Disruptive Mood Dysregulation Disorder

1. Disruptive Mood Dysregulation Disorder Kirran Bakhshi Child Psychopathology October 2, 2013

2. What is… Disruptive Mood Dysregulation Disorder? “Persistent irritability and frequent episodes of extreme behavioural dyscontrol” (DSM-V, American Psychiatric Association, 2013)

3. DSM-V

4. What is this (and why do we care)? • a diagnosis added to the newly-released DSM-V, amid much controversy • based on a cluster of symptoms previously called ‘severe mood dysregulation’ • specifically for children • to reduce the threat of overdiagnosing (and overtreating!) children for bipolar disorder (BD)

5. Criteria I • Severe recurrent temper outbursts, verbal and/or behavioural, out of proportion in intensity or duration to the situation • Outbursts inconsistent with developmental level • Outbursts occur ~3+/week • Mood between outbursts is persistently irritable most of the day, almost every day, and is observable by others • Criteria are present for at least 12 mos, in at least 2 settings (home/school/peers), and is severe in at least 1 setting

6. Criteria II • Should only be diagnosed between 6-18 years, with age at onset before 10 years • Criteria for a manic/hypomanic episode have never been met • Does not occur exclusively during MDD, and is not better explained by another disorder, effects of substance use, or other medical/neurological condition • CANNOT COEXIST with: ODD, IED, BD • MAY COEXIST with: MDD, ADHD, CD, substance use disorders

7. Clinical manifestations • IRRITABILITY • frequent temper tantrums • typically occur in response to frustration • persistent irritable/angry mood • most of the day, almost every day • Must be distinguished from episodic (typical) bipolar disorder: no manic or hypomanic episodes in DMDD

8. Prevalence • Common in children presenting to mental health clinics, although rates unknown in community • Overall 6 month-1 year period-prevalence: 2-5% of children and adolescents • Rates higher in males and children (than females and adolescents) • These are distinguishing features from bipolar disorder, where rates are much lower prior to adolescence and steadily increase into early adulthood, and where there is equal gender prevalence

9. Course • Age of onset: must be before 10 years; must have a developmental age of at least 6 years • Use of diagnosis should be limited to 7-18 years • ~1/2 will still meet criteria 1 year later • Very low risk of conversion to bipolar disorder, although there is risk of developing depressive/anxiety disorders later in adulthood

10. Risk factors Temperamental • Extensive history of chronic irritability, potentially even qualifying for a diagnosis of ODD • Many also meet criteria for ADHD and anxiety disorders, or even MDD, with symptoms present at an early age Genetic • DMDD and BD do not differ in family-based risk, but both have deficits in face-emotion labeling, decision-making, cognitive control • DMDD: specific dysfunction has been shown when assessing attention deployment in response to emotional stimuli

11. Functional consequences • Marked disruption in family & peer relationships • Low frustration tolerance: difficulty succeeding in school, unable to participate in activities w/other children, trouble initiating/sustaining friendships • Dangerous behaviour, suicidal ideation, suicidal attempts, severe aggression, psychiatric hospitalization common [although DSM-V states more research is needed to document this]

12. Differential I: Bipolar disorders • Primary differential feature: longitudinal course of symptoms • Bipolar disorders: episodic illness; discrete episodes of mood perturbation that are different from the usual • During manic episode: onset/worsening of cognitive, behavioural, physical symptoms that are different from the usual • DMDD: mood is persistent • Elevated/expansive mood, grandiosity: characteristic of mania and bipolar disorders, but NOT DMDD

13. Differential II: ODD • Symptoms of ODD do occur in DMDD, but the opposite is rarely true: there are not often symptoms of DMDD in ODD • Most children who meet criteria for DMDD will also meet criteria for ODD: due to criteria of severe and frequent outbursts, and necessary impairment in at least 2 settings • However, even if criteria for ODD are met in DMDD, only the diagnosis of DMDD should be given: mood symptoms are prominent, as is risk for future mood/anxiety disorders

14. Differential III: ADHD, MDD, anxiety disorders, ASD • Can be comorbid with ADHD, MDD, anxiety disorders • MDD • If irritability only present during the course of MDD or dysthymia, DMDD should not be given • Anxiety disorders • If irritability only present in exacerbation of anxiety disorder, DMDD should not be given • Autism spectrum • Temper outbursts occur frequently, should not be considered secondary diagnosis but part of ASD

