Clozapine–Aripiprazole Association in a 7-Year-Old Girl with Schizophrenia: Clinical Efficacy and Successful Management of Neutropenia with Lithium

Case Description

A.M. is a 7-year-old Caucasian girl with normal development. Psychotic symptoms started when she was 7.1 years old, with manic-like symptoms, such as aggressive and agitated behavior, hyperactivity and inattentiveness, magical thinking (she believed herself to be a cartoon character), grandiose delusion (she believed herself to be a teenager and she asked to go out alone for a walk), and sexual poses. At the same time, idiopathic precocious puberty with thelarche and pubarche occurred, with high levels of β-human chorionic gonadotropin, α-fetoprotein, and estradiol. Treatment with an estrogen antagonist was started (tamoxifen, 10 mg/day), with positive clinical response on thelarche.

The psychiatric symptoms worsened over the next 3 months, with both auditory (commenting voices), visual, and tactile hallucinations (insects on her body). Negative symptoms became rapidly predominant, with massive cognitive regression, lack of spontaneous initiatives, low affective responsivity, and decreased self-care skills. Speech became stereotyped and of poor content; social withdrawal became more severe, and school and social relations were stopped. Schizophrenia was diagnosed, and risperidone treatment was started, up to 1.5 mg/day. Hallucinations disappeared rapidly, but negative symptoms worsened further, namely negativism, avolition, anhedonia and anergia, and confabulations (whispers and incomprehensible talking). The girl appeared markedly withdrawn, with absence of spontaneous initiative and eye contact, severe mutism (only few words, often incomprehensible), and fixed facial expression. Behavior was grossly disorganized, with sudden episodes of aggression against her parents and sister; the subject needed constant one-on-one assistance. Risperidone was given for 4 months without any significant improvement. At this time, she was admitted to our clinic.

During the hospitalization, brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and all laboratory values were within normal ranges. Genome analysis was done to check the 22q11.2 deletion syndrome (22q11.2 DS), a common microdeletion syndrome associated with higher risk of intellectual disability, brain abnormalities, and a complex spectrum of psychiatric disorders, including schizophrenia (Prasad et al. 2008). However, the analysis results were normal.

The worsening of negative symptoms, as well as the cognitive and behavioral regression, suggested the addition of aripiprazole at the starting dose of 2.5 mg twice a day (b.i.d.) with further increases of 2.5 mg every 4 days up to 7.5 mg b.i.d. Aripiprazole was well tolerated, with only mild and transient nausea. But the combination of aripiprazole and risperidone was not effective during the next 4 weeks.

The severity of this clinical picture and the prevalence of negative symptoms suggested clozapine, which is more effective on negative symptoms (Kumra et al. 1996; Kumra et al. 2008a). Risperidone was gradually tapered off and clozapine was started at a dosage of 25 mg/day with further increases of 25 mg every 4 days up to a first target dose of 100 mg/day (50 + 50 mg/day). Given the possible enhancement of cognitive functioning, aripiprazole was continued.

At this point (baseline), the Clinical Global Impressions–Severity (CGI) score was 7, the Children Global Assessment Scale (CGAS) score was 25, the Brief Psychiatric Rating Scale (BPRS) total score was 83, the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) scores were, respectively, 71 and 97. At weeks 4 and 8 of combined treatment, the Clinical Global Impressions–Improvement (CGI-I) revealed a mild improvement (score 3) (Table 1). Clozapine was increased at week 12, up to 75 +75 mg/day, with a further improvement (CGI-I score 3 at week 16). During the next 4 months, psychotic symptoms (both positive and negative), as well as behavioral and cognitive functioning, improved markedly, even though episodes of psychomotor agitation seldom persisted. For this reason, valproic acid at 900 mg/day was added, with a clear improvement of behavioral control. At week 24, the CGI-I score was 2, and the SANS, SAPS, and BPRS improved more than 20% (Table 1); cognitive functioning improved as well.

At week 32, the weekly monitoring of WBCs revealed an acutely decreased WBC count, with marked neutropenia. Both clozapine and valproic acid were stopped, and the girl continued to take aripiprazole alone (15 mg/day), until week 36. The WBC count normalized, but the clinical picture worsened rapidly (Table 1). Thus, at week 36, lithium was added to aripiprazole, up to 900 mg/day, and after 10 days, clozapine was rechallenged up to 150 mg/day. A massive and dramatic improvement in psychotic symptoms and behavior was observed (Table 1), as well as cognitive and social abilities, including reading, writing, drawing, and use of her personal computer. This improvement progressively increased during all the follow-up, with new cognitive and behavioral skills even at the 24^th month after the clozapine rechallenge. The white blood count and total neutrophil count remained stable (4000–5000/mm³). The treatment was well tolerated, with only moderate sedation (difficulty waking up in the morning), enuresis, and increased appetite with weight gain (body mass index [BMI] increased from 19 to 26).

