The Diagnosis and The Diagnosis and Treatment of Pediatric Treatment of Pediatric

DepressionDepression

Jess P. Shatkin, MD, MPHJess P. Shatkin, MD, MPH

Vice Chair for EducationVice Chair for Education

NYU Child Study CenterNYU Child Study Center

New York University School of MedicineNew York University School of Medicine

Presentation OutlinePresentation OutlineWe will review the followingWe will review the following:: Pediatric Depression Disease StatePediatric Depression Disease State Medication TreatmentMedication Treatment

1.1. Tricyclic AntidepressantsTricyclic Antidepressants2.2. Serotonin Specific Reuptake InhibitorsSerotonin Specific Reuptake Inhibitors3.3. Other antidepressantsOther antidepressants4.4. Augmenting medications & ECTAugmenting medications & ECT

Psychotherapy TreatmentPsychotherapy Treatment1.1. Manualized therapies (CBT, IPT)Manualized therapies (CBT, IPT)2.2. Psychodynamic psychotherapyPsychodynamic psychotherapy

Current FDA ControversyCurrent FDA Controversy Evidence based treatment Evidence based treatment

recommendationsrecommendations

Learning ObjectivesLearning Objectives

Participants will be able to:1. Describe the primary differences

between pediatric and adult depression.

2.2. Identify evidence-based Identify evidence-based pharmacologic and non-pharmacologic pharmacologic and non-pharmacologic treatments for pediatric depression.treatments for pediatric depression.

3.3. Make rational treatment Make rational treatment recommendations for children and recommendations for children and adolescents with depression. adolescents with depression.

A Brief History of A Brief History of Depression in Children and Depression in Children and

AdolescentsAdolescents Case reports on childhood depression date to the Case reports on childhood depression date to the

early 17early 17thth century century Melancholia in children was first reported in the Melancholia in children was first reported in the

mid-19mid-19thth century century In general, however, the existence of depression In general, however, the existence of depression

prior to 1960 was seriously doubted because it prior to 1960 was seriously doubted because it was felt that childrenwas felt that children’’s immature superego s immature superego would not permit the development of depressionwould not permit the development of depression

Research from Europe and NIMH funded Research from Europe and NIMH funded American studies in the 1970American studies in the 1970’’s increased the s increased the awareness & acceptance of childhood depressionawareness & acceptance of childhood depression

Psychoanalytic Psychoanalytic PerspectivePerspective

Psychoanalytic theory posits that Psychoanalytic theory posits that depression results from an intrapsychic depression results from an intrapsychic conflict between the ego and a conflict between the ego and a persecutory superegopersecutory superego

Psychoanalysis held that the superego Psychoanalysis held that the superego was formalized only after resolution of was formalized only after resolution of the Oedipal Conflict, which occurred by the Oedipal Conflict, which occurred by late adolescencelate adolescence

By this theory, then, children could not By this theory, then, children could not experience intrapsychic conflict and, experience intrapsychic conflict and, ergo, could not develop mood disordersergo, could not develop mood disorders

EpidemiologyEpidemiology Varying rates have been reported; no large, Varying rates have been reported; no large,

well accepted epidemiologic studieswell accepted epidemiologic studies Generally accepted 1-year incidence is:Generally accepted 1-year incidence is:

*Preschool age 1%*Preschool age 1%*School age 2%*School age 2%*Adolescent age 4 - 8%*Adolescent age 4 - 8%

Gender ratio of 1:1 in childhood and 2:1 Gender ratio of 1:1 in childhood and 2:1 (female to male) by adolescence(female to male) by adolescence

Lifetime prevalence of MDD among Lifetime prevalence of MDD among adolescents is 15 – 20% (similar to adults); adolescents is 15 – 20% (similar to adults); 15.3% per NCS15.3% per NCS Kashani & Sherman, 1988; Fleming & Offord, 1990; Lewinsohn et al, Kashani & Sherman, 1988; Fleming & Offord, 1990; Lewinsohn et al,

1993 & 1994; Kessler & Walters, 19981993 & 1994; Kessler & Walters, 1998

Epidemiology (2)Epidemiology (2)

Studies on Dysthymia suggest a wide range in Studies on Dysthymia suggest a wide range in point prevalence: children from 0.6 – 1.7%; and point prevalence: children from 0.6 – 1.7%; and adolescents from 1.6 – 8.0%adolescents from 1.6 – 8.0%

Garrison et al, 1992; Kashani et al, 1987; Lewinsohn et al 1993 Garrison et al, 1992; Kashani et al, 1987; Lewinsohn et al 1993 & 1994& 1994

Studies in specialized populations show Studies in specialized populations show increased incidence, such as 40% among increased incidence, such as 40% among children on neurology wards with unexplained children on neurology wards with unexplained headaches (Ling et al, 1970); 7% of general headaches (Ling et al, 1970); 7% of general pediatric inpatients (Kashani et al, 1981); 28% pediatric inpatients (Kashani et al, 1981); 28% of children in psychiatric clinics (Carlson & of children in psychiatric clinics (Carlson & Cantwell, 1980); 59% of child psychiatry Cantwell, 1980); 59% of child psychiatry inpatients (Petti, 1978); and 27% of adolescent inpatients (Petti, 1978); and 27% of adolescent inpatients (Robbins et al, 1982)inpatients (Robbins et al, 1982)

Epidemiology (3)Epidemiology (3) Prevalence increases during Prevalence increases during

adolescence, possibly due to:adolescence, possibly due to:1.1. Biological factors (e.g., sexual maturation)Biological factors (e.g., sexual maturation)

2.2. Environmental factors (e.g., increased Environmental factors (e.g., increased social/academic expectations, more chance social/academic expectations, more chance of exposure to negative events)of exposure to negative events)

3.3. Psychological & cognitive factors (e.g., Psychological & cognitive factors (e.g., increased autonomy and abstract thinking)increased autonomy and abstract thinking)

Since 1940, each successive generation Since 1940, each successive generation has been at higher risk for MDDhas been at higher risk for MDD

Ordinary PeopleOrdinary People Conrad Jarrett is 16 and has survived a Conrad Jarrett is 16 and has survived a

boating accident in which his brother, Buck, boating accident in which his brother, Buck, died.died.

The book takes place as Conrad tries to The book takes place as Conrad tries to readjust to life back at home after a readjust to life back at home after a psychiatric hospitalization for a suicide psychiatric hospitalization for a suicide attempt.attempt.

He sees a psychiatrist, Dr. Berger, who tries He sees a psychiatrist, Dr. Berger, who tries to address Conradto address Conrad’’s chief desire upon s chief desire upon presenting (e.g., he wants to be in control).presenting (e.g., he wants to be in control).

This scene takes place as Berger is asking This scene takes place as Berger is asking Conrad about quitting the swim team.Conrad about quitting the swim team.

Etiology: Theories of Etiology: Theories of DepressionDepression

Psychodynamic: anger turned inward; Psychodynamic: anger turned inward; severe superegosevere superego

Attachment: insecure early attachmentAttachment: insecure early attachment Behavioral: inability to obtain reinforcementBehavioral: inability to obtain reinforcement Cognitive: depressive mindsetCognitive: depressive mindset Self-Control: deficits in self-monitoring, self-Self-Control: deficits in self-monitoring, self-

evaluation, and self-reinforcementevaluation, and self-reinforcement Interpersonal: characteristic to individual, Interpersonal: characteristic to individual,

roles and eventsroles and events Socioenvironmental: stressful life Socioenvironmental: stressful life

circumstances exacerbate vulnerabilitiescircumstances exacerbate vulnerabilities Neurobiological: neurochemical, endocrine, Neurobiological: neurochemical, endocrine,

and receptor abnormalitiesand receptor abnormalities

Genetics (1)Genetics (1) Findings from twin studies suggest a moderate Findings from twin studies suggest a moderate

genetic influence on depression in community genetic influence on depression in community samples with heritability ranging from 35 – 75% samples with heritability ranging from 35 – 75% across studies (Eley, 1999; Glowinski et al, 2003)across studies (Eley, 1999; Glowinski et al, 2003)

Twin/adoption studies have not been conducted, Twin/adoption studies have not been conducted, so the extent to which clinical depression in so the extent to which clinical depression in children and adolescents is genetically driven is children and adolescents is genetically driven is not knownnot known

Still, children with a parent who suffered from Still, children with a parent who suffered from depression as a child are up to 14x more likely depression as a child are up to 14x more likely than controls to become depressed prior to age than controls to become depressed prior to age 13 (Weissman et al, 1988)13 (Weissman et al, 1988)

Children of parents with depression have about Children of parents with depression have about 2-3x the risk of having depression (Beardslee et 2-3x the risk of having depression (Beardslee et al, 1998; Weissman et al, 1997)al, 1998; Weissman et al, 1997)

Genetics (2)Genetics (2) Children of depressed parents have an earlier age Children of depressed parents have an earlier age

of onset for their depression by 3 years (Weissman of onset for their depression by 3 years (Weissman et al, 1997)et al, 1997)

The lifetime history of MDD in mothers of children The lifetime history of MDD in mothers of children with MDD is also high, about 50 – 75% (Kovacs, with MDD is also high, about 50 – 75% (Kovacs, 1997)1997)

A family history of depression is more common in A family history of depression is more common in 11stst degree relatives of children with MDD than in degree relatives of children with MDD than in children without MDD (Wickramaratne et al, 2000)children without MDD (Wickramaratne et al, 2000)

Adults with one or two copies of the short allele of Adults with one or two copies of the short allele of the 5-HT Transporter gene have been shown to the 5-HT Transporter gene have been shown to exhibit more depressive symptoms, diagnosable exhibit more depressive symptoms, diagnosable depression, and suicidality in relation to stressful depression, and suicidality in relation to stressful life events (Caspi et al 2003)life events (Caspi et al 2003)

More about MothersMore about Mothers A 20-year follow-up of offspring of A 20-year follow-up of offspring of

depressed and non-depressed parents depressed and non-depressed parents found that the risks for anxiety disorders, found that the risks for anxiety disorders, major depression, and substance major depression, and substance dependence were ~3x higher in the dependence were ~3x higher in the offspring of depressed parents vs. non-offspring of depressed parents vs. non-depressed parents; social impairment was depressed parents; social impairment was also greater. The time of greatest also greater. The time of greatest incidence was 15 – 20 y/o; higher rates of incidence was 15 – 20 y/o; higher rates of medical problems and mortality in the medical problems and mortality in the offspring of depressed parents were offspring of depressed parents were beginning to emerge as the offspring enter beginning to emerge as the offspring enter middle age (Weissman et al, 2006)middle age (Weissman et al, 2006)

Even More about Even More about MothersMothers Effective treatment of mothers with MDD is Effective treatment of mothers with MDD is

associated with a reduction of anxiety, depressive, associated with a reduction of anxiety, depressive, and disruptive disorders and symptoms in their and disruptive disorders and symptoms in their offspring (Weissman et al, 2006; STAR*D trial which offspring (Weissman et al, 2006; STAR*D trial which follows 151 mother/child pairs at 3 month intervals)follows 151 mother/child pairs at 3 month intervals) Remission of maternal depression after 3 months of Remission of maternal depression after 3 months of

medication treatment was significantly associated medication treatment was significantly associated reductions in childrenreductions in children’’s diagnoses and symptoms; s diagnoses and symptoms; diagnoses dropped by 11% vs. an 8% increase in diagnoses diagnoses dropped by 11% vs. an 8% increase in diagnoses among those children whose mothers did not respond to among those children whose mothers did not respond to medication treatmentmedication treatment

Of the children with MDE at baseline, remission occurred Of the children with MDE at baseline, remission occurred in 33% of those whose motherin 33% of those whose mother’’s depression remitted vs. s depression remitted vs. 12% of those whose mother12% of those whose mother’’s depression did not remits depression did not remit

17% of children (without dx at baseline) whose mothers 17% of children (without dx at baseline) whose mothers remained depressed developed a psychiatric diagnosis at 3 remained depressed developed a psychiatric diagnosis at 3 month f/u vs. none of those whose mothers responded to month f/u vs. none of those whose mothers responded to treatmenttreatment

And Fathers?And Fathers? Medical Expenditure Panel Survey data (N Medical Expenditure Panel Survey data (N

= 22K US children, ages 5 – 17) of both = 22K US children, ages 5 – 17) of both mothers and fathers; data generated by mothers and fathers; data generated by parents only.parents only. Scales used: PHQ-2, SF-12, MCS, CIS, PCSScales used: PHQ-2, SF-12, MCS, CIS, PCS

Risks of child emotional/behavioral Risks of child emotional/behavioral problems are much greater if mothers, problems are much greater if mothers, rather than fathers, have such problems:rather than fathers, have such problems: Paternal MH problems are independently Paternal MH problems are independently

associated with a 33 – 70% increased riskassociated with a 33 – 70% increased risk Maternal MH problems are associated with a 50 -Maternal MH problems are associated with a 50 -

350% increased risk350% increased risk Weitzman et al, 2011Weitzman et al, 2011

Serotonin GeneSerotonin Gene

Among those with pervasive suicidal Among those with pervasive suicidal thoughts and intent, levels of the major thoughts and intent, levels of the major serotonin metabolite (5-HIAA) are lower serotonin metabolite (5-HIAA) are lower in the cerebrospinal fluid.in the cerebrospinal fluid.

