Pediatric Mood Disorders: From Neurobiology to Clinical Practice Fadi Maalouf, M.D. Assistant Professor of Psychiatry Child and Adolescent Psychiatry / AUBMC Adjunct Asst Prof of Psychiatry University of Pittsburgh Outline • Introduction • Pediatric Depression o Clinical Presentations and Epidemiology o Etiology (genetics and neurobiology) o Treatment • Pediatric Bipolar Disorder • Conclusion Mood Disorders • Unipolar disorders: Major depressive disorder (Pediatric Depression) Dysthymic disorder Depressive disorder not otherwise specified (nos) • Bipolar disorders: Bipolar Type I, II, nos Cyclothymic disorder • Mood disorders secondary to a general medical condition or substances.. Pediatric Depression • Doubted the existence of pediatric depression until mid 1970’s– immature personality structures. • In 1970 4th congress of European child psychiatrist- Depressive states in children and adolescents”. • DSM III early 80’s criteria adjustment for children. Omar • Omar is a 13 year-old boy who presents to his pediatrician with a few-month-history of recurrent asthma attacks resulting from non-compliance with his inhalers. Upon further questioning, • He has been failing his tests which is unusual for him. • In addition, he has not been spending as much time with friends • He dropped out of basketball practice and has not been going to family events. • His mother, who is being treated for a “nervous breakdown” reports that Omar has been quite irritable lately. • He has had difficulty getting up in the morning, and appears tired. • She reports that she found “dark poems” written in his room. Criteria • MDD in children and adolescents is characterized by one or more major depressive episode, defined as at least 2 weeks of persistent change in mood manifested by either depressed or irritable mood (in children) or loss of interest or pleasure AND at least 4 additional symptoms of depression, • Changes in appetite or weight (or failure to achieve expected weight gain in children) • Changes in sleep • Psychomotor activity, • Decreased energy, • Feelings of worthlessness or guilt, • Difficulty thinking or concentrating, • Recurrent thoughts of death or suicidal ideation, plans, or attempts. • The symptoms must persist for most of the day nearly every day, and must be associated with an impairment in functioning (social, academic or other), must not represent the direct physiologic effect of a substance or a general medical condition and must not be better accounted for by bereavement. Clinical Presentation • Preschoolers may exhibit irritability, withdrawal, temper tantrums or regression as symptoms of depression. • School-age children may display crying spells, or somatic complaints such as headaches and stomachaches. They look sad and describe themselves in a negative manner “ I am dumb”, “ I am stupid”, “ nobody likes me”. School performance deteriorate. • Adolescents: Irritability, loss of interest, substance use, suicidal thoughts, hypersomnia. Probability of Experiencing an Episode of Major Depressive Disorder as a Function of Age and Gender (Lewisnshon et. al 1998) Course Social Developmental Changes in adolescence as risk factors: • Decreased adult supervision and support • Increased concern about social status and social rejection • Increased parent-child conflict. • Lifestyle changes that can predispose to depression, such as substance use and sleep deprivation (Dahl, 2004; Nelson et al., 2005) Health risk behaviors Tobacco and substance abuse Overeating and obesity Low physical activity Engagement in unprotected sex and Antisocial behavior Brooks et al., 2002 Course It is recurrent: 40% experiencing a second episode within 2 years, and nearly 75% within 5 years. Almost all will go on to experience another episode in their adult life. Age-Specific Rates of Major Depressive Disorder Over 20 Years in Offspring of Depressed and Nondepressed Parents ( Weissman et.al American Journal of Psychiatry 2006) The percentage of individuals meeting diagnostic criteria for depression at age 26, as a function of 5HT T genotype and number of stressful life events between the ages of 21 and 26. The figure shows individuals with either one or two copies of the short allele (left) and individuals homozygous for the long allele (right). (Caspi et. al Science 2003) Results of regression analysis estimating the association between childhood maltreatment (between the