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Treatment of pediatric bipolar disorder 82010
 

Treatment of pediatric bipolar disorder 82010

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This is a presentation I did for Pediatric Grand Rounds at Akron Children's Hospital in the summer of 2010 on the diagnosis and treatment of bipolar disorder in kids. The content is still very current ...

This is a presentation I did for Pediatric Grand Rounds at Akron Children's Hospital in the summer of 2010 on the diagnosis and treatment of bipolar disorder in kids. The content is still very current in 2012...the term "Disruptive Mood Dysregulation Disorder" has been substituted for "Temper Dysregulation Disorder" in the debate on the DSM-V. Here's a link to the video:

https://www.akronchildrens.org/cms//b42450956e85aa39/index.html

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  • Average duration of treatment=10.8 weeks The Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SAIETY) study was conducted between December 2001 and September 2007 at tertiary-care, academic inpatient and outpatient clinics in Queens, New York. Participants included 272 antipsychotic-naive patients aged 4 to 19 years. A total of 130 participants (47.8%) had mood spectrum disorder, 82 patients (30.1%) had schizophrenia, and 60 participants (22.1%) had disruptive or aggressive behavior spectrum disorder "We always thought that most of the effect on glucose and lipid metabolism was really coming through the indirect effect of weight gain," Dr. Correll said. "So in other words, if you gain weight, with or without the medications, it affects both glucose and lipid metabolism. This appears to be true to some degree, but there also appears to be a weight-independent effect that some of these medications have more than others.” Furthermore, the study also showed that adverse changes reached statistical significance for olanzapine only for fasting glucose, insulin, and insulin resistance. Moreover, quetiapine showed significant worsening of total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and ratio of triglycerides to HDL cholesterol. With risperidone, only triglycerides increased significantly. However, at least during the first 3 months of treatment, baseline-to-endpoint changes were not significant with aripiprazole or in the untreated comparison group
  • Olanzapine has been associated with lipid, cholesterol elevation in other studies (TEOSS) Aripiprazole-frequently associated with akathisia Risk of dystonic reactions is age-related…the younger the child, the greater the vulnerability
  • Differences In Bipolar Disorder Between Children And Adults: Children often have less well-defined beginning and end points to a specific episode of a mood disturbance Children may be more predisposed to “rapid-cycling” between episodes, as compared to adults Because of the early age of onset, Bipolar illness originating in childhood has been hypothesized as a potentially more severe form of the illness “ Pearls”: Early-onset bipolar disorder has been closely associated with an increased risk of substance abuse. Probably a greater risk with adolescent-onset than childhood onset. Bipolar disorder is in the differential whenever a prepubescent child is diagnosed with a substance abuse or chemical dependency disorder.
  • Doubt “ultrarapid” and “ultradian” cycling represent bipolar disorder as we understand it-AACAP agrees
  • Bipolar Disord. 2010 Mar;12(2):185-95. Clinical characteristics of comorbid obsessive-compulsive disorder and bipolar disorder in children and adolescents. Joshi G, Wozniak J, Petty C, Vivas F, Yorks D, Biederman J, Geller D. Rate of comorbid OCD=21%-Joshi study
  • Geller et al assessed diagnostic data from the first 60 BPD and first 60 ADHD cases from 270 consecutively ascertained subjects and found that elated mood, grandiosity, hypersexuality, decreased need for sleep, racing thoughts, and all other mania items (except hyperenergetic and distractibility) were significantly and substantially more frequent among BDP than ADHD cases. Prepubertal and adolescent BPD cases differentiate from ADHD by mania-specific criteria and commonly present with ultra-rapid or ultradian cycling. Journal of the American Academy of Child & Adolescent Psychiatry 
October 1998 (Vol. 37, Issue 10, Page 1005) This was a letter to the editor of JAACAP Great question for boards!