Adults with one or two copies of the Adults with one or two copies of the short allele of the 5-HT Transporter short allele of the 5-HT Transporter gene have been shown to exhibit more gene have been shown to exhibit more depressive symptoms, diagnosable depressive symptoms, diagnosable depression, and suicidality in relation to depression, and suicidality in relation to stressful life events (Caspi et al 2003)stressful life events (Caspi et al 2003)

Biogenic Amine Biogenic Amine HypothesisHypothesis

The biogenic amine or catecholamine hypothesis The biogenic amine or catecholamine hypothesis suggests that too much neurotransmitter causes suggests that too much neurotransmitter causes mania and too little causes depression.mania and too little causes depression.

Too simplistic, but supported by the observation Too simplistic, but supported by the observation that medications that increase dopamine, that medications that increase dopamine, norepinephrine, and serotonin improve norepinephrine, and serotonin improve depression and worsen mania.depression and worsen mania.

Many limitations to this hypothesis, including the Many limitations to this hypothesis, including the fact that L-dopa and tryptophan, direct fact that L-dopa and tryptophan, direct precursors of amines, have no effect on mood; precursors of amines, have no effect on mood; and cocaine and amphetamines which block and cocaine and amphetamines which block amine reuptake do not generally improve amine reuptake do not generally improve depression.depression.

Neuroendocrine MarkersNeuroendocrine Markers

70% of adults do not show normal 70% of adults do not show normal suppression of cortisol secretion suppression of cortisol secretion following administration of following administration of dexamethasone (DST), suggesting an dexamethasone (DST), suggesting an alteration in stress response.alteration in stress response.

Blunting of normal growth hormone Blunting of normal growth hormone release in response to insulin challenge.release in response to insulin challenge.

Blunted production of thyroid Blunted production of thyroid stimulating hormone in response to stimulating hormone in response to thyroid releasing hormone thyroid releasing hormone

Annie HallAnnie Hall

Woody AllenWoody Allen’’s 1976 breakthrough film s 1976 breakthrough film about his relationships with womenabout his relationships with women

Won the Academy Award for Best PictureWon the Academy Award for Best Picture Early in the film he reflects upon his Early in the film he reflects upon his

childhood in Brooklyn, which is filled with childhood in Brooklyn, which is filled with exaggerations of how he exaggerations of how he ““remembersremembers”” his his childhoodchildhood

He also demonstrates the increased He also demonstrates the increased abstract thinking which can sometimes abstract thinking which can sometimes overwhelm children as they enter overwhelm children as they enter adolescence adolescence

Clinical PresentationClinical Presentation

DSM-IV Criteria do not differ for DSM-IV Criteria do not differ for children & adolescentschildren & adolescents

Generally, children show fewer Generally, children show fewer neurovegetative signs than adultsneurovegetative signs than adults

Irritability may substitute for depressed Irritability may substitute for depressed moodmood

Diagnosis (1)Diagnosis (1) The DSM-IV requires 5 of 9 symptoms for The DSM-IV requires 5 of 9 symptoms for

the diagnosisthe diagnosis At least two straight weeks in duration At least two straight weeks in duration

with symptoms present pretty much every with symptoms present pretty much every day or most of every dayday or most of every day

Not better accounted for by another illnessNot better accounted for by another illness MDE = Major Depressive EpisodeMDE = Major Depressive Episode MDD = Major Depressive Disorder (2 or MDD = Major Depressive Disorder (2 or

more episodes, lifetime)more episodes, lifetime) Specifiers Specifiers

Severity, psychosis, chronic, atypical, Severity, psychosis, chronic, atypical, postpartum, melancholicpostpartum, melancholic

Diagnosis (2)Diagnosis (2)1)1) Depressed MoodDepressed Mood

*in children, can substitute *in children, can substitute ““irritableirritable”” mood mood

2)2) Anhaedonia (diminished interest & pleasure)Anhaedonia (diminished interest & pleasure)3)3) Significant decrease in weight (5%)Significant decrease in weight (5%)

*in children, failure to make expected weight gains*in children, failure to make expected weight gains

4)4) Insomnia or hypersomniaInsomnia or hypersomnia5)5) Psychomotor agitation or retardationPsychomotor agitation or retardation6)6) Fatigue or loss of energyFatigue or loss of energy7)7) Feelings of worthlessness or excessive guiltFeelings of worthlessness or excessive guilt8)8) Diminished ability to think or concentrate or Diminished ability to think or concentrate or

indecisivenessindecisiveness9)9) Recurrent thoughts of death or suicidal Recurrent thoughts of death or suicidal

ideationideation

Developmental Variants Developmental Variants of MDDof MDD

Children:Children: More symptoms of More symptoms of

anxiety (e.g., phobias, anxiety (e.g., phobias, separation anxiety), separation anxiety), somatic complaints, and somatic complaints, and auditory hallucinationsauditory hallucinations

Depression is expressed Depression is expressed as temper tantrums & as temper tantrums & behavior problemsbehavior problems

Fewer delusions and Fewer delusions and serious suicide attemptsserious suicide attempts

By middle childhood, By middle childhood, preoccupations w/death, preoccupations w/death, lowered self-esteem, lowered self-esteem, social social withdrawal/rejection, & withdrawal/rejection, & poor school performancepoor school performance

Adolescents:Adolescents: More cognitive More cognitive

components to their components to their depression than childrendepression than children

Guilt and hopelessness Guilt and hopelessness become apparentbecome apparent

More sleep & appetite More sleep & appetite disturbances, delusions, disturbances, delusions, suicidal ideation & suicidal ideation & attemptsattempts

Compared to adults, still Compared to adults, still more behavior problems more behavior problems and fewer and fewer neurovegetative neurovegetative difficultiesdifficulties

Clinical Variants of MDDClinical Variants of MDD

Unipolar DepressionUnipolar Depression Psychotic DepressionPsychotic Depression Bipolar DepressionBipolar Depression Atypical DepressionAtypical Depression Seasonal Affective DisorderSeasonal Affective Disorder Subclinical or subsyndromal Subclinical or subsyndromal

DepressionDepression Treatment-Resistant DepressionTreatment-Resistant Depression

ComorbiditiesComorbidities Most children with MDD have a comorbid psychiatric Most children with MDD have a comorbid psychiatric

diagnosis:diagnosis:*40 – 90% have a second psychiatric disorder*40 – 90% have a second psychiatric disorder*20 – 50% have two or more comorbid disorders*20 – 50% have two or more comorbid disorders

Dysthymia and Anxiety Disorders (30 – 80%); Dysthymia and Anxiety Disorders (30 – 80%); Disruptive Disorders (10 – 80%); and Substance Use Disruptive Disorders (10 – 80%); and Substance Use Disorders (20 – 30%)Disorders (20 – 30%)

MDD usually manifests after the onset of other MDD usually manifests after the onset of other psychiatric disorders, except substance abusepsychiatric disorders, except substance abuse

Conduct problems may develop secondary to Conduct problems may develop secondary to depression and persist after the depression is depression and persist after the depression is effectively treatedeffectively treated

Separation anxiety is more common in children, Separation anxiety is more common in children, whereas SUDS, conduct disorder, social phobia, and whereas SUDS, conduct disorder, social phobia, and GAD are more common in adolescentsGAD are more common in adolescents-Birmaher et al, 1996; Goodyer et al, 1997; Kovacs, 1996; Rohde et al, 1991; -Birmaher et al, 1996; Goodyer et al, 1997; Kovacs, 1996; Rohde et al, 1991;

Biederman et al, 1995; Weissman et al, 1997Biederman et al, 1995; Weissman et al, 1997

ThirteenThirteen Tells the story of Tracy, who is a straight-laced, Tells the story of Tracy, who is a straight-laced,

geeky, 13 y/o A student growing up in LA with geeky, 13 y/o A student growing up in LA with her brother, Mason. her brother, Mason.

Her divorced mother is a recovering drug addict Her divorced mother is a recovering drug addict living with her former cocaine addict boyfriend; living with her former cocaine addict boyfriend; her absent & generally unsuccessful father is her absent & generally unsuccessful father is struggling with earning enough money to support struggling with earning enough money to support the kids and develop something for himself.the kids and develop something for himself.

She becomes friends with Evie, a cool kid, by She becomes friends with Evie, a cool kid, by acting out and as teen stress mounts in her life, acting out and as teen stress mounts in her life, she begins to cut to cope.she begins to cut to cope.

In this scene, her father, who has not been In this scene, her father, who has not been paying close attention, struggles to figure out paying close attention, struggles to figure out whatwhat’’s going on with his daughter.s going on with his daughter.

Differential DiagnosisDifferential Diagnosis

Adjustment Disorder with Depressed MoodAdjustment Disorder with Depressed Mood BereavementBereavement General Medical Conditions (e.g., General Medical Conditions (e.g.,

hypothyroidism, cancer, lupus, anemia, hypothyroidism, cancer, lupus, anemia, HIV, diabetes, epilepsy, etc.)HIV, diabetes, epilepsy, etc.)

Chronic Fatigue SyndromeChronic Fatigue Syndrome Medication induced (stimulants, Medication induced (stimulants,

neuroleptics, corticosteroids, neuroleptics, corticosteroids, contraceptives)contraceptives)

Differential Diagnosis (2): Differential Diagnosis (2): Nonaffective Psychiatric Nonaffective Psychiatric

D/OD/O’’ss Anxiety DisordersAnxiety Disorders ADHD ADHD Externalizing DisordersExternalizing Disorders Learning DisordersLearning Disorders SUDSSUDS Eating DisordersEating Disorders Personality Disorders Personality Disorders Premenstrual Dysphoric DisorderPremenstrual Dysphoric Disorder

Clinical CourseClinical Course

Median durationMedian duration: : Clinically referred: 7 – Clinically referred: 7 – 9 months; community: 9 months; community: 1 – 2 months1 – 2 months

Predictors of Predictors of increased durationincreased duration: : depression severity, depression severity, comorbidity, negative comorbidity, negative life events, parental life events, parental psychiatric disorders, psychiatric disorders, poor psychosocial poor psychosocial functioningfunctioning

90% of MDD episodes 90% of MDD episodes remit w/in 1-2 years after remit w/in 1-2 years after onset (where remission is onset (where remission is 2 weeks – 2 months with 2 weeks – 2 months with only 1 clinically only 1 clinically significant symptom)significant symptom)

≈ ≈ 50% relapse 50% relapse 6 – 10% of MDD are 6 – 10% of MDD are

protractedprotracted Clarke et al, 1992; Goodyer Clarke et al, 1992; Goodyer

et al, 1997; Kovacs, 1996; et al, 1997; Kovacs, 1996; Lewinsohn et al, 1994 & Lewinsohn et al, 1994 & 1997; Reinecke et al, 1998; 1997; Reinecke et al, 1998; Sanford et al, 1995; Sanford et al, 1995; Warner et al, 1992Warner et al, 1992

RelapseRelapse Relapse is an episode of MDD during a Relapse is an episode of MDD during a

period of remissionperiod of remission 40 – 60% of youth with MDD experience 40 – 60% of youth with MDD experience

relapse after successful treatment of acute relapse after successful treatment of acute episode (indicates the need for continual episode (indicates the need for continual treatment)treatment)

Predictors of relapsePredictors of relapse: natural course of : natural course of MDD, lack of compliance, negative life MDD, lack of compliance, negative life events, rapid decrease/discontinuation of events, rapid decrease/discontinuation of therapeutic treatmenttherapeutic treatment Emslie et al, 1997; Kovacs, 1996; Lewinsohn et al, 1994; Vostanis Emslie et al, 1997; Kovacs, 1996; Lewinsohn et al, 1994; Vostanis

et al, 1996; Wood et al, 1996et al, 1996; Wood et al, 1996

RecurrenceRecurrence Recurrence is the Recurrence is the

emergence of MDD emergence of MDD symptoms during a symptoms during a period of recovery period of recovery (asymptomatic period (asymptomatic period of more than 2 months)of more than 2 months)

