Authors: Sandra Mitchell (sandra.mullen@vcuhealth.org)
Categories: Applied Psychopharmacology, disruptive mood dysregulation disorder, stimulants, second generation antipsychotics
Source: The Mental Health Clinician
Authors: Sandra Mitchell
Disruptive mood dysregulation disorder (DMDD) is characterized by nonepisodic, chronic irritability occurring nearly every day of the week in 2 or more settings for a minimum of 12 months with diagnosis between 6 and 18 years of age.1 Onset is often by 10 years of age, and no more than 3 consecutive symptom-free months may occur. Persistent negative mood and severe temper outbursts disproportionate to the trigger are hallmark symptoms of DMDD.2 Diagnosis is limited by the lack of available rating scales and diagnostic screening tools to identify DMDD and differentiate it from other psychiatric disorders. In addition, there are no available treatment guidelines and minimal available literature to aid in the pharmacologic management of DMDD symptoms.
Since the addition of DMDD into the Diagnostic and Statistical Manual for Mental Disorders, 5th Edition (DSM-5), the 3-month prevalence of DMDD has been estimated to be 0.8% to 3.3% with the highest rate in preschoolers using post hoc analysis of large data sets primarily focused on other disease states.3 Using data from a longitudinal assessment of manic symptoms, 26% of children 6 to 12 years of age met criteria for DMDD, but this was not the focus of the study.4 In a more recent Norwegian clinical sample of children 6 to 12 years of age, the prevalence was estimated at 24%.5 In another analysis, the prevalence was estimated to be much higher; however, because of significant overlap with disruptive behavior disorders, an exact percentage for DMDD alone was not reported.6
The above studies illustrate the difficulty with identifying the exact prevalence of DMDD. Irritable mood and temper dysregulation overlap with many psychiatric disease states generating high rates of comorbidities with disruptive behavior disorders such as oppositional defiant disorder (ODD) and conduct disorder (CD).3,6,7 Although there is significant symptom overlap with ODD, DMDD and ODD should not be diagnosed together.1 Irritability may be observed with other psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, and anxiety (Table 1).4-8 With ADHD and ASD also commonly diagnosed in childhood, it is important to consider the overlap of irritability. Impacts on concentration and attention resulting from chronic irritability may be difficult to identify as primarily caused by ADHD or DMDD when both are present together.2 Comorbid DMDD and ASD may result in increased frustration and negative responses because of the failure to understand social and emotional responses.8
A 9-year-old male seen for the past 5 years in clinic presents accompanied by his father for a routine follow-up for the management of ADHD, ASD, and DMDD. Today, the patient initially engages until conversation shifts to discussing his behavior at school and home and the benefit of his current medications. At this time, he crawls under his chair facing the wall, lies on the floor, refuses to participate, flips over furniture, attempts to leave the room, and responds with hisses and grunts when addressed. Dad reports similar behaviors occur at home and school when demands are placed on him to participate in activities. Dad reports the family feels as if they are walking on eggshells waiting for the next temper outburst. Despite his individualized education plan accommodations and 1 aid at school, the patient minimally participates and experiences multiple temper outbursts during the school day. The only trigger identified by parents and teachers is when demands are asked of the patient, resulting in outbursts occurring at any time during the day. On a few occasions, his outbursts have escalated to property destruction or physical aggression. In addition, nothing has been identified to help alleviate the aggression or irritability except the patient’s “I have to get to 100 before my brain lets me calm down.” Once calm, parents report the patient expresses remorse for his outburst.
The patient is currently prescribed aripiprazole 5 mg by mouth twice daily, guanfacine extended release (GXR) 2 mg by mouth every morning, and lisdexamfetamine (LDX) 30 mg by mouth every morning. He is not currently participating in any therapy services. He previously participated in applied behavioral analysis (ABA) 2 to 4 times a week for 2 years, but it was discontinued because of the lack of progress and out-of-pocket expense to the family. His school is considering alternative placement because of continued aggressive outbursts and lack of participation in learning.
During the last 4 appointments, which occur approximately every 6 to 8 weeks, the patient refused to engage during the clinic interview and displayed behaviors similar to those described above. Multiple attempts with various modalities and interviewing styles have produced limited engagement. The behaviors continue even when the focus shifts away from him. He has never become physically aggressive during appointments. Previous medications and ABA have been minimally effective in symptom management or development of distress tolerance skills. Parents are interested in options for the management of his temper outbursts because of increased intensity and frequency of physical aggression and property destruction.
