Pediatric Bipolar Disorder David Camenisch, MD/MPH PAL Conference Jackson, WY May 5, 2012 - No financial disclosures to share. Jim is responsible for any and all compensation related to this talk so if you like it, please let him know. PAL Conference May 5, 2012

Cody (RR 2.5) - History 6 year old mixed-race (NA/AA) boy new to your practice ADHD diagnosis at age 4. On and off stimulants for 2 years. Has been tried on both methylphenidate and amphetamine preparations. They tend to work for a while but then things “go back to normal.” He has always been “moody.” Struggling at school socially but “really smart.” Per mom, “He reads real history books and remembers everything.” - Certain names (usually varies by region) seem to confer their own risk of behavioral issues if not outright mental illness. In a highly biased, purely retrospective, naturalistic study, having the name “Cody” increases risk of “bipolar” diagnosis by 2.5 times. PAL Conference May 5, 2012

Cody – Presentation Mom thinks he is bipolar. She just got diagnosed and medications have really helped her. Mom says she can’t control him at home. A little better with mom’s boyfriend of who has been in and out of the picture for 2 years. Actually, mom just stopped stimulants because she heard they can make things worse if your kid has bipolar. She thinks he is doing better. She asks you to prescribe “something” to treat his bipolar mood swings…… PAL Conference May 5, 2012

What To Do? What role should a primary care provider take regarding the question of child bipolar disorder? Psychoeducation? Referral? Treatment? How do you assess for childhood bipolar disorder? When does it make sense to… Wait Prescribe a mood stabilizer? Refer to a therapist? Refer to a (child and adolescent) psychiatrist? - How many of you diagnose Bipolar Disorder? - How many of you are comfortable diagnosing Bipolar Disorder? (Notice I didn’t raise my hand) Role for therapy versus MDD. Less clear but appears to be role for individual, group and family in different ways. In MDD, “therapy” more directly impacts core symptoms of MDE. Less so in case of hypomania/mania. PAL Conference May 5, 2012

Bipolar Is A Hot Topic Bipolar disorder in kids is much talked about “Child Anxiety Disorder” on Google 26,600,000 hits (3,120,000) “Child Bipolar Disorder” on Google 33,100,000 hits (4,370,000) (Camenisch 2012, Camenisch 2011) Child anxiety disorders are actually about 10 times more common than child bipolar disorder 40 fold increase in office visits for child bipolar disorder from 1994 to 2003 (Also 40-fold increase in diagnosis.) National Center for Health Statistics PAL Conference May 5, 2012

Frequency of Childhood Bipolar Very controversial Some assert a high frequency of all children have bipolar disorder “The Bipolar Child” by Papolos and Papolos Assert 1/3 of all children with ADHD States about 6% of all children are bipolar “Is Your Child Bipolar” by McDonnell and Wozniak States more than 3 million US kids have it Based on their estimates, incidence is 4%. PAL Conference May 5, 2012

Quoted Child Rates Don’t Match Our Adult Knowledge Adult Lifetime prevalence rates of bipolar disorder 1 to 2% Greater diagnostic certainty with adults Bipolar disorder is a lifelong diagnosis – need plausible explanation if pediatric bipolar is 3-6X > adult bipolar Lessons from Great Smoky Mountain data set child bipolar NOS ≠ bipolar adult Kids with bad mood swings cannot all have “true” bipolar disorder PAL Conference May 5, 2012

Why is diagnosis so challenging? Symptom overlap + high rates of co-morbidity Confounding developmental issues Environmental influences Limited ability of (many) children to verbalize emotions Many different “expert” opinions Influence of popular media/pharmaceutical industry Requires extensive history – assessment of both current symptoms and past episodes (subject to recall bias.) PAL Conference May 5, 2012

DSM-IV TR (Hypo)Manic Episode Manic Episode – 7 days + impairment, or hospitalization or psychosis Distinct period of abnormal and persistently elevated*, expansive or irritable mood Plus 3 (4 if “irritable-only” mood) of the following: Distractible Grandiose/inflated self-esteem* Decrease need for sleep (< 3 hrs) More talkative/pressured speech Indiscretions/risk taking Flight of ideas/racing thoughts Increased goal directed activities/PMA Hypomanic Episode – 4 days. No hospitalizations. No impairment. Quick primer on dx criteria of mood episodes so controversies have some context. Though debate continues to some extent, dx criteria exclude situations where anti-depressant treatment, light therapy or ECT cause manic episode. PAL Conference May 5, 2012