15. Differential IV: Intermittent explosive disorder • Intermittent explosive disorder: may also present with severe temper outbursts; however, no persistent mood disruption in-between • Requires 3 mos of symptoms, while DMDD requires 12 mos • These disorders should NOT be comorbid

16. Comorbidity • Rates of comorbidity are very high: rare to find only DMDD • Strongest overlap with ODD • Wide range of comorbid illnesses: disruptive behaviour, mood, anxiety, autism spectrum symptoms • In case of comorbid symptoms of bipolar disorder: only BD diagnosed • In case of comorbid symptoms of ODD or IED: only DMDD diagnosed

17. Model: DSM-V • Risk factors • history of irritability • emotional-processing deficits • Core Features • chronic and persistent irritability • temper tantrums • Secondary features • impaired relationships with family and peers • problems in school • ADHD, MDD, anxiety disorders

18. Literature

19. Severe mood dysregulation & Ellen Leibenluft • Ellen Leibenluft: senior investigator at NIH & Associate Professor of Psychiatry, Georgetown University School of Medicine • Spearheaded characterization and diagnostic criteria for severe mood dysregulation (SMD) in 2003 • Widely involved in ongoing efforts to describe and further understand the disorder and its deficits • Her lab studies both BD and SMD: structural MRI, fMRI, DTI, MEG, genotyping, behavioural paradigms; clinical treatment trials, psychological functioning, neural circuitry

20. Epidemiology & prevalence • There have been 2 studies to date looking at epidemiology of either SMD (Brotman et al, 2006) or DMDD (Copeland et al, 2013); both were retrospective, both large samples • Lifetime prevalence of SMD among 9-19yo: 3.3% (Brotman et al, 2006) • 67.7% had comorbid axis I diagnosis • ADHD: 26.9%; CD: 25.9%; ODD: 24.5% • Copeland et al, 2013: DMDD relatively uncommon after early childhood • applying all of the DMDD criteria (especially duration) decreased prevalence to ~1%

21. SMD & bipolar disorder: I • Category of SMD initially came out of desire to make explicit the various phenotypes of bipolar disorder • THE IMPORTANCE OF MAKING CORRECT DIAGNOSIS! • Done to optimize treatment plans, as well as to describe a “relatively homogeneous population of patients with mood disturbance, hyperarousal, and decreased frustration tolerance” (Leibenluft, Charney et al, 2003) • Phenotypes may have different course and family history • However, the phenotypic populations are still likely to be heterogenous

22. SMD & bipolar disorder: II • 2 main phenotypes were characterized (Leibenluft, Charney et al, 2003) • narrow BD phenotype: “[must] meet the full DSM-IV diagnostic criteria for (hypo)mania, strictly construed, with the hallmark symptoms of elevated mood or grandiosity and clear episodes meeting the duration criteria” • broad BD phenotype: “chronic, nonepisodic illness that lacks the hallmark symptoms of (hypo)mania but that shares with the narrower phenotypes the symptoms of severe irritability and hyperarousal” • Essentially, SMD = DMDD, except for the criteria of hyperarousal (required for SMD but not DMDD)

23. Differentiating between SMD & BD • Several studies have investigated: • Familial risk (Brotman et al, 2007) • Parents of children with BD are significantly more likely to have been diagnosed with BD themselves than are parents of children with SMD (r=0.25) • Risk for mania at follow-up (Stringaris et al, 2010) • Children with SMD are unlikely to develop manic episodes at FU, ~2yr (1/84 SMD, vs 58/93 BD) • Cognitive flexibility (Dickstein et al, 2007) • Ability to adapt to changing contigencies • BD and SMD children performed differently on two stages: simple reversal (BD<SMD: r=0.22), compound reversal (BD~SMD), change task reaction time (BD<SMD: r=0.21)

24. Emotional-processing deficits • Numerous studies looking at attention and emotional-processing in SMD, due to known deficits in BD • Face-emotion labeling: Rich et al, 2008 • Compared to HC, SMD & BD both required increased intensity of facial expressions in order to identify the emotion (r=0.37) but did not differ from each other Fig 2. From Rich et al, 2008: facial morphs for ‘disgust’

