Abstract
Christos Pantelis and Adesina Adesanya, Cognitive Neuropsychiatry Research and Academic Unit, Department of Psychiatry, The University of Melbourne and Sunshine Hospital, Melbourne, Australia:
Clozapine is the most effective available drug for the management of treatment-resistant schizophrenia [1]. However, because of the high incidence of neutropaenia and agranulocytosis [2], the use of adjunctive treatments that also affect white cells (e.g. carbamazepine) are contraindicated. Another drug often used adjunctively with clozapine, either to manage seizures or for affective symptoms, is sodium valproate. We report here a case in which a decrease in the white cell count occurred in the context of adjunctive use of sodium valproate with clozapine and was reversed when the valproate was ceased.
Ms S. was a 25-year-old patient with a 9-year history of schizophrenia with inadequate response to conventional neuroleptics. She suffered several relapses of her illness requiring hospitalization, which were characterized by regressed and disorganized behaviour, sexual disinhibition, affective lability, grandiose and bizarre delusions, loosening of associations and third-person auditory hallucinations. She previously received adequate trials of various antipsychotics of between 4 and 24 months duration, with only partial symptom remission. She had not been treated previously with any mood stabilisers. Introduction of clozapine to 300 mg/day led to a rapid resolution of symptoms. A period of non-complianceafter 3 months of good compliance and treatment response resulted in a relapse of her psychosis, 2 weeks after stopping clozapine. Recommencement of clozapine following readmission, with gradual increase in doseto 600 mg/day (serum levels to 420 μg/L) over several weeks, was associated with improved mental state. Amitriptyline (25 mg nocte) was added to manage hypersalivation. Because of persistent affective symptoms she was commenced on adjunctive sodium valproate to 800 mg/day (serum level 450 μmol/L). Regular blood tests including repeated full blood count and liver function tests prior to and following the commencement of sodium valproate were normal. Ms S. responded well to this regimen and was able to participate in various psychosocial activities as part of her rehabilitation programme. The improvement in her mental state was sustained and her discharge was planned 6 weeks after commencing combination therapy. However, at this time there was marked reduction in white cell and neutrophil counts. Total white cell and neutrophil counts dropped from an averageof 6.2 × 109/L and 3.9 × 109/L, respectively, in the 6 weeks prior to commencing valproate, to 3.3 × 109/L and 1.8 × 109/L, respectively. There was no change in serum clozapine and norclozapine levels at this time. Also, there was no eosinophilia or other abnormalities in her blood count profiles or other parameters, including liver function tests.
Ms S. was very concerned that the clozapine might need to be discontinued as she felt the best she had been over the last several years. Because of the possibility that the adjunctive treatments may have contributed to the drop in the cell counts, amitriptyline was initially discontinued. The white cell and neutrophil counts remained unchanged at their low levels over the subsequent 2 weeks and it was decided to gradually reduce and cease valproate. Two weeks after the discontinuation of sodium valproate white cell and neutrophil counts gradually returned to normal. This trend continued even though she was maintained on clozapine, and her leucocyte and neutrophil counts over the subsequent 6 weeksaveraged 4.6 × 109/L and 2.6 × 109/L, respectively. These improvements in the patient's blood parameters were sustained and she was discharged from hospital 2 weeks later. Blood counts and mental state remained stable 8 weeks after she was discharged from hospital.
This case suggests that sodium valproate used adjunctively with clozapine may be associated with a potentially serious drop in white cell and neutrophil counts. Whereas the blood count levels remained above the threshold at which clozapine must be ceased, it was likely that continued adjunctive treatment may have caused the levels to reach these thresholds, at which point clozapine would have been discontinued. This would have been accompanied by a marked deterioration in this patient's mental state and plans for discharge would have been abandoned.
While amitriptyline has been implicated as a rare cause of agranulocytosis [3], cessation of this in Ms S. did not result in any change to the low white cell counts. It was only when sodium valproate was ceased that the white cell and neutrophil counts normalized. This would suggest that valproate used adjunctively with clozapine was implicated in causing the low white cell and neutrophil counts, though it is not possible to determine in this case whether valproate alone would have caused this. There are few reports of sodium valproate resulting in low white cell and neutrophil counts, though it is listed as a potential problem in MIMS. In a reviewof 55 cases in which valproate was used adjunctively with clozapine, Kando et al. [4] reported no blood dyscrasias or other major adverse events. This suggests that the occurrence of rare events requires studies with large numbers of patients, or must rely on individual case reports.
While valproate has been reported to affect plasma levels of clozapine and its metabolites [5], to the best of our knowledge this is the first reported case of low white cell and neutrophil counts resulting from the adjunctive use of sodium valproate and clozapine. This raises at least two important issues in the management of patients commencing adjunctive treatment while on clozapine. First, given that sodium valproate is often used adjunctively with clozapine, if there is any drop in the white cell count to low levels, consideration should be given to ceasing the sodium valproate before thresholds are reached for the discontinuation of clozapine. Second, if a drop in neutrophils occurs with any medication used adjunctively with clozapine, the potential role of such adjunctive medication as being causative should also be considered.