  • ADHD is the most significant condition in the differential diagnosis. Most researchers note that nearly 100% of patients with bipolar disorder also meet criteria for ADHD. Most ADHD kids do not have Bipolar Disorder, but data from a large HMO (Biederman) suggests that as many as 25% of patients with ADHD are eventually diagnosed as bipolar. Anxiety spectrum disorders may the issue in kids with SMD/TDD Medical conditions to be ruled out would include metabolic conditions (thyroid, parathyroid, adrenal disease), autoimmune conditions (SLE), infectious diseases (hepatitis, mononucleosis, HIV), and neurologic conditions. Culturally, studies have noted that members of minority groups with new onset of bipolar illness may often be misdiagnosed with schizophrenia. (Many clinicians are very reluctant to diagnose schizophrenia in children and adolescents when in doubt, because bipolar disorder presumably has a better prognosis). Adolescents with prominent features of an emerging Borderline Personality Disorder are often misdiagnosed with bipolar disorder, because these adolescents often complain of “mood swings”. With this population, it is important to note the duration of the shifts in mood, and to evaluate these shifts in the context of diagnostic criteria for mood disorders.
  • We’re not sure what these kids have! SMD? Suspect they’ll go on to be ADHD/Depressed, ADHD/anxious
  • What are differences with SMD? The name SMD would subsequently be changed to TDD and the hyperarousal criterion dropped. So what did we learn from research on SMD? We learned that children with SMD are as severely impaired as those who suffer from classical (episodic) Bipolar Disorder. But there are important differences between those who met criteria for SMD and those who met criteria for Bipolar Disorder (BD). The groups differed in their outcome, gender ratio, and possibly family history. Let me focus on just a few of the most significant findings here: Children with SMD/chronic irritability were at risk for later anxiety and unipolar depressive disorders — they did not turn out to be risk of developing BD. That finding, which was replicated by several studies, suggests that diagnosing children with non-episodic chronic irritability as having Bipolar Disorder may not only be inaccurate as opposed to premature, it may lead to offering these children ineffective or possibly harmful treatments. In children and adults with classic (episodic) BD, the gender ratio is approximately even. That means that males and females are equally likely to have the disorder. In children with SMD, however, boys outnumbered girls by a ratio of about 3:1.SMD is a serious mood disorder and is as impairing as BD in the short-term and long-term.85% of children and teens diagnosed with SMD also met diagnostic criteria for ADHD and Oppositional Defiant Disorder (ODD). That is not surprising when you think about chronically irritable children look like and how disruptive their behavior can be. But SMD is more than just ADHD+ODD, as it involves mood. Furthermore, children with severe irritability frequently meet diagnostic criteria for an anxiety disorder and have a family history of depression.
  • AACAP resource document regarding APA’s proposed criteria for DSM-V
  • This is all personal opinion-I think these kids have subsyndromal OCD/anxiety They get irritability as a side effect of ADHD meds-exacerbates their awareness of anxiety, irritabiity comes from inability to tolerate thoughts, emotions Bet serotonin interferes with PFC pathways modulating emotional self-regulation!
  • Clinical Implications: These drugs should be considered a first-line intervention in treatment of acute manic and mixed bipolar disorder symptoms. Patients should receive a complete physical prior to the start of antipsychotic medications. Prescribers must assess for any medical problems that could complicate medical treatment, such as liver, kidney, thyroid or cardiac problems Prescribers must monitor for weight gain, increased pulse and presence of EPS. AIMs exams should be administered at medication appointments to assess for symptoms of tardive dyskinesia, and routine blood pressure should be assessed. Baseline laboratory tests should include liver enzymes, triglycerides, cholesterol level, fasting glucose levels, prolactin levels, bilirubin, serum ammonia and complete blood count, including platelets. Correll has several excellent articles on this. Patients should be weighed at baseline and each subsequent visit. Laboratory values should be repeated to assess any changes in lipids, triglycerides, cholesterol and liver enzymes. A baseline ECG and repeat ECG can be administered for patients if there is concern of cardiac problems in the patient or a family history of cardiac problems. If a patient is on ziprasidone, an ECG should be used to evaluate prolongation of QTC intervals, especially in higher doses. [84] Somnolence should also be evaluated, and dosing should be adjusted for adverse effects. Attention should be paid to the type of antipsychotic chosen that both reduces symptoms and minimizes weight gain for those patients with a high BMI. For example, olanzapine has demonstrated the greatest amount of weight gain and risperidone has demonstrated elevation in prolactin levels, whereas aripiprazole has demonstrated less weight gain. However, in some studies aripiprazole has resulted in weight loss after treatment with a different antipsychotic medication. Starting with an antipsychotic that minimized weight gain or switching the type of antipsychotic used should be considered for patients who demonstrate a significant amount of weight gain. Nutritional coaching and an exercise plan should be included in every patient's treatment plan. Metformin was evaluated in 39 youths with mood and psychotic disorders whose weight increased by 10% during 1 year on olanzapine, risperidone or quetiapine therapy in a 16-week double-blind, placebo-controlled trial. [85] Patients who received metformin had weight stabilization, whereas those receiving placebo continued to gain weight at a rate of 0.68 lb per week. [85] Patients should be seen frequently while initiating medication, as dose adjustments with the antipsychotics may be warranted to achieve remission of symptoms. Monitoring of adverse effects and symptoms can occur in these visits.
