Effective Use of Aripiprazole Augmentation in a Clozapine-Treated Adolescent with Autism Spectrum Disorder

Case Report

A 13-year-old boy admitted to our outpatient clinic with complaints of severe temper tantrums, destroying household objects, and being aggressive toward his mother. He also had compulsive symptoms such as cleaning and ordering. He had been diagnosed with autism when he was 3 years old. For the last 3 years he had received mirtazapine (max 15 mg/day), fluoxetine (max 40 mg/day), sodium valproate (max 1000 mg/day), risperidone (max 3 mg/day), quetiapine (max 600 mg/day), olanzapine (max 5 mg/day), aripiprazole (max 10 mg/day), haloperidol (max 15 mg/day), chlorpromazine (max 150 mg/day), clonazepam (max 4mg/day), carbamazepine (max 400 mg/day), and oxcarbazepine (max 150 mg/day) either alone or in combination for his disruptive behaviors, with no significant effect. After obtaining his legal guardian's consent and completing routine neurological and cardiac examination, blood screen, and liver and kidney function tests, he was started on clozapine and the dose was gradually increased to 300 mg/day, and 500 mg/day sodium valproate was combined for potential seizures. His aggressiveness and disruptive behaviors markedly improved within 2 weeks after the target dose for clozapine (300 mg/day) was reached. His global improvement rating on Clinical Global Impressions–Improvement Scale (CGI-I) was 2 (much improved). Drawing blood was not troublesome, and white blood cell (WBC) counts were obtained weekly at the beginning of the treatment and monthly thereafter. Clozapine was well tolerated by the patient with no hematological, neurological, cardiac, or metabolic side effects, except for a slight increase in his compulsive behaviors. At the end of the 1st year, his cleaning and ordering compulsions were exacerbated and caused significant distress for his parents. Because his spoken language was limited to a few words, we could not assess whether his compulsive behaviors were accompanied by obsessive thoughts. Aripiprazole was started at 5 mg/day and increased to 7.5 mg/day because of its well-known effects on clozapine-associated obsessive compulsive symptoms (Englisch et al. 2009) and aggressive behaviors in patients with ASD (Politte and McDougle 2014). At the end of the 1st month, his compulsive behaviors ceased, and further improvement was seen in his disruptive behaviors. His CGI was improved from 2 to 1 (very much improved). His aggressive outbursts and compulsive behaviors remained decreased for the following 6 months, and no other side effects or hematological changes were seen.

Discussion

Clozapine has been shown to be effective for aggressive behaviors in schizophrenia and other psychiatric disorders, including bipolar disorder, severe borderline personality disorder, posttraumatic stress disorder, and intellectual disability. Clozapine's effectiveness in aggressive behaviors is considered to be linked to its complex receptor binding affinities for D2, D4, and, particularly, 5-HT2A receptors, which fits with the view that the serotonergic system may have a role in the biology of impulsivity and aggression (Frogley et al. 2012). There are limited data on the use of clozapine for aggressive or disruptive behaviors in individuals with ASD, consisting of two case series and three case reports, for a total number of 11 cases; of those only 5 are patients <18 years of age. Although the quality of the overall data is insufficient to draw firm conclusions, clozapine appears to be an effective and tolerable option for disruptive behaviors previously not responding to other psychotropic agents in patients with ASD (Zuddas et al. 1996; Chen et al. 2001; Gobbi and Pulvirenti 2001; Lambrey et al. 2010; Beherec et al. 2011). Nevertheless, its side effect profile may necessitate drug cessation, or limit dose escalation in cases of inadequate response. Under these circumstances, augmentation of clozapine with other psychotropic agents might be needed. Adding aripiprazole to clozapine has been shown to have some beneficial effects in adolescent and adult patients with schizophrenia both on overall symptoms and side effects including weight gain, fasting glucose, lipid profile, hypersalivation, and obsessive compulsive behaviors related to clozapine (Englisch and Zink 2008; Bachmann et al. 2009; Englisch et al. 2009; De Risio et al. 2011). Partial agonist properties of aripiprazole on D2 dopamine and 5-HT1A receptors are postulated as being responsible for its complementary profile to clozapine both in boosting its effectiveness and in reducing side effects (Englisch and Zink 2008; De Risio et al. 2011).

There is an emerging need for treatment alternatives for the large group of child and adolescents with ASD, as those disruptive behaviors have serious deteriorating effects on personal and family functioning (Bauminger et al. 2010). Our case suggests that adding aripiprazole to clozapine may improve treatment outcome and reduce side effects in clozapine- treated patients with ASD.