Depressive Episode 5 or more of following in same 2 week period + depressed/irritable mood OR lost of interest/anhedonia Sleep Interest Guilt Energy (fatigue) Concentration Attention PMA/PMR (observable) Suicidal thoughts/feelings/behaviors Functional Impairment No Mixed Episode, R/O Substance, R/O GMC, R/O Bereavement PAL Conference May 5, 2012

Diagnosis of Mood Disorders Current None MDE Hypo Manic Mixed Past None No Dx MDD No Dx BP1 BP1 MDE MDD MDD BP2 BP1 BP1 Hypo No Dx BP2 BP, NOS BP1 BP1 Manic BP1 BP1 BP1 BP1 BP1 Mixed BP1 BP1 BP1 BP1 BP1 Remember to ask about past mood symptoms, otherwise bipolar will be misdiagnosed as depression. If evaluating for BP based exclusively on mood “episodes” (presence of depressive, hypomanic or manic episodes) should only use BP, NOS if there has been at least one hypomanic episode and no manic or depressive episodes. - If history (of mood episodes) not explored, will likely end up with over dx of MDD b/c of the relatively higher prevalence of major depressive episodes. PAL Conference May 5, 2012

Bipolar, NOS DSM-IV TR Rapid alternation between manic and depressive symtpoms that do not meet duration criteria Recurrent hypomanic episodes w/o depressive symptoms Manic or mixed episode in context of thought disorder Hypomanic episodes w/ chronic depressive symptoms Hypomanic/manic symptoms but haven’t yet been able to rule out influence of substance use or general medical condition. PAL Conference May 5, 2012

Bipolar Disorder, NOS Contributes to the current bipolar “epidemic” Label often given to impulsive, aggressive kids Prognosis could be normal, MDD, or (rarely) true bipolar Diagnosis confused with: ADHD Depression Abuse (current and PTSD) Anxiety Disorders Disruptive Behaviors Disorders Reactive Attachment Disorder Intermittent Explosive Disorder PAL Conference May 5, 2012

Why is Bipolar, NOS so common? Broad Category/catch-all Not (yet) another more suitable diagnosis that captures complex behavioral picture (SMD, TDDD) Sounds better to us than “I don’t know” Justifies the limited(medication) treatment options. If we give a child medicine as if bipolar, parents often report improvement Bipolar medicines have many non-specific effects All decrease impulsivity and aggression - In fact, aggregated evidence at this point, indicates that atypical anti- psycohtics are more effective in non-psychotic disorders (pediatric bipolar disorder, disruptive behavior disorders) - Improvement is seen in cases of non-specific, symptomatic treatment. This can erroneously lead to justification of with (non-specific) treatment used to justify diagnosis. PAL Conference May 5, 2012

If not bipolar, then what? Depression Ongoing abuse/neglect Post-trauma symptoms or syndrome Environmental Instability (frequent change in living arrangement/primary care giver; parental mental illness) Disordered Attachment (RAD) Temperament Mismatch (Parent-Child Relational Problem) Anxiety (especially brief, episodic, reactive “mood swings” ) Disruptive Behavior Disorders (ADHD,ODD) Affective lability in context of autism spectrum disorder (co- morbidity versus core disorder attribution) Not sure answer is more choices under “bipolar” heading is the answer. Based on my past and current clinical work with high-risk, multiply affected kids, rarely find myself wishing I had more “bipolar” options to tidy up the balance sheet. The key is keeping broader, ecological and developmental perspective in mind. Such an approach is likely to be more helpful and (more accurate) that further clarification of bipolar subtypes. To be fair, more discriminate validity among bipolar subtypes could definitely impact treatment in certain specialty care environments, but not typically at a primary care level. PAL Conference May 5, 2012

