Introduction
The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [American Psychiatric Association, 2013] has introduced the diagnosis of disruptive mood dysregulation disorder (DMDD). The prevalence of DMDD ranges from 0.8% to 3.3%, with higher rates in preschool age children [Copeland et al. 2013].
DMDD is characterized primarily by frequent, severe, recurrent temper outbursts and chronically irritable and/or angry mood. These symptoms must be present for at least 12 months in multiple settings, have an onset before age 10, and the child must be at least 6 years old [American Psychiatric Association, 2013].
Neuroimaging studies demonstrated that children with irritability exhibited markedly decreased activation of neural regions associated with reward processing, attention and emotional salience after negative feedback (frustrating) trials [Deveney et al. 2013]. These neural circuits are principally mediated by dopamine [Goschke et al. 2014].
Although the clinical characterization of DMDD has attracted attention, behavioural treatment strategies have been poorly studied and there are no evidence-based pharmacological treatments for DMDD. Antipsychotics have a long history of treatment efficacy for irritability and dysregulated behaviour at all ages. The US Food and Drug Administration (FDA) has approved aripiprazole for the treatment of irritability in young autistic patients aged between 6 and 17 years of age [Owen et al. 2009].
Aripiprazole has a unique mechanism of action, as it has a combination of partial agonism at the D2 and 5-HT1A receptors and antagonism at the 5-HT2A receptor. Mamo and colleagues observed that D2 occupancy levels were significantly correlated with plasma drug concentrations, with low dose leading to 85% D2 occupancy [Mamo et al. 2007]. The neural networks dysfunctions documented in children with severe irritability, the core symptom of DMDD, led us to hypothesize that a low dose of aripiprazole could be an effective treatment for irritability in DMDD.
To the best of our knowledge this is the first case report of a young patient with DMDD who was successfully treated with low-dose aripiprazole monotherapy.
Case report
S. is an 11-year-old boy. He is the third child of a nonconsanguineous healthy couple. His mother had an uneventful pregnancy and a spontaneous, uncomplicated delivery. The familial history is unremarkable. The patient has always been described as a difficult child. As a baby, he cried incessantly for several hours each day and, as a toddler, he threw tantrums multiple times per day. At the time of the evaluation, the patient was exhibiting temper outbursts several times a day that lasted approximately 10 minutes, and more intense 30-minute outbursts multiple times a week, during which he became physically aggressive. His parents described him as irritable and cranky many times a day. Despite the absence of cognitive disabilities, he struggled academically due to the large amount of time he spent out of the classroom following his disruptive behaviour. He was highly distractible and exhibited strong opposition when asked to do homework. The patient also started to make hostile attributions regarding his peers’ intentions and thus his peers began to avoid him.
Procedures
The diagnostic assessment included medical history, the intelligence quotient (IQ) evaluation, the Child Behavior Check List dysregulation profile (CBCL-DP) [Althoff et al. 2010], the K-SADS clinical interview (Kaufman et al. 1997), the Children’s Global Assessment Scale (CGAS), and the Clinical Global Impression–Severity (CGI-S) and Clinical Global Impression–Improvement (CGI-I) scales.
The CBCL-DP is characterized by simultaneous extreme values on Anxious/Depressed, Attention Problems, and Aggressive Behaviour syndrome scales; it has been considered a possible diagnostic tool for identifying children with DMDD [Dougherty et al. 2014]. The K-SADS was used to exclude other psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and the CGAS was used for the assessment of social and cognitive competence. Symptom severity and clinical improvement of the patient were assessed with the CGI-S and CGI-I subscales.
The clinical evaluation using DSM-5 criteria [American Psychiatric Association, 2013], confirmed a severe form of DMDD (CGI-S = 6; seriously ill; CGAS = 48). His parents and S. consulted with a child psychiatrist (R.A.) to discuss medication. The patient was drug-naïve. The electrocardiogram (ECG), electroencephalography (EEG), heamogram (complete blood count), renal, liver and thyroid functions tests were normal. Aripiprazole was started at 2.5 mg/day and increased up to 5 mg/day after 7 days of treatment. No cognitive behavioural interventions were started with the boy for the first 12 weeks and clinical follow up has been performed each month. CBCL-DP, CGI-S, CGI-I, as well as side effect rating, were performed at baseline, and after 12 weeks. At the baseline and at the endpoint, the patient had a body mass index (BMI) of 19. The CBCL-DP T scores decreased significantly between the baseline and the endpoint. CGI-S, CGI-I, CGAS and CBCL scores indicated that aripiprazole led to a significant control of symptoms; Table 1 summarizes these results. Small and not significant increase in weight and prolactin levels were documented.