As mentioned above, a complicating factor for DMDD is the lack of validated scales and treatment guidelines to aid with diagnosis and treatment. The most commonly used measure in recent research is the semistructured Kiddie Schedule for Affective Disorders and Schizophrenia for school-aged children with focus on disruptive behaviors; however, in clinical practice, a combination of evaluation tools or portions of standardized rating scales focused on irritability measures are often used.9,10
Along with the lack of available diagnostic tools and treatment guidelines, there are limited clinical trials targeting DMDD. Some data may be extrapolated from previous research with severe mood dysregulation disorder (SMD), which is considered the precursor to DMDD. Other studies focus on irritability associated with other primary disorders such as ADHD, ASD, pediatric bipolar disorder, and disruptive behavior disorders.11
Prior to the advent of DMDD into the DSM-5, available literature for SMD focused on pharmacotherapy, specifically stimulants, mood stabilizers, and second generation antipsychotics (SGAs), for symptomatic treatment. Whereas this literature is scarce, the following is a very brief review of some of the SMD studies. Lithium and divalproex have shown benefit for SMD and explosive temper outbursts in small studies.12,13 Risperidone demonstrated efficacy at reducing irritability in a small open-label trial of 7- to 17-year-olds.14
Additional SMD studies focus on subjects with explosive outbursts or irritability in combination with ADHD, ASD, or disruptive behavior disorders. The majority of studies are small, short duration, and require further investigation into the effect of the medication on the treatment of DMDD. Two open-label studies demonstrate a reduction in irritability with methylphenidate (MPH) when used for DMDD with comorbid ADHD.10,15 Open-label trials of SGAs, specifically aripiprazole and risperidone, for DMDD or SMD with or without ADHD or ASD demonstrate a reduction in irritability, disruptive behaviors, ODD symptoms, and social problems.14,16 Divalproex and alpha-agonists demonstrate some limited evidence for ADHD-related aggression.17-19 These small studies suggest MPH, risperidone, or aripiprazole may be beneficial for reducing irritability when comorbid DMDD and ADHD or ASD are present.
Surveys of clinical practice often favor the use of SGAs over stimulants with the latter preferred when comorbid ADHD is present.11-14,20-23 A systematic review identified stimulants and risperidone as having the largest effect sizes when addressing aggression with or without comorbid ADHD, ODD, and CD.19,24
Although DMDD was introduced with the DSM-5 in 2013, there are limited studies assessing the pharmacologic treatment of DMDD. Two recent reviews attempted to provide some guidance for the pharmacologic treatment of DMDD.25,26 A review by Orsolini et al25 suggests stimulants as first-line agents for DMDD with comorbid ADHD followed by the addition of aripiprazole or risperidone for augmentation or if aggression continues or worsens and rapid reduction is needed. The same review suggests risperidone may be considered as an initial option for comorbid DMDD and ASD. It should be noted that aripiprazole and risperidone are FDA-approved for irritability associated with ASD. When depression and anxiety are present, then selective serotonin reuptake inhibitors may be considered. Finally, this review suggests lithium could be considered but requires further investigation. Other drugs, such as naltrexone and alpha-2 agonists, were mentioned, but further investigation was cited as the reason for not being included as potential options for the management of DMDD. Divalproex evidence has only been anecdotal for DMDD. A systematic review by Zhang et al26 suggests that atomoxetine, stimulants in combination with antipsychotics or antidepressants, or cognitive behavioral therapy have potential benefits at decreasing irritability. More than half of the studies included in this second review were open-label trials and included fewer than 30 subjects. The differing conclusions provide further evidence that future studies are necessary to determine the effect of medications for the symptoms of DMDD.
When assessing this patient for next steps in treatment, it should be noted that some level of aggression with varying intensity and frequency has been reported and observed at each appointment over the last several years. In the interest of shared decision making, multiple pharmacologic and nonpharmacologic strategies have been discussed with parents. Participation in therapy services has been limited by the integration of these services into the patient’s and parents’ daily routine.
At his initial appointment 5 years ago, ADHD was identified as the primary target of pharmacotherapy and behavioral interventions. ASD was diagnosed within the first year of services by a licensed clinical psychologist with the Autism Diagnostic Observation Schedule-2 resulting in the implementation of ABA 3 months later.27 Dextroamphetamine immediate-release was initially started because the patient was 5 years of age at the time and it is FDA-approved for ADHD for patients aged 3 to 5 years. Parents felt this was effective but did not last long enough. At 6 years of age, he was transitioned to mixed amphetamine salts (MAS)-XR. This was initially beneficial for decreasing ADHD symptoms, but aggression persisted. Current and past medication trials are outlined in Table 2.