Severe Mood Dysregulation (SMD) Clinical syndrome not a diagnosis (3.3% lifetime prevalence ages 9-19) “chronically irritable children whose diagnosis is in doubt.” (Often the “Bipolar, NOS crew) IS real and confers risk of psychopathology down the line, but is NOT bipolar disorder (also not Axis II) Presence of SMD increases risk of depressive disorder and GAD at 20 year follow-up. Stringaris et al, 2010 PAL Conference May 5, 2012

Bipolar Disorder Frequency Depends On Where You Look Prevalence of “true” adolescent bipolar 0.6% of high school students 1% in general outpatient practice 6 % of child psychiatry outpatients (CMHC) 22% incarcerated adolescents 26-34% of child psychiatry inpatients manic symptoms (1996-2004 CDC survey of discharge diagnosis) - As a primary provider, you should be seeing bipolar disorder pretty infrequently. - If you find yourself making the diagnosis frequently, ask yourself “Why am I seeing more bipolar disorder than your local child psychiatrist? Youngstrom et al, CAPC Vol 18 PAL Conference May 5, 2012

Cody – The Questions Test out whether un/under-treated ADHD (haven’t found right medication, right dose; hasn’t had behavioral help, parenting support) or do you need to consider mood disorder? Or co-morbidity (depression, anxiety, ODD) Ask for more detail than just “labile moods” (hyper- arousal)and “won’t listen” (distractibility) How is his mood most of the day? What causes (if anything) his mood to change? When not upset, what does he look like? Can he “pull out of it” Does he “listen” when he is asked to do something he wants to do? “Regression to the mean” = return to baseline after each med change/dose increase. Suggests something else is going on. Doesn’t mean “bipolar” but also should prompt a more thorough assessment of developmental and psycho-social factors that may be impacting presentation. Perform ad hoc “functional behavioral analysis”. Identify circumstances, patterns, antecedents to “mood swings.” Is distractability “selective”? (e.g. for chores, homework, non-preferred activities.) PAL Conference May 5, 2012

Cody – The Answers Mom says he “never listens to me” especially when asked to do chore/homework/go to bed. Goes into rages when doesn’t get his way Throws things at mom, hits her. Says “I hate you.” Tried “everything,” even spanking, taking away the Xbox. With dad or other adults he behaves better. Some talking back, but manageable. Knows he needs to cool it or he going to get in trouble. PAL Conference May 5, 2012

Cody – At School In 2nd grade, teacher said he was not listening well in beginning of year, is better now In kindergarten he didn’t follow rules well Performing at grade level Not having rages at school Generally more of a problem at home more than at school variability in responsiveness/behavior is more hallmark of disruptive behavior disorders (ODD) - same environment over time - to different caregivers - between environments (at home versus school) for example may see “honeymoon” followed by regression/reversion as gets more comfortable OR may seen worsening of behavior initially (similar to extinction burst) as adjusts to structure and consistency -starts to paint a picture of something other than bipolar disorder PAL Conference May 5, 2012

Cody – Social History and Development Mom is primary caregiver. 1 younger brother, mom thinks she might be pregnant. No contact with dad. Left before Cody was born. Mom has few supports. Mom’s family and tribe “disowned” her and Cody because his father is AA. Developmental milestones were OK “Read early. Very verbal. Reads “anything about history” and “remembers everything.” No in utero drug exposure identified. PAL Conference May 5, 2012

How to answer Mom’s Question if this is Bipolar Disorder? Difficult diagnosis (no “tests”) Diagnosis best made “over time” ; usually not point-in-time diagnosis --especially with chronic presentation Many different opinions, even among specialists Down side of labeling too early If you think NOT bipolar, continue with… Psycho-education. (Non-specific nature of “mood swings” and “irritability” e.g. cough analogy) Reasonable to consider treatment depending on potential consequences. (Sx-driven versus dx-driven treatment*) - * risk-benefit analysis based on potential consequences of problematic behaviors (expulsion, juvenile detention, harm to others, involvement of CPS, etc) PAL Conference May 5, 2012