ages of 3 and 11 years) and adult depression (ages 18 to 26), as a function of 5-HT T genotype. (Caspi et. al Science 2003) Genotype-based parametric comparisons illustrating significantly greater activity in the right amygdala of the s group versus the l group (A Hariri, Science 2002) Neural model of emotion regulation illustrating neural systems implicated in voluntary and automatic subprocesses of emotion regulation, (a) Feedforward pathway: medial prefrontal cortical system, including the OFC, subgenual ACG, rostral ACG, hippocampus and parahippocampus and MdPFC. (b) Feedback pathway: lateral prefrontal cortical system, including DLPFC and VLPFC. DLPFC, dorsolateral prefrontal cortex; MdPFC, dorsomedial prefrontal cortex; ACG, anterior cingulate gyrus; VLPFC, ventrolateral prefrontal cortex; OFC, orbital frontal cortex; hipp/parahip, hippocampus-parahippocampus region. Why these domains Phillips, M et. al 2003 “CANTABeclipse can be used with your own desktop, laptop or tablet PC running Windows XP or 2000. Also available is the system pre-installed and ready for use, on high specification tablet PCs with built-in touch screen”. www.cantab.com Subjects tested require no computer skills, interacting directly with the touch screen and, for accurate reaction times, the supplied press pad. Stockings of Cambridge The subject must use the balls in the lower display to copy the pattern shown in the upper one. The balls may be moved one at a time by touching the required ball then touching the position to which it should be moved. Forward Planning • Maalouf et. al under review Affective Go/ No-Go The Affective Go/No-go (AGN) test assesses information processing biases and inhibitory control for positive and negative stimuli. A series of words is rapidly presented in the centre of the screen. These words are positive, negative or neutral valence. The subject is given a target valence and is asked to press the press pad when they see a word that matches this valence. Affective Go/No-Go Three dependent measures of interest: Response time (time to respond to each target), error rate (response to distractor stimuli) and omissions (failure to respond to target). Affective Bias Maalouf et. al, 2009 Treatment • Why is it important to treat? It is associated with substantial impairment in school and interpersonal relationships, tobacco and substance abuse, suicide attempts, and a 30-fold increased risk of completed suicide. Treatment • Clinical guidelines for the acute management of adolescent depression recommend the prescribing of selective serotonin reuptake inhibitor (SSRI) medications, with or without psychotherapy, with the best-studied psychotherapy being cognitive behavioral therapy (CBT). Weiz et. al 2006, Birmaher et al 2007 Mechanism of Action • SSRI antidepressants work by inhibiting reuptake of serotonin by pre-synaptic neurons, with at least 70% reuptake inhibition required to result in clinical improvement. • Studies in adults show that antidepressants increase dorsal prefrontal activity and decrease limbic activity, which allows the patient to better modulate emotional reactions. Axelson et al., 2005 and Lesch et al., 1993. SSRI They include • Fluoxetine (Prozac) – FDA apporved (age 8-18) • Sertraline (Zoloft) • Paroxetine ( Seroxat, Paxil CR) • Fluvoxamine (Faverin), • Citalopram (Cipram), • and Escitalopram (Cipralex)- FDA approved(12-17) . Treatment of Adolescent Depression Study • 439 adolescent outpatients with major depression • Randomized to twelve weeks 1. Fluoxetine (10-40 mg/day) 2. CBT with fluoxetine (10-40 mg/day) 3. CBT alone 4. Placebo (Treatment for Adolescents with Depression Study Team (TADS), JAMA, 2004; 292: 807-820) TADS Response Rate FLX + CBT FLX CBT PLB 73% (Differed from PLB) 62% (Differed from PLB) 48% (Did not Differ from PLB) 35% Positive Double-blind Placebo Controlled Depression Trials Medication Ages Number of studies Citalopram 7-17 1 Escitalopram 12-17 1 Fluoxetine 7-17 8-17 12-17 3 Sertraline 6-17 2 Negative Double-blind Placebo Controlled Depression Trials Medication Ages Number of studies Citalopram 13-18 1 Escitalopram 6-17 1 Mirtazapine 7-18 7-18 2 Paroxetine 7-17 12-18 13-18 3 Venlafaxine 7-17 7-17 2 SSRI-side effects • • • • Suicidality Activation Mood switching Misc: Agitation, insomnia, nausea, initial weight loss, decreased libido, irritability. • Others-rare but serious (Serotonin syndrome, EPS, elevated