High doses of aripiprazole therapy for a patient with treatment-resistant schizophrenia responsive to,but intolerant of,clozapine

To the Editor

Clozapine is the gold standard of treatment for cases with treatment resistant schizophrenia (TRS) but a significant proportion of patients are intolerant to clozapine. The management of a patient of TRS who is responsive to, but intolerant of, clozapine is not well established. We present a case of successful management of such a patient with high dose aripiprazole. A 29-year-old female with a 4-year history of paranoid schizophrenia and unresponsiveness to three adequate trials of antipsychotics was commenced on clozapine after relevant investigations. The dose was increased to 400 mg/day over 6 weeks with regular blood monitoring and the patient was discharged with a significant improvement.

After 26 weeks on clozapine treatment, she reported complaints of giddiness, mostly postural. After ruling out other causes a diagnosis of clozapine-induced postural hypotension was entertained. An objective causality assessment of score 7 (on the Naranjo adverse drug reaction probability scale) (Naranjo et al., 1981) revealed that this drug-related adverse effect (i.e. postural hypotension) was probably associated with clozapine. No improvement was observed in giddiness despite adequate water intake, postural exercises and a dose reduction of clozapine to 250 mg/day. It was decided to cross-taper clozapine with aripiprazole. The latter was initiated at a dose of 10 mg/day and increased to 25 mg/day. After cessation of clozapine, the signs and symptoms of postural hypotension disappeared. The patient was maintained on 25 mg/day of aripiprazole without any emergence of psychotic symptoms at follow up 1 year later.

The temporal relationship and remission of postural hypotension after ceasing of clozapine was suggestive of a causative effect. This report also highlights that troublesome postural hypotension can appear as late as 6 months into treatment and may be severe enough to warrant clozapine discontinuation. Aripiprazole has a unique pharmacological profile with high affinity partial agonist at dopaminergic D₂ and D₃ receptors and serotonergic 5-HT_1A receptors, and antagonism at 5-HT_2A and 5-HT_2C receptors (Burris et al., 2002). This is quite similar to the receptor profile of N-desmethylclozapine (NDMC), the primary active metabolite of clozapine and which is also a partial agonist at D2/D3 receptors (Burstein et al., 2005). The similarity in receptor profile could be a putative mechanism and could explain the successful switch from clozapine to aripiprazole. The findings from this case report suggest that in patients with clozapine intolerant side effects, clinicians should be aware of the option of switching to high doses of aripiprazole.