Indiscretions/risk taking Grandiose Flight of ideas/racing thoughts Consider the large differential for each of these Mania symptoms in kids: Distractible Indiscretions/risk taking Grandiose Flight of ideas/racing thoughts Activity (goal directed) increase Sleep need decreased Talkative (pressured speech) Which can mimic ADHD symptoms? Obviously need to take in to consideration degree, duration, etc - Remember important temporal distinctions. ADHD requires fairly consistent symptom picture across environments, manic episodes are just that, “episodes” and when present may/may not be present to the same degree in different settings. Usually not subtle or fully suppressible. PAL Conference May 5, 2012

Manic symptoms versus ADHD (Kowatch et al, 2005) Symptom ADHD PBD* Irritability 72% 98% Accelerated Speech 82% 97% Distractibility 96% 94% Unusual Energy 95% 100% * Pediatric Bipolar Disorder - Shared symptoms have lack of specificity for ADHD vs mania. - In addition to poor specificity, there are high rates of co-morbidity complicating the picture further. PAL Conference May 5, 2012

Diagnostic Perspective Experience with adult mania helps, but can be challenging to translate to kids. (Different patterns of diagnosis between Adult and C&A psychiatrists?) Compare child to a prototypic “manic” patient Pressured speech -- not just talkative Having no doubt about their grandiose ideas -- impaired reality testing/lack of insight) Thought process is fast and jumping around Episodes that most commonly last days not minutes or hours Little need for sleep (versus poor sleep.) PAL Conference May 5, 2012

Look for Episodes and Patterns Individual episodes represent a clear departure from baseline with some hallmark symptoms Hopefully, the presence of hallmark symptoms will help distinguish irritable mania from irritable depression The correct mood diagnosis (and treatment) requires establishing the pattern of mood episodes, not just presenting (current) episode. PAL Conference May 5, 2012

Rapid Cycling Controversy Typical adult pattern is episodic. Rapid cycling is rare in adult bipolar populations. Kids are more reactive and more common to get story of “rapid cycling.” Consider “rapid cycling” in kids if there is no trigger identifiable for the mood changes Where many “episodes” become static, chronic mood state is controversial. ADHD plus irritability should not generate a bipolar diagnosis Youth with BP do spend more time cycling and have more changes in mood polarity that adult populations. (Birmaher et al, 2006) PAL Conference May 5, 2012

Chronic versus Episodic Irritability Objective: Test validity of distinction between chronic and episodic irritability. (Central debate in pediatric bipolar) Method: Community sample of 776 children and adolescents interviewed at 3 points in time (T0, T2y, T7y). Irritability rating scales used to tease out chronic versus episodic irritability. Association with age, gender and diagnosis were examined. (Liebenluft et al, 2006) PAL Conference May 5, 2012

Chronic vs Episodic Irritability Those with episodic irritability were more likely than those with chronic irritability to have: A parent diagnosed with Bipolar Disorder Experienced elation and/or grandiosity More symptoms of mania Psychotic symptoms Had a depressive episode Made a suicide attempt (Liebenluft et al, 2006) PAL Conference May 5, 2012

Irritability and Later Psychopathology Chronic irritability at TI - associated with ADHD at T2 and depression at T3 Episodic Irritability – associate with simple phobia at T2 and mania at T3 Conclusions: - Episodic and chronic irritability are distinct constructs. - Episodic irritability is associated with bipolar disorder and confers higher risk of future manic episodes than chronic irritability. (Liebenluft et al, 2006) PAL Conference May 5, 2012

Irritability Controversy Geller: Irritability is not diagnostic of PBD; it is very common and shows high sensitivity, but poor specificity for PBD Wozniak: irritability may be primary mood symptom; episodicity not relevant. Leibenluft: In diagnosing PBD, episodic irritability is more suggestive of PBD than is chronic irritability Hunt/Birmaher – episodic irritability alone can represent manic phase of illness; “irritable-only” mania exists but is rare; more common in younger children. (COBY). PAL Conference May 5, 2012

Look for “Hallmark” Symptoms Increased specificity More likely bipolar… Elation Hyperactivity Grandiosity Hypersexuality Decreased need for sleep PAL Conference May 5, 2012

