The Diagnosis and Treatment of Pediatric Depression

1. The Diagnosis and Treatment of Pediatric Depression Jess P. Shatkin, MD, MPH Vice Chair for Education NYU Child Study Center New York University School of Medicine

2. Presentation Outline We will review the following: • Pediatric Depression Disease State • Medication Treatment • Tricyclic Antidepressants • Serotonin Specific Reuptake Inhibitors • Other antidepressants • Augmenting medications & ECT • Psychotherapy Treatment • Manualized therapies (CBT, IPT) • Psychodynamic psychotherapy • Current FDA Controversy • Evidence based treatment recommendations

3. Learning Objectives Participants will be able to: • Describe the primary differences between pediatric and adult depression. • Identify evidence-based pharmacologic and non-pharmacologic treatments for pediatric depression. • Make rational treatment recommendations for children and adolescents with depression.

4. A Brief History of Depression in Children and Adolescents • Case reports on childhood depression date to the early 17th century • Melancholia in children was first reported in the mid-19th century • In general, however, the existence of depression prior to 1960 was seriously doubted because it was felt that children’s immature superego would not permit the development of depression • Research from Europe and NIMH funded American studies in the 1970’s increased the awareness & acceptance of childhood depression

5. Psychoanalytic Perspective • Psychoanalytic theory posits that depression results from an intrapsychic conflict between the ego and a persecutory superego • Psychoanalysis held that the superego was formalized only after resolution of the Oedipal Conflict, which occurred by late adolescence • By this theory, then, children could not experience intrapsychic conflict and, ergo, could not develop mood disorders

6. Epidemiology • Varying rates have been reported; no large, well accepted epidemiologic studies • Generally accepted 1-year incidence is: *Preschool age 1% *School age 2% *Adolescent age 4 - 8% • Gender ratio of 1:1 in childhood and 2:1 (female to male) by adolescence • Lifetime prevalence of MDD among adolescents is 15 – 20% (similar to adults); 15.3% per NCS • Kashani & Sherman, 1988; Fleming & Offord, 1990; Lewinsohn et al, 1993 & 1994; Kessler & Walters, 1998

7. Epidemiology (2) • Studies on Dysthymia suggest a wide range in point prevalence: children from 0.6 – 1.7%; and adolescents from 1.6 – 8.0% • Garrison et al, 1992; Kashani et al, 1987; Lewinsohn et al 1993 & 1994 • Studies in specialized populations show increased incidence, such as 40% among children on neurology wards with unexplained headaches (Ling et al, 1970); 7% of general pediatric inpatients (Kashani et al, 1981); 28% of children in psychiatric clinics (Carlson & Cantwell, 1980); 59% of child psychiatry inpatients (Petti, 1978); and 27% of adolescent inpatients (Robbins et al, 1982)

8. Epidemiology (3) • Prevalence increases during adolescence, possibly due to: • Biological factors (e.g., sexual maturation) • Environmental factors (e.g., increased social/academic expectations, more chance of exposure to negative events) • Psychological & cognitive factors (e.g., increased autonomy and abstract thinking) • Since 1940, each successive generation has been at higher risk for MDD

9. Ordinary People Conrad Jarrett is 16 and has survived a boating accident in which his brother, Buck, died. The book takes place as Conrad tries to readjust to life back at home after a psychiatric hospitalization for a suicide attempt. He sees a psychiatrist, Dr. Berger, who tries to address Conrad’s chief desire upon presenting (e.g., he wants to be in control). This scene takes place as Berger is asking Conrad about quitting the swim team.

10. Etiology: Theories of Depression • Psychodynamic: anger turned inward; severe superego • Attachment: insecure early attachment • Behavioral: inability to obtain reinforcement • Cognitive: depressive mindset • Self-Control: deficits in self-monitoring, self-evaluation, and self-reinforcement • Interpersonal: characteristic to individual, roles and events • Socioenvironmental: stressful life circumstances exacerbate vulnerabilities • Neurobiological: neurochemical, endocrine, and receptor abnormalities

12. Genetics (1) • Findings from twin studies suggest a moderate genetic influence on depression in community samples with heritability ranging from 35 – 75% across studies (Eley, 1999; Glowinski et al, 2003) • Twin/adoption studies have not been conducted, so the extent to which clinical depression in children and adolescents is genetically driven is not known • Still, children with a parent who suffered from depression as a child are up to 14x more likely than controls to become depressed prior to age 13 (Weissman et al, 1988) • Children of parents with depression have about 2-3x the risk of having depression (Beardslee et al, 1998; Weissman et al, 1997)

13. Genetics (2) • Children of depressed parents have an earlier age of onset for their depression by 3 years (Weissman et al, 1997) • The lifetime history of MDD in mothers of children with MDD is also high, about 50 – 75% (Kovacs, 1997) • A family history of depression is more common in 1st degree relatives of children with MDD than in children without MDD (Wickramaratne et al, 2000) • Adults with one or two copies of the short allele of the 5-HT Transporter gene have been shown to exhibit more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events (Caspi et al 2003)