Clinical & community Clinical & community samples show samples show probability of probability of recurrence 20 – 60% recurrence 20 – 60% w/in 1-2 years post-w/in 1-2 years post-remission and 70% remission and 70% after 5 yearsafter 5 years

Predictors of RecurrencePredictors of Recurrence:: Earlier age at onsetEarlier age at onset Increased number of Increased number of

prior episodesprior episodes Severity of initial Severity of initial

episodeepisode PsychosisPsychosis Psychosocial stressorsPsychosocial stressors Dysthymia & other Dysthymia & other

comorbiditiescomorbidities Treatment Treatment

noncompliancenoncompliance Emslie et al, 1997; Kovacs Emslie et al, 1997; Kovacs

et al, 1996 & 1997; et al, 1996 & 1997; Lewinsohn et al, 1994Lewinsohn et al, 1994

Risk of Bipolar DisorderRisk of Bipolar Disorder 20 – 40% of depressed children & adolescents 20 – 40% of depressed children & adolescents

develop bipolar disorder within 5 years of develop bipolar disorder within 5 years of index episode of MDDindex episode of MDD

Predictors of Bipolar I Disorder onsetPredictors of Bipolar I Disorder onset:: Early onset MDDEarly onset MDD Psychomotor retardationPsychomotor retardation Psychotic featuresPsychotic features Family history of bipolar disorderFamily history of bipolar disorder Family history of psychotic depressionFamily history of psychotic depression Heavy familial loading for mood disordersHeavy familial loading for mood disorders Pharmacologically induced (hypo)maniaPharmacologically induced (hypo)mania

Geller & Luby, 1997; Kovacs, 1996; Strober & Carlson, 1982Geller & Luby, 1997; Kovacs, 1996; Strober & Carlson, 1982

TreatmentTreatment

Opinions vary as to whether one should Opinions vary as to whether one should start with psychotherapy or medication or start with psychotherapy or medication or bothboth

Psycho-education of patient, family, and Psycho-education of patient, family, and teachers is criticalteachers is critical

Parental (and other family membersParental (and other family members’’) ) mental health issues should be addressedmental health issues should be addressed

Certainly, the least restrictive treatment Certainly, the least restrictive treatment and setting should be a starting pointand setting should be a starting point

Typical Exclusion Criteria Typical Exclusion Criteria for Pediatric Depression for Pediatric Depression

StudiesStudies ADHDADHD PTSDPTSD Bipolar DisorderBipolar Disorder Pervasive Pervasive

Developmental Developmental DisordersDisorders

Mental RetardationMental Retardation Externalizing Externalizing

DisordersDisorders PsychosisPsychosis

Any recent Any recent medication medication treatment (within treatment (within 2-4 weeks)2-4 weeks)

EtOH/drugsEtOH/drugs Eating DisorderEating Disorder Recent initiation of Recent initiation of

psychotherapypsychotherapy Potentially suicidal Potentially suicidal

patients (attempts patients (attempts in past year)in past year)

WhatWhat’’s in a Study?s in a Study?

The The ““gold standardgold standard”” for any type of for any type of clinical intervention study clinical intervention study (medication, therapy, community (medication, therapy, community intervention, etc.) is that it be:intervention, etc.) is that it be: RandomizedRandomized Double-BlindDouble-Blind

Blinded to subjectBlinded to subject Blinded to treatment teamBlinded to treatment team

Placebo ControlledPlacebo Controlled

Research Study Research Study InstrumentsInstruments

Kids are often not very good informants about their Kids are often not very good informants about their own mood stateown mood state

They often underestimate medication effects and They often underestimate medication effects and side effectsside effects

As a result various rating scales and surveys have As a result various rating scales and surveys have been designed to assess their responses to been designed to assess their responses to treatmenttreatment

Some of these are clinician administered:Some of these are clinician administered: ChildrenChildren’’s Depression Rating Scale (most commonly used)s Depression Rating Scale (most commonly used) Clinical Global ImpressionClinical Global Impression ChildrenChildren’’s Global Assessment Scales Global Assessment Scale Hamilton Depression Rating ScaleHamilton Depression Rating Scale

Some of these are child self-administered:Some of these are child self-administered: ChildrenChildren’’s Depression Inventorys Depression Inventory Beck Depression InventoryBeck Depression Inventory

Placebo EffectPlacebo Effect Typically very high in most medicationsTypically very high in most medications Studies of antidepressants in both children Studies of antidepressants in both children

and adults reveal approximately a 30% and adults reveal approximately a 30% placebo rateplacebo rate

Overall response rates to antidepressants are Overall response rates to antidepressants are about 65% at highest; consequently, about about 65% at highest; consequently, about half of that is due to placebohalf of that is due to placebo

True antidepressant response rate is about True antidepressant response rate is about 35%35%

Remember, the average length of a Remember, the average length of a depressive episode (not chronic) is 6 – 9 depressive episode (not chronic) is 6 – 9 months with or without treatmentmonths with or without treatment

Tricyclic Antidepressants (TCAs): Tricyclic Antidepressants (TCAs): HistoryHistory

The TCA story begins with the synthesis of The TCA story begins with the synthesis of chlorpromazine in 1950 from synthetic antihistamines chlorpromazine in 1950 from synthetic antihistamines first produced in the 1940s. Chlorpromazine was thought first produced in the 1940s. Chlorpromazine was thought to be an antihistamine, but in 1952 it was found to have to be an antihistamine, but in 1952 it was found to have profound psychiatric effects. By 1955 chlorpromazine was profound psychiatric effects. By 1955 chlorpromazine was widely used and rapidly revolutionized the world of widely used and rapidly revolutionized the world of inpatient psychiatry as the first effective antipsychotic. inpatient psychiatry as the first effective antipsychotic.

Imipramine, the first TCA, is an analogue of Imipramine, the first TCA, is an analogue of chlorpromazine, which was not designed for the treatment chlorpromazine, which was not designed for the treatment of depression but rather for psychosis. The drug's of depression but rather for psychosis. The drug's tendency to induce manic effects (and generally tendency to induce manic effects (and generally worsening psychosis in schizophrenics), however, was worsening psychosis in schizophrenics), however, was noted, and the paradoxical observation of a sedative noted, and the paradoxical observation of a sedative inducing mania lead to testing with depressed patients. inducing mania lead to testing with depressed patients. The first trial of imipramine took place in 1955, and the The first trial of imipramine took place in 1955, and the first report of its antidepressant effects was published in first report of its antidepressant effects was published in 1957. 1957.

Merck introduced the second member of the TCA family, Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.amitriptyline (Elavil), in 1961.

Tricyclic AntidepressantsTricyclic Antidepressants The The ““originaloriginal”” antidepressants antidepressants Examples:Examples:

DesipramineDesipramine AmitriptyleneAmitriptylene ImipramineImipramine ClomipramineClomipramine NortriptyleneNortriptylene

Putative Mechanism of Action: Block the Putative Mechanism of Action: Block the reuptake of norepinephrine, dopamine, and reuptake of norepinephrine, dopamine, and serotonin by neuronal presynaptic receptorsserotonin by neuronal presynaptic receptors

Unfortunately, while effective for adult Unfortunately, while effective for adult depression, they have shown little utility in depression, they have shown little utility in the treatment of pediatric depressionthe treatment of pediatric depression

TCA Mechanism of TCA Mechanism of ActionAction

Tricyclic Antidepressants Tricyclic Antidepressants (2)(2)

Open trials of TCAs have found that 60 – 80% of Open trials of TCAs have found that 60 – 80% of depressed children and 44 – 75% of depressed depressed children and 44 – 75% of depressed adolescents respond positivelyadolescents respond positively

At least 11 randomized DBPC trials each At least 11 randomized DBPC trials each demonstrated no difference between placebo demonstrated no difference between placebo and active TCA treatment (5 in adolescents, 6 in and active TCA treatment (5 in adolescents, 6 in children)children) Dulcan et al, 1998; Ryan & Varma, 1998Dulcan et al, 1998; Ryan & Varma, 1998

One study (Preskorn, 1987; n = 22) of depressed One study (Preskorn, 1987; n = 22) of depressed children (ages 6 – 14) treated with imipramine children (ages 6 – 14) treated with imipramine was positivewas positive

Meta-Analysis (Hazell et al, 1995) found no Meta-Analysis (Hazell et al, 1995) found no effecteffect

Tricyclic Antidepressants Tricyclic Antidepressants (3)(3)Problems with child & adolescent TCA studiesProblems with child & adolescent TCA studies::

Small sample sizesSmall sample sizes Diagnostic heterogeneity (e.g., mild, mod, severe Diagnostic heterogeneity (e.g., mild, mod, severe

depression) & included patients with secondary depression) & included patients with secondary depression (higher placebo response)depression (higher placebo response)

Studies of limited duration (6 – 8 weeks)Studies of limited duration (6 – 8 weeks) Lower doses were used because of cardiac safety Lower doses were used because of cardiac safety

concernsconcerns Noradrenergic (secondary amines) TCAs were Noradrenergic (secondary amines) TCAs were

exclusively used (receptors not fully developed in exclusively used (receptors not fully developed in children); except imipramine studychildren); except imipramine study

High prevalence of comorbid conditionsHigh prevalence of comorbid conditions More adolescents transition into Bipolar D/O than More adolescents transition into Bipolar D/O than

adults (and BP depression may be less responsive adults (and BP depression may be less responsive to TCAs)to TCAs)

More efficient hepatic metabolism of drugs in More efficient hepatic metabolism of drugs in childrenchildren

AminesAmines Tricyclics are sometimes classified as Tricyclics are sometimes classified as

secondary or tertiary amines. In general, the secondary or tertiary amines. In general, the tertiary amines boost serotonin as well as nor-tertiary amines boost serotonin as well as nor-epinephrine (adrenergic) and produce more epinephrine (adrenergic) and produce more sedation, anticholinergic effects, and sedation, anticholinergic effects, and orthostatic hypotension. The secondary orthostatic hypotension. The secondary amines act primarily on nor-epinephrine and amines act primarily on nor-epinephrine and tend to have a lower side-effect profile.tend to have a lower side-effect profile.

Tertiary amines include: Amitriptyline, Tertiary amines include: Amitriptyline, imipramine, trimipramine, doxepin, imipramine, trimipramine, doxepin, clomipramine, and lofepramine.clomipramine, and lofepramine.

Secondary amines include: Nortriptyline, Secondary amines include: Nortriptyline, desipramine, protriptyline, and amoxapine.desipramine, protriptyline, and amoxapine.

More About AminesMore About Amines Amines are organic Amines are organic

compounds whose compounds whose functional group functional group contains a nitrogen contains a nitrogen atom with a lone pair of atom with a lone pair of electrons. electrons.

A primary amine has A primary amine has one of the 3 hydrogen one of the 3 hydrogen atoms replaced by a atoms replaced by a carbon group.carbon group.

A secondary amine has A secondary amine has 2 hydrogen atoms 2 hydrogen atoms replaced by carbon replaced by carbon groups.groups.

A tertiary amine has 3 A tertiary amine has 3 hydrogen atoms hydrogen atoms replaced by carbon replaced by carbon groups. groups.

Desipramine Desipramine (Secondary)(Secondary)

Amitriptyline(TertiAmitriptyline(Tertiary)ary)

Clinical UseClinical Use

DepressionDepression Anxiety (particularly serotonergic Anxiety (particularly serotonergic

TCAs)TCAs) ADHDADHD AnalgesiaAnalgesia

Migraine headache preventionMigraine headache prevention Neuropathic pain (PNS)Neuropathic pain (PNS)

EnuresisEnuresis

TCA Side EffectsTCA Side Effects Most common TCA side effects are related to antimuscarinic Most common TCA side effects are related to antimuscarinic

(anticholinergic) activity, including:(anticholinergic) activity, including: Dry mouth (salivary secretion is affected) Dry mouth (salivary secretion is affected) Dry nose Dry nose Blurred vision (accommodation in the eye is affected) Blurred vision (accommodation in the eye is affected) Decreased gastro-intestinal motility and secretion Decreased gastro-intestinal motility and secretion

(constipation)(constipation) Urinary retention or difficulty with urination Urinary retention or difficulty with urination HyperthermiaHyperthermia

Tolerance to these adverse effects often develops if Tolerance to these adverse effects often develops if treatment is continuedtreatment is continued

Side effects may also be less troublesome if treatment is Side effects may also be less troublesome if treatment is initiated with low dose and then gradually increased, initiated with low dose and then gradually increased, although this may delay the clinical effect.although this may delay the clinical effect.