Bipolar Diagnostic Aides Rating Scales Young Mania Rating Scale Useful for monitoring symptoms over time Not a diagnostic tool (very low specificity) DISC or KSADS Used in research, have flaws Impractical for your office practice Rating scales are too misleading to recommend for diagnostic use and are intentionally excluded from the PAL guide. PAL Conference May 5, 2012

Cody Rage episodes seem directed mostly at mom, and mom’s attempts to set limits at home Mood changes occur mostly in response to frustrations There are not any hallmark symptoms of grandiosity, euphoria, hypersexuality No history of days-long episodes He is very young to diagnose as bipolar PAL Conference May 5, 2012

What about Family History? Mom says she has been diagnosed with bipolar and his uncle is bipolar, “just like him” Avoid overcalling a positive family history many adults who call themselves bipolar may not have that illness first degree relative bipolar disorder, increases OR by 5 second degree relative bipolar, increase OR by 2.5 given a generous prevalence of 2% bipolar in the population, most children of a bipolar parent (~90%) will not have bipolar disorder Was mom/uncle diagnosed? Based on manic episode? Based on depressive episode? Based on “mood swings” ? Was mom/uncle treated? What medicines have helped? Hospitalized? …should start to give you better sense of likelihood of “true” bipolar PAL Conference Youngstrom E & Duax J, JAACAP 44:7, 2005 May 5, 2012

Looking back at adult bipolar…. Several studies have asked adults with bipolar about onset of their symptoms retrospectively Bipolar adults look back and note symptoms became bipolar- like in their teen years (50-66%) Many bipolar adults had major depression episodes as children The younger the child’s first major depression, the more likely bipolar disorder is in the future PAL Conference May 5, 2012

What if a “Bipolar” Child Really is Bipolar? Though rare in a PCP practice, becomes more likely the older the child. Typical pattern is early onset depression, and during teenage years getting first symptoms of mania. Expect mood “episodes”. COBY study established validity of episodic course. Assemble a team. Real deal bipolar disorder is a big problem. PAL Conference May 5, 2012

Course Of True Bipolar Disorder Suicidalilty up to 15% eventually complete suicide Substance Abuse in up to 60% Anxiety disorders in up to 50% Psychotic features in up to 50% Relationship Disruptions Work Disruptions Hospitalizations PAL Conference Stern TA and Herman JB, 2004 May 5, 2012

Bipolar Treatment If clear manic episodes, strongly recommend get them to child psychiatrist Management difficult because: High rate of substance abuse High rate of medication non-compliance Even with medication, recurrences happen High rates of family disruption from the illness Suicidal behavior is common PAL Conference Brent et al, 1988, 1993 May 5, 2012

If No Child Psychiatrist Can Assume Care, Then What? Get collateral evaluations to help establish correct diagnosis Strongly advise against rushing to offer diagnosis of bipolar disorder. Seek consultant advice on medication (when they are appropriate to consider) Preferred model of care: MH specialist is primary prescriber PCP is a partner in the treatment team Call the Provider Access Line. Sometimes PCP is left holding the bag PAL Conference May 5, 2012

Bipolar Treatments (for when you are left holding the bag) Atypical antipsychotics Mood Stabilizers Combination therapy Antidepressants if used cautiously Family therapy (support/education/adherence) Sleep hygeine Psychotherapy for: depression treatment coping skills supporting medication treatment adherence PAL Conference May 5, 2012

Bipolar Medications PAL Conference May 5, 2012

What Is A Mood Stabilizer? Includes both atypical anti-psychotics and anti-epileptic drugs (AEDs) Generic term – clarify what they mean when taking history and what you mean when proposing treatment. FDA does not recognize this term As relates to treatment of bipolar disorder, ideally treats both depressive and manic episodes as well as prevents recurrence of mood episodes. Since no one compound does this well, multiple meds are often used together (but little evidence base to support it.) PAL Conference May 5, 2012

Mood Stabilizers are Non-Specific to PBD Maladaptive aggression Mental retardation (lithium, risperidone) Autism (risperidone, aripiprazole) Conduct Disorder (risperidone, valproic acid, lithium) Seizure Disorders – kindling hypothesis; neuroprotective effects in mood disorders (lithium) Depression (risperidone, aripiprazole, quetiapine, lamotrigine) Psychosis (primary, mood disorder, delirium) OCD (refractory) PTSD (intrusive thoughts) - Some support for use outside of bipolar for related behavioral and psychiatric issues, so don’t need diagnosis of bipolar to justify. PAL Conference May 5, 2012

