PSYCHOPHARMACOLOGIC APPROACHES TO DEPRESSION IN CHILDREN AND ADOLESCENTS
Learning Objectives
• Describe the evidence for selective serotonin reuptake inhibitors (SSRIs) in youth with depressive disorders
• List predictors of treatment response in adolescents with SSRI-resistant major depressive disorder
• List specific patient characteristics that may guide treatment selection in adolescents with major depressive disorder
Off-Label Medication Use
Dr. Strawn does intend to discuss the use of off-label/unapproved use of drugs.
AdolescencePreschool School-AgeAge 7Age 4 Puberty
Irritability3
Moodiness3
Loss of interest3
Depressed mood, lack of concentration, insomnia, suicidal ideation
Somatic complaints
Increase in suicide attempts and suicide completion
Hypersomnia (increases with age)2
Ryan et al. The Clinical Picture of Major Depression in Children & Adolescents. Arch Gen Psychiatry 1987;44:854-61; Luby et al. Modification of DSM-IV Criteria for Depression in Depressed Preschool Children. Am J Psychiatry 2003;160:1169-72; Lewinsohn et al. Major depression in community adolescents: age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry 1994;33:809-18.
Weight loss (increases with age)1
Clinical Aspects of Depression Vary
Delusions
EDSP: Incidence and Onset of Depression
Beesdo et al. Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Arch Gen Psychiatry 2010;67:47-57.
Treatment of Depression in Youth• Multimodal treatment—psychotherapy and pharmacotherapy
• Psychotherapies • cognitive behavioral, • supportive, • group, • family therapy, • social skills training, and • psychodynamic
Strawn and Walkup. The quest to identify the best treatment for pediatric depression. Lancet Psychiatry 2020 (in press);Birmahar et al. Practice Parameter for the Assessment and Treatment of Children and Adolescents with Depressive Disorders. J Am Acad. Child Adolesc Psychiatry 2007;46:1503-26.
• Pharmacotherapies• SSRIs are 1st line
psychopharmacologic treatment for children with depression
• SNRIs are also being used by many clinicians, but data are limited
• No positive trials for MAOIs• No positive trials for TCAs
Treatment of Adolescent Depression Study
Treatment Week
Adj
uste
d M
ean
Chi
ldre
n’s
Dep
ress
ion
Rat
ing
Scal
e Sc
ore
45
60
306 120
PlaceboCBT AloneFluoxetine alone
Fluoxetine + CBT
March et al. JAMA 2004;292:807-20; Emslie et al. J Am Acad Child Adolesc Psychiatry 2006;45:1440–55.
• Fluoxetine + CBT > placebo, p=.001 • Fluoxetine + CBT > fluoxetine, p=.02 • Fluoxetine > CBT alone, p=.01 • Response rates:
• fluoxetine + CBT, 71%; • fluoxetine alone, 61%; • CBT alone, 43%; • placebo, 35%
Symptomatic Improvement in MDD
Tao et al. J Child and Adolesc Psychopharmacology 2010.
Fluoxetine Treatment Week
Mea
n S
cale
Sco
re
1
2
0 6 8 10 120 1 2
Morbid ThoughtsAnhedoniaObserved Depression
Reported Depression
3 4
3
4
Time Course of Response and Side Effects
Duration of antidepressant treatment
Weight gain (if applicable)
Monoamine levels
activation
Symptoms
Receptor sensitivity
SSRI Response: How long to wait?
Varigonda et al. JAACAP 2015;54(7):557-64; Strawn et al. JAACAP 2018;57(4):235-44.