Discussion

Possible points of interest in this case report are the following: (1) This case was characterized by very early onset of the psychotic disorder (7 years), with acute onset, early positive symptoms, rapid shift to negative symptoms, disorganized behavior, and cognitive and behavioral regression. (2) There was a chronological association with idiopathic precocious puberty (thelarche and pubarche), high levels of β-human chorionic gonadotropin, α-fetoprotein, and estradiol, and effective treatment with an estrogen antagonist (tamoxifen, 10 mg/day). (3) There was a poor response to risperidone, aripiprazole, and their combined administration and the improvement with clozapine augmentation of aripiprazole. (4) Neutropenia, after 32 weeks of treatment, determined the clozapine discontinuation. (5) During aripiprazole monotherapy, normalization of the WBC count, but severe worsening of the clinical picture, with cognitive and behavioral regression occurred. (6) Clozapine rechallenge in combination with lithium, produced normalization of the WBC count, and rapid and persisting improvement of clinical picture during the long-term follow up (24 months).

Our case can be considered atypical in at least two aspects: The normal premorbid development and functioning, and the acute onset, with positive symptoms (both delusions and hallucinations), and a rapid shift to negative symptoms (massive cognitive regression, isolation, mutism, and severe behavioral disorganization). The role of precocious puberty and hormonal treatment remains unclear. Karaguzel and colleagues (2006) reported on a case of precocious puberty associated with psychiatric disorder, hypoparathyroidism precocious puberty, and 22q11 deletion syndrome, but this genetic abnormality was not found in our girl. An effect of estrogenic antagonists on psychotic disorders has not been reported in the literature. On the contrary, tamoxifen was effective in the treatment of adult patients with acute mania through an inhibition of protein kinase C (Zarate et al. 2007; Yildiz et al. 2008). Ovarian hyperstimulation with clomiphene, a selective estrogen receptor modulator, was associated with onset of psychotic symptoms (Oyffe et al.1997).

The severity of negative symptoms, often associated with treatment refractoriness and poorer outcome, induced us to choose clozapine as an augmentation of aripiprazole, given the evidence of its efficacy on negative symptoms (Kumra et al. 1996). The maintenance of aripiprazole was based on the evidence from the adult literature of an enhancing effect on cognitive functioning (Kern et al. 2006). A recent study in children aged 8–12 years supports the efficacy and tolerability of aripiprazole in symptoms of ADHD, including cognitive functioning (attentional, reading, and math tests) (Findling et al. 2008b). Although our case report supports efficacy of clozapine–aripiprazole association on both negative and cognitive symptoms, our data do not allow us to test the hypothesis that the efficacy of clozapine monotherapy was augmented by aripiprazole. In fact, efficacy of clozapine monotherapy is supported by controlled studies, even in children and adolescents with treatment-resistant schizophrenia (Kumra et al. 1996; Shaw et al. 2006; Kumra et al. 2008b). The progressive improvement, continuing 2 years after starting clozapine, is not unusual during monotherapy with this medication. Because the rechallenge of clozapine supports this medication as the most effective treatment, a progressive tapering of aripiprazole will be considered in the next weeks.

It cannot be excluded that the occurrence of neutropenia may have been negatively affected by the cumulative effect of the two antipsychotics on WBCs. The increased risk of neutropenia during polypharmacy is still not explored. In our subject, lithium was effective in allowing the clozapine rechallenge, and it may represent an alternative to clozapine discontinuation in treatment-refractory children. The safety of this strategy needs to be supported by further studies, as it may increase the risk of neuroleptic malignant syndrome (NMS) (Pope et al. 1986; Ty and Rothner, 2001).

A significant side effect was the weight gain, with a significant increase of BMI. The antipsychotic-induced weight gain is important, given the morbidity in subjects with obesity and the paucity of data on the management of this adverse effect (Shin et al. 2008).

In summary, our case report suggests that when negative and cognitive symptoms of childhood schizophrenia do not improve after a monotherapy with SGAs (including clozapine), clozapine–aripiprazole association may ameliorate the clinical picture in the medium and long term, namely when cognitive and behavioral regressions are prominent. The need for an intensive monitoring of hematologic side effects is warranted, because the risk may be increased by this association. Our case report also supports the efficacy of lithium in allowing clozapine rechallenge after its discontinuation for drug-induced neutropenia.