive Dyskinesia
• Annualized incidence rate – 4% per year
• Higher rates in females, African-Americans,
patients with intellectual disabilities
• AIMS test recommended by APA at baseline
prior to initiating antipsychotics, q6 months with
FGAs, q12 months with SGAs.

8. TADS: Suicidal ideation in acute
treatment

9. Do risks and benefits vary by the condition
being treated?
(Number Needed to Harm)
0
50
100
150
200
250
Depression Anxiety OCD
Risks and benefits of antidepressant therapy
Harm=New onset suicidal thinking, behavior
NNH

10. Risk/Benefit Ratio of SSRIs by
condition treated
0
5
10
15
20
25
30
35
40
Depression Anxiety OCD
Risks and benefits of antidepressant therapy
Harm=New onset suicidal thinking, behavior
NNT Risk/Benefit

11. Predictors of Suicidal Events
Grcevich SJ et al. Presented at American Academy of Child and Adolescent Psychiatry, October 2009

12. SSRI side effects:
• Nausea
• Weight gain
• Behavioral activation/disinhibition
• Restlessness
• Vivid dreams
• Increased clotting time
• Fatigue
• Sexual side effects

13. SSRI Withdrawal

14. Mood Stabilizer Side Effects
• Lithium: toxicity, potential lethality in overdose, gastroenteritis
(compounded by NSAIDs), renal, thyroid toxicity, acne, weight gain,
tremor, polyuria
• Divalproex: PCOS, weight gain, hair loss, tremor
• Lamotrigine: rare cases of Stevens-Johnson (need slow titration)
David Axelson, MD, AACAPBoard ReviewCourse, 2012

15. Side effect, safety issues
with stimulants:
• Cardiovascular safety: sudden death, heart
rate, BP
• Effects upon growth
• Relationship to substance abuse risk
• Other long-term consequences?
• Management of effects upon appetite, sleep

16. Sudden Death Overview in
Children and Adolescents on
Stimulants:
• Rate in children, adolescents:
AMP: 0.36/1,000,000 RX
MPH: 0.16/1,000,000 RX (difference is non-
significant)
• Background rate in pediatric population: 1.3-
8.5/100,000 patient years (more common in
males than females)
• FDA Pediatric Advisory Committee
recommended against boxed warnings for
stimulants
Liberthson RR. New England Journal of Medicine 1996:(334) 1039-1044
Meeting of the FDA Pediatric Advisory Committee, Washington DC, March 22, 2006

17. Sudden death overview in
adults on stimulants:
• Rate in adults:
AMP: 0.53/1,000,000 RX
MPH: 0.07/1,000,000 RX (difference is non-significant)
• Background rate in adult population:
1-2/1000 patient years
• 3 of 5 deaths in adult patients occurred in individuals
over 40 with preexisting HTN (coronary artery disease
and dysrhythmia was a pre-existing condition in one
case)
• More data needed to evaluate risk in patients over 40
with HTN, preexisting cardiovascular disease, obesity
Janse MJ. Pharmacol and Therapeutics 2003(100) 89-99
Cardiovascular Safety Review, Office of Drug Safety , February 9, 2006 (www.fda.gov)

18. Screening for Cardiac Risk:
American Heart Association Guidelines
• Medical history
• History of congenital or acquired cardiac disease
• Family history of or premature cardiac disease (<30 years of
age)
• Palpitations, chest pain, syncope, seizures, post-exercise
symptoms
• Ask about other medications (including OTC)
• Routine medical exam
• Monitor blood pressure & pulse at baseline and follow-up
• No need for baseline ECG, Holter, ECHO in children
• Adults: Work-up as medically indicated
• Suspicion of CV defect (e.g., idiopathic hypertrophic sub-aortic
stenosis): work-up as indicated
Gutgesell H et al. Circulation. 1999:99:979-982.

19. Hypertension and ADHD
medication in adults
• Cardiovascular data from five controlled
studies (MPH, MAS-XR, pemoline, buproprion,
desipramine)
• Stimulants and non-stimulants associated with
increases in heart rate, blood pressure
• Also common on placebo
• New-onset systolic or diastolic hypertension
(BP>140/90)
• 10% of patients on active drug
• 8% on placebo
• Baseline HR and BP measurement, along with
periodic monitoring is recommended in adults
Wilens TE, Hammerness PG, Biederman J et al. J Clin Psychiatry 2005:66(2) 253-259

