| Alma Mater Europaea University – ECM, Slovenska 17, Maribor, SloveniaJournal of Health and Rehabilitation Sciences |
| Received: 02-December-2022 Revised: 04-January-2023Accepted: 06-January-2023Online first: 07-January-2023 |
Citation: Parentau, C., Hendren, R. (2022). Disruptive Mood Dysregulation Disorder Associated with Autism Spectrum Disorder: Literature Review and Case Illustrations.
Corresponding address:
Department of Psychiatry and Behavioral Sciences,
University of California, San Francisco
675 18th Street, San Francisco CA, 94143, USA
Email: China.Parenteau@ucsf.edu
Extreme irritability, sometimes referred to as Disruptive Mood Dysregulation Disorder (DMDD), is increasingly recognized as a treatment target for children with autism spectrum disorder (ASD). We review the appreciation of irritability in ASD, the development of DMDD as a recognized disorder, and potential treatments for the combination of ASD and DMDD followed by three illustrative cases. The primary reason families seek psychiatric evaluations for their children is irritability (Kelly et al., 2010; Peterson et al., 1996). Irritability is a symptom observed across numerous psychiatric disorders and is unique in that it affects both internalizing and externalizing problems (Stringaris, 2011). Irritability can be extremely impairing due to its hallmark characteristics of anger and temper outbursts (Stringaris, 2011). Historically, extreme irritability in children was seen as a precursor to adulthood manic episodes, so it was sometimes categorized as pediatric bipolar disorder (BD) (Leibenluft, 2017; Leibenluft et al., 2003; Leibenluft et al., 2006). However, in the early 2000’s, the reported prevalence of pediatric BD was increasing at an alarming rate—an approximate 500% increase was observed in the United States within a decade. This led researchers to take a closer look into the diagnostic reliability of pediatric bipolar disorder (Blader & Carlson, 2007; Moreno et al., 2007). In 2010, Stringaris et al. operationalized the syndrome called “severe mood dysregulation” (SMD) to describe the nonepisodic irritability observed in many of the children who were formerly diagnosed with BD. As a part of the initial efforts to distinguish SMD and BD, Stringaris et al. (2010) conducted a 2-year longitudinal study that revealed that children with SMD were 50 times less likely to experience a manic or mixed episode than children with BD. Further longitudinal studies revealed that nonepisodic irritability in childhood was more commonly associated with ADHD in adolescence, and anxiety and depression in adulthood, rather than BD in adulthood (Brotman et al., 2006; Copeland et al., 2014; Liebenluft et al., 2006; Stringaris et al., 2009; Vidal-Ribas et al., 2016). Additionally, children with BD were more likely to have parents who also had a diagnosis of BD, compared to parents of children with SMD (Brotman et al., 2007). Moreover, neurological differences between individuals with SMD and BD also exist (i.e., hypoactivation in the amygdala for individuals with SMD compared to BD) (Brotman et al., 2010; Deveney et al., 2013; Leibenluft & Stoddard, 2013; Rich et al., 2007). These factors combined provide evidence that SMD and BD are likely separate constructs. The research surrounding SMD led to the inception of DMDD in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-V; American Psychiatric Association, 2013). While symptoms must be present by 12 years old in SMD, DMDD requires that symptoms are present before 10 years old. Another key difference is that a diagnosis of DMDD does not require the hyperarousal criterion (distractibility, insomnia, racing thoughts/flight of ideas, and agitation) that is associated with SMD and BD.
Currently, the DMDD diagnosis is given to children and adolescents between the ages of 6 and 18 who meet the following criteria: 1) Severe temper outbursts (verbally or behaviorally) that occur at least three times a week, with reactions disproportionate to the situation or inappropriate based on developmental level 2) sad, irritable, or angry mood almost every day, 3) symptoms beginning before the age of 10 and present for at least a year, and 4) symptoms impede on child’s functioning in more than one context (i.e. school, home, amongst peers; American Psychiatric Association, 2013).
In a subsample of 766 children between the ages of 6-16 (580 autistic participants, 186 neurotypical participants), DMDD symptoms were prevalent in 45% of the participants with autism spectrum disorder (ASD), whereas DMDD symptoms were only present in 3% of the neurotypical population (Mayes et al., 2015). While irritability and temper outbursts are core symptoms of DMDD, and they are also common symptoms for autistic youth (Dickstein et al., 2021). The main difference being that irritability and outbursts present differently in standalone ASD as they are typically tied to specific contexts and triggers (Bruno et al., 2019). Additionally, the DSM-V states that DMDD symptoms generally lessen with age (APA, 2013). This is also supported by studies in neurotypical populations that examine symptoms related to DMDD overtime (i.e., tantrums and negative mood decrease with age in young children; Copeland et al., 2013; Osterman & Bjorkqvist, 2010). However, age has not been significantly related to temper outburst and irritability in autistic youth (Lecavalier, 2006; Mayes et al., 2017). This suggests that DMDD symptoms might manifest differently in children with ASD, and thus treatment approaches should also be tailored to the symptoms. Despite the high prevalence of DMDD symptoms in children with ASD, there has been little evidence-based research into effective treatments for these co-occurring diagnoses.