  • Clinical Implications: Modest improvement can be anticipated in youths with acute-phase bipolar disorder. Adjunctive medications for symptom management of bipolar and comorbid diagnoses may be warranted. Lithium's small therapeutic window (0.8 to 1.2 mEq/l) can precipitate significant adverse effects, particularly at toxic levels. To achieve an accurate lithium level, blood should be drawn 12 h after a dose. A physical examination should be completed before the start of lithium treatment, and the patient should not have any renal problems. Baseline blood work should include a lithium level, blood urea nitrogen, creatinine concentration, thyroid function tests, electrolytes and a complete blood count, and should be repeated every 6 months once steady state is achieved (usually reached after 1 week in children). Pregnancy tests should be obtained for adolescents of childbearing age and education on appropriate measures to prevent pregnancy should be discussed. The starting dose is usually 300 mg per day titrated up every 3–5 days until the level is within a therapeutic range. Patients should be educated regarding adequate fluid intake and the use of a reliable contraception method due to lithium's potential to cause birth defects. Lithium has demonstrated significant weight gain, and weight should be monitored. Adverse effects of lithium include nausea, vomiting, diarrhea, hypothyroidism, renal function abnormalities, polyuria, polydipsia, leukocytosis, tremors and acne. The dose should be either discontinued or lowered if lithium toxicity occurs. Lithium toxicity symptoms include loss of balance, increased diarrhea, vomiting, anorexia, weakness, ataxia, blurred vision, tinnitus, polyuria, coarse tremor, muscle twitching, irritability and agitation. Several drugs have been found to increase lithium levels including carbamazapine, nonsteriodal anti-inflammatory drugs, tetracyclines and thiazide diuretics. [37] Theophylline and caffeine promote lithium excretion, resulting in lower serum levels of lithium at the same oral dose. Clinicians should discuss these potential interactions with patients and families.
  • Clinical Implications of Anticonvulsant Treatment: requires monitoring of amylase, liver function tests, estrogen, progesterone, fasting blood sugar and hemoglobin A1C to check for polycystic ovarian syndrome. Importance of effective birth control. Adverse effects include hirsutism, acne, alopecia, male pattern hair loss and elevated testosterone. Additionally, common side effects of all anticonvulsants include weight gain, nausea, sedation, dizziness, tremor, headache, visual disturbances, blood dyscrasias and elevated thyrotropin levels. Rash and Stevens–Johnson syndrome should be monitored. Lamotrigine: The low initial dose and gradual titration of the dose of lamotrigine, required for safety due to concerns of developing rash and Stevens–Johnson syndrome, does not make lamotrigine a good first-line choice for acute stabilization of mania. Skin rash was a pronounced adverse effect in two of these studies, resulting in discontinuation of treatment. Problems of adherence may arise in children and adolescents due to skin rash. Furthermore, lamotrigine needs double-blind, placebo-controlled trials. Carbamazapine: Carbamazepine extended release treatment demonstrated modest levels of improvement on the YMRS, suggesting a lack of complete resolution of mania 2] Scores for oxcarbazepine were not statistically significant as compared with those for placebo. [40 Topiramate: Evaluated in a 28-day, double-blind placebo-controlled study with 56 children and adolescents with bipolar I disorder. [41] With topiramate, YMRS scores were not statistically significant as compared with placebo. The study was discontinued due to topiramate trials failing to demonstrate efficacy in treating bipolar disorder in adults.