Pharmacotherapy of Pediatric Bipolar (Liu et al, JAACAP 2011) Method PubMed 1989-2010 + unpublished studies from FDA website + 3 submitted for publication Study Characteristics - Treatment of mania only (excluded studies looking at bipolar depression) Only open-label studies and RCTs (retrospective chart reviews or case studies) Outcome measures and analysis >50 % decrease in YMRS Treatment effect measured separately for OT and RCTs Results 46 studies (29 OT, 17 RCT) - n = 2666 PAL Conference May 5, 2012

Positive Randomized Trials Blinded RCT knowledge base in kids is low Aytpical anti-psychotics Olanzapine Aripiprazole (2) Quetiapine (3) Risperidone (1) AEDs Divalproex sodium (Depakote) Li (maintenance) PAL Conference May 5, 2012

Atypical Antipsychotics risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone 11 OTs with 53% response rate 8 DBRCTs with 66% response rate N = 1474 That DBRCTs showed greater efficacy than placebo is encouraging and noteworthy Better tolerated than AEDs as a group. PAL Conference May 5, 2012

Risks common to all Atypical Antipsychotics (Correll, JAACAP. 2008) Sedation (olanzapine, quetiapine) Tardive Dyskinesia (0.4% annual incidence) Increased Cholesterol/ Triglycerides (olanzapine) Akathesia (aripiprazole) (youth<adults) Increase glucose (olanzapine, quetiapine) EPS (risperidone) Lower seizure threshold (mildly) QT interval change (~20ms for ziprasidone) Weight gain (olanzapine > quetiapine, risperidone >the rest) Neuroleptic Malignant Syndrome Tardive Dyskinesia (TD). A recent meta-analysis of 10 studies lasting at least 11 months reported on TD rates in 783 pediatric patients ages 4 to 18 (weighted mean 9.8) years old. Most patients were prepubertal (79.2%), male (81.7%), and white (78.4%). Across these studies, only three cases of TD were reported, resulting in an annualized incidence rate of 0.4%. Although this pediatric rate is approximately half the risk found in another meta-analysis of 1,964 nonelderly adults, firm conclusions are precluded by the facts that none of the pediatric studies were designed specifically to detect TD, antipsychotic doses were low, and lifetime exposure was relatively short. Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal medical emergency that can result from antipsychotic treatment. The clinical picture consists of severe (Blead pipe[) rigidity, tachycardia, fever, arterial hyper- or hypotension, elevated creatinine phosphokinase, and elevated white cell count. It has been suggested that SGAs may be associated less with NMS than FGAs and that SGAs are associated with a more benign course of NMS, but this is unclear. In children and adolescents, several cases of NMS have been reported, even with SGAs. Thus, clinicians should be vigilant and rule out NMS in antipsychotic-treated children and adolescents presenting with fever, tachycardia, and rigidity. PAL Conference May 5, 2012

Atypical Heterogeneity PAL Conference May 5, 2012

Adverse and Therapeutic Effects of Occupancy and Withdrawal Adverse and Therapeutic Effects of Occupancy and Withdrawal (Correll, JAACAP. 2008) PAL Conference May 5, 2012

Risperidone (Risperdal) PROS QD-BID dosing (T½ = 20 hours) FDA for mania > 10 years old, irritability/aggression in ASD Multiple dosage forms (liquid, dissolving tab, tabs, depot) Low doses (<2 mg) adequate for non-specific aggression TD incidence reported less than 0.5% CONS Weight gain and sedation common Hyperprolactinemia risk Relatively high rates of dystonic reactions/EPS PAL Conference May 5, 2012

Aripiprazole (Abilify) PROS QD-BID dosing ( T½=75 hrs) But kids may do better BID FDA for mania (>10 yrs) and limited RCT support Mixed agonist/antagonist (less dystonia/EPS) Often less sedation CONS Limited dosage forms Misperception of less weight gain/metabolic SE Agitation/activation not uncommon Higher rates of akithesia Long T ½ -may take longer to see impact of changes PAL Conference May 5, 2012