25. Emotional-processing deficits • Numerous studies looking at attention and emotional-processing in SMD, due to known deficits in BD • Affective prosody: Deveney et al, 2012 • Identifying the emotional tone of verbal information • SMD made more errors than HC (η2=0.05) • When broken down by medication: unmedicated SMD made more errors than HC (η2=0.07), but medicated SMD did not differ from HC (η2=0.03) Fig 1. From Deveney et al, 2012: mean number of errors (not differentiated by medication)

26. Emotional-processing deficits: amygdala activation • Numerous studies looking at attention and emotional-processing in SMD, due to known deficits in BD • Brotman et al, 2010: fMRI (BOLD signal) • Face-emotion processing (w neutral faces) • SMD: showed L amygdala hypoactivation compared to HC, BD, ADHD Fig 1. From Brotman et al, 2010: mean activation in L amygdala

27. Emotional-processing deficits: amygdala activation • Numerous studies looking at attention and emotional-processing in SMD, due to known deficits in BD • Thomas et al, 2013 • Responses to emotional faces • SMD: increased activity in R amygdala for all expressions (angry, fearful, neutral) compared to HC [no diff w/BD] • SMD: deactivation of posterior cingulate cortex, posterior insula, IPL, for fearful expressions only Fig 1. From Thomas et al, 2013: % change in R amygdala across all expressions

28. Emotional-processing deficits: amygdala activation • Thomas et al, 2013: Fig 2-4. From Thomas et al, 2013: % change in L posterior cingulate cortex & L IPL, respectively

29. Emotional-processing deficits: attentional bias • Numerous studies looking at attention and emotional-processing in SMD, due to known deficits in BD • Attentional bias to threat faces: Hommer et al, 2013 • Tendency to allocate attention to threat is characteristic of anxiety • SMD showed attention bias towards threatening faces compared to HC (d=0.54), and this did not differ between SMD with or without comorbid anxiety disorder Fig 1. From Hommer et al, 2013: Threat bias (ms) in SMD and HC

30. Emotional-processing deficits: attentional bias • Psychophysiological responses during frustration task: Rich et al, 2007 • SMD reported more arousal (ie. frustration) during task, compared to HC (r=0.25) • ERPs: SMD also showed a lower N1 amplitude compared to HC and BD (“indicates deficient attention”), whereas the P3 amplitude in SMD was similar to HC but different from BD (impairments in executive attention in BD but not SMD) Figs 2 & 3. From Rich et al, 2007: P3 & N1 amplitudes, respectively, in response to frustration task

31. Emotional-processing deficits: attentional bias • Attention to emotional stimuli: Rich et al, 2010: how attention is affected by positive, negative and neutral distractors • SMD showed decreased interference from emotional distracters (η2=0.03), compared to BD (η2=0.17) & HC (η2=0.26) [insinuating SMD less sensitive to emotional stimuli] • SMD had decreased response interference for positive (η2=0.14) & negative (η2=12) stimuli Figs 2 & 3. From Rich et al, 2010: effect of emotional distracters on reaction time and effect of positive/negative images, respectively

32. Neural mechanisms • Brain structure abnormalities: Adleman et al, 2012 • Looking at the difference in gray matter volume using VBM • Differences were found in BD compared to HC & SMD [inc GM in globuspallidus, abnormal inc GM over time in SPL/IPL], and in HC compared to BD & SMD [inc GM in DLPFC, insula], but nothing to differentiate SMD specifically • Neural pathways using MEG: Rich et al, 2011 • SMD reported greater agitation than BD & HC, & BD/SMD reported being less happy than HC, after blocked goal attainment task (negative feedback) • SMD: increased activation of ACC & medial frontal gyrus compared to HC Figs 3 & 4. From Rich et al, 2011: greater agitation in SMD and BD/SMD more unhappy after negative feedback

33. Neural mechanisms Fig 5. From Rich et al, 2011: difference in MEG activation in L ACC after negative/positive feedback

34. Suggested treatment: I • Group therapy • Waxmonsky et al, 2012: specifically for children w/comorbid ADHD & SMD • integrates CBT (affect regulation), parent-training intervention (manage behaviour); 10 wks • Resulted in: • decrease in clinician-rated mood symptoms (d=0.81) [maintained at FU, 6 wks post-treatment] • decrease in parent ratings of ADHD (d=0.30), ODD (d=0.26), CD behaviours (d=0.27) [not maintained at FU] • decrease in impairment (d=2.17), but not fully maintained at FU • Lithium: Dickstein et al, 2009 • not found to have significant clinical/neurometabolic effect

