Affiliations : John Hopkins Hospital, Baltimore, USA
Journal reference: DOI: 10.1016/j.jaac.2019.05.015
Summary: Is a child you know suffering from chronic severe irritability? A diagnosis called Disruptive Mood Dysregulation Disorder encapsulates this and is quite controversial in psychiatry. This article describes a study conducted to determine how effective medication is in treating this disorder.
Background
It’s common to hear people speak of mania or bipolar disorder, but what do they mean? From a strictly diagnostic standpoint, manic episodes are discrete periods of increased energy, mood lability, grandiosity, changes of speech characteristics and decreased need for sleep for at least 1 week. These episodes can be due to medications, substances or underlying medical/neurological conditions, including bipolar affective disorder (BD).
BD itself can be seen across age groups, but its characteristics in children and adolescents have been subject to much debate since the mid-1990s, with consequent impact on treatment recommendations. Pediatric onset mania was initially described as a severe non episodic irritability with extended periods of very rapid mood cycling within the day. This rather broad conceptualization of pediatric mania was associated with a sizable increase in the use of medications such as antipsychotics and mood stabilizers. This was a problem both because of concerns of misdiagnosis and because prescribed medications are not benign: they have side effects.
Disruptive Mood Dysregulation Disorder (DMDD) is a diagnosis which was introduced to address these concerns. It was described to help distinguish chronic irritability with outbursts, from the manic episodes of bipolar disorder. The validity of this diagnosis remains a controversial topic in psychiatry.
What is DMDD?
DMDD is a pediatric psychiatric diagnosis described in the major psychiatry diagnostic manual: the Diagnostic and statistical manual of mental disorders (DSM -5). DMDD typically starts by age 10 (age range is between 6 and 17) and is seen in 1-3% of the population. Someone with DMDD will have severe recurrent temper outbursts, in at least 2 settings at least 3 x per week and in the context of a general chronic irritability.
Is it a problem?
It can be. It can cause functional impairment and is associated with adolescent attention-deficit hyperactivity disorder (ADHD) and adult anxiety/depression. In fact, we sometimes start by treating ADHD in kids with DMDD. ADHD treatment includes stimulants (methylphenidates or amphetamines) that can actually help this irritability. Irritability is also frequently seen in kids with depression and anxiety. So antidepressants are also reasonable treatment options to consider.
What can we do?
There are many psychotherapy and medication options available, but they all require more studying and testing in DMDD per say. Towbin et al. wanted to study the effect of a type of antidepressant (a selective serotonin reuptake inhibitor- SSRI) on this chronic/constant irritability in kids who are still struggling despite treatment with a stimulant. They used one SSRI: citalopram (Celexa).
Their study was the first randomized control trial (RCT) to address this specific question.
What is an RCT, what did they do?
An RCT is a type of clinical experiment. Patients with similar characteristics are randomly divided into a minimum of 2 groups: one group is given the medication being tested (citalopram, in this case) and one group is given a placebo. None of the patients nor the examiners know the group assignments. The purpose is to try to get the ‘cleanest’ possible comparison and really test the efficacy of the medication under study.
This group’s main question (or primary outcome) was whether citalopram is efficacious in treating irritability in children and adolescents with DMDD, who are still symptomatic despite taking a therapeutic dose of a stimulant. Primary outcome was tangibly assessed through clinical rating scales. Presence of irritability and outbursts was measured with the Clinical Global Impression Improvement (CGI-I) scale. Severity of irritability was measured with the Clinical Global Impression Severity (CGI-S) scale. Scores were given at baseline and tracked until the end point. They also looked at overall functional impairment, anxiety and depression (we call these secondary outcomes).
The study was conducted at the National Institute of Mental Health Division of Intramural Research Programs from 2008 until 2018. They screened 1,264 patients with DMDD aged 7–17 years and ended up with 53 who met the inclusion criteria and completed the whole study. Patients could have concomitant ADHD and anxiety disorder, but other diagnoses were excluded, such as : borderline personality disorders, depression, intellectual disability, autism, psychosis, trauma, severe medical illnesses.
All patients were admitted to a hospital facility for an extended period of time for close monitoring and observation. They gradually stopped all the psychotropic medications they were on, over a period of 8 weeks.
A few weeks later they were all started on methylphenidate. If they remained irritable after 5 weeks on a therapeutic dose, they remained in the study and were split into 2 groups. One group was given add-on citalopram and one group was given placebo. While all patients/parents knew the patients were given methylphenidate (we call this ‘open label’), the citalopram versus placebo options were ‘blinded’. Patients were all started on 1 pill per day (it means 5 mg if it’s a citalopram pill). They gradually increased the dose. Once patients reached 4 capsules or 20 mg per day, they were observed for 3 weeks and discharged home. Subsequently, monitoring was done weekly via phone calls for 5 weeks (so 8 weeks in total). Citalopram increase was allowed until 40 mg daily with an average achieved dose of about 29.23 mg daily.
Results
At week 8, a significantly higher percentage of patients on citalopram had improvement in their irritability, compared to those who received placebo; this was also true throughout the prior weeks, starting from week 5. SSRIs like citalopram take about 4-6 weeks to really start working. There were no significant differences in functional impairment, anxiety or depressive symptoms between the 2 groups. Improvements in irritability did not translate into improvement in overall impairment. There were no differences in the total number of adverse effects between treatment groups.
Limitations of the study
While the researchers screened a lot of patients, they were only left with a few throughout the study.
At the time this study was started, irritability-specific measures were not yet available. The CGI used to measure the primary outcome is not ideal and future studies may need more specific clinical tools. The CGI is also a very subjective tool, so results ought to be interpreted with caution.
Importantly, a large portion of this study was in an atypical context: patients were hospitalized to provide more detailed observation and minimal variability. This raises the question of how generalizable the results are; meaning: would we see the same results in real life settings?
Take home message
When treating children and adolescents with DMDD, it’s reasonable to start with a stimulant, though treatment optimization may be needed if irritability is unresponsive to stimulants alone. Severe irritability symptoms may improve with add-on citalopram. Improvements in irritability may be seen in the absence of change in depression or anxiety and would not necessarily have an effect on general impairment.