Treatment of Aggressive Behavior and Agitation in a 11-Year-Old Boy With Co-occurring Autism and ADHD: A Case Report and Literature Review on the Use of Intravenous Valproate in Emergency Psychiatry

1. Introduction

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that affects communication, social interaction and behavioral skills. It is characterized by restricted interests, repetitive and stereotyped behaviors, and abnormal sensory processing. Neurodevelopmental atypia can be observed early in the development of most children with ASD [1], and it persists life long. Both clinical presentation of symptoms and their severity can vary greatly depending on age, cognitive and language abilities. Frequently co-occurring conditions include Attention-deficit hyperactivity disorder (ADHD), depression, phobias, anxiety, intellectual disability, sleep issues, restrictive/avoidant food intake, sensory processing issues, and genetic alterations. Comorbidities often make diagnosis and clinical management of ASD extremely complex [2]. Furthermore, an unpredictable response to treatment associated with the frequent apperance of side effects can make the pharmacological therapy of ASD a heavy challenge for clinicians. However, indirect improvement has been seen when therapies are targeted to comorbidity symptoms [3].

ADHD is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, causing functional impairment. Its prevalence is approximately 5% in children and adolescents and about 2.5% in adults [4]. According to international guidelines, the most efficient managing for ADHD include a multimodal approach that involves both behavioral and pharmacological treatments. Methylphenidate (MPH) is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries, including Europe, where it is the first treatment choice [5,6].

Comorbidity between ADHD and ASD is a common condition, being ADHD the commonest disorder to co-occur with ASD. Clinical similarities between the two disorders are frequent as they share symptoms of inattention and hyperactivity/impulsivity and a high occurrence of at least one psychiatric condition (around 80% in ADHD and 2/3 in ASD patients) [7]. In individuals where ASD and ADHD co-occur, pharmacological interventions may facilitate their participation in behavioral therapy and enhance their daily functioning. However, children with ASD are more sensitive to medication side-effects and have a higher likelihood of experiencing adverse events compared to those without ASD. Therefore, in patients with ASD-ADHD comorbidity, the pharmacological treatment should be started at lower doses and adjusted slower than in subjects with ADHD diagnosis alone [2].

Furthermore, these patients frequently experience psychomotor agitation, defined as a state of heightened anxiety, irritability, increased motor and verbal activities, uncooperativeness, and threatening gestures. Pharmacological treatment in acute agitations and aggressive behaviours is sometimes challenging for clinicians. Complex neurodevelopmental disorders associated with ASD and ADHD, but also with schizophrenia, schizoaffective disorder, bipolar mania, and illicit drug use are even more complex and risky to treat [8]. In principle, an effective psychopharmacological intervention should obtain reduction of psychoagitation, reach calmness and restore contact, within two hours [9]. Most severe agitations can be treated with neuroleptics and a close monitoring of their total daily dose. Olanzapine is potentially the most sedating second-generation antipsycotic (SGA) compared to risperidone and haloperidol, with a lower risk of cardiac adverse events and extrapyramidal signs [10]. Due to the risk of respiratory suppression when given add-on, olanzapine should not be given parenterally within one hour from benzodiazepines administration [10].

Valproate (2-propylpentanoate, VPA) is available as valproic acid, sodium valproate and semisodium formulations. Its mechanism of action involves the enhancement of inhibitory neurotransmission and the modulation of voltage-gated ion channels. It has actions on dopamine, GABA and glutamate neurotransmission and intracellular signaling. VPA is a common and approved drug used in children and adults as a safe and effective antiepileptic, both with oral [11] and intravenous (IV) administration routes [12,13,14]. Apart from its FDA indications for treatment of epilepsy, oral VPA can find off-label applications in several psychiatric conditions, such as maniac episodes associated with bipolar disorder, impulsivity, agitation, and aggression [15,16,17]. Oral VPA has also been shown to reduce aggressive, repetitive symptoms and irritability in children with ASD compared to controls [18,19,20].