Impr
ovem
ent i
n D
epre
ssiv
e Sy
mpt
oms
0 2 4 6 8 10
0
-0.1
-0.2
-0.3
-0.4
-0.5
Week
Titration Strategies Based on RCTs
Initial 5 mg 25 mg 5 mg
Week 1 10 mg 50 mg 20 mg
Week 2 10 mg 50 mg 20 mg
Week 3 10 mg 100 mg 20 mg
Week 4 10 mg 100 mg 20 mg
Optional increases
Week 5 15 mg 100 mg 40 mg
Week 6 15 mg 150 mg 40 mg
Week 7 20 mg 150 mg 40 mg
Week 8 20 mg 150 mg 40 mg
Week 9 20 mg 150 mg 40 mg
Week 10 20 mg 150 mg 40 mg
fluoxetineescitalopram sertraline
Age 7–11
Titration Strategies Based on RCTs
Initial 5 mg 25 mg 10 mg
Week 1 5 mg 50 mg 10 mg
Week 2 10 mg 50 mg 20 mg
Week 3 10 mg 50 mg 20 mg
Week 4 15 mg 75 mg 20 mg
Optional increases
Week 5 15 mg 100 mg 20 mg
Week 6 20 mg 100 mg 20 mg
Week 7 20 mg 150 mg 40 mg
Week 8 20 mg 150 mg 40 mg
Week 9 20 mg 200 mg 60 mg
Week 10 20 mg 200 mg 60 mg
fluoxetineescitalopram sertraline
Age 12–17
Rationale for Focus on Adolescents WithTreatment-Resistant Depression (TRD)
• Remission rate around 30%• TRD associated with increased
morbidity and development of chronic depression
• Identify the next, best steps for SSRI-resistant depression in adolescents
Brent et al. Treatment of Resistant Depression In Adolescents. JAMA 2008;299(8):901-13.Strawn and Walkup. The quest to identify the best treatment for pediatric depression. Lancet Psychiatry 2020 (in press).Strawn et al. Treatment Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance. J Child Adolesc.Psychopharm 2020 (in press).
Defining “Adequate” SSRI Treatment
• > 8 weeks
• Last 4+ weeks at equivalent of 40 mg of fluoxetine
• May use 20 mg equivalent if unable to tolerate higher dose
Fluoxetine20 mg
Fluoxetine40 mg
Brent D et al. JAMA 2008;299(8):901-13.
Fluoxetine40 mg
SSRI Non-responders(>2 mos of tx)
Week0
Week12
Wk-3
Brent D et al. JAMA 2008;299(8):901-13.
N=334Age: 12–18 years Dx: MDD + no response to 2-month initial SSRI
Primary Outcome: CGI-I <2 + >50% decrease in CDRS-R and dCDRS-R.
SNRI + CBTVenlafaxine XR
SNRIVenlafaxine XR
SSRI + CBTCitalopram + CBTParoxetine + CBTFluoxetine + CBT
SSRICitalopramParoxetineFluoxetine
TORDIA Design
What did they find?
Treatment Week
40
60
20 6 120
SSRIVenlafaxine
30
50
CD
RS
Scor
e
Treatment Week
2
4
6 120
1
3
Antidepressant withoutCBTAntidepressant + CBT
Clin
ical
Glo
bal I
mpr
essi
on
Scal
e—Se
verit
y
5
Brent D et al. JAMA 2008;299(8):901-13.
TORDIA: Primary Findings
TORDIA: Primary Findings
Impr
ovem
ent i
n D
epre
ssiv
e Sy
mpt
oms
Mills, Croarkin Strawn. Under review 2020.
TORDIA: Primary Findings
Impr
ovem
ent i
n D
epre
ssiv
e Sy
mpt
oms
Mills, Croarkin Strawn. Under review 2020.
p=0.01
Anhedonia and Treatment Response
• Only symptom that predicts lack of remission when controlling for others
• Strongest predictor of fewer depression free days
• Treatment did not target positive affect (only 1.5 sessions of behavioral activation)
• May need to more specifically target behavioral activation
anhedonia
Drug and Alcohol Use in TORDIA
Goldstein BI et al. J Am Acad Child Adolesc Psychiatry 2009;48(12):1182-92.
No response
Response
Subs
tanc
e U
se S
ever
ity
Time (weeks)
Plasma Concentration and Response
Sakolsky DJ et al. J Clin Psychopharmacol 2011;31(1):92-7.
01020304050607080
VEN FLX/CIT FLX CIT PAR
≥ GM<GM
P=.04
P=.07P=.005
Adolescent SSRI Exposure
Ramsey et al. Gene-Based Dose Optimization in Children. Annu Rev Pharmacol Toxicol 2020;60:4.1–4.21.
16-year-old female
14-year-old female
Cytochrome P450 Enzymes and Pharmacokinetics in Adolescents
Ramsey et al. Annu Rev Pharmacol Toxicol 2020;60:4.1–4.21.
