DEPRESSION IN CHILDREN AND ADOLESCENTS Jan Buitelaar, MD, PhD Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center and Karakter Child and Adolescent Psychiatry, University Center, Nijmegen, NL

One-Year Prevalence of Depression over Age Children 2-4% M = F Adolescents 4-8% F > M Adults 10-15% F > M

Depression in children and adolescents Of those who will become depressed in their life, has 15% a first episode between age 14-19 year, and 10% a first episode before age 14 About 20% of adolescents have 1 episode before age 18; 50-60% of those have recurrent episodes 65% of adolescents have transient depressive symptoms 20% have suicidal thoughts, 5-8% make suicide attempts Burden of illness is as large in children and adolescents as in adults

Long-term risk of subthreshold depression in adolescence- Outcome at age 25 Fergusson et al., Archives GP 2005, 62, 66-72 Odds Ratio’s

Adolescence Young Adults no previous disorder 27.9 % mood disorder at age 21 previous mood disorder 45.3 % previous other disorder 26.9 % Dunedin study, Newman et al., 1996

Cumulative incidence of anxiety and depressive disorders Wittchen et al., 2000. In: Childhood Onset of Adult Psychopathology,

Model Sequence of Comorbidity Anxiety Symptoms MDD with Anxiety Disorders PersistentDisability Social Anxiety GAD Panic Disorder Early Childhood Stressors Age 5-20 15-20 20+

Psychotherapie en andere niet-medische behandelingen (richtlijntekst) 9 systematic reviews, wisselende inclusie, wisselende resultaten Effect sizes bescheiden 0.34 (Weisz, 2006 over 35 RCTs) 0.34 – 0.59 (Klein, 2007 over 11 RCTs met CGT) Overall 50 vs 35% geen depressie-diagnose, na 2 jaar veel lager (Watanabe, 2007 over 27 RCTs) Vooral CGT / IPT effectief, inzetten als behandeling 1e keuze Gezinstherapie en non-directieve therapie effectief maar minder dan CGT / IPT

Psychotherapie en andere niet-medische behandelingen (richtlijntekst) Running overall niet effectief Internet (grip op je dip, praten online) veelbelovend, open studies. Inzetten als CGT niet voorhanden is. Psycho-educatie aan ouders effectief in klinische settingen Onderzoek naar bibliotherapie, zelfhulp, psycho-educatie, vaktherapie ontbreekt Onderzoek doen naar vergroting effectiviteit CGT Veel aandacht besteden aan terugvalpreventie: doorbehandelen en boostersessies

Cochrane Review and Meta-analysis (Hetrick et al Cochrane Review and Meta-analysis (Hetrick et al., 2008) on efficacy and safety of SSRIs) for depressive disorders in children and adolescents Twelve trials were eligible for inclusion, with ten providing usable data. At 8-12 weeks, there was evidence that children and adolescents ’responded’ to treatment with SSRIs (RR 1.28, 95% CI 1.17 -1.41) There was also evidence of an increased risk of suicidal ideation and behaviour for those prescribed SSRIs (RR 1.80, 95% CI 1.19 - 2.72) Fluoxetine was the only SSRI with consistent evidence from three trials that it was effective in reducing depression symptoms in both children and adolescents (CDRS-R treatment effect -5.63, 95% CI -7.38 to -3.88), and ’response’ to treatment (RR 1.86, 95% CI 1.49 to 2.32). Where rates of adverse events were reported, this was higher for those prescribed SSRIs.

Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis (Hazell et al., BMJ 1995, 310:897-901) Design: Meta-analysis of 12 randomised controlled trials comparing the efficacy of tricyclic antidepressants with placebo in depressed subjects aged 6-18 years. Results: From the six studies presenting data which enabled an estimation of effect size the pooled effect size was 0.35 (95% CI of -0.16 to 0.86). From the five studies presenting data on the number of "responders" in each group, the pooled odds ratio was 1.08 (95% CI of 0.53 to 2.17) Conclusions: Tricyclic antidepressants appear to be no more effective than placebo in the treatment of depression in children and adolescents.

TADS – Treatment for Adolescent with Depression Study Randomized Controlled Trial (12 weeks): Fluoxetine 10-40 mg/day Fluoxetine 10-40 mg/day + CBT CBT alone Placebo Medication treatments were masked 439 patients 12-17 year with Major Depressive Disorder Main Outcome: CDRS, CGI-improvement March et al. JAMA 2004, 292, 807-820

Treatment for Adolescent with Depression Study

TADS – Treatment for Adolescent with Depression Study at 12 wks % clinical response on CGI-Improvement

Treatment for Adolescent with Depression Study - Limitations Patients with suicidality were excluded Only Fluoxetine alone and Placebo alone conditions were blinded Differences in contact time between conditions CBT perhaps not delivered in optimal format Somewhat discrepant findings of different statistical approaches

TADS –continuation till 36 weeks Cognitive behavior and combination therapies were not masked, whereas administration of placebo and fluoxetine was double-blind through 12 weeks, after which treatments were unblinded. Patients assigned to placebo were treated openly after week 12, and the placebo group is not included in these analyses by design.