  • Most patients with bipolar disorder will also meet criteria for ADHD. A recent study by Kowatch (JAACAP, 2000) suggested that >70% of bipolar patients in his sample met criteria for ADHD. This rate has been estimated to be as high as 95% in other samples.
  • Despite its recognition as an important aspect of multimodal treatment, the development and study of psychosocial interventions for childhood BD are in their relative infancy. However, there are several adjunctive psychosocial treatments that are being developed or tested for children and/or adolescents with bipolar spectrum disorders. There is little research on how psychosocial treatment used in conjunction with medication might enhance treatment, prevent poor outcomes, and improve the quality of life for these families. In the 2007 American Academy of Child and Adolescent Psychiatry Practice Parameters for the treatment of Childhood BD, McClellan and colleagues stated that, ‘‘a comprehensive multimodal treatment approach combining psychopharmacology with adjunctive psychosocial therapies is almost always indicated for early-onsetBD.’’19 Yet, to date, there are few empirically supported psychosocial treatments for PBD. The psychosocial treatments discussed above represent the entirety of burgeoning evidence-based psychotherapeutic approaches to treating BD in children and adolescents. Although they may have different populations of interest (eg, school-aged versus adolescents) and different theoretical orientations (eg, psychoeducation vs. cognitive-behavioral vs. interpersonal) driving their targeted interventions, they share many ingredients in common. Components of treatment emphasized in all these approaches include psychoeducation about the disorder, the importance of effective communication and problem solving, and the development of healthy coping skills, for example.

Treatment of pediatric bipolar disorder 82010 Treatment of pediatric bipolar disorder 82010 Presentation Transcript

  • Bipolar: To Be or Not To Be… Pediatric Bipolar Update
    • Stephen Grcevich, MD
    • President and Founder, Family Center by the Falls Chagrin Falls, OH
    • Department of Psychiatry Northeastern Ohio Universities College of Medicine
    • Presented at: Children’s Hospital Medical Center of Akron August 20, 2010
    E-mail: drgrcevich@fcbtf.com Phone: (440) 543-3400 Twitter: @drgrcevich
  • Educational objectives:
    • Familiarize health care professionals with current information regarding the diagnosis of Bipolar Disorder in Children Review recent evidence-based literature regarding Bipolar Spectrum Disorders Identify treatment options, including medication management, of mood disorders in children
  • Stephen Grcevich, MD: disclosures: Pharmaceutical Industry Consulting: Shire US (100% of compensation donated to charity since 1/1/08) Grant/Research Support Child and Adolescent Psychiatry Trials (CAPTN) Network-ASK, PARCA, NOTA studies funded through NIMH Speakers’ Bureaus None since 2006 Other Financial/Material Support Web MD/Medscape Leerink-Swann Major Shareholder None
  • The greatest controversy in our field?
    • 40X increase in outpatient visits for pediatric bipolar disorder between 1994-95 and 2002-03 (6X increase in prevalence of bipolar diagnosis)
    • The majority of kids receiving the diagnosis don’t meet traditional DSM-IV criteria for the disorder
    • Average number of psychotropic medications: 3.4
    • Average number of medication trials: 6.3 (+/- 3.7)
    • Medications approved for pediatric bipolar disorder associated with rapid, large increases in weight, lipid, cholesterol elevation, Type 2 diabetes
    Moreno C, Laje G, Blanco C, et al. Arch. Gen. Psychiatry 64, 1032–1039 (2007).
  • Weight gain in antipsychotic naïve pediatric patients: Correll, CU et al., JAMA. 2009;302:1765–1773.