Other side effects may include drowsiness, anxiety, Other side effects may include drowsiness, anxiety, restlessness, cognitive and memory difficulties, confusion, restlessness, cognitive and memory difficulties, confusion, dizziness, akathisia, increased appetite with weight gain, dizziness, akathisia, increased appetite with weight gain, sweating, decrease in sexual ability and desire, muscle sweating, decrease in sexual ability and desire, muscle twitches, weakness, nausea and vomiting, hypotension, twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely irregular heart rhythm.tachycardia, and rarely irregular heart rhythm.

TCA Side EffectsTCA Side Effects

Safety Concerns with Safety Concerns with TCAsTCAs

Concern related to at least 8 reported Concern related to at least 8 reported cases of cases of ““suddensudden”” death in children and death in children and adolescents using TCAs for the adolescents using TCAs for the treatment of depression treatment of depression

QT prolongation and subsequent QT prolongation and subsequent torsade de pointes is the suggested torsade de pointes is the suggested cause of deathcause of death

Level of risk remains unclearLevel of risk remains unclear

Monoamine Oxidase Inhibitors Monoamine Oxidase Inhibitors (MAOI)(MAOI)

Monoamine oxidase inhibitors (MAOIs) are a Monoamine oxidase inhibitors (MAOIs) are a class of powerful antidepressantsclass of powerful antidepressants

They work by decreasing the function of They work by decreasing the function of monoamine oxidase, an intracellular enzyme monoamine oxidase, an intracellular enzyme which metabolizes neurotransmitterswhich metabolizes neurotransmitters

Due to potentially lethal dietary and drug Due to potentially lethal dietary and drug interactions, MAOIs had been reserved as a interactions, MAOIs had been reserved as a last line of defense, used only when other last line of defense, used only when other classes of antidepressant drugs have been classes of antidepressant drugs have been tried unsuccessfully. tried unsuccessfully.

Recently, however, a patch form of the drug Recently, however, a patch form of the drug selegiline (Emsam) was developed (2006). selegiline (Emsam) was developed (2006). When applied transdermally the drug does not enter When applied transdermally the drug does not enter

the gastro-intestinal system as it does when taken the gastro-intestinal system as it does when taken orally, thereby decreasing the dangers of dietary orally, thereby decreasing the dangers of dietary interactions associated with MAOI pills.interactions associated with MAOI pills.

MAOIs ContinuedMAOIs Continued

Isocarboxazid (Marplan) Isocarboxazid (Marplan) Phenelzine (Nardil) Phenelzine (Nardil) Tranylcypromine (Parnate) Tranylcypromine (Parnate) Selegiline (Eldepryl & Emsam)Selegiline (Eldepryl & Emsam)

Clinical UseClinical Use

In the past MAOIs were prescribed for In the past MAOIs were prescribed for those resistant to TCA therapy, but those resistant to TCA therapy, but newer MAOIs are now sometimes used newer MAOIs are now sometimes used as first-line therapy. as first-line therapy.

DepressionDepression Social Anxiety Social Anxiety Smoking CessationSmoking Cessation Atypical DepressionAtypical Depression NO data in children & adolescentsNO data in children & adolescents

Side EffectsSide Effects Hypertensive crisis (when foods containing tyramine Hypertensive crisis (when foods containing tyramine

are consumed) or hyperserotonemia (if foods are consumed) or hyperserotonemia (if foods containing tryptophan are consumed). MAO typically containing tryptophan are consumed). MAO typically degrades these products.degrades these products.

Assumed that tyramine displaces norepinephrine from Assumed that tyramine displaces norepinephrine from the storage vesicles, which may trigger a cascade in the storage vesicles, which may trigger a cascade in which excessive amounts of norepinephrine can lead to which excessive amounts of norepinephrine can lead to a hypertensive crisis. a hypertensive crisis.

Examples of foods and drinks with potentially high Examples of foods and drinks with potentially high levels of tyramine include fermented substances, such levels of tyramine include fermented substances, such as red chianti and other aged red wines and aged as red chianti and other aged red wines and aged cheeses. cheeses.

The most significant risk associated with the use of The most significant risk associated with the use of MAOIs is the potential for interactions with over-the-MAOIs is the potential for interactions with over-the-counter and prescription medicines, illicit drugs and counter and prescription medicines, illicit drugs and certain supplements (e.g. St. Johncertain supplements (e.g. St. John’’s Wort). s Wort).

MAOIs should not be combined with other psychoactive MAOIs should not be combined with other psychoactive substances (antidepressants, illicit drugs, painkillers, substances (antidepressants, illicit drugs, painkillers, stimulants, etc.) except under expert care. stimulants, etc.) except under expert care.

Serotonin Specific Serotonin Specific Reuptake Inhibitors Reuptake Inhibitors

(SSRIs)(SSRIs) The The ““newnew”” antidepressants; much safer and easier antidepressants; much safer and easier

to prescribe and tolerateto prescribe and tolerate Examples:Examples:

Fluoxetine (Prozac®)Fluoxetine (Prozac®) Sertraline (Zoloft®)Sertraline (Zoloft®) Paroxetine (Paxil®)Paroxetine (Paxil®) Citalopram (Celexa®)Citalopram (Celexa®) Fluvoxamine (Luvox®)Fluvoxamine (Luvox®) Escitalopram (Lexapro®)Escitalopram (Lexapro®)

Putative Mechanism of Action: Block the Putative Mechanism of Action: Block the reuptake of serotonin by neuronal presynaptic reuptake of serotonin by neuronal presynaptic receptorsreceptors

Very useful for pediatric anxiety disorders; Very useful for pediatric anxiety disorders; generally less effective (but often useful) for generally less effective (but often useful) for pediatric depressionpediatric depression

Clinical UseClinical Use

DepressionDepression AnxietyAnxiety

OCD, Panic, Social, Generalized AnxietyOCD, Panic, Social, Generalized Anxiety Eating Disorders (especially Bulimia)Eating Disorders (especially Bulimia) Chronic PainChronic Pain Premature EjaculationPremature Ejaculation

Chemical StructureChemical Structure

SSRIs may look different from one SSRIs may look different from one another, but all of them block the another, but all of them block the reuptake of serotonin in the synapse reuptake of serotonin in the synapse between two neuronsbetween two neurons

SSRI Mechanism of SSRI Mechanism of ActionAction

Serotonin Specific Serotonin Specific Reuptake InhibitorsReuptake Inhibitors

Numerous open label studies report a 70 – 90% Numerous open label studies report a 70 – 90% response rate to SSRIs in adolescentsresponse rate to SSRIs in adolescents Ambrosini et al, 1999; Apter et al, 1994; Masi et al, 1997; McConville et Ambrosini et al, 1999; Apter et al, 1994; Masi et al, 1997; McConville et

al, 1996; Rey-Sanchez & Gutierrez-Casares, 1997; Rodriguez-Ramos et al, 1996; Rey-Sanchez & Gutierrez-Casares, 1997; Rodriguez-Ramos et al, 1996; Simeon et al, 1998al, 1996; Simeon et al, 1998

Simeon et al (1990) performed the first Simeon et al (1990) performed the first randomized DBPC study of SSRIs in 32 randomized DBPC study of SSRIs in 32 adolescents (13 – 18 y/o) using 60 mg fluoxetine adolescents (13 – 18 y/o) using 60 mg fluoxetine (Prozac(Prozac®) ®) vs. placebovs. placebo Rating scales included Ham-D and CGI Rating scales included Ham-D and CGI Results did not reach clinical significanceResults did not reach clinical significance

One historical case-control study (Strober et al, One historical case-control study (Strober et al, 1999) found fluoxetine superior to imipramine in 1999) found fluoxetine superior to imipramine in a severely ill inpatient adolescent populationa severely ill inpatient adolescent population

SSRIs (2): Fluoxetine SSRIs (2): Fluoxetine (Prozac(Prozac®)®)

Two randomized DBPC studies by Emslie et al demonstrated Two randomized DBPC studies by Emslie et al demonstrated the superiority of fluoxetine (Prozacthe superiority of fluoxetine (Prozac®) over placebo, leading to ®) over placebo, leading to FDA approval of fluoxetine for the treatment of pediatric FDA approval of fluoxetine for the treatment of pediatric depression (ages 7 – 17):depression (ages 7 – 17):

1.1. 1997 Single Site Study (sponsored by NIMH)1997 Single Site Study (sponsored by NIMH)*n = 90, 8-week study, nonpsychotic MDD, 20 mg of *n = 90, 8-week study, nonpsychotic MDD, 20 mg of fluoxetine vs. placebo; CDRS-R & CGIfluoxetine vs. placebo; CDRS-R & CGI56% (fluoxetine) vs. 33% (placebo) showed 56% (fluoxetine) vs. 33% (placebo) showed improvement on CGI; significant differences in weekly improvement on CGI; significant differences in weekly CDRS-R also noted (fluoxetine vs. placebo); no CDRS-R also noted (fluoxetine vs. placebo); no difference in complete symptom remissiondifference in complete symptom remission

2.2. 2002 Multisite Study (sponsored by Eli Lilly)2002 Multisite Study (sponsored by Eli Lilly)*n = 219, 9-week study, nonpsychotic MDD, 20 mg of *n = 219, 9-week study, nonpsychotic MDD, 20 mg of fluoxetine vs. placebo; CDRS-R & CGIfluoxetine vs. placebo; CDRS-R & CGI52% (fluoxetine) vs. 37% (placebo) showed 52% (fluoxetine) vs. 37% (placebo) showed improvement on CGI; greater mean improvement on improvement on CGI; greater mean improvement on fluoxetine by week #1 (and maintained through study) fluoxetine by week #1 (and maintained through study) on CDRS-R; remission rates 41% (fluoxetine) vs. 20% on CDRS-R; remission rates 41% (fluoxetine) vs. 20% (placebo)(placebo)

SSRIs (3): Paroxetine SSRIs (3): Paroxetine (Paxil(Paxil®)®)

One recognized favorable open label study (Rey-One recognized favorable open label study (Rey-Sanchez & Gutierrez-Casares, 1997)Sanchez & Gutierrez-Casares, 1997)

Keller et al (2001) performed a multisite Keller et al (2001) performed a multisite randomized DBPC trial of paroxetine in 275 randomized DBPC trial of paroxetine in 275 adolescents (12 – 18 y/o) vs. imipramine vs. adolescents (12 – 18 y/o) vs. imipramine vs. placebo (sponsored by GSK)placebo (sponsored by GSK) A priori primary outcomes (all not significant) A priori primary outcomes (all not significant)

included:included: Ham-D score Ham-D score ≤≤8 or a >50% reduction8 or a >50% reduction Statistically significant change in mean Ham-D scoreStatistically significant change in mean Ham-D score

Post hoc analysis of primary and secondary outcomes Post hoc analysis of primary and secondary outcomes (statistically significant) included:(statistically significant) included:

Revised Ham-D outcome to Revised Ham-D outcome to ≤≤8 8 ““onlyonly”” Depression item sub-scores on Ham-D and K-SADS-L Depression item sub-scores on Ham-D and K-SADS-L CGI (65.6% for paroxetine vs. 52.1% for imipramine and 48.3% CGI (65.6% for paroxetine vs. 52.1% for imipramine and 48.3%

for placebo)for placebo)

SSRIs (4): Paroxetine SSRIs (4): Paroxetine (Paxil(Paxil®) cnt®) cnt’’dd

Berard et al (2006) reported on a prospective Berard et al (2006) reported on a prospective international multicenter, RDBPC trial of paroxetine international multicenter, RDBPC trial of paroxetine for adolescents (13 – 18 y/o) with depressionfor adolescents (13 – 18 y/o) with depression Data collected from 286 adolescents in 10 countries (not Data collected from 286 adolescents in 10 countries (not

USA)USA) Response rate (at least 50% reduction from baseline) for Response rate (at least 50% reduction from baseline) for

paroxetine vs. placebo was not statistically significant for paroxetine vs. placebo was not statistically significant for Montgomery-Asberg Depression Rating Scale (MADRS) Montgomery-Asberg Depression Rating Scale (MADRS) scale nor K-SADSscale nor K-SADS