With the continuation of aggression, risperidone was added to the stimulant medication. It was quickly stopped by parents because “his heart felt weird,” resulting in tachycardia. As a replacement, aripiprazole was initiated and titrated to 2 mg by mouth twice a day. Although not recommended in the literature, aripiprazole was divided into twice daily dosing because of the parents’ observational report of decreased temper outbursts following morning aripiprazole administration and return of temper outbursts in the evening.
The ABA therapist conceptualized the patient’s temper outbursts as a result of impulsivity and hyperactivity; this precipitated the addition and titration of GXR to 2 mg by mouth every morning. At the time, parents were averse to increasing the stimulant medication because they were observing increased behaviors when the medication effect weaned in the evenings; however, they did not want to discontinue it because of perceived, although minimal, benefit at school.
Eventually, MAS-XR was discontinued by parents when unable to obtain it consistently due to ongoing supply chain issues. LDX was substituted, but the same issue arose, so it was stopped by parents between appointments. After some time, collateral from teachers suggested ADHD symptoms were impeding the patient’s ability to concentrate in school, and temper outbursts appeared to be associated with impulsivity, so LDX was retried. Symptoms initially appeared to alleviate with the combination of aripiprazole, LDX, and GXR.
As temper outbursts continued, a slow titration of aripiprazole ensued, eventually reaching 5 mg by mouth twice daily. This was eventually tapered and discontinued because of increased appetite and weight gain of 9 pounds in 8 weeks following the last increase from 7.5 mg/day to 10 mg/day. Over time, the patient’s cholesterol and hemoglobin A1c have remained within normal limits, but his body mass index increased from low normal (14.4 kg/m^2^) to overweight (24.66 kg/m^2^). This has left the patient’s current medications as LDX 30 mg and GXR 2 mg by mouth every morning. At the most recent appointment, information about divalproex, lithium, haloperidol, and chlorpromazine was discussed with the family, but no medications were initiated at this time.
This patient is an example of management based on symptomatology for comorbid DMDD, ADHD, and ASD. Because of the limited available evidence, the lack of treatment guidelines and rating scales for DMDD, symptomatic management and clinical experience have become the mainstays of treatment. The goal of pharmacologic treatment for DMDD is to decrease the frequency and intensity of temper outbursts, whereas for ADHD, it is to improve attention and decrease hyperactive and impulsive behaviors. As discussed above, the available literature suggests MPH would be an option for this patient with comorbid DMDD and ADHD; however, parents were opposed to the initiation of any MPH formulation because of dad’s own negative experience with it. If MPH were initiated, the preference would be for a long-acting formulation such as MPH controlled delay or long acting starting at 10 to 20 mg every morning and titrating to effect.
Lithium and divalproex may not be ideal options for this patient as he frequently refuses laboratory monitoring. Haloperidol is FDA-approved for patients 3 years of age or older for severe aggressive outbursts; however, the patient would be at increased risk of extrapyramidal symptoms as they may occur more frequently in pediatric patients.28 Chlorpromazine is FDA-approved for the treatment of severe behavior problems in children 1 to 12 years of age marked by combative and/or explosive hyperexcitable behavior.29 Neither review mentioned above suggestions haloperidol or chlorpromazine for the treatment of DMDD.25,26 Table 3 highlights some possible pharmacologic options for DMDD and related psychiatric disorders.
As for nonpharmacologic modalities, parents have been encouraged to reconsider these services. Limited evidence exists for nonpharmacologic therapies for DMDD; however, interpretation bias training is a potential new form that assists individuals to evaluate ambiguous faces and perceive them as happy instead of angry.30 Behavioral parent training is another pathway that could be explored with the patient’s family.22 Reinitiation of ABA services with another provider has been suggested; however, parents are reluctant to revisit ABA at this time. Transition of educational services to a special needs–based school could provide additional occupational services.
It is important for clinicians to assess the symptoms of each concomitant diagnosis and consider parent and/or teacher report when deciding on a medication regimen. Further research needs to be conducted along with the development of consensus guidelines for DMDD with and without comorbidities to help guide clinicians not only in pharmacologic management but also nonpharmacologic interventions.