A recent study shows that off-label IV-VPA can be effective and safe in treating psychomotor agitation of adolescents aged between 13 and 17 years [22]. Overall, data on the efficacy of IV-VPA in acute and aggressive agitations of children with ASD are currently not available in literature.

To implement the increasing knowledge on IV-VPA treatment option in emergency psychiatry, and ASD in particular, we describe a clinical case in the light of previous related reports and a literature review.

2. Methods and Case Report

With the present study we aim at reviewing the available literature, i.e., clinical reports (case or clinical series), narrative and systematic reviews, on the use of VPA in the treatment of acute agitation. Pertinent literature was obtained from PubMed database, which included only English-written, full-text clinical studies, clinical reports and reviews. With regard to interventional studies, we only included those that provided the ethical approval code. The search was started on September 18th, 2023 by applying the following key terms: “autism” and “aggressive behavior” and “acute agitation” and “valproic acid”. The temporal interval for search was between 1995 and 2023. Data extraction consisted of a total of 93 articles and study selection flow chart, in line with the PRISMA 2020 flow diagrams, is reported in the Figure 1. After removal of duplicated, among a total 65 articles, 34 were screened by title and abstract, and 20 were considered eligible with respect to key words and methods criteria, and evaluated at a full-text level. Of them, in order to produce a qualitative synthesis on treatment efficacy, 4 studies were considered eligible with respect to the patients’ age (children and adolescents) and IV administration of VPA.

This figure shows the flow-chart selection criteria of the collected articles.

To date, to the best of our knowledge, only one report describes the use of IV-VPA in acute agitation in children with autism; we found no studies evaluating its efficacy in complex neurodevelopmental conditions or in patients with co-occurring ASD and ADHD. We report a case of a young boy with a complex neurodevelopmental disorder characterized ASD with comorbid ADHD.

3. Case Report

We describe a 11-years-old boy with a diagnosis of level 1-ASD, Attention-Deficit/Hyperactivity Disorder - Combined presentation, Oppositional Defiant Disorder and Adjustment Disorder, according with DSM-5 criteria.

On March 2023, he was re-admitted in our emergency Hospital department due to the acute onset of a bizarre behavior (e.g., stripped naked in public), disruptive mood (verbal oppositional and role-breaking behaviours with all people including family members), and severe aggressive symptoms (he destroyed tools and furniture complements). His parents dated a decline in their child behavior since January 2023, the alleged trigger being represented by the unsupervised internet access and the contact with unknown adults who had solicited virtual sexual interactions.

Medical history: The patient had a family history for alcohol abuse and socio-economical problems. He was born by a regular pregnancy, through a natural delivery at the 41 week of pregnancy. Parents denied any suffering at birth. A delay in language skills was reported with first words at 2 years. Firsts problems in social abilities were reported at kindergarden, for a deficit in showing spontaneously interest to others and in starting any interaction during activities with peers. He also showed difficulty accepting variations from his routines, in removing the diapers, putting on new clothes or shoes, or eating foods other than unseasoned pasta or bread. The game was extremely poor, excessively chaotic, but characterized by repetitiveness: rolling objects, throwing them and going up and down in rigid and afinalistic sequences.

Repetitive patterns overactivity, delay aversion and concentration problems emerged during preschool stages and he received a diagnosis of Pervasive Developmental Disorder and rehabilitation treatments at local Community Services for Child and Adolescent Neuropsychiatry since he was 3 years old.