CGI was statistically better for paroxetine than placebo CGI was statistically better for paroxetine than placebo (69% vs. 57%), a secondary endpoint, with older (69% vs. 57%), a secondary endpoint, with older adolescents generally doing better than younger (>16). adolescents generally doing better than younger (>16). Generally tolerated well with a greater incidence of Generally tolerated well with a greater incidence of suicidal behavior (4.4% vs. 2.1%) in the paroxetine treated suicidal behavior (4.4% vs. 2.1%) in the paroxetine treated group, but not statistically significantgroup, but not statistically significant

SSRIs (5): Paroxetine SSRIs (5): Paroxetine (Paxil(Paxil®) cnt®) cnt’’dd

Emslie et al (2006) completed a randomized, multicenter, Emslie et al (2006) completed a randomized, multicenter, double-blind, placebo-controlled trial of Paroxetinedouble-blind, placebo-controlled trial of Paroxetine 206 patients, aged 7 to 17 years old with major depressive 206 patients, aged 7 to 17 years old with major depressive

disorder, received paroxetine (10-50 mg/day) or placebo for 8 disorder, received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to 2001weeks from 2000 to 2001

The primary efficacy measure was change from baseline in the The primary efficacy measure was change from baseline in the Children's Depression Rating Scale-Revised total score at week 8 Children's Depression Rating Scale-Revised total score at week 8 (LOCF)(LOCF)

Safety was primarily assessed by spontaneous reporting of Safety was primarily assessed by spontaneous reporting of adverse eventsadverse events

104 patients received paroxetine vs 102 who received placebo104 patients received paroxetine vs 102 who received placebo CDRS-R total score adjusted mean changes from baseline for CDRS-R total score adjusted mean changes from baseline for

patients receiving paroxetine and placebo were -22.58 (SE 1.47) patients receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38 points (SE 1.60), respectively (0.80, 95% confidence and -23.38 points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to 4.69, p = 0.684); thus, paroxetine was not shown interval -3.09 to 4.69, p = 0.684); thus, paroxetine was not shown to be more efficacious than placeboto be more efficacious than placebo

Side Effects included increased cough (5.9% versus 2.9%), Side Effects included increased cough (5.9% versus 2.9%), dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0% versus 1.0%). The incidence of adverse events of dizziness (5.0% versus 1.0%). The incidence of adverse events of suicidal behavior and/or ideation while taking study medication suicidal behavior and/or ideation while taking study medication (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo.(1/102) for placebo.

SSRIs (6): Sertraline SSRIs (6): Sertraline (Zoloft(Zoloft®)®)

One recognized favorable multicenter open label One recognized favorable multicenter open label study (Ambrosini et al, 1999)study (Ambrosini et al, 1999)

Wagner et al (2003) reported on two multisite-Wagner et al (2003) reported on two multisite-international separate controlled trials; data were international separate controlled trials; data were aggregated (sponsored by Pfizer)aggregated (sponsored by Pfizer) N = 376; age range 6 – 17 yearsN = 376; age range 6 – 17 years Primary outcome measures were mean change from baseline Primary outcome measures were mean change from baseline

in CDRS-R, and CGI & CGASin CDRS-R, and CGI & CGAS Changes in mean CDRS-R & CGI between drug & placebo Changes in mean CDRS-R & CGI between drug & placebo

were significantwere significant Based on a 40% decrease in adjusted CDRS-R total score at Based on a 40% decrease in adjusted CDRS-R total score at

study endpoint, 69% vs. 59% were respondersstudy endpoint, 69% vs. 59% were responders The treatment effect was only noted for adolescents (when The treatment effect was only noted for adolescents (when

broken down by age groups)broken down by age groups) When the trials are considered separately, no effect was When the trials are considered separately, no effect was

noted, possibly due to very high placebo rates (59% for CDRS, noted, possibly due to very high placebo rates (59% for CDRS, 53% for CGI)53% for CGI)

SSRIs (7): Citalopram SSRIs (7): Citalopram (Celexa(Celexa®)®)

Chart review by Bostic et al (1997) at CMHC Chart review by Bostic et al (1997) at CMHC of 21 adolescents showed favorable results on of 21 adolescents showed favorable results on CGI by 76% of patientsCGI by 76% of patients

Multisite DBPC study by Wagner et al (2004) Multisite DBPC study by Wagner et al (2004) randomly assigned 178 children and randomly assigned 178 children and adolescents (7 – 17 y/o) to 20 – 40 mg/d adolescents (7 – 17 y/o) to 20 – 40 mg/d citalopram or placebo for 8 weekscitalopram or placebo for 8 weeks Primary outcome measure was CDRS-R; secondary Primary outcome measure was CDRS-R; secondary

measure included CGImeasure included CGI Statistically significant improvement on the CDRS-Statistically significant improvement on the CDRS-

R was noted by week #1; by week #8 36% of R was noted by week #1; by week #8 36% of citalopram-treated patients vs. 24% of placebo citalopram-treated patients vs. 24% of placebo patients demonstrated a statistically significant patients demonstrated a statistically significant treatment responsetreatment response

CGI results were not significant (47% vs. 45%)CGI results were not significant (47% vs. 45%)

SSRIs (8): Citalopram SSRIs (8): Citalopram (Celexa(Celexa®)®)

Von Knorring et al (2006) reported on a randomized, double-blind, Von Knorring et al (2006) reported on a randomized, double-blind, multisite (Europe) placebo-controlled study of citalopram in multisite (Europe) placebo-controlled study of citalopram in adolescents with major depressive disorderadolescents with major depressive disorder 244 adolescents, 13 to 18 years old, with major depression were 244 adolescents, 13 to 18 years old, with major depression were

randomized to treatment with citalopram (n = 124) or placebo (n = 120)randomized to treatment with citalopram (n = 124) or placebo (n = 120) No significant differences in improvement of scores from baseline to No significant differences in improvement of scores from baseline to

week 12 between citalopram and placebo were found. The response rate week 12 between citalopram and placebo were found. The response rate was 59% to 61% in both groups according to the K-SADS and was 59% to 61% in both groups according to the K-SADS and Montgomery Asberg Depression Rating Scale (MADRS) Montgomery Asberg Depression Rating Scale (MADRS)

Remission (MADRS score < or =12) was achieved by 51% of patients Remission (MADRS score < or =12) was achieved by 51% of patients with citalopram and 53% with placebo. with citalopram and 53% with placebo.

A post hoc analysis revealed that more than two thirds of all patients A post hoc analysis revealed that more than two thirds of all patients received psychotherapy during this study. For those patients not received psychotherapy during this study. For those patients not receiving psychotherapy, there was a higher percentage of Kiddie-SADS-receiving psychotherapy, there was a higher percentage of Kiddie-SADS-P responders with citalopram (41%) versus placebo (25%) and a P responders with citalopram (41%) versus placebo (25%) and a significantly higher percentage of MADRS responders and remitters with significantly higher percentage of MADRS responders and remitters with citalopram (52% and 45%, respectively) versus placebo (22% and 19%, citalopram (52% and 45%, respectively) versus placebo (22% and 19%, respectively). respectively).

Side effects were mild. Suicide attempts, including suicidal thoughts and Side effects were mild. Suicide attempts, including suicidal thoughts and tendencies, were reported by 5 patients in the placebo group and by 14 tendencies, were reported by 5 patients in the placebo group and by 14 patients in the citalopram group (not significant) with no pattern with patients in the citalopram group (not significant) with no pattern with respect to duration of treatment, time of onset, or dosage. In contrast, respect to duration of treatment, time of onset, or dosage. In contrast, the suicidal ideation (Kiddie-SADS-P) single item showed worsening more the suicidal ideation (Kiddie-SADS-P) single item showed worsening more frequently in the placebo (18%) than in the citalopram group (8%). frequently in the placebo (18%) than in the citalopram group (8%).

SSRIs (9): Escitalopram SSRIs (9): Escitalopram (Lexapro(Lexapro®)®) A RDBPC trial by Wagner et al (2006) A RDBPC trial by Wagner et al (2006)

examined efficacy of escitalopram in 131 examined efficacy of escitalopram in 131 children and adolescents (6 – 17 y/o dosed children and adolescents (6 – 17 y/o dosed flexibly 10 – 20 mg/d) vs. 133 treated with flexibly 10 – 20 mg/d) vs. 133 treated with placeboplacebo

82% of patients completed treatment with no 82% of patients completed treatment with no major AEs (HA & GI pain more common in major AEs (HA & GI pain more common in active treatment group) and no induction of active treatment group) and no induction of SI/SASI/SA

Active treatment did not statistically separate Active treatment did not statistically separate from placebo at endpoint by CDRS-R with from placebo at endpoint by CDRS-R with LOCFLOCF

Post-hoc analysis of adolescent completers (12 Post-hoc analysis of adolescent completers (12 – 17 y/o) did statistically separate active drug – 17 y/o) did statistically separate active drug from placebo by CDRS-Rfrom placebo by CDRS-R

SSRIs (10): Escitalopram SSRIs (10): Escitalopram (Lexapro(Lexapro®)®) 8 week RDBPC trial of 10 – 20 mg escitalopram per 8 week RDBPC trial of 10 – 20 mg escitalopram per

day in adolescents 12 – 17 y/oday in adolescents 12 – 17 y/o 155 active treatment, 157 on placebo (n=312)155 active treatment, 157 on placebo (n=312) Statistically significant separation between drug Statistically significant separation between drug

and placebo at end of trial (LOCF, 83% completion and placebo at end of trial (LOCF, 83% completion rate) with a 22.1 point reduction in CDRS-R on rate) with a 22.1 point reduction in CDRS-R on active treatment versus 18.8 point reduction on active treatment versus 18.8 point reduction on placebo (p = 0.22), Effect Size = 0.27 (Emslie et al, placebo (p = 0.22), Effect Size = 0.27 (Emslie et al, 2009)2009)

16-week double-blind extension of Emslie study 16-week double-blind extension of Emslie study found that statistical separation was maintained for found that statistical separation was maintained for escitalopram treated group (Findling et al, 2008)escitalopram treated group (Findling et al, 2008)

The FDA review concluded that maintenance The FDA review concluded that maintenance efficacy could be extrapolated from data in adults, efficacy could be extrapolated from data in adults, although not systemically evaluated in adolescents.although not systemically evaluated in adolescents.

Side EffectsSide Effects When present, most notable during the first 1-4 weeks while the body When present, most notable during the first 1-4 weeks while the body

adapts to the drug (with the exception of sexual side effects, which adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment but often improve with time). Almost tend to occur later in treatment but often improve with time). Almost all SSRIs are known to cause one or more of these symptoms:all SSRIs are known to cause one or more of these symptoms: nausea, vomiting, diarrheanausea, vomiting, diarrhea drowsinessdrowsiness headache headache clenching of teeth clenching of teeth extremely vivid and strange dreams extremely vivid and strange dreams dizziness dizziness changes in appetite changes in appetite weight loss/gain (measured by a change in bodyweight of 7 pounds) weight loss/gain (measured by a change in bodyweight of 7 pounds) decreased sexual interest and/or anorgasmia decreased sexual interest and/or anorgasmia increased feelings of depression and anxiety increased feelings of depression and anxiety tremors tremors Autonomic dysfunction including orthostatic hypotension or sweatingAutonomic dysfunction including orthostatic hypotension or sweating AkathisiaAkathisia hyponatremia hyponatremia liver or renal impairment liver or renal impairment suicidal ideation suicidal ideation photosensitivity (increased risk of sunburn) photosensitivity (increased risk of sunburn)

Bupropion (WellbutrinBupropion (Wellbutrin®)®) Daviss et al (2001) treated 24 adolescents Daviss et al (2001) treated 24 adolescents

(11 – 16 y/o) w/ADHD and either MDD or (11 – 16 y/o) w/ADHD and either MDD or Dysthymia in an open label fashion with Dysthymia in an open label fashion with buproprion SRbuproprion SR

After a 1-2 week single-blind lead in, all After a 1-2 week single-blind lead in, all subjects were dosed with buproprion SR subjects were dosed with buproprion SR to a target dose of 3 mg/kg BID for up to to a target dose of 3 mg/kg BID for up to 10 weeks10 weeks

Clinician rating was the CGIClinician rating was the CGI 30% improvement during placebo lead in, 30% improvement during placebo lead in,

followed by an 88% improvement in followed by an 88% improvement in clinician rated depression by CGIclinician rated depression by CGI

