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Disruptive Mood Dysregulation Disorder (DMDD)Developing Treatment StrategiesCopyright UHS 2016, All Rights ReservedDan Matthews, M.D.UHS Neurobehavioral Systems – Austin, TXDan Matthews, M.D.Corporate Director ofNeuropsychiatric Services

For More Information: Dan Matthews, M.D.Corporate Director, Neuropsychiatric ServicesUHS Neurobehavioral Systems12710 Research Blvd., Suite 255Austin , TX 78759512-257-3468; fax-512-257-3478Email: [email protected]: uhsinc.comWebsite: neurobehavioralsystems.net

Medication Usage Disclaimer The following 2 medications that will be discussedin this presentation are being used off-label: 1) oxcarbazepine 2) amantadine HCl

OUTLINE 1) Disruptive Mood Dysregulation Disorder(DMDD): What is it? 2) How does DMDD compare to Bipolar Disorderor to Severe Mood Dysregulation? 3) What are the criteria; how common is it? Whatcomorbid conditions are there? 4) What is known about the neuropathology? 5) What about treatment: Any research? 6) What about crisis management?

DMDD: What is it?(McGough, 2014) A new diagnosis for DSM-5 (2013) for children withsevere and chronic irritability with explosive temperoutbursts. AREN’T ALL CHILDREN IRRITABLE AT TIMES?Yes but DMDD refers to:– Temper outbursts - at least three times a week– Irritable/angry moods almost daily for a year– Onset at least age 6 but before age 10; may continue asadult, if had childhood onset– With trouble functioning in multiple settings

DMDD: New DSM-5 Diagnosis(Axelson et al., 2012) Designed to replace “broad spectrum” BipolarDisorder in children and adolescence.– In DSM IV, mania describes discrete episodes of irritatedmoods (episodic irritability).– In DSM 5, DMDD describes non-episodic (chronic)irritability with frequent temper outbursts.– DMDD has very little research base, but it is very similarto the concept of Severe Mood Dysregulation (withouthyper-arousal).

Epidemic of Bipolar Disorder (BD)?(Leibenluft, 2011) Between 1994 and 2003 there was a 40 foldincrease in the diagnosis of BD in children andadolescents. (Moreno,C. et al., 2007)– Psychiatrists had broadened the phenotype for pediatricbipolar, to include chronic irritability as a subtype ofBipolar Disorder. But, research does not support this change fromnarrow (episodic) to broad (chronic) phenotype.– Non-episodic irritability is unique; not a subtype of BipolarDisorder (Geller et al. , 2008)

DSM-5 & Pediatric Neuropsychiatry(Fisher et al., 2013; Schieveld et al., 2013) The vast majority of the children being diagnosedwith Bipolar Disorder were not classic, or narrowphenotype, Bipolar Disorder.– They show non-episodic (chronic) irritability, rather thanclassic (episodic) irritability. Non-episodic (or chronic) irritability appears to be adistinct condition, separate from Bipolar.– This is the basis for Disruptive Mood DysregulationDisorder ( DMDD) in DSM-5.

DMDD versus Bipolar Disorder How does DMDD differ from Bipolar?– Non-episodic irritability (chronic)Bipolar Disorder has episodes of irritability with mania– No euphoria or grandiosityBipolar Disorder may show this during mania– No psychosisBipolar Disorder may show this

Abnormal Irritability(Leibenluft, 2011)– Abnormal Irritability:– Is an impairing, and long-lasting mood disorder withtemper outbursts:– “Temper outbursts that are developmentallyinappropriate, frequent, and extreme with anger orsadness between outbursts.”– may occur in association with mental illness:– Depression, Anxiety, Post-Traumatic Stress Disorder,Attention Deficit Hyperactivity Disorder, Bipolar Disorder,Autistic Spectrum

DMDD Research Epidemiologic studies:– Copeland et al. (2013) showed: that– Non-episodic (chronic) irritability with rage outbursts(meeting DMDD criteria; age 6-10) are reported in only3% of children.– This population shows many co-occurring conditions,particularly depressive disorders, with higher rates ofsocial and behavioral difficulties, poverty, use of mentalhealth services, and school problems.– Dougherty et al. (2014) found an 8.2% prevalence forDMDD in 6-year-old children.