20. Cardiovascular effects of
stimulants in kids
• Amphetamine, atomoxetine associated with,
small, statistically significant changes in heart
rate, systolic, diastolic BP
• Methylphenidate associated with significant
increase in systolic BP
• No difference in severity of effects between
treatments
• Long term significance unclear
Hennissen, L., Bakker, M.J., Banaschewski, T. et al. CNS Drugs (2017) 31: 199.
doi:10.1007/s40263-017-0410-7

21. Effects on Stature: MTA
• Statistically, but not clinically significant differences
in height, weight
• Effects appear primarily in first 12-18 months
• Kids with ADHD experience growth spurts later
than peers
• Group averages at 14 months (end of MTA study):
• Gain in height:
• Medical management only: 4.75 cm
• Behavioral therapy only: 6.19 cm
• Variance: –1.44 cm/14 months (= –1.23 cm/year)
• Gain in weight:
• Medical management only: 1.64 kg
• Behavioral therapy only: 4.53 kg
• Variance: –2.89 kg/14 months (= –2.48 kg/year)
MTA Cooperative Group. Pediatrics. 2004;113:762-769.

22. ADHD and Substance Abuse
• ADHD is a significant risk factor for substance
abuse disorders in teens, adults
• Medication during adolescence may reduce
risk, but protective effects disappear by age 25
• Smoking
• Adults with ADHD smoke more, experience more
difficulty quitting
• Children with ADHD start younger, smoke more
Biederman et al. Pediatrics. 1999;104:e20.
Pomerleau et al. J Subst Abuse. 1995;7:373-378.
Milberger et al. J Am Acad Child Adolesc Psychiatry. 1997;36:37-44.

23. Trends in stimulant misuse,
abuse
• Rate of stimulant misuse, diversion calculated
at 2.0%
• Statistically significant reduction in misuse,
diversion of stimulants (p<0.01) between 2002
and 2004
• Reduction in abuse rates corresponds to time
period during which use of extended release
products was rapidly expanding
• Misuse rates at college proportional to mean
SAT scores of incoming freshman class
2004 National Survey on Drug Use and Health, DHHS Publication #SMA 05-4062
McCabe SE et al. Addiction, 99, 96–106

24. Stimulants and rebound
effects:
• Rate: 8.6% vs 1.9% on placebo (Adderall XR)
• Possible causes
• Fatigue factor
• Hypoglycemia
• Comorbid anxiety
• Patients with anxiety/OCD often experience
more irritability on stimulants-decreased
distractibility may intensify anxiety awareness
Biederman J et al. Pediatrics (2002) 110:258-266
Swanson JM et al. J Am Acad Child Adolesc Psychiatry (1998) 37:519-526
Grcevich S. Future Neurology. 2006; 1(5) 525-534

25. Do stimulants cause long term
changes in brain function?
Wang G-J, Volkow ND, Wigal T, Kollins SH, Newcorn JH, et al. (2013) PLoS ONE 8(5): e63023. doi:10.1371/journal.pone.0063023
• Study examined long-term changes in DA
transporter in never-treated adults with ADHD
after 12 months on Concerta vs. controls
• 24% increase in DA transporter in caudate and
putamen after 12 months (significant)
• Does long term use of ADHD medication make
ADHD symptoms worse when medication is
stopped?
• More studies needed of other medications,
impact upon functional impairment

26. Do stimulants cause long term
changes in brain function?
Wang G-J, Volkow ND, Wigal T, Kollins SH, Newcorn JH, et al. (2013) PLoS ONE 8(5): e63023. doi:10.1371/journal.pone.0063023

27. Drug Holidays
• Recommended by many pediatricians,
especially during summer months
• Driven by concerns that kids aren’t eating
enough, achieving expected growth
• Often driven by difficulty tolerating stimulant-
related side effects
• Does ADHD significantly impact functioning in
one or more major life domains (school/work,
family, friends, community) during weekends,
vacation?

28. Managing stimulant-related
side effects:
• Appetite/weight:
• Eat Breakfast
• Encourage small snacks throughout day
• Bedtime snacks replace missing lunchtime calories
• Sleep:
• Limit access to electronics before bed
• Melatonin (3-6 mg, two hours before bedtime)
• Consider adjusting duration of medication coverage
• Adjunctive clonidine
• Irritability:
• Evaluate for comorbid conditions
• Consider “dose-sculpting” in late afternoon
• Consider alternative medication
• Most stimulant related side effects resolve within
three months of treatment initiation
McGough JJ et al. J Am Acad Child Adolesc Psychiatry (2005) 44:530-538

29. Components of a
Clinical Case
Presentation
Stephen Grcevich, MD
Child and Adolescent Behavioral Health
September 26, 2018

30. The purpose