Venlafaxine (EffexorVenlafaxine (Effexor®)®) Mandoki et al (1997) treated 33 children & Mandoki et al (1997) treated 33 children &

adolescents in a randomized DBPC fashion for 6-adolescents in a randomized DBPC fashion for 6-weeks (8-17 y/o) with MDD with either venlafaxine weeks (8-17 y/o) with MDD with either venlafaxine plus CBT or placebo plus CBT. The dose in the 8-12 plus CBT or placebo plus CBT. The dose in the 8-12 year olds was 37.5 mg/d whereas in the 13-17 year year olds was 37.5 mg/d whereas in the 13-17 year olds was 75 mg/d olds was 75 mg/d Rating scales included HAMD for those 12+ y/o and Rating scales included HAMD for those 12+ y/o and

CDRS for those < 12 y/o, parent ratings (CBCL) and CDRS for those < 12 y/o, parent ratings (CBCL) and patient ratings (CDI)patient ratings (CDI)

Improvement noted in many subjects, but results Improvement noted in many subjects, but results were not statistically significantwere not statistically significant

The authors suggest that the negative findings are due to The authors suggest that the negative findings are due to low dosages, high rates of hepatic metabolism in pediatric low dosages, high rates of hepatic metabolism in pediatric populations, short duration of treatment, and the fact that populations, short duration of treatment, and the fact that CBT may have distorted any medication effectCBT may have distorted any medication effect

CBT was beneficial regardless of active medication CBT was beneficial regardless of active medication treatment treatment

Venlafaxine (EffexorVenlafaxine (Effexor®) ®) contcont’’dd

Emslie et al (2007) reported on the use of Venlafaxine ER in two multicenter, randomized, placebo-controlled trials in children and adolescents, ages 7 – 17 years, with MDD conducted between October 1997 and August 2001 conducted between October 1997 and August 2001 Patients received venlafaxine ER (flexible dose, based on body Patients received venlafaxine ER (flexible dose, based on body

weight; intent to treat, n = 169) or placebo (intent to treat, n weight; intent to treat, n = 169) or placebo (intent to treat, n = 165) for up to 8 weeks. The primary measure was the = 165) for up to 8 weeks. The primary measure was the change from baseline in the CDRS-R at week 8change from baseline in the CDRS-R at week 8

There were no statistically significant differences between There were no statistically significant differences between venlafaxine ER and placebo on the CDRS-R. A post hoc age venlafaxine ER and placebo on the CDRS-R. A post hoc age subgroup analysis of the pooled data showed greater subgroup analysis of the pooled data showed greater improvement on the CDRS-R w/venlafaxine ER than with improvement on the CDRS-R w/venlafaxine ER than with placebo (-24.4 versus -19.9; p = .022) among adolescents placebo (-24.4 versus -19.9; p = .022) among adolescents (ages 12-17), but not among children (ages 7-11).(ages 12-17), but not among children (ages 7-11).

The most common adverse events were anorexia and The most common adverse events were anorexia and abdominal pain. Hostility and suicide-related events were abdominal pain. Hostility and suicide-related events were more common in venlafaxine ER-treated participants than in more common in venlafaxine ER-treated participants than in placebo-treated participants. There were no completed placebo-treated participants. There were no completed suicides.suicides.

Nefazodone (SerzoneNefazodone (Serzone®)®) Wilens et al (1997) reported on 7 cases of Wilens et al (1997) reported on 7 cases of

children & adolescents (average age = 12 children & adolescents (average age = 12 y/o) with depression (4 with BP depression) y/o) with depression (4 with BP depression) who took nefazodone for an average of 13 who took nefazodone for an average of 13 ((±±8) weeks at dosages averaging 350 mg/d8) weeks at dosages averaging 350 mg/d 56% of adolescents were 56% of adolescents were ““muchmuch”” or or ““very muchvery much””

improved on CGIimproved on CGI 2 of the 4 BP patients did well and 2 experienced 2 of the 4 BP patients did well and 2 experienced

mild manic activationmild manic activation Findling et al (2000) studied 23 youth (7 – Findling et al (2000) studied 23 youth (7 –

17 y/o) in a 8-week open label fashion to 17 y/o) in a 8-week open label fashion to explore the pharmacokinetics of nefazodoneexplore the pharmacokinetics of nefazodone Statistically significant improvements were noted Statistically significant improvements were noted

on the CDRS-R, CGI, and CGASon the CDRS-R, CGI, and CGAS Pharmacokinetics were variable, but the Pharmacokinetics were variable, but the

medication appeared medication appeared ““safesafe””

Mirtazapine (RemeronMirtazapine (Remeron®)®)

One published study; a multicenter open One published study; a multicenter open label study of mirtazapine in adolescents label study of mirtazapine in adolescents (12 – 18 y/o) with MDD (Haapasalo-Pesu (12 – 18 y/o) with MDD (Haapasalo-Pesu et al, 2004); n = 24et al, 2004); n = 24

Rating scales included Ham-D, BDI, & CGIRating scales included Ham-D, BDI, & CGI Doses of mirtazapine varied from 30 – 45 Doses of mirtazapine varied from 30 – 45

mg/dmg/d Statistically significant improvement Statistically significant improvement

noted on all rating scales (Ham-D = 78%; noted on all rating scales (Ham-D = 78%; CGI = 74%)CGI = 74%)

Currently FDA Approved Currently FDA Approved Antidepressants & Antidepressants &

IndicationsIndications Major Depressive DisorderMajor Depressive Disorder

Fluoxetine (ProzacFluoxetine (Prozac®) 8 – 17 y/o®) 8 – 17 y/o Escitalopram (Lexapro®) 12 – 17 y/oEscitalopram (Lexapro®) 12 – 17 y/o

Obsessive Compulsive DisorderObsessive Compulsive Disorder Fluoxetine (ProzacFluoxetine (Prozac®) 7 – 17 y/o®) 7 – 17 y/o Sertraline (ZoloftSertraline (Zoloft®) 6 – 17 y/o®) 6 – 17 y/o Fluvoxamine (LuvoxFluvoxamine (Luvox®) 8 – 17 y/o®) 8 – 17 y/o Clomipramine (Anafranil®) 11 – 17 y/oClomipramine (Anafranil®) 11 – 17 y/o

Antidepressant Antidepressant AugmentationAugmentation

LithiumLithium:: Strober et al (1992) examined the effect of LiCO3 Strober et al (1992) examined the effect of LiCO3

augmentation (300 mg TID) on imipramine in 24 augmentation (300 mg TID) on imipramine in 24 treatment refractory adolescent MDD (DSM-III or treatment refractory adolescent MDD (DSM-III or DSM-III-R) patients in a 3-week open label trial. DSM-III-R) patients in a 3-week open label trial. Mild beneficial effects notedMild beneficial effects noted

Walter et al (1998) noted effective LiCO3 Walter et al (1998) noted effective LiCO3 augmentation of venlafaxine (Effexor XRaugmentation of venlafaxine (Effexor XR®) in ®) in two adolescent casestwo adolescent cases

Ryan et al (1988) found LiCO3 augmentation in Ryan et al (1988) found LiCO3 augmentation in adolescents with a partial response to adolescents with a partial response to imipramine effective in a chart reviewimipramine effective in a chart review

Electroconvulsive Electroconvulsive TherapyTherapy

Case reports in children and adolescents dating to 1942; Case reports in children and adolescents dating to 1942; most cases suffer from lack of diagnostic clarity, small most cases suffer from lack of diagnostic clarity, small samples, and heterogeneous diagnosessamples, and heterogeneous diagnoses

Since 1990 numerous studies (all retrospective) have Since 1990 numerous studies (all retrospective) have reported success with ECT in adolescents with a variety reported success with ECT in adolescents with a variety of psychiatric disorders (but primarily unipolar or bipolar of psychiatric disorders (but primarily unipolar or bipolar mood disorders)mood disorders) Response rates vary from 51 – 100% in these studies, Response rates vary from 51 – 100% in these studies,

with higher response rates noted among those with with higher response rates noted among those with mood disorders (Ghaziuddin et al, 2004)mood disorders (Ghaziuddin et al, 2004)

Only one study (Kutcher & Robertson, 1995) compared Only one study (Kutcher & Robertson, 1995) compared treated patients with those who refused treatmenttreated patients with those who refused treatment

Significant improvements noted among those who received Significant improvements noted among those who received ECTECT

Treated patients had shorter hospital stays (74 vs. 176 days)Treated patients had shorter hospital stays (74 vs. 176 days)

ECT (2)ECT (2) Use estimates vary worldwideUse estimates vary worldwide

NIMH Study (Thompson & Blaine, 1987) NIMH Study (Thompson & Blaine, 1987) revealed about 1.5% of all ECT performed in revealed about 1.5% of all ECT performed in 1980 in the USA (or about 500 cases) were 1980 in the USA (or about 500 cases) were between 11 – 20 y/obetween 11 – 20 y/o

No mandatory reporting system currently existsNo mandatory reporting system currently exists Safety Safety

Guttmacher & Cretella (1988) noted that ECT Guttmacher & Cretella (1988) noted that ECT was ineffective in 4 cases and that prolonged was ineffective in 4 cases and that prolonged seizures (>4 minutes) were causedseizures (>4 minutes) were caused

This finding has not been replicated; all other This finding has not been replicated; all other studies have found ECT effective and with no studies have found ECT effective and with no greater side effects than those routinely found in greater side effects than those routinely found in adult studiesadult studies

Algorithm for Treatment of Algorithm for Treatment of Depression in Children and Depression in Children and

AdolescentsAdolescents

1.1. Fluoxetine*Fluoxetine*2.2. Alternate SSRI or SNRI*Alternate SSRI or SNRI*3.3. TCA*TCA*4.4. MAOIMAOI5.5. ECTECT*May augment with: lithium, T3, *May augment with: lithium, T3,

stimulant, buspar, pindolol, stimulant, buspar, pindolol, antipsychotic, 2antipsychotic, 2ndnd antidepressant, antidepressant, benzodiazepinebenzodiazepine

Psychotherapy StudiesPsychotherapy Studies 7 of 9 studies indicate that CBT is more efficacious than a 7 of 9 studies indicate that CBT is more efficacious than a

wait-list condition or than a non-CBT alternative wait-list condition or than a non-CBT alternative psychotherapy (Curry, 2001)psychotherapy (Curry, 2001)

Harrington et alHarrington et al’’s (1998) systematic review of CBT in s (1998) systematic review of CBT in depressed children & adolescents indicated a beneficial depressed children & adolescents indicated a beneficial effect in 62% of treated patients vs. 36% in placebo effect in 62% of treated patients vs. 36% in placebo groupsgroups

CBT is associated with more rapid remission of symptoms CBT is associated with more rapid remission of symptoms than is family or supportive therapy (Brent et al, 1997)than is family or supportive therapy (Brent et al, 1997)

Long term follow-up indicates high rates of remission or Long term follow-up indicates high rates of remission or recovery among adolescents with MDD but no superiority recovery among adolescents with MDD but no superiority of CBT over other psychotherapies (Birmaher et al, 2000)of CBT over other psychotherapies (Birmaher et al, 2000)

No single type of CBT has been shown to be more No single type of CBT has been shown to be more efficacious than any otherefficacious than any other

IPT has been shown more efficacious than a wait-list IPT has been shown more efficacious than a wait-list condition or minimal clinical management in two acute condition or minimal clinical management in two acute treatment studies (Mufson et al, 1999; Rossello & Bernal, treatment studies (Mufson et al, 1999; Rossello & Bernal, 1999)1999)

Ordinary PeopleOrdinary People

Based on a novel by Judith Guest about an Based on a novel by Judith Guest about an affluent familyaffluent family’’s painful adjustment to s painful adjustment to tragedy, Mary Tyler Moore and Donald tragedy, Mary Tyler Moore and Donald Sutherland play a seemingly happy couple Sutherland play a seemingly happy couple who lose the older of their two sons in a who lose the older of their two sons in a boating accident. boating accident.