Retrospective Study of DMDD(Copeland et al., 2013) Used data from existing studies of school agechildren with mental illness to evaluate DMDD– About 50% had temper outbursts, but only 6-7% of theseaveraged 3 or more per week.– 8-13% showed negative moods (sad or irritable) but only1.5%-2.8% had chronic irritability.– Cumulative prevalence after 4 separate assessmentswas 4.4% (Close to 1 child in 20 of this sample)– High rates of other co-existing psychiatric disorders.– High rates of impairment (family, school, social)– High rates of mental health service utilization

Disruptive Mood Dysregulation Disorder(DMDD) DSM-5 (Zepf & Holtmann, 2012)A. Temper OutburstB. Frequency Severe recurrenttemper outbursts tocommon stressors Beyond provocation Not consistent withage (developmentalage 6 ) Onset before age 10 Never elevated moodor grandiosity Temper outbursts occur, onaverage, three or more timesper week Between outbursts:– Mood chronically negative– Irritable, angry– Observed by others suchas parents, teachers– For at least a year– In at least two settings Home, school, peers

Underlying NeuropathologyDMDD versus Bipolar Disorder Ryan, N.D. (2013) reported:– DMDD exhibited markedly decreased activation ofparalimbic system (cingulate gyrus, striatal, thalamic,parietal, and parahippocampal regions) after negativefeedback (frustrating) trials (not in Bipolar). Deveney et al. (2013) reported:– In DMDD, the frontal lobe tends to show underactivityin comparison to Bipolar Disorder which shows overactivity.

Underlying Brain DisordersCause of DMDD is Unknown:Possible genetic disorder?Chen, T., Blum, K, Matthews, D., Fisher, L., et al. (2007).Premature birth with hypoxia, drugs/alcohol inpregnancy, difficult birth, malnutrition, abuse? (Fisher, L., Matthews, D., & Matthews, G. (2013). Two JuvenileCases of Disruptive Mood Dysregulation Disorder (DSM-5).Poster at Texas Psychological Association, November, Houston,TX)

Biological Markers for DMDD?(Kowatch et al. , 2009) BD rates do not vary by gender, but chronicirritability kids are mostly male (66-77%)(suggesting a distinct gender-based disorder). Parents of Bipolar kids are more likely (33%) tohave BD themselves than parents of DMDD kids(2.7%), (suggesting a distinct genetic pattern). Gene mapping may be a way to find biologicalmarkers for DMDD.

5) TREATMENT FOR DMDD? No treatment strategies have been established:– Deveney et al. (2013) But, Bipolar medications may NOT be needed.– Matthews, D., Fisher, L. & Matthews, G. (2012) The selection of medications for the managementof maladaptive aggression in youth is a majorclinical challenge in pediatric mental health– Kowatch et al., (2009); Fisher, Matthews & Matthews.(2013); Fisher, W., Johnson, A., Fisher, L., Sharma, S., &Ceballos, N., (2013)

TREATMENT OPTIONS?Most experts suggest medication, parent trainingand psychotherapy. Alderman (2003)Psychosocial interventions have low risk, butit may require a combination of medicationand psychosocial interventions to managethe severity. Aman et al. (2014)But, what medication protocol? Matthews, D., Fisher, L., & Matthews, G. (2013)

Medication Protocol:(Matthews et al., 2006; Matthewset al., 2009, Matthews et al., 2013) A Neuropsychiatric approach to DMDD wouldsuggest that medication strategies be based onbrain issues. If it is true that DMDD represents a combination oftop-down and bottom-up brain issues, then:– Medications should enhance frontal lobe function (topdown) to control irritability, and;– Medications should stabilize temporal-limbic (bottom-up)to stop explosive outbursts

Angry kid

Explosive Kid Glassy-eyed, jaw clenched, tight muscles RAGE

Impulse Control & Concentration

Emotion Generation System[Limbic Brain]

Auditory Evoked Response

Visual Evoked Response

P-300’s

Treatment Interventions Medications1) Anticonvulsants – Limbic instability2) Amantadine HCl or alpha-adrenergic agonists – Frontallobe dysfunction3) Stimulants – attentional deficits Psychosocial and Psycho-educational1) Psychotherapy (family and individual)2) Specialized academic interventions3) Skill-based therapies