Quetiapine (Seroquel) PROS Lower potency - may be experienced as “milder” FDA approval (>10 years old)/limited RCT evidence Effective anxiolytic Cross indication for bipolar and unipolar depression CONS Short half-life (T½ = 6 hours); multiple daily dose; mixed results w/ XR preparation Large tablets - may be hard to swallow Effective sleep aide (high risk, high cost sleep aide) Cataract risk PAL Conference May 5, 2012

Olanzapine (Zyprexa) PROS QD-BID dosing (T½ = 30 hours) FDA approval (> 13 years) and limited RCT evidence Multiple dosage forms (tablets, oral disintegrating, IM) Very effective for acute stabilization of mania and psychosis CONS Weight gain (dose related, less of plateau than others) High rates of metabolic side effects Sedation common PAL Conference May 5, 2012

Ziprasidone (Geodon) PROS Often less sedating Most weight neutral Fewer metabolic side effects Unique receptor profile CONS BID-QID dosing (T ½ = 7 hrs) No FDA approval for pediatric mania No pediatric RCT support Concern for EKG changes has lowered its usage PAL Conference May 5, 2012

- A resource for you summarizing some of what I just broke down for you. Didn’t want to blow the surprise by showing you this first. Monitoring for all atypical antipsychotics: AIMS exam at baseline and Q6months due to risk of tardive dyskinesia. Warn of dystonia risk. Weight checks, fasting glucose/lipid panel Q6months at minimum. PAL Conference May 5, 2012

Anti-convulsants Lithium (Li), divalproex sodiumm(VPA), carbamazepine (CBZ) 14 OTs (41% response rate) 6 RCTs (40 % response rate) n = 915 Only RCTs for divalproex sodium No RCTs for Li or CBZ Lamotrigine, oxcarbazepine, topiramate 3 OTs (43% response rate) 2 RCTs (39%) n = 244 - In general, demonstrate anti-manic properties as a class - Caution in interpreting response rates due to lack of RCTs PAL Conference May 5, 2012

Lithium PROS FDA approved for mania >12 years Some evidence in refractory depression Anti-suicide properties Some EB dosing guidelines (adjust for age/GFR) CONS Narrow therapeutic index (close monitoring for toxicity w/ illness/dehydration; no NSAIDs) Usually best in combination, so committing to polypharmacy if you start here (best w/ atypical or VPA) SE in therapeutic range similar to early toxicity (tremor, diarrhea) SE often limit use (weight gain, acne, GI); HS dosing can minimize Hard to predict who will respond No evidence for maintenance treatment /slow anti-manic effects EB dosing - 300mg TID with 300 mg increase/week +/- additional dose increase in week 1 ( mania only; not helpful for depressive episode or maintanence) (Findling et al, JCAP 2011) - Less effective for mixed episodes and dysphoric mania (similar to adult populations.) PAL Conference May 5, 2012

Early Signs PAL Conference May 5, 2012

Valproic Acid (Depakote) PROS Single daily dosing can be effective (Depakote ER) Can be useful for maladaptive/non-specific aggression Studies suggest helpful, usually in combination CONS Requires blood draws (levels, LFTs, amylase, CBC) Risk of hepatotoxicity (highest in first 6 months) High side-effect burden (weight gain, GI, tremor, sedation, rash) Less ideal for females (risk of birth defects (NTD), PCOS) PAL Conference May 5, 2012

Depakote How well does it work? Fair, usually works best in adolescents in combination with an antipsychotic (better than either one alone) Some RCT’s have suggested that it works better than lithium on acute manic symptoms Broad effects: also used for externalizing behavior disorders, conduct disorder Lost in head-to-head trial with quetiapine Similar long-term stabilizing effect to Lithium after stabilization with both divalproex and lithium 8 OT (response rates 53-61%; higher response rates involved frequent use of additional psychotropic medications) 3 DBRCT (mixed results) - acute mania study; quetiapine superior to divalproex. (DelBello 2006.) - maintenance study; no difference b/t lithium and divalproex following stablization with both agents; no difference in time to discontinuation or time to relapse. (Findling 2005) - “pediatric bipolar” ; did not separate from placebo (Wagner et al, 2009) DelBello MP et al, 2002, 2006 Bowden C et al, 2004 Rana M et al, 2005 Findling, R et al 2005 PAL Conference May 5, 2012