The guidelines to treat DMDD are currently in progress, thus treatment outcomes have primarily been focused on targeting core symptoms of chronic irritability and temper outbursts in SMD populations (Breaux et al., 2022; Bruno et al., 2019; Tourian et al., 2015). Below, common pharmacological treatments for symptoms related to BP, SMD, and DMDD are explored.
Prior to the establishment of DMDD, psychostimulants and antidepressants were seldomly prescribed for irritability because it was believed that they may worsen mania and hyperarousal (Bruno et al., 2019). However, with the longitudinal associations between DMDD, and adulthood depression and anxiety, psychostimulants and antidepressants became a potential treatment option. As attention deficit hyperactivity disorder (ADHD) and DMDD frequently co-occur, the effects of psychostimulants on aggression have been consequently explored. In 2006, Pappadopulos et al., identified 18 randomized control trials that delivered psychostimulants to a total of 1057 participants with various diagnoses (ADHD, autism, “mental retardation”, and disruptive behavior disorder). Methylphenidate was most commonly administered, with an average dose of .93 mg/kg/day. Analyses of the aggregated results across the studies revealed significant decreases in aggression in children through the use of psychostimulants. Additionally, a recent study on youth with SMD found that combination of citalopram and methylphenidate elicited a higher proportion of responses based on improvements of irritability after 8 weeks, compared to those solely receiving a placebo and methylphenidate (Towbin et al., 2020). Furthermore, a retrospective review of six children with DMDD showed significant decreases in irritability with the use of atomoxetine (Benarous et al., 2020).
The majority of the studies on alpha-2 agonist had a focus on individuals with ADHD. For example, clonidine and guanfacine showed improvements in aggressive symptoms (Connor et al., 2003; Connor et al., 2010; Hazell & Stuart, 2003; Jaselskis et al., 1992; Palumbo et al., 2008; Scahill et al., 2001; Wilens et al., 2012). However, a study on 12 children diagnosed with DMDD revealed reductions in the frequency of rage episodes upon administration of guanfacine and accompanying behavioral supports (Jain, 2017).
Lithium has long been utilized and approved by the FDA to treat mania associated with pediatric BD (Findling et al., 2015; Findling et al., 2019; Patino et al., 2015; Pisano et al., 2019). However, in children with SMD, the first randomized double-blind, placebo-controlled trial revealed no significant differences in irritability and aggression between participants receiving lithium versus a placebo (Dickstein et al., 2009). In a review of treatments on DMDD, Hendrickson et al., (2020) further punctuates the claim that the data does not currently support benefits of lithium for youth with DMDD. While lithium has demonstrated benefits for treating acute mania in bipolar disorder, studies of its effectiveness for chronic irritability experienced by youth with DMDD has not been demonstrated in clinical trials; although there are anecdotal and case series reports suggesting that lithium may be beneficial for some children with DMDD, supporting the need for further study (Mattes, 1986).
Atypical antipsychotics are commonly used to treat irritability and temper outbursts in children with autism (Fallah et al., 2019; Politte & McDougle, 2014), with risperidone and aripiprazole showing the most promising outcomes (Cohen et al, 2013; Owen et al., 2009; Shea et al., 2004). In fact, Fung et al., (2016) reviewed forty-six randomized controlled trials on treatments for irritability in autism and found risperidone and aripiprazole to exhibit the largest effect sizes. There has also been inspection of the use of atypical antipsychotics for direct treatment of SMD. Krieger et al., (2011) examined 21 participants with SMD and found that irritability significantly decreased with the intake of risperidone. Given the success of risperidone and aripiprazole for managing irritability in ASD and SMD, randomized control trials should be conducted directly on DMDD and ASD to further understand its efficacy in this population.
While there are currently no non-pharmacological treatments that address the co-occurrence of DMDD and ASD, psychosocial treatments do exist for youth with BD. Commonly implemented psychosocial therapy for BD includes multi-family psychoeducation groups (MFPG; Fristad et al., 2002; Young & Fristad, 2007), Family-Focused Therapy (FFT; Miklowitz et al., 2000; Miklowitz et al., 2004), Interpersonal and Social Rhythm Therapy (Hlastala et al., 2010), Dialectical Behavioral Therapy (DBT; Goldstein et al., 2015), and Child- and Family-Focused Cognitive-Behavioral Therapy (Pavuluri et al., 2004; West et al., 2009). These therapies explore a range of outcome variables from parental skills and knowledge surrounding BD, to child outcomes such as mood, aggression, and irritability. It is often recommended that the psychosocial treatments are paired with pharmacological treatments for maximum efficacy (Fristad et al., 2003; McClellan et al., 2007). In the future, during the development and/or adaptation of psychosocial treatment for children with co-occurring DMDD and ASD, it will be important to consider the additional communication and attentional challenges that have the potential to arise.
