Use of Antidepressants in

Adolescents
WHEN? HOW? WHAT?
ANTIDEPRESSANTS IN ADOLESCENTS
–Why and Whether
EVIDENCE IN ADOLESCENT
DEPRESSION
 BEGINNINGS

 FDAMA (1997) - Motivated Pharma - Children and adolescents

 Trials use the same indication as in adults

 September 2000 - >191 proposed studies, 58 completed

 Studies included fluoxetine, sertraline, mirtazapine, paroxetine,

citalopram, nefazodone, and venlafaxine ER

 PITFALLS

 Industry-sponsored

 Methodology challenges (High Placebo response)

 Failed trials

 Largely uninformative - Not of use for meta-analyses

 By the time of TADS - 14 industry-sponsored trials completed

 NIMH TRIALS
 Depression trials by the NIMH
 Methodological strengths
 Lower placebo response rates (30%−35%),
 Meaningful between-group differences (25%−30%)
 Support antidepressant efficacy
 Efficacy adolescent-onset Depression, OCD and the Anxiety disorders
 Non industry trials
 Treatment of Adolescents With Depression Study (TADS)

 Treatment of Resistant Depression in Adolescents (TORDIA) study

 Adolescent Depression AD and Psychotherapy Trial (ADAPT)

 Treatment of Adolescent Suicide Attempters (TASA) study

 Child/Adolescent Anxiety Multimodal Study (CAMS)

 Pediatric OCD Treatment Study I and II (POTS)

 RUPP Autism group efficacy and safety

 Evidence - Depression

 TADS long term outcome

 6- to 9-month treatment - 80% experienced symptom improvement

 TORDIA

 50%−60% teens not responding to one AD responded to a second AD

 Longer-term outcomes - Upwards of 60% of participants remitted

 Evidence - Depression

 ADAPT trial recruited a sample of

 Severely impaired teens - Psychotherapy non responders randomly assigned to

fluoxetine alone or fluoxetine + CBT.

 Slightly less than 50% responded acutely

 More than 80% response after longer-term intervention

 Evidence – Depression and Suicidality

 TASA study

 Open trial- most severely affected teen cohort of all the NIMH-funded studies

 Patients with depression and a recent suicide attempt

 Participants could choose from among three interventions

Antidepressant

CBT

Combination

J Am Acad Child Adolesc Psychiatry. 2009 October

 Evidence – Depression and Suicidality

 Response rate - over 70%

 Reattempt rate was less than that of community samples

J Am Acad Child Adolesc Psychiatry. 2009 October

Lancet. 2016 Aug 27;388(10047):881-90.
 Meta-analytic evidence

 34 trials - 5260 participants- 14 antidepressant treatments

 Fluoxetine significantly more effective than other AD

Lancet. 2016 Aug 27;388(10047):881-90.

 EVIDENCE
 Fluoxetine, sertraline, and escitalopram more efficacious than placebo in both

continuous and dichotomous outcomes

 Paroxetine – Significant overall change in symptoms (Response- NS)

 Venlafaxine significantly increased risk of suicidal behaviour or ideation

Lancet. 2016 Aug 27;388(10047):881-90.

 EVIDENCE

 Clinical guidelines – First Line - Psychotherapy (CBT/IPT)

 Fluoxetine

 No access to psychotherapy

 Not responded to non-pharmacological interventions

Lancet. 2016 Aug 27;388(10047):881-90.

 DEPRESSION
When? How? and What?
 WHEN

 Psychiatric Assessment of Adolescents Routinely Include Screening

Questions About Depressive Symptomatology

 Significant Depressive Symptomatology - Evaluation to Determine the

Presence of Depressive and Other Comorbid Psychiatric and Medical

Disorders
J. Am. Acad. Child Adolesc. Psychiatry, 2007; 46(11):1503Y1526.
 WHEN
 Crucial to evaluate for the presence of lifetime manic or hypomanic symptoms

 Assess for the Presence of Ongoing or Past Exposure to Negative Events, the

Environment In Which Depression Is Developing, Support, and Family Psychiatric

History

 Evaluation Must Include Assessment for the Presence of Harm to Self or Others

J. Am. Acad. Child Adolesc. Psychiatry, 2007; 46(11):1503Y1526.

 WHEN

 Questions to be Answered
 Proper Diagnostic Assessment (Rule out Bipolarity)
 Comorbidity Assessment and Management
 Harm Assessment
 Treatment Setting Decision
 Psychoeducation
 WHEN
 Clinician Should Maintain a Confidential Relationship with the Adolescent

 Adolescents Who

 Do Not Respond to Supportive Psychotherapy

 Who Have More Complicated Depression

 Trial With Antidepressants Is Indicated

J. Am. Acad. Child Adolesc. Psychiatry, 2007; 46(11):1503Y1526.

 WHEN

 Antidepressants are usually considered

 Moderate depression for which psychotherapy is not feasible

 severe depression with or without psychotic symptoms, and

 Depression that fails to respond to an adequate trial of psychotherapy.