In 2019, at the age of 7 years, he was firstly admitted to our Unit of Child Neuropsychiatry of Sassari Hospital, due to progressively increasing psychomotor agitation and aggressive behaviors towards teachers and peers at school. He experienced agitation with both self- and hetero-aggressiveness in response to minimal frustrations. During hospitalization, he exhibited quantitative and qualitative abnormalities in social interaction skills, communication deficits, narrow and repetitive interests, poor flexibility and intolerance to frustrations, difficulty in maintaining and modulating eye contact, and poor abilities in theory of mind understanding. The child also tended to have high levels of hyperactivity with impulsiveness, acting without previous reflection and engaging in danger awareness. To quantify ADHD symptoms severity, several standardized tests were performed: Swanson, Nolan, and Pelham Rating Scale-SNAP-IV [23], Conners’ Parent Rating Scale [24], and Child Behavior Check List to parents [25], resulting in high scores for both hyperactivity and impulsivity and Oppositional Defiant Disorder (ODD) symptoms. To assess cognitive functioning, we administered the Leiter International Performance Scale - Third Edition [26] which showed fluid reasoning of 77 and a short nonverbal IQ of 74. He received a diagnosis of severe ADHD with combined clinical manifestation with severe Oppositional and Defiant Disorder (ODD). Finally the 2nd version of the Autism Diagnostic Observational Schedule - ADOS-2 [27] test was administered, which confirmed a co-occurring, level 1, ASD condition. Genetics analysis (karyotype, FMR1A gene, Pompe disease, Duchenne/Becker disease, Gaucher and Niemann-Pick disease), electroencephalogram, brain MRI, complete abdomen ultrasound and cardiological examination with echocardiogram, all resulted negative; dermatological examination showed 6 café-au-lait macules, neck and large folds hyperpigmentation and follicular hyperkeratosis. At discharge, a psycho-stimulant therapy, in addition to a Cognitive Behavioral Therapy (CBT) to treat ADHD were suggested, but his parents initially refused. After one year, when kids was 8 years old, they come back for a new visit at our outpatients service to evaluate the introduction of methilphenidate (MPH) treatement due to difficulties in manging ADHD symptoms at school and at home. Immediate-release MPH was initially introduced at a dose of 0.3 mg/kg. Absence of adverse events, good control of inattention symptoms and a reduction in motor hyperactivity were observed. For this reason, the equivalent dose of prolonged-release MPH was subsequently prescribed to continue the therapy at home. The child continueted the prescribed therapy and for the following three years the effectiveness was reported in periodic checks.

Emergency Acceptance

At the emergency room, blood exams (including kidneys, liver and thyroid), neurological assessment and urine toxicological tests were all normal. On 2nd March 2023 a preliminar Electrocardiogram was performed, to search for possible contraindications of pharmacological treatment, was also normal (see Table 1).

After this preliminary step, the boy was immediately treated with multiple medications at high dosages (haloperidol, benzodiazepines, and chlorpromazine), although with poor efficacy on aggressive behavior and with the rapid appearance of several adverse event, e.g., sedation, sialorrhea and rigidity (pharmacological timeline is detailed on Figure 1).

MPH was immediately interrupted to avoid a maniac phase induction. Olanzapine was introduced and used at a dosage to 10 mg/die, before being interrupted after four days, due to the lack of a positive response. Risperidone was gradually modulated up to 6 mg per day and extended-release Lithium sulfate therapy was introduced, to potentiate the neuroleptic effect, and titrated up until the blood range of 0.8 mEq/L (Figure 1).

Unfortunately, acute symptoms persisted. Therefore, on the third day of hospitalization, we carried out a IV bolus of 20 mg/kg VPA in a temporal range of 30 minutes. After that, we started a 24-h infusion with the same dosage, followed by three days IV infusion at a lower dosage (15 mg/kg/day). Vital signs, blood pressure and heart frequency were costantly checked.

An immediate response was observed after the first few hours and IV-VPA. On the fourth day, IV-VPA was replaced by its extended oral formulation and tapered off in one week (Figure 2) with a good response and no adverse drug effects. Contextually, benzodiazepines and olanzapine were gradually tapered off and Lithium continuated.

We used the Modified Version of the Overth Aggression Scale (MOAS) [28] to assess and measure aggressive behaviors, which showed a decrease from a score of 49 upon admission to a score of 0 upon discharge. Despite a mild sedation, an important and rapid decrease of aggressive behavior occurred after IV-VPA, associated with a reduction in the MOAS score (Figure 3).

