Adolescent Mood Disorders: Management and Medication David C. Rettew, M.D. Associate Professor of Psychiatry and Pediatrics Director, Pediatric Psychiatry Clinic UVM College of Medicine

Conflicts of Interest None Will be discussing off-label uses of some medications

Objectives Brief outline of adolescent mood disorders General assessment and treatment strategies Update on antidepressants and suicidality Bipolar disorder controversy

Understanding Psychiatric Disorders (New School) Genetics Prenatal environment Attachment Temperament Parenting Exposures Phenotype SES Comprehensive Treatment

Pediatric Depression Diagnosis: 5 of 9 - Distinct 2 Week Period) Depressed mood (Irritability) Anhedonia Weight change (Failure to make expected gains) Sleeping Disturbance Psychomotor Agitation/Retardation Energy Loss Guilt/Worthlessness Concentration Impairment/Indecisive Suicidal Thoughts/Recurrent Thoughts of Death

Dysthymia Long, term mood symptoms More chronic (most days for at least a year), less intense Need 2 neurovegetative symptoms Studies show equivalent or even greater impairment compared to depression

USA Teen Suicide Rates Note: 2005 data (Bridge et al., JAMA 2008) shows a Reduction of 5.3% from 2004 but still above earlier levels

Predictors of Suicidal Behavior Prior attempts Other psychiatric disorders Impulsivity/aggression Availability of firearms Exposure to negative events Family history of suicidal behavior Substance abuse Attempt:completion ratio about 6000:1 in girls and 400:1 in boys

Pediatric Depression Comorbidity Spencer T, MGH Study of Depression

Assessment and Treatment

Overall Assessment Plan Visit 1 Is there a problem? Safety assessment Other medical conditions Distribute general rating scale Visit 2 Review general rating scale Establish primary diagnosis Initial treatment plan Visit 3 and Beyond Track progress Check gaps and assumptions From D Rettew, OCD in the Primary Care Setting, 2007

Broad Based Rating Scales

General Treatment Guidelines Medication Environment –Sleep, structure, media Psychotherapy (evidence based) Parents School Resources

Guidelines for Treatment of Adolescent Depression in Primary Care (GLAD-PC) Expert consensus driven guidelines published in Pediatrics (2007) Conducted focus groups, surveys, literature reviews,

GLAD-PC Recommendations Identification Patients at risk for depression should be identified and systematically monitored Assessment/Diagnosis High-risk adolescents should be evaluated for depression as well as those with a chief complaint of emotional problems Clinicians should use standardized tools to aid in the assessment

GLAD-PC Recommendations Assessment Tools Reliance on presenting complaint or family concerns underidentify cases No “gold standard” screening tool –Beck Depression Inventory –Reynolds Adolescent Depression Scale –Mood and Feelings Questionnaire –Kutcher Adolescent Depression Scale

GLAD-PC Recommendations Assessment should include… Interviews with family members Degree of impairment across domains Other psychiatric conditions

GLAD-PC Recommendations Initial Management Educate patient and family about depression Outline confidentiality and its limits Develop a treatment plan with specific goals in key areas of functioning Establish links with resources (mental health, family members) Develop a safety plan – contract?

GLAD-PC Recommendations Further Management Mild depression – consider active support and monitoring Moderate/severe/complicated – consider consultation with a mental health specialist Establish roles of primary care and mental health specialist with family Recommend scientifically tested treatments Monitor for adverse effects of treatment

Severity of Depression

GLAD-PC Recommendations Further Management Continue to track outcomes and functional targets Reassess diagnosis and treatment if no response in 6-8 weeks Consider consultation with mental health professional if treatments produced only partial response Ensure adequate management

First Line Treatment Moderate/Severe Depression Cognitive Behavioral Therapy Interpersonal Therapy Antidepressants Both

Pharmacotherapy Response 40-70% with medications vs 30-60% for placebo Remission with medications lower (30-40%) Little efficacy evidence for non SSRIs Bupropion effective in open trials

Medications in Depression MedStart DoseMaxFDAGenerics Citalopram10mg60mgNY Fluoxetine10mg60mgY Y Fluvoxamine25mg300mgNY Sertraline mg200mgNY

Pharmacotherapy Tips Half life of antidepressants often shorter in children and adolescents –Watch for withdrawal symptoms on qd dosing Goal for remission at 12 weeks (consider switch if no or little response at 8 weeks)

Text of Black Box Warning 2/05

Proposed Mechanisms of Increased Suicidal Behavior Medication adverse affects: insomnia, agitation, irritability Switching patients with bipolar disorder Acute effects on serotonin that differ from long-term effects Greater comfort in disclosing ideation

Criticism of Data Significant differences found only when combine suicidal thoughts and behavior and combine depressive and anxiety disorders Signal only for spontaneously reported suicidality No increase in ‘emergence’ or ‘worsening’ or suicidal symptoms when systematically assessed Overall rate lower than found in community samples No actual suicides

Change in Youth Antidepressant Prescribing Psychiatric News, September 2005

Official Monitoring Guidelines Once per week x 4 weeks Every 2 weeks for next 8 weeks At end of week 12 and regularly thereafter More often if problems or questions arise No scales recommended Fluoxetine alone, or Fluoxetine + CBT, or CBT alone as 1 st line Monitor consistent with FDA guidelines (though no specific data to support such frequency of contact) FDAAACAP From: “FDA Proposed Medication Guide: About Using Antidepressants in Children or Teenagers” (Center for Drug Evaluation and Research)