35. Suggested treatment: II • Methylphenidate: Waxmonsky et al, 2008 • Varying levels of behaviour modification therapy and methylphenidate [dosage level varied daily] • SMD (w/ADHD) had improvement in externalizing symptoms: • ADHD symptoms: r=0.44-0.58 • ODD symptoms: r=0.51 • BUT: unclear if criteria for SMD included mania symptoms • One suggested treatment has been chronotherapy (Heiler et al, 2011) • To retrain the circadian rhythms via exposure to light • Has been shown to decrease depressive symptoms in MDD, and to have a positive influence on symptoms in ADHD & BD (part. inattention & irritability)

36. Controversy • Several studies have raised questions about the ‘pathologizing’ of irritability, and the small amount of data/evidence supporting SMD/DMDD • Axelson et al, 2011: questions the inclusion of SMD in DSM-V • primarily citing insufficient scientific support and potential adverse impact on patient care, research, & public’s perceptiom of child psychiatry • SMD does not have symptom criteria that are specific to it as a disorder

37. Inclusion in DSM-V • Axelson et al, 2012: longitudinal assessment of diagnostic validity of DMDD • DMDD was not associated with current or future or parental history of mood/anxiety disorders • DMDD had limited diagnostic stability: 50% met criteria at only one assessment, 29% at two assessment, and 19% at three assessments [2 yr FU] • DMDD not diagnostically distinct: 96% of DMDD had comorbid diagnoses of ODD or CD, and 77% were comorbid with ADHD & ODD/CD • 40% of BD were comorbid with ODD/CD; 41% of MDD comorbid with ODD/CD • Conclusion: concerns about diagnostic utility

38. New model • Emotional-processing deficits • amygdala responses Symptoms of ADHD & ODD • Family risk • incl family history of BD Frustration • Core features • chronic and persistent irritability • temper tantrums Therapeutic/behavioural interventions Δ’ neural pathways Psychopharmacology • Secondary features • impaired relationships with family and peers • problems in school Other disorders: MDD/anxiety

39. Thank you! Questions?

40. References I • Diagram slide 1: http://www.philly.com/philly/blogs/healthy_kids/What-is-Disruptive-Mood-Dysregulation-Disorder.html • American Psychiatric Association. (2013). Diagnostic andstatistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. • Slide 19: http://neuroscience.nih.gov/lab.asp?Org_ID=457 • Brotman, M. A., Schmajuk, M., Rich, B. A., Dickstein, D. P., Guyer, A. E., Costello, E. J.,…Leibenluft, E. (2006). Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children. Biol Psychiatry 60, 991-997. • Copeland, W. E., Angold, A., Costello, E. J., & Egger, H. (2013). Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder. Am J Psychiatry, 170, 173-179. • Leibenluft, E., Charney, D. S., Towbin, K. E., Bhangoo, R. K., & Pine, D. S. (2003). Defining clinical phenotypes of juvenile mania. Am J Psychiatry, 160, 430-437. • Brotman, A. A., Kassem, L., Reising, M. M., Guyer, A. E., Dickstein, D. P., Rich, B. A., … Leibenluft, E. (2007). Parental diagnosis in youth with narrow phenotype bipolar disorder or severe mood dysregulation. Am J Psychiatry, 164, 1238-1241. • Stringaris, A., Baroni, A., Haimm, C., Brotman, M., Lowe, C. H., Myers, F., … Leibenluft, E. (2010). Pediatric bipolar disorder verses severe mood dysregulation: risk for manic epsidoes on follow- up. J Am Acad Child Adolesc Psychiatry, 49, 397-405. • Dickstein, D. P., Nelson, E. E., McClure, E. B., Grimley, M. E., Knopf, L., Brotman, M. A., … Leibenluft, E (2007). Cognitive flexibility in phenotypes of pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry, 46, 3441-3555.