AnticonvulsantsNameCarbamazepine (Tegretol)Oxcarbazepine (Trileptal)Levetiracetam (Keppra)Valproate sodium (Depakote)Lamotrigine (Lamictal)

Abnormal Hippocampal Attention Abnormal P-300 (cognitive evoked) responses indicateinadequate Hippocampal attentional function. P-300 responses and attentional function are normalized atappropriate dosages of neuro-stimulant medications. Dextroamphetamine 0.2-0.3 mg/kg/dose 3x/day. Methylphenidate 0.4-0.6 mg/kg/dose 3x/day. Stimulants can be transitioned to a long-acting formulationafter the most efficacious dosage has been determined.

Abnormal Frontal Lobe FunctionSymptoms are:Chronic irritability, impulsivity, memory problems andconcentration problems.Best addressed with amantadine HCl.

Angry kid

Explosive Kid Glassy-eyed, jaw clenched, tight muscles RAGE

What is Crisis Mgt. for DefensiveRAGE? SEE RAGE? Stop VERBAL de-escalation, don’ttouch him/her– No more talk, remove others, allow rage (if safe) SEE RAGE FACE: Slowly, very slowly, back away– Even if he/she follows, threatens, curses, throws stuff Don’t look threatening – it is a defensive “seizure”– Make your face, body posture - non-threatening Don’t approach or touch – unless hold must occur,– but only for absolutely imminent danger

Crisis Managementfor Explosive Kid RAGE-like a seizure (time limited, OUT-OFCONTROL)- just keep it safe, it will go away in afew minutes. Do not try to de-escalate rage (NO MORE TALK)– Do not touch or it will take an hour to stop it. You let it wind down on its own (like an emotionalseizure). No restraint, or you will hold for an hour. Remove others from the room (don’t move enragedkid). Defensive rage will subside on its own.

Explosive Kid: Crisis Management No show of force by staff (THIS WILL TRIGGERAN ATTACK) Back off and watch for safety (HOLDING IS ALAST RESORT) Rage will run out of steam on its own (IF NOTHREAT) Afterwards, expect fatigue, poor recall (remorse?) No point to punishment of out-of-control RAGE Use this strategy, not verbal de-escalation.

SUMMARY DMDD is a new diagnosis in DSM-5 for 2013. This severe mood disorder is relatively common(DMDD at least 3%, versus 1% for BD) DMDD is a distinct condition, with chronic (nonepisodic) irritability, that does not evolve into BD. No established treatment strategies for DMDD. DMDD might be managable with combination of : 1) Medication Protocol, 2) Parent Training, 3)Cognitive Behavioral Therapy, 4) Modified crisismanagement strategies.

References Alderman, N. (2003). Contemporary approaches to the management ofirritability and aggression following traumatic brain injury.Neuropsychology Rehabilitation, 12(1/2), 211-240. Adleman, N.E., et al. (2012). Cross-sectional and longitudinalabnormalities in brain structure in children with severe mooddysregulation or bipolar disorder, J Child Psychology , Psychiatry, andAllied Disciplines, 53, 11, 1149-1156. Althoff, R.R., Verhulst, F.C., Retters, D.C., Hudziak, UJ.J., & van derEnde, J. (2010). Adult Outcomes of Childhood Dysregulation: A 14Year Follow-up Study. Amer Acad Child Adol Psychiatry, 49 (11), 11051116.

References Aman, M.G., Bukstein, O.G., Gadow, K.D., Arnold, L. E., Molina, B.S.G.,McNamara, N.K. et al. (2014). What does risperdone add to parenttraining and stimulant for severe aggression in child ADHD? J. Am AcadChild Adolesc Psychiatry, 53, 1, 47-61. Axelson, M.D. (2013). Taking disruptive mood dysregulation out for atest drive. Am J. Psychiatry, 170, 136-139. Axelson, D., Findling, R.L., Fristad, M.A., Kowatch,R.A., Yougstrom,E.A., McCue-Horwitz, S., Frazier, T.W., et al., (2012). Examining theproposed DMDD diagnosis in children in the Longitudinal Assessment ofManic Symptoms study. J. Clin. Psychiatry, 73, 1342-1350