EP, female, was born to a 23-year-old mother who had an unclear medical history and was adopted at 3 years of age in South America. In the US., observed difficulties occurred at school, where EP was often disruptive and displayed signs of mood instability. If peers or teachers interfered with a desired task, EP became aggressive and violent. Due to these concerns, EP was frequently asked to leave her specialized school. At six years old she was diagnosed with ASD and attention deficit hyperactivity disorder (ADHD - combined). Throughout her education, she attended five different non-public school placements for children with NDD. To treat her challenging behaviors and unstable mood, psychiatrists prescribed risperidone, aripiprazole, quetiapine, ziprasidone, clonidine, and guanfacine over the years. They all showed modest benefits and expected side effects including weight gain and anticholinergic effects. Her irritable, aggressive, and impulsive behavior continued.
At the age of fourteen, she developed symptoms of further anxiety, obsessive compulsive disorder (OCD), and intrusive thoughts. To treat her OCD symptoms, she was trialed on sertraline, escitalopram, and fluoxetine and also, cognitive behavior therapy. While the medications helped with her OCD symptoms, they also increased her irritability. EP was later prescribed olanzapine and lamotrigine, but no clear benefits emerged. Asenapine (10 mg) appeared to have the most benefit of all the antipsychotics when taken concurrently with lithium (1500mg). While her mood dysregulation is still episodically present, asenapine and lithium have created the most stability when the dosage levels are maintained. Currently she is in a residential program with the following diagnoses: ASD, DMDD and OCD and has been doing well there for 3 years on the same medications.
LN, male, was adopted at 5 ½ months. His adoptive parents reported that his biological mother was likely abusing substances during the pregnancy. At the age of 3, LN was not interacting with others in a social manner, and he was diagnosed with ID and ADHD. Around this time LN also became anxious and moderately depressed when introduced to new situations. He also developed new phobias and fears. LN was first seen at the UCSF Center for ASD and NDD’s at the age of 11 and was given the additional diagnoses of Psychosis NOS, ADHD, PDDNOS, and Borderline ID. Treatment included risperidone, clonidine, dexmethylphenidate and sertraline.
Dexmethylphenidate and sertraline were removed from his regime as the former increased his anxiety and the latter increased his activation and hypomania. This led to a hospitalization, where his medicines were adjusted to aripiprazole and valproic acid, which showed modest benefits. For the past four years, he has been on Abilify (20mg/da), bupropion (450mg/da), quetiapine (200mg bid), and lithium (1500mg/da). Currently, he lives in a residential home and is diagnosed with ASD and DMDD and is stable on the same medications.
CL, male, was diagnosed with ASD at age 2 ½. His aggression became increasingly concerning between the ages of 6 and 7 years old. At that time, he was also undereating. He was prescribed risperidone which helped address both concerns. His first consultation with the UCSF Center for ASD and NDD’s occurred at 15 years old, because his aggression with family members and students at school was becoming harmful. Over the next several years he was trialed on aripiprazole, quetiapine, clonidine, lisdexamfetamine, methylphenidate, and sertraline, mirtazapine, and as needed lorazepam.
At 20 years old, CL experienced increasing aggression to the extent that he began to hurt and threaten his family members again. To address the aggression, he was prescribed lithium titrated up to 600mg BID along with mirtazapine for sleep, and 1.75mg of risperidone and his aggression markedly decreased and his mood was stable.
After six months, his father requested a decrease in dosage of lithium (.5mg), however his aggression worsened. After returning to 600mg BID, his aggression and mood has been stable for the past 4 years while living in a residential facility. He also takes gabapentin, aripiprazole and low dose quetiapine for sleep.
Currently, there are no studies that explore treatment for a person with cooccurring ASD, bipolar disorder, DMDD or psychosis despite its the relatively high prevalence but there are increasing studies of the irritability common to each (Breaux et al, 2022). This could potentially be because misdiagnosis often occurs with some of the symptoms being indistinguishable from one disorder to the next. Potentially due to the indistinctness and common genetic origins, antipsychotics are used to treat both disorders when comorbid with ASD. It is also suggested to pair treatment with CBT to assist with the anxiety and emotions that may accompany the disorders.
The common theme is the symptom of irritability rather than one or more diagnostic groups. Antipsychotics and CBT are reported the most effective, but mood stabilizers may have a strong role for certain combinations of ASD and DMDD.
Dr. Robert Hendren received research grants from Curemark, Otsuka, GW, Ltd, and Axial Biotherapeutics and is on the advisory boards for BioMarin, Axial Biotherapeutics and Janssen. China Parenteau has no conflicts of interest to declare.
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