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

W
H
A
T

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 FDA APPROVAL

 Fluoxetine MDD in children age 8 years and older

 Escitalopram - MDD in adolescents aged 12 years and

older
SUMMARY - Depression
 HOW AND WHAT

Acute‑phase treatment
 Goals

 Effectively treat depression to achieve remission

 Prevent relapse and recurrence of symptoms

 Elimination of dysfunction and improvement in QOL

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Acute‑phase treatment
 Adequate information to parents and significant others
 Informed consent to from the parents or other legal guardians
 Explain about
Side effects
Dose

Timing of therapeutic effect

Possible suicidality
Danger of overdose

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT

 Parents - Giving medications

 Especially during the acute phase and during the initial 2–4 months after

complete remission

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT

Acute‑phase treatment

 Fluoxetine should be the first‑line

 Escitalopram will be the reasonable next choice first lime

 Followed by Sertraline

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Acute‑phase treatment
 Started in low doses (usually, half the starting dose of adults)
 Gradually titrated to balance symptom control and avoidance of side effects
 Eg: Fluoxetine can be started in the dose of 10 mg/day, and this can be
escalated to 20 mg/day after 1 week if there are no side effects.

 Evidence for the effectiveness in doses above 20 mg/day is meager

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Acute‑phase treatment
 Keep the frequency of patient’s visit to once in 1–2 weeks
 Monitor the status of the depression (improvement or worsening)

 Emergence of suicidality, if any

 Monitor bothersome adverse effects and

 Increase patient adherence

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Acute‑phase treatment

 Lack of consensus on adequate trial

 Extrapolated from the adult data

 Adequate and tolerable doses for at least 4–6 weeks

 Wait till 8 weeks before considering the failure of response

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
 No response by 4 weeks - Maximum tolerable dose

 Go up-to 8 weeks then Switch

 Partial response by 4–6 weeks - Maximum tolerable dose

 Go up-to 8 weeks then Augment

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Acute‑phase treatment

 Non response to an adequate trial of the first SSRI may benefit from a

second SSRI

 Some evidence superiority of combination of AD and CBT to AD only

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Acute‑phase treatment

 Augmentation may be a useful strategy

 Adolescents who show initial response with optimal doses, but fail to achieve

remission.

 Augmentation recommendations from adult data can be extrapolated.

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Acute‑phase treatment
 Failure of two consecutive AD
 Re‑evaluation

 Diagnosis

 Comorbidity

 Noncompliance

 Psychosocial

 Adequacy of psychotherapy
 Patient still fails to respond -based on adult data,
 Venlafaxine, bupropion, or mirtazapine

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019
 HOW AND WHAT
Continuation Phase

 Lack of data

 Minimum of 6–12 months after the resolution of acute symptoms

 Frequency of visits can be reduced to once a month

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

 HOW AND WHAT
Maintenance Phase
 Maintenance therapy is not indicated after the first episode

 Insufficient data about maintenance treatment

 Two (if episodes are characterized by psychotic symptoms) or three episodes of depression,
 Severe suicidality / Severe dysfunction
 Family history of affective disorders
 History of treatment resistance

 Optimal duration not well established

 Vary between 3 years and lifetime (depending on risk factors)

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019
ANTIDEPRESSANTS IN OCD –Why and
Whether?
 Evidence- OCD
 Pediatric OCD Treatment Study I and II (POTS)
 SRI treatment of OCD
 Pediatric literature is consistent with the adult trials

 30–40% reduction in OCD symptoms

6 point decrease CY-BOCS

 Clinical effects beginning at 3 weeks, reaching a plateau at after 10 weeks

 OCD
When? How? and What?
 WHEN
 If screening suggests OC symptoms - fully evaluate the child using the

criteria and scalar assessment.

 Complete psychiatric evaluation - history and MSE, with attention to the

presence of common comorbid disorders

 When possible, CBT is the first line treatment for mild to moderate cases

J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(1):98 –113.

 HOW AND WHAT
 For moderate to severe medication is indicated
 Scores higher than 23 on the CY-BOCS
 CGI-S Scale - marked to severe impairment
 Combined treatment is also favoured

 SRIs are the first-line medications and should be used according to AACAP
guidelines

J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(1):98 –113.

 HOW AND WHAT
 FDA Approval

 Clomipramine (ages 5 and above)

 Fluoxetine (ages 8 and above)

 Fluvoxamine (ages 8 and above)

 Sertraline (ages 6 and above)

 Paroxetine (ages 8 and above)

J Cent Nerv Syst Dis. 2011; 3: 125–142.