References Berntson, G. & Cacioppo, J. (Eds.), (2009). Handbook ofNeuroscience for the Behavioral Sciences, John Wiley &Sons, Hoboken, N.J. Brotman, M. et al. (2010). Amygdala activation duringemotion processing of neutral faces in children with severemood dysregulation versus ADHD or bipolar disorder. Am JPsychiatry, Jan. 167(1), 61-69. Carlson, G.A., Potegal, M, Margulies, D., Gutkovich, Z., &Basile, J. (2009). Rages: what are they and who has them?J. Child Adolesc Psychopharmacol, 19, 281-288. Caraulia, A.P., & Steiger, L.K., (1997). Nonviolent crisisintervention: Learning to diffuse explosive behavior. WI:CPI Publishing.

References Copland, W.E., Angold, A., Costello, E.J., & Egger, H.(2013). Prevalence, comorbidity, correlates of DSM-5DMDD Am J. Psychiatry, 170, 173-179. Copland, W.E. Shanahan, L., Egger, H., Angold, A., &Costello, E.J. (2014). Adult diagnostic and functionaloutcomes of DSM-5 Disruptive Mood DysregulationDisorder, Am J of Psychiatry, 171 (6), 668-674. Denmark, J., & Gemeinhardt, M. (2002). Anger and itsmanagement for survivors of acquired brain injury. BrainInjury, 16 (2), 91-108. Chen, T., Blum, K, Matthews, D., Fisher, L., et al. (2007).Preliminary association of the TaqA1 allele of the DopamineD2 Receptor Gene and the Dopamine Transporter (DAT1)480 bp Allele with pathological violent behavior inadolescents. Gene Ther. Mol. Bio., Vol. 11, 93-112.

References Deveney, C.M., Connolly, AM.E., Haring, C.T., Bones, B.L.,Reynolds, R.C Leibenluft, E. (2013). Neural mechanismsof frustration in chronically irritable children. Am J.Psychiatry, 170, 1186-1194. Dougherty, L.R. Smith, V.C., Bufferd, S.J., Carlson, G.A.Stringaris, A Klein, D.N. (2014). DSM-5 disruptive mooddysregulation disorder: correlates and predictors in youngchildren. Psychol Med (epub). Fisher, L., Matthews, D., & Matthews, G. (2014).Maladaptive Aggression in Residential Childcare: CrisisIntervention Programs. Poster at American PsychologicalAssociation, Orlando, FL. Fisher, W., Johnson, A., Fisher, L., Sharma, S., & Ceballos,N. (2013). Impulsive-Aggressive Behavior in Adolescents:In Aggressive Behavior: New Research, 45-92, NovaScience Publishers, Hauppauge, N.Y.

References Fisher, L., Matthews, D., & Matthews, G. (2013). Two Juvenile Cases ofDisruptive Mood Dysregulation Disorder (DSM-5). Poster at TexasPsychological Association, November, Houston, TX. Fisher, W., Ceballos, N., Matthews, D., & Fisher, L. (2011). EventRelated Potentials in Juveniles with Impulsive Aggression: ARetrospective Chart Review Study. Psychiatry Research, 187, 409-413. Fisher, W., Matthews, D., Fisher, L., and Ceballos, N., (2008).Neurophysiological Correlates of Impulsive Aggression. Presentation atthe International Society for Research on Aggression, Budapest,Hungary. Fisher, W., Kroll, G., Matthews, D., and Fisher, L. (2007). Youth withImpulsive Aggression:. ANPA Abstracts J. Neuropsychiatry ClinNeurosci 19: 208.

References Fisher, L. & Matthews, D. (Feb. 21, 2004). AnticonvulsantMedication for Impulsive Aggression: An Outcome Study.ANPA Abstracts at J. Neuropsychiatry Clin Neurosci, 16:215-217. Geller, B. et al. (2009). Controlled, blindly rated, familystudy of prepubertal and early-adolescent bipolar I disorderphenotype. Arch Gen Psychiatry, 63(10), 1130-1138. Greene, R.W. (2010). The Explosive Child. Harper Collins,New York. Holtmann, M., Buchmann, A.R., Esser, G., Schmidt, M.H.,Banaschewski, T., & Laucht, M. (2010). The Child BehaviorChecklist-Dysregulation Profile predicts substance use,suicidality, and functional impairment: a longitudinalanalysis, J. Child Psychology & Psychiatry, 52, 2, 139-147.