Pediatric Escitalopram and CYP2C19
Strawn, Poweleit, Ramsey. CYP2C19-guided escitalopram and sertraline dosing in pediatric patients: a pharmacokinetic modeling study. J Child Adol Psychop 2019;29(5):340-7.
Intermediate metabolizerPoor metabolizer
Normal metabolizerRapid metabolizerUltrarapid metabolizer
Phenotype Equivalent dose
Poor metabolizer
10 mg
Intermediatemetabolizer
15 mg
Normalmetabolizer
20 mg
Rapid metabolizer
25 mg
Ultrarapidmetabolizer
30 mg
Pediatric Sertraline and CYP2C19
Strawn JR et al. J Child Adol Psychop 2019;29(5):340-7.
Intermediate metabolizerPoor metabolizer
Normal metabolizerRapid metabolizerUltrarapid metabolizer
Phenotype Equivalent dose
Poor metabolizer
50 mg
Intermediatemetabolizer
125 mg
Normalmetabolizer
150 mg
Rapid metabolizer
175 mg
Ultrarapidmetabolizer
225 mg
TORDIA: Self-Harm in High Ideators
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
SSRI VLX
LowHigh
p=0.75
p=0.02
Adapted from G. Emslie. Annual Meeting of the American Academy of Child & Adolescent Psychiatry 2012.
TORDIA: Treatment and Suicidal Events
Brent DA et al. Am J Psychiatry 2009;166:418–26.
TORDIA: Early Response
20253035404550556065
0 6 12 24
CD
RS-
R
Week
Non-Remitters
Emslie GJ et al. Am J Psychiatry. 2010;167(7):782-91.
TORDIA: Early Response
20253035404550556065
0 6 12 24
CD
RS-
R
Week
Non-RemittersRemitters
Emslie GJ et al. Am J Psychiatry 2010;167(7):782-91.
TORDIA: Insomnia• Trazodone-treated patients, 6x < likely
to respond than patients who did not receive any soporific (p=0.001)
• Trazodone-treated patients 3x more likely to self-harm (OR=3, p=0.03)
• No patient receiving trazodone + paroxetine or fluoxetine responded (0/13)
• Patients treated with other soporifics responded similarly to those who received no sleep medication (60% vs. 50%)
Shamseddeen W et al. J Child Adolesc Psychopharmacol 2012;22(1):29-36.
Trazodone mCPP
TORDIA: Insomnia• Trazodone-treated patients, 6x < likely
to respond than patients who did not receive any soporific (p=0.001)
• Trazodone-treated patients 3x more likely to self-harm (OR=3, p=0.03)
• No patient receiving trazodone + paroxetine or fluoxetine responded (0/13)
• Patients treated with other soporifics responded similarly to those who received no sleep medication (60% vs. 50%).
ParoxetineFluoxetine
2D6
Trazodone mCPP
mCPP
Shamseddeen W et al. J Child Adolesc Psychopharmacol 2012;22(1):29-36.
TORDIA Take Homes
• Medication + Therapy > Medication (NNT=7)• Venlafaxine
• more side effects• less efficacy than another SSRI as 2nd line
• Medication dose/exposure is IMPORTANT• COMBO >> MED with comorbidity• Poorer response:
• substance use, • family conflict, • sleep difficulties
When to Adjust Treatment in Adolescent MDD
Gunlicks-stoessel M et al. J Am Acad Child Adolesc Psychiatry 2019;58(1):80-91.
IPT-AEarly decision
>20% reduction
<20% reduction
IPT-AEarly decision
>20% reduction Continue IPT-A
IPT-A Frequency
<20% reduction
Fluoxetine
When to Adjust Treatment in Adolescent MDD
Gunlicks-stoessel M et al. J Am Acad Child Adolesc Psychiatry. 2019;58(1):80-91.
IPT-AEarly decision
>20% reduction Continue IPT-A
IPT-A Frequency
<20% reduction
Fluoxetine
When to Adjust Treatment in Adolescent MDD
IPT-ALate decision
>40% reduction
<40% reduction
Gunlicks-stoessel M et al. J Am Acad Child Adolesc Psychiatry. 2019;58(1):80-91.