 WHEN

Indian J Psychiatry 2019;61:226-40

 HOW AND WHAT
Acute‑phase treatment

 SSRI (but not clomipramine) should be the first choice of management

 Fluoxetine or sertraline ahead of paroxetine and fluvoxamine

 An adequate trail should be given

 Monitoring should be done on CYBOCS and CGI‑I

Indian J Psychiatry 2019;61:226-40

 HOW AND WHAT
Acute‑phase treatment

 Moderate‑to‑severe cases

 CBT plus SSRI (COMBO) first‑line treatment

 Fluoxetine or sertraline before paroxetine and fluvoxamine

Indian J Psychiatry 2019;61:226-40

 HOW AND WHAT
Acute‑phase treatment

 Adequate trial of maximum tolerable dose

 At least for12 weeks

 ≥35% reduction on CY‑BOCS and remission definition

Indian J Psychiatry 2019;61:226-40

 HOW AND WHAT

(CYBOCS score improvement between 35% and 50%)

(<35% symptom remission)

Indian J Psychiatry 2019;61:226-40

 HOW AND WHAT

Indian J Psychiatry 2019;61:226-40

 HOW AND WHAT
Maintenance treatment

 On remission (CYBOCS score <11)

 SSRI should at an optimal dose for a minimum of 12 months

 Combination – Optimal doses of CBT and SSRI for 12 months

Indian J Psychiatry 2019;61:226-40

EVIDENCE IN ADOLESCENT ANXIETY
DISORDERS
 Evidence – Anxiety Disorders

 Child/Adolescent Anxiety Multimodal Study (CAMS)

 CBT and SRT reduced the severity of anxious symptoms in moderate to
severe SAD, GAD or Social Phobia

 Combination of the two therapies showed the most benefit.

Compton et al. Child and Adolescent Psychiatry and Mental Health 2010
 Scenario – OCD and Anxiety
 GAD, Separation and Social anxiety disorders – AD effective
 NIMH studies - NNTs of 3–5
 Good data on the efficacy and safety of AD
 FDA labeling is lacking
 Forces prescribers who practice EBM to prescribe off-label
 WHEN
 AACAP recommends CBT first for 6 to 18 years old with social anxiety,
generalized anxiety, separation anxiety, specific phobia, or panic disorder
 AACAP recommends SSRIs
 AACAP suggests SNRI use
 SSRIs and SNRIs reported helpful in somatoform disorders, when
symptoms severe and resistant to psychological approaches (Indian J Psychiatry 2019;61:241-6)

J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(1):98 –113.

 WHAT AND HOW
 SSRIs with sufficient data

 Fluoxetine, fluvoxamine, paroxetine, and sertraline

 No specific SSRI has FDA approval

 Duloxetine – FDA approved –GAD (7-17 years old)

 Venlafaxine greater suicide risk than the other SNRIs

J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(1):98 –113.

EVIDENCE IN ADOLESCENT BIPOLAR
DEPRESSION
 WHEN AND WHAT

Indian J Psychiatry 2019;61:294-305

EVIDENCE IN ADOLESCENT ADHD
 What and When

 TCAs and Bupropion are considered third‑line drugs

 TCAs are generally not recommended due to their side effect profile.

Indian J Psychiatry 2019;61:176-93.

EVIDENCE IN ADOLESCENT ODD/CD
 EVIDENCE

 There are few case reports indicating SSRI effective in reducing aggression

in male youth

 Better avoided

Indian J Psychiatry 2019;61:270-6.

EVIDENCE IN ADOLESCENT ASD
 When and What

 Depression: SSRIs, TCA’s recommended

 SSRI’s for anxiety is recommended

 SSRIs for treatment of repetitions/ compulsions (off label.....Fluoxetine/

citalopram)

Indian J Psychiatry 2019;61:254-69.

EVIDENCE IN ADOLESCENT EATING
DISORDERS
 When and What

 Medications reserved for comorbid conditions and refractory cases

 SSRIs - may prevent relapse in Anorexia -Larger studies do not support this

 Fluoxetine is FDA approved for Bulimia (60 mg per day)

J Am Acad Child Adolesc Psychiatry 2015;54(5):412–425

AD AND SUICIDALITY
 EVIDENCE
 2004 -FDA warning affixed to all antidepressants

 Meta-analysis of 24 RCTs AD use

 Increased risk for suicidal events in depressed youth (OR= 1.66)

 Across indications (OR= 1.95)

Psychiatr Clin N Am 39 (2016) 503–512.

 EVIDENCE
 11 times more responded to AD than experienced a suicidal event

 Higher benefit-risk ratios for - OCD or anxiety disorders

 Cochrane review of adolescent depression RCTs

 Increased risks for suicidal events (OR=1.6)

 4.5 times the number get clinical remission than suicidal events

Psychiatr Clin N Am 39 (2016) 503–512.

SUMMARY
 SUMMARY

 Good quality evidence in Depression, OCD, anxiety disorders

 Risk Benefit w.r.t suicidality is high

 Good Evidence in Bulimia

 Fair evidence in ASD

J Am Acad Child Adolesc Psychiatry 2015;54(5):412–425

 SUMMARY

 Lower tier recommendation in Bipolar Depression and ADHD

 Poor evidence in CD and Anorexia

 Use when absolutely indicated

 Monitor carefully for AE and Suicidality

J Am Acad Child Adolesc Psychiatry 2015;54(5):412–425

W
H
E
N

Indian Journal of Psychiatry, Volume 61 (Supplement 2), January 2019