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

15. Even More about Mothers • Effective treatment of mothers with MDD is associated with a reduction of anxiety, depressive, and disruptive disorders and symptoms in their offspring (Weissman et al, 2006; STAR*D trial which follows 151 mother/child pairs at 3 month intervals) • Remission of maternal depression after 3 months of medication treatment was significantly associated reductions in children’s diagnoses and symptoms; diagnoses dropped by 11% vs. an 8% increase in diagnoses among those children whose mothers did not respond to medication treatment • Of the children with MDE at baseline, remission occurred in 33% of those whose mother’s depression remitted vs. 12% of those whose mother’s depression did not remit • 17% of children (without dx at baseline) whose mothers remained depressed developed a psychiatric diagnosis at 3 month f/u vs. none of those whose mothers responded to treatment

16. And Fathers? • Medical Expenditure Panel Survey data (N = 22K US children, ages 5 – 17) of both mothers and fathers; data generated by parents only. • Scales used: PHQ-2, SF-12, MCS, CIS, PCS • Risks of child emotional/behavioral problems are much greater if mothers, rather than fathers, have such problems: • Paternal MH problems are independently associated with a 33 – 70% increased risk • Maternal MH problems are associated with a 50 -350% increased risk • Weitzman et al, 2011

17. Serotonin Gene • Among those with pervasive suicidal thoughts and intent, levels of the major serotonin metabolite (5-HIAA) are lower in the cerebrospinal fluid. • Adults with one or two copies of the short allele of the 5-HT Transporter gene have been shown to exhibit more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events (Caspi et al 2003)

18. Biogenic Amine Hypothesis The biogenic amine or catecholamine hypothesis suggests that too much neurotransmitter causes mania and too little causes depression. Too simplistic, but supported by the observation that medications that increase dopamine, norepinephrine, and serotonin improve depression and worsen mania. Many limitations to this hypothesis, including the fact that L-dopa and tryptophan, direct precursors of amines, have no effect on mood; and cocaine and amphetamines which block amine reuptake do not generally improve depression.

19. Neuroendocrine Markers 70% of adults do not show normal suppression of cortisol secretion following administration of dexamethasone (DST), suggesting an alteration in stress response. Blunting of normal growth hormone release in response to insulin challenge. Blunted production of thyroid stimulating hormone in response to thyroid releasing hormone

20. Annie Hall • Woody Allen’s 1976 breakthrough film about his relationships with women • Won the Academy Award for Best Picture • Early in the film he reflects upon his childhood in Brooklyn, which is filled with exaggerations of how he “remembers” his childhood • He also demonstrates the increased abstract thinking which can sometimes overwhelm children as they enter adolescence

22. Clinical Presentation • DSM-IV Criteria do not differ for children & adolescents • Generally, children show fewer neurovegetative signs than adults • Irritability may substitute for depressed mood

23. Diagnosis (1) • The DSM-IV requires 5 of 9 symptoms for the diagnosis • At least two straight weeks in duration with symptoms present pretty much every day or most of every day • Not better accounted for by another illness • MDE = Major Depressive Episode • MDD = Major Depressive Disorder (2 or more episodes, lifetime) • Specifiers • Severity, psychosis, chronic, atypical, postpartum, melancholic

24. Diagnosis (2) • Depressed Mood *in children, can substitute “irritable” mood • Anhaedonia (diminished interest & pleasure) • Significant decrease in weight (5%) *in children, failure to make expected weight gains • Insomnia or hypersomnia • Psychomotor agitation or retardation • Fatigue or loss of energy • Feelings of worthlessness or excessive guilt • Diminished ability to think or concentrate or indecisiveness • Recurrent thoughts of death or suicidal ideation

25. Children: More symptoms of anxiety (e.g., phobias, separation anxiety), somatic complaints, and auditory hallucinations Depression is expressed as temper tantrums & behavior problems Fewer delusions and serious suicide attempts By middle childhood, preoccupations w/death, lowered self-esteem, social withdrawal/rejection, & poor school performance Adolescents: More cognitive components to their depression than children Guilt and hopelessness become apparent More sleep & appetite disturbances, delusions, suicidal ideation & attempts Compared to adults, still more behavior problems and fewer neurovegetative difficulties Developmental Variants of MDD

26. Clinical Variants of MDD • Unipolar Depression • Psychotic Depression • Bipolar Depression • Atypical Depression • Seasonal Affective Disorder • Subclinical or subsyndromal Depression • Treatment-Resistant Depression