References Kinney, A. (2001). Cognitive therapy and brain injury: Theoretical andclinical issues. J Contemporary Psychotherapy, 31 (2), 89-102. Kowatch, A. R., et al., (Eds), (2009). Clinical Manual for Managementof Bipolar Disorder in Children and Adolescents. American PsychiatricPub. Co., Wash, D.C. Krieger, F.V, Leibenluft, E., Stringaris, A., & Polanczyk, G.V. (2013).Irritability in children and adolescents: past concepts, current debates,and future opportunities. Rev Bras Psiquiatr, 35 (suppl 1), S32-S39. Leibenluft, E., Cohen, P., Gorrindo, B.S., Brook, J.S. & Pine, D.S.(2006). Chronic Versus Episodic Irritability in Youth. J Child AdolescPsychopharmacology, 12, 4, 456-466. Leibenluft, E. (2011). Severe mood dysregulation, irritability, and thediagnostic boundaries of bipolar disorder in youths. Am . J. Psychiatry,168, 129-142.

References Matthews, D., Fisher, L., & Matthews, G. (2013). MedicalManagement of Explosive Aggression. Abstract ofpresentation Am Neuropsychiatric Assn, Boston. Matthews, D., Fisher, L. & Matthews, G. (2012). ExplosiveJuveniles: Medical Management Without AntipsychoticMedication. ANPA Abstracts at J Neuropsychiary ClinNeurosci, 24, 2, 256. Matthews, D., Fisher, W., Ceballos, N., and Fisher, L.(2009). Event Related Potentials in Juveniles with ImpulsiveAggression. Am Neuropsychiatric Assn, San Antonio, TX. Matthews, D., Kroll, G., Seals, J., & Fisher, L. (2006).Evidence Based Treatment of Impulsive Aggression inYouth. 58th Institute on Psychiatric Services, October, NYC.

References Matthews, D., Fisher, L. & Matthews, G. (2012). Explosive Juveniles:Medical Management Without Antipsychotic Medication. ANPAAbstracts at J Neuropsychiary Clin Neurosci, 24, 2, 256. Medd, J. & Tate, R.L. (2000). Evaluation of an anger managementtherapy program following acquired brain injury: NeuropsychologicalRehabilitation, 10 (2), 185-201. McGough, J.J. (2014). Chronic non-episodic irritability in childhood:Current and future challenges. Am J Psychiatry, 171, 607-610. Moreno, C. et al. (2007). National trends in outpatient diagnosis andtreatment of bipolar disorder in youth. Arch Gen Psychiatry, Sep; 64(9),1032-1039.

References Prigatano, G.P. (1986). Psychotherapy after brain injury. InG.P. Prigatano, D.J. Fordyce, H.K. Zeiner, J.R. Roeche, M.Pepping, & B.C. Woods (Eds.), NeuropsychologicalRehabilitation After Brain Injury. Baltimore: John HopkinsUniversity Press. Puvuluri, M.N., Schenkel, L.S.m, Aryal, S. et al., (2006).Impact of neurocognitive function on academic difficulties inbipolar disorder. Biol. Psychiatry, 60:951-956. Recupero, P.R., Price, M., Garvey, K.A., Daly, B., & Xavier,S.L. (2011). Restraint and seclusion in psychiatric treatmentsettings. J Am Acad Psychiatry Law, 39, 465-476.

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References Wetherill, R., Kroll, G., Fisher, L., and Matthews, D. (2006). Youth withImpulsive Aggression: Anticonvulsant Medication Compliance andOutcome. ANPA Abstracts at J. Neuropsychiatry Clin Neurosci 18: 252255. Wood, R.L., (2001). Neurobehavioral disorders: Their origin, nature andrehabilitation. Seminar at Ontario Brain Injury Association, St.Catharines, Ontario. Zepf F.D. & Holtmann, M. (2012). Disruptive Mood DysregulationDisorder. In Rey, J.M. (Ed.), IACAPAP e-Textbook of Child andAdolescent Mental Health, Geneva: International Association for Childand Adolescent Psychiatry and Allied Professions.