Carbamazepine (Tegretol) PROS Some empirical supports for aggression 2 OTs Similar response rates as Li and VPA (38%) (Kowatch et al, 2005) CONS Drug/drug interactions (OCPs, Lithium) Blood draws to check levels (auto-induced metabolism) Weak evidence of benefit in bipolar (McClellan and Werry, 1997) Risk of aplasia and liver failure PAL Conference May 5, 2012

Hard to Compare Effectiveness 42 child outpatients with Bipolar 1 or 2, randomized to one of three open label treatments R Kowatch et al, 2000 PAL Conference May 5, 2012

Lamotrigine (Lamictal) PROS Bipolar depression treatment Less sedation and lower side effect profile in general CONS Not helpful for manic phase Requires monitoring of CBC and liver function Significant rash risk Slow titration (age >12) - Recommended titration schedule 25QD 2 weeks, 50 QD 2 weeks, 50 BID 2 weeks, goal 150-200mg per day - B/c of rash risk, ff miss more than a few days, safer to start back at beginning PAL Conference May 5, 2012

Oxcarbazepine (Trileptal) PROS FDA approval for adults bipolar disorder Weight neutral Less risks/side effects than carbamazepine Monitoring of levels not required CONS Levels do not correlate well with efficacy or toxicity Negative adolescent bipolar trial (Cochrane Review. Vasudev et al. 2008) Hyponatremia not uncommon PAL Conference May 5, 2012

Anticonvulsants Shown Not To Help In Adult Bipolar Disorder topiramate (Topamax) (1 negative pediatric trial) gabapentin (Neurontin) levetiracetam (Keppra) - can cause psychiatric symptoms zonisamide (Zonegran) pregabalin (Lyrica) felbamate (Felbatol) - can cause psychiatric symptoms Topiramate – 2 OT found decrease in SGA associate weight gain; did not separate out from placebo for acute mania ( based on YMRS) PAL Conference May 5, 2012

Bipolar Take-Home Message Diagnosis of bipolar disorder made with relative confidence in the presence of manic (Bipolar I) or hypomanic (Bipolar II) episodes. It gets tricky after that. Mood episodes (all) involve distinct change from baseline with alternations in behavior and evidence of impairment. Bipolar diagnosis is a serious diagnosis that has a life-long course and many management challenges. True bipolar has high rates of morbidity and mortality. If suspected, strongly recommend involving a child and adolescent psychiatrist . If you, as PCP, are playing central role in management, check-in frequently to monitor side effects of medication(s) and surveillance of mood symptoms. PAL Conference May 5, 2012

“Not-Bipolar” Take-Home Message Currently, there is no single diagnosis for chronically dysregulated or irritable kids. Evidence is more suggestive of current and/or future depressive disorder. Kids with severe, non-episodic irritability differ from those with bipolar in course, family history and performance in many cognitive tasks linked to more severe psychopathology. Still a major role for parent support/training and mental health support. These kids can be draining and are high risk. There can be a role for medications to decrease maladaptive aggression and affective instability. PAL Conference May 5, 2012

At PCP level, recommend…. …keeping in mind many possible causes of mood swings and irritability. …resisting temptation to label impulsive, difficult kids as “bipolar.” …reminding yourself and parents who are struggling that most disruptive, irritable children do not have bipolar disorder but can still benefit from help. …getting help with diagnostic and treatment questions as often as necessary. PAL Conference May 5, 2012

Selected Bibliography Pharmacologic Treatments for Pediatric Bipolar Disorder: A Review and Meta-Analysis. Liu et al. JAACAP. August 2011. Practitioner Review: The Assessment of Bipolar Disorder in Children and Adolescents. Baroni et al. JCPP. 2009. Antipsychotic Use in Children and Adolescents:Minimizing Adverse Effects to Maximize Outcomes. Correll. JAACAP. January 2008. PAL Conference May 5, 2012