The Potential Benefit of Atomoxetine for Treating Aggression and Violence in an Adult Patient with Down Syndrome and Intellectual Disability

Atomoxetine (ATX) has been approved to treat attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults. The efficacy of ATX is not inferior to methylphenidate. Since it is nonstimulant, it has rare risk of abuse. ATX also improves emotional control in adult ADHD patients, which is associated with improved quality-of-life and core ADHD symptoms including impulsivity [1]. As stated in Neuroscience-based Nomenclature (www.NbN3.org), ATX is an inhibitor of the presynaptic norepinephrine transporter. It also inhibits 5-HT reuptake transporter, but the highest dose of ATX reaches only 40% 5-HT inhibition, not to a clinically relevant degree [2]. The precise mechanism of ATX to treat ADHD is unknown. It is hypothesized that ATX activates prefrontal cortex (PFC) through promoting norepinephrine and dopamine effects, and appropriate catecholamine actions can improve PFC regulation of attention, behavior, and emotion [3]. Patients with intellectual disability are prone to having aggression, self-mutilation, and property destruction. Here, we are reporting a case about ATX to treat aggression in an adult patient with Down syndrome and intellectual disability. This 29 year-old male patient was a victim of Down syndrome with sleep apnea status post operation and moderate intellectual disability. He was reared up by his grandmother. He received psychiatric treatment since childhood but the previous medication was unknown. There is no past history of ADHD. He was brought to our outpatient clinic at the age of 15 years due to agitation, excitement before sleep, and head-bumping. He received risperidone 1–4 mg/day in the first three years. It was shifted to paliperidone 3 mg/day due to extrapyramidal symptoms and metabolic side effects. His head bumping and aggression were on and off in the follow-up years. At the age of 24 years, he was suspected to have auditory hallucination of a blaming voice, and the dosage of paliperidone was increased to 6 mg/day. In the past year, his head-bumping, aggression, and destructive behavior were aggravated because he was placed in a nursing home most of the time and could not see his demented grandmother. He was admitted to our acute ward for the first time at the age of 29 years due to fierce and indiscriminate physical attacks to institute staff. Physical restraints were needed frequently in the beginning. Paliperidone 6 mg/day was kept as used at outpatient clinic after admission. In the consideration of depression and anxiety, sertraline 50 mg/day was given. But binge eating was observed, leading to a switch from sertraline to ATX (40 mg/day) to improve his binge eating and impulsivity. While his binge eating and aggression were improved, he continued to experience agitation and insomnia. As a result, paliperidone (6 mg/day) was replaced with quetiapine (100 mg/day). He improved more after shifting to quetiapine. With a one-month hospitalization, he was discharged with quetiapine 100 and ATX 40 mg/day. The drug adherence was fine as his medication was given by the staff of the nursery home. Unfortunately, he was admitted two months later due to the same problem of agitation, shouting, and aggression. ATX was increased to 80 mg/day, but he suffered seizure. ATX was discontinued in the suspicion of causing his seizure. After discontinuing ATX, his mood was unstable. ATX was resumed, and seizure recurred. Hence, ATX was replaced by valproic acid. At last, he was discharged with quetiapine 75 and valproic acid 1500 mg/day. One month later, he needed to be admitted again due to fierce and unexpected violence. This time, venlafaxine up to 225 mg/day could be given in the hypothesis that his agitation could be secondary to anxiety or depression. However, his mood was elated therefore and got more aggressive and violent. Venlafaxine was shifted to lithium plus low-dosed adjunctive clozapine (25 mg/day). Unfortunately, he suffered from drooling and suspected aspiration pneumonia. He was discharged with daily medications of quetiapine 75 mg, valproic acid 1500 mg, lithium 750 mg, and clozapine 12.5 mg. There was a total of 12 weeks of hospitalization in one year. At outpatient clinics, his ATX was gradually titrated up to 80 mg/day again, and clozapine was discontinued due to drooling. No seizure was noted. He could remain stable without previous violence/aggression thereafter with ATX 80 mg/day. (This case report was approved by the institutional review board at Chi Mei Medical Center [IRB Serial No = 11303-009 and date of approval = June 13, 2024] requiring that patient’s mother signed an informed consent on behalf of the patient). To treat the aggression of adult patients with intellectual disability is always challenging [4]. The patients often have multiple disabilities including autism and/or ADHD which are not diagnosed of. We faced difficulty of psychotropic medication in our patient because we could not communicate with him verbally and he was easy to have side effect of EPS. We did our best with trial and error. We gave many kinds of psychotropics including antipsychotics, anticonvulsants, lithium, selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, and benzodiazepines in this patient. Polypharmacy was not inevitable, but the efficacy was not satisfactory. We initiated ATX primarily to treat binge eating, impulsivity, and associated aggression, rather than for ADHD or depression. The response was positive. This patient could remain stable at outpatient clinic with less quetiapine after titrating up ATX to higher dosage. According to a review [5], methylphenidate and ATX have shown clear benefits for patient with intelligent disability in behavioral and/or cognitive domains, particularly at higher doses. We had the same experience. We were initially cautious about the potential side effect of irritability with the introduction of ATX, but fortunately, he did not experience it. While his aggression and impulsivity were improved with ATX at 80 mg/day, he suffered from a seizure at that dosage. Although ATX is not typically associated with an increased risk of seizures, it occurred in this patient. When the 80 mg/day dosage was retested, the seizure recurred. We suspect this may have been due to either the rapid titration of ATX on our ward or the patient’s individual constitutional response. ATX had been tried in a few disorders other than ADHD, including executive dysfunction in Parkinson disease [6], hoarding disorder [7], and binge eating disorder [8]. All of the clinical trials above were interrelated with impulsivity. Recently, the medical society paid attention to cognitive disengagement syndrome (CDS) again [9]. CDS is a set of symptoms defined by excessive mind-wandering, mental confusion, and slowed behaviors separable from ADHD inattention. CDS is related with social withdrawal, and ATX is more effective than methylphenidate. The research about ATX up to date reveals that our knowledge is limited about norepinephrine in the brain. Although our preliminary experience of ATX for aggression in this developmentally disabled adult was positive, the efficacy of ATX to treat impulsivity/aggression in this population needs further investigation about its indicating dimensions in symptomatology. Declaration of Patient Consent The authors certify that they have obtained all appropriate patient consent forms. In the form, patient’s mother has given her consent for his clinical information to be reported in the journal. She understands that her son’s name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial Support and Sponsorship The authors deny any support in writing this case report. Conflicts of Interest The authors report no conflicts of interest in all drugs mentioned in this case report.