41. References II • Rich. B. A., Grimley, M. E., Schmajuk, M., Blair, K. A., Blair, R. J. R., & Leibenluft, E. (2008). Face emption labeling deficits in children with bipolar disorder and severe mood dysregulation. Dev Psychopathol, 20, 529-546. • Deveney, C. m>, broman, M. A., Decker, A. M., Pine, D. S., & Leibenluft, E. (2012). Affective prosody labeling in youths with bipolar disorder or severe mood dysregulation. Journal of Child Psychology and Psychiatry, 53, 262-270. • Brotman, A., A., Rich, B. A., Guyer, A. E., Lunsford, J. R., Horsey, S. E., Reising, M. M., Thomas, L. A., … Leibenluft, E. (2010). Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder. Am J Psychiatry, 167, 61-69. • Thomas, L. A., Kim, P., Bones, B. L., Hinton, K. E., Milch, H. S., Reynolds, R. C., … Leibenluft, E. (2013). Elevated amygdala responses to emotional faces in youths with chronic irritability or bipolar disorder. NeuroImage: Clinical, 2, 637-645. • Hommer, R. E., Meyer, A., Stoddard, J., Connolly, M. E., Mogg, K. Bradley, B. P., … Brotman, M. A. (2013). Attention bias to threat faces in severe mood dysregulation. Depression and Anxiety, 00, 1-7. • Rich, B. A., Schmajuk, M. Perez-Edgar, K. E., Fox, N. A., Pine, D. S., & Leibenluft, E. (2007). Different psychophysiological and behavioural responses elicited by frustration in pediatric bipolar disorder and severe mood dysregulation. Am J Psychiatry, 164, 309-317. • Rich, B. A., Brotman, M. A., Dickstein, D. P., Mitchell, D. G. V., Blair, R. J. R., & leibenluft, E. 2010). Deficits in attention to emotional stimuli dinstinguish youth with sevre mood dysregulation from youth with bipolar disorder. J Abnorm Child Psychol, 38, 695-706.

42. References III • Adleman, N. E., Fromm, S. J., Razdan, V., Kayser, R., Dickstein, D. P., Brotman, M. A., Pine, D. S., & Leibenluft, E. (2012). Cross-sectional and longitudinal abnormalities in brain structure in children with severe mood dysregulation or bipolar disorder. Journal of Child Psychology and Psychiatry, 53, 1149-1156. • Rich, B. A., Carver, F. W., Holroyd, T., Rosen, H. R., Mendoza, J. K., Cornwell, B. R.,… Leibenluft, E. (2011). Different neural pathways to negative affect in youth with pediatric bipolar disorder and severe mood dysregulation. Journal of Psychiatric Research, 45, 1283-1294. • Waxmonsky, J. G., Wymbs, F. A., Pariseau, M. E., Belin, P.J., Waschbusch, D. A., Babocsai, L., … Pelham, W. E. (2013). A novel group therapy for children with AdHD and severe mood dysregulation. J of AttDis, 17, 527-541. • Dickstein, D. P., Towbin, K. E., Van DerVeen, J. W., Rich, B. P., Brotman, M. A., Knopf, L., … Leibenluft, E. (2009). Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation. Journal of Child and Adolescent Psychopharmacology 19, 61-73. • Waxmonsky, J., Pelham, W. E., Gnagy, E., Cummings, M. R., O’Connor, B. Majumdar, A., … Robb, J. A. (2008). The efficacy and tolerability of methylphenidate and behavioural modification in children with attention-deficit/hyperactivity disorder and severe mood dysregulation. Journal of Child and Adolescent Psychopharmacology 18, 573-588. • Heiler, S., Legenbauer, T., Bogen, T., Jensch, T., & Holtmann, M. (2011). Severe mood dysreulation: in the “light” of circadian functioning. Medical Hypotheses 77, 692-695. • Axelson, D. A., Birmaher, B., Findling, R. L., Fristad, M. A., Kowatch, R. A., Youngstrom, E. A, … Diler, R. S. (2011). Concerns regarding the inclusion of temper dysregulation disorder with dysphoria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition . J Clin Psychiatry 72, 1257-1262.

43. References IV • Axelson, R., Findling, R. L., Fristad, M.A., Kowatch, R.A., Youngstrom, E.A., Horwitz, S.M, … Birmaher, B. (2012). Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms Study. J Clin Psychiatry 73, 1342-1350. • Effect size calculator: http://www.uccs.edu/~lbecker/