bleeding time) USA TODAY Antidepressants and Suicide By Marilyn Elias, Could antidepressants prescribed for more than 1 million U.S. children and teenagers cause some of them to attempt suicide? SSRI-Suicidality • But what is the true story and how did everything start? SSRI-Suicidality • On Oct 15th 2004, a black box warning was issued. “Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders”. Suicidal Story-Ctn’d • FDA pooled data from 24 studies that examined SSRI use in a total of 4400 children/teenagers with MDD and/or anxiety. • The FDA performed post-hoc analyses employing many sub-analyses since none of the original 24 studies were designed to study the impact of SSRI on suicidality. Suicidal story-Ctn’d • Which means a panel of expert tried to best determine whether an event recorded years ago may have reflected suicidality. What did the numbers show? Suicidality • 78 events of suicidal thinking/behavior identified among 4400 patients. Efficacy vs suicide Risk of Antidepressants in Pediatric Patients But wait a minute . Annual Rates of Depression in the Pediatric General Medical and Specialty Managed Care Enrollee Population, (libby et al , AJP, 2007 Suicide Rate in Children and Adolescents (Ages 5–19 Years) in the United States, 1988–2004 (Gibbons et. al AJP 2007) Clinical Course: Risk of Bipolar Disorder • 20%-40% MDD youth develop bipolar disorder in 5 years of onset of MDD. • • • • • • Predictors of Bipolar I Disorder Onset: Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Pharmacologically induced hypomania What is Bipolar Disorder ? • Costly, common (1%+), treatable • Defined by recurrent episodes of mania (or hypomania) and depression • Often misdiagnosed The DSM-IV categorizes it into: • Bipolar I Disorder • Bipolar II Disorder • Cyclothymia • Bipolar N.O.S. Criteria for mania • A. A distinct period of abnormally and persistently elevated , expansive or irritable mood (class clown, giddy, goofy) • B. At least 3/7 (4/7 if mood is irritable) 1- D Distractibility 2- I Increased Activity/ psychomotor agitation 3- G Grandiose or elevated self-esteem (bossy, defiant) 4- F Flight of ideas or racing thoughts 5- A Activities with painful consequences 6- S Sleep decreased 7- T Talkative or pressured speech • http://www.gcbf.org/books/Did_You_Ever_ Feel/index.html Parent Support group-Humor You might have a child with bipolar disorder if .... • • • • • • • • • • You spend more money on meds than on food You have the psychiatrist on speed dial. The school has YOU on speed dial! You have holes in your walls and doors coming off the hinges, but that' s the last thing you' re worried about. Everyone at the school knows your child, and gives you "the look". All of your friends and family are ready, willing, and able to give YOU advice on what to do with your child(ren), but refuse to even babysit for you for one night. You drive like you' re 100 years old for fear of an object being hurled at your head. . You' re on a first name basis with your pharmacist. Instead of passing condescending looks, you' re sympathetic when you see a mom with another child who is raging in public. You' ve been kicked out of every daycare in town. Some ways Pediatric Mood Disorders differ from adult Mood Disorders • Children with Bipolar disorder have much faster and more frequent cycles than adults . • Children rarely have pure euphoric mania as defined by the DSM-IV. They are more likely to have oppositional bossiness and irritability. • The co-morbidity of other disorders can make medical treatment very difficult in children. Children are more likely to be activated by certain medications, namely antidepressants and psychostimulants, than adults. • Bipolar disorder in children is often misdiagnosed as unipolar depression with hyperactivity. Treatment for unipolar depression is vastly different from treatment for bipolar disorder . Some ways Pediatric Mood Disorders are similar to adult Mood Disorders • Children can be suicidal. These ideations can quickly develop into plans and actions. • Children with mania have the same urges that adults do, they also become hypersexual, grandiose, obsessive and desire to spend money. • Children, like adults, require medication to stabilize their mood. Therapy when coupled with medications has been quite successful. • Stress, just as with adults, can trigger a relapse. Towards mentally healthy children--- Thanks