27. Comorbidities • Most children with MDD have a comorbid psychiatric diagnosis: *40 – 90% have a second psychiatric disorder *20 – 50% have two or more comorbid disorders • Dysthymia and Anxiety Disorders (30 – 80%); Disruptive Disorders (10 – 80%); and Substance Use Disorders (20 – 30%) • MDD usually manifests after the onset of other psychiatric disorders, except substance abuse • Conduct problems may develop secondary to depression and persist after the depression is effectively treated • Separation anxiety is more common in children, whereas SUDS, conduct disorder, social phobia, and GAD are more common in adolescents -Birmaher et al, 1996; Goodyer et al, 1997; Kovacs, 1996; Rohde et al, 1991; Biederman et al, 1995; Weissman et al, 1997

29. Thirteen • Tells the story of Tracy, who is a straight-laced, geeky, 13 y/o A student growing up in LA with her brother, Mason. • Her divorced mother is a recovering drug addict living with her former cocaine addict boyfriend; her absent & generally unsuccessful father is struggling with earning enough money to support the kids and develop something for himself. • She becomes friends with Evie, a cool kid, by acting out and as teen stress mounts in her life, she begins to cut to cope. • In this scene, her father, who has not been paying close attention, struggles to figure out what’s going on with his daughter.

31. Differential Diagnosis • Adjustment Disorder with Depressed Mood • Bereavement • General Medical Conditions (e.g., hypothyroidism, cancer, lupus, anemia, HIV, diabetes, epilepsy, etc.) • Chronic Fatigue Syndrome • Medication induced (stimulants, neuroleptics, corticosteroids, contraceptives)

32. Differential Diagnosis (2): Nonaffective Psychiatric D/O’s • Anxiety Disorders • ADHD • Externalizing Disorders • Learning Disorders • SUDS • Eating Disorders • Personality Disorders • Premenstrual Dysphoric Disorder

33. Median duration: Clinically referred: 7 – 9 months; community: 1 – 2 months Predictors of increased duration: depression severity, comorbidity, negative life events, parental psychiatric disorders, poor psychosocial functioning 90% of MDD episodes remit w/in 1-2 years after onset (where remission is 2 weeks – 2 months with only 1 clinically significant symptom) ≈ 50% relapse 6 – 10% of MDD are protracted Clarke et al, 1992; Goodyer et al, 1997; Kovacs, 1996; Lewinsohn et al, 1994 & 1997; Reinecke et al, 1998; Sanford et al, 1995; Warner et al, 1992 Clinical Course

34. Relapse • Relapse is an episode of MDD during a period of remission • 40 – 60% of youth with MDD experience relapse after successful treatment of acute episode (indicates the need for continual treatment) • Predictors of relapse: natural course of MDD, lack of compliance, negative life events, rapid decrease/discontinuation of therapeutic treatment • Emslie et al, 1997; Kovacs, 1996; Lewinsohn et al, 1994; Vostanis et al, 1996; Wood et al, 1996

35. Recurrence is the emergence of MDD symptoms during a period of recovery (asymptomatic period of more than 2 months) Clinical & community samples show probability of recurrence 20 – 60% w/in 1-2 years post-remission and 70% after 5 years Predictors of Recurrence: Earlier age at onset Increased number of prior episodes Severity of initial episode Psychosis Psychosocial stressors Dysthymia & other comorbidities Treatment noncompliance Emslie et al, 1997; Kovacs et al, 1996 & 1997; Lewinsohn et al, 1994 Recurrence

36. Risk of Bipolar Disorder • 20 – 40% of depressed children & adolescents develop bipolar disorder within 5 years of index episode of MDD Predictors of Bipolar I Disorder onset: • Early onset MDD • Psychomotor retardation • Psychotic features • Family history of bipolar disorder • Family history of psychotic depression • Heavy familial loading for mood disorders • Pharmacologically induced (hypo)mania • Geller & Luby, 1997; Kovacs, 1996; Strober & Carlson, 1982

37. Treatment • Opinions vary as to whether one should start with psychotherapy or medication or both • Psycho-education of patient, family, and teachers is critical • Parental (and other family members’) mental health issues should be addressed • Certainly, the least restrictive treatment and setting should be a starting point

38. ADHD PTSD Bipolar Disorder Pervasive Developmental Disorders Mental Retardation Externalizing Disorders Psychosis Any recent medication treatment (within 2-4 weeks) EtOH/drugs Eating Disorder Recent initiation of psychotherapy Potentially suicidal patients (attempts in past year) Typical Exclusion Criteria for Pediatric Depression Studies

39. What’s in a Study? • The “gold standard” for any type of clinical intervention study (medication, therapy, community intervention, etc.) is that it be: • Randomized • Double-Blind • Blinded to subject • Blinded to treatment team • Placebo Controlled