Robert RedfordRobert Redford’’s Oscar winning directorial s Oscar winning directorial debut, and Tim Huttondebut, and Tim Hutton’’s film debut in 1980s film debut in 1980

After Tim Hutton, the younger son, tries to After Tim Hutton, the younger son, tries to kill himself, he is sent to a psychiatrist, Judd kill himself, he is sent to a psychiatrist, Judd HirschHirsch

New DataNew Data NIMH sponsored NIMH sponsored ““Treatment of Adolescents Treatment of Adolescents

with Depression Studywith Depression Study”” (TADS) (TADS) Multicenter controlled clinical trialMulticenter controlled clinical trial 12 – 17 y/o with MDD12 – 17 y/o with MDD Aims to compare the efficacy of fluoxetine, CBT, Aims to compare the efficacy of fluoxetine, CBT,

combination, and placebo at 36 weeks with 1 year combination, and placebo at 36 weeks with 1 year f/uf/u

NIMH sponsored NIMH sponsored ““Treatment of Resistant Treatment of Resistant Depression in AdolescentsDepression in Adolescents”” (TORDIA) (TORDIA) Multicenter controlled clinical trialMulticenter controlled clinical trial 12 – 17 y/o treatment resistant adolescents12 – 17 y/o treatment resistant adolescents Aims to compare the efficacy of fluoxetine, Aims to compare the efficacy of fluoxetine,

paroxetine, or venlafaxine, either alone or in paroxetine, or venlafaxine, either alone or in combination with CBT for 24 weeks with 1 year f/ucombination with CBT for 24 weeks with 1 year f/u

Medication + Therapy: The Medication + Therapy: The TADS StudyTADS Study

Multisite study of adolescents, aged 12 – 17 y/o; n = Multisite study of adolescents, aged 12 – 17 y/o; n = 439; tested for short (12 weeks) and longer term 439; tested for short (12 weeks) and longer term (36 weeks) effectiveness with durability (1 year (36 weeks) effectiveness with durability (1 year naturalistic follow-up) [March et al, 2004]naturalistic follow-up) [March et al, 2004]

Participants were randomly assigned to fluoxetine Participants were randomly assigned to fluoxetine alone (10 – 40 mg/d), CBT alone, fluoxetine with alone (10 – 40 mg/d), CBT alone, fluoxetine with CBT, or placebo; medications blinded, all CBT CBT, or placebo; medications blinded, all CBT conditions unblindedconditions unblinded

Rating scales included CDRS-R and CGIRating scales included CDRS-R and CGI Rates of response on the CDRS-R indicate that Rates of response on the CDRS-R indicate that

combined treatment (fluoxetine + CBT) was combined treatment (fluoxetine + CBT) was statistically superior to fluoxetine alone and CBT statistically superior to fluoxetine alone and CBT alone alone

Fluoxetine alone was superior to CBT alone, which Fluoxetine alone was superior to CBT alone, which did not separate from placebodid not separate from placebo

Rates of response on CGI for fluoxetine + CBT Rates of response on CGI for fluoxetine + CBT (71%), fluoxetine alone (61%), CBT alone (43%), (71%), fluoxetine alone (61%), CBT alone (43%), and placebo (35%)and placebo (35%)

TADS (2)TADS (2) Effect sizes at week 12 on the CDRS-R:Effect sizes at week 12 on the CDRS-R:

Combined = 0.98; Fluoxetine = 0.68; CBT = -0.03Combined = 0.98; Fluoxetine = 0.68; CBT = -0.03

Rates of Remission (<28 on CDRS-R):Rates of Remission (<28 on CDRS-R): Total by week 12 = 23% (37% COMB, 23% FLX, 16% CBT, 17% PBO)Total by week 12 = 23% (37% COMB, 23% FLX, 16% CBT, 17% PBO) Total by week 36 = 60% (60% COMB, 55% FLX, 64% CBT)Total by week 36 = 60% (60% COMB, 55% FLX, 64% CBT)

By 36 week extension, CBT had By 36 week extension, CBT had ““caught upcaught up”” with with fluoxetine and response rates were 69% for fluoxetine fluoxetine and response rates were 69% for fluoxetine and 65% for CBTand 65% for CBT

Combined CBT + fluoxetine reached maximum benefit Combined CBT + fluoxetine reached maximum benefit at week 18 (85% response rate), 3 months earlier than at week 18 (85% response rate), 3 months earlier than CBT or fluoxetine alone (all Rx converged at week 36, CBT or fluoxetine alone (all Rx converged at week 36, with med + CBT at 86%, med and CBT alone each at with med + CBT at 86%, med and CBT alone each at 81%)81%) Younger, less chronically depressed, higher functioning, less hopeless Younger, less chronically depressed, higher functioning, less hopeless

w/less SI, fewer melancholic features and comorbid dx, and those with w/less SI, fewer melancholic features and comorbid dx, and those with greater expectations for improvement were more likely to benefit from greater expectations for improvement were more likely to benefit from treatmenttreatment

24 suicide related events occurred in the 12 week study; only fluoxetine 24 suicide related events occurred in the 12 week study; only fluoxetine had more suicide related events than placebo; 5 total attempts; no suicide had more suicide related events than placebo; 5 total attempts; no suicide completioncompletion

TADS (3)TADS (3) Treatment consisted of 3 stages: (1) acute (12 weeks), (2) Treatment consisted of 3 stages: (1) acute (12 weeks), (2)

continuation (6 weeks more to 18continuation (6 weeks more to 18thth week), and (3) maintenance (18 week), and (3) maintenance (18 week to 36week to 36thth week) week)

242 FLX, CBT, and COMB patients in their assigned treatment at the 242 FLX, CBT, and COMB patients in their assigned treatment at the end of stage 1 were included in this studyend of stage 1 were included in this study

Stage 2 treatment varied based on stage 1 response. Stage 3 Stage 2 treatment varied based on stage 1 response. Stage 3 consisted of 3 CBT and/or pharmacotherapy sessions and, if consisted of 3 CBT and/or pharmacotherapy sessions and, if applicable, continued medicationapplicable, continued medication

Sustained response was defined as 2 consecutive Clinical Global Sustained response was defined as 2 consecutive Clinical Global Impression-Improvement ratings of 1 or 2 ("full response")Impression-Improvement ratings of 1 or 2 ("full response")

Among 95 patients (39.3%) who had not achieved sustained response Among 95 patients (39.3%) who had not achieved sustained response by week 12 (29.1% COMB, 32.5% FLX, and 57.9% CBT), sustained by week 12 (29.1% COMB, 32.5% FLX, and 57.9% CBT), sustained response rates during stages 2 and 3 were 80.0% COMB, 61.5% FLX, response rates during stages 2 and 3 were 80.0% COMB, 61.5% FLX, and 77.3% CBT (difference not significant)and 77.3% CBT (difference not significant)

Among the remaining 147 patients (60.7%) who achieved sustained Among the remaining 147 patients (60.7%) who achieved sustained response by week 12, CBT patients were more likely than FLX response by week 12, CBT patients were more likely than FLX patients to maintain sustained response through week 36 (96.9% vs patients to maintain sustained response through week 36 (96.9% vs 74.1%; P = .007; 88.5% of COMB patients maintained sustained 74.1%; P = .007; 88.5% of COMB patients maintained sustained response through week 36)response through week 36)

Total rates of sustained response by week 36 were 88.4% COMB, Total rates of sustained response by week 36 were 88.4% COMB, 82.5% FLX, and 75.0% CBT82.5% FLX, and 75.0% CBT

Thus, most adolescents with depression who had not achieved Thus, most adolescents with depression who had not achieved sustained response during acute treatment did achieve that level of sustained response during acute treatment did achieve that level of improvement during continuation and maintenance therapiesimprovement during continuation and maintenance therapies

Rohde et al, 2008Rohde et al, 2008

TADS (4)TADS (4) 196 patients followed 5 years out196 patients followed 5 years out 96% eventually recovered from the index 96% eventually recovered from the index

episode of MDE within 3.5 yearsepisode of MDE within 3.5 years Nearly half (46%) of those who recovered from Nearly half (46%) of those who recovered from

MDE became depressed again within 5 years, MDE became depressed again within 5 years, regardless of the initial treatment they receivedregardless of the initial treatment they received

Girls were more likely than boys to have a Girls were more likely than boys to have a repeat episode (58% versus 33%)repeat episode (58% versus 33%)

Those with an anxiety disorder were also more Those with an anxiety disorder were also more likely to have a recurrence (62% versus 42%)likely to have a recurrence (62% versus 42%)

Curry et al, 2010Curry et al, 2010

TORDIATORDIA RCT of 334 patients 12 – 18 years with MDD who had not RCT of 334 patients 12 – 18 years with MDD who had not

responded to 2 months of initial treatment with SSRI responded to 2 months of initial treatment with SSRI (CGI of 2 or less & 50% decrease on CDRS)(CGI of 2 or less & 50% decrease on CDRS)

12 weeks of:12 weeks of:1)1) Switch to a second SSRI (Paxil, Celexa, Prozac)Switch to a second SSRI (Paxil, Celexa, Prozac)2)2) Switch to a second SSRI + CBTSwitch to a second SSRI + CBT3)3) Switch to Effexor (150-225 mg)Switch to Effexor (150-225 mg)4)4) Switch to Effexor + CBTSwitch to Effexor + CBT

CBT + a switch to either medication regimen showed a CBT + a switch to either medication regimen showed a higher response rate (55%) than med switch alone (41%)higher response rate (55%) than med switch alone (41%)

No difference in response rate between a second SSRI No difference in response rate between a second SSRI and Effexor; more SEfx with Effexor (BP, rash)and Effexor; more SEfx with Effexor (BP, rash)

No differential effects on self harm or SINo differential effects on self harm or SI Less severe depression, less family conflict, and absence Less severe depression, less family conflict, and absence

of NS-SIB predicted better treatment response. COMB of NS-SIB predicted better treatment response. COMB treatment was more evident among youths who had more treatment was more evident among youths who had more comorbid disorders (esp ADHD and anxiety disorders), no comorbid disorders (esp ADHD and anxiety disorders), no abuse history, and less hopelessness. abuse history, and less hopelessness.

TORDIA (2)TORDIA (2) Patients were reassessed 48 and 72 weeks from intakePatients were reassessed 48 and 72 weeks from intake Remission defined as Remission defined as ≥ 3 weeks with ≤ 1 clinically significant ≥ 3 weeks with ≤ 1 clinically significant

symptom and no associated functional impairment and symptom and no associated functional impairment and relapse as ≥ 2 weeks with probable or definite depressive relapse as ≥ 2 weeks with probable or definite depressive disorder disorder

By 72 weeks, 61% had reached remissionBy 72 weeks, 61% had reached remission The group assigned to an SSRI had a more rapid decline in The group assigned to an SSRI had a more rapid decline in

self-reported depressive symptoms and SI than those self-reported depressive symptoms and SI than those assigned to venlafaxine (p>0.3)assigned to venlafaxine (p>0.3)

Those with more severe depression, greater dysfunction, and Those with more severe depression, greater dysfunction, and EtOH or drug use at baseline were less likely to remitEtOH or drug use at baseline were less likely to remit

Remitters diverged from nonremitters by 6 weeks of Remitters diverged from nonremitters by 6 weeks of treatmenttreatment

Of 130 in remission by week 24, 25% relapsed within the next Of 130 in remission by week 24, 25% relapsed within the next yearyear

Summary: Most achieved remission but more than 1/3 did Summary: Most achieved remission but more than 1/3 did not and ¼ of remitters experienced a relapsenot and ¼ of remitters experienced a relapse

Vitiello et al, 2010Vitiello et al, 2010

ADAPTADAPT Adolescent Depression Antidepressant and Adolescent Depression Antidepressant and

Psychotherapy TrialPsychotherapy Trial RDBPC trial of 208 adolescents, 11 – 17 y/o RDBPC trial of 208 adolescents, 11 – 17 y/o

(74% female), at six outpatient clinics in (74% female), at six outpatient clinics in EnglandEngland

Fluoxetine + CBT or Fluoxetine alone Fluoxetine + CBT or Fluoxetine alone 10 mg/d x 1 week, 20 mg/d x 5 weeks; if no response 10 mg/d x 1 week, 20 mg/d x 5 weeks; if no response

by week 6, 40 mg/d; if no response by week 12, 60 by week 6, 40 mg/d; if no response by week 12, 60 mg/dmg/d

CBT delivered for 12 weeks plus 1 session week 28CBT delivered for 12 weeks plus 1 session week 28 Groups did not differ at F/U at 12 and 28 weeksGroups did not differ at F/U at 12 and 28 weeks