Completed Suicides in NYC 41 NYC suicides in children less than 18 Antidepressants (bupropion and sertraline) detected in 1/38 (2.8%) available cases JAACAP, Sept 2006

Recent Meta-Analysis Bridge et al., JAMA 2007 Covered 27 controlled studies in depression and anxiety MDD medication response vs placebo: 61% vs 50% Less response for younger children, except with fluoxetine Suicidality on medications vs placebo: 2% vs 1% (statistically significant across all disorders but not MDD alone) More efficacy with shorter depression duration Concluded a favorable benefit to risk comparison for cautious use as first line treatment

Suicide Rates by County Gibbons et al, AJP, 2006 Highest rates often in rural western areas and lowest in most major cities More SSRI Rxs, less suicides even after controlling for mental health care and income

Treatment for Adolescents with Depression Study (TADS) – JAMA, 2004 Funded by NIMH (not pharmaceutical company) 439 subjects aged from 13 sites Randomized to CBT, fluoxetine (10-40mg), combination, or placebo Short term (12 week) and long term follow- up (36 weeks) Suicidal ideation in 29% - “severe” suicidality exclusionary criteria

TADS Study Acute Response Combin, Fluox > CBT, Placebo More med response for more severely affected

TADS Study Sustained Response At 36 weeks, 80% of acutely nonresponding patients had achieved definite or probably sustained response (didn’t differ by treatment type) If did get sustained response, most kept it (80%) –BUT higher loss of response in fluoxetine group 26% compared to CBT 3% Rodhe et al., Arch Gen Psychiatry, April, 2008

TADS Follow- up

TADS summary CBT can work very well but can take a little longer If you get better with CBT, you are very likely to stay that way Medications may result in better acute response but also more relapses without other interventions

Summary Depression in children and adolescents is a serious problem with potentially disastrous outcomes Practical and effective approaches to assessment and treatment have now been organized Several well supported treatment options exist both pharmacologically and nonpharmacologically Antidepressants should be respected, but not feared

Major References GLAD-PC: Zuckerbrot et al., Pediatrics, 120:e , 2007 AACAP Parameters: Birhamer et al., J Am Acad Child Adolsc Psychiat, 46: , TADS study: March et al., JAMA, 292: , 2004

Pediatric Bipolar Disorder One of most controversial topics in child psychiatry Underdiagnosed vs. Overdiagnosed? In forefront of physician/pharma discussions

Pediatric Bipolar Disorder Criteria Overlap with ADHD Distractibility Increased activity/psychomo tor agitation Grandiosity Flight of ideas Activities with painful consequences Sleep decrease Talkativeness In children, characterized by ultradian cycling in about 75% and prominent suicidality in about 25%

Proposed New Categories Liebenluft et al., 2003 Narrow : Mood elevation + duration Intermediate : –Clear symptoms but 1-3 day duration OR –Clear episodes but irritable Broad: Chronic, nonepisodic, irritability

Dilemma in Pediatric Bipolar Disorder Risks with Medications Increased Stigma Worse Course? Safety if untreated Lack of efficacy data

Special Communication JAACAP, March 2005

The FIND Threshold JAACAP, 2005 F requency – most days in a week I ntensity – extreme disturbance in one setting or moderate disturbance in two N umber – 3 or more times a day D uration – occur 4 or more hours a day total

Psychopharmacology Bipolar 1 in acute phase – No psychosis Adequate trial means 4-6 weeks at therapeutic blood level or therapeutic dose (perhaps 8 weeks for lithium) Start with mood stablizer (lithium, valproate, carbamazapine) or atypical antipsychotic (risperidone, olanzapine, quetiapine) monotherapy If no response, switch If partial response, augment Consensus panel did not/could not favor particular agent Trials of lamotragine (Lamictal), oxcarbazepine (Trileptal), ziprasidone (Geodon), aripiprazole (Abilify) recommended only after combination treatment fails

Antipsychotic FDA Approvals in Pediatrics Risperidone (Risperdal): Schizophrenia (age ) Bipolar Disorder (age 10-17); Autism irritabiltiy/aggression (age 5-16) Aripiprazole (Abilify): Bipolar Disorder (ages ) Olanzapine (Zyprexa): None Quetiapine (Seroquel): None Ziprasidone (Geodon): None

Risks of Treatment Informed Consent Weight gain and diabetes – new monitoring protocol published by ADA, 2004 Cognitive dulling Polycystic Ovarian Syndrome Hypothyroidism Abnormal involuntary movements Liver disease Pancreatitis Prolactin elevation Cardiac effects?? Neuroleptic malignant syndrome

ADA Protocol Prior to Using Atypical Antipsychotics Personal and family history of obesity, diabetes, dyslipidemia, hypertension, cardiovascular disease Weight, height, BMI, Waist circumference at umbilicus Blood pressure Fasting glucose Fasting lipid profile Reassess at 4, 8, and 12 weeks Switch agents if gains > 5% of body weight

My Treatment Approach If meets criteria for narrowly phenotype then proceed directly to bipolar treatment If broad phenotype, attempt non- medication and treatment of other conditions first

11 Reasons for why “the medicine is not working” Diurnal Variation Nonpsychiatric Causes Dose and Duration of Treatment Comorbidity (child) Comorbidity (parent) Medication Side Effects Compliance Multinformant Variation Substance abuse Medication Limitations Lack of Commitment

THANK YOU Questions and Discussion