40. Research Study Instruments • Kids are often not very good informants about their own mood state • They often underestimate medication effects and side effects • As a result various rating scales and surveys have been designed to assess their responses to treatment • Some of these are clinician administered: • Children’s Depression Rating Scale (most commonly used) • Clinical Global Impression • Children’s Global Assessment Scale • Hamilton Depression Rating Scale • Some of these are child self-administered: • Children’s Depression Inventory • Beck Depression Inventory

41. Placebo Effect • Typically very high in most medications • Studies of antidepressants in both children and adults reveal approximately a 30% placebo rate • Overall response rates to antidepressants are about 65% at highest; consequently, about half of that is due to placebo • True antidepressant response rate is about 35% • Remember, the average length of a depressive episode (not chronic) is 6 – 9 months with or without treatment

42. Tricyclic Antidepressants (TCAs): History • The TCA story begins with the synthesis of chlorpromazine in 1950 from synthetic antihistamines first produced in the 1940s. Chlorpromazine was thought to be an antihistamine, but in 1952 it was found to have profound psychiatric effects. By 1955 chlorpromazine was widely used and rapidly revolutionized the world of inpatient psychiatry as the first effective antipsychotic. • Imipramine, the first TCA, is an analogue of chlorpromazine, which was not designed for the treatment of depression but rather for psychosis. The drug's tendency to induce manic effects (and generally worsening psychosis in schizophrenics), however, was noted, and the paradoxical observation of a sedative inducing mania lead to testing with depressed patients. The first trial of imipramine took place in 1955, and the first report of its antidepressant effects was published in 1957. • Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.

43. Tricyclic Antidepressants • The “original” antidepressants • Examples: • Desipramine • Amitriptylene • Imipramine • Clomipramine • Nortriptylene • Putative Mechanism of Action: Block the reuptake of norepinephrine, dopamine, and serotonin by neuronal presynaptic receptors • Unfortunately, while effective for adult depression, they have shown little utility in the treatment of pediatric depression

44. TCA Mechanism of Action

45. Tricyclic Antidepressants (2) • Open trials of TCAs have found that 60 – 80% of depressed children and 44 – 75% of depressed adolescents respond positively • At least 11 randomized DBPC trials each demonstrated no difference between placebo and active TCA treatment (5 in adolescents, 6 in children) • Dulcan et al, 1998; Ryan & Varma, 1998 • One study (Preskorn, 1987; n = 22) of depressed children (ages 6 – 14) treated with imipramine was positive • Meta-Analysis (Hazell et al, 1995) found no effect

46. Tricyclic Antidepressants (3) Problems with child & adolescent TCA studies: • Small sample sizes • Diagnostic heterogeneity (e.g., mild, mod, severe depression) & included patients with secondary depression (higher placebo response) • Studies of limited duration (6 – 8 weeks) • Lower doses were used because of cardiac safety concerns • Noradrenergic (secondary amines) TCAs were exclusively used (receptors not fully developed in children); except imipramine study • High prevalence of comorbid conditions • More adolescents transition into Bipolar D/O than adults (and BP depression may be less responsive to TCAs) • More efficient hepatic metabolism of drugs in children

47. Amines • Tricyclics are sometimes classified as secondary or tertiary amines. In general, the tertiary amines boost serotonin as well as nor-epinephrine (adrenergic) and produce more sedation, anticholinergic effects, and orthostatic hypotension. The secondary amines act primarily on nor-epinephrine and tend to have a lower side-effect profile. • Tertiary amines include: Amitriptyline, imipramine, trimipramine, doxepin, clomipramine, and lofepramine. • Secondary amines include: Nortriptyline, desipramine, protriptyline, and amoxapine.

48. Amines are organic compounds whose functional group contains a nitrogen atom with a lone pair of electrons. A primary amine has one of the 3 hydrogen atoms replaced by a carbon group. A secondary amine has 2 hydrogen atoms replaced by carbon groups. A tertiary amine has 3 hydrogen atoms replaced by carbon groups. Desipramine (Secondary) Amitriptyline(Tertiary) More About Amines

49. Clinical Use • Depression • Anxiety (particularly serotonergic TCAs) • ADHD • Analgesia • Migraine headache prevention • Neuropathic pain (PNS) • Enuresis

50. TCA Side Effects • Most common TCA side effects are related to antimuscarinic (anticholinergic) activity, including: • Dry mouth (salivary secretion is affected) • Dry nose • Blurred vision (accommodation in the eye is affected) • Decreased gastro-intestinal motility and secretion (constipation) • Urinary retention or difficulty with urination • Hyperthermia • Tolerance to these adverse effects often develops if treatment is continued • Side effects may also be less troublesome if treatment is initiated with low dose and then gradually increased, although this may delay the clinical effect. • Other side effects may include drowsiness, anxiety, restlessness, cognitive and memory difficulties, confusion, dizziness, akathisia, increased appetite with weight gain, sweating, decrease in sexual ability and desire, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely irregular heart rhythm.