Table 1.
CBCL T scores, CGI-S, CGI-I and CGAS before and after aripiprazole treatment.
| CBCL variable | Before | After |
|---|---|---|
| Anxiety/Depression | 85 | 76 |
| Attention | 71 | 61 |
| Aggression | 95 | 65 |
| Rule breaking | 68 | 51 |
| Internalizing Problems | 74 | 74 |
| Externalizing Problems | 80 | 60 |
| Oppositional | 75 | 58 |
| Conduct | 81 | 56 |
| CGI-S | 6 | 2 |
| CGI-I | 4 | 2 |
| CGAS | 48 | 64 |
CBCL 6–18, Child Behavior Checklist (50–65: normal; 65–75: borderline clinical range; >70: clinical range).
CGI-I, Clinical Global Impressions – Improvement (1 − greatly improved; 2 − much improved; 3 − improved a little; 4 − no improvement; 5 − worsened a little; 6 − much worse; 7 − extremely deteriorated).
CGI-S, Clinical Global Impressions – Severity (1 − normal; 2 − borderline; 3 − mildly ill; 4 − moderately ill; 5 − strongly ill; 6 − seriously ill; 7 − extremely ill).
CGAS (100–91 Superior functioning in all areas; 90–81 Good functioning in all areas; 80–71 No more than slight impairment in functioning at home, at school, or with peers; 70–61 Some difficulties in a single area, but generally functioning pretty well; 60–51 Variable functioning with sporadic difficulties or symptoms in several but not all social areas; 50–41 Moderate degree of interference in functioning in most social areas or severe impairment of functioning in one area; 40–31 Major impairment in functioning in several areas and unable to function in one of these areas; 30–21 Unable to function in almost all areas; 20–11 Needs considerable supervision; 10–1 Needs constant supervision.
Discussion and conclusion
In recent years, the use of atypical antipsychotics in the treatment of disruptive behaviour disorders has increased. Furthermore, no controlled pharmacological trials have been conducted in children with DMDD and thus treatment decisions are based on studies about other psychiatric disorders in which irritability is occurring (i.e. autism, conduct disorder).
Aripiprazole is an effective and well-tolerated treatment for conduct disorder and irritability. Additional studies are required to better define the clinical use of aripiprazole in children and adolescents [Ercan et al. 2012]. In our patient, low-dose aripiprazole monotherapy was effective in reducing irritability and aggressive behaviour. Finding the effective dose of antipsychotic treatment is a key issue in psychiatric clinical practice. Aripiprazole is a novel atypical antipsychotic drug that is reported to have a high-affinity D2 receptor with a partial agonist effect at low dose. The unique mechanism of action of this drug prompted us to hypothesize the existence of a possible dose–effect relationship for aripiprazole in DMDD treatment.
Although the theoretical pharmacological properties of aripiprazole suggest that it might be an effective monotherapy to treat DMDD, there are few data supporting this hypothesis in the literature. In our case report we found a significant improvement of DMDD symptoms after 12 weeks of pharmacological treatment. Aripiprazole was well tolerated. Our report supports the theoretical assumption that D2 agonist properties of aripiprazole are beneficial for the treatment of DMDD symptoms. Additional studies, particularly placebo-controlled and double-blind trials using a larger sample size and a longer treatment period, are required to better define the clinical use of aripiprazole in children and adolescents with DMDD.
Footnotes
Funding: This research received no specific grant from any funding agency in public, commercial, or not-for-profit sectors.
Conflict of interest statement: The authors declare no conflicts of interest in preparing this letter.
Contributor Information
Roberto Averna, Department of Neuroscience, Unit of Child Neuropsychiatry, Children’s Hospital Bambino Gesù, IRCCS, Piazza S. Onofrio 4, Rome, Italy.
Elisa D’Agati, Department of Neuroscience, Unit of Child Neuropsychiatry, Children’s Hospital Bambino Gesù, IRCCS, Rome, Italy.
Stefano Vicari, Department of Neuroscience, Unit of Child Neuropsychiatry, Children’s Hospital Bambino Gesù, IRCCS, Rome, Italy.
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