% clinical response on CGI-Improvement TADS – Treatment for Adolescent with Depression Study at 12, 18 and 36 wks % clinical response on CGI-Improvement

TADS – Treatment for Adolescent with Depression Study at 12, 18 and 36 wks

TADS – 36 weeks - Conclusions In adolescents with moderate to severe depression, treatment with fluoxetine alone or in combination with CBT accelerates the response. Suicidal ideation decreased with treatment, but less so with fluoxetine therapy than with combination therapy or CBT Suicidal events were more common in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%). Thus, adding CBT to medication enhances the safety of medication. Taking benefits and harms into account, combined treatment appears superior to either monotherapy as a treatment for major depression in adolescents.

The TORDIA Randomized Controlled Trial Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression 334 patients aged 12 to 18 years with MDD that had not responded to a 2-month initial treatment with an SSRI Twelve weeks of switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); switch to a different SSRI plus CBT; switch to venlafaxine (150-225 mg); or switch to venlafaxine plus CBT. Brent et al., JAMA 2008, 299(8):901-913

TORDIA - Clinical Outcome by Treatment Group With Intent-to-Treat and Completer Analyses Brent, D. et al. JAMA 2008;299:901-913. Copyright restrictions may apply.

TORDIA - Conclusions For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects.

The adolescent depression antidepressant and psychotherapy trial (ADAPT) To determine whether a combination of an SSRI and CBT together with clinical care is more effective than an SSRI and clinical care alone in adolescents with moderate to severe MDD. 208 adolescents, aged 11-17, with moderate to severe major or probable major depression who had not responded to a brief initial intervention. Adolescents with suicidality, depressive psychosis, or conduct disorder were included

ADAPT - Mean outcome by treatment group for the Health of the Nation outcome scale Goodyer, I. et al. BMJ 2007;335:142

ADAPT - Conclusions There was no evidence of a protective effect of CBT on suicidal thinking or action. For adolescents with moderate to severe MDD there is no evidence that the combination of CBT plus an SSRI in the presence of routine clinical care contributes to an improved outcome by 28 weeks compared with the provision of routine clinical care plus an SSRI alone.

Clinical Recommendation Assess clinical severity of depression Psychosis Suicidality Duration Psychosocial impairment Comorbidities

Ernstbeoordeling (richtlijntekst) Ernstbeoordeling depressie licht matig ernstig Aantal symptomen volgens DSM-IV-TR 5-6 symptomen 6-8 symptomen 8-9 symptomen Aard van de symptomen psychotische kenmerken en / of suicidaliteit Zelfrapportage Children’s Depression Inventory (CDI-27) score tot 12 score 12-16 score >16 GAF-score: dagelijks functioneren 65 en hoger 45-65 lager dan 45 Aantal gebieden waarop de stoornis duidelijk interfereert met de dagelijkse gang van zaken (school, vrienden, hobby's/activiteiten, thuis) 1 gebied 2 of 3 gebieden 4 gebieden

Clinical Recommendation Mild-Moderate depression Start psychosocial interventions (psychoeducation, counselling, crisis-management, system approach) Specific psychological interventions: CBT or IPT Monitor severity and other clinical signs

Clinical Recommendation When insufficient response to psychological interventions after 3 months, or when severe depression: Start with / add medication First-line Fluoxetine (start 10 mg, after 1 week 20 mg, max 40 mg/day) Monitor carefully

Screening en diagnostiek (richtlijntekst) Wie bevragen? Overeenstemming ouder – kind laag -> altijd tenminste kind bevragen Screening op scholen of huisarts: breed vanwege comorbiditeit S-PSY (inclusief suicide-item) YSR / CBCL affectieve problemen Altijd suicide-item meenemen (CDI / YSR / CBCL / SPSY; niet CES-D / RCADS) Alleen screenen als er een vervolg mogelijk is Klinische praktijk Klinisch interview (KiddieSADS of ADIS) wordt aangeraden of tenminste check van alle symptomen CDI als procesmaat Talloze risicofactoren (uit de NICE-guidelines) Kindfactoren, omgevingsfactoren, gebeurtenissen Professionals trainen op herkennen symptomen en actief luisteren / gespreksvaardigheden

Preventie (richtlijntekst) Meta-analyses (30 RCT’s), CGT en 1x IPT Universele preventie geen direct effect op afname klachten of voorkómen depressie Geïndiceerde preventie effectief Hoogscoorders, bijv op scholen of via huisartsen Selectieve preventie effectief Volwassen patiënten vragen naar hun kinderen Kinderen bij blijvende neerslachtigheid na eenmalige akelige gebeurtenis Professionals trainen op herkennen symptomen en actief luisteren / gespreksvaardigheden

Gezinscontext en behandeling Toevoegen oudertraining naast CGT leidt niet tot effectievere behandeling CGT effectiever dan gezinstherapie Nog ruimte voor verbetering -> verder onderzoek Psycho-educatie gezinsleden belangrijk (ondersteunen en voorkomen drop-outs) Ouders bij behandeling betrekken op basis klinisch oordeel

Stepped care