References (Outcome Studies) Fisher, L., Kroll, G., Matthews, D., and Fisher, W. (2007). Youth with ImpulsiveAggression: Anticonvulsant Compliance and Outcome for 2006. Presentation atthe American Neuropsychiatric Association, Tucson, Arizona. Fisher, L. and Matthews, D. (2004). Anticonvulsant Medication for ImpulsiveAggression: An Outcome Study. Paper presented at the AmericanNeuropsychiatric Association, Feb., 2004, Bal Harbour, Florida. Matthews, D. Fisher, L. and Kroll, G. (2012). Explosive Aggression in Youth:Medical Management Without the use of Antipsychotic Medication. ScientificPoster presented at the American Neuropsychiatric Association, New Orleans,Louisiana. Marshall, R., Matthews, D. Fisher, L., et al., (1999). Efficacy of medicaltreatment for children and adolescents with impulsive aggression. Paper read atthe American Neuropsychiatric Association, Feb., 2000, Fort Myers, Florida.

References (Outcome) Matthews, D., & Fisher, L., (1995). Successful treatment of pathologicalviolence. Paper presented at the Annual Meeting of The American PsychiatricAssociation, May, Miami, Florida. Matthews, D., Williamson, B., Seals, J., & Fisher, L. (1993). Treatment planningfor violent juveniles (for 1991). Paper presented at Annual Meeting of TheNational Association of Private Psychiatric Hospitals, Jan. 25, 1993, Ft.Lauderdale, Florida. Wetherill, R., Kroll, G., Fisher, L., and Matthews, D. (2006). Youth withImpulsive Aggression: Anticonvulsant Medication Compliance and Outcome for2005. Presentation at the American Neuropsychiatric Association, Feb. 21,2006, La Jolla, California.

References (Amantadine Studies) Coccaro, E. F. (2003). Aggression: Psychiatric Assessment and Treatment,Marcel Dekker, New York. Kraus, M.F. & Maki, P.M. (1997). The combined use of Amantadine and ldopa/carbidopa in the treatment of chronic brain injury. Brain Injury, 11(6), 455460. Horrigan, J.P. & Barnhill, J. (2002, Winter). Amantadine for psychostimulantresistant attention-deficit/hyperactivity disorder in boys (Abstract). Paperpresented at the annual meeting of the American Neuropsychiaric Association.J. Neuropsychiatry Clin Neurosci 14(1), 105. Karli, D.C., Burke, D.T., Kim, J.J., Calvanio, R., Fitzpatrick, M., Temple, D., etal., (1999). Effects of dopaminergic combination therapy for frontal lobedysfunction in traumatic brain injury rehabilitation. Brain Injury, 13(1), 63-68. Kraus, M.F. & Maki, P.M. (1997). Effect of Amantadine hydrochloride onsymptoms of frontal lobe dysfunction in brain injury: Case studies and review. J.Neuropsychiatry Clin Neurosci 9(2), 222-230.

References (Amantadine) Kraus, M.F., Smith, G.S., Butters, M., Donnell, A.J., Dixon, E., & Yilong, et al.,(2005). Effects of the dopaminergic agent and NMDA receptor antagonistAmantadine on cognitive function, cerebral glucose metabolism and D2 receptoravailability in chronic traumatic brain injury: A study using positron emissiontomography (PET), Brain Injury, 19(7), 471-489. Lyketsos, C.G., Rosenblatt, A., & Rabins, P., (2004). Forgotten Frontal LobeSyndrome or “Executive Dysfunction Syndrome”. Psychosomatics, 45(3), 247255. Meythaler, J. M., Brunner, R.C., Johnson, A., & Novack, T.A. (2002).Amantadine to improve neurorecovery in traumatic brain injury-AssociatedDiffuse Axonal Injury: A pilot Double-blind randomized trial. J. Head TraumaRehabil, 17(4), 300-313. Williams, S. E. (2007). Amantadine treatment following traumatic brain injury inchildren. Brain Injury, 21(9), 885-889.

Epidemic of Bipolar Disorder (BD)? (Leibenluft, 2011) Between 1994 and 2003 there was a 40 fold increase in the diagnosis of BD in children and