  • Metabolic effects of second-generation antipsychotics in pediatric patients: Correll, CU et al., JAMA. 2009;302:1765–1773. Agent: Metabolic Effects: Olanzapine  fasting glucose  insulin  insulin resistance Quetiapine  total cholesterol  triglycerides  HDL cholesterol  triglyceride:HDL ratio Risperidone  triglycerides Aripiprazole No significant metabolic effects
  • Diagnostic criteria for Bipolar Disorder:
    • A distinct period of elevated, expansive or irritable mood lasting at least one week in which three or more of the following are present (four if mood is only irritable):
    • Inflated self-esteem, grandiosity
    • Decreased need for sleep
    • Pressured speech
    • Flight of ideas, racing thoughts
    • Increased distractibility
    • Increased goal-directed activity (psychomotor agitation)
    • Involvement in pleasurable behaviors with potential for painful consequences
    Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM IV-TR)
  • Diagnostic criteria for Bipolar Disorder:
    • Mixed episodes: symptoms of mania and depression last at least seven days
    • Bipolar II: major depression and hypomania last at least four days
    • Rapid Cycling: four or more full episodes in a calendar year
    • Bipolar NOS: cases that don’t meet criteria for other bipolar conditions…the majority of pediatric cases
    • *Ultrarapid Cycling: brief, frequent episodes lasting from a few hours to less than four days
    • *Ultradian Cycling: cycles last minutes to hours, >365 cycles/year
    • *Condition not listed in DSM-IV
    Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM IV-TR)
  • Comorbidity and pediatric bipolar disorder:
    • ADHD: 90% in children with bipolar disorder, 60% in teens with bipolar disorder, 13% in adults with bipolar disorder
    • Prevalence of anxiety disorders: 56-76%
    • Increased substance abuse risk-greater risk in adolescent-onset vs. childhood onset BPD
    • 4X greater risk of post-traumatic stress disorder
    Joshi G, Wilens T. Child Adolesc Psychiatric Clin N Am 18 (2009) 291–319
  • Differentiating between ADHD and BPD in early adolescence: Geller et al. J Affect Disord. 1998;51:81. Geller B, Luby J. J Am Acad Child Adolesc Psychiatry (1998): 37(10) 1005 Symptom BPD (n=60) % ADHD (n=60) % P Value Elated mood 86.7 5 0.001 Grandiosity 85 6.7 0.001 Hypersexuality 45 8.3 0.001 Decreased need for sleep 43.3 5 0.001 Racing thoughts 48.3 0 0.001 Hyperenergetic 96.7 91.7 0.44 Distractibility 91.7 95 0.72
  • Differential diagnosis of pediatric bipolar disorder :
    • Medical/neurologic concerns (iatrogenic)
    • ADHD/Conduct Disorder
    • Anxiety disorders
    • Psychotic disorders
    • Substance use disorders
    • Borderline Personality Disorder (and other Cluster B conditions)
    • Environmental, psychosocial, parenting factors
  • The center of the controversy:
    • There’s a large group of kids who demonstrate:
    • Irritability as their predominant mood state
    • Problems with emotional self-regulation often resulting in aggression
    • Problems with attention, concentration, academic performance
    • “At-risk” behaviors…self-injury, substance use, suicidal threats
  • Temper Dysregulation Disorder (TDD) with Dysphoria (proposed in DSM-V):
    • Characterized by severe recurrent temper outbursts in response to common stressors
    • Temper outbursts are manifest verbally and/or behaviorally, such as in the form of verbal rages, or physical aggression towards people or property
    • The reaction is grossly out of proportion in intensity or duration to the situation or provocation
    • Responses inconsistent with developmental level
    • Temper outbursts occur, on average, three or more times per week.
    • Mood between temper outbursts is persistently negative (irritable, angry, and/or sad).
    • Negative mood is observable by others (e.g., parents, teachers, peers).
    DSM-V Task Force, American Psychiatric Association, 2010
  • AACAP concerns about “TDD”
    • Diagnosis Is imprecise
    • Syndrome based on work in patients described as “SMD”
    • Invites criticism for “pathologizing” temper tantrums
    • Proposed criteria are almost certainly premature
    • Research hasn’t clarified boundaries between “TDD”, ADHD, Oppositional Defiant Disorder and developmentally acceptable behavior
    • More information needed on how the phenotype changes over the lifespan
    American Academy of Child and Adolescent Psychiatry, March 30, 2010
  • What will kids with SMD/TDD look like in your clinic?