During hospitalization, electrocardiograms and regular blood tests were carried out to monitor serum levels of VPA, ammonia, lithium, and liver enzymes. During acute IV treatement, the highest value of VPA was 92.7 μg/mL (in the normality range). All the other range are reported in Tabel 1 above. After 11 days, he was discharged with a DSM-5-oriented diagnoses of psychotic onset with psychomotor agitation in patient with co-morbidity for ASD level 1, severe ADHD-Combined clinical presentation, adjustment disorder with mixed emotionality and conduct symptoms. Home therapy with long-acting Lithium sulfate 249 mg/day and Risperidone 3.5 mg/day. In fact, VPA is used during the state of agitation and then replaced by another stabilizer: lithium.

One-year follow-up. The patient attended all the monthly programmed outpatient visits at our Unit. He had come back to school two weeks after the last hospital discharge and continued his psychotherapy twice per week. In October 2023 he presented with occasional agitation episodes, irritable mood with anger and frustration over small things (i.e., after denial of food). He displayed short temper and might snap at people in different contexts (classmates, teacher, medical doctors and caregivers). Lithium blood level was reduced (0.45 mEq/l) compared to one month before (0.66). Therefore long-acting lithium solfate was increased. A good clinical response was reported in some weeks. At last examination on March 2024, pharmacological therapy was substantially stable. Parents received benefit supports from the social assistence and pursued a specific parent’s program to improve their educational competences.

This little boy still refers at the outpatiens service at our institution. Him history and clinical trajectory are at high risk to develop other mood or psychosis event, moreover when further environmental stressors will occur.

4. Discussion

Treating young patients with acute agitation and comorbid neurodevelopmental conditions of ASD and ADHD, is one of the most challenging task for clinicians [2,8,9]. Most severe agitations are treated with neuroleptics although, in complex neurodevelopmental disorders, they should be started at lower doses and with slower adjustement compared to other patients [2]; also, a close monitoring of the total daily dose is recommended. Oral second generation antipsychotics, such as risperidone, olanzapine, aripiprazole and ziprasidone, or the first generation haloperidol, in monotherapy or in association with benzodiazepines, have been shown to be at least similarly effective than oral VPA.

Our case report as well as our literature review both indicate that, compared to oral VPA [18,19,20], the IV use of VPA in add-on with neuroleptics in critical patients between 8 and 17 years, is rapidly effective and fairly safe [22] even in the presence of ASD comorbidity [21,22].

The IV route of administration of VPA in children and adolescents is, currently, limited to non-responders and non-compliant patients which is mainly due to the evidence that it has been tested mainly in adults patients with Bipolar disorder. However, the qualitative analysis of our selected papers and the description of our case, can encourage IV-VPA as an effective and safe treatement for acute agitation and aggressive behaviours in children and adolescents with neurodevelopmental disorders, such as ASD and ADHD. Furthermore, the safety profile of IV VPA can make it the elective drug even in agitated situations in patients with a history of substance abuse [42].

In literature, stressor events contribute to promote acute symptoms in patients with previous diagnosis of neurodevelopmental disorders; accordingly, our case was exposed to a traumatic event some months before the acute phase. This may be important to consider in order prevent environmental factors to trigger aggressive behaviours and agitation in susceptible children.

There are limitations while interpreting overall results. The first is that among the 34 selected reports, only 4 met the requirements to be included in our review. The second is that IV-VPA has a limited degree of evidence, particularly in children and adolescents with neurodevelopmental disorders; also, the majority of observations are reviews, retrospective case-control studies or anecdotal reports and, with the exception of our case (one-year follow-up), clinical monitoring is not longer than 6 months.

5. Conclusions

Our case is the first clinical case on the empirical use of IV-VPA for acute agitation and aggressive behaviors in a child boy with co-occurring ASD and ADHD.

Our report and our review of the recent studies, suggest IV-VPA as an effective alternative treatment that limits the risk of adverse events related to the high-dose standard medications in the emergency psychiatry.

Further studies are needed to assess whether IV-VPA might be a first-line choice therapy to treat acute and drug-resistant agitation in children.