IPT-AEarly decision
>20% reduction Continue IPT-A
IPT-A Frequency
<20% reduction
Fluoxetine
When to Adjust Treatment in Adolescent MDD
IPT-ALate decision
>40% reduction
Continue IPT-A
IPT-A Frequency
<40% reduction
Fluoxetine
Gunlicks-stoessel M et al. J Am Acad Child Adolesc Psychiatry. 2019;58(1):80-91.
TMS in Adolescents With Treatment-Resistant Depression
Croarkin et al. In preparation.
• Multi-site, N=103• Age 12-21, ATR >1• No concurrent medication
Left dorsolateral prefrontal cortex stimulation, 5 days/week
• It has been the first medication trial
• It has been poorly tolerated• There is <25% improvement • There is more time to wait (i.e.,
less functional impairment)• There may be drug interaction• There may be adherence
concerns
• The initial antidepressant was well tolerated
• There is a partial response to the initial agent (>25% improvement)
• There is less time to wait for a response (e.g., more functional impairment)
Switching vs. Augmentation
Switching Medications
• Direct switch: stop first antidepressant and start new antidepressant
Keks N et al. Aust Prescr 2016;39(3):76-83; Stahl. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 4th Edition.
Switching Medications
• Direct switch: stop first antidepressant and start new antidepressant
• Taper and switch immediately:gradually taper the first antidepressant and start the new antidepressant immediately after discontinuation
Keks N et al. Aust Prescr 2016;39(3):76-83; Stahl. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 4th Edition.
Switching Medications
• Direct switch: stop first antidepressant and start new antidepressant
• Taper and switch immediately:gradually taper the first antidepressant and start the new antidepressant immediately after discontinuation
• Taper and switch after a washout: gradually withdraw the first antidepressant then start the new antidepressant after a wash out period
Keks N et al. Aust Prescr 2016;39(3):76-83; Stahl. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 4th Edition.
Switching Medications
Keks N et al. Aust Prescr 2016;39(3):76-83; Stahl. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 4th Edition.
• Direct switch: stop first antidepressant and start new antidepressant
• Taper and switch immediately:gradually taper the first antidepressant and start the new antidepressant immediately after discontinuation
• Taper and switch after a washout: gradually withdraw the first antidepressant then start the new antidepressant after a wash out period
• Cross-tapering: taper or maintain the first antidepressant while beginning the new antidepressant
Conclusions• Treatment should be multimodal• Consider augmentation EARLY• Changing antidepressants and/or adding other treatment
strategies leads to treatment response in 50–60% of patients with treatment-refractory depression
• In patients who fail to respond to an SSRI, a second SSRI trial is warranted rather than a switch to an SNRI
• Medication dose (and exposure) is important in improving outcomes!
• Caution with venlafaxine, particularly those with suicidal ideation at the beginning of treatment
Posttest QuestionFollowing unsuccessful treatment with paroxetine and fluoxetine, a 15-year-old girl, who meets DSM-5 criteria for major depressive disorder, is prescribed extended-release venlafaxine which is initiated at 37.5 mg daily and titrated to 150 mg daily for 8 weeks. She has had minimal improvement in depressive symptoms. Which of the following represents a significant clinical consideration?1. Venlafaxine treatment may increase her likelihood of treatment-emergent
suicidality2. Addition of cognitive-behavioral therapy is unlikely to confer any significant
benefit3. Her likelihood of clinical improvement is directly related to her serum
venlafaxine concentration4. Addition of trazodone to manage her initial insomnia may increase her
likelihood of remission
A 13-year-old boy meets DSM-5 criteria for major depressive disorder and has been treated with paroxetine 40 mg daily for 8 weeks. He has had minimal improvement in depressive symptoms. Which of the following represents an evidence-based treatment option?
1. Continue for an additional 4 weeks at the current dose. 2. Discontinue paroxetine and begin duloxetine 30 mg qAM3. Discontinue paroxetine and begin citalopram 10 mg qAM4. Augment with buspirone 10 mg BID
Posttest Question
Higher blood levels of which of the following medications have been associated with a greater likelihood of improving in adolescents with treatment-resistant depression?
1. Venlafaxine2. Citalopram3. Fluvoxamine4. Duloxetine
Posttest Question