    • They have ADHD
    • They have difficulty with transitions
    • They tend to “ruminate”…indecisive, think too much about things, perseverate
    • They may experience some improvement in some settings from ADHD medication, but become more irritable, have more meltdowns at home
    • They have a higher than expected prevalence of anxiety disorders, but are probably subsyndromal for OCD
    • They’re prone to behavioral activation on SSRIs, often mistaken for mania, hypomania
  • AACAP Practice Parameters for Assessment and Treatment of Bipolar Disorder (2007)
    • Pharmacotherapy is the primary treatment in well-defined DSM-IV Bipolar I disorder
    • A comprehensive treatment plan, combining medications with psychotherapeutic interventions is needed to address the symptomatology and confounding psychosocial factors found in children and adolescents with bipolar disorder
    J . Am. Acad. Child Adolesc. Psychiatry, 46:1, January 2007
  • FDA-approved medications for youth with Bipolar Disorder
    • Risperidone: Bipolar mania (10-17)
    • Aripiprazole: Bipolar mania (10-17)
    • Quetiapine: Bipolar mania (10-17)
    • Olanzapine: (labeling-consider other drugs first) Bipolar mania (13-17)
    • Lithium Carbonate: Bipolar mania (12-17)
    http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM193200.pdf
  • Second generation antipsychotics in pediatric bipolar disorder:
    • As of July, 2010: 26 studies published, including 5 RCTs (but several others completed)-all RCTs published in 2007 or later
    • Response rates in acute RCTs 45-89%, remission achieved in 25-72%
    • Treatment-refractory nature of patients enrolled at academic medical centers attenuated magnitude of AEs
    • Little data examining long-term course on SGAs, efficacy in preventing relapse
    Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088.
  • Lithium in pediatric bipolar disorder:
    • One acute RCT: Li>PBO (46% response rate vs. 8%)
    • Didn’t appear to prevent relapse
    • Negative RCT in SMD
    • Narrow therapeutic window, toxicity in overdose concerns in adolescents
    Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088
  • Anticonvulsants in pediatric bipolar disorder:
    • Divalproex sodium: open-label studies have demonstrated response rates of 56-92%, but two RCTs have failed to demonstrate efficacy
    • Lamotrigine: Three open-label studies suggest 50-60% remission rates, helpful with bipolar depression results confounded by adjunct meds
    • Topiramate, oxcarbazepine: Negative RCTs
    Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088
  • Strategies for treating ADHD with comorbid Bipolar Disorder:
    • Effective mood stabilization may be necessary before patients will respond to stimulants
    • Stimulants will be used in combination with mood stabilizers/antipsychotics
    • Many patients have histories of failed stimulant trials, or use of high doses of stimulant before bipolar disorder identified
    • RCT: Mixed amphetamine salts highly effective for ADHD in patients who had achieved mood stabilization on divalproex
    Scheffer R et al. Am J Psychiatry (2005) 162:58-64
  • Psychotherapy/psychosocial treatment:
    • Multi-family psychoeducational groups: 1 RCT (N=35), families did better, no effect on severity of child’s mood symptoms
    • IFP (Individual/family psychoeducation) 1 RCT (N=20) improved children’s mood symptoms
    • FFT (Family focused therapy) psychoeducation, communication enhancement training, and problem solving skills training-two year RCT indicated improvement in depressive sx. With bipolar disorder
    • DBT: One open label trial (N=10)
    • CFF-CBT: Open-label trial (N=34) with three year follow-up showed benefits of treatment were maintained
    West A, Pavuluri M. Child Adolesc Psychiatric Clin N Am 18 (2009) 471–482
  • Take-home points:
    • Use of the term “Bipolar Disorder” in pediatric population should be reserved for mood episodes lasting four days or longer
    • A large subset of patients exists with chronic irritability, explosive outbursts, chronic negativism, long-term risk of ADHD, depression, differences in neural circuitry and cognitive flexibility. Little research is available to inform our treatment of them.
    • Careful evaluation and a comprehensive treatment plan developed by a fully trained child and adolescent psychiatrist, combining medications with psychotherapeutic interventions, are essential
  • Resources for pediatricians:
    • AACAP Bipolar Disorder Resource Center http://www.aacap.org/cs/BipolarDisorder.ResourceCenter
    • Child and Adolescent Bipolar Foundation http://www.bpkids.org/
    • Psychopharmacology of Pediatric Bipolar Disorder Expert Review of Neurotherapeutics http://www.medscape.com/viewarticle/724852 (Medscape membership required-membership, article free. Click on print version for summary tables of all studies)
  • Questions?