Low-dose quetiapine complements stimulant response in attention deficit hyperactivity disorder and more

Introduction

Attention deficit hyperactivity disorder (ADHD), a neurobehavioural syndrome, is one of the most commonly encountered Child and Adolescent Psychiatric disorders in clinical practice, affecting 5–9% of school-age children [Polanczyk et al. 2007]. Children with ADHD usually suffer concomitantly from other psychiatric comorbidities, both externalizing and internalizing disorders with oppositional defiant disorder (ODD), conduct disorder, anxiety disorders, depression, learning disability and tics among the most frequent. ADHD is characterized by symptom clusters of inattention, hyperactivity and/or impulsivity [Spencer, 2006]. The literature is consistent with regard to the effectiveness of stimulant medications, whether methylphenidate or amphetamine based, with effect sizes of 0.8–1.1, as well as behavioural interventions for the management of the core symptoms of ADHD [Reddy, 2013]. Nonetheless, 20–35% of subjects in clinical trials show inadequate response that could be attributed in part to dose-limiting side effects of medications or disorder severity or complexity [Childress and Sallee, 2014]. Use of stimulants is generally safe in the paediatric population but, unfortunately, fraught with problematic side effects, notably weight loss and insomnia [Mohammadi and Akhondzadeh, 2011]. Antipsychotics have been used increasingly to successfully address the disruptive behavioural ‘bouquet’ associated with ADHD, although the quality of evidence for this practice remains to be defined [Elbe et al. 2014].

Parents’ consent as well as patient’s assent, for both the off-label medication trialled and the reporting of the case, was obtained beforehand.

Case report

A 13-year-old male Kuwaiti was escorted by his father for subpar scholastic achievement, mischievous behaviours and transient motor tics. He was seen by a private psychiatrist, diagnosed with ADHD/ODD/provisional tic disorder. He was prescribed methylphenidate LA (Concerta) up to 54 mg/day. Results, academic and behavioural, were mediocre at best, as reported both by his father and confirmed from school reports. Moreover, tics were exacerbated. Insomnia, anorexia and dysphoria were noted and distressing. The patient had been tried previously on atomoxetine (Strattera) with no tangible improvement. In addition, the patient could not tolerate an add-on treatment with clonidine (Catapres) for symptomatic bradycardia and hypotension. We opted for a trial with quetiapine (Seroquel). Baseline psychometry, including the Parent/Teacher Disruptive Behaviour Disorders (DBD) Rating Scale (with scores of 46 and 50, respectively), Conners Continuous Performance Test (CPT 3) (showed low correct detection/delayed reaction time/high omission and commission errors), and the Yale Global Tic Severity Scale (Y-GTSS) (with a score of 75), were considered before embarking on the quetiapine trial. A low dose (300 mg/day) was used. Over 4 weeks, the results were very impressive, spanning different domains, namely, behavioural facets, insomnia, anorexia, anxiety, tics and, surprisingly, scholastic attainment. These were noted clinically, supported by parents’ and school reports, and objectified by repeating the DBD, CPT and Y-GTSS. Results were maintained at 8, 12, 16 and 20 weeks follow up. No cardiometabolic derangement was noted, albeit it might be tempered by co-administered stimulant therapy.

Discussion

Review of the literature reveals limited randomized controlled trial data for combination psychostimulant and antipsychotic use [Linton et al. 2013]. Although several guidelines recommend combination therapy with psychostimulants and antipsychotics to treat comorbid aggression and ADHD, it is suggested only as a third-line option following sequential monotherapy trials of psychostimulants and behaviour interventions [Yanofski, 2010; Pliszka et al. 2006; Pappadopulos et al. 2003]. Despite the established efficacy of psychostimulant and antipsychotic monotherapy, the evidence for the efficacy of combination therapy is limited and not based on strong data.

In our case, the addition of quetiapine was advantageous. It curbed both behavioural facets and tics by D₂ blockade, and helped with insomnia by antihistaminic action at H₁ and possibly α₁ adrenolytic action. By virtue of 5HT_2c antagonism and antihistaminic action, quetiapine counteracted the anorexogenic effect of methylphenidate. At this relatively low dose, quetiapine is an agonist at 5HT_1A and inhibits the norepinephrine transporter (NET), which brings about anxiolytic actions. Procognitive actions of quetiapine in this case might be attributed to NET inhibition by its metabolite, norquetiapine, 5HT_2c antagonism which translates pharmacologically into norepinephrine-dopamine disinhibitor in the prefrontal cortex, and possibly by actions at 5HT_1A/5HT₆ as well [Masi et al. 2015].

Conclusion

Quetiapine, with an attractive pharmacological portfolio, at a relatively low dose (300 mg/day), might be an appealing augmentation strategy to stimulant treatment of ADHD, with multifold caveats, to offset side effects, complement response and address comorbidities. Clinicians should maintain a lower threshold to judiciously use add-on atypical antipsychotics given the complexity of ADHD presentations.