Goodyer et al, 2007Goodyer et al, 2007

CBT + SertalineCBT + Sertaline Melvin et al (2006) evaluated the effects of CBT Melvin et al (2006) evaluated the effects of CBT

and sertraline, alone and in combination, for 73 and sertraline, alone and in combination, for 73 adolescents (12 – 18 years) in the Netherlandsadolescents (12 – 18 years) in the Netherlands Diagnoses included MDD, DD, or Dep NOSDiagnoses included MDD, DD, or Dep NOS Randomly assigned to one of 3 treatments (med, CBT, Randomly assigned to one of 3 treatments (med, CBT,

combined) at 3 community clinicscombined) at 3 community clinics Measures included the Reynolds Adolescent Depression Measures included the Reynolds Adolescent Depression

Scale, Revised ChildrenScale, Revised Children’’s Manifest Anxiety Scale, s Manifest Anxiety Scale, Suicidal Ideation Questionnaire, self report and CGISuicidal Ideation Questionnaire, self report and CGI

CBT demonstrated a superior acute treatment response CBT demonstrated a superior acute treatment response to sertraline at 12 weeks (OR = 6.86, CI 1.12 – 41.82), to sertraline at 12 weeks (OR = 6.86, CI 1.12 – 41.82), but all groups showed improvement maintained at 6 but all groups showed improvement maintained at 6 months; of those w/MDD 71% achieved partial months; of those w/MDD 71% achieved partial remission (CBT = 71%, Med = 33%, Comb = 47%)remission (CBT = 71%, Med = 33%, Comb = 47%)

Medication doses were lower than in prior sertraline Medication doses were lower than in prior sertraline studies and a slow titration schedule was utilizedstudies and a slow titration schedule was utilized

Black Box WarningBlack Box Warning

Recent FDA Recent FDA Antidepressant ControversyAntidepressant Controversy

9 drugs included in FDA review (fluoxetine, 9 drugs included in FDA review (fluoxetine, sertraline, paroxetine, fluvoxamine, sertraline, paroxetine, fluvoxamine, citalopram, bupropion, venlafaxine, citalopram, bupropion, venlafaxine, nefazodone, mirtazapine)nefazodone, mirtazapine)

Approximately 4400 patientsApproximately 4400 patients 25 placebo controlled studies (ranging from 25 placebo controlled studies (ranging from

4 – 16 weeks in duration):4 – 16 weeks in duration): 16 in MDD16 in MDD 4 in OCD4 in OCD 2 in GAD2 in GAD 1 in social anxiety disorder1 in social anxiety disorder 2 in ADHD2 in ADHD

Recent FDA Recent FDA Antidepressant Controversy Antidepressant Controversy

(2)(2) Pooled analyses of these studies found an excess Pooled analyses of these studies found an excess

of SI and attempts noted in children and of SI and attempts noted in children and adolescents taking antidepressants (roughly 4% adolescents taking antidepressants (roughly 4% in those taking medication vs. 2% in those taking in those taking medication vs. 2% in those taking placebo)placebo)

No suicides occurred in these trialsNo suicides occurred in these trials FDA could not rule out an increased risk of FDA could not rule out an increased risk of

suicidality for any of these medicationssuicidality for any of these medications Data was adequate to establish effectiveness in Data was adequate to establish effectiveness in

MDD only for fluoxetine based upon Emslie et alMDD only for fluoxetine based upon Emslie et al’’s s two studiestwo studies

Black Box Warning to apply to all antidepressantsBlack Box Warning to apply to all antidepressants

FDA Recommended FDA Recommended GuidelinesGuidelines

““After starting an antidepressant, your After starting an antidepressant, your child should generally see his/her child should generally see his/her healthcare provider:healthcare provider: Once a week for the first 4 weeksOnce a week for the first 4 weeks Every 2 weeks for the next 4 weeksEvery 2 weeks for the next 4 weeks After taking the antidepressant for 12 weeksAfter taking the antidepressant for 12 weeks After 12 weeks, follow your healthcare After 12 weeks, follow your healthcare

providerprovider’’s advice about how often to come s advice about how often to come backback

More often if problems or questions ariseMore often if problems or questions arise”” FDA Medication guide (rev 1/26/05)FDA Medication guide (rev 1/26/05) http://www.fda.gov/cder/drug/antidepressants/http://www.fda.gov/cder/drug/antidepressants/

default.htmdefault.htm

How Real is the Concern?How Real is the Concern? 12.5% (11 of 88) adolescents enrolled in a 12-16 12.5% (11 of 88) adolescents enrolled in a 12-16

week psychotherapy for depression trial week psychotherapy for depression trial (randomly assigned to CBT, systemic behavioral (randomly assigned to CBT, systemic behavioral family therapy, or nondirective supportive family therapy, or nondirective supportive therapy) reported suicidality at some point during therapy) reported suicidality at some point during treatment (no meds used) even though they treatment (no meds used) even though they denied suicidality on initial intake interview.  denied suicidality on initial intake interview. 

The detection of suicidality was improved by The detection of suicidality was improved by specific and systemmatic assessment, whereas in specific and systemmatic assessment, whereas in prior clinical trials of depression adverse events prior clinical trials of depression adverse events were reported by patients or observed.  Self-were reported by patients or observed.  Self-reported suicidality in the week prior to intake reported suicidality in the week prior to intake predicted the onset of emergent suicidality to a predicted the onset of emergent suicidality to a much greater extent than did interview-rated much greater extent than did interview-rated suicidality, treatment assignment, cognitive suicidality, treatment assignment, cognitive distortions, and depression severity.distortions, and depression severity.

Bridge et al 2005:  Emergent Suicidality in a Clinical Psychotherapy Trial for Adolescent Bridge et al 2005:  Emergent Suicidality in a Clinical Psychotherapy Trial for Adolescent Depression Depression

The Reality Is…The Reality Is…

The vast majority of teen The vast majority of teen suicide completers are not on suicide completers are not on an SSRI at the time of the an SSRI at the time of the eventevent

The risk of suicide increases The risk of suicide increases greatly for those with chronic greatly for those with chronic MDD, as opposed to those MDD, as opposed to those suffering a single MDE.suffering a single MDE.

The FDA and Adult The FDA and Adult SuicideSuicide

The FDA has recently reported that The FDA has recently reported that antidepressants double the risk of antidepressants double the risk of suicidal behavior in young adults (18 – suicidal behavior in young adults (18 – 25 years) from about 0.25% among 25 years) from about 0.25% among adults who took placebos to 0.5% among adults who took placebos to 0.5% among adults who took an antidepressantadults who took an antidepressant

The analysis found no increased risk of The analysis found no increased risk of completed suicides in patients taking completed suicides in patients taking the medicationsthe medications

The risk appears to decline with ageThe risk appears to decline with age

Antidepressant SalesAntidepressant Sales Prescriptions for antidepressants have Prescriptions for antidepressants have

dropped by 20% for those 18 y/o and younger dropped by 20% for those 18 y/o and younger since 2004 when FDA initial warnings were since 2004 when FDA initial warnings were publishedpublished

After concerns were raised in the After concerns were raised in the Netherlands about the suicide risk, there was Netherlands about the suicide risk, there was a 22 percent drop from 2003 to 2005 in a 22 percent drop from 2003 to 2005 in antidepressant prescriptions for patients antidepressant prescriptions for patients under 18 years and a corresponding 50 under 18 years and a corresponding 50 percent increase in suicides (the number of percent increase in suicides (the number of suicides increased from 34 to 51)suicides increased from 34 to 51)

Sales of antidepressants among adults were Sales of antidepressants among adults were down 14% in 2005down 14% in 2005

Sales are climbing again in 2006Sales are climbing again in 2006

Antidepressant Sales & Antidepressant Sales & Suicide RatesSuicide Rates

Recent data suggest that antidepressant sales Recent data suggest that antidepressant sales of Prozac, amongst others, may be tied to a of Prozac, amongst others, may be tied to a decrease in overall suicide ratedecrease in overall suicide rate

The U.S. suicide rate held fairly steady for 15 The U.S. suicide rate held fairly steady for 15 years from 1973 – 1988 at 12.2 – 13.7/100,000years from 1973 – 1988 at 12.2 – 13.7/100,000

Subsequent to the introduction of Prozac in Subsequent to the introduction of Prozac in 1988, the suicide rate gradually declined to 1988, the suicide rate gradually declined to 10.4/100,000 in 2000. This drop is associated 10.4/100,000 in 2000. This drop is associated with an increase in Prozac prescriptions from with an increase in Prozac prescriptions from 2.47 million in 1988 to 33.32 million in 2002.2.47 million in 1988 to 33.32 million in 2002.

Adopting this data, the decrease in suicides Adopting this data, the decrease in suicides totals 33,600 (Licinio et al, 2006)totals 33,600 (Licinio et al, 2006)

Uh Oh…Uh Oh… From 2003 to 2004, the suicide rate among Americans From 2003 to 2004, the suicide rate among Americans

younger than 19 years rose 18 percent, the most dramatic younger than 19 years rose 18 percent, the most dramatic one-year change since the government started collecting one-year change since the government started collecting suicide statistics in 1979. Between 2003 and 2005 the suicide statistics in 1979. Between 2003 and 2005 the number of SSRI prescriptions for pediatric depression (ages number of SSRI prescriptions for pediatric depression (ages 5 – 18) dropped by more than 50%.5 – 18) dropped by more than 50%.

The rise followed a sharp decrease in the prescribing of The rise followed a sharp decrease in the prescribing of SSRI antidepressants after placement of the Black Box SSRI antidepressants after placement of the Black Box Warning. Warning.

The data suggest that for every 20 percent decline in The data suggest that for every 20 percent decline in antidepressant use among patients of all ages in the United antidepressant use among patients of all ages in the United States, an additional 3,040 suicides per year would occur. States, an additional 3,040 suicides per year would occur. About 32,000 Americans commit suicide each year.About 32,000 Americans commit suicide each year.

If the drugs were causing a high rate of suicide, then the If the drugs were causing a high rate of suicide, then the reduction in prescriptions should have caused a decrease in reduction in prescriptions should have caused a decrease in the suicide rate.the suicide rate.

The study included the Netherlands, which had a 22 The study included the Netherlands, which had a 22 percent decrease in antidepressant use among children percent decrease in antidepressant use among children between 2003 and 2005. The suicide rate among youngsters between 2003 and 2005. The suicide rate among youngsters there increased by 49 percent in that period.there increased by 49 percent in that period.

Gibbons, 2007Gibbons, 2007

TADS Lessons About TADS Lessons About SuicideSuicide Remember that 24 suicide related events Remember that 24 suicide related events

occurred in the 12 week study; only fluoxetine occurred in the 12 week study; only fluoxetine had more suicide related events than placebo; 5 had more suicide related events than placebo; 5 total attempts; no suicide completiontotal attempts; no suicide completion

Findings across 36 weeks demonstrates that Findings across 36 weeks demonstrates that patients treated with FLX alone were twice as patients treated with FLX alone were twice as likely as patients treated with combined FLX + likely as patients treated with combined FLX + CBT or CBT alone to show both clinically CBT or CBT alone to show both clinically significant SI (on patient report) and to significant SI (on patient report) and to experience treatment emergent suicide events (on experience treatment emergent suicide events (on clinician report): FLX 14.7%, COMB 8.4%, and clinician report): FLX 14.7%, COMB 8.4%, and CBT alone 6.3%CBT alone 6.3%

Thus: (1) There is no increased risk of a suicide Thus: (1) There is no increased risk of a suicide event with CBT; (2) there is a protective effect on event with CBT; (2) there is a protective effect on suicidality from adding CBT to medicationsuicidality from adding CBT to medication

The Other Side of The Other Side of Summer Summer

After a decade long decline in the After a decade long decline in the suicide rate among youths, 10 – 19 suicide rate among youths, 10 – 19 y/o, there was an 18% increase in y/o, there was an 18% increase in suicide rates in 2004, a trend that suicide rates in 2004, a trend that persisted in 2005persisted in 2005

This analysis shows 326 more deaths This analysis shows 326 more deaths than expected in 2004 and 292 more than expected in 2004 and 292 more deaths than expected in 2005deaths than expected in 2005

Bridge et al, 2008Bridge et al, 2008

Evidence Based Treatment Evidence Based Treatment Recommendations:Recommendations:Take Home PointsTake Home Points

When treating pediatric depression, When treating pediatric depression, start with either CBT and/or medicationstart with either CBT and/or medication

If medication is employed, you should If medication is employed, you should seriously consider using fluoxetine first seriously consider using fluoxetine first lineline

You need to develop a monitoring You need to develop a monitoring strategy to comply with FDA guidelinesstrategy to comply with FDA guidelines