Amisulpride and valproate in residual schizophrenia: a promising therapeutic approach

Marc Ziegenbein, M.D., Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany, Marcel Sieberer, M.D., Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany, Stefan Kropp, M.D., Clinical Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany

It has been proposed that low-dose atypical antipsychotic drugs like amisulpride are beneficial in schizophrenic patients with negative symptoms (1). The second-generation atypical drug amisulpride is a substituted benzamide derivative with specific antagonistic properties, which target dopamine D2 and D3 receptors, preferentially in the limbic system rather than in the striatum (2).

At low doses, amisulpride binds preferentially to presynaptic receptors, increasing dopaminergic transmission, and at high doses the postsynaptic receptor blockade induces a decrease in dopaminergic transmission.

A few studies suggest that the combination of clozapine and amisulpride is useful in patients with treatment-resistant schizophrenia (3). Despite the fact that amisulpride has been licensed in France for more than one decade, there are neither reports nor studies available about the usefulness of this compound in elderly schizophrenic patients or patients with residual schizophrenia.

Case Report

We describe a 55-year-old female Caucasian patient with paranoid schizophrenia who was first seen in our department 28 years ago. In 1999 she was admitted to our psychiatric hospital again. To our knowledge there was no exposure to classic or atypical antipsychotics for at least 11 years. The patient was alert but neither oriented towards person, situation, nor time. Speech was reduced to short answers, without modulation. The affect was emotionless, indifferent and flat. While answering questions, the face was emotionless, psychomotoric movements were sparse. Visual contact was absent. There were acoustic hallucinations (commenting voices without threat but of indifferent character). Suicidal thoughts were absent.

The physical examination showed a stiff left hip after a pelvis- and hip-fracture and a scar in the right renal area after renal explantation after a truck-accident at the age of eigth years. Blood tests, ECG and EEG revealed no abnormal findings, whereas the MRI revealed an old small ischemic area of the A. cerebri posterior. An antipsychotic pharmacotherapy with risperidone up to 4mg daily was started, in combination with 450mg valproate. As a generalized stiffness and slight rigor appeared, 4mg retarded bipiridine daily was added. As the psychopathological pattern improved only gradually and with first signs of extrapyramidal side effects (EPS) risperidone was discontinued. Amisulpride in combination with valproate was given instead an the dose was increased up to 500mg daily. Hallucinations disappeared and the patient was beginning to concentrate on reading and took part in many activities.

It has been proposed that the atypical antipsychotic amisulpride might be beneficial in case of primary negative schizophrenic symptoms. In this paticcular case clinical and social symptoms now improved beyond our expectations, neurological or renal side-effects were absent until discharge. In our case 500mg amisulpride appeared to be safe and very effective in ameliorating primary negative symptoms in this patient with residual schizophrenia. In contrast to recent clinical studies which recommend a much lower dose for chronic patients (4), we found 500mg of amisulpride daily very effective.

We conclude that primary negative symptoms of chronic schizophrenia in elderly patients might be improved substancially with amisulpride in combination with mood stabilizers and controlled studies should further elucidate this therapeutic option.


1. Boyer P, Lecrubier Y, Puech AJ, Dewailly J, Aubin F. Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiat 1995;166(1):68-72
2. Curran MP, Perry CM. Amisulpride: a review of its use in the managent of schizophrenia. Drugs 2001; 61(14):2123-2150
3. Zink M, Knopf U, Henn FA, Thome J. Combination of clozapine and amisulpride in treatment-resistant schizophrenia- case reports and review of the literature. Pharmacopsychiatry 2004; 37(1):26-31
4. Danion JM, Rein W, Fleurot O. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am J Psychiat 1999; 156(4): 610-616

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First Published April 30 2005