Augmentation of Clozapine with Amisulpride: A Promising Therapeutic Approach to Refractory Schizophrenic Symptoms

Data on the efficacy of combining clozapine with another, more D₂-receptor binding atypical neuroleptic, such as amisulpride is limited. In particular, it is still unclear, whether patients who either do not improve or suffer from severe side effects during clozapine monotherapy could benefit from such an add-on medication.

To shed light on the question whether there is a synergistic add-on effect of combining clozapine with amisulpride, Zink et al. [6] retrospectively summarized the data of 15 patients with mostly paranoid-hallucinatory psychosis and found an improvement of positive schizophrenic symptoms in 13 out of 15 patients. Negative symptoms improved in two cases and did not change in another case.

To underline these promising results we would like to draw the attention to a previous study from our group [2]. In our study 14 patients (mean age of 34.4 years; 8 of them were suffering from paranoid schizophrenia and 6 from a schizoaffective disorder according to ICD-10 criteria) had received a combined clozapine/amisulpride treatment over a mean period of 20 weeks at daily dosages of clozapine and amisulpride quite similar to those applied in the study of Zink and colleagues. Before amisulpride was added, all patients had received a clozapine monotherapy for at least 4 weeks without significant improvement of schizophrenic symptoms. Combined treatment resulted in a significant decrease of the mean CGI score (severity of illness item) from 5.6 (SD 0.5) to 3.9 (SD 1.0) (p < 0.01). According to the CGI score (global improvement item) 11 patients were classified as at least ”much improved”; only one patient did not improve [2].

These very similar results from two retrospective studies suggest that combined treatment with clozapine and amisulpride might be mostly effective in reducing positive symptoms and to a lesser extent in improving treatment-resistant negative symptoms, whereby the overall treatment response rate of more than 80 % was remarkably high. Moreover, this pharmacological regimen might generally be well tolerated since adverse effects are lacking with the exception of a reversible, clozapine-induced leukopenia in a single case [6].

Another small study recently obtained serial electrocardiography (ECG) recordings before and after adding amisulpride to clozapine and found neither significant changes in the frequency corrected QTc times nor changes in clozapine plasma levels after the addition of amisulpride [1].

The additive pharmacodynamic effect on D₂- and D₃-receptors might be the most important synergistic mechanism to explain the favorable therapeutic outcome under clozapine and amisulpride combination. Results of newer neuroimaging studies using PET and SPECT also point to such a pharmacodynamic mechanism. A clozapine dosage of 125-600 mg/d resulted in a D₂-receptor blockade of 20-67 %, whereas amisulpride leads to a dose-dependent blockade increase of 70-85 % [3] [5]. In patients receiving clozapine monotherapy, dopamine receptor occupancy in the basal ganglia was 46 % increasing to 73 % after the addition of amisulpride [4]. Again, the drug combination induced in all patients also some degree of clinical improvement.

Considering the promising results provided by both retrospective clinical studies on the combined application of clozapine and amisulpride, a larger double-blind, placebo-controlled study seems to be justified to confirm the potential therapeutic benefit of this regimen.

References

• 1 Agelink M W, Kavuk I, Ak I. Clozapine combined with amisulpride for refractory schizophrenia: a retrospective analysis of 7 cases. Am J Psychiatry 2004; in press
• 2 Kämpf P, Agelink M W, Maß R, Jahn H, Schäfer I, Naber D. Amisulpride in addition to clozapine: a retrospective study indicates improved efficacy an good tolerability.  German J Psychiatry. 2003;  6 64-68
• 3 Martinot J L, Paillere-Martinot M L, Poirier M F, Dao-Castellana M H, Loch C, Maziere B. In vivo characteristics of dopamine D₂ receptor occupancy by amisulpride in schizophrenia.  Psychopharmacology. 1996;  124 154-158
• 4 Matthiasson P, Costa D C, Erlandsson K, Waddington W, Visvikis D, Cullum I, Cobb A M, Ell P J, Kerwin R W, Travis M J. The relationship between dopamine D2 receptor occupancy and clinical response in amisulpride augmentation of clozapine non-response.  J Psychopharmacol. 2000;  14 (3, Suppl.) A57 (Abs.PG19)
• 5 Nordstrom A L, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G. D₁, D₂, and 5-HT₂ receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients.  Am J Psychiatry. 1995;  152 1444-1449
• 6 Zink M, Knopf U, Henn F A, Thome J. Combination of clozapine and amisulpride in treatment-resistent schizophrenia - case reports and review of the literature.  Pharmacopsychiatry. 2004;  37 26-31